This chapter deals primarily with APGO Educational Topic Area:
TOPIC 44 HIRSUTISM AND VIRILIZATION
Students should be able to define hirsutism and virilization, distinguishing normal and abnormal variants of normal secondary sexual characteristics and describing etiology and pathophysiology of both of these diagnoses. They should outline a basic approach to evaluation and management in these patients. They should identify associated diseases, common presenting signs and symptoms, and physical examination findings.
Clinical Case
A 57-year-old woman presents with concerns about a growing problem of visible hair on her upper lip. She underwent menopause at the age of 49 years and has not taken any hormonal therapy or herbal supplements. The hair has slowly appeared over the past year or so and gradually darkened. Upon questioning, she has noted some additional hair growth on her chin.
Hirsutism is excess terminal hair in a male pattern of distribution. It is manifested initially by the appearance of midline terminal hair. Terminal hair is darker, coarser, and kinkier than vellus hair, which is soft, downy, and fine. Care must be taken to evaluate the possibility that excess terminal hair is familial, not pathological, in origin. A scale used for the evaluation of hirsutism is shown in Figure 40.1. When a woman is exposed to excess androgens, terminal hair first appears on the lower abdomen and around the nipples, next around the chin and upper lip, and finally between the breasts and on the lower back. Usually, a woman with hirsutism also has acne. For women in Western cultures, terminal hair on the abdomen, breasts, and face is considered unsightly and presents a cosmetic problem. As a result, at the first sign of hirsutism, women often consult their physician to seek a cause for the excess hair growth and seek treatment to eliminate it.
Virilization is defined as masculinization of a woman and is associated with a marked increase in circulating testosterone. As a woman becomes virilized, she first notices enlargement of the clitoris, followed by temporal balding, deepening of the voice, involution of the breasts, and a remodeling of the limb–shoulder girdle as well as hirsutism. Over time, she takes on a more masculine appearance. Hirsutism and virilization may be clinical clues to an underlying androgen excess disorder.
When evaluating and treating hirsutism and virilization, the sites of androgen production and the mechanisms of androgen action should be considered. Idiopathic (constitutional or familial) hirsutism, a diagnosis of exclusion, is the most common nonpathologic etiology, representing about one half of all cases. The most common pathologic cause of hirsutism is polycystic ovarian syndrome (PCOS), followed by congenital adrenal hyperplasia (CAH). These conditions must be diagnosed by laboratory evaluations. Treatment of androgen excess should be directed at suppressing the source of androgen excess or blocking androgen action at the receptor site.
ANDROGEN PRODUCTION AND ANDROGEN ACTION
In women, androgens are produced in the adrenal glands, the ovaries, and adipose tissue, where there is extraglandular production of testosterone from androstenedione. The following three androgens may be measured when evaluating a woman with hirsutism and virilization:
1. Dehydroepiandrosterone (DHEA): a weak androgen secreted principally by the adrenal glands. This is generally measured as dehydroepiandrosterone sulfate (DHEA-S) because of its longer half-life, making it a more reliable measure.
2. Androstenedione: a weak androgen secreted in equal amounts by the adrenal glands and ovaries.
3. Testosterone: a potent androgen secreted by the adrenal glands and ovaries and produced in adipose tissue from the conversion of androstenedione.
FIGURE 40.1. Modified Ferrima-Gallwey scale, a clinical tool for assessing the extent and distribution of hirsutism.
The sites of androgen production and proportions produced are presented in Table 40.1. In addition, testosterone is also converted within hair follicles and within genital skin to dihydrotestosterone (DHT), which is an androgen even more potent than testosterone. This metabolic conversion is the result of the local action of 5α-reductase on testosterone at these sites. This is the basis for constitutional hirsutism, which is discussed later.
Adrenal androgen production is controlled by reciprocal feedback regulation through pituitary secretion of adrenocorticotropic hormone (ACTH). ACTH stimulates the adrenal cortical production of cortisol. In the metabolic sequence of cortisol production, DHEA is one precursor hormone. In enzymatic deficiencies of adrenal steroidogenesis (21-hydroxylase deficiency and 11β-hydroxylase deficiency), DHEA accumulates and is further metabolized to androstenedione and testosterone. The flow of adrenal hormone production is shown in Figure 40.2.
Ovarian androgen production is regulated by luteinizing hormone (LH) secretion from the pituitary gland. LH stimulates theca lutein cells surrounding the ovarian follicles to secrete androstenedione and, to a lesser extent, testosterone. These androgens are precursors for estrogen production by granulosa cells of the ovarian follicles. In conditions of sustained or increased LH secretion, androstenedione and testosterone increase.
Extraglandular testosterone production occurs in adipocytes (fat cells) and depends on the magnitude of adrenal and ovarian androstenedione production. When androstenedione production increases, there is a dependent increase in extraglandular testosterone production. In obese women, the conversion of androstenedione to testosterone is increased.
Testosterone is the primary androgen that causes increased hair growth, acne, and the physical changes associated with virilization. After testosterone is secreted, it is bound to a carrier protein—sex hormone–binding globulin (SHBG)— and primarily circulates in plasma as a bound steroid hormone. Bound testosterone is unable to attach to testosterone receptors and is, therefore, metabolically inactive. Only a small fraction (1%–3%) of testosterone is unbound (free). It is this small fraction of free hormone that results in testosterone’s effects. The liver produces SHBG, and estrogens stimulate hepatic production of SHBG. As a result, greater estrogen production is associated with less free testosterone, whereas decreased estrogen production is associated with increased free testosterone. Therefore, measurement of total testosterone alone may not reflect the amount of biologically active testosterone.
FIGURE 40.2. Flowchart of adrenal steroidogenesis. DHEA, dehydroepiandrosterone.
Testosterone receptors are scattered throughout the body. For the purpose of this discussion, testosterone receptors are considered only in hair follicles, sebaceous glands, and genital skin. Free testosterone enters the cytosol of testosterone-dependent cells. There it is bound to a testosterone receptor and carried into the nucleus of the cell to initiate its metabolic action. When testosterone is excessive, increased hair growth, acne, and rugation (a fold, crease, or wrinkle) of the genital skin is seen. Some individuals have increased 5α-reductase within hair follicles, resulting in excessive local production of DHT.
Excess androgen production has several causes, including PCOS, testosterone-secreting tumors, adrenal disorders, and iatrogenic as well as idiopathic causes. Figure 40.3 presents a scheme for the evaluation of hirsutism that encompasses the various conditions that lead to this condition.
POLYCYSTIC OVARY SYNDROME
PCOS is the most common cause of androgen excess and hirsutism in women. The etiology of this disorder is unknown. Some cases appear to result from a genetic predisposition, whereas others seem to result from obesity or other causes of LH excess.
Symptoms of PCOS include oligomenorrhea or amenorrhea, acne, hirsutism, and infertility. The disorder is characterized by chronic anovulation or extended periods of infrequent ovulation (oligo-ovulation). It is a syndrome primarily defined by excess androgen. The definition of PCOS has varied in the past.
The Rotterdam criteria, which supplanted the National Institutes of Health diagnostic criteria established in 1990 and 2000, incorporated the appearance of the ovary based on ultrasound examination into the schema. Ultrasound criteria for the diagnosis of polycystic ovaries were decided by expert consensus (Fig. 40.4). These criteria have been criticized for including more mild phenotypes, which increases the prevalence of PCOS and may complicate treatment decisions. The Androgen Excess Society criteria recognize hyperandrogenism as a necessary diagnostic factor, in combination with other symptoms of the syndrome. Hyperandrogenism can be established on the basis of clinical findings (e.g., hirsutism, acne, or serum hormone measurement). To establish the diagnosis, the patient should have two of the following criteria:
• Oligo-ovulation or anovulation usually marked by irregular menstrual cycles
• Biochemical or clinical evidence of hyperandrogenism
• Polycystic-appearing ovaries on ultrasound
It is also important to rule out other endocrine disorders that can mimic PCOS, such as CAH, Cushing syndrome, and hyperprolactinemia.
Obesity
In many women with PCOS, obesity seems to be the common factor (seen in 50% of patients), and the acquisition of body fat coincides with the onset of PCOS. Stein and Leventhal first described PCOS patients as women with hirsutism, irregular cycles, and obesity. Originally called Stein-Leventhal syndrome, PCOS does not currently have obesity as one of its diagnostic criteria. In fact, approximately 20% of women with PCOS are not obese. PCOS is related to obesity by the following mechanism: LH stimulates the theca lutein cells to increase androstenedione production. Androstenedione undergoes aromatization to estrone within adipocytes. Although estrone is a weak estrogen, it has a positive-feedback action or stimulating effect on the pituitary secretion of LH. LH secretion is, therefore, stimulated by increased estrogen. With increasing obesity comes increased conversion of androstenedione to estrone. With the increased rise in androstenedione, there is coincident increased testosterone production, which causes acne and hirsutism (Fig. 40.5). In obesity, compensatory hyperinsulinemia may result in decreased levels of SHBG and, thus, more bioavailable circulating androgen serves as a trophic stimulus to androgen production in the adrenal gland and ovary. Insulin may also have direct hypothalamic effects, such as abnormal appetite stimulation and gonadotropin secretion. Hyperandrogenism, although central to the syndrome, may have multiple etiologies, some not related to insulin resistance.
FIGURE 40.3. Scheme for the evaluation of hirsutism. ACTH, adrenocorticotropic hormone; CT, computed tomography.
Hormonal studies in women with PCOS show the following: 1) increased LH:FSH (follicle-stimulating hormone) ratio, 2) estrone in greater concentration than estradiol, 3) androstenedione at the upper limits of normal or increased, and 4) testosterone at the upper limits of normal or slightly increased.
Therefore, PCOS can be viewed as one of excess androgen and excess estrogen. The unopposed long-term elevated estrogen levels that characterize PCOS increases the risk of abnormal uterine bleeding, endometrial hyperplasia, and, in some cases, the development of endometrial carcinoma.
Metabolic Syndrome
The typical woman with PCOS has many of the signs of metabolic syndrome (syndrome X), which is defined by the presence of at least three of the following components:
• Waist circumference 35 inches or greater
• Triglyceride level 150 mg/dL or higher
• High-density lipoprotein cholesterol less than 50 mg/dL
• Blood pressure 130/85 mm Hg or higher
• Fasting glucose level 100 mg/dL or higher
Approximately 40% of patients with PCOS have impaired glucose tolerance, and 8% have overt type 2 diabetes mellitus. These patients should be screened for diabetes. Classic lipid abnormalities include elevated triglyceride levels, low high-density lipoprotein levels, and elevated low-density lipoprotein levels. Hypertension is also common in individuals with this condition. The combination of the preceding abnormalities potentially increases the risk of cardiovascular disease. The genetic contribution to PCOS remains uncertain, and there is currently no recommended genetic screening test.
FIGURE 40.4. Ultrasound of polycystic ovary showing the characteristic “string-of-pearls” appearance of the cysts. (From Guzick DS. Polycystic ovary syndrome. Obstet Gynecol. 2004;103(1):187.)
HAIR-AN Syndrome
Acanthosis nigricans has also been found in a significant percentage of these patients. The HAIR-AN syndrome (hyperandrogenism, insulin resistance, acanthosis nigricans) constitutes a defined subgroup of patients with PCOS. Administration of the insulin-sensitizing agent metformin in these patients also reduces androgen and insulin levels.
Treatment
PCOS is a functional disorder, the treatment of which should be targeted to interrupt the disorder’s positive-feedback cycle. The most common therapy for PCOS is the administration of oral contraceptives, which suppresses pituitary LH production. Suppressing LH causes decreased production of androstenedione and testosterone. The ovarian contribution to the total androgen pool is thereby decreased. Acne clears, new hair growth is prevented, and there is decreased androgenic stimulation of existing hair follicles. By preventing estrogen excess, oral contraceptives also prevent endometrial hyperplasia, and women have cyclic, predictable, withdrawal bleeding episodes.
If a woman with PCOS wishes to conceive, oral contraceptive therapy is not a suitable choice. If the patient is obese, a weight reduction diet designed to restore the patient to a normal weight should be encouraged. With body weight reduction alone, many women resume regular ovulatory cycles and conceive spontaneously. In some women, ovulation induction with clomiphene citrate is needed and is facilitated by weight reduction. Aromatase inhibitors, such as letrozole and anastrozole, have been proposed as both primary and secondary treatment for ovulation induction in these women, and results appear comparable to clomiphene from small trials. Insulin sensitizers (e.g., metformin alone or with clomiphene citrate) may be used to reduce insulin resistance, control weight, and facilitate ovulation. No antidiabetic agents are currently approved by the U.S. Food and Drug Administration for treatment of PCOS-related menstrual dysfunction.
Hyperthecosis
Hyperthecosis is a more severe form of PCOS. In cases of hyperthecosis, androstenedione production may be so great that testosterone reaches concentrations that cause virilization. Women with this condition may exhibit temporal balding, clitoral enlargement, deepening of the voice, and remodeling at the limb–shoulder girdle. Hyperthecosis is often refractory to oral contraceptive suppression. It is also more difficult to successfully induce ovulation in women with this condition.
FIGURE 40.5. Proposed mechanism that demonstrates how obesity leads to polycystic ovary syndrome. LH, luteinizing hormone.
OVARIAN NEOPLASMS
Several androgen-secreting ovarian tumors can cause hirsutism and virilization, including Sertoli-Leydig cell tumors and three rare neoplasms.
Sertoli-Leydig Cell Tumors
Sertoli-Leydig cell tumors (also called androblastoma and arrhenoblastoma) are ovarian neoplasms that secrete testosterone. These tumors constitute <0.4% of ovarian tumors and usually occur in women between the ages of 20 and 40 years. The tumor is most often unilateral (95% of cases) and may reach a size of 7 to 10 cm in diameter.
The history and physical examination give critical clues in diagnosing subjects who present with hirsutism and testosterone-secreting ovarian tumors. Testosterone-secreting tumors usually have a more rapid onset and more severe hirsutism with virilizing signs. Women with a Sertoli-Leydig cell tumor have a rapid onset of acne, hirsutism (75% of patients), amenorrhea (30% of patients), and virilization. A characteristic clinical course of two overlapping stages comprises first, the stage of defeminization, characterized by amenorrhea, breast atrophy, and loss of the subcutaneous fatty deposits responsible for the rounding of the feminine figure, and second, the stage of masculinization, characterized by clitoral hypertrophy, hirsutism, and deepening of the voice. These changes may occur over 6 months or less.
Laboratory studies of this disorder show suppression of FSH and LH, low plasma androstenedione, and marked elevation of testosterone. An ovarian mass may be palpable on pelvic examination. Once the diagnosis is suspected, there should be no delay in surgical removal of the involved ovary. The contralateral ovary should be inspected, and if it is found to be enlarged, it should be bisected for gross inspection.
Following surgical removal of a Sertoli-Leydig cell tumor, ovulatory cycles return spontaneously, and further progression of hirsutism is arrested. If the clitoris has become enlarged, it does not revert to its pretreatment size. However, temporal hair is generally restored, and the body habitus becomes feminine once again. Terminal hair in a sexual distribution will not revert to vellus hair, but the growth and pigmentation will slow. Most patients will require mechanical removal of excess hair following removal of the ovarian tumor. The 10-year survival rates for this low-grade malignant ovarian tumor approximate 90% to 95%.
Uncommon Virilizing Ovarian Tumors
Gynandroblastoma is a rare ovarian tumor, having both granulosa cell and arrhenoblastoma components. The predominant clinical feature is masculinization, although estrogen production may simultaneously produce endometrial hyperplasia and irregular uterine bleeding.
Lipid (lipoid) cell tumors are usually small ovarian tumors containing sheets of round, clear, pale staining cells with a differential histologic diagnosis of hilar cell tumors, stromal luteoma of pregnancy, and Sertoli-Leydig cell tumors. The clinical presentation is masculinization or defeminization associated with elevated 17-ketosteroids in many cases.
Hilar cell tumors arise from an overgrowth of mature hilar cells or from ovarian mesenchyme and are typically found in postmenopausal women. They are characterized clinically by masculinization, which supports the idea that hilar cells are the homologues of the interstitial or Leydig cells of the testis. Histologically, the tumors contain pathognomonic Reinke albuminoid crystals in most cases, and grossly, they are always small, unilateral, and benign. Treatment is surgical removal for these three rare tumors.
ADRENAL ANDROGEN EXCESS DISORDERS
Adrenal disorders that cause an increase in androgen production can lead to hirsutism and virilization; the most common are CAH, Cushing syndrome, and adrenal neoplasms.
Congenital Adrenal Hyperplasia
CAH is caused by enzyme deficiencies that result in precursor (substrate) excess, thereby resulting in androgen excess. DHEA is a precursor for androstenedione and testosterone.
21-Hydroxylase Deficiency
The most common cause of increased adrenal androgen production is adrenal hyperplasia as a result of 21-hydroxylase deficiency; 21-hydroxylase catalyzes the conversion of progesterone and 17α-hydroxyprogesterone (17-OH progesterone) to desoxycorticosterone and compound S. When 21-hydroxylase is deficient, there is an accumulation of progesterone and 17-OH progesterone, which are metabolized subsequently to DHEA. This disorder affects approximately 2% of the population and is caused by an alteration in the genes for 21-hydroxylase, which are carried on chromosome 6. The genetic defect is autosomal recessive and has variable penetrance.
In the most severe form of 21-hydroxylase deficiency, the newly born female infant is simply virilized (ambiguous genitalia) or is virilized and suffers from life-threatening salt wasting (Box 40.1). However, milder forms are more common and can appear at puberty or even later in adult life. A mild deficiency of 21-hydroxylase is frequently associated with terminal body hair, acne, subtle alterations in menstrual cycles, and infertility. These patients can also have sonographic evidence of polycystic-appearing ovaries. When 21-hydroxylase deficiency manifests at puberty, adrenarche may precede thelarche. The history of pubic hair growth occurring before the onset of breast development may be a clinical clue to this disorder. The diagnosis of 21-hydroxylase deficiency is made by measuring increased 17-OH progesterone in plasma during the follicular phase (preferably measured while fasting). Patients with classic 21-hydroxylase deficiency will have significantly elevated plasma 17-OH progesterone levels, usually over 2,000 ng/dL. Those with less severe 21-hydroxylase deficiency may have mildly elevated basal levels, 200 ng/dL, and an increase to usually 1,000 ng/ dL in response to ACTH stimulation. DHEA-S and androstenedione will also be elevated and contribute to the hirsutism and virilizing signs.
BOX 40.1 Manifestations of 21-Hydroxylase Deficiency
• Severe
• Newborn female infant
• Virilized (ambiguous genitalia), or virilized and has life-threatening salt wasting
• Mild
• Frequently associated with terminal body hair, acne, subtle alterations in menstrual cycles and infertility
• Patients can also have sonographic evidence of polycystic-appearing ovaries
• Manifested at puberty
• Adrenarche may precede thelarche
• History of pubic hair growth occurring before the onset of breast development may be a clinical clue
11β-Hydroxylase Deficiency
A less common cause of adrenal hyperplasia is 11β-hydroxylase deficiency. The enzyme 11β-hydroxylase catalyzes the conversion of desoxycorticosterone to cortisol. A deficiency in this enzyme also results in increased androgen production. The clinical features of 11β-hydroxylase deficiency are mild hypertension and mild hirsutism. The diagnosis of 11β-hydroxylase deficiency is made by demonstrating increased plasma desoxycorticosterone.
Treatment
Treatment of CAH is aimed at restoring normal cortisol levels. In CAH, cortisol production is reduced as a result of enzymatic block. This decreased cortisol production results in a compensatory increase in ACTH secretion, which is the body’s attempt to stimulate cortisol production. This increased ACTH production results in the oversecretion of precursor molecules proximal to the enzymatic block, which results in overproduction of androgens. In patients with a high-grade enzymatic block, inadequate amounts of glucocorticoids and mineralocorticoids are made, resulting in salt loss, which can be life threatening. Nonclassic CAH can be managed easily by supplementing glucocorticoids. Usually, prednisone, 2.5 mg daily (or its equivalent), suppresses adrenal androgen production to within the normal range. When this therapy is instituted, facial acne usually clears promptly, ovulation is restored, and there is no new terminal hair growth.
Medical therapy for adrenal and ovarian disorders cannot resolve hirsutism. It can only suppress new hair growth. Hair that is present must be controlled by shaving, bleaching, using depilatory agents, electrolysis, or laser hair ablation.
Cushing Syndrome
Cushing syndrome is an adrenal disease resulting in adrenal excess. As a result of an adrenal neoplasm or an ACTHproducing tumor, the patient demonstrates signs of corticosteroid excess that include truncal obesity, moonlike facies, glucose intolerance, skin thinning with striae, osteoporosis, proximal muscle weakness in addition to evidence of hyperandrogenism, and menstrual irregularities.
Adrenal Neoplasms
Androgen-secreting adrenal adenomas cause a rapid increase in hair growth associated with severe acne; amenorrhea; and, sometimes, virilization. In androgen-secreting adenomas, DHEA-S is usually elevated above 6 mg/mL. The diagnosis of this rare tumor is established by computed axial tomography or magnetic resonance imaging of the adrenal glands. Adrenal adenomas must be removed surgically.
CONSTITUTIONAL HIRSUTISM
Occasionally, after a diagnostic evaluation for hirsutism, there is no explanation for the cause of the disorder. By exclusion, this condition is often called constitutional hirsutism. Data support the hypothesis that women withconstitutional hirsutism have greater activity of 5α-reductase and, therefore, more free testosterone than do unaffected women.
Treatment
Treatment of constitutional hirsutism is primarily androgen blockade and mechanical removal of the excess hair. Spironolactone 100 mg/day is the most commonly used androgen blocker. Spironolactone also inhibits testosterone production by the ovary and reduces 5α-reductase activity. Other androgen blockers include flutamide and cyproterone acetate. The activity of 5α-reductase can also be inhibited directly through the use of drugs such as finasteride (5 mg orally daily). Eflornithine hydrochloride 13.9% is an irreversible inhibitor of l-ornithine decarboxylase, which slows and shrinks hair. This cream has been approved for facial use with satisfactory local effects. Patients taking an androgen receptor or 5α-reductase blocker should be placed on concomitant oral contraceptives because of the teratogenic and demasculinizing effects on a fetus should pregnancy occur. Oral contraceptives may also improve the efficacy of these treatments through the decreased androgen and increased SHBG production effects associated with their use.
IATROGENIC ANDROGEN EXCESS
Some drugs with androgen activity have been implicated in hirsutism and virilization, including danazol and progestin-containing oral contraceptives.
Danazol
Danazol is an attenuated androgen used for the suppression of pelvic endometriosis. It has androgenic properties, and some women develop hirsutism, acne, and deepening of the voice while taking the drug. If these symptoms occur, the value of the danazol should be weighed against the side effects before continuing therapy. Symptoms of voice changes may be irreversible upon discontinuation of treatment. Pregnancy should be ruled out before initiating a course of danazol therapy, because it can produce virilization of the female fetus.
Oral Contraceptives
The progestins in oral contraceptives are impeded androgens. Rarely, a woman taking oral contraceptives develops acne and even hirsutism. If this occurs, another product with a less androgenic progestin should be selected, or the pill should be discontinued. Moreover, evaluation for the coincidental development of late-onset adrenal hyperplasia should be done.
Clinical Follow-Up
Physical examination shows a normal female body hair distribution with just a few scant hairs noted around the nipples. Examination of her face shows a few dark hairs on her chin and fine dark hairs over her upper lip. Her family history reveals that this hair pattern is similar to other postmenopausal women in her family. The patient is reassured when she is told that the changes of menopause result in a reduced level of hormones but a relative dominance of androgens.
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