Oumar Kuzbari
Jessie Dorais
C. Matthew Peterson
• Hyperandrogenism most often presents as hirsutism, which usually arises as a result of androgen excess related to abnormalities of function in the ovary or adrenal glands. By contrast, virilization is rare and indicates marked elevation in androgen levels.
• The most common cause of hyperandrogenism and hirsutism is polycystic ovarian syndrome (PCOS). There are only two major criteria for the diagnosis of PCOS: anovulation and the presence of hyperandrogenism as established by clinical or laboratory means. Patients with PCOS frequently exhibit insulin resistance and hyperinsulinemia.
• Combination oral contraceptives (OCs) decrease adrenal and ovarian androgen production and reduce hair growth in nearly two-thirds of hirsute patients.
• Because hyperinsulinemia appears to play a role in PCOS-associated anovulation, treatment with insulin sensitizers may shift the endocrine balance toward ovulation and pregnancy, either alone or in combination with other treatment modalities.
• Excluding cases that are of iatrogenic or factitious etiology, adrenocorticotropic hormone–independent forms of Cushing syndrome are adrenal in origin. Adrenal tumors are usually very large by the time Cushing syndrome is manifest.
• Congenital adrenal hyperplasia is transmitted as an autosomal recessive disorder. Deficiency of 21-hydroxylase is responsible for more than 90% of cases of adrenal hyperplasia resulting from an adrenal enzyme deficiency.
• Patients with severe hirsutism, virilization, or recent and rapidly progressing signs of androgen excess require careful investigation for the presence of an androgen-secreting neoplasm. Ovarian neoplasms are the most frequent androgen-producing tumors.
• Elevations in prolactin may cause amenorrhea or galactorrhea. Amenorrhea without galactorrhea is associated with hyperprolactinemia in approximately 15% of women. In patients with both galactorrhea and amenorrhea, approximately two-thirds will have hyperprolactinemia; of those, approximately one-third will have a pituitary adenoma. In more than one-third of women with hyperprolactinemia, a radiologic abnormality consistent with a microadenoma (>1 cm) is found.
• Because levels of thyroid-stimulating hormone (TSH) are sensitive to excessive or deficient levels of circulating thyroid hormone, and because most disorders of hyperthyroidism and hypothyroidism are related to dysfunction of the thyroid gland, TSH levels are used to screen for these disorders. The most common thyroid abnormalities in women, autoimmune thyroid disorders, represent the combined effects of the multiple antibodies produced. Severe primary hypothyroidism is associated with amenorrhea or anovulation. The classic triad of exophthalmos, goiter, and hyperthyroidism in Graves disease is associated with symptoms of hyperthyroidism.
The endocrine disorders encountered most frequently in gynecologic patients are those related to disturbances in the regular occurrence of ovulation and accompanying menstruation. The most prevalent are those characterized by androgen excess, often with insulin resistance, including what is arguably the most common endocrinopathy in women—polycystic ovary syndrome (PCOS). Other conditions leading to ovulatory dysfunction, hirsutism, or virilization, and common disorders of the pituitary and thyroid glands associated with reproductive abnormalities, are reviewed in this chapter.
Hyperandrogenism
Hyperandrogenism most often presents as hirsutism, which arises as a result of androgen excess related to abnormalities of function in the ovary or adrenal glands, constitutive increase in expression of androgen effects at the level of the pilosebaceous unit, or a combination of the two. By contrast, virilization is rare and indicates marked elevations in androgen levels. An ovarian or adrenal neoplasm that may be benign or malignant commonly causes virilization.
Hirsutism
Hirsutism, the most frequent manifestation of androgen excess in women, is defined as excessive growth of terminal hair in a male distribution. This refers particularly to midline hair, side burns, moustache, beard, chest or intermammary hair, and inner thigh and midline lower back hair entering the intergluteal area. The response of the pilosebaceous unit to androgens in these androgen responsive areas transforms vellus hair (fine, nonpigmented, short) that is normally present into terminal hair (coarse, stiff, pigmented, and long).
Androgen effects on hair vary in relation to specific regions of the body surface. Hair that shows no androgen dependence includes lanugo, eyebrows, and eyelashes. The hair of the limbs and portions of the trunk exhibits minimal sensitivity to androgens. Pilosebaceous units of the axilla and pubic region are sensitive to low levels of androgens, such that the modest androgenic effects of adult levels of androgens of adrenal origin are sufficient for substantial expression of terminal hair in these areas. Follicles in the distribution associated with male patterns of facial and body hair (midline, facial, inframammary) require higher levels of androgens, as seen with normal testicular function or abnormal ovarian or adrenal androgen production. Scalp hair is inhibited by gonadal androgens, in varying degrees, as determined by age and genetic determination of follicular responsiveness, resulting in the common frontal-parietal balding seen in some males and in virilized females. Hirsutism results from both increased androgen production and skin sensitivity to androgens. Skin sensitivity depends on the genetically determined local activity of 5α-reductase, the enzyme that converts testosterone to dihydrotestosterone (DHT), the bioactive androgen in hair follicles.
Hair demonstrates cyclic activity between growth (anagen), involution (catagen), and resting (telogen) phases. The durations of both the growth and resting phases vary according to region of the body, genetic factors, age, and hormonal effects. The cycles of growth, rest, and shedding are normally asynchronous, but when synchronous entry into telogen phase is triggered by major metabolic or endocrine events, such as pregnancy and delivery, or severe illness, dramatic (although transient) hair loss may occur in the following months (telogen effluvium).
Hirsutism is a relative, rather than absolute, designation. What is normal in one setting may be considered abnormal in others; social and clinical reactions to hirsutism can vary significantly, reflecting ethnic variation in skin sensitivity to androgens and cultural ideals. Androgen-dependent hair (excluding pubic and axillary hair) occurs in only 5% of premenopausal white women and is considered abnormal by white women of North America, whereas considerable facial and male pattern hair in other areas may be more common and more often considered acceptable and normal among such groups as the Inuit and women of Mediterranean background.
Hypertrichosis and Virilization
Two conditions should be distinguished from hirsutism. Hypertrichosis is the term reserved for androgen-independent terminal hair in nonsexual areas, such as the trunk and extremities. This may be the result of an autosomal-dominant congenital disorder, a metabolic disorder (such as anorexia nervosa, hyperthyroidism, porphyria cutanea tarda), or medications (e.g., acetazolamide, anabolic steroids, androgenic progestins, androgens, cyclosporine, diazoxide, dehydroepiandrosterone (DHEA), heavy metals, interferon, methyldopa, minoxidil, penicillamine, phenothiazines, phenytoin, streptomycin,reserpine, valproic acid). Virilization is a marked and global masculine transformation that includes coarsening of the voice, increase in muscle mass, clitoromegaly (normal clitoral dimensions ± standard deviation [SD] are 3.4 + 1 mm width by 5.1 + 1.4 mm length) and features of defeminization (loss of breast volume and body fat contributing to feminine body contour) (1). Although hirsutism accompanies virilization, the presence of virilization indicates a high likelihood of more serious conditions than are common with hirsutism alone and should prompt evaluation to exclude ovarian or adrenal neoplasm. Although rare, these diagnoses become likely when onset of androgen effects is rapid or sufficiently pronounced to produce the picture of virilization.
The history should focus on the age of onset and rate of progression of hirsutism or virilization. A rapid rate of progression or virilization is associated with a more severe degree of hyperandrogenism and should raise suspicion of ovarian and adrenal neoplasms or Cushing syndrome. This is true whether rapid progression or virilization occurs before, during, or after puberty. Anovulation, manifesting as amenorrhea or oligomenorrhea, increases the probability that there is underlying hyperandrogenism. Hirsutism occurring with regular cycles is more commonly associated with normal androgen levels and thus is attributed to increased genetic sensitivity of the pilosebaceous unit and is termed idiopathic hirsutism. When virilization is present, anovulation virtually always occurs.
In determining the extent of hirsutism, a sensitive and tactful approach by the physician is mandatory and should include questions regarding the use and frequency of shaving and/or chemical or mechanical depilatories. Typically, clinical evaluation of the degree of hirsutism is subjective. Most physicians arbitrarily classify the degree of hirsutism as mild, moderate, or severe. Objective assessment is helpful, especially in establishing a baseline from which therapy can be evaluated. The Ferriman–Gallwey Scoring System for Hirsutism quantitates the extent of hair growth in the most androgen sensitive sites. It is a scoring scale of androgen-sensitive hair in nine body areas rated on a scale of 0 to 4 (2). A total score higher than 8 is defined as hirsutism (Fig. 31.1) (3). Although widely used, this scoring system has limitations, one of which is the fact that the scale does not include the sideburn, buttocks, and perineal areas. Substantial hirsutism may be confined to one or two areas without exceeding the cutoff value in total hirsutism score. The score does not reflect the extent to which hirsutism affects a woman’s well being (3,4).
Figure 31.1 Ferriman-Gallwey hirsutism scoring system. Each of the nine body areas most sensitive to androgen is assigned a score from 0 (no hair) to 4 (frankly virile), and these separate scores are summed to provide a hormonal hirsutism score. (Reproduced from Hatch R, Rosefield RL, Kim MH, et al. Hirsutism: implications, etiology, and management. Am J Obstet Gynecol 1981;140:815–830. ©Elsevier.)
Figure 31.2 Major steroid biosynthesis pathway.
A family history should be obtained to disclose evidence of idiopathic hirsutism, PCOS, congenital or adult onset adrenal hyperplasia (CAH or AOAH), diabetes mellitus, and cardiovascular disease. A history of drug use should be obtained. In addition to drugs that commonly cause hypertrichosis, anabolic steroids and testosterone derivatives may cause hirsutism and even virilization. During the physical examination, attention should be directed to obesity, hypertension, galactorrhea, male-pattern baldness, acne (face and back), and hyperpigmentation. With virilization, the presence of an androgen-producing ovarian neoplasm or Cushing syndrome must be considered. In many cases of Cushing syndrome, the patient’s presenting symptom is hirsutism. This devastating disorder may masquerade as other disorders such as AOAH and PCOS. Before making these diagnoses, the physician should search for the physical signs of the syndrome such as “moon face,” plethora, purple striae, dorsocervical and supraclavicular fat pads, and proximal muscle weakness. A moon-shaped face, upper body obesity, muscle weakness, and the development of a pad of fat between the shoulder blades are particularly notable to both patients and diagnosticians considering the diagnosis of Cushing syndrome.
Role of Androgens
Androgens and their precursors are produced by both the adrenal glands and the ovaries in response to their respective trophic hormones, adrenocorticotropic hormone (ACTH) and luteinizing hormone (LH), respectively (Fig. 31.2). Biosynthesis begins with the rate-limiting conversion of cholesterol to pregnenolone by side-chain cleavage enzyme. Thereafter, pregnenolone undergoes a two-step conversion to the 17-ketosteroid DHEA along the Δ-5 steroid pathway. This conversion is accomplished by CYP17, an enzyme with both 17α-hydroxylase and 17,20-lyase activities. In a parallel fashion, progesterone undergoes transformation to androstenedione in the Δ-4 steroid pathway. The metabolism of Δ-5 to Δ-4 intermediates is accomplished via a Δ-5-isomerase, 3β-hydroxysteroid dehydrogenase (3β-HSD).
Adrenal 17-Ketosteroids
Secretion of adrenal 17-ketosteroids increases prepubertally and independently of pubertal maturation of the hypothalamic–pituitary–ovarian axis. This alteration in adrenal steroid secretion is termed adrenarche and is characterized by a dramatic change in the response of the adrenal cortex to ACTH and with preferential secretion of Δ-5 steroids, including 17-hydroxypronenolone, DHEA, and dehydroepiandrosterone sulfate (DHEAS). The basis for this action is related to the increase in the zona reticularis and in the increased activity of the 17-hydroxylase and the 17,20-lyase enzymes. Independent of the increase in ovarian androgen secretion accompanying puberty, the increase in adrenal androgens owing to adrenarche can account for significant increases in pubic and axillary hair and sweat production by the axillary pilosebaceous units.
Testosterone
Approximately half of a woman’s serum testosterone is derived from peripheral conversion of secreted androstenedione and the other half is derived from direct glandular (ovarian and adrenal) secretion. The ovaries and adrenal glands contribute almost equally to testosterone production in women. The contribution of the adrenals is achieved primarily through secretion of androstenedione.
Approximately 66% to 78% of circulatory testosterone is bound to sex hormone–binding globulin (SHBG) and is considered biologically inactive. Most of the proportion of serum testosterone that is not bound to SHBG is weakly associated with albumin (20% to 32%). A small percentage (1% to 2%) of testosterone is entirely unbound or free. The fraction of circulating testosterone that is unbound by SHBG has an inverse relationship with the SHBG concentration. Increased SHBG levels are noted in conditions associated with high estrogen levels. Pregnancy, the luteal phase, use of estrogen (including oral contraceptives), and conditions causing elevated thyroid hormone levels and cirrhosis of the liver are associated with reduced fractions of free testosterone caused by elevated SHBG levels. Conversely, levels of SHBG decrease and result in elevated free testosterone fractions in response to androgens, androgenic disorders (PCOS, adrenal hyperplasia or neoplasm, Cushing syndrome), androgenic medications (i.e., progestational agents with androgenic biologic activities, such as danazol, glucocorticoids, and growth hormones), hyperinsulinemia, obesity, and prolactin.
Laboratory Assessment of Hyperandrogenemia
In hyperandrogenic states, increases in testosterone production are not proportionately reflected in increased total testosterone levels because of the depression of SHBG levels that occurs concomitant with increasing androgen effects on the liver. Therefore, when moderate hyperandrogenism, characteristic of many functional hyperandrogenic states, occurs, elevations in total testosterone levels may remain within the normal range, and only free testosterone levels will reveal the hyperandrogenism. Severe hyperandrogenism, as occurs in virilization and that results from neoplastic production of testosterone, is reliably detected by measures of total testosterone. Therefore, in practical clinical evaluation of the hyperandrogenic patient, determination of the total testosterone level in concert with clinical assessment is frequently sufficient for diagnosis and management. When more precise delineation of the degree of hyperandrogenism is desired, measurement or estimation of free testosterone levels can be undertaken and will more reliably reflect increases in testosterone production. These measurements are not necessary in evaluating the majority of patients, but they are common in clinical research studies and may be useful in some clinical settings. Because many practitioners measure some form of testosterone level, they should understand the methods used and their accuracy. Although equilibrium dialysis is the gold standard for measuring free testosterone, it is expensive, complex, and usually limited to research settings. In a clinical setting, free testosterone levels can be estimated by assessment of testosterone binding to albumin and SHBG.
Testosterone, that is nonspecifically bound to albumin (AT), is linearly related to free testosterone (FT) by the equation:
AT = Ka [A] × FT,
where AT is the albumin-bound testosterone, Ka is the association constant of albumin for testosterone, and [A] is the albumin concentration.
In many cases of hirsutism, albumin levels are within a narrow physiologic range and thus do not significantly affect the free testosterone concentration. When physiologic albumin levels are present, the free testosterone level can be estimated by measuring the total testosterone and SHBG. In individuals with normal albumin levels, this method has reliable results compared with those of equilibrium dialysis. It provides a rapid, simple, and accurate determination of the total and calculated free testosterone level and the concentration of SHBG.
The bioavailable testosterone level is based on the relationship of albumin and free testosterone and incorporates the actual albumin level with the total testosterone and SHBG. This combination of total testosterone, SHBG, and albumin level measurements can be applied to derive a more accurate estimate of available bioactive testosterone and thus the androgen effect derived from testosterone. Bioactive testosterone determined in this manner provides a superior estimate of the effective androgen effect derived from testosterone (5).
Pregnancy can alter the accuracy of measurements of bioavailable testosterone. During pregnancy, estradiol, which shares with testosterone a high affinity for SHBG, occupies a large proportion of SHBG binding sites, so that measurement of SHBG levels can overestimate the binding capacity of SHBG for testosterone. Derived estimates of free testosterone, as opposed to direct measure by equilibrium dialysis, are therefore inaccurate during pregnancy. Testosterone measurements in pregnancy are primarily of interest when autonomous secretion by tumor or luteoma is in question, and for these, total testosterone determinations provide sufficient information for diagnosis.
For testosterone to exert its biologic effects on target tissues, it must be converted into its active metabolite, DHT, by 5α-reductase (a cytosolic enzyme that reduces testosterone and androstenedione). Two isozymes of 5α-reductase exist: type 1, which predominates in the skin, and type 2, or acidic 5α-reductase, which is found in the liver, prostate, seminal vesicles, and genital skin. The type 2 isozyme has a 20-fold higher affinity for testosterone than type 1. Both type 1 and 2 deficiencies in males result in ambiguous genitalia, and both isozymes may play a role in androgen effects on hair growth. Dihydrotestosterone is more potent than testosterone, primarily because of its higher affinity and slower dissociation from the androgen receptor. Although DHT is the key intracellular mediator of most androgen effects, measurements of circulating levels are not clinically useful.
The relative androgenicity of androgens is as follows:
DHT = 300
Testosterone = 100
Androstenedione = 10
DHEAS = 5.
Until adrenarche, androgen levels remain low. Around 8 years of age, adrenarche is heralded by a marked increase in DHEA and DHEAS. The half-life of free DHEA is extremely short (about 30 minutes) but extends to several hours if DHEA is sulfated. Although no clear role is identified for DHEAS, it is associated with stress and levels decline steadily throughout adult life. After menopause, ovarian estrogen secretion ceases, and DHEAS levels continue to decline, whereas testosterone levels are maintained or may even increase. Although postmenopausal ovarian steroidogenesis contributes to testosterone production, testosterone levels retain diurnal variation, reflecting an ongoing and important adrenal contribution. Peripheral aromatization of androgens to estrogens increases with age, but because small fractions (2% to 10%) of androgens are metabolized in this fashion, such conversion is rarely of clinical significance.
Laboratory Evaluation
The 2008 Endocrine Society Clinical Practice Guidelines suggest testing for elevated androgen levels in women with moderate (Ferriman–Gallwey hirsutism score 9 or greater) or severe hirsutism or hirsutism of any degree when it is sudden in onset, rapidly progressive, or associated with other abnormalities such as menstrual dysfunction, infertility, significant acne, obesity, or clitoromegaly. These guidelines suggest against testing for elevated androgen levels in women with isolated mild hirsutism because the likelihood of identifying a medical disorder that would change management or outcome is extremely low (Fig. 31.3) (4). Medications that cause hirsutism are listed and should be considered (Table 31.1).
When laboratory testing for the assessment of hirsutism is indicated, either a bioavailable testosterone level (includes a total testosterone, SHBG, and albumin level) or a calculated free testosterone level (if albumin levels are assumed to be normal) provides the most accurate assessment of the androgen effect derived from testosterone. In clinical situations requiring a testosterone evaluation, the addition of 17-hydroxyprogesterone will screen for adult onset adrenal hyperplasia, when indicated (Table 31.2). When hirsutism is accompanied by absent or abnormal menstrual periods, assessment of prolactin and thyroid-stimulating hormone (TSH) values are required to diagnose an ovulatory disorder. Hypothyroidism and hyperprolactinemia may result in reduced levels of SHBG and may increase the fraction of unbound testosterone levels, occasionally resulting in hirsutism. In cases of suspected Cushing syndrome, patients should undergo screening with a 24-hour urinary cortisol (most sensitive and specific) assessment or an overnight dexamethasone suppression test. For this test, the patient takes 1 mg of dexamethasone at 11 p.m., and a blood cortisol assessment is performed at 8 a.m. the next day. Cortisol levels of 2 μg/dL or higher after overnight dexamethasone suppression require a further workup for evaluation of Cushing syndrome. Elevated 17-hydroxyprogesterone (17-OHP) levels identify patients who may have AOAH, found in 1% to 5% of hirsute women. The 17-OHP levels can vary significantly within the menstrual cycle, increasing in the periovulatory period and luteal phase, and may be modestly elevated in PCOS. Standardized testing requires early morning testing during the follicular phase.
According to the Endocrine Society clinical guidelines, patients with morning follicular phase 17-OHP levels of less than 300 ng/dL (10 nmol/L) are likely unaffected. When levels are greater than 300 ng/dL but less than 10,000 ng/dL (300 nmol/L), ACTH testing should be performed to distinguish between PCOS and AOAH. Levels greater than 10,000 ng/dL (300 nmol/L) are virtually diagnostic of congenital adrenal hyperplasia.
Precocious pubarche precedes the diagnosis of adult onset congenital adrenal hyperplasia in 5% to 20% of cases. Measurement of 17-OHP should be performed in patients presenting with precocious pubarche, and a subsequent ACTH stimulation test is recommended if basal 17-OHP is greater than 200 ng/dL. A study using a 200 ng/dL threshold for basal 17-OHP plasma levels to prompt ACTH stimulation testing offered 100% (95% confidence interval [CI], 69–100) sensitivity and 99% (95% CI, 96–100) specificity for the diagnosis of adult onset congenital adrenal hyperplasia within the cohort with precocious puberty (6).
Because increased testosterone production is not reliably reflected by total testosterone levels, the clinician may choose to rely on typical male pattern hirsutism as confirmation of its presence, or may elect measures that reflect levels of free or unbound testosterone (bioavailable or calculated free testosterone levels). Total testosterone does serve as a reliable marker for testosterone-producing neoplasms. Total testosterone levels greater than 200 ng/dL should prompt a workup for ovarian or adrenal tumors.
Although the ovary is the principal source of androgen excess in most of PCOS patients, 20% to 30% of patients with PCOS will demonstrate supranormal levels of DHEAS. Measuring circulating levels of DHEAS has limited diagnostic value, and overinterpretation of DHEAS levels should be avoided (7).
In the past, testing for androgen conjugates (e.g., 3α-androstenediol G [3α-diol G] and androsterone G [AOG] as markers for 5α-reductase activity in the skin) was advocated. Routine determination of androgen conjugates to assess hirsute patients is not recommended, because hirsutism itself is an excellent bioassay of free testosterone action on the hair follicle and because these androgen conjugates arise from adrenal precursors and are likely markers of adrenal and not ovarian steroid production (8).
Figure 31.3 Evaluation of hirsute women for hyperandrogenism. Evaluation includes more than the assessment of the degree of hirsutism. When hirsutism is moderate (>9) or severe or if mild hirsutism is accompanied by features that suggest an underlying disorder, elevated androgen levels should be ruled out. Disorders to be considered include endocrinopathies, of which PCOS is the most common, and neoplasms. Plasma testosterone is best assessed in the early morning on day 4 to 10 in regularly cycling women. A 17-hydroxyprogesterone is also indicated when symptoms warrant a bioavailable testosterone measurement. *3β-hydroxysteroid dehydrogenase deficiency in severe forms presents with mineralocorticoid and cortisol deficiency. Mild forms are diagnosed with a mean post-ACTH(1-24) stimulation: 17-hydroxypregnenolone/17-hydroxyprogesterone ratio of 11 compared to 3.4 in normals. 11β-hydroxylase deficiency presents with hypertension in the first years of life in two thirds of patients. The mild form presents with vitalization or precocious puberty without hypertension. Undiagnosed adults demonstrate hirsutism, acne, and amenorrhea. Diagnosis is confirmed with an 11-desoxycortisol level >25 ng/mL 60 minutes after ACTH(1-24) stimulation. ACTH, adrenocorticotropic hormone; AOAH, adult-onset adrenal hyperplasia; DHEAS, dehydroepiandrosterone sulfate; HAIR-AN, hyperandrogenemia, insulin resistance- acanthosis nigricans. (See references 2--11,15.)
Table 31.1 Medications Associated with Hirsutism
|
Acetazolamide |
methyldopa |
|
anabolic steroids |
minoxidil |
|
androgenic progestins |
penicillamine |
|
androgens |
phenothiazines |
|
Cyclosporine |
phenytoin |
|
Diazoxide |
streptomycin |
|
DHEA |
reserpine |
|
heavy metals |
valproic acid |
|
Interferon |
Table 31.2 Normal Values for Serum Androgensa
|
Testosterone (total) |
20–80 ng/dL |
|
Free testosterone (calculated) |
0.6–6.8 pg/mL |
|
Percentage free testosterone |
0.4–2.4% |
|
Bioavailable testosterone |
1.6–19.1 ng/dL |
|
SHBG |
18–114 nmol/L |
|
Albumin |
3,300–4,800 mg/dL |
|
Androstenedione |
20–250 ng/dL |
|
Dehydroepiandrosterone sulfate |
100–350 μg/dL |
|
17-hydroxyprogesterone (follicular phase) |
30–200 ng/dL |
|
SHBG, sex hormone–binding globulin. aNormal values may vary among different laboratories. Free testosterone is calculated using measurements for total testosterone and sex hormone–binding globulin, whereas bioavailable testosterone is calculated using measured total testosterone, sex hormone–binding globulin, and albumin. Calculated values for free and bioavailable testosterone compare well with equilibrium dialysis methods of measuring unbound testosterone when albumin levels are normal. Bioavailable testosterone includes free plus very weakly bound (non-SHBG, nonalbumin) testosterone. Bioavailable testosterone is the most accurate assessment of bioactive testosterone in the serum without performing equilibrium dialysis. |
|
In the zona reticularis layer of the adrenal cortex, DHEAS is generated by SULT2A1 (9). This layer of the adrenal cortex is thought to be the primary source of serum DHEAS. DHEAS levels decline as a person ages and the reticularis layer diminishes in size. In most laboratories, the upper limit of a DHEAS level is 350 μg/dL (9.5 nmol/L). A random sample is sufficient because the level of variation is minimized as a result of the long half-life characteristic of sulfated steroids. DHEAS is used as a screen for androgen-secreting adrenocortical tumors; however, moderate elevations are a common finding in the presence of PCOS, obesity, and stress, which reduces specificity (10).
A study of women with androgen-secreting adrenocortical tumors (ACT-AS) (N = 44), compared to women with nontumor androgen excess (NTAE) (N = 102), sheds additional light on the choice of hormones used to screen for an adrenocortical tumor. In the study, the demographics and the prevalence of hirsutism, acne, oligomenorrhea and amenorrhea were not different in each group. Free testosterone (free T) was the most commonly elevated androgen in ACT-AS (94%), followed by androstenedione (A) (90%), DHEAS (82%), and total testosterone (total T) (76%), and all three androgens were simultaneously elevated in 56% of the cases. Serum androgen levels became subnormal in all ACT-AS patients after the tumor was removed. In nontumor androgen excess alone, the most commonly elevated androgen was androstenedione (93%), while all three androgens (T, A, and DHEAS) were elevated in only 22% of the cases. Free testosterone values above 6.85 pg/mL (23.6 pmol/L) had the best diagnostic value for ACT-AS (sensitivity 82%; CI, 57%–96%; specificity 97%, CI, 91%–100%) (Table 31.3). The large overlap of androstenedione, testosterone, and DHEAS levels between ACT-AS and androgen excess groups suggests that thoughtful consideration should be employed when choosing hormone studies for this evaluation (11).
Table 31.3 Sensitivity and Specificity of Basal Hormone Levels in the Evaluation of Female Patients with Androgen-secreting Adrenocortical Tumors (ACT-AS) and Nontumor Causes of Androgen Excess (NTAE)
The heterogeneity of hormone secretion patterns in the adrenocortical tumor group reveals the complexities of hormone level screening for adrenocortical tumors: 7 of 44 patients (15.9%) had tumors secreting androgens alone, 2 of 44 (4.5%) had tumors secreting androgens and estrogens, 28 of 44 (63.6%) had tumors secreting both androgens and cortisol, and 7 of 44 (15.9%) had tumors secreting androgens, cortisol, and estrogens. Compound S or 11-desoxycortisol was increased (≥10 ng/mL or 28.9 nmol/L) in 23 of 27 ACT-AS patients (85%); 20 of 21 patients with malignant tumors, and 3 of 6 patients with apparently benign tumors, although 11-desoxycortisol was normal and inferior to 6 ng/mL (17.3 nmol/L) in 35 of 35 nontumor androgen excess patients (100%). Youden’s index displayed that a 11-desoxycortisol level above 7 ng/mL (20.2 nmol/L) has a sensitivity of 89% (95% CI, 71%–98%) and a specificity of 100% (95% CI, 90%–100%) for the detection of ACT-AS (11,12).
When clinical signs of androgen excess reach the point of virilization or the free testosterone level is above 6.85 pg/mL (23.6 pmol/L), follow-up testing with a 11-desoxycortisol (>7 ng/mL), DHEAS (>3.6 μg/mL), and 24-hour urinary cortisol (>45 μg per day) are the most sensitive and specific for the detection of an androgen-secreting adrenocortical tumor. Careful consideration of the sensitivity and specificity, diurnal variation, and age-related variation of potentially measureable androgens will aid in choosing the most useful measurements (Table 31.3).
Polycystic Ovary Syndrome
PCOS is arguably one of the most common endocrine disorders in women of reproductive age, affecting 5% to 10% of women worldwide. This familial disorder appears to be inherited as a complex genetic trait (13). It is characterized by a combination of hyperandrogenism (either clinical or biochemical), chronic anovulation, and polycystic ovaries. It is frequently associated with insulin resistance and obesity (14). PCOS receives considerable attention because of its high prevalence and possible reproductive, metabolic, and cardiovascular consequences. It is the most common cause of hyperandrogenism, hirsutism, and anovulatory infertility in developed countries(15,16). The association of amenorrhea with bilateral polycystic ovaries and obesity was first described in 1935 by Stein and Leventhal (17). Its genetic origins are likely polygenic and/or multifactorial (18).
Diagnostic Criteria
In an international conference on PCOS organized by the National Institutes of Health (NIH) in 1990, diagnostic criteria for PCOS were based on consensus rather than clinical trial evidence. Their diagnostic criteria recommended clinical and/or biochemical evidence of hyperandrogenism, chronic anovulation, and exclusion of other known disorders. These criteria were an important initial step in standardizing diagnosis and led to a number of landmark randomized clinical trials in PCOS (19).
Table 31.4 Revised Diagnostic Criteria of Polycystic Ovary Syndrome
|
1990 Criteria (both 1 and 2) |
|
1. Chronic anovulation and |
|
2. Clinical and/or biochemical signs of hyperandrogenism and exclusion of other etiologies. |
|
Revised 2003 criteria (2 out of 3) |
|
1. Oligoovulation or anovulation |
|
2. Clinical and/or biochemical signs of hyperandrogenism |
|
3. Polycystic ovaries and exclusion of other etiologies (congenital adrenal hyperplasia, androgen-secreting tumors, Cushing’s syndrome) |
|
From Rotterdam ESHRE/ASRM-Sponsored PCOS Consensus Workshop Group. Revised 2003 consensus on diagnostic criteria and long-term health risks related to polycystic ovary syndrome. Fertil Steril2004;81:19–25, with permission. Permission granted Elsevier 10.13.10. |
Since the 1990 NIH-sponsored PCOS conference, evolving perception is that the syndrome may constitute a broader spectrum of signs and symptoms of ovarian dysfunction than those set forth in the original NIH diagnostic criteria. The 2003 Rotterdam Consensus Workshop concluded that PCOS is a syndrome of ovarian dysfunction along with the cardinal features hyperandrogenism and polycystic ovary (PCO) morphology (Table 31.4).
It is recognized that women with regular cycles, hyperandrogenism, and PCO morphology may be part of the syndrome. Some women with the syndrome will have PCO morphology without clinical evidence of androgen excess, but will display evidence of ovarian dysfunction with irregular cycles. In this new schema, PCOS remains a diagnosis of exclusion with the need to rule out other disorders that mimic the PCOS phenotype (19).
Using the Rotterdam PCOS Diagnostic Criteria, the presence of two of the three criteria is sufficient to diagnosis PCOS: menstrual cycle anomalies (amenorrhoea, oligomenorrhea), clinical and/or biochemical hyperandrogenism, and/or the ultrasound appearance of polycystic ovaries after all other diagnoses are ruled out. Other pathologies that can result in a POCS phenotype include AOAH, adrenal or ovarian neoplasm, Cushing syndrome, hypo- or hypergonadotropic disorders, hyperprolactinemia, and thyroid disease (Fig. 31.4).
All other frequently encountered manifestations offer less consistent findings and therefore qualify only as minor diagnostic criteria for PCOS. They include elevated LH-to-FSH (follicle-stimulating hormone) ratio, insulin resistance, perimenarchal onset of hirsutism, and obesity.
Clinical hyperandrogenism includes hirsutism, male pattern alopecia, and acne (19). Hirsutism occurs in approximately 70% of patients with PCOS in the United States and in only 10% to 20% of patients with PCOS in Japan (20,21). A likely explanation for this discrepancy is the genetically determined differences in skin 5α-reductase activity (22,23).
Nonclassic adrenal hyperplasia and PCOS may present with similar clinical features. It is important to measure the basal follicular phase 17-hydroxyprogesterone level in all women presenting with hirsutism to exclude the presence of nonclassic congenital adrenal hyperplasia, regardless of the presence of polycystic ovaries or metabolic dysfunction (24).
The menstrual dysfunction in PCOS arises from anovulation or oligo-ovulation and ranges from amenorrhea to oligomenorrhea. Regular menses in the presence of anovulation in PCOS is uncommon, although one report found that among hyperandrogenic women with regular menstrual cycles, the rate of anovulation is 21% (25). Classically, the disorder is lifelong, characterized by abnormal menses from puberty with acne and hirsutism arising in the teens. It may arise in adulthood, concomitant with the emergence of obesity, presumably because this is accompanied by increasing hyperinsulinemia (26).
Figure 31.4 Diagnostic algorithm for polycystic ovary syndrome. (From Rosenfield RL. Clinical practice. Hirsutism. N Engl J Med 2005;353:2578–2588, with permission.)
The sonographic criteria for PCO requires the presence of 12 or more follicles in either ovary measuring 2 to 9 mm in diameter and/or increased ovarian volume (>10 mL). A single ovary meeting these criteria is sufficient to affix the PCO diagnosis (19). The appearance of PCO on ultrasound scanning is common. Only a fraction of those with PCO appearance have the clinical and/or endocrine features of PCOS. A PCO appearance is found in about 23% of women of reproductive age, while estimates of the incidence of PCOS vary between 5% and 10% (27). Polycystic appearing ovaries in women with PCOS was not associated with increased cardiovascular disease risk, independent of body mass index (BMI), age, and insulin levels (28). An English study demonstrated that without symptoms of polycystic ovary syndrome, a PCO appearance alone is not associated with impaired fecundity or fertility (29).
Obesity occurs in more than 50% of patients with PCOS. The body fat is usually deposited centrally (android obesity), and a higher waist-to-hip ratio is associated with insulin resistance indicating an increased risk of diabetes mellitus and cardiovascular disease (30). Among women with PCOS, there is widespread variability in the degree of adiposity by geographic location and ethnicity. In studies in Spain, China, Italy, and the United States, the percentage of obese women with PCOS were 20%, 43%, 38%, and 69%, respectively (31).
Insulin resistance resulting in hyperinsulinemia is commonly exhibited in PCOS. Insulin resistance may eventually lead to the development of hyperglycemia and type 2 diabetes mellitus (32). About one-third of obese PCOS patients have impaired glucose tolerance (IGT), and 7.5% to 10% have type 2 diabetes mellitus (33). These rates are mildly increased in nonobese women who have PCOS (10% IGT; 1.5% diabetes, respectively), compared with the general population of the United States (7.8% IGT; 1% diabetes, respectively) (34,35).
Abnormal lipoproteins are common in PCOS and include elevated total cholesterol, triglycerides, and low-density lipoproteins (LDL); and,low levels of high-density lipoproteins (HDL), and apoprotein A-I (30,36). According to one report, the most characteristic lipid alteration is decreased levels of HDL2α (37).
Other observations in women with PCOS include impaired fibrinolysis, as shown by elevated circulating levels of plasminogen activator inhibitor, an increased incidence of hypertension over the years (which reaches 40% by perimenopause), a greater prevalence of atherosclerosis and cardiovascular disease, and an estimated sevenfold increased risk for myocardial infarction (36,38–41).
Pathology
Macroscopically, ovaries in women with PCOS are two to five times the normal size. A cross-section of the surface of the ovary discloses a white, thickened cortex with multiple cysts that are typically less than a centimeter in diameter. Microscopically, the superficial cortex is fibrotic and hypocellular and may contain prominent blood vessels. In addition to smaller atretic follicles, there is an increase in the number of follicles with luteinized theca interna. The stroma may contain luteinized stromal cells (42).
Pathophysiology and Laboratory Findings
The hyperandrogenism and anovulation that accompany PCOS may be caused by abnormalities in four endocrinologically active compartments: (i) the ovaries, (ii) the adrenal glands, (iii) the periphery (fat), and (iv) the hypothalamus–pituitary compartment (Fig. 31.5).
Figure 31.5 Pathophysiological characteristics of the polycystic ovary syndrome (PCOS). Insulin resistance results in a compensatory hyperinsulinemia, which stimulates ovarian androgen production in an ovary genetically predisposed to PCOS. Arrest of follicular development (red “X”) and anovulation could be caused by the abnormal secretion of gonadotropins such as follicle-stimulating hormone (FSH) or luteinizing hormone (LH) (perhaps induced by hyperinsulinemia), intraovarian androgen excess, direct effects of insulin, or a combination of these factors. Insulin resistance, in concert with genetic factors, may also lead to hyperglycemia and an adverse profile of cardiovascular risk factors. (From Rosenfield RL. Clinical practice. Hirsutism. N Engl J Med 2005;353:2578–2588, with permission.)
In patients with PCOS, the ovarian compartment is the most consistent contributor of androgens. Dysregulation of CYP17, the androgen-forming enzyme in both the adrenals and the ovaries, may be one of the central pathogenetic mechanisms underlying hyperandrogenism in PCOS (43). The ovarian stroma, theca, and granulosa contribute to ovarian hyperandrogenism and are stimulated by LH (44). This hormone relates to ovarian androgenic activity in PCOS in a number of ways.
1. Total and free testosterone levels correlate directly with LH levels (45).
2. The ovaries are more sensitive to gonadotropic stimulation, possibly as a result of CYP17 dysregulation (43).
3. Treatment with a gonadotropin-releasing hormone (GnRH) agonist effectively suppresses serum testosterone and androstenedione levels (46).
4. Larger doses of a GnRH agonist are required for androgen suppression than for endogenous gonadotropin-induced estrogen suppression (47).
The increased testosterone levels in patients with PCOS are considered ovarian in origin. The serum total testosterone levels are usually no more than twice the upper normal range (20 to 80 ng/dL). However, in ovarian hyperthecosis, values may reach 200 ng/dL or more (48). The adrenal compartment plays a role in the development of PCOS. Although the hyperfunctioning CYP17 androgen-forming enzyme coexists in both the ovaries and the adrenal glands, DHEAS is increased in only about 50% of patients with PCOS (49,50). The hyperresponsiveness of DHEAS to stimulation with ACTH, the onset of symptoms around puberty, and the observation of 17,20-lyase activation (one of the two CYP17 enzymes) are key events in adrenarche that led to the hypothesis that PCOS arises as an exaggeration of adrenarche (48).
The peripheral compartment, defined as the skin and the adipose tissue, manifests its contribution to the development of PCOS in several ways.
1. The presence and activity of 5α-reductase in the skin largely determines the presence or absence of hirsutism (22,23).
2. Aromatase and 17β-hydroxysteroid dehydrogenase activities are increased in fat cells and peripheral aromatization is increased with increased body weight (51,52).
3. With obesity the metabolism of estrogens, by way of reduced 2-hydroxylation and 17α-oxidation, is decreased and metabolism via estrogen active 16-hydroxyestrogens (estriol) is increased (53).
4. Whereas estradiol (E2) is at a follicular phase level in patients with PCOS, estrone (E1) levels are increased as a result of peripheral aromatization of androstenedione (54).
5. A chronic hyperestrogenic state, with reversal of the E1-to-E2 ratio, results and is unopposed by progesterone.
The hypothalamic–pituitary compartment participates in aspects critical to the development of PCOS.
1. An increase in LH pulse frequency relative to those in the normal follicular phase is the result of increased GnRH pulse frequency (55).
2. This increase in LH pulse frequency explains the frequent observation of an elevated LH and LH-to-FSH ratio.
3. FSH is not increased with LH, likely because of the combination of increased gonadotropin pulse frequency and the synergistic negative feedback of chronically elevated estrogen levels and normal follicular inhibin.
4. About 25% of patients with PCOS exhibit mildly elevated prolactin levels, which may result from abnormal estrogen feedback to the pituitary gland. In some patients with PCOS, bromocriptine has reduced LH levels and restored ovulatory function (56).
Polycystic ovary syndrome is a complex multigenetic disorder that results from the interaction between multiple genetic and environmental factors. Genetic studies of PCOS reported allele sharing in large PCOS patient populations and linkage studies focused on candidate genes most likely to be involved in the pathogenesis of PCOS. These genes can be grouped in four categories: (i) insulin resistance–related genes, (ii) genes that interfere with the biosynthesis and the action of androgens, (iii) genes that encode inflammatory cytokines, and (iv) other candidate genes (57).
Linkage studies identified the follistatin, CYP11A, Calpain 10, IRS-1 and IRS-2 regions and loci near the insulin receptor (19p13.3), SHBG, TCF7L2, and the insulin genes, as likely PCOS candidate genes (58–64). A polymorphic variant, D19S884, in FBN3 was found to be associated with risk of PCOS (65). Using theca cells derived from women with PCOS elevated mRNA levels was noted for CYP11A, 3BHSD2, and CYP17 genes with corresponding overproduction of testosterone, 17-α-hydroxyprogesterone, and progesterone. Despite the characteristically heightened steroidogenesis in POCS, the STARBgene was not overexpressed (58). Microarray data using theca cells from PCOS women did not identify any genes near the 19p13.3 locus that were differentially expressed; however, the mRNAs of several genes that map to 19p13.3, including the insulin receptor, p114-Rho-GEF, and several expressed sequence tags, were detected in both PCOS and normal theca cells. Those studies identified new factors that might impact theca cell steroidogenesis and function, including cAMP-GEFII, genes involved in all-transretinoic acid (atRA) synthesis signaling, genes that participate in the Wnt signal transduction pathway, and transcription factor GATA6. These findings suggest that a 19p13.3 locus or some other candidate gene may be a signal transduction gene that results in overexpression of a suite of genes downstream that may affect steroidogenic activity (66). Polymorphisms in major folliculogenesis genes, GDF9, BMP15, AMH, and AMHR2, are not associated with PCOS susceptibility (67).
Insulin Resistance
Patients with PCOS frequently exhibit insulin resistance and hyperinsulinemia. Insulin resistance and hyperinsulinemia participate in the ovarian steroidogenic dysfunction of PCOS. Insulin alters ovarian steroidogenesis independent of gonadotropin secretion in PCOS. Insulin and insulin-like growth factor I (IGF-I) receptors are present in the ovarian stromal cells. A specific defect in the early steps of insulin receptor–mediated signaling (diminished autophosphorylation) was identified in 50% of women with PCOS (68).
Insulin has direct and indirect roles in the pathogenesis of hyperandrogenism in PCOS. Insulin in collaboration with LH enhances the androgen production of theca cells. Insulin inhibits the hepatic synthesis of sex hormone–binding globulin, the main circulating protein that binds to testosterone, thus increasing the proportion of unbound or bioavailable testosterone (13).
The most common cause of insulin resistance and compensatory hyperinsulinemia is obesity, but despite its frequent occurrence in PCOS, obesity alone does not explain this important association(56). The insulin resistance associated with PCOS is not solely the result of hyperandrogenism based on the following:
1. Hyperinsulinemia is not a characteristic of hyperandrogenism in general but is uniquely associated with PCOS (69).
2. In obese women with PCOS, 30% to 45% have glucose intolerance or frank diabetes mellitus, whereas ovulatory hyperandrogenic women have normal insulin levels and glucose tolerance (69). It seems that the associations between PCOS and obesity on the action of insulin are synergistic.
3. Suppression of ovarian steroidogenesis in women with PCOS with long-acting GnRH analogues does not change insulin levels or insulin resistance (70).
4. Oophorectomy in patients with hyperthecosis accompanied by hyperinsulinemia and hyperandrogenemia does not change insulin resistance, despite a decrease in androgen levels (70,71).
Acanthosis nigricans is a reliable marker of insulin resistance in hirsute women. This thickened, pigmented, velvety skin lesion is most often found in the vulva and may be present on the axilla, over the nape of the neck, below the breast, and on the inner thigh (72). The HAIR-AN syndrome consists of hyperandrogenism (HA), insulin resistance (IR), and acanthosis nigricans (AN) (68,73). These patients often have high testosterone levels (>150 ng/dL), fasting insulin levels of greater than 25 μIU/mL (normal <20 to 24 μIU/mL), and maximal serum insulin responses to glucose load (75 gm) exceeding 300 μIU/mL (normal is <160 μIU/m: at 2 hours postglucose load).
Screening Strategies for Diabetes and Insulin Resistance
The 2003 Rotterdam Consensus Group recommends that obese women with PCOS and nonobese PCOS patients with risk factors for insulin resistance, such as a family history of diabetes, should be screened for metabolic syndrome, including glucose intolerance with an oral glucose tolerance test (19). The standard 2-hour oral glucose tolerance test (OGTT) provides an assessment of both the degrees of hyperinsulinemia and glucose tolerance and yields the highest amount of information for a reasonable cost and risk (7).
Multiple other testing or screening schema were proposed to assess the presence of hyperinsulinemia and insulin resistance. In one, the fasting glucose-to-insulin ratio is determined, and values less than 4.5 indicate insulin resistance. Using the 2-hour GTT with insulin levels, 10% of nonobese and 40% to 50% of obese PCOS women have impaired glucose tolerance (IGT = 2-hour glucose level ≥140 but ≤199 mg/dL) or overt type 2 diabetes mellitus (any glucose level >200 mg/dL). Some research studies utilized a peak insulin level of over 150 μIU/mL or a mean level of over 84 μIU/mL over the three blood draws of a 2-hour GTT as a criteria to diagnoses hyperinsulinemia.
The documentation of hyperinsulinemia using either the glucose to insulin ratio or the 2-hour GTT with insulin is problematic. When compared to the gold standard measure for insulin resistance, the hyperinsulemic-euglycemic clamp, it shows that the glucose-to-insulin ratio does not always accurately portray insulin resistance. When hyperglycemia is present, a relative insulin secretion deficit is present. This deficient insulin secretion exacerbates the effects of insulin resistance and renders inaccurate the use of hyperinsulinemia as an index of insulin resistance. Thus, routine measurements of insulin levels may not be particularly useful.
Although detection of insulin resistance, per se, is not of practical importance to the diagnosis or management of PCOS, testing women with PCOS for glucose intolerance is of value because their risk of cardiovascular disease correlates with this finding. An appropriate frequency for such screening depends on age, BMI and waist circumference, all of which increase risk.
Interventions
Two-Hour Glucose Tolerance Test Normal Glucose Ranges (World Health Organization criteria, after 75-gm glucose load)
• Fasting 64 to 128 mg/dL
• One hour 120 to 170 mg/dL
• Two hour 70 to 140 mg/dL
Two-Hour Glucose Values for Impaired Glucose Tolerance and Type 2 Diabetes (World Health Organization criteria, after 75-gm glucose load)
• Normal (2-hour) <140 mg/dL
• Impaired (2-hour) = 140 to 199 mg/dL
• Type 2 diabetes mellitus (2-hour) ≥200 mg/dL
Abnormal glucose metabolism may be significantly improved with weight reduction, which may reduce hyperandrogenism and restore ovulatory function (74). In obese, insulin-resistant women, caloric restriction that results in weight reduction will reduce the severity of insulin resistance (a 40% decrease in insulin level with a 10-kg weight loss) (75). This decrease in insulin levels should result in a marked decrease in androgen production (a 35% decrease in testosterone levels with a 10-kg weight loss) (76). Exercise reduces insulin resistance, independent from any associated weight loss, but data on the impact of exercise on the principal manifestations of PCOS are lacking.
In addition to addressing the increased risk for diabetes, the clinician should recognize insulin resistance or hyperinsulinemia as a cluster syndrome called metabolic syndrome or dysmetabolic syndrome X. Recognition of the importance of insulin resistance or hyperinsulinemia as a risk factor for cardiovascular disease led to diagnostic criteria for the dysmetabolic syndrome. The more dysmetabolic syndrome X criteria are present, the higher the level of insulin resistance and its downstream consequences. The presence of three of the following five criteria confirm the diagnosis, and an insulin-lowering agent and/or other interventions may be warranted (19).
Metabolic Syndrome Diagnostic Criteria
• Female waist >35 inches
• Triglycerides >150 mg/dL
• HDL <50 mg/dL
• Blood pressure >130/85 mmHg
• Fasting glucose: 110–126 mg/dL
• Two-hour glucose (75 gm OGTT): 140–199 mg/dL
Risk factors for the dysmetabolic syndrome include nonwhite race, sedentary lifestyle, BMI greater than 25, age over 40 years, cardiovascular disease, hypertension, PCOS, hyperandrogenemia, insulin resistance, HAIR-AN syndrome, nonalcoholic steatohepatitis (NASH), and a family history of type 2 diabetes mellitus, gestational diabetes, or impaired glucose tolerance.
Long-Term Risks and Interventions
Comprehensive treatment of PCOS addresses reproductive, metabolic and psychological features.
Metabolic Syndrome
A report by the Androgen Excess and PCOS Society concluded that lifestyle management, either alone or combined with antiobesity pharmacologic and/or surgical treatments, should be used as the primary therapy in overweight and obese women with PCOS (31). Lifestyle management of obesity in PCOS is multifactorial. Dietary management of obesity should focus on reducing body weight, maintaining a lower long-term body weight, and preventing weight gain. An initial weight loss of greater than or equal to 5% to 10% is recommended. In obese and overweight women with PCOS, dietary interventions with a resultant weight reduction of more than 5% to less than 15% over the starting body weight is associated with a reduction in either total or free testosterone, adrenal androgens, and improvement in SHBG levels. Metabolic improvements in fasting insulin, glucose, glucose tolerance, total cholesterol, triglycerides, plasminogen activator inhibitor-1, and free fatty acids are reported. Clinically, hirsutism, menstrual function, and ovulation are all improved (31).
Structured exercise improves insulin resistance and offers significant benefits in PCOS. The incorporation of structured exercise, behavior modification, and stress management strategies as fundamental components of lifestyle management increases the success of the weight loss strategy (Table 31.5).
Even though lifestyle management strategies should be used as the primary therapy in obese and overweight women with PCOS, they are difficult to maintain long term. Alternative approaches to the treatment of obesity include the use of pharmacologic agents, such as orlistat, sibutramine, and rimonabant, or bariatric surgery (31). The NIH clinical recommendations advise bariatric surgery when BMI is greater than 40 kg/m2 or greater than 35 kg/m2 in patients with a high-risk, obesity-related condition after failure of other treatments for weight control (31,77).
Dyslipidemia is one of the most common metabolic disorders seen in PCOS patients (up to 70% prevalence in a US PCOS population) (78). It is associated with insulin resistance and hyperandrogenism in combination with environmental (diet, physical exercise) and genetic factors. Various abnormal patterns include decreased levels of HDL, elevated levels of triglycerides, decreased total and LDL levels, and altered LDL quality (79,80).
Table 31.5 Lifestyle Modification Principles Suggested for Obesity Management in Polycystic Ovary Syndrome (PCOS)
|
Guidelines for dietary and lifestyle intervention in PCOS |
|
1. Lifestyle modification is the first form of therapy, combining behavioral (reduction of psychosocial stressors), dietary, and exercise management. 2. Reduced-energy diets (500–1,000 kcal/day reduction) are effective options for weight loss and can reduce body weight by 7% to 10% over a period of 6 to 12 months. 3. Dietary plans should be nutritionally complete and appropriate for life stage and should aim for <30% of calories from fat, <10% of calories from saturated fat, with increased consumption of fiber, whole-grain breads and cereals, and fruit and vegetables. 4. Alternative dietary options (increasing dietary protein, reducing glycemic index, reducing carbohydrate) may be successful for achieving and sustaining a reduced weight but more research is needed in PCOS specifically. 5. The structure and support within a weight-management program is crucial and may be more important than the dietary composition. Individualization of the program, intensive follow-up and monitoring by a physician, and support from the physician, family, spouse, and peers will improve retention. 6. Structured exercise is an important component of a weight-loss regime; aim for >30 min/day. |
|
Reprinted with permission from Moran LJ, Pasquali R, Teede HJ, et al. Treatment of obesity in polycystic ovary syndrome: a position statement of the Androgen Excess and Polycystic Ovary Syndrome Society. Fertil Steril 2009;92:1966–1982. |
To assess cardiovascular risks and prevent disease in patients with PCOS, the Androgen Excess and Polycystic Ovary Syndrome (AE-PCOS) Society recommend the following monitoring activities (80):
1. Waist circumference and BMI measurement at every visit, using the National Health and Nutrition Examination Survey method.
2. A complete lipid profile based using the American Heart Association guidelines (Fig. 31.6). If the fasting serum lipid profile is normal, it should be reassessed every 2 years or sooner if weight gain occurs.
3. A 2-hour post-75-g oral glucose challenge measurement in PCOS women with a BMI greater than 30 kg/m2, or alternatively in lean PCOS women with advanced age (40 years), personal history of gestational diabetes, or family history of type 2 diabetes.
4. Blood pressure measurement at each visit. The ideal blood pressure is 120/80 or lower. Prehypertension should be treated because blood pressure control has the largest benefit in reducing cardiovascular diseases.
5. Regular assessment for depression, anxiety, and quality of life.
Figure 31.6 Lipid guidelines in PCOS to prevent cardiovascular disease risk (values in mg/dL). (Non-HDL = Total Cholesterol - HDL, if TG <400 mg/dL). (Data for figure derived from Wild RA, Carmina E, Diamanti-Kandarakis E, et al. Assessment of cardiovascular risk and prevention of cardiovascular disease in women with the polycystic ovary syndrome: a consensus statement by the Androgen Excess and Polycystic Ovary Syndrome (AE-PCOS) Society. J Clin Endocrinol Metab 2010;95(5):2038–2049.)
A significant proportion of the population and particularly the obese population have inadequate vitamin D levels. Because vitamin D plays a role in many metabolic activities, assessment and supplementation when indicated are recommended.
25-hydroxy Vitamin D Levels
• Deficient: 8 ng/mL or less (≤20 nmol/L)
• Insufficient: 8–20 ng/mL (20–50 nmol/L)
• Optimal: 20–60 ng/mL (50–150 nmol/L; 40–50 ng/mL is treatment goal)
• High: 60–90 ng/mL (150–225 nmol/L)
• Toxic: >90 ng/mL or greater (≥225 nmol/L)
Supplementation Facts
1. The body uses 3,000 to 5,000 IU D3 per day.
2. In the absence of the sun, 600 IU of D3 are required to maintain vitamin D levels.
3. D2 is more rapidly metabolized and is less potent than D3.
4. Patients receiving 50,000 IU of vitamin D2 once a week for 8 weeks will usually correct a vitamin D deficiency, and this can be followed by giving 50,000 U of vitamin D2 once every other week to maintain vitamin D sufficiency.
5. D3 is more potent and appropriate dosing to correct levels is still under investigation.
Cancer
In chronic anovulatory patients with PCOS, persistently elevated estrogen levels, which are uninterrupted by progesterone, increase the risk of endometrial carcinoma (81,82). These endometrial cancers are usually well differentiated, stage I lesions with a cure rate of more than 90% (see Chapter 35). Endometrial biopsy should be considered in PCOS patients, because they may occasionally harbor these cancers as early as the third decade of life. Abnormal bleeding, increasing weight, and age are factors that should lower the threshold for endometrial sampling. Prevention of endometrial cancer is a core management goal for patients with PCOS. If other dimensions of management do not induce regular ovulation (e.g. clomiphene) or impose continuous progestation influence (e.g., oral contraceptives), regular secrectory transformation and menstruation should be induced with periodic administration of a progestational agent. Even though the hyperestrogenic state is associated with an increased risk of breast cancer, studies examining the relationship between PCOS and breast cancer have not always identified a significantly increased risk (82–86). The risk of ovarian cancer is increased two- to threefold in women with PCOS (82,87).
Depression and Mood Disorders
The clinical features of PCOS, such as infertility, acne, hirsutism, and obesity, promote psychological morbidity. Women with PCOS face challenges to their feminine identity that can lead to loss of self-esteem, anxiety, poor body image, and depression (88).
Table 31.6 Medical Treatment of Hirsutism
|
Treatment Category |
Specific Regimens |
|
Weight loss |
|
|
Hormonal suppression |
Oral contraceptives |
|
Medroxyprogesterone |
|
|
Gonadotropin-releasing hormone analogues |
|
|
Glucocorticoids |
|
|
Steroidogenic enzyme inhibitors |
Ketoconazole |
|
5α-reductase inhibitors |
Finasteride |
|
Antiandrogens |
Spironolactone |
|
Cyproterone acetate |
|
|
Flutamide |
|
|
Insulin sensitizer |
Metformin |
|
Mechanical |
Temporary |
|
Permanent |
|
|
Electrolysis |
|
|
Laser hair removal |
A study examining the prevalence of depression and other mood disorders in women with PCOS reported a significantly increased prevalence of depression (35% to 40%) when compared with controls (10.7%), after adjusting for BMI, and a family history of depression and/or infertility. Other mood disorders such as anxiety and eating disorders were common in women with PCOS (89). The high prevalence of depression and other mental health disorders in women with PCOS suggests that assessment and treatment of mental health disorders should be included in the evaluation and management plan (89). Lifestyle management improves quality of life and depression in obese and overweight and women with PCOS (88).
Treatment of Hyperandrogenism and PCOS
Treatment depends on a patient’s goals. Some patients require hormonal contraception, whereas others desire ovulation induction. In all cases where there is significant ovulatory dysfunction, progestational interruption of the unopposed estrogen effects on the endometrium is necessary. This may be accomplished by periodic luteal function resulting from ovulation induction, progestational suppression via contraceptive formulations, or intermittent administration of progestational agents for endometrial or menstrual regulation. Interruption of the steady state of hyperandrogenism and control of hirsutism usually can be accomplished simultaneously. Patients desiring pregnancy are an exception, and for them effective control of hirsutism may not be possible. Treatment regimens for hirsutism are listed in Table 31.6. The induction of ovulation and treatment of infertility are discussed in Chapter 32.
Weight Reduction
Weight reduction is the initial recommendation for patients with accompanying obesity because it promotes health, reduces insulin, SHBG, and androgen levels, and may restore ovulation either alone or combined with ovulation-induction agents (75). Weight loss of as little as 5% to 7% over a 6-month period can reduce the bioavailable or calculated free testosterone level significantly and restore ovulation and fertility in more than 75% of women (90). Exercise involving large muscle groups reduces insulin resistance and can be an important component of nonpharmacologic, lifestyle-modifying management.
Oral Contraceptives
Combination oral contraceptives (OCs) decrease adrenal and ovarian androgen production and reduce hair growth in nearly two-thirds of hirsute patients (91–94). Treatment with OCs offers the following benefits:
1. The progestin component suppresses LH, resulting in diminished ovarian androgen production.
2. The estrogen component increases hepatic production of SHBG, resulting in decreased free testosterone concentration (95,96).
3. Circulating androgen levels are reduced, including those of DHEAS, which to some extent is independent of the effects of both LH and SHBG (30,97).
4. Estrogens decrease conversion of testosterone to DHT in the skin by inhibition of 5α-reductase.
When an OC is used to treat hirsutism, a balance must be maintained between the decrease in free testosterone levels and the intrinsic androgenicity of the progestin. Three progestin compounds that are present in OCs (norgestrel, norethindrone, and norethindrone acetate) are believed to be androgen dominant. The androgenic bioactivity of these steroids may be a factor of their shared structural similarity with 19-nortestosterone steroids (98). Oral contraceptives containing the so-called new progestins (desogestrel, gestodene, norgestimate, and drospirenone) have minimized androgenic activity. However, there is limited evidence of clinically measurable differences in outcome resulting from the disparity of in vitro estimates of androgenic potency.
The use of OCs alone may be relatively ineffective (<10% success rate) in the treatment of hirsutism in women with PCOS, and the OCs may exacerbate insulin resistance in these patients (99,100). Effective protocols for pharmacologic management of significant hirsutism with OCs usually include coadministration of agents that impede androgen action.
Medroxyprogesterone Acetate
Oral or intramuscular administration of medroxyprogesterone acetate (MPA) successfully treats hirsutism (101). It directly affects the hypothalamic–pituitary axis by decreasing GnRH production and the release of gonadotropins, thereby reducing testosterone and estrogen production by the ovary. Despite a decrease in SHBG, total and free androgen levels are decreased significantly (102). The recommended oral dose for GnRH suppression is 20 to 40 mg daily in divided dosages or 150 mg given intramuscularly every 6 weeks to 3 months in the depot form. Hair growth is reduced in up to 95% of patients (103). Side effects of the treatment include amenorrhea, bone mineral density loss, depression, fluid retention, headaches, hepatic dysfunction, and weight gain. MPA is not commonly used for hirsutism.
Gonadotropin-Releasing Hormone Agonists
Administration of GnRH agonists may allow the differentiation of androgen produced by adrenal sources from that of ovarian sources (47). It was shown to suppress ovarian steroids to castrate levels in patients with PCOS (104). Treatment with leuprolide acetate given intramuscularly every 28 days decreases hirsutism and hair diameter in both idiopathic hirsutism and hirsutism secondary to PCOS (105). Ovarian androgen levels are significantly and selectively suppressed. The addition of OC or estrogen replacement therapy to GnRH agonist treatment (add-back therapy) prevents bone loss and other side effects of menopause, such as hot flushes and genital atrophy. The hirsutism-reducing effect is retained (102,106). Suppression of hirsutism is not potentiated by the addition of estrogen replacement therapy to GnRH agonist treatment (107).
Glucocorticoids
Dexamethasone may be used to treat patients with PCOS who have either adrenal or mixed adrenal and ovarian hyperandrogenism. Doses of dexamethasone as low as 0.25 mg nightly or every other night are used initially to suppress DHEAS concentrations to less than 400 μg/dL. Because dexamethasone has 40 times the glucocorticoid effect of cortisol, daily doses greater than 0.5 mg every evening should be avoided to prevent the risk of adrenal suppression and severe side effects that resemble Cushing syndrome. To avoid oversuppression of the pituitary–adrenal axis, morning serum cortisol levels should be monitored intermittently (maintain at >2 μg/dL). Reduction in hair growth rate was reported, and significant improvement in acne associated with adrenal hyperandrogenism (108).
Ketoconazole
Ketoconazole inhibits the key steroidogenic cytochromes. Administered at a low dose (200 mg per day), it can significantly reduce the levels of androstenedione, testosterone, and calculated free testosterone (109). It is rarely used for the chronic inhibition of androgen production in women with hyperandrogenism because of the serious risk of adrenocortical suppression and development of adrenal crisis (15).
Spironolactone
Spironolactone is a specific antagonist of aldosterone, which competitively binds to the aldosterone receptors in the distal tubular region of the kidney. It is an effective potassium-sparing diuretic that originally was used to treat hypertension. The effectiveness of spironolactone in the treatment of hirsutism is based on the following mechanisms:
1. Competitive inhibition of DHT at the intracellular receptor level (22).
2. Suppression of testosterone biosynthesis by a decrease in the CYP enzymes (110).
3. Increase in androgen catabolism (with increased peripheral conversion of testosterone to estrone).
4. Inhibition of skin 5α-reductase activity (22).
Although total and free testosterone levels are reduced significantly in patients with both PCOS and idiopathic hirsutism (hyperandrogenism with regular menses) after treatment with spironolactone, total and free testosterone levels in patients with PCOS remain higher than those with idiopathic hirsutism (hyperandrogenism with regular menses) (111). In both groups, SHBG levels are unaltered. The reduction in circulating androgen levels observed within a few days of spironolactone treatment partially accounts for the progressive regression of hirsutism.
At least a modest improvement in hirsutism can be anticipated in 70% to 80% of women using at least 100 mg of spironolactone per day for 6 months (112). Spironolactone reduces the daily linear growth rate of sexual hair, hair shaft diameters, and daily hair volume production (113). Combination therapy with spironolactone and oral contraceptives seems effective via their differing but synergistic activities (15,114).
The most common dose is 50 to 100 mg twice daily. Women treated with 200 mg per day show a greater reduction in hair shaft diameter than women receiving 100 mg per day (115). Maximal inhibition of hirsutism is noted between 3 and 6 months but continues for 12 months. Electrolysis can be recommended 9 to 12 months after the initiation of spironolactone for permanent hair removal.
The most common side effect of spironolactone is menstrual irregularity (usually metrorrhagia), which may occur in over 50% of patients with a dosage of 200 mg per day (115). Normal menses may resume with reduction of the dosage. Infrequently, other side effects such as mastodynia, urticaria, or scalp hair loss may occur. Nausea and fatigue can occur with high doses (112). Because spironolactone can increase serum potassium levels, its use is not recommended in patients with renal insufficiency or hyperkalemia. Periodic monitoring of potassium and creatinine levels is suggested.
Return of normal menses in amenorrheic patients is reported in up to 60% of cases (111). Patients must be counseled to use contraception while taking spironolactone because it theoretically can feminize a male fetus.
Cyproterone Acetate
Cyproterone acetate is a synthetic progestin derived from 17-OHP, which has potent antiandrogenic properties. The primary mechanism of cyproterone acetate is competitive inhibition of testosterone and DHT at the level of the androgen receptor (116). This agent induces hepatic enzymes and may increase the metabolic clearance rate of plasma androgens (117).
A European formulation of ethinyl estradiol with cyproterone acetate significantly reduces plasma testosterone and androstenedione levels, suppresses gonadotropins, and increases SHBG levels (118). Cyproterone acetate shows mild glucocorticoid activity (and may reduce DHEAS levels) (116,119). Administered in a reverse sequential regimen (cyproterone acetate 100 mg per day on days 5 to 15, and ethinyl estradiol 30 to 50 mg per day on cycle days 5 to 26), this cyclic schedule allows regular menstrual bleeding, provides excellent contraception, and is effective in the treatment of even severe hirsutism and acne (120).
Side effects of cyproterone acetate include fatigue, weight gain, decreased libido, irregular bleeding, nausea, and headaches. These symptoms occur less often when ethinyl estradiol is added. Cyproterone acetate administration is associated with liver tumors in beagles and is not approved by the U.S. Food and Drug Administration (FDA) for use in the United States.
Flutamide
Flutamide, a pure nonsteroidal antiandrogen, is approved for treatment of advanced prostate cancer. Its mechanism of action is inhibition of nuclear binding of androgens in target tissues. Although it has a weaker affinity to the androgen receptor than spironolactone or cyproterone acetate, larger doses (250 mg given two or three times daily) may compensate for the reduced potency. Flutamide is a weak inhibitor of testosterone biosynthesis.
In a single, 3-month study of flutamide alone, most patients demonstrated significant improvement in hirsutism with no change in androgen levels (121). Significant improvement in hirsutism with a significant drop in androstenedione, DHT, LH, and FSH levels was observed in an 8-month follow-up of flutamide and low-dose OCs in women who did not respond to OCs alone (122). The side effects of flutamide treatment combined with a low-dose OC included dry skin, hot flashes, increased appetite, headaches, fatigue, nausea, dizziness, decreased libido, liver toxicity, and breast tenderness (123).
In hyperinsulinemic hyperandrogenemic nonobese PCOS adolescents on a combination of metformin (850 mg per day) and flutamide (62.5 mg per day), the low-dose OC containing drospirenone resulted in a more effective and more efficient reduction in total and abdominal fat excess than was demonstrated by those utilizing an OC with gestodene as the progestin (124). The combination of ethinyl-drospirenone,metformin, and flutamide is effective in reducing excess total and abdominal fat and attenuating dysadipocytokinemia in young women with hyperinsulinemic PCOS. The use of the antiandrogen flutamideappeared to emphasize effects (125). Many patients taking flutamide (50% to 75%) report dry skin, blue-green discoloration of urine, and liver enzyme elevation. Liver toxicity or failure and death are rare but severe side effects of flutamide appear to be dose related (126). The 2008 Endocrine Society clinical practice guidelines do not recommend using flutamide as first-line therapy for treating hirsutism. If it is used, the lowest effective dose should be given, and the patient’s liver function should be monitored closely (4). Flutamide should not be used in women desiring pregnancy.
Finasteride
Finasteride is a specific inhibitor of type 2 5α-reductase enzyme activity, approved in the United States at a 5-mg dose for the treatment of benign prostatic hyperplasia, and at a 1-mg dose to treat male-pattern baldness. In a study in which finasteride (5 mg daily) was compared with spironolactone (100 mg daily), both drugs resulted in similar significant improvement in hirsutism, despite differing effects on androgen levels (127). Most of the improvement in hirsutism with finasteride occurred after 6 months of therapy with 7.5 mg of finasteride daily (128). The improvement in hirsutism in the presence of rising testosterone levels is convincing evidence that it is the binding of DHT, and not testosterone, to the androgen receptor that is responsible for hair growth. Finasteride does not prevent ovulation or cause menstrual irregularity. The increase in SHBG caused by OCs further decreases free testosterone levels; OCs in combination with finasteride are more effective in reducing hirsutism than finasteride alone. As with spironolactone and flutamide, finasteride could theoretically feminize a male fetus; therefore, both of these agents are used only with additional contraception.
Ovarian Wedge Resection
Bilateral ovarian wedge resection is associated with only a transient reduction in androstenedione levels and a prolonged minimal decrease in plasma testosterone (129,130). In patients with hirsutism and PCOS who had wedge resection, hair growth was reduced by approximately 16% (17,131). Although Stein and Leventhal’s original report cited a pregnancy rate of 85% following wedge resection and maintenance of ovulatory cycles, subsequent reports show lower pregnancy rates and a concerning incidence of periovarian adhesions (17,132). Instances of premature ovarian failure and infertility were reported (133).
Laparoscopic Electrocautery
Laparoscopic ovarian electrocautery is used as an alternative to wedge resection in patients with severe PCOS whose condition is resistant to clomiphene citrate. In a recent series, ovarian drilling was achieved laparoscopically with an insulated electrocautery needle, using 100-W cutting current to assist entry and 40-W coagulating current to treat each microcyst over 2 seconds (8-mm needle in ovary) (134). In each ovary, 10 to 15 punctures were created. This led to spontaneous ovulation in 73% of patients, with 72% conceiving within 2 years. Of those who underwent a follow-up laparoscopy, 11 of 15 were adhesion free. To reduce adhesion formation, a technique that cauterized the ovary in only four points led to a similar pregnancy rate, with a miscarriage rate of 14% (135). Other laparoscopic techniques using laser instead of electrocautery for laparoscopic ovarian drilling were described (136). Most series report a decrease in both androgen and LH concentrations and an increase in FSH concentrations (137,138). The beneficial endocrinological effects of laparoscopic ovarian drilling and the improvement in hirsutism were sustained for up to 9 years in patients with PCOS (139). Unilateral diathermy results in bilateral ovarian activity (140). Further studies are anticipated to define candidates who may benefit most from such a procedure. The risk of adhesion formation should be discussed with the patient.
Physical Methods of Hair Removal
Depilatory creams remove hair only temporarily. They break down and dissolve hair by hydrolyzing disulfide bonds. Although depilatories can have a dramatic effect, many women cannot tolerate these irritative chemicals. The topical use of corticosteroid cream may prevent contact dermatitis. Eflornithine hydrochloride cream, also known as difluoromethylornithine (DMFO), irreversibly blocks ornithine decarboxylase (ODC), the enzyme in hair follicles that is important in regulating hair growth. It is effective in the treatment of unwanted facial hair (141). Noticeable results take about 6 to 8 weeks of therapy. Treatment must be continued while inhibition of hair growth is desired, and when the cream is discontinued, hair returns to pretreatment levels after about 8 weeks (4).
Shaving is effective and, contrary to common belief, it does not change the quality, quantity, or texture of hair. Plucking, if done unevenly and repeatedly, may cause inflammation and damage to hair follicles and render them less amenable to electrolysis. Waxing is a grouped method of plucking in which hairs are plucked out from under the skin surface. The results of waxing last longer (up to 6 weeks) than shaving or depilatory creams (142).
Bleaching removes the hair pigment through the use of hydrogen peroxide (usually 6% strength), which is sometimes combined with ammonia. Although hair lightens and softens during oxidation, this method is frequently associated with hair discoloration or skin irritation and is not always effective (141).
Electrolysis and laser hair removal are the only permanent means recommended for hair removal. Under magnification, a trained technician destroys each hair follicle individually. When a needle is inserted into a hair follicle, galvanic current, electrocautery, or both used in combination (blend) destroy the hair follicle. After the needle is removed, a forceps is used to remove the hair. Hair regrowth ranges from 15% to 50%. Problems with electrolysis include pain, scarring, and pigmentation. Cost can be an obstacle (143). Laser hair removal destroys the hair follicle through photoablation. These methods are most effective after medical therapy arrests further growth.
Insulin Sensitizers
Because hyperinsulinemia appears to play a role in PCOS-associated anovulation, treatment with insulin sensitizers may shift the endocrine balance toward ovulation and pregnancy, either alone or in combination with other treatment modalities.
Metformin (Glucophage) is an oral biguanide antihyperglycemic drug used extensively for non–insulin-dependent diabetes. Metformin is pregnancy category B drug with no known human teratogenic effect. It lowers blood glucose mainly by inhibiting hepatic glucose production and by enhancing peripheral glucose uptake. Metformin enhances insulin sensitivity at the postreceptor level and stimulates insulin-mediated glucose disposal (144).
Metformin has been used extensively to treat oligo-ovulatory infertility, insulin resistance, and hyperandrogenism in PCOS patients. Metformin is used to treat PCOS oligo-ovulatory infertility either alone or in combination with dietary restriction, clomiphene, or gonadotropins. In randomized control studies, metformin improves the odds of ovulation in women with PCOS when compared with placebo (145,146). A large multicenter, randomized control trial in women with PCOS concluded that clomiphene is superior to metformin in achieving live births in infertile women with PCOS. When ovulation was used as the outcome, the combination of metformin and clomiphenewas superior to either clomiphene alone or metformin alone (147). Multiple births are a complication of clomiphene therapy.
The most common side effects are gastrointestinal, including nausea, vomiting, diarrhea, bloating, and flatulence. Because the drug caused fatal lactic acidosis in men with diabetes who have renal insufficiency, baseline renal function testing is suggested (148). The drug should not be given to women with elevated serum creatinine levels (144).
Concepts regarding the role of obesity and insulin resistance or hyperinsulinemia in PCOS suggest that the primary intervention should be recommending and assisting with weight loss (5% to 10% of body weight). In those with an elevated BMI, orlistat proved helpful in initiating and maintaining weight loss. A percentage of PCOS patients will respond to weight loss alone with spontaneous ovulation. In those who do not respond to weight loss alone or who are unable to lose weight, the sequential addition of clomiphene citrate followed by an insulin sensitizer, followed by the combination of these agents may promote ovulation without resorting to injectable gonadotropins.
A prevailing concern over the increased incidence of spontaneous abortions in women with PCOS and the potential reduction afforded by insulin sensitizers suggests that insulin sensitizers may be beneficial in combination with gonadotropin therapy for ovulation induction or in vitro fertilization (149). Women with early pregnancy loss have a low level of insulin-like growth factor (IGF) binding protein-1 (IGFBP-1), and of circulating glycodelin, which has immunomodulatory effects protecting the developing fetus. Use of metformin increased levels of both factors, which might explain early findings suggesting that metformin use may reduce the high spontaneous abortion rates seen among women with PCOS (150).
A number of observational studies suggested that metformin reduces the risk of pregnancy loss (151,152). However, there are no adequately designed and sufficiently powered randomized control trials to address this issue. In the prospective randomized pregnancy and PCOS (PPCOS) trial, there was a concerning nonsignificant trend toward a greater rate of miscarriages in the metformin only group (151). This trend was not noted in other trials.
There are no conclusive data to support a beneficial effect of metformin on pregnancy loss, and the trend toward a higher miscarriage rate in the PPCOS trial, which used extended release metformin, is of some concern (145,147).
The incidence of ovarian hyperstimulation syndrome is reduced with adjuvant metformin in PCOS patients at risk for severe ovarian hyperstimulation syndrome (153).
Cushing Syndrome
The adrenal cortex produces three classes of steroid hormones: glucocorticoids, mineralocorticoids, and sex steroids (androgen and estrogen precursors). Hyperfunction of the adrenal gland can produce clinical signs of increased activity of any or all of these hormones. Increased glucocorticoid action results in nitrogen wasting and a catabolic state. This causes muscle weakness, osteoporosis, atrophy of the skin with striae, nonhealing ulcerations and ecchymoses, reduced immune resistance that increases the risk of bacterial and fungal infections, and glucose intolerance resulting from enhanced gluconeogenesis and antagonism to insulin action.
Although most patients with Cushing syndrome gain weight, some lose it. Obesity is typically central, with characteristic redistribution of fat over the clavicles around the neck and on the trunk, abdomen, and cheeks.Cortisol excess may lead to insomnia, mood disturbances, depression, and even overt psychosis. With overproduction of sex steroid precursors, women may exhibit hyperandrogenism (hirsutism, acne, oligomenorrhea or amenorrhea, thinning of scalp hair). Masculinization is rare, and its presence suggests an autonomous adrenal origin, most often an adrenal malignancy. With overproduction of mineralocorticoids, patients may manifest arterial hypertension and hypokalemic alkalosis. The associated fluid retention may cause pedal edema (Table 31.7) (154).
Table 31.7 Overlapping Conditions and Clinical Features of Cushing Syndrome
|
Symptoms |
Signs |
Overlapping Conditions |
|
Features that best discriminate Cushing syndrome; most do not have a high sensitivity |
||
|
Easy bruising |
||
|
Facial plethora |
||
|
Proximal myopathy (or proximal muscle weakness) |
||
|
Striae (especially if reddish purple and >1 cm wide) |
||
|
In children, weight gain with decreasing growth velocity |
||
|
Cushing syndrome features in the general population that are common and/or less discriminatory |
||
|
Depression |
Dorsocervical fat pad (“buffalo hump”) |
Hypertension* |
|
Fatigue |
Facial fullness |
Incidental adrenal mass |
|
Weight gain |
Obesity |
Vertebral osteoporosis* |
|
Back pain |
Supraclavicular fullness |
Polycystic ovary syndrome |
|
Changes in appetite |
Thin skin* |
Type 2 diabetes* |
|
Decreased concentration |
Peripheral edema |
Hypokalemia |
|
Decreased libido |
Acne |
Kidney stones |
|
Impaired memory (especially short term) |
Hirsutism or female balding |
Unusual infections |
|
Insomnia |
Poor skin healing |
|
|
Irritability |
||
|
Menstrual abnormalities |
||
|
In children, slow growth |
In children, abnormal genital virilization |
|
|
In children, short stature |
||
|
In children, pseudoprecocious puberty or delayed puberty |
||
|
Features are listed in random order. *Cushing’s syndrome is more likely if onset of the feature is at a younger age. |
||
Table 31.8 Causes of Cushing Syndrome
|
Category |
Cause |
Relative Incidence |
|
ACTH-dependent |
Cushing syndrome |
60% |
|
Ectopic ACTH-secreting tumors |
15% |
|
|
Ectopic CRH-secreting tumors |
Rare |
|
|
ACTH-independent |
Adrenal cancer |
15% |
|
Adrenal adenoma |
10% |
|
|
Micronodular adrenal hyperplasia |
Rare |
|
|
Iatrogenic/factitious |
Common |
|
|
ACTH, adrenocorticotropic hormone; CRH, corticotropin-releasing hormone. |
||
|
ACTH-dependent Cushing syndrome may be caused by pituitary adenoma, basophil hyperplasia, nodular adrenal hyperplasia, or cyclic Cushing syndrome. |
||
Characteristic clinical laboratory findings associated with hypercortisolism are confined mainly to a complete blood count showing evidence of granulocytosis and reduced levels of lymphocytes and eosinophils. Increased urinary calcium secretion may be present.
Causes
The six recognized noniatrogenic causes of Cushing syndrome can be divided between those that are ACTH dependent and those that are ACTH independent (Table 31.8). The ACTH-dependent causes can result from ACTH secreted by pituitary adenomas or from an ectopic source. The hallmark of ACTH-dependent forms of Cushing syndrome is the presence of normal or high plasma ACTH concentrations with increased cortisol levels. The adrenal glands are hyperplastic bilaterally. Pituitary ACTH-secreting adenoma, or Cushing disease, is the most common cause of endogenous Cushing syndrome (154). These pituitary adenomas are usually microadenomas (<10 mm in diameter) that may be as small as 1 mm. They behave as though they are resistant, to a variable degree, to the feedback effect of cortisol. Like the normal gland, these tumors secrete ACTH in a pulsatile fashion; unlike the normal gland, the diurnal pattern of cortisol secretion is lost. Ectopic ACTH syndrome most often is caused by malignant tumors (155). About one-half of these tumors are small-cell carcinomas of the lung (156). Other tumors include bronchial and thymic carcinomas, carcinoid tumors of the pancreas, and medullary carcinoma of the thyroid.
Ectopic corticotropin-releasing hormone (CRH) tumors are rare and include such tumors as bronchial carcinoids, medullary thyroid carcinoma, and metastatic prostatic carcinoma (156). The presence of an ectopic CRH-secreting tumor should be suspected in patients whose dynamic testing suggests pituitary ACTH-dependent disease but who have rapid disease progression and very high plasma ACTH levels.
Figure 31.7 Algorithm for testing patients suspected of having Cushing syndrome (CS). Diagnostic criteria that suggest Cushing syndrome are a urinary-free cortisol (UFC) greater than the normal range for the assay, serum cortisol greater than 1.8 μg/dL (50 nmol/L) after 1 mg dexamethasone (1 mg DST), and a late night salivary cortisol greater than 145 ng/dL (4 nmol/L). (Based on recommendations from Nieman LK, Biller BM, Findling JW, et al. The diagnosis of Cushing’s syndrome: an Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab 2008;93:1526–1540.)
The most common cause of ACTH-independent Cushing syndrome is exogenous or iatrogenic (i.e., superphysiologic therapy with corticosteroids) or factitious (self-induced). Corticosteroids are used in pharmacologic quantities to treat a variety of diseases with an inflammatory component. Over time, such therapy will result in Cushing syndrome. When corticosteroids are taken by the patient but not prescribed by a physician, the diagnosis may be especially challenging. The diagnostic workup for Cushing syndrome focuses on the ability to suppress autonomous cortisol secretion and whether ACTH is elevated or suppressed. According to the 2008 Endocrine Society’s clinical practice guidelines for the diagnosis of Cushing syndrome, the initial use of one test with high diagnostic accuracy (24-hour urine free cortisol, late night salivary cortisol, 1 mg overnight or 2 mg 48-hour dexamethasone suppression test) is recommended. The 24-hour urine-free cortisol (UFC) should be used to diagnose Cushing syndrome in pregnant women and in patients with epilepsy, whereas the 1-mg overnight dexamethasone suppression test, rather than UFC, should be used for initial testing for Cushing syndrome in patients with severe renal failure and adrenal incidentaloma. The 2-mg 48-hour dexamethasone suppression test is the optimal test in conditions that are associated with overactivation of the hypothalamic–pituitary–adrenal (HPA) axis: depression, morbid obesity, alcoholism, and diabetes mellitus.
Patients with an abnormal result should see an endocrinologist and undergo a second test, either one of the above or, in some cases, a serum midnight cortisol or dexamethasone CRH test. These guidelines are summarized in (Fig. 31.7) (154).
Treatment of ACTH-independent Forms of Cushing Syndrome
Excluding cases that are of iatrogenic or factitious etiology, ACTH-independent forms of Cushing syndrome are adrenal in origin. Adrenal cancers are usually very large by the time Cushing syndrome is manifest. This is because the tumors are relatively inefficient synthesizers of steroid hormones. Tumors are larger than 6 cm in diameter and are easily detectable by computed tomography (CT) scanning or magnetic resonance imaging (MRI). Adrenal cancers often produce steroids other than cortisol. Thus, when Cushing syndrome is accompanied by hirsutism or virilization in women or feminization in men, adrenal cancer should be suspected.
An adrenal tumor that appears large and irregular on radiologic imaging is suggestive of carcinoma. In these cases, a unilateral adrenalectomy through an abdominal exploratory approach is preferable. In most malignant tumors, complete resection is virtually impossible. However, a partial response to postoperative chemotherapy or radiation may be achieved. Most patients with malignancy die within 1 year. When administered immediately after surgery, mitotane (O,P-DDD, an adrenocorticolytic drug) may be of benefit in preventing or delaying recurrent disease (157). Manifestations of Cushing syndrome in these patients are controlled by adrenal enzyme inhibitors.
Adrenal adenomas are smaller than carcinomas and average 3 cm in diameter. These tumors are usually unilateral and infrequently associated with other steroid-mediated syndromes. Micronodular adrenal disease is a disorder of children, adolescents, and young adults. The adrenal glands contain numerous small (>3 mm) nodules, which often are pigmented and secrete sufficient cortisol to suppress pituitary ACTH. This condition can be sporadic or familial.
Surgical removal of a neoplasm is the treatment of choice (158,159). If a unilateral, well-circumscribed adenoma is identified by MRI or CT scanning, the flank approach may be the most convenient. The cure rate following surgical removal of adrenal adenomas approaches 100%. Because normal function of the HPA axis is suppressed by autonomous cortisol production, cortisol replacement follows surgery and is titrated downward over several months, during which recovery of normal adrenal function is monitored.
Treatment of Cushing Disease
The main goals of treatment in ACTH-dependent Cushing syndrome are reversal of clinical features, normalization of biochemical changes with minimal morbidity, and long-term control without recurrence (155).
The treatment of choice for Cushing disease is transsphenoidal resection. The remission rate is approximately 70% to 90% and the recurrence rate is 5% to 10% at 5 years and 10% to 20% at 10 years in patients with microadenomas who undergo surgery by an experienced surgeon (160–164). Patients with macroadenoma have lower remission rates (<60%) and higher recurrence rates (12% to 45%) (165–167). Following surgery, transient diabetes insipidus and enduring compromise of anterior pituitary secretion of growth hormone, gonadotropins, and TSH are common (167,168).
Radiation Therapy
Fractionated external beam radiotherapy or stereotactic radiosurgery is used to treat patients with Cushing disease in whom transsphenoidal microsurgery was not successful or in patients who are poor surgical candidates. This therapy can achieve control of hypercortisolemia in approximately 50% to 60% of patients within 3 to 5 years (155,169,170). Hypopituitarism is the most common side effect of pituitary irradiation, and long-term follow-up is essential to detect relapse, which can occur after an initial response to radiotherapy.
High-voltage external pituitary radiation (4,200 to 4,500 cGy) is given at a rate not exceeding 200 cGy per day. Only 15% to 25% of adults show total improvement, but approximately 80% of children respond (168,171).
Medical Therapy
Mitotane can be used to induce medical adrenalectomy during or after pituitary radiation (157). The role of medical therapy is to prepare the severely ill patient for surgery and to maintain normal cortisol levels while a patient awaits the full effect of radiation. Occasionally, medical therapy is used for patients who respond to therapy with only partial remission. Adrenal enzyme inhibitors include aminoglutethimide, metyrapone, trilostane, and etomidate.
A combination of aminoglutethimide and metyrapone may cause a total adrenal enzyme block, requiring corticosteroid-replacement therapy. Ketoconazole, an FDA-approved antifungal agent, inhibits adrenal steroid biosynthesis at the side arm cleavage and 11β-hydroxylation steps. The dose of ketoconazole for adrenal suppression is 600 to 800 mg per day for 3 months to 1 year (172). Ketoconazole is effective for long-term control of hypercortisolism of either pituitary or adrenal origin.
Nelson syndrome results from adenomatous progression of ACTH-secreting cells in patients with Cushing syndrome treated by bilateral adrenalectomy. The macroadenoma that causes this syndrome produces sellar pressure symptoms of headaches, visual field disturbances, and ophthalmoplegia. Extremely high ACTH levels in Nelson syndrome are associated with severe hyperpigmentation (melanocyte-stimulating hormone activity). The treatment is surgical removal or radiation. The offending adenomatous tissue is often resistant to complete surgical removal (173). This syndrome reportedly complicates 10% to 50% of bilateral adrenalectomy cases. Measuring pituitary MRI and ACTH plasma levels at regular intervals after bilateral adrenalectomy will allow detection of the early progression of corticotroph tumors and the possibility of cure by surgery, particularly with microadenomas (155). Nelson syndrome is less common today because bilateral adrenalectomy is less frequently used as initial treatment.
Congenital Adrenal Hyperplasia
CAH is transmitted as an autosomal recessive disorder. Several adrenocortical enzymes necessary for cortisol biosynthesis may be affected. Failure to synthesize the fully functional enzyme has the following effects:
1. A relative decrease in cortisol production.
2. A compensatory increase in ACTH levels.
3. Hyperplasia of the zona reticularis of the adrenal cortex.
4. An accumulation of the precursors of the affected enzyme in the bloodstream.
21-Hydroxylase Deficiency
Deficiency of 21-hydroxylase is responsible for over 90% of all cases of adrenal hyperplasia due to adrenal synthetic enzyme deficiency. The disorder produces a spectrum of conditions; CAH, with or without salt wasting, and milder forms that are expressed as hyperandrogenism of pubertal onset (adult onset adrenal hyperplasia, AOAH). Salt-wasting CAH, the most severe form, affects 75% of patients with congenital manifestations during the first 2 weeks of life and results in a life-threatening hypovolemic salt-wasting crisis, accompanied by hyponatremia, hyperkalemia, and acidosis. The salt-wasting form results from a severity of enzyme deficiency sufficient to result in ineffective aldosterone synthesis. With or without salt-wasting and newborn adrenal crisis, the condition is usually diagnosed earlier in affected female newborns than in males as genital virilization (e.g., clitoromegaly, labioscrotal fusion, and abnormal urethral course) is apparent at birth.
In simple virilizing CAH, affected patients are diagnosed as virilized newborn females or as rapidly growing masculinized boys at 3 to 7 years of age. Diagnosis is based on basal levels of the substrate for 21-hydroxylase, 17-OHP; in cases of congenital adrenal hyperplasia caused by 21-hydroxylase deficiency and in milder forms of the disorder with manifestations later in life (acquired, late onset, or adult-onset adrenal hyperplasia), diagnosis depends on basal and ACTH-stimulated levels of 17-OHP.
Patients with morning follicular phase 17-OHP levels of less than 300 ng/dL (10 nmol/L) are likely unaffected. When levels are greater than 300 ng/dL, but less than 10,000 ng/dL (300 nmol/L), ACTH testing should be performed to distinguish between 21-hydroxylase deficiency and other enzyme defects or to make the diagnosis in borderline cases. Levels greater than 10,000 ng/dL (300 nmol/L) are virtually diagnostic of congenital adrenal hyperplasia.
Nonclassic Adult Onset Congenital Adrenal Hyperplasia
The nonclassic type of 21-hydroxylase deficiency represents partial deficiency in 21-hydroxylation, which produces a late-onset, milder hyperandrogenemia. Its occurrence depends on some degree of functional deficit resulting from mutations affecting both alleles for the 21-hydroxylase enzyme. Heterozygote carriers for mutations in the 21-hydroxylase enzyme will demonstrate normal basal and modestly elevated stimulated levels of 17-OHP, but no abnormalities in circulating androgens. Some women with mild gene defects in both alleles demonstrate modest elevations in circulating 17-OHP concentrations, but no clinical symptoms or signs.
The hyperandrogenic symptoms of AOAH are mild and typically present at or after puberty. The three phenotypic varieties are (174):
1. Those with ovulatory abnormalities and features consistent with PCOS (39%)
2. Those with hirsutism alone without oligomenorrhea (39%)
3. Those with elevated circulating androgens but without symptoms (cryptic) (22%).
Precocious puberty reveals late-onset congenital adrenal hyperplasia in 5% to 20% of cases that mainly are caused by nonclassic 21-hydroxylase deficiency.
Measurement of 17-OHP should be performed in patients presenting with precocious puberty, and a subsequent ACTH stimulation test is recommended if basal 17-OHP is greater than 200 ng/dL.
The need for screening patients with hirsutism for adult-onset adrenal hyperplasia depends on the patient population. The frequency of some form of the disorder varies by ethnicity and is estimated at 0.1% of the general population, 1% to 2% of Hispanics and Yugoslavs, and 3% to 4% of Ashkenazi Jews (175).
Genetics of 21-Hydroxylase Deficiency
1. The 21-hydroxylase gene is located on the short arm of chromosome 6, in the midst of the HLA region.
2. The 21-hydroxylase gene is now termed CYP21. Its homologue is the pseudogene CYP21P (176).
3. Because CYP21P is a pseudogene, the lack of transcription renders it nonfunctional. The CYP21 is the active gene.
4. The CYP21 gene and the CYP21P pseudogene alternate with two genes called C4B and C4A, both of which encode for the fourth component (C4) of serum complement (176).
5. The close linkage between the 21-hydroxylase genes and HLA alleles allowed the study of 21-hydroxylase inheritance patterns in families through blood HLA typing (e.g., linkage of HLA-B14 was found in Ashkenazi Jews, Hispanics, and Italians) (177).
Prenatal Diagnosis and Treatment
Women with congenital and adult-onset forms of the disorder are at a significant risk for having affected infants, owing to the high frequency of 21-hydroxylase mutations in the general population. This presents an important rationale for screening hyperandrogenic women for this disorder when they anticipate childbearing. In families at risk for CAH and in instances where one partner expresses the congenital or adult onset form of the disease, first-trimester prenatal screening using chorionic villus sampling is advocated (176). The fetal DNA is used for specific amplification of the CYP21 gene using polymerase chain reaction (PCR) amplification (178). When the fetus is at risk for CAH, maternal dexamethasone treatment can suppress the fetal HPA axis and prevent genital virilization in affected females (179). The dose is 20 μg/kg in three divided doses administered as soon as pregnancy is recognized and no later than 9 weeks of gestation. This is done prior to performing chorionic villus sampling or amniocentesis in the second trimester. Dexamethasone crosses the placenta and suppresses ACTH in the fetus. If the fetus is determined to be an unaffected female or a male, treatment is discontinued. If the fetus is an affected female, dexamethasone therapy is continued.
The practice of prenatal dexamethasone treatment for women whose fetuses are at risk for CAH is controversial; seven of eight pregnancies will be treated with dexamethasone unnecessarily, albeit briefly, to prevent one case of ambiguous genitalia. The efficacy and safety of prenatal dexamethasone treatment is not established, and long-term follow-up data on the offspring of treated pregnancies are lacking (180).
Numerous studies in experimental animal models showed that prenatal dexamethasone exposure could impair somatic growth, brain development, and blood pressure regulation. A human study of 40 fetuses at risk for CAH who were treated prenatally with dexamethasone to prevent virilization of affected females reported long-term effects on neuropsychological functions and scholastic performance (179,181).
The 2010 Endocrine Society guidelines conclude that prenatal dexamethasone therapy should be pursued only through institutional review boards' approved protocols at centers capable of collecting sufficient outcome data (182).
11β-Hydroxylase Deficiency
In a small percentage of patients with CAH, hypertension, rather than mineralocorticoid deficiency, develops. The hypertension responds to corticosteroid replacement (183–186). Many of these patients have a deficiency in 11β-hydroxylase (184,185). In most populations, 11β-hydroxylase deficiency accounts for 5% to 8% of the cases of CAH, or 1 in 100,000 births (187). A much higher incidence, 1 in 5,000 to 7,000, was described in Moroccan Jewish immigrants (186).
Two 11β-hydroxylase isoenzymes are responsible for cortisol and aldosterone synthesis, respectively, CYP11-B1 and CYP11-B2. They are encoded by two genes on the middle of the long arm of chromosome 8 (187–189).
Inability to synthesize a fully functional 11β-hydroxylase enzyme causes a decrease in cortisol production, a compensatory increase in ACTH secretion, and increased production of androstenedione, 11-deoxycortisol, 11-deoxycorticosterone, and DHEA. The diagnosis of 11β-hydroxylase-deficient late-onset adrenal hyperplasia is determined when 11-deoxycortisol levels are higher than 25 ng/mL 60 minutes after ACTH(1–24) stimulation (190).
Patients with 11β-hydroxylase deficiency may present with either a classic pattern of the disorder or symptoms of a mild deficiency. The severe classic form is found in about two-thirds of the patients with mild-to-moderate hypertension during the first years of life. In about one-third of the patients it is associated with left ventricular hypertrophy, with or without retinopathy, and occasionally death is reported from cerebrovascular accident (183). Signs of androgen excess are common in the severe form and are similar to those seen in the 21-hydroxylase deficiency.
In the mild, nonclassic form, children have virilization or precocious puberty but not hypertension. Adult women will seek treatment for postpubertal onset of hirsutism, acne, and amenorrhea.
3β-Hydroxysteroid Dehydrogenase Deficiency
Deficiency of 3β-hydroxysteroid dehydrogenase occurs with varying frequency in hirsute patients (191,192). The enzyme is found in both the adrenal glands and ovaries (unlike 21- and 11-hydroxylase) and is responsible for transforming Δ-5 steroids into the corresponding Δ-4 compounds, a step integral to the synthesis of glucocorticoids, mineralocorticoids, and testosterone and estradiol. In severe forms, cortisol and mineralocorticoids are deficient. The clinical spectrum of 3β-hydroxysteroid dehydrogenase deficiency ranges from the classic salt wasting, hypogonadism, and ambiguous genitalia in males and females, to nonclassic hyperandrogenic symptoms in children and young women (193). In mild forms, elevated ACTH levels overcome these critical deficiencies, and the diagnosis of this disorder relies on the relationship of Δ-5 and Δ-4 steroids. A marked elevation of DHEA and DHEAS in the presence of normal, or mildly elevated, testosterone or androstenedione can suggest the initiation of a screening protocol for 3β-hydroxysteroid dehydrogenase deficiency using exogenous ACTH stimulation (191). Following intravenous administration of a 0.25-mg ACTH(1-24) bolus, within 60 minutes 17-hydroxypregnenolone levels rise significantly in women with 3β-hydroxysteroid dehydrogenase deficiency, compared with normal women (2,276 ng/dL compared with normal of 1,050 ng/dL). The mean poststimulation ratio between 17-hydroxypregnenolone and 17-OHP is markedly elevated (mean ratio of 11 compared with 3.4 in normal controls and 0.4 in 21-hydroxylase deficiency). The rarity of this disorder indicates that routine screening of hyperandrogenic patients is not justified (191,192).
Treatment of Adult-Onset Congenital Adrenal Hyperplasia
Many patients with congenital AOAH do not need treatment. Glucocorticoid treatment should be avoided in asymptomatic patients with AOAH because the potential adverse effects of glucocorticoids probably outweigh any benefits (180,182).
Glucocorticoid therapy is recommended only to reduce hyperandrogenism for those with significant symptoms. Dexamethasone and antiandrogen drugs (both cross the placenta) should be used with caution and in conjunction with oral contraceptives in adolescent girls and young women with signs of virilization or irregular menses. When fertility is desired, ovulation induction might be necessary, and a glucocorticoid that does not cross the placenta (e.g., prednisolone or prednisone) should be used (179).
Many patients who are undiagnosed but who actually have AOAH are treated with therapies for ovarian hyperandrogenism and/or PCOS, with progestins for endometrial regulation, clomiphene or gonadotropins for ovulation induction, or progestins and antiandrogens for control of hirsutism. These therapies may be appropriate, as an alternative to glucocorticoid therapy, even when AOAH is recognized as the cause for the patient’s symptoms.
Androgen-Secreting Ovarian and Adrenal Tumors
Patients with severe hirsutism, virilization, or recent and rapidly progressing signs of androgen excess require careful investigation for the presence of an androgen-secreting neoplasm. The two most common sources of androgen-secreting tumors are the adrenal glands and the ovaries. To assess the symptoms, serum and urine tests for androgens and their metabolites should be obtained along with modern abdominal imaging techniques such as CT, MRI, and ultrasound scans (194). In prepubertal girls, virilizing tumors may cause signs of heterosexual precocious puberty in addition to hirsutism, acne, and virilization. In patients suspected of harboring an adrenal or ovarian tumor because of rapidly progressing or severe hyperandrogenism, the bioavailable testosterone level (free testosterone level above 6.85 pg/mL; 23.6 pmol/L), followed by an11-desoxycortisol (above 7 ng/mL; 20.2 nmol/L), DHEAS (>3.6 μg/mL) and a 24-hour urinary cortisol (>45 μg per day) are the most sensitive and specific for the detection of an androgen-secreting adrenocortical tumor (Table 31.3). A markedly elevated free testosterone level (2.5 times the upper normal range) is considered typical of an adrenal androgen-secreting tumor, while moderately elevated free testosterone levels are often ovarian in origin. A DHEAS level greater than 800 μg/dL is typical of an adrenal tumor. An adrenal tumor is unlikely when serum DHEAS and urinary 17-ketosteroid excretion measurements are in the normal basal range and the serum cortisol concentration is less than 3.3 μg/dL after dexamethasoneadministration (195). The results of other dynamic tests, especially testosterone suppression and stimulation, are unreliable (196).
A vaginal and abdominal ultrasonographic examination is the first step in the evaluation of findings suggesting ovarian neoplasm. Duplex Doppler scanning may increase the accuracy of tumor diagnosis and localization (197).
CT scanning can reveal tumors larger than 10 mm (1 cm) in the adrenal gland but may not help to distinguish among different types of solid tumors or benign incidental nodules (198). In the ovaries, CT scanning cannot help differentiate hormonally active from functional tumors (197,198).
MRI is comparable, if not superior, to CT scanning in detecting ovarian neoplasms, but is neither more sensitive than high-quality ultrasound nor more useful in clinical decision making when ultrasound identifies a likely neoplasm. Nuclear medicine imaging of the abdomen and pelvis after injection with NP-59 ((131-iodine) 6-beta-iodomethyl-19-norcholesterol), preceded by adrenal and thyroid suppression, may facilitate tumor localization. In the rare circumstances when imaging fails to provide clear evidence for a neoplastic source of excess androgens, selective venous catheterization with measurement of site-specific androgen levels to identify an occult source of for androgen excess may be utilized (199). If all four vessels are catheterized transfemorally, selective venous catheterization allows direct localization of the tumor. Samples are obtained for hormonal analysis, with positive localization defined as a 5:1 testosterone gradient compared with lower vena cava values (200). Under such circumstances specificity approaches 80%, but this rate should be weighed against the 5% rate of significant complications, such as adrenal hemorrhage and infarction, venous thrombosis, hematoma, and radiation exposure (201).
Androgen-Producing Ovarian Neoplasms
Ovarian neoplasms are the most frequent androgen-producing tumors. Granulosa cell tumors constitute 1% to 2% of all ovarian tumors and occur mostly in adult women (in postmenopausal more frequently than in premenopausal women) (see Chapter 37). Usually associated with estrogen production, they are the most common functioning tumors in children and can lead to isosexual precocious puberty (202). Patients can present with vaginal bleeding caused by endometrial hyperplasia or endometrial cancer resulting from prolonged exposure to tumor-derived estrogen (203). Total abdominal hysterectomy and bilateral salpingo-oophorectomy are the treatments of choice. If fertility is desired, a more conservative approach involving unilateral salpingo-oophorectomy with careful staging can be performed in women with stage IA (the cancer does not extend outside the involved ovary and a concomitant uterine cancer is excluded) (203). The malignant potential of these lesions is variable. The 10-year survival rates vary from 60% to 90%, depending on the stage, tumor size, and histologic atypia (202).
Thecomas are rare and occur in older patients. In one study only 11% were androgenic, even in the presence of steroid-type cells (luteinized thecomas) (202). They are unilateral in more than 90% of the cases and rarely malignant. A unilateral oophorectomy is adequate treatment (204).
Sclerosing stromal tumors are benign neoplasms that usually occur in patients younger than 30 years (202). A few cases with estrogenic or androgenic manifestations were reported.
Sertoli-Leydig cell tumors, previously classified as androblastoma or arrhenoblastoma, account for 11% of solid ovarian tumors. They contain various proportions of Sertoli cells, Leydig cells, and fibroblasts (202). Sertoli-Leydig cell tumors are the most common virilizing tumors in women of reproductive age; however, masculinization occurs in only one-third of patients. The tumor is bilateral in 1.5%. In 80% of cases, it is diagnosed at stage IA (202). Sertoli-Leydig cell tumors are frequently low-grade malignancies, and their prognosis is related to their degree of differentiation and stage of disease (205). Treatment with unilateral salpingo-oophorectomy is justified in patients with stage IA disease who desire fertility. Total abdominal hysterectomy, bilateral salpingo-oophorectomy, and adjuvant therapy are recommended for postmenopausal women who have advanced-stage disease.
Pure Sertoli cell tumors are usually unilateral. For a premenopausal woman with stage I disease, a unilateral salpingo-oophorectomy is the treatment of choice. Malignant tumors are rapidly fatal (206).
Gynandroblastomas are benign tumors with well-differentiated ovarian and testicular elements. A unilateral oophorectomy or salpingo-oophorectomy is sufficient treatment.
Sex cord tumors with annular tubules (SCTAT) are frequently associated with Peutz-Jeghers syndrome (gastrointestinal polyposis and mucocutaneous melanin pigmentation) (207). Their morphologic features range between those of the granulosa cell and Sertoli cell tumors.
Whereas SCTAT with Peutz-Jeghers syndrome tend to be bilateral and benign, SCTAT without Peutz-Jeghers syndrome is almost always unilateral and malignant in one-fifth of cases (202).
Steroid Cell Tumors
According to Young and Scully, steroid cell tumors are composed entirely of steroid-secreting cells subclassified into stromal luteoma, Leydig cell tumors (hilar and nonhilar), and steroid cell tumors that are not otherwise specific (202). Virilization or hirsutism is encountered with three-fourths of Leydig cell tumors, with one-half of steroid cell tumors not otherwise specific, and with 12% of stromal luteomas.
Nonfunctioning Ovarian Tumors
Ovarian neoplasms that do not directly secrete androgens are occasionally associated with androgen excess, resulting from excess secretion by adjacent ovarian stroma, and include serous and mucinous cystadenomas, Brenner tumors, Krukenberg tumors, benign cystic teratomas, and dysgerminomas (208). Gonadoblastomas arising in the dysgenetic gonads of patients with a Y chromosome are rarely associated with androgen and estrogen secretion (209,210).
Stromal Hyperplasia and Stromal Hyperthecosis
Stromal hyperplasia is a nonneoplastic proliferation of ovarian stromal cells. Stromal hyperthecosis is defined as the presence of luteinized stromal cells at a distance from the follicles (211). Stromal hyperplasia, which is typically seen in patients between 60 and 80 years of age, may be associated with hyperandrogenism, endometrial carcinoma, obesity, hypertension, and glucose intolerance (211,212). Hyperthecosis is seen in a mild form in older patients. In patients of reproductive age, hyperthecosis may demonstrate severe clinical manifestations of virilization, obesity, and hypertension (213). Hyperinsulinemia and glucose intolerance may occur in up to 90% of patients with hyperthecosis and may play a role in the etiology of stromal luteinization and hyperandrogenism (72). Hyperthecosis is found in many patients with HAIR-AN syndrome (hyperandrogenemia, insulin resistance, and acanthosis nigricans).
In patients with hyperthecosis, levels of ovarian androgens, including testosterone, DHT, and androstenedione, are increased, usually in the male range. The predominant estrogen, as in PCOS, is estrone, which is derived from peripheral aromatization. The E1-to-E2 ratio is increased. Unlike in PCOS, gonadotropin levels are normal (214). Ovaries with stromal hyperthecosis have variable sonographic appearances (215).
Wedge resection for the treatment of mild hyperthecosis was successful and resulted in resumption of ovulation and in a pregnancy (216). In cases of more severe hyperthecosis and high total testosterone levels, the ovulatory response to wedge resection is transient (214). In a study in which bilateral oophorectomy was used to control severe virilization, hypertension and glucose intolerance sometimes disappeared (217). When a GnRH agonist was used to treat patients with severe hyperthecosis, ovarian androgen production was dramatically suppressed (218).
Virilization During Pregnancy
Luteomas of pregnancy are frequently associated with maternal and fetal masculinization. This is not a true neoplasm but rather a reversible hyperplasia, which usually regresses postpartum. A review of the literature reveals a 30% incidence of maternal virilization and a 65% incidence of virilized female newborns in the presence of a pregnancy luteoma and maternal masculinization (219–221).
Other tumors causing virilization in pregnancy include (in descending order of frequency) Krukenberg tumors, mucinous cystic tumors, Brenner tumors, serous cystadenomas, endodermal sinus tumors, and dermoid cysts (202).
Virilizing Adrenal Neoplasms
The most common virilizing adrenal neoplasms are adrenal carcinomas. Adrenocortical carcinomas are rare aggressive tumors that have a bimodal age incidence, with most cases presenting at ages 40 to 50 years (222). Virilization was reported in 20% to 30% of adults with functional adrenocortical carcinoma (223).
When these malignancies virilize, frequently they are associated with elevations in 11-deoxycortisol, cortisol, and DHEAS. These tumors are commonly large and often detectable on abdominal examination. Adrenal tumors that secrete androgens exclusively, whether benign or malignant, are extraordinarily rare (194,224). Modern imaging techniques, such as CT, ultrasonography, MRI, or venous sampling, are extremely useful for distinguishing between an ovarian and an adrenal tumor as a cause of virilization (222).
Prolactin Disorders
Prolactin was first identified as a product of the anterior pituitary in 1933 (225). It is found in nearly every vertebrate species. Its presence in humans was long inferred by the association of the syndrome of amenorrhea and galactorrhea in the presence of pituitary macroadenomas, though it was not definitively identified as a human hormone until 1971. The specific activities of human prolactin (hPRL) were defined by the separation of its activity from growth hormone and subsequently by the development of radioimmunoassays (226–228). Although the initiation and maintenance of lactation is the primary function of prolactin, many studies document roles for prolactin activity both within and beyond the reproductive system.
Prolactin Secretion
There are 199 amino acids within human prolactin, with a molecular weight (MW) of 23,000 D (Fig. 31.8). Although human growth hormone and placental lactogen have significant lactogenic activity, they have only a 16% and 13% amino acid sequence homology with prolactin, respectively. In the human genome, a single gene on chromosome 6 encodes prolactin. The prolactin gene (10 kb) has five exons and four introns, and its transcription is regulated in the pituitary by a proximal promotor region and in extrapituitary locations by a more upstream promotor (229).
Figure 31.8 Amino acid sequence of prolactin. Three cysteine disulfide bands are located within the molecule. (From Bondy PK. Rosenberg leukocyte esterase: metabolic control and disease, 8th ed. Philadelphia: WB Saunders, 1980, with permission.)
In the basal state three forms are released: a monomer, a dimer, and a multimeric species, called little, big, and big-big prolactin, respectively (230–232). The two larger species can be degraded to the monomeric form by reducing disulfide bonds (233). The proportions of each of these prolactin species vary with physiologic, pathologic, and hormonal stimulation (233–236). The heterogeneity of secreted forms remains an active area of research. Studies indicate that little prolactin (MW 23,000 D) constitutes more than 50% of all combined prolactin production and is most responsive to extrapituitary stimulation or suppression (233,235,236). Clinical assays for prolactin measure the little prolactin, and in all but extremely rare circumstances, these measures are sufficient to assess diseases of abnormal pituitary production of the hormone. Prolactin, and its relatives growth hormone and placental lactogen, do not require glycosylation for most of their primary activities, as is the case for the gonadotropins and TSH. Glycosylated forms are secreted, and glycosylation does affect the bioactivity and immunoreactivity of little prolactin (237–240). It appears that the glycosylated form is the predominant species secreted, but the most potent biologic form appears to be the 23,000-D nonglycosylated form of prolactin (239). Prolactin has over 300 known biological activities. Prolactin’s most recognized activities include those associated with reproduction (lactation, luteal function, reproductive behavior) and homeostasis (immune responsivity, osomoregulation, and angiogenesis) (241). Despite these many activities, the only recognized disorder associated with deficiency of prolactin secretion is inability to lactate.
Table 31.9 Chemical Factors Modulating Prolactin Release and Conditions that Result in Hyperprolactinemia
|
Inhibitory factors |
|
Dopamine |
|
γ-Aminobutyric acid |
|
Histidyl-proline diketopiperazine |
|
Pyroglutamic acid |
|
Somatostatin |
|
Stimulatory factors |
|
β-Endorphin |
|
17β-Estradiol |
|
Enkephalins |
|
Gonadotropin-releasing hormone |
|
Histamine |
|
Serotonin |
|
Substance P |
|
Thyrotropin-releasing hormone |
|
Vasoactive intestinal peptide |
|
Physiologic conditions |
|
Anesthesia |
|
Empty sella syndrome |
|
Idiopathic |
|
Intercourse |
|
Major surgery and disorders of chest wall (burns, herpes, chest percussion) |
|
Newborns |
|
Nipple stimulation |
|
Pregnancy |
|
Postpartum (nonnursing: days 1–7; nursing: with suckling) |
|
Sleep |
|
Stress |
|
Postpartum |
|
Hypothalamic conditions |
|
Arachnoid cyst |
|
Craniopharyngioma |
|
Cystic glioma |
|
Cysticercosis |
|
Dermoid cyst |
|
Epidermoid cyst |
|
Histiocytosis |
|
Neurotuberculosis |
|
Pineal tumors |
|
Pseudotumor cerebri |
|
Sarcoidosis |
|
Suprasellar cysts |
|
Tuberculosis |
|
Pituitary conditions |
|
Acromegaly |
|
Addison disease |
|
Craniopharyngioma |
|
Cushing syndrome |
|
Hypothyroidism |
|
Histiocytosis |
|
Lymphoid hypophysitis |
|
Metastatic tumors (especially of the lungs and breasts) |
|
Multiple endocrine neoplasia |
|
Nelson syndrome |
|
Pituitary adenoma (microadenoma or macroadenoma) |
|
Post—oral contraception |
|
Sarcoidosis |
|
Thyrotropin-releasing hormone administration |
|
Trauma to stalk |
|
Tuberculosis |
|
Metabolic dysfunction |
|
Ectopic production (hypernephroma, bronchogenic sarcoma) |
|
Hepatic cirrhosis |
|
Renal failure |
|
Starvation refeeding |
|
Drug conditions |
|
α Methyldopa |
|
Antidepressants (amoxapine, imipramine, amitriptyline) |
|
Cimetidine |
|
Dopamine antagonists (phenothiazines, thioxanthenes, butyrophenone, diphenylbutylpiperidine, dibenzoxazepine, dihydroindolone, procainamide, metoclopramide) |
|
Estrogen therapy |
|
Opiates |
|
Reserpine |
|
Sulpiride |
|
Verapamil |
To some degree, the physical heterogeneity of prolactin may explain the biologic heterogeneity of this hormone, and although this complicates the physiologic evaluation of prolactin’s myriad effects, it is of little import to the diagnosis and management of hyperprolactinemic states.
In contrast to other anterior pituitary hormones, which are controlled by hypothalamic-releasing factors, prolactin secretion is primarily under inhibitory control mediated by dopamine. Multiple lines of evidence suggest that dopamine, which is secreted by the tuberoinfundibular dopaminergic neurons into the portal hypophyseal vessels, is the primary prolactin-inhibiting factor. Dopamine receptors were found on pituitary lactotrophs, and treatment with dopamine or dopamine agonists suppresses prolactin secretion (242–248). The dopamine antagonist metoclopramide abolishes the pulsatility of prolactin release and increases serum prolactin levels (244,245,249). Interference with dopamine transit from the hypothalamus to the pituitary by mass lesions, or blockade of the dopamine receptor as occurs with antipsychotic and other medications, increases serum prolactin levels.Thyrotropin-releasing hormone (TRH) causes prolactin release when present at supraphysiologic levels (as in primary hypothyroidism), but does not appear to play an important modulatory role in the normal physiologic regulation of prolactin secretion. γ-Aminobutyric acid (GABA) and other neurohormones and neurotransmitters may function as prolactin-inhibiting factors (250–253). Several hypothalamic polypeptides that modulate prolactin-releasing activity are listed in Table 31.9. It appears that dopamine and TRH act as primary neurohormones, while others (i.e., neuropeptide Y, galanin, and enkephalin) act as modulators. It is likely that under differing physiologic conditions (i.e., pregnancy, lactation, stress, aging) a modulator may become a principal regulator of hormone secretion.
The prolactin receptor is a member of the class 1 cytokine receptor superfamily and is encoded by a gene on chromosome 5 (254). Transcriptional regulation of the prolactin receptor is accomplished through three tissue-specific promoter regions; promoter I for the gonads, promoter II for the liver, and promoter III, a generic promoter that includes the mammary gland (255).
Hyperprolactinemia
Physiologic disturbances, pharmacologic agents, or markedly compromised renal function may cause elevations in prolactin levels, and transient elevations occur with acute stress or painful stimuli. The most common cause of elevated prolactin levels is likely pharmacologic; most patients using antipsychotic medications and many other patients using agents with antidopaminergic properties will exhibit moderately elevated prolactin levels. Drug-related and physiologic conditions resulting in hyperprolactinemia do not always require direct intervention to normalize prolactin levels.
Evaluation
Plasma levels of immunoreactive prolactin are 5 to 27 ng/mL throughout the normal menstrual cycle. Samples should not be drawn soon after the patient awakes or after procedures. Prolactin is secreted in a pulsatile fashion with a pulse frequency ranging from about 14 pulses per 24 hours in the late follicular phase to about 9 pulses per 24 hours in the late luteal phase. There also is a diurnal variation, with the lowest levels occurring in midmorning. Levels rise 1 hour after the onset of sleep and continue to rise until peak values are reached between 5 and 7 a.m. (256,257). The pulse amplitude of prolactin appears to increase from early to late follicular and luteal phases (258–260). Because of the variability of secretion and inherent limitations of radioimmunoassay, an elevated level should always be rechecked. This sample preferably is drawn midmorning and not after stress, previous venipuncture, breast stimulation, or physical examination, all of which transiently increase prolactin levels.
When prolactin levels are found to be elevated, hypothyroidism and medications should first be ruled out as a cause. Prolactin and TSH determinations are basic evaluations in infertile women. Infertile men with hypogonadism should be tested. Likewise, prolactin levels should be measured in the evaluation of amenorrhea, galactorrhea, hirsutism with amenorrhea, anovulatory bleeding, and delayed puberty (Fig. 31.9).
Physical Signs
Elevations in prolactin may cause amenorrhea, galactorrhea, both, or neither. Amenorrhea without galactorrhea is associated with hyperprolactinemia in approximately 15% of women (261–263). The cessation of normal ovulatory processes resulting from elevated prolactin levels is primarily caused by the suppressive effects of prolactin, via hypothalamic mediation, on GnRH pulsatile release (243,261,262,264–272). In addition to causing a hypogonadotropic state, prolactin elevations may secondarily impair the mechanisms of ovulation by causing a reduction in granulosa cell number and FSH binding, inhibition of granulosa cell 17β-estradiol production by interfering with FSH action, and by causing inadequate luteinization and reduced luteal secretion of progesterone (273–278). Other etiologies for amenorrhea are detailed in Chapter 30.
Although isolated galactorrhea is considered indicative of hyperprolactinemia, prolactin levels are within the normal range in nearly 50% of such patients (279–281) (Fig. 31.9). In these cases, whether caused by a prior transient episode of hyperprolactinemia or other unknown factors, the sensitivity of the breast to the lactotrophic stimulus engendered by normal prolactin levels is sufficient to result in galactorrhea. This situation is very similar to that observed in nursing mothers in whom milk secretion, once established, continues and even increases despite progressive normalization of prolactin levels. Repeat testing is occasionally helpful in detecting hyperprolactinemia. Approximately one-third of women with galactorrhea have normal menses. Conversely, hyperprolactinemia commonly occurs in the absence of galactorrhea (66%), which may result from inadequate estrogenic or progestational priming of the breast.
In patients with both galactorrhea and amenorrhea (including the syndromes described and named by Forbes, Henneman, Griswold, and Albright in 1951, Argonz and del Castilla in 1953, and Chiari and Frommel in 1985), approximately two-thirds will have hyperprolactinemia; in that group, approximately one-third will have a pituitary adenoma (282). In anovulatory women, 3% to 10% of women diagnosed with polycystic ovary disease have coexistent and usually modest hyperprolactinemia (283,284) (Fig. 31.10).
Figure 31.9 Workup for hyperprolactinemia. TSH, thyroid-stimulating hormone; MRI, magnetic resonance imaging; CT, computed tomography; HRT, hormone replacement therapy; OCPs, oral contraceptive pills; CNS, central nervous system.
Figure 31.10 Prolactin levels in 235 patients with galactorrhea. Among patients with a tumor, open triangles denote associated acromegaly, and solid circles and solid triangles denote previous radiotherapy or surgical resection, respectively. (From Kleinberg DL, Noel GL, Frantz AG. Galactorrhea: a study of 235 cases, including 48 with pituitary tumors. N Engl J Med 1977;296:589–600, with permission.)
Prolactin and TSH levels should be measured in all patients with delayed puberty. Pituitary abnormalities, including craniopharyngiomas and adenomas, should be considered in all cases of delayed puberty accompanied by low levels of gonadotropins, regardless of whether prolactin levels are elevated. When prolactin-secreting pituitary adenomas are present, the condition of multiple endocrine neoplasia type 1 (MEN-1) syndrome (gastrinomas, insulinoma, parathyroid hyperplasia, and pituitary neoplasia) should be considered, although symptoms of pituitary adenoma are rarely the presenting symptom. Patients who have a pituitary adenoma and a family history of multiple adenomas warrant special attention (285). Prolactinomas are noted in approximately 20% of patients with MEN-1. The MEN-1 gene is localized to chromosome 11q13 and appears to act as a constitutive tumor suppressor gene. An inactivating mutation results in development of the tumor. It is thought that prolactin-secreting pituitary adenomas that occur in patients with MEN-1 may be more aggressive than sporadic cases (286).
When an elevated prolactin level is documented and medications or hypothyroidism as the underlying cause is excluded, knowledge of neuroanatomy and imaging techniques and their interpretation is essential to further evaluation (see Chapter 7). Pituitary hyperprolactinemia is most often caused by a microadenoma or associated with normal imaging findings. These patients can be reassured that the probable course of their condition is benign.Macroadenomas or juxtasellar lesions are less common and require more complex evaluation and treatment, including surgery, radiation, or both.Levels of TSH should be measured in all patients with hyperprolactinemia (Fig. 31.9).
Imaging Techniques
In patients with larger microadenomas and macroadenomas, prolactin levels usually are higher than 100 ng/mL. However, levels lower than 100 ng/mL may be associated with smaller microadenomas, macroadenomas that produce a “stalk section” effect, and suprasellar tumors that may be missed on a “coned-down” view of the sella turcica. Modest elevations of prolactin can be associated with microadenomas or macroadenomas, nonlactotroph pituitary tumors, and other central nervous system abnormalities; thus, imaging of the pituitary gland must be considered when otherwise unexplained and persistent prolactin elevation is present. In patients with a clearly identifiable drug-induced or physiologic hyperprolactinemia, imaging is not necessary unless accompanied by symptoms suggesting a mass lesion (headache, visual field deficits). MRI with gadolinium enhancement of the sella and pituitary gland appears to provide the best anatomic detail (287). The cumulative radiation dose from multiple CT scans may cause cataracts, and the “coned-down” views or tomograms of the sella are very insensitive and expose the patient to radiation. For patients with hyperprolactinemia who desire future fertility, MRI is indicated to differentiate a pituitary microadenoma from a macroadenoma and to identify other potential sellar-suprasellar masses. Although rare, when pregnancy-related complications of a pituitary adenoma occur, they occur more frequently in the presence of macroadenomas.
In over 90% of untreated women, microadenomas do not enlarge over a 4- to 6-year period. The argument that medical therapy will prevent a microadenoma from growing is false. Although prolactin levels correlate with tumor size, both elevations and reductions in prolactin levels may occur without any change in tumor size. If during follow-up a prolactin level rises significantly or central nervous system symptoms (headache, visual changes) are noted, repeat imaging may be indicated. Treatment is discussed below.
Hypothalamic Disorders
Dopamine was the first of many substances whose production was demonstrated in the arcuate nucleus. Dopamine-releasing neurons innervate the external zone of the median eminence. When released into the hypophyseal portal system, dopamine inhibits prolactin release in the anterior pituitary. Lesions that disrupt dopamine release can result in hyperprolactinemia. Such lesions may arise from the suprasellar area, pituitary gland, and infundibular stalk, and from adjacent bone, brain, cranial nerves, dura, leptomeninges, nasopharynx, and vessels. Numerous pathologic entities and physiologic conditions in the hypothalamic–pituitary region can disrupt dopamine release and cause hyperprolactinemia.
Pituitary Disorders
Microadenoma
In over one-third of women with hyperprolactinemia, a radiologic abnormality consistent with a microadenoma (<1 cm) is found. Release of pituitary stem cell growth inhibition via activation or loss-of-function mutations results in cell cycle dysregulation and is critical to the development of pituitary microadenomas and macroadenomas. Microadenomas are monoclonal in origin. Genetic mutations are thought to release stem cell growth inhibitors and result in autonomous anterior pituitary hormone production, secretion, and cell proliferation. Additional anatomic factors that may contribute to adenoma formation include reduced dopamine concentrations in the hypophyseal portal system and vascular isolation of the tumor or both. Recently, the heparin-binding secretory-transforming (HST) gene was noted in a variety of cancers and in prolactinomas (288). Patients with microadenomas can be reassured of a probable benign course, and many of these lesions exhibit gradual spontaneous regression (289,290).
Both microadenomas and macroadenomas are monoclonal in origin. Pituitary prolactinomas and lactotrope adenomas are sparsely or densely granulated histologically. The sparsely granulated lactotrope adenomas have trabecular, papillary, or solid patterns. Calcification of these tumors may take the form of a psammoma body or a pituitary stone. Densely granulated lactotrope adenomas are strongly acidophilic tumors and appear to be more aggressive than sparsely granulated lactotrope adenomas. Unusual acidophil stem cell adenomas can be associated with hyperprolactinemia, with some clinical or biochemical evidence of growth hormone excess.
Microadenomas rarely progress to macroadenomas. Six large series of patients with microadenomas reveal that, with no treatment, the risk of progression for microadenoma to a macroadenoma is only 7% (291). Treatments include expectant, medical, or, rarely, surgical therapy. All affected women should be advised to notify their physicians of chronic headaches, visual disturbances (particularly tunnel vision consistent with bitemporal hemianopsia), and extraocular muscle palsies. Formal visual field testing is rarely helpful, unless imaging suggests compression of the optic nerves.
Autopsy and radiographic series reveal that 14.4% to 22.5% of the US population harbor microadenomas, and approximately 25% to 40% stain positively for prolactin (292). Clinically significant pituitary tumors requiring some type of intervention affect only 14 per 100,000 individuals (292)
Expectant Management
In women who do not desire fertility, expectant management can be used for both microadenomas and hyperprolactinemia without an adenoma while menstrual function remains intact.Hyperprolactinemia-induced estrogen deficiency, rather than prolactin itself, is the major factor in the development of osteopenia (293). Therefore, estrogen replacement with typical hormone replacement regimens or hormonal contraceptives is indicated for patients with amenorrhea or irregular menses. Patients with drug-induced hyperprolactinemia can be managed expectantly with attention to the risks of osteoporosis. In the absence of symptoms of pituitary enlargement, imaging may be repeated in 12 months, and if prolactin levels remain stable, less frequently thereafter, to assess further growth of the microadenoma.
Medical Treatment
Ergot alkaloids are the mainstay of therapy. In 1985, bromocriptine was approved for use in the United States to treat hyperprolactinemia caused by a pituitary adenoma. These agents act as strong dopamine agonists, thus decreasing prolactin levels. Effects on prolactin levels occur within hours, and lesion size may decrease within 1 or 2 weeks. Bromocriptine decreases prolactin synthesis, DNA synthesis, cell multiplication, and overall size of prolactinomas. Bromocriptine treatment results in normal prolactin blood levels or return of ovulatory menses in 80% to 90% of patients.
Because ergot alkaloids, like bromocriptine, are excreted via the biliary tree, caution is required when using it in the presence of liver disease. The major adverse effects include nausea, headaches, hypotension, dizziness, fatigue and drowsiness, vomiting, headaches, nasal congestion, and constipation. Many patients tolerate bromocriptine when the dose is increased gradually, by 1.25 mg (one-half tablet) daily each week until prolactin levels are normal or a dose of 2.5 mg twice daily is reached. A proposed regimen is as follows: one-half tablet every evening (1.25 mg) for 1 week, one-half tablet morning and evening (1.25 mg) during the second week, one-half tablet in the morning (1.25 mg) and a full tablet every evening (2.5 mg) during the third week, and one tablet every morning and every evening during the fourth week and thereafter (2.5 mg twice a day). The lowest dose that maintains the prolactin level in the normal range is continued (1.25 mg twice daily often is sufficient to normalize prolactin levels in individuals with levels less than 100 ng/mL). Pharmacokinetic studies show peak serum levels occur 3 hours after an oral dose, with a nadir at 7 hours. Because little detectable bromocriptine is in the serum by 11 to 14 hours, twice-a-day administration is required. Prolactin levels can be checked soon (6 to 24 hours) after the last dose.
One rare, but notable, adverse effect of bromocriptine is a psychotic reaction. Symptoms include auditory hallucinations, delusional ideas, and changes in mood that quickly resolve after discontinuation of the drug (294).
Many investigators report no difference in fibrosis, calcification, prolactin immunoreactivity, or the surgical success in patients pretreated with bromocriptine compared to those not receiving bromocriptine(291).
An alternative to oral administration is the vaginal administration of bromocriptine tablets, which is well tolerated, and actually results in increased pharmacokinetic measures (295). Cabergoline, another ergot alkaloid, has a very long half-life and can be given orally twice per week. Its long duration of action is attributable to slow elimination by pituitary tumor tissue, high affinity binding to pituitary dopamine receptors, and extensive enterohepatic recirculation.
Cabergoline, which appears to be as effective as bromocriptine in lowering prolactin levels and in reducing tumor size, has substantially fewer adverse effects than bromocriptine. Very rarely, patients experience nausea and vomiting or dizziness with cabergoline; they may be treated with intravaginal cabergoline as with bromocriptine. A gradually increasing dosage helps avoid the side effects of nausea, vomiting, and dizziness. Cabergoline at 0.25 mg twice per week is usually adequate for hyperprolactinemia with values less than 100 ng/mL. If required to normalize prolactin levels, the dosage can be increase by 0.25 mg per dose on a weekly basis to a maximum of 1 mg twice weekly.
Recent studies reveal an increased risk of cardiac valve regurgitation in patients with Parkinson disease who were treated with high doses of cabergoline or pergolide but not with bromocriptine (296,297). Higher doses and a longer duration of therapy were associated with a higher risk of valvulopathy. It is postulated that 5HT2b-receptor stimulation leads to fibromyoblast proliferation (298). A recent cross-sectional study showed a higher rate of asymptomatic tricuspid regurgitation among cabergoline-treated patients compared to untreated patients with newly diagnosed prolactinomas as well as normal controls (299,300).
The demonstrated relative safety of bromocriptine in reproductive-aged women and during more than 2,500 pregnancies suggest bromocriptine is the first choice for hyperprolactinemia and micro- and macroadenomas (301).
When bromocriptine or cabergoline cannot be used, other medications such as pergolide or metergoline may be used. In patients with a microadenoma who are receiving bromocriptine therapy, a repeat MRI scan may be performed 6 to 12 months after prolactin levels are normal, if indicated. Further MRI scans should be performed if new symptoms appear.
Discontinuation of bromocriptine therapy after 2 to 3 years may be attempted in a select group of patients who have maintained normoprolactinemia while on therapy (302,303). In a retrospective series of 131 patients treated with bromocriptine for a median of 47 months, normoprolactinemia was sustained in 21% at a median follow-up of 44 months after treatment discontinuation (303). Discontinuation of cabergoline therapy was successful in patients treated for 3 to 4 years who maintained normoprolactinemia (304). In cabergoline discontinuers who met stringent inclusion criteria, a recurrence rate of 64% was noted (305). A recent meta-analysis involving 743 patients noted sustained normoprolactinemia in only a minority of patients (21%) after discontinuation. Patients with 2 years or more of therapy before discontinuation and no demonstrable tumor visible on MRI had the highest chance of persistent normoprolactinemia (306). Recurrence rates are higher for macroadenomas (as compared to microadenomas or hyperprolactinemia without adenoma) after cessation of bromocriptine or cabergoline, warranting close follow-up with serum prolactin and MRI after cessation of therapy. In patients with macroadenomas, withdrawal of therapy should proceed with caution, as rapid tumor reexpansion may occur.
Macroadenomas
Macroadenomas are pituitary tumors that are larger than 1 cm in size. Bromocriptine is the best initial and potentially long-term treatment option, but transsphenoidal surgery may be required. High-dose cabergoline therapy was used in bromocriptine resistant or intolerant macroadenoma patients with success; however, cautions remain regarding the development of cardiac valve abnormalities (307).
Evaluation for pituitary hormone deficiencies may be indicated. Symptoms of macroadenoma enlargement include severe headaches, visual field changes, and, rarely, diabetes insipidus and blindness. After prolactin has reached normal levels following ergot alkaloid treatment, a repeat MRI is indicated within 6 months to document shrinkage or stabilization of the size of the macroadenoma. This examination may be performed earlier if new symptoms develop or if there is no improvement in previously noted symptoms.
Medical Treatment
Treatment with bromocriptine decreases prolactin levels and the size of macroadenomas; nearly one-half show a 50% reduction in size, and another one-fourth show a 33% reduction after 6 months of therapy. Because tumor regrowth occurs in more than 60% of cases after discontinuation of bromocriptine therapy, long-term therapy is usually required.
After stabilization of tumor size is documented, the MRI scan is repeated 6 months later and, if stable, yearly for several years. This examination may be performed earlier if new symptoms develop or if there is no improvement in symptoms. Serum prolactin levels are measured every 6 months. Because tumors may enlarge despite normalized prolactin values, a reevaluation of symptoms at regular intervals (6 months) is prudent. Normalized prolactin levels or resumption of menses should not be taken as absolute proof of tumor response to treatment (306,308).
Surgical Intervention
Tumors that are unresponsive to bromocriptine or that cause persistent visual field loss require surgical intervention. Some neurosurgeons have noted that a short (2- to 6-week) preoperative course of bromocriptine increases the efficacy of surgery in patients with larger adenomas (291). Unfortunately, despite surgical resection, recurrence of hyperprolactinemia and tumor growth is common. Complications of surgery include cerebral carotid artery injury, diabetes insipidus, meningitis, nasal septal perforation, partial or panhypopituitarism, spinal fluid rhinorrhea, and third nerve palsy. Periodic MRI scanning after surgery is indicated, particularly in patients with recurrent hyperprolactinemia.
Metabolic Dysfunction and Hyperprolactinemia
Occasionally, patients with hypothyroidism exhibit hyperprolactinemia with remarkable pituitary enlargement caused by thyrotroph hyperplasia. These patients respond to thyroid replacement therapy with reduction in pituitary enlargement and normalization of prolactin levels (309).
Hyperprolactinemia occurs in 20% to 75% of women with chronic renal failure. Prolactin levels are not normalized through hemodialysis but are normalized after transplantation (310–312). Occasionally, women with hyperandrogenemia also have hyperprolactinemia. Elevated prolactin levels may alter adrenal function by enhancing the release of adrenal androgens such as DHEAS (313).
Drug-Induced Hyperprolactinemia
Numerous drugs interfere with dopamine secretion and can be responsible for hyperprolactinemia and its attendant symptoms (Table 31.9). If medication can be discontinued, resolution of hyperprolactinemia is uniformly prompt. If not, endocrine management should be directed at estrogen replacement and normalization of menses for those with disturbed or absent ovulation. Treatment with dopamine agonists may be utilized if ovulation is desired and the drug-inducing hyperprolactinemia cannot be discontinued.
Use of Estrogen in Hyperprolactinemia
In rodents, pituitary prolactin-secreting adenomas occur with high-dose estrogen administration (314). Elevated levels of estrogen, as found in pregnancy, are responsible for hypertrophy and hyperplasia of lactotrophic cells and account for the progressive increase in prolactin levels in normal pregnancy. The increase in prolactin during pregnancy is physiologic and reversible; adenomas are not fostered by the hyperestrogemia of pregnancy. Pregnancy may have a favorable influence on preexisting prolactinomas (315,316). Estrogen administration is not associated with clinical, biochemical, or radiologic evidence of growth of pituitary microadenomas or the progression of idiopathic hyperprolactinemia to an adenoma status (317–320). For these reasons, estrogen replacement or OC use is appropriate for hypoestrogenic patients with hyperprolactinemia secondary to microadenoma or hyperplasia.
Monitoring Pituitary Adenomas During Pregnancy
Prolactin-secreting microadenomas rarely create complications during pregnancy. Monitoring of patients with serial gross visual field examinations and funduscopic examination is recommended. If persistent headaches, visual field deficits, or visual or funduscopic changes occur, MRI scanning is advisable. Because serum prolactin levels progressively rise throughout pregnancy, prolactin measurements are rarely of value.
For those women who become pregnant while taking bromocriptine to treat a return of spontaneous ovulations, discontinuation of bromocriptine is recommended. This does not preclude subsequent use of bromocriptineduring the pregnancy to treat symptoms (visual field defects, headaches) that arise from further enlargement of the microadenoma (301,321–323). Bromocriptine did not exhibit teratogenicity in animals, and observational data do not suggest harm to pregnancy or fetus in humans.
Pregnant women with previous transsphenoidal surgery for microadenomas or macroadenomas may be monitored with monthly Goldman perimetry visual field testing. Periodic MRI scanning may be necessary in women with symptoms or visual changes. Breastfeeding is not contraindicated in the presence of microadenomas or macroadenomas (301,321–323). The use of bromocriptine and presumably other dopaminergic agents that may cause blood pressure elevation during the postpartum period is contraindicated (324–328).
Thyroid Disorders
Thyroid disorders are 10 times more common in women than men. Approximately 1% of the female population of the United States will develop overt hypothyroidism (329). Even prior to the discovery of the long-acting thyroid stimulator (LATS) in women with Graves disease in 1956, numerous investigations demonstrated a link between these autoimmune thyroid disorders and reproductive physiology and pathology (330).
Thyroid Hormones
Iodide is a critical component of the class of hormones known as thyronines, among which the most important are triiodothyronine (T3) and thyroxine (T4). Iodide obtained from dietary sources is actively transported into the thyroid follicular cell for the synthesis of these hormones. The sodium–iodide symporter (NIS) is a key molecule in thyroid function. It allows the accumulation of iodide from the circulation into the thyrocyte against an electrochemical gradient. The NIS requires energy that is supplied by Na-K ATPase, and iodine uptake is stimulated by TSH or thyrotropin. The enzyme thyroid peroxidase (TPO) then oxidizes iodide near the cell-colloid surface and incorporates it into tyrosyl residues within the thyroglobulin molecule, which results in the formation of monoiodotyrosine (MIT) and diiodotyrosine (DIT). T3 and T4, formed by secondary coupling of MIT and DIT, are catalyzed by TPO. The membrane-bound, heme-containing oligomer, TPO, is localized in the rough endoplasmic reticulum, Golgi vesicles, lateral and apical vesicles, and on the follicular cell surface. Thyroglobulin, the major protein formed in the thyroid gland, has an iodine content of 0.1% to 1.1% by weight. About 33% of the iodine is present in thyroglobulin in the form of T3 and T4, and the remainder is present in MIT and DIT or found as unbound iodine. Thyroglobulin provides a storage capacity capable of maintaining a euthyroid state for nearly 2 months without the formation of new thyroid hormones. The thyroid antimicrosomal antibodies found in patients with autoimmune thyroid disease are directed against the TPO enzyme (331,332).
TSH regulates thyroidal iodine metabolism by activation of adenylate cyclase. This facilitates endocytosis as a component of iodide uptake, digestion of thyroglobulin-containing colloid, and the release of thyroid hormones T4, T3, and reverse T3. T4 is released from the thyroid at 40 to 100 times the concentration of T3. The concentration of reverse T3, which has no intrinsic thyroid activity, is 30% to 50% of T3, and 1% of T4 concentration. Of thyroid hormones released, 70% are bound by circulating thyroid-binding globulin (TBG). T4 is present in higher concentrations in the circulating storage pool and has a slower turnover rate than T3. Approximately 30% of T4 is converted to T3 in the periphery. Reverse T3 participates in regulation of the conversion of T4 to T3. T3 is the primary physiologically functional thyroid hormone at the cellular level. T3 binds the nuclear receptor with 10 times the affinity of T4. Thyroid hormone effects on cells include increased oxygen consumption, heat production, and metabolism of fats, proteins, and carbohydrates. Systemically, thyroid hormone activity is responsible for the basal metabolic rate. It balances fuel efficiency with performance. Hyperthyroid states result in excessive fuel consumption with marginal performance.
Iodide Metabolism
Normal function of the thyroid gland is dependent on iodine. The World Health Organization recommends 150 μg of iodine per day in women of reproductive age and 250 μg per day is recommended during pregnancy and nursing. Adequate iodination of household salt is defined as salt containing 15 to 40 mg of iodine per kilogram of salt (333).
Optimal iodine intake to prevent disease lies within a relatively narrow range around the recommended daily consumption. Extreme iodine deficiency states are associated with cretinism, goiter, and hypothyroidism, while iodine sufficiency is associated with autoimmune thyroid disease and reduced remission rates in Graves disease (334).
Risk Factors for Autoimmune Thyroid Disorders
Environmental factors associated with the occurrence of autoimmune thyroid diseases include pollutants (plasticizers, polychlorinated biphenyls) and exposure to infections such as yersinia enterocolitica, coxsackie B, Helicobacter pylori, and hepatitis C (335,336). For reasons not entirely known, women experience a 5- to 10-fold increased incidence of autoimmune thyroid disease (337). This difference is postulated to be the result of differences in sex steroid hormone levels, differences in environmental exposures, innate differences in female and male immune systems, and inherent chromosomal differences in the sexes (338,339). The immunoglobulins produced against the thyroid are polyclonal, and the multiple combinations of various antibodies consolidate to create the clinical spectrum of autoimmune thyroid diseases that may affect health and reproductive function.
Evaluation
Thyroid Function
Measurements of free serum T4 and T3 are complicated by the low levels of free hormone in systemic circulation, with only 0.02% to 0.03% of T4 and 0.2% to 0.3% of T3 circulating in the unbound state (340). Of the T4 and T3 in circulation, approximately 70% to 75% is bound to TBG, 10% to 15% attached to prealbumin, 10% to 15% bound to albumin, and a minor fraction (<5%) is bound to lipoprotein (340,341). Total thyroid measurements are dependent on levels of TBG, which are variable and affected by many conditions such as pregnancy, oral contraceptive pill use, estrogen therapy, hepatitis, and genetic abnormalities of TBG. Thus, assays for the measurement of free T4 and T3are more clinically relevant than measuring total thyroid hormone levels.
There are many different laboratory techniques to measure estimated free serum T4 and T3. These methods invariably measure a portion of free hormone that is dissociated from the in vivo protein bound moiety. This is of little clinical significance assuming the same proportions are measured for all assays and considered in the calibration of the assay (342). The T3 resin uptake test is an example of one laboratory method used to estimate free T4 in the serum. The T3 resin uptake (T3 RU) determines the fractional binding of radiolabeled T3, which is added to a serum sample in the presence of a resin that competes with TBG for T3 binding. The binding capacity of TBG in the sample is inversely proportional to the amount of labeled T3 bound to the artificial resin. Therefore, a low T3 resin uptake indicates high TBG T3 receptor site availability and implies high circulating TBG levels.
The free T4 index (FTI) is obtained by multiplying the serum T4 concentration by the T3 resin uptake percentage, yielding an indirect estimate of the levels of free T4:
T3 RU% × T4 total = free T4 index.
A high T3 RU percentage indicates reduced TBG receptor site availability and high free T4 index and thus hyperthyroidism, whereas a low T3 resin uptake percentage is a result of increased TBG receptor site binding and thus hypothyroidism. Equilibrium dialysis and ultrafiltration techniques may be used to determine the free T4 directly. Free T4 and T3 may also be determined by radioimmunoassay. Most available laboratory methods used for determining estimations of free T4 are able to correct for moderate variations in serum TBG but are prone to error in the setting of large variations of serum TBG, when endogenous T4 antibodies are present, and in the setting of inherent albumin abnormalities (340).
Table 31.10 Thyroid Autoantigens
|
Antigen |
Location |
Function |
|
Thyroglobulin (Tg) |
Thyroid |
Thyroid hormone storage |
|
Thyroid peroxidase (TPO) |
Thyroid |
Transduction of signal from TSH |
|
TSH receptor (TSHR) |
Thyroid, lymphocytes, fibroblasts, adipocytes (including retro-orbital), and cancers |
Transduction of signal from TSH |
|
Na+/I− symporter (NIS) |
Thyroid, breast, salivary or lacrimal gland, gastric or colonic mucosa, thymus, pancreas |
ATP-driven uptake of I− along with Na1 |
|
TSH, thyroid-stimulating hormone; ATP, adenosine triphosphate |
||
Table 31.11 Prevalence of Thyroid Autoantibodies and Their Role in Immunopathology
Table 31.12 Nomenclature of Anti-TSH Receptor Antibodies
Because most disorders of hyperthyroidism and hypothyroidism are related to dysfunction of the thyroid gland and TSH levels are sensitive to excessive or deficient levels of circulating thyroid hormone, TSH levels are used to screen for these disorders. Current thyrotropin or TSH sandwich immunoassays are extremely sensitive and capable of differentiating low-normal from pathologic or iatrogenically subnormal values and elevations. TSH measurements provide the best way to screen for thyroid dysfunction and accurately predict thyroid hormone dysfunction in about 80% of cases (343). Reference values for TSH are traditionally based on the central 95% of values for healthy individuals, and some controversy exists regarding the upper limit of normal. Values in the upper limit of normal may predict future thyroid disease (342,344). In a longitudinal study, women with positive thyroid antibodies (TPOAbs or TgAbs), the prevalence of hypothyroidism at follow-up was 12.0% (3.0% to 21.0%; 95% CI) when baseline TSH was 2.5 mU/L or less, 55.2% (37.1%–73.3%) for TSH between 2.5 and 4.0 mU/L, and 85.7% (74.1%–97.3%) for TSH above 4.0 mU/L (345). Physicians ordering thyrotropin values should be aware of their limitations in the setting of acute illness, central hypothyroidism, the presence of heterophile antibodies, and TSH autoantibodies. In the setting of heterophile antibodies or TSH autoantibodies, TSH values will be falsely elevated (342). In cases of central hypothyroidism, decreased sialylation of TSH results in a longer half-life and a reduction in bioactivity (346,347). TSH levels may be elevated or normal when the patient remains clinically hypothyroid in states of central hypothyroidism, and successful treatment is often associated with low or undetectable TSH levels.
Immunologic Abnormalities
Many antigen–antibody reactions affecting the thyroid gland can be detected. Antibodies to TgAb, the TSH receptor (TSHRAb), TPOAb, the sodium iodine symporter (NISAb), and to thyroid hormone were identified and implicated in autoimmune thyroid disease states (348). A number of recognized thyroid autoantigens are listed in Table 31.10. Antibody production to thyroglobulin depends on a breach in normal immune surveillance (349,350). The incidence of thyroid autoantibodies in various autoimmune thyroid disorders is shown in Table 31.11.
Antithyroglobulin antibodies are predominantly in the noncomplement fixing, polycolonal, immunoglobulin-G (IgG) class. Antithyroglobulin antibodies are found in 35% to 60% of patients with hypothyroid autoimmune thyroiditis, 12% to 30% of patients with Graves disease, and 3% of the general population (351–353). Antithyroglobulin antibodies are associated with acute thyroiditis, nontoxic goiter, and thyroid cancer (348).
Previously referred to as antimicrosomal antibodies, TPO antibodies are directed against thyroid peroxidase and are found in Hashimoto thyroiditis, Graves disease, and postpartum thyroiditis. The antibodies produced are characteristically cytotoxic, complement-fixing IgG antibodies. In patients with thyroid autoantibodies, 99% will have positive anti-TPO antibodies, whereas only 36% will have positive antithyroglobulin antibodies, making anti-TPO a more sensitive test for autoimmune thyroid disease (353). Anti-TPO antibodies are present in 80% to 99% of patients with hypothyroid autoimmune thyroiditis, 45% to 80% of patients with Graves disease, and 10% to 15% of the general population (352–354). These antibodies can cause artifact in the measurement of thyroid hormone levels. Antithyroid peroxidase antibodies are used clinically in the diagnosis of Graves disease, the diagnosis of chronic autoimmune thyroiditis, in conjunction with TSH testing as a means to predict future hypothyroidism in subclinical hypothyroidism, and to assist in the diagnosis of autoimmune thyroiditis in euthyroid patients with goiter or nodules (348).
Another group of antibodies important in autoimmune thyroid disease bind the TSH receptor (TSHR). The TSHR belongs to the family of G-protein coupled receptors. TSHRAb are pathogenic and capable of activating (TSI) or blocking (TBI) TSH receptor functions. TBIs are detectable in two varieties: those that block TSH binding and those that block both pre- and postreceptor processes. Several investigators detected such blocking antibodies in patients with primary hypothyroidism and atrophic thyroid glands (355,356). The nomenclature and detection assay of TSH receptor antibodies are listed in Table 31.12. Anti-TSH receptor antibodies were reported in 6% to 60% of patients with hypothyroid autoimmune thyroiditis, 70% to 100% of patients with Graves disease, and 1% to 2% of the general population (357–361). Untreated Graves disease patients tested with third-generation immunometric assays are uniformly positive (362). TSHRAb are classified as binding inhibitory immunoglobulins by competitive binding assays (TBII); and in functional assays: stimulating (TSI)—according to their capacity to increase cyclic adenosine monophosphate (cAMP) production; blocking (TBI)—which possesses the capacity to reduce TSH effects; and, neutral (TNI)—with no effect on TSH binding or alteration of cAMP levels. A number of competitive and functional assays are available to determine the levels of each antibody type, which, in toto, correlate with severity of disease, extraglandular signs, risk of fetal effects, and chances for remission and recurrence. TSHRAb are used clinically to distinguish postpartum thyroiditis from Graves disease, to predict the risk of fetal and neonatal thyrotoxicosis in women with prior ablative treatment or current thionamide therapy in the setting of Graves disease, and in the diagnosis of euthyroid Graves ophthalmopathy (348). These assays will increasingly optimize individual patient testing and treatment (363).
Antibodies to the NIS are prevalent in a number of thyroid conditions. Anti-NISAbs were detected in 24% of patients with Hashimoto disease and 22% of patients with Graves disease (364). Anti-NISAbs are used experimentally (348).
Autoimmune Thyroid Disease
The most common thyroid abnormalities in women, autoimmune thyroid disorders, represent the combined effects of the multiple thyroid autoantibodies (365). The various antigen–antibody reactions result in the wide clinical spectrum of these disorders. Transplacental transmission of some of these immunoglobulins may affect thyroid function in the fetus. The presence of autoimmune thyroid disorders, particularly Graves disease, is associated with other autoimmune conditions: Hashimoto thyroiditis, Addison disease, ovarian failure, rheumatoid arthritis, Sjögren syndrome, diabetes mellitus (type 1), vitiligo, pernicious anemia, myasthenia gravis, and idiopathic thrombocytopenic purpura. Other factors that are associated with the development of autoimmune thyroid disorders include low birth weight, iodine excess and deficiency, selenium deficiency, parity, oral contraceptive pill use, reproductive age span, fetal microchimerism, stress, seasonal variation, allergy, smoking, radiation damage to the thyroid, and viral and bacterial infections (366).
Recommendations for Testing and Treatment
Overt and subclinical hypothyroidism are defined as an elevated TSH with a low T4 and an elevated TSH and normal T4, respectively, using appropriate patient ranges (nonpregnant and pregnant). A number of professional organizations published various recommendations for thyroid function assessment via a TSH in women. Because of the long interval from development of disease to diagnosis, the nonspecific nature of symptoms, and the potential adverse neonatal and maternal outcomes associated with untreated hypothyroidism in pregnancy, the American Association of Clinical Endocrinologists (AACE) recommended screening women prior to conceiving or at the first prenatal appointment (367,368). The AACE also recommended screening for the presence of hypothyroidism in patients with type 1 diabetes mellitus (threefold increased risk of postpartum thyroid dysfunction and 33% prevalence overall), patients taking lithium therapy (35% prevalence), and consideration of testing in patients presenting with infertility (>12% prevalence) or depression (10% to 12% prevalence), as these populations are at an increased risk of hypothyroidism (368). A screening TSH was recommended in women starting at the age of 50 because of the increased prevalence of hypothyroidism in this population (369). Thyroid function testing at 6-month intervals was recommended for patients taking amiodarone, as hyperthyroidism or hypothyroidism occurs in 14% to 18% of these patients (368). Any woman with a history of postpartum thyroiditis should be offered annual surveillance of thyroid function, as 50% of these patients will develop hypothyroidism within 7 years of diagnosis (370). Because there is a high prevalence of hypothyroidism in women with Turner and Down syndromes, an annual check of thyroid function is recommended for these patients (371,372).
Alternatively, the Endocrine Society’s clinical practice guidelines regarding the management of thyroid dysfunction during pregnancy and postpartum recommends targeted screening for the following individuals: history of thyroid disorder, family history of thyroid disease, goiter, thyroid autoantibodies, clinical signs or symptoms of thyroid disease, autoimmune disorders, infertility, head and/or neck radiation, and preterm delivery (373). The American Congress of Obstetricians and Gynecologists accepted these recommendations for TSH testing (374). Because of the (i) potentially significant neurologic affects on the fetus and other adverse pregnancy events; (ii) physiologic rise in TBG and the TSH-like activity of hCG in pregnancy, and (iii) potential for the targeted screening groups to have overt or subclinical hypothyroidism defined by the reference ranges for pregnancy (TSH <2.5, 3.1, and 3.5 μIU/mL for the first, second, and third trimesters, respectively), targeted maternal testing for hypothyroidism is encouraged. The targeted screening protocol allows that 30% of subclinical hypothyroidism cases may be missed. According to these recommendations, preconceptionally diagnosed hypothyroid women (overt or subclinical) should have their T4 dosage adjusted such that the TSH value is less than 2.5 μIU/mL before pregnancy. The T4 dosage in women already on replacement will routinely require a dose escalation (30% to 50%) at 4 to 6 weeks gestation in order to maintain a TSH value less than 2.5 μIU/mL. Pregnant women with overt hypothyroidism should be normalized as rapidly as possible to maintain TSH at less than 2.5 and 3 μIU/mL in the first, second, and third trimesters, respectively. Euthyroid women with thyroid autoantibodies are at risk of hypothyroidism and should have TSH screening in each trimester. After delivery, hypothyroid women need a reduction in T4 dosage used during pregnancy. Because subclinical hypothyroidism is associated with adverse outcomes for mother and the fetus, T4 replacement is recommended.
Hashimoto Thyroiditis
Hashimoto thyroiditis, or chronic lymphocytic thyroiditis, was first described in 1912 by Dr. Hakaru Hashimoto. Hashimoto thyroiditis can manifest as hyperthyroidism, hypothyroidism, euthyroid goiter, or diffuse goiter. High levels of antimicrosomal and antithyroglobulin antibody are usually present, and TSHRAb may be present (353,375,376). Typically, glandular hypertrophy is found, but atrophic forms are also present. Three classic types of autoimmune injury are found in Hashimoto thyroiditis: (i) complement-mediated cytotoxicity, (ii) antibody-dependent cell-mediated cytotoxicity, and (iii) stimulation or blockade of hormone receptors, which results in hypo- or hyperfunction or growth (Fig. 31.11).
Figure 31.11 Types of autoimmune injury found in Hashimoto thyroiditis. A: Complement-mediated cytotoxicity, which can be abolished by inactivating the complement system. B: Antibody-dependent cell-mediated cytotoxicity (ADCC) function through killer T cells, monocytes, and natural killer cells that have immunoglobulin G fragment receptors. C: Stimulation of blockade of hormone receptors leading to hyperfunction or hypofunction or growth, depending on the types of immunoglobulins acting on the target cell. TBII, TSH-binding inhibitor immunoglobulin; TGI, thyroid growth–promoting immunoglobulin; TSAb, thyroid-stimulating antibodies; TSH, thyroid-stimulating hormone. (From Coulam CB, Faulk WP, McIntyre JA. Immunologic obstetrics. New York: Norton Medical Books, 1992:658, with permission.)
The histologic picture of Hashimoto thyroiditis includes cellular hyperplasia, disruption of follicular cells, and infiltration of the gland by lymphocytes, monocytes, and plasma cells. Occasionally, adjacent lymphadenopathy may be noted. Some epithelial cells are enlarged and demonstrate oxyphilic changes in the cytoplasm (Askanazy cells or Hürthle cells, which are not specific to this disorder). The interstitial cells show fibrosis and lymphocytic infiltration. Graves disease and Hashimoto thyroiditis may cause very similar histologic findings manifested by a similar mechanism of injury.
Clinical Characteristics and Diagnosis of Hashimoto Thyroiditis
Patients with Hashimoto thyroiditis may present with typical symptoms of hypothyroidism or may be relatively asymptomatic. Patients often present with a goiter, which can involve the parietal lobe. At later stages of the disease, hypothyroidism can be found without a goiter. Notable clinical manifestations associated with Hashimoto thyroiditis include fatigue, weight gain, hyperlipidemia, dry hair, dry skin, cold intolerance, depression, menstrual irregularities, bradycardia, and or memory impairment. Hashitoxicosis, the hyperthyroid manifestation of Hashimoto thyroiditis, may occur after a hypothyroid state and development into a euthyroid or hyperthyroid state and is thought to be the result of development of TSH-stimulating antibodies (TSI) associated with Graves disease (368). This variant is estimated to occur in 4% to 8% of patients with Hashimoto thyroiditis. In the setting of Hashitoxicosis, the patient requires frequent follow-up and the potential for adjustments in thyroid supplementation. These patients often become hypothyroid during the course of treatment.
Table 31.13 Potential Causes of Hypothyroidism
|
Primary |
|
Congenital absence of thyroid gland |
|
External thyroid gland radiation |
|
Familial disorders and thyroxine synthesis |
|
Hashimoto thyroiditis |
|
Iodine-131 ablation for Graves disease |
|
Ingestion of antithyroid drugs |
|
Iodine deficiency |
|
Idiopathic myxedema (autoimmune) |
|
Surgical removal of thyroid gland |
|
Secondary |
|
Hypothalamic thyrotropin-releasing hormone deficiency |
|
Pituitary or hypothalamic tumors or disease |
In many cases, an elevated serum TSH is detected during routine screening. Elevated serum anti-TPO antibodies confirm the diagnosis, and free T4 and T3 document overt or subclinical hypothyroidsim. The sedimentation rate may be elevated, depending on the course of the disease at the time of recognition. Other causes of hypothyroidism should be considered, as listed in Table 31.13. Progression from subclinical to clinically overt hypothyroidism is reported to vary from 3% to 20%, with a higher risk noted in patients with goiter or thyroid antibodies (329,377). Treatment of subclinical hypothyroidism is somewhat controversial, but clinical studies suggested treatment of subclinical hypothyroidism is associated with a reduction in neurobehavioral abnormalities, a reduction in cardiovascular risk factors, and an improvement in lipid profile (378,379).
Treatment
Thyroxine replacement is initiated in patients with clinically overt hypothyroidism or subclinical hypothyroidism with a goiter. Regression of gland size usually does not occur, but treatment often prevents further growth of the thyroid gland. Treatment is recommended for patients with subclinical hypothyroidism in the setting of a TSH greater than 10 mIU/L on repeat measurements, pregnant patients, a strong habit of tobacco use, signs or symptoms associated with thyroid failure, or patients with severe hyperlipidemia (380). All pregnant patients with an elevated TSH level should be treated with levothyroxine. Treatment does not slow progression of the disease. The initial dosage of levothyroxine may be as little as 12.5 μg per day up to a full replacement dose. The mean replacement dosage of levothyroxine is 1.6 μg/kg of body weight per day, although the dosage varies greatly between patients (368). Aluminum hydroxide (antacids), cholestyramine, iron, calcium, and sucralfate may interfere with absorption. Rifampin and sertraline hydrochloride may accelerate the metabolism of levothyroxine. The half-life of levothyroxine is nearly 7 days; therefore, nearly 6 weeks of treatment are necessary before the effects of a dosage change can be evaluated.
Hypothyroidism appears to be associated with decreased fertility resulting from disruption in ovulation, and thyroid autoimmune disease is associated with an increased risk of pregnancy loss with or without overt thyroid dysfunction (381). A meta-analysis of case-control and longitudinal studies performed since 1990 reveals a possible association between miscarriage and thyroid antibodies with an odds ratio of 2.73 (95% CI, 2.20–3.40). This association may be explained by a heightened autoimmune state affecting the fetal allograft or a slightly higher age of women with antibodies compared with those without antibodies (0.7 ± 1 year, p <.001) (382). Studies suggest that early subclinical hypothyroidism may be associated with menorrhagia (383).
Severe primary hypothyroidism is associated with menstrual irregularities in 23% of women, with oligomenorrhea being the most common (382). Reproductive dysfunction in hypothyroidism may be caused by a decrease in the binding activity of sex hormone–binding globulin, resulting in increased estradiol and free testosterone and from hyperprolactinemia (382). The increase in prolactin levels is the result of enhanced sensitivity of the prolactin-secreting cells to TRH (with elevated TRH seen in primary hypothyroidism) and defective dopamine turnover resulting in hyperprolactinemia (384–387). Hyperprolactinemia-induced luteal phase defects are associated with less severe forms of hypothyroidism (388,389). Replacement therapy appears to reverse the hyperprolactinemia and correct ovulatory defects (390,391).
Combined thyroxine and triiodothyronine therapy is no more effective than thyroxine therapy alone, and patients with hypothyroidism should be treated with thyroxine alone (392). Treatment should target normalizing TSH values, and a daily dose of 0.012 mg up to a full replacement dose of levothyroxine (1.6 μg/kg of body weight per day) may be required with dosage dependent on the patient’s weight, age, cardiac status, and duration and severity of hypothyroidism (368).
Graves Disease
Graves disease, characterized by exophthalmos, goiter, and hyperthyroidism, was first identified as an association of findings in 1835. A heritable specific defect in immunosurveillance by suppressor T lymphocytes is believed to result in the development of a helper T-cell population that reacts to multiple epitopes of the thyrotropin receptor. This activity induces a B-cell–mediated response, resulting in the clinical features of Graves disease (389). The TSHRAb bind to conformational epitopes in the extracellular domain of the thyrotropin receptor and are uniformly detected in patients with untreated Graves disease (390).
Graves disease is a complex autoimmune disorder in which several genetic susceptibility loci and environmental factors are likely to play a role in the development of the disease. Human leukocyte antigen and polymorphisms in the cytotoxic T-lymphocyte antigen 4 (CTLA-4) gene were established as susceptibility loci; however, the magnitude of their contributions seems to vary among patient populations and study groups. Additional loci are likely to be identified by a combination of genome-wide linkage analyses and allelic association analyses of candidate genes. The rate of concordance for Graves disease is only 20% in monozygotic twins and even lower in dizygotic twins, consistent with a multifactorial inheritance pattern highly influenced by environmental factors. Linkage analysis identified loci on chromosomes 14q31, 20q11.2, and Xq21 that are associated with susceptibility to Graves disease (393).
Clinical Characteristics and Diagnosis
The classic triad in Graves disease consists of exophthalmos, goiter, and hyperthyroidism. The symptoms associated with Graves disease include frequent bowel movements, heat intolerance, irritability, nervousness, heart palpitations, impaired fertility, vision changes, sleep disturbances, tremor, weight loss, and lower extremity swelling. Physical findings may include lid lag, nontender thyroid enlargement (two to four times normal), onycholysis, dependent lower extremity edema, palmar erythema, proptosis, staring gaze, and thick skin. A cervical venous bruit and tachycardia may be noted. The tachycardia does not respond to increased vagal tone produced with a Valsalva maneuver. Severe cases may demonstrate acropachy, chemosis, clubbing, dermopathy, exophthalmos with ophthalmoplegia, follicular conjunctivitis, pretibial myxedema, and vision loss.
Approximately 40% of patients with new onset of Graves disease and many of those previously treated have elevated T3 and normal T4 levels. Abnormal T4 or T3 results are often caused by protein binding changes rather than altered thyroid function; therefore, assessment of free T4 and free T3 is indicated in conjunction with TSH. In Graves disease, the TSH levels are suppressed, and levels may remain undetectable for some time even after the initiation of treatment. Thyroid autoantibodies, including TSI, may be useful during pregnancy to more accurately predict fetal risk of thyrotoxicosis (368). Autonomously functioning, benign thyroid neoplasms that exhibit a similar clinical picture include toxic adenomas and toxic multinodular goiter. A radioactive iodine uptake thyroid scan may help differentiate these two conditions from Graves disease. Rare conditions resulting in thyrotoxicosis include metastatic thyroid carcinoma causing thyrotoxicosis, amiodarone induced thyrotoxicosis, iodine induced thyrotoxicosis, postpartum thyroiditis, a TSH-secreting pituitary adenoma, an hCG-secreting choriocarcinoma, struma ovarii, and “de Quervan's” or subacute thyroiditis (394). Factitious ingestion of thyroxine or desiccated thyroid should be considered in patients with eating disorders. Patients with thyrotoxicosis factitia demonstrate elevated T3 and T4, suppressed TSH, and a low serum thyroglobulin level, whereas other causes of thyroiditis and thyrotoxicosis demonstrate high levels of thyroglobulin. Potential causes of hyperthyroidism are listed in Table 31.14.
Table 31.14 Potential Causes of Hyperthyroidism
|
Factitious hyperthyroidism |
|
Graves disease |
|
Metastatic follicular cancer |
|
Pituitary hyperthyroidism |
|
Postpartum thyroiditis |
|
Silent hyperthyroidism (low radioiodine uptake) |
|
Struma ovarii |
|
Subacute thyroiditis |
|
Toxic multinodular goiter |
|
Toxic nodule |
|
Tumors secreting human chorionic gonadotropin (molar pregnancy, choriocarcinoma) |
Treatment
Iodine-131 Ablation
Treatment of women with hyperthyroidism of an autoimmune origin presents unique challenges to the physician who must consider the patient’s needs and her reproductive plans. Because the drugs used to treat this disorder have potentially harmful effects on the fetus, special attention must be given to the use of contraception and the potential for pregnancy.
A single dose of radioactive iodine-131 is an effective cure in about 80% of cases and is the definitive treatment in nonpregnant women. Any woman of childbearing age should be tested for pregnancy before undergoing diagnostic or therapeutic administration of iodine. Ablation of a second-trimester fetal thyroid gland and congenital hypothyroidism (cretinism) from treatment during the first trimester were reported (395). Nuclear medicine professionals provide expertise in the administration of the radioactive isotope, and because the effect of the radioactive iodine is not immediate, the endocrinologist continues to provide suppressive medical treatment for 6 to 12 weeks after administration of iodine while the patient remains hyperthyroid. As early as 2 to 3 months after treatment, patients may become hypothyroid and should be supplemented with thyroxine as indicated by serum levels of free thyroid hormone levels (368). TSH testing is not sensitive for predicting thyroid function during this time as changes in TSH lag 2 weeks to several months behind thyroid function changes (368). Failure to respond to iodine 6 months after treatment may require a repeat treatment with radioactive iodine (394). Postablative hypothyroidism develops in 50% of patients within the first year after iodine therapy and in more than 2% of patients per year thereafter.
A higher rate of miscarriage was noted in women treated with iodine therapy in the year preceding therapy, but there is no reported increase in the rate of stillbirths, preterm birth, low birth weight, congenital malformation, or death after therapy (396). Many thyroidologists and nuclear medicine specialists are willing to allow pregnancy earlier than 1 year after therapy if patients receive replacement therapy with levothyroxine.
Thyroid-Stimulating Receptor Antibody in Graves Disease
The level of TSHRAb of the TBII class grossly parallels the degree of hyperthyroidism as assessed by the serum levels of thyroid hormones and total thyroid volume. Studies suggest that the combination of a small goiter volume (<40 mL) and a low TBII level (<30 U/L) results in a 45% chance of remission during the 5 years after completion of a 12- to 24-month course of antithyroid drug therapy (397). In contrast, the overall rate of relapse exceeded 70% in patients with a large goiter volume (>70 mL) and a higher TBII level (>30 U/L). The subgroup of patients with larger goiters and higher TBII levels had less than a 10% chance to remain in remission in the 5 years after treatment. Although it is not necessary for the diagnosis of Graves disease, except in some cases of multinodular goiter, a TSHRAb measurement may be a useful marker of disease severity. Used in combination with other clinical factors, it may contribute to initial decisions regarding treatment. See Table 31.12 for a review of the nomenclature and assay methods for TSHRAb.
Measurements of TSHRAb (TBII category) during treatment with antithyroid drugs are predictive of subsequent outcome. In one series, 73% of TBII-negative patients had remission compared with only 28% of TBII-positive patients who achieved remission after 12 months of antithyroid drug therapy (398). The duration of a course of antithyroid drug therapy may potentially be modified according to the TSHRAb status. In patients whose TSHRAb status became negative and antithyroid drug therapy was discontinued, the relapse rate was 41% compared with a rate of 92% for those patients who remained TSHRAb positive (399). Regardless of the rapidity of the disappearance of TSHRAb, it does seem that antithyroid drug therapy should be maintained for 9 to 12 months to minimize the risk of relapse. TSHRAb status appears to determine, in an inverse relationship, the reduction in thyroid volume after radioactive iodine therapy.
Third-generation TSHRAb assays have been developed, and their utility in evaluation and treatment monitoring is being evaluated. Many patients with Graves disease have or will develop antineutrophil cytoplasmic antibodies (ANCA) after treatment, but the significance of this finding is still under study. Smoking appears to be an independent risk factor for relapse after medical therapy and should be considered when planning treatment.
Antithyroid Drugs
Antithyroid drugs of the thioamide class include propylthiouracil (PTU) and methimazole. Low doses of either agent block the secondary coupling reactions that form T3 and T4 from MIT and DIT. At higher doses, they also block iodination of tyrosyl residues in thyroglobulin. Propylthiouracil additionally blocks the peripheral conversion of T4 to T3. Approximately one-third of patients treated by this approach alone go into remission and become euthyroid (397).
In 2009, the FDA published a warning on the use of propylthiouracil because of 32 reported cases of serious liver injury associated with its use (400,401). The average daily dose associated with liver failure was 300 mg, and liver failure was reported to occur anywhere from 6 days to 450 days after initiation of therapy (402). Traditionally PTU was the drug of choice to treat hyperthyroidism for the duration of pregnancy because it less readily crosses the placenta, and methimazole was associated with an increased risk of choanal atresia and aplasia cutis (403–406). Because of the case reports of PTU-related liver failure and the increased risk of birth defects associated with methimazole use during embryogenesis, the FDA and the Endocrine Society recommend PTU never be used as first-line medical treatment of hyperthyroidism for nonpregnant patients. It is recommended that its use be limited to pregnant women during the first trimester; situations where surgery or radioactive iodine treatment are contraindicated, and individuals who have developed a toxic reaction to methimazole (400,402). The FDA recommends monitoring patients closely for signs and symptoms of liver injury while taking PTU. If liver injury is suspected, PTU should be promptly discontinued (400). The American Thyroid Association recommends an initial dose of 100 to 600 mg per day in three divided doses with a goal to maintain T4 in the upper limit of normal using the lowest possible dose. Minor reactions such as pruritus affect 3% to 5% of patients treated with thionamide therapy, and antihistamines may eliminate symptoms and allow continued use. Agranulocytosis is a rare and potentially fatal complication of PTU and methimazole therapy, and developing in 0.2% of women treated, and it mandates immediate discontinuation of the drug (403). Agranulocytosis most commonly presents with fever and a sore throat followed by sepsis; the occurrence of fever, sore throat, or a viral-like syndrome should prompt an urgent evaluation.
Methimazole is the first-line drug for the treatment of hyperthyroidism, except in the first trimester of pregnancy, as it has been shown to be more effective than PTU at controlling severe hyperthyroidism and is associated with higher adherence rates and less toxicity (407). The American Thyroid Associated recommends initial daily doses of 10 to 40 mg per day in a single dose. Like treatment with PTU, the goal is to maintain a free T4 level in the upper limits of normal using the lowest possible dose. Free T4 levels show improvement 4 weeks after therapy, and TSH levels take 6 to 8 weeks to normalize (403). Methimazole use in pregnancy is associated with an 18-fold risk of fetal choanal atresia compared with the general population (95% CI, 3–121) (408). Congenital aplasia cutis was associated with maternal use of methimazole during pregnancy; however, it is not known at this time whether the risk (0.03%) is greater than that seen in the general population (409).
Studies suggest a potential role for an intrathyroid dexamethasone injection to prevent relapse (410). Other medical therapies include iodide and lithium, both of which reduce thyroid hormone release and inhibit the organification of iodine. Iodide leads to the secondary coupling of T3 and T4. Iodide inhibition of thyroid metabolism is only transient, and complete escape from inhibition occurs within 1 to 2 weeks of iodide therapy, making this useful only for acute management of severe thyrotoxicosis (394). Lithium may be used when thionamide therapy is contraindicated or in combination with PTU or methimazole (394). To avoid toxicity during treatment, serum lithium levels should be monitored. Lithium has been associated with fetal Ebstein anomaly, and iodide has been associated with congenital goiter; these medications should not be used in pregnant women and should be used with caution in women of reproductive age. Because of the complications related to medical therapy of hyperthyroidism, women desiring pregnancy should be counseled to strongly consider surgical treatment or radioactive iodine treatment prior to pregnancy (402).
Surgery
Thyroidectomy was used for the treatment of Graves disease but is now rarely used unless there is a suspicion for coexisting thyroid malignancy (368). Potential candidates for surgical intervention include pregnant women refusing or not tolerating antithyroid medical therapy, pediatric patients presenting with Graves disease, or patients who refuse radioactive iodine therapy. Surgery is the most rapid and consistent method of achieving a euthyroid state in Graves disease and avoids the possible long-term risks of radioactive iodine. Surgical intervention may be considered in severe Graves ophthalmopathy. Patients should be rendered euthyroid before a thyroidectomy. The risks of surgery include postoperative hypoparathyroidism, recurrent laryngeal nerve paralysis, routine anesthetic and surgical risks, hypothyroidism, and failure to relieve thyrotoxicosis.
β-Blockers
Propranolol occasionally is used with or without concurrent antithyroid medications before radioactive iodine or surgery to provide relief of symptoms. Larger and more frequent doses may be required because of a relative resistance to β-adrenergic antagonists in the setting of hyperthyroidism.
Thyroid Storm
Thyroid storm is an acute, life-threatening exacerbation of hyperthyroidism and should be treated as a medical emergency in an intensive care unit setting. Symptoms include tachycardia, tremor, diarrhea, vomiting, fever, dehydration, and altered mental status that may proceed to coma. Patients with poorly controlled hyperthyroidism are most susceptible. Beta-blocker agents, glucocorticoids, PTU (the action of which includes inhibition of T4-T3conversion), and iodides are all key elements of therapy.
Hyperthyroidism in Gestational Trophoblastic Disease and Hyperemesis Gravidarum
Because of the weak TSH-like activity of hCG, conditions with high levels of hCG, such as molar pregnancy, may be associated with biochemical and clinical hyperthyroidism. Symptoms regress with removal of the abnormal trophoblastic tissue and resolution of elevated levels of hCG. In a similar fashion, when hyperemesis gravidarum is associated with high levels of hCG, mild biochemical and clinical features of hyperthyroidism may be seen (411,412). Gestational trophoblastic disease is reviewed in Chapter 39.
Thyroid Function in Pregnancy
Physicians should be aware of the changes in thyroid physiology during pregnancy. Pregnancy is associated with reversible changes in thyroid physiology that should be noted before diagnosing thyroid abnormalities (see Fig. 31.12for pregnancy associated changes in TBG, total T4, hCG, TSH, and free T4) (403). Women with a history of hypothyroidism often require increased thyroxine replacement during pregnancy, and patients should have thyroid function tests performed at the first prenatal visit and during each trimester thereafter. Evidence suggests that optimal fetal and infant neurodevelopmental outcomes may require careful titration of replacement thyroxine that meets the frequently increased requirements of pregnancy (413,414). Postpartum, women should return to their prepregnancy dosage of levothyroxine and have a follow-up TSH checked 6 to 8 weeks postpartum.
Figure 31.12 Pregnancy-associated changes in TSH relative to hCG and free T4 in relation to TBG. Relative serum concentration changes throughout pregnancy highlighting a fall in TSH associated with an increase in hCG early in pregnancy and a fall in free T4 as TBG levels rise during pregnancy. hCG, human chorionic gonadotropin; TSH, thyroid-stimulating hormone; TBG, thyroid-binding globulin, total T4, total thyroxine; free T4, free thyroxine. (Based on data from Brent GA. Maternal thyroid function: interpretation of thyroid function tests in pregnancy. Clin Obstet Gynecol 1997;40:3–15.)
Reproductive Effects of Hyperthyroidism
High levels of TSAb (TSI) in women with Graves disease are associated with fetal-neonatal hyperthyroidism (415,416). Despite both the inhibition and elevation of gonadotropins seen in thyrotoxicosis, most women remain ovulatory and fertile (387,417). Severe thyrotoxicosis can result in weight loss, menstrual cycle irregularities, and amenorrhea. An increased risk of spontaneous abortion is noted in women with thyrotoxicosis. An increased incidence of congenital anomalies, particularly choanal atresia and possibly aplasia cutis, can occur in the offspring of women treated with methimazole (404,405,408).
Autoimmune hyperthyroid Graves disease may improve spontaneously, in which case antithyroid drug therapy may be reduced or stopped. TSHRAb production may persist for several years after radical radioactive iodine therapy or surgical treatment for hyperthyroid Graves disease. In this circumstance, there is a risk of exposing a fetus to TSHRAb. Fetal–neonatal hyperthyroidism is observed in 2% to 10% of pregnancies occurring in mothers with a current or previous diagnosis of Graves disease, secondary to the transplacental passage of maternal TSHRAb. This is a serious condition with a 16% neonatal mortality rate and a risk of intrauterine fetal death, stillbirth, and skeletal developmental abnormalities, such as craniosynostosis. Caution against overtreatment with antithyroid medication is warranted, as these medications may cross the placenta in sufficient quantities to induce fetal goiter. Guidelines for TSHRAb testing during pregnancy in women with previously treated Graves disease are found in Table 31.15. Fetal goiters and the associated fetal hypo- or hyperthyroid status were diagnosed accurately in mothers with Graves disease using a combination of fetal ultrasonography of the thyroid with Doppler, fetal heart rate monitoring, bone maturation, and maternal TSHRAb and antithyroid drug status (418).
Postpartum Thyroid Dysfunction
Postpartum thyroid dysfunction is much more common than recognized; it is often difficult to diagnose because its symptoms appear 1 to 8 months postpartum and are often confused with postpartum depression and difficulties adjusting to the demands of the neonate and infant. Postpartum thyroiditis appears to be caused by the combination of a rebounding immune system in the postpartum state and the presence of thyroid autoantibodies. Histologically, lymphocytic infiltration and inflammation are found and anti-TPO antibodies are often present (419,420). The following are criteria for the diagnosis of postpartum thyroiditis: (i) no history of thyroid hormonal abnormalities either before or during pregnancy, (ii) documented abnormal TSH level (either depressed or elevated) during the first year postpartum, and (iii) absence of a positive TSH-receptor antibody titer (Graves disease) or a toxic nodule. A number of studies describe clinical and biochemical evidence of postpartum thyroid dysfunction in 5% to 10% of new mothers (421,422).
Table 31.15 Guidelines for TSHRAb Testing During Pregnancy with Previously Treated Graves Disease
|
1. In the woman with antecedent Graves disease in remission after ATD treatment, the risk for fetal–neonatal hyperthyroidism is negligible, and systematic measurement of TSHRAb is not necessary. 2. In the woman with antecedent Graves disease previously treated with radioiodine or thyroidectomy and regardless of the current thyroid status (euthyroidism with or without thyroxine substitution), TSHRAb should be measured early in pregnancy to evaluate the risk for fetal hyperthyroidism. 3. In the woman with concurrent hyperthyroid Graves disease, regardless of whether it has preceded the onset of pregnancy, ATD treatment should be monitored and adjusted to keep free T4 in the high-normal range to prevent fetal hypothyroidism and minimize toxicity associated with higher doses of these medications. 4. In any woman who has previously given birth to a newborn with hyperthyroidism, a TSHR-Ab assay should be performed early in the course of pregnancy. |
|
TSHRAb, thyroid-stimulating hormone receptor antibodies; ATD, autoimmune thyroid disease; T4, thyroxine; TBII, TSH-binding inhibitory immunoglobulin; TSAb, thyroid-stimulating antibody. |
Clinical Characteristics and Diagnosis
Postpartum thyroiditis usually begins with a transient hyperthyroid phase between 6 weeks and 6 months postpartum followed by a hypothyroid phase. Only one-fourth of the cases follow this classic clinical picture, and more than one-third have either hyperthyroidism or hypothyroidism alone. Individuals with type 1 diabetes have a threefold increased risk of developing postpartum thyroiditis. Women with a history of postpartum thyroiditis in a previous pregnancy have nearly a 70% chance of recurrence in a subsequent pregnancy. Although psychotic episodes are rare, postpartum thyroid dysfunction should be considered in all women with postpartum psychosis. The thyrotoxic phase may be subclinical and overlooked, particularly in areas where iodine intake is low (423). Unlike patients with Graves disease, those with the hyperthyroidism caused by postpartum thyroiditis have a low level of radioactive isotope uptake. Women with a history of postpartum thyroiditis should be followed closely as they have a 20% risk of permanent hypothyroidism immediately following the onset of thyroiditis, up to a 60% risk of permanent hypothyroidism over the next 5 to 10 years, and up to a 70% risk of postpartum thyroiditis in future pregnancies (424,425).
The absence of thyroid tenderness, pain, fever, elevated sedimentation rate, and leukocytosis helps to rule out subacute thyroiditis (de Quervain thyroiditis). Evaluation of TSH, T4, T3, T3 resin uptake, and antimicrosomal antibody titer confirms the diagnosis.
Treatment
Most patients are diagnosed during the hypothyroid phase and require 6 to 12 months of thyroxine replacement if they are symptomatic (370). Because approximately 60% of women develop permanent hypothyroidism, TSH should be evaluated following discontinuation of replacement therapy.
Rarely, patients are diagnosed during the hyperthyroid phase (426). Antithyroid medications are not routinely used for these women. Propranolol may be used for relief of symptoms but should be used with appropriate counseling in nursing mothers.
Antithyroid Antibodies and Disorders of Reproduction
Women who have antithyroid autoantibodies before and after conception appear to be at an increased risk for spontaneous abortion (427,428). Nonorgan-specific antibody production and pregnancy loss are documented in cases of antiphospholipid abnormalities (429). The concurrent presence of organ-specific thyroid antibodies and nonorgan-specific autoantibody production is not uncommon (429–431). In cases of recurrent pregnancy loss, thyroid autoantibodies may serve as peripheral markers of abnormal T-cell function and further implicate an immune component as the cause of reproductive failure. The clinical implications of these findings in the management of patients with recurrent pregnancy loss are not known. Recurrent pregnancy loss is covered in Chapter 33.
Thyroid Nodules
Thyroid nodules are a common finding on physical examination and are demonstrated by high frequency ultrasonography in over two-thirds of patients (432). Occasionally such nodules are functional, and clinical and laboratory evaluation should be applied to distinguish these nodules from nonfunctional nodules, which are occasionally malignant. For nonfunctional “cold” nodules, fine-needle biopsy and aspiration are required to rule out malignancy. In the case of indeterminate aspirates, 2% to 20% are malignant; therefore, surgical biopsy often is indicated (433). Molecular diagnosis screening of the BRAF mutation improves the diagnosis of cancer on fine-needle aspiration (434).
Turner Syndrome and Down Syndrome
Patients with Turner syndrome (and other forms of hypergonadotropic hypogonadism associated with abnormalities of the second sex chromosome) exhibit a high prevalence of autoimmune thyroid disorders. Approximately 50% of adult patients with Turner syndrome have antithyroid peroxidase (anti-TPO) and antithyroglobulin (anti-TG) autoantibodies. Of these patients, approximately 30% will develop subclinical or clinical hypothyroidism. The disorder is indistinguishable from Hashimoto thyroiditis. A susceptibility locus for Graves disease is noted on chromosome X (435). Because of the increased risk of autoimmune thyroid disease, it is recommended that women with Turner syndrome be screened with yearly TSH testing starting at the age of 4 (436).
Down syndrome, caused by an extra chromosome 21, is characterized by an atypical body habitus, mental retardation, cardiac malformations, an increased risk of leukemia, and a reduced life expectancy. The extra chromosome is almost always of maternal origin. Autoimmune thyroid disorders are more common in patients with Down syndrome than in the general population. The gene for autoimmune polyglandular syndrome I (APECED) was mapped to chromosome 21 and is thought to be a transcription factor involved in immune regulation (AIRE). This gene may play a role in the development of autoimmune thyroid disease in these patients (437). Hashimoto thyroiditis is the most common type of thyroid disease in individuals with Down syndrome. Hypothyroidism develops in as many as 50% of patients older than age 40 with Down syndrome. These clinical syndromes and other evidence suggest part of the genetic susceptibility to Hashimoto thyroiditis may reside on chromosomes X and 21. Because of the increased frequency of hypothyroidism associated with Down syndrome, it is recommended to screen individuals at 6 months, 12 months, and then annually thereafter (372).
References
1. Verkauf BS, Von Thron J, O'Brien WF. Clitoral size in normal women. Obstet Gynecol 1992;80:41–44.
2. Ferrimann D, Gallway JD. Clinical assessment of body hair growth in women. J Clin Endocrinol Metab 1961;21:1440.
3. Rosenfield RL. Clinical practice. Hirsutism. N Engl J Med 2005; 353:2578–2588.
4. Martin KA, Chang RJ, Ehrmann DA, et al. Evaluation and treatment of hirsutism in premenopausal women: an endocrine society clinical practice guideline. J Clin Endocrinol Metab 2008;93:1105–1120.
5. Vermeulen A, Verdonck L, Kaufman JM. A critical evaluation of simple methods for the estimation of free testosterone in serum. J Clin Endocrinol Metab 1999;84:3666–3672.
6. Armengaud JB, Charkaluk ML, Trivin C, et al. Precocious pubarche: distinguishing late-onset congenital adrenal hyperplasia from premature adrenarche. J Clin Endocrin Metab 2009;94:2835– 2840.
7. Azziz R, Carmina E, Dewailly D, et al. The Androgen Excess and PCOS Society criteria for the polycystic ovary syndrome: the complete task force report. Fertil Steril 2009;91:456–488.
8. Rittmaster RS. Clinical relevance of testosterone and dihydrotestosterone metabolism in women. Am J Med 1995;98:17S–21S.
9. Rainey WE, Nakamura Y. Regulation of the adrenal androgen biosynthesis. J Steroid Biochem Mol Biol 2008;108:281–286.
10. Siegel SF, Finegold DN, Lanes R, et al. ACTH stimulation tests and plasma dehydroepiandrosterone sulfate levels in women with hirsutism. N Engl J Med 1990;323:849–854.
11. d'Alva CB, Abiven-Lepage G, Viallon V, et al. Sex steroids in androgen-secreting adrenocortical tumors: clinical and hormonal features in comparison with non-tumoral causes of androgen excess. Eur J Endocrinol 2008;159:641–647.
12. Youden WJ. Index for rating diagnostic tests. Cancer 1950;3:32–35.
13. Ehrmann DA. Polycystic ovary syndrome. N Engl J Med 2005;352:1223–1236.
14. Toulis KA, Goulis DG, Kolibianakis EM, et al. Risk of gestational diabetes mellitus in women with polycystic ovary syndrome: a systematic review and a meta-analysis. Fertil Steril 2009;92:667–677.
15. Practice Committee of the American Society of Reproductive Medicine. The evaluation and treatment of androgen excess. Fertil Steril 2006;86:S173–S180.
16. Nestler JE. Metformin for the treatment of the polycystic ovary syndrome. N Engl J Med 2008;358:47–54.
17. Stein IF, Leventhal ML. Amenorrhea associated with bilateral polycystic ovaries. Am J Obstet Gynecol 1935;29:181–191.
18. Zawadzki JK, Danif A. Diagnostic criteria for polycystic ovary syndrome towards a rational approach. In: Dunaif A, Givens JR, Hasetine FP, et al., eds. Polycystic ovary syndrome. Cambridge: Blackwell Science, 1992:377–384.
Rotterdam ESHRE/ASRM-Sponsored PCOS Consensus Workshop Group. Revised 2003 consensus on diagnostic criteria and long-term health risks related to polycystic ovary syndrome. Fertil Steril 2004;81:19–25.
20. Goldzieher JW, Axelrod LR. Clinical and biochemical features of polycystic ovarian disease. Fertil Steril 1963;14:631–653.
21. Aono T, Miyazaki M, Miyake A, et al. Responses of serum gonadotrophins to LH-releasing hormone and oestrogens in Japanese women with polycystic ovaries. Acta Endocrinol (Copenh) 1977;85:840–849.
22. Serafini P, Ablan F, Lobo RA. 5-Alpha-reductase activity in the genital skin of hirsute women. J Clin Endocrinol Metab 1985;60:349–355.
23. Lobo RA, Goebelsmann U, Horton R. Evidence for the importance of peripheral tissue events in the development of hirsutism in polycystic ovary syndrome. J Clin Endocrinol Metab 1983;57:393–397.
24. Pall M, Azziz R, Beires J, et al. The phenotype of hirsute women: a comparison of polycystic ovary syndrome and 21-hydroxylase-deficient nonclassic adrenal hyperplasia. Fertil Steril 2010;94:684–689.
25. Carmina E, Lobo RA. Do hyperandrogenic women with normal menses have polycystic ovary syndrome? Fertil Steril 1999;71:319–322.
26. Peserico A, Angeloni G, Bertoli P, et al. Prevalence of polycystic ovaries in women with acne. Arch Dermatol Res 1989;281:502–503.
27. Polson DW, Adams J, Wadsworth J, et al. Polycystic ovaries—a common finding in normal women. Lancet 1988;1:870–872.
28. Loucks TL, Talbott EO, McHugh KP, et al. Do polycystic-appearing ovaries affect the risk of cardiovascular disease among women with polycystic ovary syndrome? Fertil Steril 2000;74:547–552.
29. Hassan MA, Killick SR. Ultrasound diagnosis of polycystic ovaries in women who have no symptoms of polycystic ovary syndrome is not associated with subfecundity or subfertility. Fertil Steril 2003;80:966–975.
30. Wild RA. Obesity, lipids, cardiovascular risk, and androgen excess. Am J Med 1995;98:27S–32S.
31. Moran LJ, Pasquali R, Teede HJ, et al. Treatment of obesity in polycystic ovary syndrome: a position statement of the Androgen Excess and Polycystic Ovary Syndrome Society. Fertil Steril 2009;92:1966–1982.
32. Kenny SJ, Aubert RE, Geiss LS. Prevalence and incidence of non-insulin-dependent diabetes. In: Harris MI ed. Diabetes in America. Washington, DC: US National Institutes of Health, NIH Publication. No.95-1468, Bethesda MD, 1995:179–220.
33. Ehrmann DA, Barnes RB, Rosenfield RL, et al. Prevalence of impaired glucose tolerance and diabetes in women with polycystic ovary syndrome. Diabetes Care 1999;22:141–146.
34. Legro RS, Kunselman AR, Dodson WC, et al. Prevalence and predictors of risk for type 2 diabetes mellitus and impaired glucose tolerance in polycystic ovary syndrome: a prospective, controlled study in 254 affected women. J Clin Endocrinol Metab 1999;84:165–169.
35. Harris MI, Hadden WC, Knowler WC, et al. Prevalence of diabetes and impaired glucose tolerance and plasma glucose levels in U.S. population aged 20–74 yr. Diabetes 1987;36:523–534.
36. Dahlgren E, Johansson S, Lindstedt G, et al. Women with polycystic ovary syndrome wedge resected in 1956 to 1965: a long-term follow-up focusing on natural history and circulating hormones. Fertil Steril 1992;57:505–513.
37. Conway GS, Agrawal R, Betteridge DJ, et al. Risk factors for coronary artery disease in lean and obese women with the polycystic ovary syndrome. Clin Endocrinol (Oxf) 1992;37:119–125.
38. Andersen P, Seljeflot I, Abdelnoor M, et al. Increased insulin sensitivity and fibrinolytic capacity after dietary intervention in obese women with polycystic ovary syndrome. Metabolism 1995;44:611–616.
39. Guzick DS, Talbott EO, Sutton-Tyrrell K, et al. Carotid atherosclerosis in women with polycystic ovary syndrome: initial results from a case-control study. Am J Obstet Gynecol 1996;174:1224–1229; discussion 9–32.
40. Birdsall MA, Farquhar CM, White HD. Association between polycystic ovaries and extent of coronary artery disease in women having cardiac catheterization. Ann Intern Med 1997;126:32–35.
41. Danigren E, Janson PO, Johansson S, et al. Polycystic ovary syndrome and risk for myocardial infarction. Acta Obstet Cynecol Scand 1992;71:559–604.
42. Clement PB. Nonneoplastic lesions of the ovary. In: Kurman RJ, ed., Blaustein’s pathology of the female genital tract, 4th ed. New York: Springer-Verlag, 1994:559–604.
43. Rosenfield RL, Barnes RB, Cara JF, et al. Dysregulation of cytochrome P450-17 α as the cause of polycystic ovarian syndrome. Fertil Steril 1990;53:785–791.
44. McNatty KP, Makris A, DeGrazia C, et al. The production of progesterone, androgens, and estrogens by granulosa cells, thecal tissue, and stromal tissue from human ovaries in vitro. J Clin Endocrinol Metab 1979;49:687–699.
45. Lobo RA, Kletzky OA, Campeau JD, et al. Elevated bioactive luteinizing hormone in women with the polycystic ovary syndrome. Fertil Steril 1983;39:674–678.
46. Chang RJ, Laufer LR, Meldrum DR, et al. Steroid secretion in polycystic ovarian disease after ovarian suppression by a long-acting gonadotropin-releasing hormone agonist. J Clin Endocrinol Metab 1983;56:897–903.
47. Biffignandi P, Massucchetti C, Molinatti GM. Female hirsutism: pathophysiological considerations and therapeutic implications. Endocr Rev 1984;5:498–513.
48. Rittmaster RS. Differential suppression of testosterone and estradiol in hirsute women with the superactive gonadotropin-releasing hormone agonist leuprolide. J Clin Endocrinol Metab 1988;67:651–655.
49. Lobo RA. Hirsutism in polycystic ovary syndrome: current concepts. Clin Obstet Gynecol 1991;34:817–826.
50. Hoffman DI, Klove K, Lobo RA. The prevalence and significance of elevated dehydroepiandrosterone sulfate levels in anovulatory women. Fertil Steril 1984;42:76–81.
51. Lobo RA. The role of the adrenal in polycystic ovary syndrome. Semin Reprod Endocrinol 1984:251–264.
52. Deslypere JP, Verdonck L, Vermeulen A. Fat tissue: a steroid reservoir and site of steroid metabolism. J Clin Endocrinol Metab 1985;61:564–570.
53. Edman CD, MacDonald PC. Effect of obesity on conversion of plasma androstenedione to estrone in ovulatory and anovulatory young women. Am J Obstet Gynecol 1978;130:456–461.
54. Schneider J, Bradlow HL, Strain G, et al. Effects of obesity on estradiol metabolism: decreased formation of nonuterotropic metabolites. J Clin Endocrinol Metab 1983;56:973–978.
55. Judd HL. Endocrinology of polycystic ovarian disease. Clin Obstet Gynecol 1978;21:99–114.
56. Bracero N, Zacur HA. Polycystic ovary syndrome and hyperprolactinemia. Obstet Gynecol Clin North Am 2001;28:77–84.
57. Deligeoroglou E, Kouskouti C, Christopoulos P. The role of genes in the polycystic ovary syndrome: predisposition and mechanisms. Gynecol Endocrinol 2009;25:603–609.
58. Urbanek M, Legro RS, Driscoll DA, et al. Thirty-seven candidate genes for polycystic ovary syndrome: strongest evidence for linkage is with follistatin. Proc Natl Acad Sci U S A 1999;96:8573–8578.
59. Gharani N, Waterworth DM, Batty S, et al. Association of the steroid synthesis gene CYP11a with polycystic ovary syndrome and hyperandrogenism. Hum Mol Genet 1997;6:397–402.
60. Ehrmann DA, Schwarz PE, Hara M, et al. Relationship of calpain-10 genotype to phenotypic features of polycystic ovary syndrome. J Clin Endocrinol Metab 2002;87:1669–1673.
61. Tucci S, Futterweit W, Concepcion ES, et al. Evidence for association of polycystic ovary syndrome in Caucasian women with a marker at the insulin receptor gene locus. J Clin Endocrinol Metab 2001;86:446–449.
62. Hogeveen KN, Cousin P, Pugeat M, et al. Human sex hormone-binding globulin variants associated with hyperandrogenism and ovarian dysfunction. J Clin Invest 2002;109:973–981.
63. Biyasheva A, Legro RS, Dunaif A, et al. Evidence for association between polycystic ovary syndrome (PCOS) and TCF7L2 and glucose intolerance in women with PCOS and TCF7L2. J Clin Endocrinol Metab 2009;94:2617–2625.
64. Waterworth DM, Bennett ST, Gharani N, et al. Linkage and association of insulin gene VNTR regulatory polymorphism with polycystic ovary syndrome. Lancet 1997;349:986–990.
65. Ewens KG, Stewart DR, Ankener W, et al. Family-based analysis of candidate genes for polycystic ovary syndrome. J Clin Endocrinol Metab 2010;95:2306–2315.
66. Wood JR, Nelson VL, Ho C, et al. The molecular phenotype of polycystic ovary syndrome (PCOS) theca cells and new candidate PCOS genes defined by microarray analysis. J Biol Chem 2003;278:26380–26390.
67. Sproul K, Jones MR, Mathur R, et al. Association study of four key folliculogenesis genes in polycystic ovary syndrome. BJOG 2010;117:756–760.
68. Barbieri RL, Ryan KJ. Hyperandrogenism, insulin resistance, and acanthosis nigricans syndrome: a common endocrinopathy with distinct pathophysiologic features. Am J Obstet Gynecol 1983;147:90–101.
69. Seibel MM. Toward understanding the pathophysiology and treatment of polycystic ovary disease. Semin Reprod Endocrinol 1984;2:297.
70. Dunaif A, Graf M, Mandeli J, et al. Characterization of groups of hyperandrogenic women with acanthosis nigricans, impaired glucose tolerance, and/or hyperinsulinemia. J Clin Endocrinol Metab 1987;65:499–507.
71. Dunaif A, Green G, Futterweit W, et al. Suppression of hyperandrogenism does not improve peripheral or hepatic insulin resistance in the polycystic ovary syndrome. J Clin Endocrinol Metab 1990;70:699–704.
72. Nagamani M, Van Dinh T, Kelver ME. Hyperinsulinemia in hyperthecosis of the ovaries. Am J Obstet Gynecol 1986;154:384–389.
73. Grasinger CC, Wild RA, Parker IJ. Vulvar acanthosis nigricans: a marker for insulin resistance in hirsute women. Fertil Steril 1993;59:583–586.
74. Dunaif A. Hyperandrogenic anovulation (PCOS): a unique disorder of insulin action associated with an increased risk of non-insulin-dependent diabetes mellitus. Am J Med 1995;98:33S–39S.
75. Kiddy DS, Hamilton-Fairley D, Bush A, et al. Improvement in endocrine and ovarian function during dietary treatment of obese women with polycystic ovary syndrome. Clin Endocrinol (Oxf) 1992;36:105–111.
76. Pasquali R, Antenucci D, Casimirri F, et al. Clinical and hormonal characteristics of obese amenorrheic hyperandrogenic women before and after weight loss. J Clin Endocrinol Metab 1989;68:173–179.
77. Escobar-Morreale HF, Botella-Carretero JI, Alvarez-Blasco F, et al. The polycystic ovary syndrome associated with morbid obesity may resolve after weight loss induced by bariatric surgery. J Clin Endocrinol Metab 2005;90:6364–6369.
78. Legro RS, Kunselman AR, Dunaif A. Prevalence and predictors of dyslipidemia in women with polycystic ovary syndrome. Am J Med 2001;111:607–613.
79. Valkenburg O, Steegers-Theunissen RP, Smedts HP, et al. A more atherogenic serum lipoprotein profile is present in women with polycystic ovary syndrome: a case-control study. J Clin Endocrinol Metab 2008;93:470–476.
80. Wild RA, Carmina E, Diamanti-Kandarakis E, et al. Assessment of cardiovascular risk and prevention of cardiovascular disease in women with the polycystic ovary syndrome: a consensus statement by the Androgen Excess and Polycystic Ovary Syndrome (AE-PCOS) Society. J Clin Endocrinol Metab2010;95:2038–2049.
81. Jafari K, Javaheri G, Ruiz G. Endometrial adenocarcinoma and the Stein-Leventhal syndrome. Obstet Gynecol 1978;51:97–100.
82. Chittenden BG, Fullerton G, Maheshwari A, et al. Polycystic ovary syndrome and the risk of gynaecological cancer: a systematic review. Reprod BioMed Online 2009;19:398–405.
83. Balen A. Polycystic ovary syndrome and cancer. Hum Reprod Update 2001;7:522–525.
84. Wild S, Pierpoint T, Jacobs H, et al. Long-term consequences of polycystic ovary syndrome: results of a 31 year follow-up study. Hum Fertil 2000;3:101–105.
85. Cowan LD, Gordis L, Tonascia JA, et al. Breast cancer incidence in women with a history of progesterone deficiency. Am J Epidemiol 1981;114:209–217.
86. Brinton LA, Moghissi KS, Westhoff CL, et al. Cancer risk among infertile women with androgen excess or menstrual disorders (including polycystic ovary syndrome). Fertil Steril 2010;94:1787–1792.
87. Schildkraut JM, Schwingl PJ, Bastos E, et al. Epithelial ovarian cancer risk among women with polycystic ovary syndrome. Obstet Gynecol 1996;88(Pt 1):554–559.
88. Thomson RL, Buckley JD, Lim SS, et al. Lifestyle management improves quality of life and depression in overweight and obese women with polycystic ovary syndrome. Fertil Steril 2009;94:1812–1916.
89. Kerchner A, Lester W, Stuart SP, et al. Risk of depression and other mental health disorders in women with polycystic ovary syndrome: a longitudinal study. Fertil Steril 2009;91:207–212.
90. Futterweit W. An endocrine approach obesity. In: Simopoulos AP, Vanltallie TB, Gullo SP, et al., eds. Obesity: new directions in assessment and management. New York: Charles Press, 1994: 96–121.
91. Givens JR, Andersen RN, Wiser WL, et al. The effectiveness of two oral contraceptives in suppressing plasma androstenedione, testosterone, LH, and FSH, and in stimulating plasma testosterone-binding capacity in hirsute women. Am J Obstet Gynecol 1976;124:333–339.
92. Raj SG, Raj MH, Talbert LM, et al. Normalization of testosterone levels using a low estrogen-containing oral contraceptive in women with polycystic ovary syndrome. Obstet Gynecol 1982;60:15–19.
93. Wiebe RH, Morris CV. Effect of an oral contraceptive on adrenal and ovarian androgenic steroids. Obstet Gynecol 1984;63:12–14.
94. Wild RA, Umstot ES, Andersen RN, et al. Adrenal function in hirsutism. II. Effect of an oral contraceptive. J Clin Endocrinol Metab 1982;54:676–681.
95. Marynick SP, Chakmakjian ZH, McCaffree DL, et al. Androgen excess in cystic acne. N Engl J Med 1983;308:981–986.
96. Schiavone FE, Rietschel RL, Sgoutas D, et al. Elevated free testosterone levels in women with acne. Arch Dermatol 1983;119:799–802.
97. Amin ES, El-Sayed MM, El-Gamel BA, et al. Comparative study of the effect of oral contraceptives containing 50 microgram of estrogen and those containing 20 microgram of estrogen on adrenal cortical function. Am J Obstet Gynecol 1980;137:831–833.
98. Goldzieher JW. Polycystic ovarian disease. Fertil Steril 1981;35:371–394.
99. Rittmaster RS. Clinical review 73: medical treatment of androgen-dependent hirsutism. J Clin Endocrinol Metab 1995;80:2559–2563.
100. Godsland IF, Walton C, Felton C, et al. Insulin resistance, secretion, and metabolism in users of oral contraceptives. J Clin Endocrinol Metab 1992;74:64–70.
101. Ettinger B, Golditch IM. Medroxyprogesterone acetate for the evaluation of hypertestosteronism in hirsute women. Fertil Steril 1977;28:1285–1288.
102. Jeppsson S, Gershagen S, Johansson ED, et al. Plasma levels of medroxyprogesterone acetate (MPA), sex-hormone binding globulin, gonadal steroids, gonadotrophins and prolactin in women during long-term use of depo-MPA (Depo-Provera) as a contraceptive agent. Acta Endocrinol (Copenh)1982;99:339–343.
103. Gordon GG, Southern AL, Calanog A, et al. The effect of medroxyprogesterone acetate on androgen metabolism in the polycystic ovary syndrome. J Clin Endocrinol Metab 1972,35:444–447.
104. Meldrum DR, Chang RJ, Lu J, et al. “Medical oophorectomy” using a long-acting GNRH agonist—a possible new approach to the treatment of endometriosis. J Clin Endocrinol Metab 1982;54:1081–1083.
105. Falsetti L, Pasinetti E. Treatment of moderate and severe hirsutism by gonadotropin-releasing hormone agonists in women with polycystic ovary syndrome and idiopathic hirsutism. Fertil Steril 1994;61:817–822.
106. Morcos RN, Abdul-Malak ME, Shikora E. Treatment of hirsutism with a gonadotropin-releasing hormone agonist and estrogen replacement therapy. Fertil Steril 1994;61:427–431.
107. Tiitinen A, Simberg N, Stenman UH, et al. Estrogen replacement does not potentiate gonadotropin-releasing hormone agonist-induced androgen suppression in treatment of hirsutism. J Clin Endocrinol Metab 1994;79:447–451.
108. Cunningham SK, Loughlin T, Culliton M, et al. Plasma sex hormone-binding globulin and androgen levels in the management of hirsute patients. Acta Endocrinol (Copenh) 1973;104:365–371.
109. Gal M, Orly J, Barr I, et al. Low dose ketoconazole attenuates serum androgen levels in patients with polycystic ovary syndrome and inhibits ovarian steroidogenesis in vitro. Fertil Steril 1994;61:823–832.
110. Menard RH, Guenthner TM, Kon H, et al. Studies on the destruction of adrenal and testicular cytochrome P-450 by spironolactone. Requirement for the 7alpha-thio group and evidence for the loss of the heme and apoproteins of cytochrome P-450. J Biol Chem1979;254:1726–1733.
111. Cumming DC, Yang JC, Rebar RW, et al. Treatment of hirsutism with spironolactone. JAMA 1982;247:1295–1298.
112. Rittmaster R. Evaluation and treatment of hirsutism. Infert Reprod Med Clin North Am 1991,2:511–545.
113. Barth JH, Cherry CA, Wojnarowska F, et al. Spironolactone is an effective and well tolerated systemic andiandrogen therapy for hirsute women. J Clin Endocrinol Metab 1989;68:966–970.
114. Pittaway DE, Maxson WS, Wentz AC. Spironolactone in combination drug therapy for unresponsive hirsutism. Fertil Steril 1985;43:878–882.
115. Lobo RA, Shoupe D, Serafini P, et al. The effects of two doses of spironolactone on serum androgens and anagen hair in hirsute women. Fertil Steril 1985;43:200–205.
116. Calaf-Alsina J, Rodriguez-Espinosa J, Cabero-Roura A, et al. Effects of a cyproterone-containing oral contraceptive on hormonal levels in polycystic ovarian disease. Obstet Gynecol 1987;69:255–258.
117. Helfer EL, Miller JL, Rose LI. Side-effects of spironolactone therapy in the hirsute woman. J Clin Endocrinol Metab 1988;66:208–211.
118. Miller JA, Jacobs HS. Treatment of hirsutism and acne with cyproterone acetate. Clin Endocrinol Metab 1986;15:373–389.
119. Mowszowicz I, Wright F, Vincens M, et al. Androgen metabolism in hirsute patients treated with cyproterone acetate. J Steroid Biochem 1984;20:757–761.
120. Girard J, Baumann JB, Buhler U, et al. Cyproteroneacetate and ACTH adrenal function. J Clin Endocrinol Metab 1978;47:581– 586.
121. Marcondes JA, Minnani SL, Luthold WW, et al. Treatment of hirsutism in women with flutamide. Fertil Steril 1992;57:543–547.
122. Ciotta L, Cianci A, Marletta E, et al. Treatment of hirsutism with flutamide and a low-dosage oral contraceptive in polycystic ovarian disease patients. Fertil Steril 1994;62:1129–1135.
123. Cusan L, Dupont A, Belanger A, et al. Treatment of hirsutism with the pure antiandrogen flutamide. J Am Acad Dermatol 1990;23(Pt 1):462–469.
124. Ibanez L, De Zegher F. Flutamide-metformin plus an oral contraceptive (OC) for young women with polycystic ovary syndrome: switch from third- to fourth-generation OC reduces body adiposity. Hum Reprod 2004;19:1725–1727.
125. Ibanez L, Valls C, Cabre S, et al. Flutamide-metformin plus ethinylestradiol-drospirenone for lipolysis and antiatherogenesis in young women with ovarian hyperandrogenism: the key role of early, low-dose flutamide. J Clin Endocrinol Metab 2004;89:4716–4720.
126. Osculati A, Castiglioni C. Fatal liver complications with flutamide. Lancet 2006;367:1140–1141.
127. Wong IL, Morris RS, Chang L, et al. A prospective randomized trial comparing finasteride to spironolactone in the treatment of hirsute women. J Clin Endocrinol Metab 1995;80:233–238.
128. Ciotta L, Cianci A, Calogero AE, et al. Clinical and endocrine effects of finasteride, a 5 alpha-reductase inhibitor, in women with idiopathic hirsutism. Fertil Steril 1995;64:299–306.
129. Judd HL, Rigg LA, Anderson DC, et al. The effects of ovarian wedge resection on circulating gonadotropin and ovarian steroid levels in patients with polycystic ovary syndrome. J Clin Endocrinol Metab 1976;43:347–355.
130. Katz M, Carr PJ, Cohen BM, et al. Hormonal effects of wedge resection of polycystic ovaries. Obstet Gynecol 1978;51:437–444.
131. Goldzieher JW, Green JA. The polycystic ovary. I. Clinical and histologic features. J Clin Endocrinol Metab 1962;22:325–338.
132. Adashi EY, Rock JA, Guzick D, et al. Fertility following bilateral ovarian wedge resection: a critical analysis of 90 consecutive cases of the polycystic ovary syndrome. Fertil Steril 1981;36:320–325.
133. Toaff R, Toaff ME, Peyser MR. Infertility following wedge resection of the ovaries. Am J Obstet Gynecol 1976;124:92–96.
134. Felemban A, Tan SL, Tulandi T. Laparoscopic treatment of polycystic ovaries with insulated needle cautery: a reappraisal. Fertil Steril 2000;73:266–269.
135. Armar NA, Lachelin GC. Laparoscopic ovarian diathermy: an effective treatment for anti-oestrogen resistant anovulatory infertility in women with the polycystic ovary syndrome. Br J Obstet Gynaecol 1993;100:161–164.
136. Pirwany I, Tulandi T. Laparoscopic treatment of polycystic ovaries: is it time to relinquish the procedure? Fertil Steril 2003;80:241–251.
137. Armar NA, McGarrigle HH, Honour J, et al. Laparoscopic ovarian diathermy in the management of anovulatory infertility in women with polycystic ovaries: endocrine changes and clinical outcome. Fertil Steril 1990;53:45–49.
138. Rossmanith WG, Keckstein J, Spatzier K, et al. The impact of ovarian laser surgery on the gonadotrophin secretion in women with polycystic ovarian disease. Clin Endocrinol (Oxf) 1991;34:223–230.
139. Amer SA, Banu Z, Li TC, et al. Long-term follow-up of patients with polycystic ovary syndrome after laparoscopic ovarian drilling: endocrine and ultrasonographic outcomes. Hum Reprod 2002;17:2851–2857.
140. Balen AH, Jacobs HS. A prospective study comparing unilateral and bilateral laparoscopic ovarian diathermy in women with the polycystic ovary syndrome. Fertil Steril 1994;62:921–925.
141. Schrode K, Huber F, Staszak J, et al. Randomized, double blind, vehicle controlled safety and efficacy evaluation of eflornithine 15% cream in the treatment of women with excessive facial hair. Presented at American Academy of Dermatology annual meeting, 2000.
142. Lynfield YL, Macwilliams P. Shaving and hair growth. J Invest Dermatol 1970;55:170–172.
Wagner RF Jr. Physical methods for the management of hirsutism. Cutis 1990;45:319–321.
144. Kim LH, Taylor AE, Barbieri RL. Insulin sensitizers and polycystic ovary syndrome: can a diabetes medication treat infertility? Fertil Steril 2000;73:1097–1098.
145. Mathur R, Alexander CJ, Yano J, et al. Use of metformin in polycystic ovary syndrome. Am J Obstet Gynecol 2008;199:596–609.
146. Creanga AA, Bradley HM, McCormick C, et al. Use of metformin in polycystic ovary syndrome: a meta-analysis. Obstet Gynecol 2008;111:959–968.
147. Legro RS, Barnhart HX, Schlaff WD, et al. Clomiphene, metformin, or both for infertility in the polycystic ovary syndrome. N Engl J Med 2007;356:551–566.
148. Hasegawa I, Murakawa H, Suzuki M, et al. Effect of troglitazone on endocrine and ovulatory performance in women with insulin resistance-related polycystic ovary syndrome. Fertil Steril 1999;71:323–327.
149. Stadtmauer LA, Toma SK, Riehl RM, et al. Metformin treatment of patients with polycystic ovary syndrome undergoing in vitro fertilization improves outcomes and is associated with modulation of the insulin-like growth factors. Fertil Steril 2001;75:505–509.
150. Jakubowicz DJ, Seppala M, Jakubowicz S, et al. Insulin reduction with metformin increases luteal phase serum glycodelin and insulin-like growth factor-binding protein 1 concentrations and enhances uterine vascularity and blood flow in the polycystic ovary syndrome. J Clin Endocrinol Metab2001;86:1126–1133.
151. Glueck CJ, Wang P, Goldenberg N, et al. Pregnancy outcomes among women with polycystic ovary syndrome treated with metformin. Hum Reprod 2002;17:2858–2864.
152. Glueck CJ, Phillips H, Cameron D, et al. Continuing metformin throughout pregnancy in women with polycystic ovary syndrome appears to safely reduce first-trimester spontaneous abortion: a pilot study. Fertil Steril 2001;75:46–52.
153. Tang T. The use of metformin for women with PCOS undergoing IVF treatment. Hum Reprod 2006;21:1416–1425.
154. Nieman LK, Biller BM, Findling JW, et al. The diagnosis of Cushing’s syndrome: an Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab 2008;93:1526–1540.
155. Biller BM, Grossman AB, Stewart PM, et al. Treatment of adrenocorticotropin-dependent Cushing’s syndrome: a consensus statement. J Clin Endocrinol Metab 2008;93:2454–2462.
156. Orth DN. Ectopic hormone production. In: Felig P, Baster JD, Broadus AE, et al., eds. Endocrinology and metabolism. New York: McGraw-Hill, 1987:1692–1735.
157. Schteingart DE, Tsao HS, Taylor CI, et al. Sustained remission of Cushing’s disease with mitotane and pituitary irradiation. Ann Intern Med 1980;92:613–619.
158. Orth DN, Liddle GW. Results of treatment in 108 patients with Cushing’s syndrome. N Engl J Med 1971;285:243–247.
159. Valimaki M, Pelkonen R, Porkka L, et al. Long-term results of adrenal surgery in patients with Cushing’s syndrome due to adrenocortical adenoma. Clin Endocrinol (Oxf) 1984;20:229– 236.
160. Hammer GD, Tyrrell JB, Lamborn KR, et al. Transsphenoidal microsurgery for Cushing’s disease: initial outcome and long-term results. J Clin Endocrinol Metab 2004;89:6348–6357.
161. Boggan JE, Tyrrell JB, Wilson CB. Transsphenoidal microsurgical management of Cushing’s disease. Report of 100 cases. J Neurosurg 1983;59:195–200.
Swearingen B, Biller BM, Barker FG 2nd, et al. Long-term mortality after transsphenoidal surgery for Cushing disease. Ann Intern Med 1999;130:821–824.
163. Hofmann BM, Fahlbusch R. Treatment of Cushing’s disease: a retrospective clinical study of the latest 100 cases. Front Horm Res 2006;34:158–184.
164. Sonino N, Zielezny M, Fava GA, et al. Risk factors and long-term outcome in pituitary-dependent Cushing’s disease. J Clin Endocrinol Metab 1996;81:2647–2652.
165. Bigos ST, Somma M, Rasio E, et al. Cushing’s disease: management by transsphenoidal pituitary microsurgery. J Clin Endocrinol Metab 1980;50:348–354.
166. De Tommasi C, Vance ML, Okonkwo DO, et al. Surgical management of adrenocorticotropic hormone-secreting macroadenomas: outcome and challenges in patients with Cushing’s disease or Nelson’s syndrome. J Neurosurg 2005;103:825–830.
Blevins LS Jr, Christy JH, Khajavi M, et al. Outcomes of therapy for Cushing’s disease due to adrenocorticotropin-secreting pituitary macroadenomas. J Clin Endocrinol Metab 1998;83:63–67.
168. Aron DC, Findling JW, Tyrrell JB. Cushing’s disease. Endocrinol Metab Clin North Am 1987;16:705–730.
169. Devin JK, Allen GS, Cmelak AJ, et al. The efficacy of linear accelerator radiosurgery in the management of patients with Cushing’s disease. Stereo Funct Neurosurg 2004;82:254–262.
170. Estrada J, Boronat M, Mielgo M, et al. The long-term outcome of pituitary irradiation after unsuccessful transsphenoidal surgery in Cushing’s disease. N Engl J Med 1997;336:172–177.
171. Jennings AS, Liddle GW, Orth DN. Results of treating childhood Cushing’s disease with pituitary irradiation. N Engl J Med 1977;297:957–962.
172. Loli P, Berselli ME, Tagliaferri M. Use of ketoconazole in the treatment of Cushing’s syndrome. J Clin Endocrinol Metab 1986;63:1365–1371.
173. Nelson DH, Meakin JW, Dealy JB, et al. ACTH-producing tumor of the pituitary gland. N Engl J Med 1958;85:731–734.
174. Azziz R, Zacur HA. 21-Hydroxylase deficiency in female hyperandrogenism: screening and diagnosis. J Clin Endocrinol Metab 1989;69:577–584.
175. New MI, Lorenzen F, Lerner AJ, et al. Genotyping steroid 21-hydroxylase deficiency: hormonal reference data. J Clin Endocrinol Metab 1983;57:320–326.
176. Speiser PW, Dupont B, Rubinstein P, et al. High frequency of nonclassical steroid 21-hydroxylase deficiency. Am J Hum Genet 1985;37:650–667.
177. New MI. Steroid 21-hydroxylase deficiency (congenital adrenal hyperplasia). Am J Med 1995;98:2S–8S.
178. Speiser PW, New MI, White PC. Molecular genetic analysis of nonclassic steroid 21-hydroxylase deficiency associated with HLA-B14,DR1. N Engl J Med 1988;319:19–23.
179. Merke DP, Bornstein SR. Congenital adrenal hyperplasia. Lancet 2005;365:2125–2136.
180. Speiser PW, White PC. Congenital adrenal hyperplasia. N Engl J Med 2003;349:776–788.
181. Hirvikoski T, Nordenstrom A, Lindholm T, et al. Cognitive functions in children at risk for congenital adrenal hyperplasia treated prenatally with dexamethasone. J Clin Endocrinol Metab 2007;92:542–548.
182. Speiser PW, Azziz R, Baskin LS, et al. A summary of the Endocrine Society clinical practice guidelines on congenital adrenal hyperplasia due to steroid 21-hydroxylase deficiency. Int J Pediat Endocrinol 2010;2010:1–6.
183. White PC. Steroid 11 beta-hydroxylase deficiency and related disorders. Endocrinol Metab Clin North Am 2001;30:61–79.
184. Nimkarn S, New MI. Steroid 11[beta]- hydroxylase deficiency congenital adrenal hyperplasia. Trends Endocrinol Metab 2008;19:96–99.
185. White PC, Curnow KM, Pascoe L. Disorders of steroid 11 beta-hydroxylase isozymes. Endocr Rev 1994;15:421–438.
186. Rosler A, Leiberman E, Cohen T. High frequency of congenital adrenal hyperplasia (classic 11 beta-hydroxylase deficiency) among Jews from Morocco. Am J Med Genet 1992;42:827–834.
187. Mornet E, Dupont J, Vitek A, et al. Characterization of two genes encoding human steroid 11 beta-hydroxylase (P-450(11) beta). J Biol Chem 1989;264:20961–20967.
188. Taymans SE, Pack S, Pak E, et al. Human CYP11B2 (aldosterone synthase) maps to chromosome 8q24.3. J Clin Endocrinol Metab 1998;83:1033–1036.
189. Parajes S, Loidi L, Reisch N, et al. Functional consequences of seven novel mutations in the CYP11B1 gene: four mutations associated with nonclassic and three mutations causing classic 11[beta]-hydroxylase deficiency. J Clin Endocrinol Metab 2010;95:779–788.
Azziz R, Boots LR, Parker CR Jr, et al. 11 beta-hydroxylase deficiency in hyperandrogenism. Fertil Steril 1991;55:733–741.
191. Pang SY, Lerner AJ, Stoner E, et al. Late-onset adrenal steroid 3 beta-hydroxysteroid dehydrogenase deficiency. I. A cause of hirsutism in pubertal and postpubertal women. J Clin Endocrinol Metab 1985;60:428–439.
Azziz R, Bradley EL Jr, Potter HD, et al. 3 beta-hydroxysteroid dehydrogenase deficiency in hyperandrogenism. Am J Obstet Gynecol 1993;168(Pt 1):889–895.
193. Carbunaru G, Prasad P, Scoccia B, et al. The hormonal phenotype of nonclassic 3[beta]-hydroxysteroid dehydrogenase (HSD3B) deficiency in hyperandrogenic females is associated with insulin-resistant polycystic ovary syndrome and is not a variant of inherited HSD3B2 deficiency. J Clin Endocrinol Metab 2004;89:783–794.
194. Cordera F, Grant C, van Heerden J, et al. Androgen-secreting adrenal tumors. Surgery 2003;134:874–880.
195. Derksen J, Nagesser SK, Meinders AE, et al. Identification of virilizing adrenal tumors in hirsute women. N Engl J Med 1994;331:968–973.
196. Ettinger B, Von Werder K, Thenaers GC, et al. Plasma testosterone stimulation-suppression dynamics in hirsute women. Am J Med 1971;51:170–175.
197. Surrey ES, de Ziegler D, Gambone JC, et al. Preoperative localization of androgen-secreting tumors: clinical, endocrinologic, and radiologic evaluation of ten patients. Am J Obstet Gynecol 1988;158(Pt 1):1313–1322.
198. Korobkin M. Overview of adrenal imaging/adrenal CT. Urol Radiol 1989;11:221–226.
199. Taylor L, Ayers JW, Gross MD, et al. Diagnostic considerations in virilization: iodomethyl-norcholesterol scanning in the localization of androgen secreting tumors. Fertil Steril 1986;46:1005–1010.
200. Moltz L, Pickartz H, Sorensen R, et al. Ovarian and adrenal vein steroids in seven patients with androgen-secreting ovarian neoplasms: selective catheterization findings. Fertil Steril 1984;42:585–593.
Wentz AC, White RI Jr, Migeon CJ, et al. Differential ovarian and adrenal vein catheterization. Am J Obstet Gynecol 1976;125:1000–1007.
202. Young RH, Scully RE. Sex-cord stromal steroid cell and other ovarian tumors with endocrine, paraendocrine, and paraneoplastic manifestations. In: Kurman RJ, ed. Blaustein’s pathology of the female genital tract, 4th ed. New York: Springer-Verlag, 1994:783–847.
203. Schumer ST, Cannistra SA. granulosa cell tumor of the ovary. J Clin Oncol 2003;21:1180–1189.
204. Nocito AL, Sarancone S, Bacchi C, et al. Ovarian thecoma: clinicopathological analysis of 50 cases. Ann Diag Pathol 2008;12:12–16.
205. Colombo N, Parma G, Zanagnolo V, et al. Management of ovarian stromal cell tumors. J Clin Oncol 2007;25:2944–2951.
206. Young RH, Scully RE. Ovarian Sertoli cell tumors: a report of 10 cases. Int J Gynecol Pathol 1984;2:349–363.
207. Young RH, Welch WR, Dickersin GR, et al. Ovarian sex cord tumor with annular tubules: review of 74 cases including 27 with Peutz-Jeghers syndrome and four with adenoma malignum of the cervix. Cancer 1982;50:1384–1402.
208. Aiman J. Virilizing ovarian tumors. Clin Obstet Gynecol 1991;34:835–847.
209. Scully RE. Gonadoblastoma. A review of 74 cases. Cancer 1970;25:1340–1356.
210. Ireland K, Woodruff JD. Masculinizing ovarian tumors. Obstet Gynecol Surv 1976;31:83–111.
211. Boss JH, Scully RE, Wegner KH, et al. Structural variations in the adult ovary. Clinical significance. Obstet Gynecol 1965;25:747–764.
212. Jongen VH, Hollema H, van der Zee AG, et al. Ovarian stromal hyperplasia and ovarian vein steroid levels in relation to endometrioid endometrial cancer. BJOG 2003;110:690–695.
213. Krug E, Berga SL. Postmenopausal hyperthecosis: functional dysregulation of androgenesis in climacteric ovary. Obstet Gynecol 2002;99(Pt 2):893–897.
214. Judd HL, Scully RE, Herbst AL, et al. Familial hyperthecosis: comparison of endocrinologic and histologic findings with polycystic ovarian disease. Am J Obstet Gynecol 1973;117:976–982.
215. Brown DL, Henrichsen TL, Clayton AC, et al. Ovarian stromal hyperthecosis: sonographic features and histologic associations. J Ultrasound Med 2009;28:587–593.
216. Karam K, Hajj S. Hyperthecosis syndrome. Clinical, endocrinologic and histologic findings. Acta Obstet Gynecol Scand 1979;58:73–79.
217. Braithwaite SS, Erkman-Balis B, Avila TD. Postmenopausal virilization due to ovarian stromal hyperthecosis. J Clin Endocrinol Metab 1978;46:295–300.
218. Steingold KA, Judd HL, Nieberg RK, et al. Treatment of severe androgen excess due to ovarian hyperthecosis with a long-acting gonadotropin-releasing hormone agonist. Am J Obstet Gynecol 1986;154:1241–1248.
219. Garcia-Bunuel R, Berek JS, Woodruff JD. Luteomas of pregnancy. Obstet Gynecol 1975;45:407–414.
220. Cronje HS. Luteoma of pregnancy. S Afr Med J 1984;66:59–60.
221. Mazza V, Di Monte I, Ceccarelli PL, et al. Prenatal diagnosis of female pseudohermaphroditism associated with bilateral luteoma of pregnancy: case report. Hum Reprod 2002;17:821–824.
222. Ng L, Libertino JM. Adrenocortical carcinoma: diagnosis, evaluation and treatment. J Urol 2003;169:5–11.
223. Latronico AC, Chrousos GP. Adrenocortical tumors. J Clin Endocrinol Metab 1997;82:1317–1324.
224. Gaudio AD, Gaudio GAD. Virilizing adrenocortical tumors in adult women. Report of 10 patients, 2 of whom each had a tumor secreting only testosterone. Cancer 1993;72:1997–2003.
225. Riddle O, Bates RW, Dykshorn S. The preparation, identification and assay of prolactin. A hormone of the anterior pituitary. Am J Physiol 1933;105:191–196.
226. Frantz AG, Kleinberg DL. Prolactin: evidence that it is separate from growth hormone in human blood. Science 1970;170:745–747.
227. Lewis UJ, Singh RN, Sinha YN, et al. Electrophoretic evidence for human prolactin. J Clin Endocrinol Metab 1971;33:153–156.
228. Hwang P, Guyda H, Friesen H. Purification of human prolactin. J Biol Chem 1972;247:1955–1958.
229. Freeman ME, Kanyicska B, Lerant A, et al. Prolactin: structure, function, and regulation of secretion. Physiol Rev 2000;80:1523–1631.
230. Suh HK, Frantz AG. Size heterogeneity of human prolactin in plasma and pituitary extracts. J Clin Endocrinol Metab 1974;39:928–935.
231. Guyda JH. Heterogeneity of human growth hormone and prolactin secreted in vitro: immunoassay and radioreceptor assay correlations. J Clin Endocrinol Metab 1975;41:953–967.
232. Farkouh NH, Packer MG, Frantz AG. Large molecular size prolactin with reduced receptor activity in human serum: high proportion in basal state and reduction after thyrotropin-releasing hormone. J Clin Endocrinol Metab 1979;48:1026–1032.
233. Benveniste R, Helman JD, Orth DN, et al. Circulating big human prolactin: conversion to small human prolactin by reduction of disulfide bonds. J Clin Endocrinol Metab 1979;48:883–886.
234. Jackson RD, Wortsman J, Malarkey WB. Characterization of a large molecular weight prolactin in women with idiopathic hyperprolactinemia and normal menses. J Clin Endocrinol Metab 1985;61:258–264.
235. Fraser IS, Lun ZG, Zhou JP, et al. Detailed assessment of big big prolactin in women with hyperprolactinemia and normal ovarian function. J Clin Endocrinol Metab 1989;69:585–592.
236. Larrea F, Escorza A, Valero A, et al. Heterogeneity of serum prolactin throughout the menstrual cycle and pregnancy in hyperprolactinemic women with normal ovarian function. J Clin Endocrinol Metab 1989;68:982–987.
237. Lewis UJ, Singh RN, Sinha YN, et al. Glycosylated human prolactin. Endocrinology 1985;116:359–363.
238. Markoff E, Lee DW. Glycosylated prolactin is a major circulating variant in human serum. J Clin Endocrinol Metab 1985:1102–1106.
239. Markoff E, Lee DW, Hollingsworth DR. Glycosated and nonglycosated prolactin in serum during pregnancy. J Clin Endocrinol Metab 1988;67:519–523.
240. Pellegrini I, Gunz G, Ronin C, et al. Polymorphism of prolactin secreted by human prolactinoma cells: immunological, receptor binding, and biological properties of the glycosylated and nonglycosylated forms. Endocrinology 1988;122:2667–2674.
241. Bole-Feysot C, Goffin V, Edery M, et al. Prolactin (PRL) and its receptor: actions, signal transduction pathways and phenotypes observed in PRL receptor knockout mice. Endocr Rev 1998;19:225–268.
242. Goldsmith PC, Cronin MJ, Weiner RI. Dopamine receptor sites in the anterior pituitary. J Histochem Cytochem 1979;27:1205–1207.
243. Quigley ME, Judd SJ, Gilliland GB, et al. Effects of a dopamine antagonist on the release of gonadotropin and prolactin in normal women and women with hyperprolactinemic anovulation. J Clin Endocrinol Metab 1979;48:718–720.
244. Quigley ME, Judd SJ, Gilliland GB, et al. Functional studies of dopamine control of prolactin secretion in normal women and women with hyperprolactinemic pituitary microadenoma. J Clin Endocrinol Metab 1980;50:994–998.
245. De Leo V, Petraglia F, Bruno MG, et al. Different dopaminergic control of plasma luteinizing hormone, follicle-stimulating hormone and prolactin in ovulatory and postmenopausal women: effect of ovariectomy. Gynecol Obstet Invest 1989;27:94–98.
246. Lachelin GC, Leblanc H, Yen SS. The inhibitory effect of dopamine agonists on LH release in women. J Clin Endocrinol Metab 1977;44:728–732.
247. Hill MK, Macleod RM, Orcutt P. Dibutyryl cyclic AMP, adenosine and guanosine blockade of the dopamine, ergocryptine and apomorphine inhibition of prolactin release in vitro. Endocrinology 1976 Dec;99(6):1612-7.
248. Lemberger L, Crabtree RE. Pharmacologic effects in man of a potent, long-acting dopamine receptor agonist. Science 1979;205:1151–1153.
249. Braund W, Roeger DC, Judd SJ. Synchronous secretion of lutei-nizing hormone and prolactin in the human luteal phase: neuroendocrine mechanisms. J Clin Endocrinol Metab 1984;58:293–297.
250. Grossman A, Delitala G, Yeo T, et al. GABA and muscimol inhibit the release of prolactin from dispersed rat anterior pituitary cells. Neuroendocrinology 1981;32:145–149.
251. Gudelsky GA, Apud JA, Masotto C, et al. Ethanolamine-O-sulfate enhances gamma-aminobutyric acid secretion into hypophysial portal blood and lowers serum prolactin concentrations. Neuroendocrinology 1983;37:397–399.
252. Melis GB, Paoletti AM, Mais V, et al. The effects of the gabaergic drug, sodium valproate, on prolactin secretion in normal and hyperprolactinemic subjects. J Clin Endocrinol Metab 1982;54:485–489.
253. Melis GB, Fruzzetti F, Paoletti AM, et al. Pharmacological activation of gamma-aminobutyric acid-system blunts prolactin response to mechanical breast stimulation in puerperal women. J Clin Endocrinol Metab 1984;58:201–205.
254. Bazan JF. Structural design and molecular evolution of a cytokine receptor superfamily. Proc Natl Acad Sci U S A 1990;87:6934–6938.
255. Hu ZZ, Zhuang L, Meng J, et al. Transcriptional regulation of the generic promoter III of the rat prolactin receptor gene by C/EBPbeta and Sp1. J Biol Chem 1998;273:26225–26235.
256. Sassin JF, Frantz AG, Weitzman ED, et al. Human prolactin: 24-hour pattern with increased release during sleep. Science 1972;177:1205–1207.
257. Sassin JF, Frantz AG, Kapen S, et al. The nocturnal rise of human prolactin is dependent on sleep. J Clin Endocrinol Metab 1973;37:436–440.
258. Carandente F, Angeli A, Candiani GB, et al. Rhythms in the ovulatory cycle. 1st: Prolactin. Chronobiological Research Group on Synthetic Peptides in Medicine. Chronobiologia 1989;16:35–44.
259. Pansini F, Bianchi A, Zito V, et al. Blood prolactin levels: influence of age, menstrual cycle and oral contraceptives. Contraception 1983;28:201–207.
260. Pansini F, Bergamini CM, Cavallini AR, et al. Prolactinemia during the menstrual cycle. A possible role for prolactin in the regulation of ovarian function. Gynecol Obstet Invest 1987;23:172–176.
261. Bohnet HG, Dahlen HG, Wuttke W, et al. Hyperprolactinemic anovulatory syndrome. J Clin Endocrinol Metab 1976;42:132–143.
262. Franks S, Murray MA, Jequier AM, et al. Incidence and significance of hyperprolactinaemia in women with amenorrhea. Clin Endocrinol (Oxf) 1975;4:597–607.
263. Jacobs HS, Hull MG, Murray MA, et al. Therapy-orientated diagnosis of secondary amenorrhoea. Horm Res 1975;6:268–287.
264. Boyar RM, Kapen S, Finkelstein JW, et al. Hypothalamic-pituitary function in diverse hyperprolactinemic states. J Clin Invest 1974;53:1588–1598.
265. Moult PJ, Rees LH, Besser GM. Pulsatile gonadotrophin secretion in hyperprolactinaemic amenorrhoea an the response to bromocriptine therapy. Clin Endocrinol (Oxf) 1982;16:153–162.
266. Buckman MT, Peake GT, Srivastava L. Patterns of spontaneous LH release in normo- and hyperprolactinaemic women. Acta Endocrinol (Copenh) 1981;97:305–310.
267. Aono T, Miyake A, Yasuda TS, et al. Restoration of oestrogen positive feedback effect on LH release by bromocriptine in hyperprolactinaemic patients with galactorrhoea-amenorrhoea. Acta Endocrinol (Copenh) 1979;91:591–600.
268. Travaglini P, Ambrosi B, Beck-Peccoz P, et al. Hypothalamic-pituitary-ovarian function in hyperprolactinemic women. J Endocrinol Invest 1978;1:39–45.
269. Glass MR, Shaw RW, Butt WR, et al. An abnormality of oestrogen feedback in amenorrhoea-galactorrhoea. BMJ 1975;3:274–275.
270. Koike J, Aono T, Tsutsumi H, et al. Restoration of oestrogen-positive feedback effect on LH release in women with prolactinoma by transsphenoidal surgery. Acta Endocrinol (Copenh) 1982;100:492–498.
271. Rakoff J, VandenBerg G, Siler TM, et al. An integrated direct functional test of the adenohypophysis. Am J Obstet Gynecol 1974;119:358–368.
272. Zarate A, Jacobs LS, Canales ES, et al. Functional evaluation of pituitary reserve in patients with the amenorrhea-galactorrhea syndrome utilizing luteinizing hormone-releasing hormone (LH-RH), L-dopa and chlorpromazine. J Clin Endocrinol Metab 1973;37:855–859.
273. McNatty KP. Relationship between plasma prolactin and the endocrine microenvironment of the developing human antral follicle. Fertil Steril 1979;32:433–438.
274. Dorrington J, Gore-Langton RE. Prolactin inhibits oestrogen synthesis in the ovary. Nature 1981;290:600–602.
275. Cutie E, Andino NA. Prolactin inhibits the steroidogenesis in midfollicular phase human granulosa cells cultured in a chemically defined medium. Fertil Steril 1988;49:632–637.
276. Adashi EY, Resnick CE. Prolactin as an inhibitor of granulosa cell luteinization: implications for hyperprolactinemia-associated luteal phase dysfunction. Fertil Steril 1987;48:131–139.
Soto EA, Tureck RW, Strauss JF 3rd. Effects of prolactin on progestin secretion by human granulosa cells in culture. Biol Reprod 1985;32:541–545.
278. Demura R, Ono M, Demura H, et al. Prolactin directly inhibits basal as well as gonadotropin-stimulated secretion of progesterone and 17β-estradol in the human ovary. J Clin Endocrinol Metab 1985;54:1246–1250.
279. Kleinberg DL, Noel GL, Frantz AG. Galactorrhea: a study of 235 cases, including 48 with pituitary tumors. N Engl J Med 1977;296:589–600.
280. Tolis G, Somma M, Van Campenhout J, et al. Prolactin secretion in sixty-five patients with galactorrhea. Am J Obstet Gynecol 1974;118:91–101.
Boyd AE 3rd, Reichlin S, Turksoy RN. Galactorrhea-amenorrhea syndrome: diagnosis and therapy. Ann Intern Med 1977;87:165–175.
282. Schlechte J, Sherman B, Halmi N, et al. Prolactin-secreting pituitary tumors in amenorrheic women: a comprehensive study. Endocr Rev 1980;1:295–308.
283. Minakami H, Abe N, Oka N, et al. Prolactin release in polycystic ovarian syndrome. Endocrinol Jpn 1988;35:303–310.
284. Murdoch AP, Dunlop W, Kendall-Taylor P. Studies of prolactin secretion in polycystic ovary syndrome. Clin Endocrinol (Oxf) 1986;24:165–175.
285. Lythgoe K, Dotson R, Peterson CM. Multiple endocrine neoplasia presenting as primary amenorrhea: a case report. Obstet Gynecol 1995;86(Pt 2):683–686.
286. Burgess JR, Shepherd JJ, Parameswaran B, et al. Spectrum of pituitary disease in multiple endocrine neoplasia type 1 (MEN-1): Clinical, biochemical, and radiologic features of pituitary disease in a large MEN-1 kindred. J Clin Endocrinol Metab 1996;81:2642–2646.
Bohler HC Jr, Jones EE, Brines ML. Marginally elevated prolactin levels require magnetic resonance imaging and evaluation for acromegaly. Fertil Steril 1994;61:1168–1170.
288. Gonsky R, Herman V, Melmed S, et al. Transforming DNA sequences present in human prolactin-secreting pituitary tumors. Mol Endocrinol 1991;5:1687–1695.
289. Sisam DA, Sheehan JP, Sheeler LR. The natural history of untreated microprolactinomas. Fertil Steril 1987;48:67–71.
290. Schlechte J, Dolan K, Sherman B, et al. The natural history of untreated hyperprolactinemia: a prospective analysis. J Clin Endocrinol Metab 1989;68:412–418.
291. Weiss MH, Wycoff RR, Yadley R, et al. Bromocriptine treatment of prolactin-secreting tumors: surgical implications. Neurosurgery 1983;12:640–642.
292. Ezzat S, Asa SL, Couldwell WT, et al. The prevalence of pituitary adenomas. Cancer 2004;101:613–619.
293. Klibanski A, Biller BM, Rosenthal DI, et al. Effects of prolactin and estrogen deficiency in amenorrheic bone loss. J Clin Endocrinol Metab 1988;67:124–130.
294. Turner TH, Cookson JC, Wass JA, et al. Psychotic reactions during treatment of pituitary tumours with dopamine agonists. Br Med J (Clin Res Ed) 1984;289:1101–1103.
295. Katz E, Weiss BE, Hassell A, et al. Increased circulating levels of bromocriptine after vaginal compared with oral administration. Fertil Steril 1991;55:882–884.
296. Schade R, Andersohn F, Suissa S, et al. Dopamine agonists and the risk of cardiac-valve regurgitation. N Engl J Med 2007;356:29–38.
297. Zanettini R, Antonini A, Gatto G, et al. Valvular heart disease and the use of dopamine agonists for Parkinson’s disease. N Engl J Med 2007;356:39–46.
298. Roth BL. Drugs and valvular heart disease. N Engl J Med 2007;356:6–9.
299. Colao A, Galderisi M, Di Sarno A, et al. Increased prevalence of tricuspid regurgitation in patients with prolactinomas chronically treated with cabergoline. J Clin Endocrinol Metab 2008;93:3777–3784.
300. Bogazzi F, Manetti L, Raffaelli V, et al. Cabergoline therapy and the risk of cardiac valve regurgitation in patients with hyperprolactinemia: a meta-analysis from clinical studies. J Endocrinol Invest 2008;31:1119–1123.
301. Krupp P, Monka C. Bromocriptine in pregnancy: safety aspects. Klin Wochenschr 1987;65:823–827.
302. Jeffcoate WJ, Pound N, Sturrock ND, et al. Long-term follow-up of patients with hyperprolactinaemia. Clin Endocrinol (Oxf) 1996;45:299–303.
303. Passos VQ, Souza JJ, Musolino NR, et al. Long-term follow-up of prolactinomas: normoprolactinemia after bromocriptine withdrawal. J Clin Endocrinol Metab 2002;87:3578–3582.
304. Colao A, Di Sarno A, Cappabianca P, et al. Withdrawal of long-term cabergoline therapy for tumoral and nontumoral hyperprolactinemia. N Engl J Med 2003;349:2023–2033.
305. Biswas M, Smith J, Jadon D, et al. Long-term remission following withdrawal of dopamine agonist therapy in subjects with microprolactinomas. Clin Endocrinol 2005;63:26–31.
306. Dekkers OM, Lagro J, Burman P, et al. Recurrence of hyperprolactinemia after withdrawal of dopamine agonists: systematic review and meta-analysis. J Clin Endocrinol Metab 2010;95:43–51.
307. Ono M, Miki N, Amano K, et al. Individualized high-dose cabergoline therapy for hyperprolactinemic infertility in women with micro- and macroprolactinomas. J Clin Endocrinol Metab 2010;95:2672–2679.
308. Mori H, Mori S, Saitoh Y, et al. Effects of bromocriptine on prolactin-secreting pituitary adenomas. Mechanism of reduction in tumor size evaluated by light and electron microscopic, immunohistochemical, and morphometric analysis. Cancer 1985;56:230–238.
309. Abram M, Brue T, Morange I, et al. [Pituitary tumor syndrome and hyperprolactinemia in peripheral hypothyroidism]. Ann Endocrinol (Paris) 1992;53:215–223.
310. Chirito E, Bonda A, Friesen HG. Prolactin in renal failure. Clin Res 1972;20:423.
311. Nagel TC, Freinkel N, Bell RH, et al. Gynecomastia, prolactin, and other peptide hormones in patients undergoing chronic hemodialysis. J Clin Endocrinol Metab 1973;36:428–432.
312. Olgaard K, Hagen C, McNeilly AS. Pituitary hormones in women with chronic renal failure: the effect of chronic intermittent haemo- and peritoneal dialysis. Acta Endocrinol (Copenh) 1975;80:237–246.
313. Thorner MO, Edwards CRW, Hanker JP. Prolactin and gonadotropin interaction in the male. In: Troen P, Nankin H, eds. The testis in normal and infertile men. New York: Raven Press, 1977:351–366.
314. Lloyd RV. Estrogen-induced hyperplasia and neoplasia in the rat anterior pituitary gland. An immunohistochemical study. Am J Pathol 1983;113:198–206.
315. Scheithauer BW, Sano T, Kovacs KT, et al. The pituitary gland in pregnancy: a clinicopathologic and immunohistochemical study of 69 cases. Mayo Clin Proc 1990;65:461–474.
316. Weil C. The safety of bromocriptine in hyperprolactinaemic female infertility: a literature review. Curr Med Res Opin 1986;10:172–195.
317. Shy KK, McTiernan AM, Daling JR, et al. Oral contraceptive use and the occurrence of pituitary prolactinoma. JAMA 1983;249:2204–2207.
318. Corenblum B, Taylor PJ. Idiopathic hyperprolactinemia may include a distinct entity with a natural history different from that of prolactin adenomas. Fertil Steril 1988;49:544–546.
319. Corenblum B, Donovan L. The safety of physiological estrogen plus progestin replacement therapy and with oral contraceptive therapy in women with pathological hyperprolactinemia. Fertil Steril 1993;59:671–673.
320. Scheithauer BW, Kovacs KT, Randall RV, et al. Effects of estrogen on the human pituitary: a clinicopathologic study. Mayo Clin Proc 1989;64:1077–1084.
321. Raymond JP, Goldstein E, Konopka P, et al. Follow-up of children born of bromocriptine-treated mothers. Horm Res 1985;22:239–246.
322. Ruiz-Velasco V, Tolis G. Pregnancy in hyperprolactinemic women. Fertil Steril 1984;41:793–805.
323. Turkalj I, Braun P, Krupp P. Surveillance of bromocriptine in pregnancy. JAMA 1982;247:1589–1591.
324. Katz M, Kroll D, Pak I, et al. Puerperal hypertension, stroke, and seizures after suppression of lactation with bromocriptine. Obstet Gynecol 1985;66:822–824.
325. Gittelman DK. Bromocriptine associated with postpartum hypertension, seizures, and pituitary hemorrhage. Gen Hosp Psychiatry 1991;13:278–280.
326. Iffy L, Lindenthal J, McArdle JJ, et al. Severe cerebral accidents postpartum in patients taking bromocriptine for milk suppression. Isr J Med Sci 1996;32:309–312.
327. Iffy L, McArdle JJ, Ganesh V. Intracerebral hemorrhage in normotensive mothers using bromocriptine postpartum. Zentralbl Gynakol 1996;118:392–395.
328. Kirsch C, Iffy L, Zito GE, et al. The role of hypertension in bromocriptine-related puerperal intracranial hemorrhage. Neuroradiology 2001;43:302–304.
329. Tunbridge WM, Evered DC, Hall R, et al. The spectrum of thyroid disease in a community: the Whickham survey. Clin Endocrinol (Oxf) 1977;7:481–493.
330. Whartona T. Adenographoa: sive glandularum totius corporis descripto. 1659.
331. Portmann L, Hamada N, Heinrich G, et al. Anti-thyroid peroxidase antibody in patients with autoimmune thyroid disease: possible identity with anti-microsomal antibody. J Clin Endocrinol Metab 1985;61:1001–1003.
332. Czarnocka B, Ruf J, Ferrand M, et al. Purification of the human thyroid peroxidase and its identification as the microsomal antigen involved in autoimmune thyroid diseases. FEBS Lett 1985;190:147–152.
333. World Heath Organization. Assessment of iodine deficiency disorders and monitoring their elimination. A guide for program managers. Geneva: WHO, 2007:1–108.
334. Laurberg P, Cerqueira C, Ovesen L, et al. Iodine intake as a determinant of thyroid disorders in populations. Best Pract Res Clin Endocrinol Metab 2010;24:13–27.
335. Bahn AK, Mills JL, Snyder PJ, et al. Hypothyroidism in workers exposed to polybrominated biphenyls. N Engl J Med 1980;302:31–33.
336. Tomer Y, Huber A. The etiology of autoimmune thyroid disease: a story of genes and environment. J Autoimmun 2009;32:231–239.
337. Wang C, Crapo LM. The epidemiology of thyroid disease and implications for screening. Endocrinol Metab Clin North Am 1997;26:189–218.
338. McCombe PA, Greer JM, Mackay IR. Sexual dimorphism in autoimmune disease. Curr Mol Med 2009;9:1058–1079.
339. Brix TH, Knudsen GP, Kristiansen M, et al. High frequency of skewed X-chromosome inactivation in females with autoimmune thyroid disease: a possible explanation for the female predisposition to thyroid autoimmunity. J Clin Endocrinol Metab 2005;90:5949–5953.
340. Stockigt JR. Free thyroid hormone measurement. A critical appraisal. Endocrinol Metab Clin North Am 2001;30:265–289.
341. Benvenga S, Cahnmann HJ, Robbins J. Characterization of thyroid hormone binding to apolipoprotein-E: localization of the binding site in the exon 3-coded domain. Endocrinology 1993;133:1300–1305.
342. Dufour DR. Laboratory tests of thyroid function: uses and limitations. Endocrinol Metab Clin North Am 2007;36:579–594.
343. Caldwell G, Kellett HA, Gow SM, et al. A new strategy for thyroid function testing. Lancet 1985;1:1117–1119.
344. Surks MI, Ortiz E, Daniels GH, et al. Subclinical thyroid disease: scientific review and guidelines for diagnosis and management. JAMA 2004;291:228–238.
345. Walsh JP, Bremner AP, Feddema P, et al. Thyrotropin and thyroid antibodies as predictors of hypothyroidism: a 13-year, longitudinal study of a community-based cohort using current immunoassay techniques. J Clin Endocrinol Metab 2010;95:1095–1104.
346. Persani L, Borgato S, Romoli R, et al. Changes in the degree of sialylation of carbohydrate chains modify the biological properties of circulating thyrotropin isoforms in various physiological and pathological states. J Clin Endocrinol Metab 1998;83:2486–2492.
347. Persani L, Ferretti E, Borgato S, et al. Circulating thyrotropin bioactivity in sporadic central hypothyroidism. J Clin Endocrinol Metab 2000;85:3631–3635.
348. Saravanan P, Dayan CM. Thyroid autoantibodies. Endocrinol Metab Clin North Am 2001;30:315–337.
349. Boukis MA, Koutras DA, Souvatzoglou A, et al. Thyroid hormone and immunological studies in endemic goiter. J Clin Endocrinol Metab 1983;57:859–862.
350. Asamer H, Riccabona G, Holthaus N, et al. [Immunohistologic findings in thyroid disease in an endemic goiter area]. Arch Klin Med 1968;215:270–284.
351. Amino N, Hagen SR, Yamada N, et al. Measurement of circulating thyroid microsomal antibodies by the tanned red cell haemagglutination technique: its usefulness in the diagnosis of autoimmune thyroid diseases. Clin Endocrinol (Oxf) 1976;5:115–125.
352. Wright-Pascoe R, Smikle MF, Barton EN, et al. Limited usefulness of antithyroperoxidase and antithyroglobulin assays in Jamaicans with Graves' disease. Hum Antibodies 1999;9:161–164.
Nordyke RA, Gilbert FI Jr, Miyamoto LA, et al. The superiority of antimicrosomal over antithyroglobulin antibodies for detecting Hashimoto’s thyroiditis. Arch Intern Med 1993;153:862–865.
354. Mariotti S, Sansoni P, Barbesino G, et al. Thyroid and other organ-specific autoantibodies in healthy centenarians. Lancet 1992;339:1506–1508.
355. Weetman AP, McGregor AM, Campbell H, et al. Iodide enhances IgG synthesis by human peripheral blood lymphocytes in vitro. Acta Endocrinol (Copenh) 1983;103:210–215.
356. Allen EM, Appel MC, Braverman LE. The effect of iodide ingestion on the development of spontaneous lymphocytic thyroiditis in the diabetes-prone BB/W rat. Endocrinology 1986;118:1977–1981.
357. Costagliola S, Morgenthaler NG, Hoermann R, et al. Second generation assay for thyrotropin receptor antibodies has superior diagnostic sensitivity for Graves' disease. J Clin Endocrinol Metab 1999;84:90–97.
358. Takasu N, Oshiro C, Akamine H, et al. Thyroid-stimulating antibody and TSH-binding inhibitor immunoglobulin in 277 Graves' patients and in 686 normal subjects. J Endocrinol Invest 1997;20:452–461.
359. Zouvanis M, Panz VR, Kalk WJ, et al. Thyrotropin receptor antibodies in black South African patients with Graves' disease and their response to medical therapy. J Endocrinol Invest 1998;21:771–774.
360. Cho BY, Kim WB, Chung JH, et al. High prevalence and little change in TSH receptor blocking antibody titres with thyroxine and antithyroid drug therapy in patients with non-goitrous autoimmune thyroiditis. Clin Endocrinol (Oxf) 1995;43:465–471.
361. Tamaki H, Amino N, Kimura M, et al. Low prevalence of thyrotropin receptor antibody in primary hypothyroidism in Japan. J Clin Endocrinol Metab 1990;71:1382–1386.
362. Davies TF, Ando T, Lin RY, et al. Thyrotropin receptor-associated diseases: from adenomata to Graves disease. J Clin Invest 2005;115:1972–1983.
363. Lytton SD, Kahaly GJ. Bioassays for TSH-receptor autoantibodies: an update. Autoimmun Rev 2010;10:116–122.
364. Spitzweg C, Morris JC. The immune response to the iodide transporter. Endocrinol Metab Clin North Am 2000;29:389–398.
365. Vanderpump M. The thyroid: a fundamental and clinical text. Philadelphia: Lippincott-Raven Publishers, 1996.
366. Prummel MF, Strieder T, Wiersinga WM. The environment and autoimmune thyroid diseases. Eur J Endocrinol 2004;150:605–618.
367. Haddow JE, Palomaki GE, Allan WC, et al. Maternal thyroid deficiency during pregnancy and subsequent neuropsychological development of the child. N Engl J Med 1999;341:549–555.
368. Baskin HJ, Cobin RH, Duick DS, et al. American Association of Clinical Endocrinologists medical guidelines for clinical practice for the evaluation and treatment of hyperthyroidism and hypothyroidism. Endocr Pract 2002;8:457–469.
369. Pearce EN. Thyroid dysfunction in perimenopausal and postmenopausal women. Menopause Int 2007;13:8–13.
370. Lazarus JH. Thyroid disorders associated with pregnancy: etiology, diagnosis, and management. Treat Endocrinol 2005;4:31–41.
371. Livadas S, Xekouki P, Fouka F, et al. Prevalence of thyroid dysfunction in Turner’s syndrome: a long-term follow-up study and brief literature review. Thyroid 2005;15:1061–1066.
372. Hardy O, Worley G, Lee MM, et al. Hypothyroidism in Down syndrome: screening guidelines and testing methodology. Am J Med Genet A 2004;124A:436–437.
373. Abalovich M, Amino N, Barbour LA, et al. Management of thyroid dysfunction during pregnancy and postpartum: an Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab 2007;92(8 Suppl):S1–S47.
374. American College of Obstetrics and Gynecology. ACOG practice bulletin. Thyroid disease in pregnancy. Number 37. Int J Gynaecol Obstet 2002;79:171–180.
375. Mariotti S, Caturegli P, Piccolo P, et al. Antithyroid peroxidase autoantibodies in thyroid diseases. J Clin Endocrinol Metab 1990;71:661–669.
376. Endo T, Kaneshige M, Nakazato M, et al. Autoantibody against thyroid iodide transporter in the sera from patients with Hashimoto’s thyroiditis possesses iodide transport inhibitory activity. Biochem Biophys Res Commun 1996;228:199–202.
377. Cooper DS. Clinical practice. Subclinical hypothyroidism. N Engl J Med 2001;345:260–265.
378. McDermott MT, Ridgway EC. Subclinical hypothyroidism is mild thyroid failure and should be treated. J Clin Endocrinol Metab 2001;86:4585–4590.
379. Danese MD, Ladenson PW, Meinert CL, et al. Clinical review 115: effect of thyroxine therapy on serum lipoproteins in patients with mild thyroid failure: a quantitative review of the literature. J Clin Endocrinol Metab 2000;85:2993–3001.
380. Devdhar M, Ousman YH, Burman KD. Hypothyroidism. Endocrinol Metab Clin North Am 2007;36:595–615.
381. Poppe K, Glinoer D. Thyroid autoimmunity and hypothyroidism before and during pregnancy. Hum Reprod Update 2003;9:149–161.
382. Prummel MF, Wiersinga WM. Thyroid autoimmunity and miscarriage. Eur J Endocrinol 2004;150:751–755.
383. Wilansky DL, Greisman B. Early hypothyroidism in patients with menorrhagia. Am J Obstet Gynecol 1989;160:673–677.
384. Feek CM, Sawers JS, Brown NS, et al. Influence of thyroid status on dopaminergic inhibition of thyrotropin and prolactin secretion: evidence for an additional feedback mechanism in the control of thyroid hormone secretion. J Clin Endocrinol Metab 1980;51:585–589.
385. Kramer MS, Kauschansky A, Genel M. Adolescent secondary amenorrhea: association with hypothalamic hypothyroidism. J Pediatr 1979;94:300–303.
386. Scanlon MF, Chan V, Heath M, et al. Dopaminergic control of thyrotropin, alpha-subunit, thyrotropin beta-subunit, and prolactin in euthyroidism and hypothyroidism: dissociated responses to dopamine receptor blockade with metoclopramide in hypothyroid subjects. J Clin Endocrinol Metab1981;53:360–365.
387. Thomas R, Reid RL. Thyroid disease and reproductive dysfunction: a review. Obstet Gynecol 1987;70:789–798.
388. del Pozo E, Wyss H, Tollis G, et al. Prolactin and deficient luteal function. Obstet Gynecol 1979;53:282–286.
389. Keye WR, Yuen BH, Knopf RF, et al. Amenorrhea, hyperprolactinemia and pituitary enlargement secondary to primary hypothyroidism. Successful treatment with thyroid replacement. Obstet Gynecol 1976;48:697–702.
390. Bohnet HG, Fiedler K, Leidenberger FA. Subclinical hypothyroidism and infertility. Lancet 1981;2:1278.
391. Wurfel W. [Thyroid regulation pathways and its effect on human luteal function]. Gynakol Geburtshilfliche Rundsch 1992;32:145–150.
392. Walsh JP, Shiels L, Lim EM, et al. Combined thyroxine/liothyronine treatment does not improve well-being, quality of life, or cognitive function compared to thyroxine alone: a randomized controlled trial in patients with primary hypothyroidism. J Clin Endocrinol Metab2003;88:4543–4550.
393. Weetman AP. Graves' disease by any other name? Thyroid 2000;10:1071–1072.
394. Nayak B, Hodak SP. Hyperthyroidism. Endocrinol Metab Clin North Am 2007;36:617–656.
395. Stoffer SS, Hamburger JI. Inadvertent 131I therapy for hyperthyroidism in the first trimester of pregnancy. J Nucl Med 1976;17:146–149.
396. Schlumberger M, De Vathaire F, Ceccarelli C, et al. Exposure to radioactive iodine-131 for scintigraphy or therapy does not preclude pregnancy in thyroid cancer patients. J Nucl Med 1996;37:606–612.
397. Vitti P, Rago T, Chiovato L, et al. Clinical features of patients with Graves' disease undergoing remission after antithyroid drug treatment. Thyroid 1997;7:369–375.
398. Michelangeli V, Poon C, Taft J, et al. The prognostic value of thyrotropin receptor antibody measurement in the early stages of treatment of Graves' disease with antithyroid drugs. Thyroid 1998;8:119–124.
399. Edan G, Massart C, Hody B, et al. Optimum duration of antithyroid drug treatment determined by assay of thyroid stimulating antibody in patients with Graves' disease. BMJ 1989;298:359–361.
400. Anonymous. Propylthioruracil-related liver toxicity: public workshop. Washington DC: Food and Drug Administration and the American Thyroid Association, 2009.
401. Rivkees SA. 63 years and 715 days to the “boxed warning”: unmasking of the propylthiouracil problem. Int J Pediatr Endocrinol 2010 (in press).
402. Cooper DS, Rivkees SA. Putting propylthiouracil in perspective. J Clin Endocrinol Metab 2009;94:1881–1882.
403. Casey BM, Leveno KJ. Thyroid disease in pregnancy. Obstet Gynecol 2006;108:1283–1292.
404. Milham S Jr. Scalp defects in infants of mothers treated for hyperthyroidism with methimazole or carbimazole during pregnancy. Teratology 1985;32:321.
405. Mandel SJ, Cooper DS. The use of antithyroid drugs in pregnancy and lactation. J Clin Endocrinol Metab 2001;86:2354–2359.
406. Karlsson FA, Axelsson O, Melhus H. Severe embryopathy and exposure to methimazole in early pregnancy. J Clin Endocrinol Metab 2002;87:947–949.
407. Cooper DS. Antithyroid drugs. N Engl J Med 2005;352:905–917.
408. Barbero P, Valdez R, Rodriguez H, et al. Choanal atresia associated with maternal hyperthyroidism treated with methimazole: a case-control study. Am J Med Genet A 2008;146A:2390–2395.
409. Van Dijke CP, Heydendael RJ, De Kleine MJ. Methimazole, carbimazole, and congenital skin defects. Ann Intern Med 1987;106:60–61.
410. Mao X-M, Li H-Q, Li Q, et al. Prevention of relapse of Graves' disease by treatment with an intrathyroid injection of dexamethasone. J Clin Endocrinol Metab 2009;94:4984–4991.
411. Yoshimura M, Hershman JM. Thyrotropic action of human chorionic gonadotropin. Thyroid 1995;5:425–434.
412. Padmanabhan LD, Mhaskar R, Mhaskar A, et al. Trophoblastic hyperthyroidism. J Assoc Physicians India 2003;51:1011–1013.
413. Alexander EK, Marqusee E, Lawrence J, et al. Timing and magnitude of increases in levothyroxine requirements during pregnancy in women with hypothyroidism. N Engl J Med 2004;351:241–249.
414. Klein RZ, Sargent JD, Larsen PR, et al. Relation of severity of maternal hypothyroidism to cognitive development of offspring. J Med Screen 2001;8:18–20.
415. Zakarija M, Garcia A, McKenzie JM. Studies on multiple thyroid cell membrane-directed antibodies in Graves' disease. J Clin Invest 1985;76:1885–1891.
416. Zakarija M, McKenzie JM. Thyroid-stimulating antibody (TSAb) of Graves' disease. Life Sci 1983;32:31–44.
417. Tanaka T, Tamai H, Kuma K, et al. Gonadotropin response to luteinizing hormone releasing hormone in hyperthyroid patients with menstrual disturbances. Metabolism 1981;30:323–326.
418. Polak M, Le Gac I, Vuillard E, et al. Fetal and neonatal thyroid function in relation to maternal Graves' disease. Best Pract Res Clin Endocrinol Metab 2004;18:289–302.
419. Iwatani Y, Amino N, Tamaki H, et al. Increase in peripheral large granular lymphocytes in postpartum autoimmune thyroiditis. Endocrinol Jpn 1988;35:447–453.
420. Vargas MT, Briones-Urbina R, Gladman D, et al. Antithyroid microsomal autoantibodies and HLA-DR5 are associated with postpartum thyroid dysfunction: evidence supporting an autoimmune pathogenesis. J Clin Endocrinol Metab 1988;67:327–333.
421. Amino N, Mori H, Iwatani Y, et al. High prevalence of transient post-partum thyrotoxicosis and hypothyroidism. N Engl J Med 1982;306:849–852.
422. Hayslip CC, Fein HG, O'Donnell VM, et al. The value of serum antimicrosomal antibody testing in screening for symptomatic postpartum thyroid dysfunction. Am J Obstet Gynecol 1988;159:203–209.
423. Jansson R. Postpartum thyroid disease. Mol Biol Med 1986;3:201–211.
424. Lucas A, Pizarro E, Granada ML, et al. Postpartum thyroiditis: long-term follow-up. Thyroid 2005;15:1177–1181.
425. Lazarus JH, Ammari F, Oretti R, et al. Clinical aspects of recurrent postpartum thyroiditis. Br J Gen Pract 1997;47:305–308.
426. Walfish PG, Chan JY. Post-partum hyperthyroidism. Clin Endocrinol Metab 1985;14:417–447.
427. Stagnaro-Green A, Roman SH, Cobin RH, et al. Detection of at-risk pregnancy by means of highly sensitive assays for thyroid autoantibodies. JAMA 1990;264:1422–1425.
428. Glinoer D, Soto MF, Bourdoux P, et al. Pregnancy in patients with mild thyroid abnormalities: maternal and neonatal repercussions. J Clin Endocrinol Metab 1991;73:421–427.
429. Maier DB, Parke A. Subclinical autoimmunity in recurrent aborters. Fertil Steril 1989;51:280–285.
430. Magaro M, Zoli A, Altomonte L, et al. The association of silent thyroiditis with active systemic lupus erythematosus. Clin Exp Rheumatol 1992;10:67–70.
431. LaBarbera AR, Miller MM, Ober C, et al. Autoimmune etiology in premature ovarian failure. Am J Reprod Immunol Microbiol 1988;16:115–122.
432. Guth S, Theune U, Aberle J, et al. Very high prevalence of thyroid nodules detected by high frequency (13 MHz) ultrasound examination. Eur J Clin Invest 2009;39:699–706.
433. McHenry CR, Walfish PG, Rosen IB. Non-diagnostic fine needle aspiration biopsy: a dilemma in management of nodular thyroid disease. Am Surg 1993;59:415–419.
434. Nikiforova MN, Nikiforov YE. Molecular diagnostics and predictors in thyroid cancer. Thyroid 2009;19:1351–1361.
435. Barbesino G, Tomer Y, Concepcion ES, et al. Linkage analysis of candidate genes in autoimmune thyroid disease. II. Selected gender-related genes and the X-chromosome. International Consortium for the Genetics of Autoimmune Thyroid Disease. J Clin Endocrinol Metab1998;83:3290–3295.
436. Davenport ML. Approach to the patient with Turner syndrome. J Clin Endocrinol Metab 2010;95:1487–1495.
437. Aaltonen J, Bjorses P, Sandkuijl L, et al. An autosomal locus causing autoimmune disease: autoimmune polyglandular disease type I assigned to chromosome 21. Nat Genet 1994;8:83–87.