Valerie L. Baker
Wendy J. Schillings
Howard D. McClamrock
• Girls experienced menarche at increasingly younger ages during the past century. Primary amenorrhea is defined as absence of menses at age 13 years when there is no visible development of secondary sexual characteristics or age 15 years in the presence of normal secondary sexual characteristics.
• Absent or irregular menses may be an indication that a woman has a medical condition that can affect her overall health. The health implications can vary depending on the etiology of the amenorrhea. Therefore, a cause for amenorrhea should be established whenever possible.
• When gonadal failure occurs in conjunction with primary amenorrhea, it is associated with a high incidence of abnormal karyotype.
• The anatomic causes of amenorrhea are relatively few, and the majority may be diagnosed by history and physical examination.
• The most important elements in the diagnosis of amenorrhea include physical examination for secondary sexual characteristics and anatomic abnormalities, measurement of human chorionic gonadotropin (hCG) to rule out pregnancy, serum prolactin and thyroid stimulating hormone (TSH) levels, and assessment of follicle-stimulating hormone (FSH) levels to differentiate between hypergonadotropic and hypogonadotropic forms of hypogonadism.
• Therapeutic measures may include specific therapies (medical or surgical) aimed at correcting the primary cause of amenorrhea, hormone therapy to initiate and maintain secondary sexual characteristics and provide symptomatic relief, treatments to maximize and maintain peak bone mass including hormone therapy, calcium, and vitamin D for cases where circulating estrogen levels are low, and ovulation induction for patients desiring pregnancy.
A complex hormonal interaction must take place in order for normal menstruation to occur. The hypothalamus must secrete gonadotropin-releasing hormone (GnRH) in a pulsatile fashion, which is modulated by neurotransmitters and hormones. The GnRH stimulates secretion of follicle-stimulating hormone (FSH) and luteinizing hormone (LH) from the pituitary, which promotes ovarian follicular development and ovulation. A normally functioning ovarian follicle secretes estrogen; after ovulation, the follicle is converted to corpus luteum, and progesterone is secreted in addition to estrogen. These hormones stimulate endometrial development. If pregnancy does not occur, estrogen and progesterone secretion decrease and withdrawal bleeding begins. If any of the components (hypothalamus, pituitary, ovary, uterus, and outflow tract) are nonfunctional, bleeding cannot occur.
The mean age of menarche became younger during this century. Therefore, the definition of primary amenorrhea changed: Primary amenorrhea is defined as the absence of menses by 13 years of age when there is no visible development of secondary sexual characteristics or by 15 years of age in the presence of normal secondary sexual characteristics. The ages defining primary amenorrhea were decreased by 1 year to continue to represent two standard deviations above the mean age of developing secondary sexual characteristics and menses (1). Failure to begin breast development by age 13 warrants investigation. A woman who previously menstruated can develop secondary amenorrhea, which is defined as absence of menstruation for three normal menstrual cycles (2). A woman with regular cycles and a delay of menses of even a week may warrant assessment with a pregnancy test. It is reasonable to evaluate a woman who has fewer than nine cycles per year. With a few exceptions, the causes of primary amenorrhea are similar to the causes of secondary amenorrhea.
Patients may develop slight alterations in the hypothalamic–pituitary–ovarian axis that are not severe enough to cause amenorrhea but instead cause irregular menses (oligomenorrhea) associated with absent or infrequent ovulation. These patients may bleed excessively during menstruation because estrogen is unopposed. The etiologies of oligomenorrhea overlap with the etiologies of amenorrhea, with the exception that certain anatomic (e.g., absent uterine development) and karyotypic abnormalities (e.g., Turner syndrome), are largely associated with primary amenorrhea.
The World Health Organization (WHO) described three classes of amenorrhea. WHO Group I includes women with no evidence of endogenous estrogen production, normal or low FSH levels, normal prolactin levels, and no lesion in the hypothalamic-pituitary region. WHO Group II is associated with evidence of estrogen production and normal levels of prolactin and FSH. WHO Group III includes individuals with elevated serum FSH indicating gonadal insufficiency or failure.
To detect the cause of amenorrhea, it is useful to determine whether secondary sexual characteristics are present (Fig. 30.1). The absence of secondary sexual characteristics indicates that a woman was never exposed to estrogen.
Figure 30.1 Decision tree for evaluation of amenorrhea. FSH, follicle-stimulating hormone; HCG, human chorionic gonadotropin; HSG, hysterosalpingogram; TSH, thyroid-stimulating hormone; PRL, prolactin; CT, computed tomography; MRI, magnetic resonance imaging; EEG, electroencephalogram; SHG, saline hysterogram.
Amenorrhea without Secondary Sexual Characteristics
Although the diagnosis and treatment of disorders associated with hypogonadism were discussed in another chapter (see Chapter 29), they will be mentioned here because these conditions may present as primary amenorrhea. Because breast development is the first sign of estrogen exposure in puberty, patients without secondary sexual characteristics typically have primary, not secondary, amenorrhea (Fig 30.1). It is helpful to categorize the causes of amenorrhea in the absence of breast development on the basis of gonadotropin status.
Causes of Primary Amenorrhea
Hypergonadotropic Hypogonadism Associated with Absence of Secondary Sexual Characteristics
Gonadal dysgenesis is a term typically used to describe abnormal development of the gonads, typically resulting in streak gonads. Gonadal dysgenesis is associated with high levels of LH and FSH because the gonad fails to produce the steroids and inhibin that would normally feed back to the pituitary gland to suppress pituitary production of LH and FSH. Karyotypic abnormalities are common in women with primary amenorrhea associated with gonadal failure (Table 30.1). In one series, approximately 30% of patients with primary amenorrhea had an associated karyotypic abnormality (3). Turner syndrome (45,X) and its variants represent the most common form of hypergonadotropic hypogonadism in women with primary amenorrhea. Other disorders associated with primary amenorrhea include structurally abnormal X chromosomes, mosaicism (e.g., 45,X in some cells and another karyotype such as 46,XX or 46,XXX in other cells), pure gonadal dysgenesis (46,XX and 46,XY individuals with gonadal streaks resulting from lack of gonad development), enzyme deficiencies that prevent normal estrogen production, and gonadotropin-receptor inactivating mutations. Individuals with these conditions have gonadal failure and cannot synthesize ovarian steroids. Therefore, gonadotropin levels are elevated because of the lack of negative estrogen feedback on the hypothalamic–pituitary axis. Most patients with these conditions have primary amenorrhea and lack secondary sexual characteristics. Occasionally patients with a partial deletion of the X chromosome, mosaicism, or pure gonadal dysgenesis (46,XX) may synthesize enough estrogen in early puberty to induce breast development and a few episodes of uterine bleeding and thus have secondary amenorrhea. Ovulation and, occasionally, pregnancy are possible.
Table 30.1 Amenorrhea Associated with a Lack of Secondary Sexual Characteristics
|
Abnormal pelvic examination |
|
5α-reductase deficiency, 17, 20-lyase deficiency, or 17α-hydroxylase deficiency in |
|
XY individual |
|
Congenital lipoid adrenal hyperplasia |
|
Luteinizing hormone receptor defect |
|
Hypergonadotropic hypogonadism |
|
Gonadal dysgenesis |
|
Follicle-stimulating hormone receptor defect |
|
Partial deletion of X chromosome |
|
Sex chromosome mosaicism |
|
Environmental and therapeutic ovarian toxins |
|
17α-hydroxylase deficiency in XX individual |
|
Galactosemia |
|
Congenital lipoid adrenal hyperplasia in XX individual |
|
Hypogonadotropic hypogonadism |
|
Physiologic delay |
|
Kallmann syndrome |
|
Central nervous system tumors |
|
Hypothalamic/pituitary dysfunction |
Genetic Disorders
Turner Syndrome
Turner syndrome (45,X) is the most common karyotypic abnormality causing gonadal failure and primary amenorrhea (3,4). It appears that patients with Turner syndrome initially have normal ovarian development in utero.Amenorrhea is the result of accelerated atresia of the follicles. The fibrotic ovaries are called streak ovaries.
In addition to gonadal failure, there are associated stigmata with Turner syndrome that include short stature, webbed neck, shield chest, cubitus valgus (increased carrying angle of the arms), low hair line, high arched palate, multiple pigmented nevi, and short fourth metacarpals (4). X inactivation is a process that inactivates most of the genes on one X chromosome. Of the genes on the X chromosome, 20% escape X inactivation, and it is believed that loss of the second copy of these genes in a 45,X patient causes the stigmata associated with Turner syndrome (5).
After the diagnosis of Turner syndrome is confirmed by karyotype, studies should be performed to ensure that cardiac (30% have coarctation of the aorta), renal (especially horseshoe kidney), and autoimmune (thyroiditis) abnormalities are diagnosed and treated. Cardiac magnetic resonance imaging (MRI) should be used in addition to echocardiography (6). Evaluation should be performed in childhood to identify potential attention-deficit or nonverbal learning disorders. Women with Turner syndrome should be screened for diabetes mellitus, aortic enlargement, hypertension, and hearing loss throughout their lives (6).
Abnormal X Chromosome
Those 46,XX individuals with partial deletions of the X chromosome have variable phenotypes depending on the amount and location of the missing genetic material. Patients with a deletion of the long arm of the X chromosome (Xq−) from Xq13 to Xq26 have sexual infantilism, normal stature, no somatic abnormalities, and streak gonads (7). Some patients may be eunuchoid in appearance and have delayed epiphyseal closure. Patients with a deletion of the short arm of the X chromosome (Xp) usually are phenotypically similar to individuals with Turner syndrome (8). Many genes on the Xp chromosome escape X inactivation and act similarly to genes on autosomes. The effective monosomy created by the deletion results in the phenotypic features of Turner syndrome (5). Most patients with a ring X have ovarian failure and phenotypes similar to Turner syndrome, although some are able to reproduce successfully. These patients differ from those with Turner syndrome in that they are more likely to have intellectual disability and have syndactyly. Patients with isochrome of the long arm of the X chromosome (i[Xq]) are similar to XO patients, with the exception that autoimmune disorders are more common. Half of the women with balanced translocations of the X chromosome to an autosome have gonadal failure. Typically, the normal X is inactivated to preserve the balance of autosomal genes. The gonadal failure can be caused by the chromosomal break occurring in a gene that is required for ovarian function, abnormal meiosis, or X inactivation of the translocated X and adjacent autosomal genes (5,9).
Mosaicism
Primary amenorrhea is associated with various mosaic states, the most common of which is 45,X/46,XX (10). The clinical findings in 45,X/47,XXX and 45,X/46,XX/47,XXX are similar to those in 45,X/46,XX and vary in estrogen and gonadotropin production, depending on the number of follicles in the gonads. When compared with the pure 45,X cell line, individuals with 45,X/46,XX are taller and have fewer abnormalities, although 80% of those with 45,X/46,XX mosaics are shorter than their peers, and 66% have some somatic abnormalities. Spontaneous menstruation occurs in approximately 20% of these patients (10).
Pure Gonadal Dysgenesis
Individuals who are phenotypically female with sexual infantilism, primary amenorrhea, normal stature, and no karyotypic abnormalities (46,XX or 46,XY) have pure gonadal dysgenesis. The gonads are usually streaks, but there may be some development of secondary sexual characteristics, and a few episodes of uterine bleeding. Pure gonadal dysgenesis in a 46,XY individual (previously known as Swyer syndrome) can occur when mutations in the SRY (sex-determining region gene on the Y chromosome) located at Yp11 result in XY females without proper gonad development (11,12).
Mutations in many other genes such as SOX9, DAX1, WT-1, and SF1, which affect testicular differentiation and inhibit antimüllerian hormone production, result in XY pure gonadal dysgenesis (13). The SOX9 gene located at 17q24 has a role in testis differentiation and promotes antimüllerian hormone secretion. Some but not all mutations in the SOX9 gene cause XY sex reversal, along with camptomelic dysplasia (severe skeletal abnormalities) (14,15). Duplications of the DAX1 gene at Xp21 cause dose-sensitive XY sex reversal (16). DAX1 is hypothesized to antagonize the SRY gene, preventing testis development. Transgenic XY mice with overexpression of the DAX1 gene develop as phenotypic females, supporting this hypothesis (17). Mutation in the WT1 gene (Wilms' tumor suppressor gene 1) located at 11p13 causes several different syndromes, depending on where the mutation in the gene occurs. In Frasier syndrome, there is alternative splicing, which causes the protein product to lack a highly conserved KTS triplet repeat. The normal +KTS isoform of the protein is believed to synergize with SF1 (steroidogenic factor 1) to promote the expression of antimüllerian hormone (AMH). Lack of the +KTS isoform in an XY patient results in normal female internal and external genitalia, streak gonads, and progressive glomerulopathy. These women frequently develop gonadoblastomas but rarely develop Wilms' tumor, which is associated with mutations in other locations in the WT1 gene. XX patients with the mutation that prevents the +KTS isoform have similar kidney abnormalities but develop normal ovaries and genitalia (17–19). One XY patient with a heterozygous mutation of the SF1 gene had adrenal failure and sex reversal (20). SF1 is an orphan nuclear receptor that regulates AMH expression and regulates all the cytochrome P450 steroid hydroxylase enzymes (19). Duplication of 1p, which encodes the WNT4 gene, causes XY sex reversal. WNT4 may upregulate DAX1 transcripts. A TRX mutation causes XY sex reversal. Other genes that cause XY gonadal dysgenesis are likely to be identified. Mutations at 9p24 and 10q cause XY sex reversal, but the exact genes causing the defects are not elucidated (17,19,21).
XX pure gonadal dysgenesis can be caused by the presence of small Y chromosome fragments in the genome. It is estimated that 5% to 40% of patients with Ullrich-Turner syndrome have Y sequences by polymerase chain reaction (PCR), depending on the DNA sequences targeted for testing (22,23). If Y sequences are present, gonadectomy is advised because of the risk of gonadoblastoma (22).
In other patients with XX gonadal dysgenesis, the condition is likely to be caused by gene mutations that lead to ovarian insufficiency before pubertal development or after the development of secondary sexual characteristics, as discussed later in this chapter.
Mixed Gonadal Dysgenesis
Most patients with mixed gonadal dysgenesis are XY and have ambiguous genitalia with a streak gonad on one side and a malformed testis on the opposite. A small proportion of these patients have mutations in the SRYgene (17).
Rare Enzyme Deficiencies
Congenital Lipoid Adrenal Hyperplasia
Patients with this autosomal recessive disorder are unable to convert cholesterol to pregnenolone, which is the first step in steroid hormone biosynthesis. A defect was not found in the P450scc gene, which is the conversion enzyme responsible for this step in the pathway. Instead, 15 different mutations were identified in the steroidogenic acute regulatory protein (StAR), which facilitates the transport of cholesterol from the outer to the inner mitochondrial membrane. This protein appears to be the rate-limiting step for steroid hormone biosynthesis stimulated by tropic hormones. These patients present in infancy with hyponatremia, hyperkalemia, and acidosis. Both XX and XY individuals are phenotypically female. Genetic clusters of the disorder are found in the Japanese, Korean, and Palestinian Arab populations. With appropriate mineralocorticoid and glucocorticoid replacement, these patients can survive into adulthood. Most patients are XY and do not have a uterus. Without hormone replacement, they remain sexually infantile. XX patients may acquire secondary sexual characteristics at puberty but develop large ovarian cysts and early ovarian failure (24,25).
17á-Hydroxylase and 17,20-lyase Deficiency
Mutations in the CYP17 gene cause abnormalities in both the 17α-hydroxylase and 17,20-lyase functions of the protein that is active in the adrenal and gonadal steroidogenic pathways. More than 20 mutations that alter the reading frame of the gene are identified, even though very few people have the disorder (26). Patients have either 46,XX or 46,XY karyotypes. The uterus is absent in individuals with 46,XY karyotype, a feature distinguishing them from individuals with the 46,XX karyotype. Individuals with CYP17 mutations have primary amenorrhea, no secondary sexual characteristics, female phenotype, hypertension, and hypokalemia (27). The diminished levels of 17α-hydroxylase that characterize this disorder lead to a reduction in cortisol production, which in turn causes an increase in adrenocorticotropic hormone (ACTH). 17α-hydroxylase is not required for production of mineralocorticoids; thus, excessive amounts of mineralocorticoid are produced, resulting in sodium retention, loss of potassium, and hypertension. Patients with 17α-hydroxylase deficiency have primordial follicles, but gonadotropin levels are elevated because the enzyme deficiency prevents synthesis of sex steroids.
Aromatase Deficiency
This very rare autosomal recessive abnormality prevents the affected individual from aromatizing androgens to estrogen (28). This syndrome may be suspected even before birth because most mothers of affected children become virilized during pregnancy. This occurs because the placenta cannot convert the fetal androgens to estrogen and they diffuse into the maternal circulation. At birth, a female child has clitoromegaly and posterior labioscrotal fusion (ambiguous genitalia). At puberty, there is no breast development, primary amenorrhea, worsening virilization, absent growth spurt, delayed bone age, and multicystic ovaries. The diagnostic hormonal pattern consists of an elevation of FSH, LH, testosterone, and dehydroepiandrosterone sulfate (DHEAS) levels, and undetectable levels of estradiol. Estrogen therapy improves the ovarian and skeletal abnormalities but must be titrated to mimic normal estrogen levels. Estrogen administration should be minimal during childhood and increased at puberty (29,30).
Galactosemia
In girls, galactosemia often is associated with ovarian failure, but this condition usually is detected by newborn screening programs. A galactose-1 phosphate uridyl transferase level can be measured to assess the patient for galactosemia or carrier status.
Rare Gonadotropin Receptor Mutations
Luteinizing Hormone Receptor Mutation
Inactivation of LH receptors is identified in XY pseudohermaphrodites with primary amenorrhea in the absence of secondary sexual characteristics caused by homozygous premature stop codon, deletions, and missense mutations in the LHR gene located on chromosome 2. The Leydig cells in these individuals are unable to respond to LH, causing Leydig cell hypoplasia. This leads to early testicular failure and prevents masculinization. XX siblings with the same mutations develop normal secondary sexual characteristics but are amenorrheic with elevated LH levels, normal FSH levels, and cystic ovaries (31,32).
Follicle-Stimulating Hormone Receptor Mutation
An autosomal recessive single amino acid substitution in the extracellular domain of the FSH receptor, which prevents FSH binding, was identified in six families in Finland. This condition leads to primary or early secondary amenorrhea, variable development of secondary sexual characteristics, and high levels of FSH and LH (33).
Other Causes of Primary Ovarian Failure without Secondary Sexual Characteristics
Severe damage to the ovaries before the onset of puberty can lead to ovarian insufficiency and failure to develop secondary sexual characteristics. Ovarian dysfunction can occur in association with irradiation of the ovaries, chemotherapy with alkylating agents (e.g., cyclophosphamide), or combinations of radiation and other chemotherapeutic agents (34,35). Other causes of premature ovarian failure (also known as primary ovarian insufficiency) are more commonly associated with amenorrhea after the development of secondary sexual characteristics, as described below.
Hypogonadotropic Hypogonadism Associated with the Absence of Secondary Sex Characteristics
Primary amenorrhea resulting from hypogonadotropic hypogonadism occurs when the hypothalamus fails to secrete adequate amounts of GnRH or when a pituitary disorder associated with inadequate production or release of pituitary gonadotropins is present.
Physiologic Delay
Physiologic or constitutional delay of puberty is the most common manifestation of hypogonadotropic hypogonadism. Amenorrhea may result from the lack of physical development caused by delayed reactivation of the GnRH pulse generator. Levels of GnRH are functionally deficient in relation to chronologic age but normal in terms of physiologic development.
Kallmann Syndrome
The second most common hypothalamic cause of primary amenorrhea associated with hypogonadotropic hypogonadism is insufficient pulsatile secretion of GnRH (Kallmann syndrome), which has varied modes of genetic transmission. Insufficient pulsatile secretion of GnRH leads to deficiencies in FSH and LH (36). Kallmann syndrome is often associated with anosmia (inability to perceive odors), although a woman may not be aware of her impaired sense of smell. The hypogonadism and anosmia arise because of failure of proper neuronal migration during fetal development.
Other Causes of Gonadotropin-Releasing Hormone Deficiency
Deficiencies in GnRH may be caused by developmental or genetic defects, inflammatory processes, tumors, vascular lesions, or trauma. Central nervous system tumors that lead to primary amenorrhea, the most common of which is craniopharyngioma, are usually extracellular masses that interfere with the synthesis and secretion of GnRH or stimulation of pituitary gonadotropins. Virtually all of these patients have disorders in the production of other pituitary hormones and LH and FSH (37,38). Prolactin-secreting pituitary adenomas are rare in childhood and more commonly occur after development of secondary sexual characteristics.
Genetic Disorders
5α-Reductase Deficiency
5α-Reductase deficiency should be considered a cause of amenorrhea (39). Patients with this disorder are genotypically XY, frequently experience virilization at puberty, have testes (because of functioning Y chromosomes), and have no müllerian structures as a result of functioning AMH. 5α-Reductase converts testosterone to its more potent form, dihydrotestosterone. Patients with 5α-reductase deficiency differ from patients with androgen insensitivity because they do not develop breasts at puberty (Fig. 30.2). These patients have low gonadotropin levels as a result of testosterone levels that are sufficient to suppress breast development and allow normal feedback mechanisms to remain intact. Normal male differentiation of the urogenital sinus and external genitalia do not occur because dihydrotestosterone is required for this development. Normal internal male genitalia derived from the wolffian ducts are present because this development requires only testosterone. Male pattern hair growth, muscle mass, and voice deepening are testosterone dependent.
Gonadotropin-Releasing Hormone Receptor Mutations
Several mutations are identified in the GnRH receptor gene that causes abnormal GnRH function. Most affected patients are compound heterozygotes, but homozygous autosomal recessive mutations are identified. The GnRH receptor is a G-protein–coupled receptor. Functional studies show that the mutations cause marked decrease in binding of GnRH to its receptor or prevent second-messenger signal transduction. Without a functional signal transduction, FSH and LH are not stimulated and are unable to promote follicular growth (40). All patients are normosomic. Receptor mutations in GnRH cause 17% of sporadic cases of idiopathic hypogonadotropic hypogonadism with normal olfaction (41).
Follicle-Stimulating Hormone Deficiency
Patients with FSH deficiency usually seek treatment for delayed puberty and primary amenorrhea associated with hypoestrogenism. They are distinguished from other hypoestrogenic patients by having decreased FSH levels and increased LH levels. These patients have low serum androgen levels despite the abnormal LH-to-FSH ratio, indicating that FSH-stimulated follicular development is a prerequisite for thecal cell androgen production. In some of these patients, autosomal recessive mutations in the FSHβ subunit, which impair dimerization of α and β subunits and prevent binding to the FSH receptor, are identified (42). Pregnancy was achieved in one patient after induction of ovulation with injectable gonadotropins (43).
Other Hypothalamic/ Pituitary Dysfunctions
Functional gonadotropin deficiency results from malnutrition, malabsorption, weight loss or anorexia nervosa, excessive exercise, chronic disease, neoplasias, and marijuana use, although these conditions are more commonly associated with amenorrhea accompanied by secondary sexual characteristics that developed before the onset of the problem, which is discussed in detail below (44–48). Hypothyroidism, polycystic ovarian syndrome (PCOS), Cushing syndrome, hyperprolactinemia, and infiltrative disorders of the central nervous system are more commonly associated with amenorrhea in the presence of development of secondary sexual characteristics, but can lead to amenorrhea accompanied by delayed puberty (49,50). Constitutional delay without underlying causes is less common in girls than in boys, and the reason for lack of development should be vigorously pursued (51).
Evaluation of Women with Amenorrhea Associated with the Absence of Secondary Sexual Characteristics
A careful history and physical examination are necessary to appropriately diagnose and treat primary amenorrhea associated with hypogonadism. The physical examination may be particularly helpful in patients with Turner syndrome. A history of short stature but consistent growth rate, a family history of delayed puberty, and normal physical findings (including assessment of smell, optic discs, and visual fields) may suggest physiologic delay. Headaches, visual disturbances, short stature, symptoms of diabetes insipidus, and weakness of one or more limbs suggest central nervous system lesions (38). Galactorrhea may be seen with prolactinomas, a condition more commonly associated with secondary amenorrhea in the presence of normal secondary sexual characteristics.
The diagnostic workup is summarized as follows:
1. The initial laboratory test should be assessment of serum FSH and LH levels unless the history and physical examination suggest otherwise in order to differentiate hypergonadotropic and hypogonadotropic forms of hypogonadism. If the FSH level is elevated, a karyotype should be obtained. An elevated FSH level in combination with a 45,X karyotype confirms the diagnosis of Turner syndrome. Partial deletion of the X chromosome, mosaicism, pure gonadal dysgenesis, and mixed gonadal dysgenesis are diagnosed by obtaining a karyotype.
2. Because of the association with coarctation of the aorta (up to 30%) and thyroid dysfunction, patients with Turner syndrome should undergo echocardiography every 3 to 5 years and thyroid function studies yearly. Cardiac MRI is considered an important component of the cardiac evaluation (6). Patients with Turner syndrome should be evaluated for hearing loss, renal malformations, diabetes, and hypertension.
3. If the karyotype is abnormal and contains the Y chromosome, as in gonadal dysgenesis, the gonads should be removed to prevent tumors (13).
4. If the karyotype is normal and the FSH level is elevated, it is important to consider the diagnosis of 17α-hydroxylase deficiency because it may be a life-threatening disease if untreated. This diagnosis should be considered when testing indicates elevated serum progesterone (>3.0 ng/mL) level, a low 17α-hydroxyprogesterone (0.2 ng/mL) level, and an elevated serum deoxycorticosterone level (52). The diagnosis is confirmed with an ACTH stimulation test. After ACTH bolus administration, affected individuals have markedly increased levels of serum progesterone compared with baseline levels and no change in serum 17α-hydroxyprogesterone levels.
5. If the screening FSH level is low, the diagnosis of hypogonadotropic hypogonadism is established. Central nervous system lesions should be ruled out by imaging using computed tomography (CT) or MRI, especially if galactorrhea, headaches, or visual field defects are identified. Suprasellar or intrasellar calcification in an abnormal sella is found in approximately 70% of patients with craniopharyngioma (38).
6. Physiologic delay is a diagnosis of exclusion that is difficult to distinguish from insufficient GnRH secretion. The diagnosis can be supported by a history suggesting physiologic delay, an x-ray showing delayed bone age, and the absence of a central nervous system lesion on CT or MRI scanning.
Treatment of Amenorrhea Associated with the Absence of Secondary Sexual Characteristics
Individuals with primary amenorrhea associated with all forms of gonadal failure and hypergonadotropic hypogonadism need cyclic estrogen and progestogen therapy to initiate, mature, and maintain secondary sexual characteristics. Prevention of osteoporosis is an additional benefit of estrogen therapy:
1. Therapy is usually initiated with 0.3 to 0.625 mg per day of conjugated estrogens or 0.5 to 1 mg per day of estradiol.
2. If the patient is short in stature, higher doses should not be used because premature closure of the epiphyses should be avoided. Most of these patients are of normal height, and higher estrogen doses may be used initially and reduced to the maintenance doses after several months.
3. Estrogen can be given daily in combination with progestogen (medroxyprogesterone acetate or progesterone) to prevent hyperplasia that could result from unopposed estrogen stimulation of the endometrium in patients with a uterus. Medroxyprogesterone acetate may be administered at a dose of 2.5 mg daily every day of the month or 5 to 10 mg for 12 to 14 days per month. Oral micronized progesterone may be administered at a daily dose 100 mg every day of the month or 200 mg daily for 12 to 14 days per month. Cyclic hormone therapy (with 12 to 14 days of progestogen per month) more closely mimics the natural menstrual cycle. Progesterone suppositories may be administered at a dose of 50 mg daily or 100 mg for 12 to 14 days monthly.
4. Occasionally, individuals with mosaicism and gonadal streaks may ovulate and be able to conceive either spontaneously or after the institution of estrogen therapy.
5. If 17α-hydroxylase deficiency is confirmed, treatment is instituted with corticosteroid replacement and estrogen. Progestogen should be added to protect the endometrium from hyperplasia.
If possible, therapeutic measures are aimed at correcting the primary cause of amenorrhea:
1. Craniopharyngiomas may be resected with a transsphenoidal approach or during craniotomy, depending on the size of the tumor. Some studies show improved prognosis with radiation therapy used in combination with limited tumor removal (38,53).
2. Germinomas are highly radiosensitive, and surgery is rarely indicated (54).
3. Prolactinomas and hyperprolactinemia often may respond to dopamine agonists (bromocriptine or cabergoline) (55).
4. Specific therapies are directed toward malnutrition, malabsorption, weight loss, anorexia nervosa, exercise amenorrhea, neoplasia, and chronic diseases. Logically, it would appear that patients with hypogonadotropic hypogonadism of hypothalamic origin should be treated with long-term administration of pulsatile GnRH. This form of therapy is impractical because it requires the use of an indwelling catheter and a portable pump for prolonged periods and the lack of availability of this equipment in the United States. The primary focus of treatment should be to correct the underlying problem that is causing the menstrual dysfunction (e.g., malnutrition). If a patient is unable to correct the underlying condition, she may be treated with cyclic estrogen and progestogen therapy at least until sexual maturity is achieved. Once sexual maturation is achieved, hormone therapy can be continued to treat hypoestrogenic symptoms until the underlying disorder leading to amenorrhea can be adequately treated.
5. Patients with Kallmann syndrome, and patients with other etiologies for hypothalamic amenorrhea, can be treated with hormone replacement, as described above. For individuals with anorexia, intensive treatment to achieve weight gain and emotional well-being is preferable to long-term treatment with hormone therapy (56).
6. If the patient has physiologic delay of puberty, the only management required is reassurance that the anticipated development will occur eventually.
Individuals whose karyotypes contain a Y cell line (45,X/46,XY mosaicism, or pure gonadal dysgenesis 46,XY) are predisposed to gonadal ridge tumors, such as gonadoblastomas, dysgerminomas, and yolk sac tumors. The gonads of these individuals should be removed when the condition is diagnosed to prevent malignant transformation. There is some evidence that hirsute individuals without Y chromosomes should undergo gonad removal. One patient with hirsutism and the karyotype 45,X was noted to have a streak gonad; the contralateral gonad was dysgenic and contained developing follicles, well-differentiated seminiferous tubules, and Leydig cells. This patient was found to be HY antigen–positive (57).
Clomiphene citrate is most often ineffective for inducing ovulation in patients with hypogonadism who desire pregnancy because such patients are hypoestrogenic. In patients with hypogonadism, ovulation induction with injectable gonadotropins is generally successful. In patients without ovarian function, oocyte donation may be appropriate. There are reports of deaths in pregnant patients with Turner syndrome resulting from aortic dissection and rupture (58). Careful counseling and investigation should be undertaken in patients with Turner syndrome before treating them with donated oocytes.
Amenorrhea with Secondary Sexual Characteristics and Abnormalities of Pelvic Anatomy
Causes
Outflow and Müllerian Anomalies
Amenorrhea occurs if there is blockage of the outflow tract, if the outflow tract is missing, or if there is no functioning uterus (Table 30.2) In order for menses to occur, the endometrium must be functional and there must be patency of the cervix and vagina. Most women with müllerian abnormalities will have normal ovarian function and thus will have normal secondary sexual characteristic development.
Table 30.2 Anatomic Causes of Amenorrhea
|
Secondary sexual characteristics present |
|
Müllerian anomalies |
|
Imperforate hymen |
|
Transverse vaginal septum |
|
Mayer-Rokitansky-Küster-Hauser syndrome |
|
Androgen insensitivity |
|
True hermaphrodism |
|
Absent endometrium |
|
Asherman syndrome |
|
Secondary to prior uterine or cervical surgery |
|
Curettage, especially postpartum |
|
Cone biopsy |
|
Loop electroexcision procedure |
|
Secondary to infections |
|
Pelvic inflammatory disease |
|
Intrauterine devise–related |
|
Tuberculosis |
|
Schistosomiasis |
Transverse Blockages
Any transverse blockage of the müllerian system will cause amenorrhea (59). Such outflow obstructions include imperforate hymen, transverse vaginal septum, and absence of the cervix or vagina.Transverse blockage of the outflow tract with an intact endometrium frequently causes cyclic pain without menstrual bleeding in adolescents. The blockage of blood flow can cause hematocolpos, hematometra, or hemoperitoneum, and endometriosis.
Müllerian Anomalies
Mayer-Rokitansky-Küster-Hauser syndrome includes vaginal agenesis with variable müllerian duct abnormalities accompanied in some cases by renal, skeletal, and auditory abnormalities (60). Müllerian agenesis accounts for approximately 10% of cases of primary amenorrhea (2). Of the patients with this syndrome, 15% have an absent, pelvic, or horseshoe kidney, 40% have a double urinary collecting system, and 5% to 12% have skeletal abnormalities (61–63). Mayer-Rokitansky-Küster-Hauser syndrome is associated with abnormal galactose metabolism (64).
Absence of Functioning Endometrium
Amenorrhea may occur if there is no functioning endometrium. When the findings of the physical examination are normal, anatomic abnormalities of the uterine cavity should be considered. A congenitally absent endometrium is a rare finding in patients with primary amenorrhea. Asherman syndrome, which is more common with secondary amenorrhea or hypomenorrhea, may occur in patients with risk factors for endometrial or cervical scarring (Fig. 30.3). Such risk factors include a history of uterine or cervical surgery, infections related to use of an intrauterine device, and severe pelvic inflammatory disease. Asherman syndrome is found in 39% of patients undergoing hysterosalpingography who previously underwent postpartum curettage (65). Infections such as tuberculosis and schistosomiasis may cause Asherman syndrome but are not common for women who have lived their whole lives in the United States. Cervical stenosis resulting from surgical removal of dysplasia (cone biopsy, loop electroexcision procedure) may lead to amenorrhea.
Figure 30.2 A: A well-developed patient with complete androgen insensitivity. Note the characteristic paucity of pubic hair and well-developed breasts. (From Yen SSC, Jaffe RB. Reproductive endocrinology. 3rd ed. Philadelphia, PA: WB Saunders, 1991:497, with permission.) B: Another patient with androgen insensitivity syndrome with a contrasting thin body hiatus. This is a 17-year-old twin 46,XY. (From Jones HW Jr, Scott WW. Hermaphrodism, genital anomalies, and related endocrine disorders. 2nd ed. Baltimore, MD: Williams & Wilkins, 1971, with permission.)
Figure 30.3 A: Intrauterine adhesion seen on hysterosalpingogram in a patient with Asherman syndrome. (From Donnez J, Nisolle M. The encyclopedia of visual medicine series—an atlas of laser operative laparoscopy and hysteroscopy. New York: Parthenon, 1994:306, with permission.) B: Hysteroscopic view of intrauterine adhesion in a patient with Asherman syndrome.
Androgen Insensitivity
Phenotypic females with complete congenital androgen insensitivity (previously called testicular feminization) develop secondary sexual characteristics but do not have menses (Fig. 30.2). Genotypically, they are male (XY) but have a defect that prevents normal androgen receptor function, leading to the development of the female phenotype. Serum testosterone is in the normal male range. The vagina may be absent or short.
Defects in the androgen receptor gene located on the X chromosome include absence of the gene that encodes for the androgen receptor and abnormalities in the binding domains of the receptor. Androgen receptor deficits are diverse and may result from diminished receptor function or concentration. The diversity of androgen receptor mutations may be related to diversity in phenotype. More than 250 extremely diverse mutations are described, with amino acid substitution being by far the most common (66,67). Postreceptor defects can exist (68). Total serum testosterone concentration is in the range of normal males. Because antimüllerian hormone is present and functions normally in these patients, internal female (müllerian) structures such as a uterus, vagina, and fallopian tubes are absent. Testes rather than ovaries are present in the abdomen or in inguinal hernias because of the presence of normally functioning genes on the Y chromosome. Patients have a blind vaginal pouch and scant or absent axillary and pubic hair. These patients experience abundant breast development at puberty; however, the nipples are immature and the areolae are pale. Testosterone is not present during development to suppress the formation of breast tissues; at puberty, the conversion of testosterone to estrogen stimulates breast growth. Patients are unusually tall with eunuchoidal tendency (long arms with big hands and feet).
True Hermaphroditism
True hermaphroditism is a rare condition that should be considered as a possible cause of amenorrhea. Both male and female gonadal tissues are present in these patients, in whom XX, XY, and mosaic genotypes are found. Two-thirds of the patients menstruate, but menstruation was never reported in XY genotypes. The external genitalia usually are ambiguous, and breast development frequently occurs in these individuals. Fifteen percent of XX true hermaphrodites have SRY translocations, and another 10% have Y chromosomal mosaicism within the gonad (17).
Evaluation of Women with Amenorrhea, Normal Secondary Sexual Characteristics, and Suspected Anatomic Abnormalities
Most congenital abnormalities can be diagnosed by physical examination:
1. An imperforate hymen is diagnosed by the presence of a bulging membrane that distends during Valsalva maneuver. Ultrasonography or MRI is useful to identify the müllerian anomaly when the abnormality cannot be found by physical examination. The patient should be examined for skeletal malformations and assessed with intravenous pyelography or renal ultrasound to detect concomitant renal abnormalities. These abnormalities occur less frequently than in müllerian agenesis (63).
2. It is difficult to differentiate a transverse septum or complete absence of the cervix and uterus in a female from a blind vaginal pouch in a male pseudohermaphrodite by examination alone. Androgen insensitivity is likely when pubic and axillary hair is absent. To confirm the diagnosis, a karyotype determination should be performed to see whether a Y chromosome is present. In some patients, the defect in the androgen receptor is not complete and virilization occurs.
3. An absent endometrium is an outflow tract abnormality that cannot be diagnosed by physical examination in a patient with primary amenorrhea. This abnormality is so rare that in a patient with normal physical findings (normal vagina, cervix, and uterus), it may be advisable to proceed with evaluation of endocrine abnormalities. Although in most cases performance of the progestogen challenge test is not recommended, this test may be of value to confirm the rare diagnosis of congenitally absent endometrium. In this case, progestogen can be administered to a woman who appears to have normal estrogen production (or if estrogen status is questioned, 2.5 mg conjugated estrogen or 2 mg micronized estradiol can be given for 25 days with 5 to 10 mg of medroxyprogesterone acetate added for the last 10 days). Congenital absence of the endometrium is confirmed if no bleeding occurs with this regimen in a patient with primary amenorrhea and no physical abnormalities. This is a very rare diagnosis and routine performance of progestogen challenge is not recommended. Transvaginal ultrasound to assess endometrial thickness may be helpful, with a thickened endometrial lining indicating endometrial response to estrogen.
4. Asherman syndrome cannot be diagnosed by physical examination. It is diagnosed by performing hysterosalpingography, saline infusion sonography (also known as saline hysterogram), or hysteroscopy. These tests will show either complete obliteration or multiple filling defects caused by synechiae. If tuberculosis or schistosomiasis is suspected, endometrial cultures should be performed.
Treatment of Women with Amenorrhea, Normal Secondary Sexual Characteristics, and Abnormalities of Pelvic Anatomy
The treatment of congenital anomalies can be summarized as follows:
1. Treatment of an imperforate hymen involves making a cruciate incision to open the vaginal orifice. Most imperforate hymens are not diagnosed until a hematocolpos forms. It is unwise to place a needle into a hematocolpos without completely removing the obstruction because a pyocolpos may occur.
2. If a transverse septum is present, surgical removal is required. Forty-six percent of transverse septa occur in the upper third of the vagina, and 40% occur in the middle third of the vagina (69). Frank dilators should be used to distend the vagina until it is healed to prevent vaginal adhesions (70). Patients have a fully functional reproductive system after surgery; however, patients with repaired high transverse septa may have lower pregnancy rates (71).
3. Hypoplasia or absence of the cervix in the presence of a functioning uterus is more difficult to treat than other outflow obstructions. Surgery to repair the cervix is rarely successful, and hysterectomy is typically required (72). Endometriosis is a common finding, and it is questionable whether this condition should be treated initially with surgery or if it will resolve spontaneously after surgical repair of the obstruction. The ovaries should be retained to provide the benefits of estrogen and to allow for the possibility of future childbearing by removing mature oocytes for in vitro fertilization and transfer of embryos to a gestational carrier.
4. If the vagina is absent or short, progressive dilation is usually successful in making it functional (70,73). If dilation fails or the patient is unable to perform dilation, the McIndoe split thickness graft technique may be performed (62,74,75). Controversy exists as to the best technique (60). The initial use of vaginal dilators is required to maintain a functional vagina.
5. In patients with complete androgen insensitivity, the testes should be removed after pubertal development is complete to prevent malignant degeneration (76). In patients with testes, 52% develop a neoplasia, most often a gonadoblastoma. Almost one-half of the testicular neoplasms are malignant (dysgerminomas), but transformation usually does not occur until after puberty (77). In patients who develop virilization and have an XY karyotype, the testes should be removed immediately to preserve the female phenotype and to promote female gender identity. Bilateral laparoscopic gonadectomy is the preferred procedure for removal of intra-abdominal testes.
6. Adhesions in the cervix and uterus (Asherman syndrome) can be removed using hysteroscopic resection with scissors or electrocautery. It is reasonable to place a pediatric Foley catheter in the uterine cavity for 7 to 10 days postoperatively (along with systemic administration of broad-spectrum antibiotic therapy). A 2-month course of high-dose estrogen therapy with monthly progestogen withdrawal is used to prevent reformation of adhesions. Eighty percent of patients thus treated achieve pregnancy, but complications including miscarriage, preterm labor, placenta previa, and placenta accreta can occur (78). Cervical stenosis can be treated by cervical dilation.
Amenorrhea with Secondary Sexual Characteristics and Normal Pelvic Anatomy
Although the complete list of potential causes is long, as noted below, the most common causes of amenorrhea in women with normal secondary sexual characteristics and normal pelvic are pregnancy, polycystic ovarian syndrome, hyperprolactinemia, primary ovarian insufficiency (also known as premature ovarian failure), and hypothalamic dysfunction. Pregnancy must be considered in all women of reproductive age with amenorrhea.
Causes
Polycystic Ovarian Syndrome
PCOS is a medical condition associated with hyperandrogenism, ovulatory dysfunction, and polycystic ovaries (79). All definitions of PCOS exclude patients with significantly elevated prolactin, significant thyroid dysfunction, adult-onset congenital adrenal hyperplasia, and androgen-secreting neoplasms from being classified as PCOS. The National Institutes of Health (NIH) 1990 criteria included hyperandrogenism and oligomenorrhea or amenorrhea as required for PCOS diagnosis. The Rotterdam 2003 criteria required two of three of the following for PCOS diagnosis: hyperandrogenism, oligomenorrhea or amenorrhea, polycystic ovaries by ultrasound (80). Although insulin resistance is noted among women with PCOS, it is not included in any of the diagnostic criteria. Obesity is common, but approximately 20% of women with PCOS are not obese. Women with PCOS are often subfertile caused by infrequent or absent ovulation. PCOS can have other general health implications, including increased risk for endometrial hyperplasia and cancer, diabetes, and possibly cardiovascular disease.
Even though PCOS usually causes irregular bleeding rather than amenorrhea, it remains one of the most common causes of amenorrhea (2). The etiology of PCOS remains largely unknown.
In patients who are hirsute and amenorrheic and appear to have PCOS, androgen-secreting adrenal tumors and congenital adrenal hyperplasia should be considered. Elevations in androgens (e.g., Sertoli-Leydig, hilus, and lipoid cell tumors) and estrogens (e.g., granulosa cell tumors) by ovarian tumors may lead to abnormal menstrual patterns, including amenorrhea. A history of rapid onset of hirsutism is suggestive of a tumor.
Hyperprolactinemia
Hyperprolactinemia is a common cause of anovulation in women. Elevation of prolactin produces abnormal GnRH secretion, which can lead to menstrual disturbances (81). Prolactin levels rise in pregnancy, but typically return to normal within 6 months after delivery in nursing mothers and within weeks in nonnursing mothers. Dopamine release suppresses prolactin secretion. Levels of prolactin can be increased by pituitary adenomas that produce prolactin, by other central nervous system (CNS) lesions that disrupt the normal transport of dopamine down the pituitary stalk, and by medications that interfere with normal dopamine secretion (such as antidepressants, antipsychotics including risperidone, metoclopramide, some antihypertensives, opiates, and H2-receptor blockers).
If elevated TSH and elevated prolactin levels are found together, the hypothyroidism should be treated before hyperprolactinemia is treated. Often, the prolactin level will normalize with treatment of hypothyroidism because thyroid-releasing hormone, which is elevated in hypothyroidism, stimulates prolactin secretion.
Primary Ovarian Insufficiency (Premature Ovarian Failure)
Primary ovarian insufficiency is suggested as the preferred term for the condition that otherwise was referred to as premature ovarian failure or premature menopause (82,83). Overt primary ovarian insufficiency (POI) is defined as the presence of amenorrhea for 4 months or more accompanied by two serum FSH levels in the menopausal range for a woman who is less than 40 years of age. Ovarian “insufficiency” is suggested to be more appropriate than “failure” in part because ovarian function can wax and wane, and function can resume even after it appears that a woman transitioned into menopause. Ovarian insufficiency may be caused by decreased follicular endowment or accelerated follicular atresia (82). Over 75% of women with POI will have at least intermittent symptoms including hot flushes, night sweats, and emotional lability (84). Symptoms are uncommon among women with primary amenorrhea who never received estrogen.
If the ovary does not develop or stops its hormone production before puberty, the patient will not develop secondary sexual characteristics without exogenous hormone therapy. If ovarian insufficiency begins later in life, the woman will have normal secondary sexual characteristics.
POI clearly compromises the chance of a woman conceiving with autologous oocytes. However, 5% to 10% of women with a diagnosis of premature ovarian failure achieve pregnancy, with approximately 80% of these pregnancies resulting in the delivery of a healthy child (85). It can be difficult to determine which women will be able to conceive. Published studies of testing for ovarian reserve have not specifically focused on the POI populations, and pregnancies may occur despite very unfavorable results for tests of ovarian reserve such as serum FSH, estradiol, and AMH.
POI is a heterogenous disorder with many potential causes. POI may be caused by sex chromosome disorders, mutations of single genes, and by FMR1 premutations. Radiation or chemotherapy may lead to POI. The cause of POI may be autoimmune. The cause remains unknown in a majority of cases (Table 30.3).
Table 30.3 Causes of Ovarian Insufficiency or Failure after Development of Secondary Sexual Characteristics
|
Chromosomal etiology (e.g., Turner mosaic) |
|
FMR1 premutation |
|
Iatrogenic causes: radiation, chemotherapy, surgical damage to ovarian blood supply |
|
or ovary |
|
Infections |
|
Autoimmune-lymphocytic autoimmune oophoritis |
|
Infections |
|
Galactosemia |
|
Perrault syndrome |
|
Idiopathic (80%–90% of cases) |
Sex Chromosome and Single Gene Disorders Associated with Primary Ovarian Insufficiency
Deletion of the X chromosome (Turner syndrome) is associated with primary ovarian insufficiency, despite normal development of the ovaries, because of accelerated atresia of the follicles (86). Although Turner syndrome may often be associated with primary amenorrhea with absence of secondary sexual characteristics, breast development may occur if ovarian function is initially present. Mosaicism of an XO or XY cell line may cause ovarian insufficiency. Individuals with a 47,XXX karyotype may develop ovarian failure (87). The most common physical features of 47,XXX are tall stature, epicanthal folds, hypotonia, and clinodactyly.
A deletion of a portion of the X chromosome may be present in patients with POI. The Xq21-28 region is critical (7,88). Several genes in this region are identified as the cause of early ovarian insufficiency in humans. Examples include the POF1B gene located at Xq21, the DIAPH2 gene located at distal Xq21, and the XPNPEP2 gene located at Xq25 (89,90). The specific functions of these genes require further investigation. In addition, a mutation of the BMP15 gene located at Xp11.2 is identified in patients with premature ovarian failure (91).
An autosomal recessive form of premature ovarian failure is associated with hearing loss in Perrault syndrome (92). Mutations in FOXL2 causes ovarian failure and ptosis (93). Familial ovarian failure is inherited by dominant Mendelian inheritance in rare cases (94). Numerous genetic mutations leading to ovarian insufficiency are identified and many more are likely to be discovered (95,96). Other than the FMR1 premutation described next, no one mutation is particularly common.
Fragile X Carriers
Fragile X syndrome, the most common cause of inherited (X-linked) intellectual disability, is caused by inactivation of the FMR1 (fragile X mental retardation 1) gene located on Xq27.3. This inactivation occurs as a result of expansion of a cytosine-guanine-guanine (CGG) triplet repeat of more than 200 copies (97). FMR1 premutation carriers (typically defined as greater than 55 but under 200 CGG repeats) may have primary ovarian insufficiency and impaired fertility. The prevalence of POI in women who carry the FMR1 premutation is estimated to be between 13% and 26%. The risk of having POI appears to increase with increasing premutation repeat size between 59 and 99. It is possible that there is an increased risk of POI among women who carry intermediate-size allele (approximately 41 to 58 repeats), but this is not conclusively proven. The risk plateaus or decreases for women with repeat sizes of 100. Interestingly, women with full mutations (200 or more CGG repeats) are not at higher risk for POI. It is hypothesized that expression of abnormal FMR1 mRNA produced by patients with the premutation causes dysfunction in the ovary, which does not occur when the FMR1gene is inactivated and not transcribed. The incidence of having a premutation is 0.8% to 7.5% of women with sporadic POI and up to 13% of women with familial POI.
FMR1 premutations carried by women are unstable and can expand in the next generation to transmit fragile X syndrome to male offspring, especially if women have more than 100 repeats. The smallest repeat to expand to the full mutation in one generation is approximately 59. In contrast to potential expansion in women, the repeat sequence is transmitted from fathers to daughters in a relatively stable manner.
Iatrogenic Causes of Primary Ovarian Insufficiency
Radiation, chemotherapy (especially alkylating agents such as cyclophosphamide) (98), surgical interference with ovarian blood supply, and infections can cause ovarian failure from early loss of follicles. A radiation dose of 800 cGy causes sterility in most individuals. Ovarian failure can be caused by as little as 150 cGy in some patients, especially if they are older than 40 years of age with limited ovarian reserve. In an evaluation of ovarian function in 100 childhood cancer survivors, 17 had premature ovarian failure. Those with spontaneous menses had smaller ovarian volume, fewer antral follicles, and lower inhibin B levels when compared with controls (99). Ovarian suppression with GnRH agonists and oral contraceptives to reduce the risk of ovarian failure was attempted with limited success (100,101). Cigarette smoking decreases the age at which menopause will occur. But smoking would not be expected to be the primary cause of amenorrhea occurring before the age of 40.
Infections
In rare cases, mumps was associated with premature ovarian failure (102). Women with human immunodeficiency virus (HIV) infection may prematurely lose ovarian function compared to women without HIV infection (103). Cytomegalovirus was shown postmortem to cause oophoritis, but premature ovarian failure had not yet developed clinically in the patient, so the relationship of cytomegalovirus to ovarian failure remains unclear (104).
Autoimmune Disorders
In one series, 4% of women with POI were noted to have steroidogenic cell immunity with lymphocytic oophoritis as the mechanism for follicle dysfunction (105). Autoimmune lymphocytic oophoritis is associated with a theca cell infiltrate that spares granulosa cells (106). Ultrasound examination reveals the presence of numerous ovarian follicles, despite elevated serum FSH levels and hypoestrogenism (82). Ovarian antibody testing is not clinically reliable for diagnosing the disorder, as women with biopsy-proven autoimmune oophoritis may have a negative test for ovarian antibody. However, women with autoimmune lymphocytic oophoritis appear to reliably test positive for adrenal antibodies. The most readily available antibody is the 21-hydroxylase antibody (by immunoprecipitation). Ideally, antibody to the adrenal gland itself, as assessed by indirect immunofluorescence, is reasonable to test if available. Testing for 21-hydroxylase antibody is strongly recommended for women who are determined to have POI because women who test positive for this antibody are at risk for potentially fatal hypoadrenalism. Signs that suggest a risk for potentially fatal adrenal insufficiency include hyperpigmentation, weakness, nausea, vomiting, diarrhea, and weight loss.
POI may be part of a polyglandular autoimmune syndrome. Antibodies are present in a variable number of patients with POI, depending on the autoimmune studies performed. One study showed that 92% of patients with premature ovarian failure had autoantibodies (107). Only 20% of these patients exhibited signs of immunologic dysfunction, most frequently in the form of a thyroid disorder that is common in the general population of women who do not have POI. Presence of antithyroid antibodies does not confirm that there is an autoimmune cause for POI. Rarely, POI is associated with myasthenia gravis, idiopathic thrombocytopenia purpura, rheumatoid arthritis, vitiligo, autoimmune hemolytic anemia, diabetes mellitus, and other autoimmune disorders (108–110).
Galactosemia
Galactosemia is caused by a lack of functional galactose-1-phosphate uridyl transferase. Galactosemia is a rare cause of POI and is typically diagnosed in childhood prior to presentation with amenorrhea. Galactose metabolites appear to have toxic effects on ovarian follicles, causing their premature destruction (111). Cataracts and mental retardation are associated with galactosemia. There is evidence that heterozygote carriers of this disorder may have suboptimal ovarian function (112). Early dietary modification may delay but not prevent the ovarian failure (26).
Pituitary and Hypothalamic Lesions
Hypothalamic Tumors
For normal menstruation to occur, the hypothalamus must be able to secrete GnRH, and the pituitary must be able to respond with production and release of FSH and LH. Tumors of the hypothalamus or pituitary, such as craniopharyngiomas, germinomas, tubercular or sarcoid granulomas, or dermoid cysts, may prevent appropriate hormonal secretion. Patients with these disorders may have neurologic abnormalities, and secretion of other hypothalamic and pituitary hormones may be abnormal. Craniopharyngiomas are the most common tumors. They are located in the suprasellar region and frequently cause headaches and visual changes. The surgical and radiologic treatment of tumors may in itself cause further abnormalities in hormone secretion (Table 30.4).
Table 30.4 Pituitary and Hypothalamic Lesions
|
Pituitary and hypothalamic |
|
Craniopharyngioma |
|
Germinoma |
|
Tubercular granuloma |
|
Sarcoid granuloma |
|
Dermoid cyst |
|
Pituitary |
|
Nonfunctioning adenomas |
|
Hormone-secreting adenomas |
|
Prolactinoma |
|
Cushing’s disease |
|
Acromegaly |
|
Infarction |
|
Lymphocytic hypophysitis |
|
Surgical or radiologic ablations |
|
Sheehan’s syndrome |
|
Diabetic vasculitis |
Pituitary Lesions
Hypopituitarism is rare because a large portion of the gland must be destroyed before decreased hormonal secretion affects the patient clinically. The pituitary gland may be destroyed by tumors (nonfunctioning or hormone secreting), infarction, or infiltrating lesions such as lymphocytic hypophysitis, granulomatous lesions, and surgical or radiologic ablations. Sheehan syndrome is associated with postpartum necrosis of the pituitary resulting from a hypotensive episode that, in its severe form (pituitary apoplexy), presents with the patient in shock. The patient may develop a localized, severe, retro-orbital headache or abnormalities in visual fields and visual acuity. Patients with a mild form of postpartum pituitary necrosis cannot lactate, lose pubic and axillary hair, and do not menstruate after delivery.
Diabetic vasculitis and sickle cell anemia rarely manifest as pituitary failure. Hypopituitarism is associated with hyposecretion of ACTH and thyroid-stimulating hormone (TSH) and gonadotropins; therefore, thyroid and adrenal function must be evaluated. If hypopituitarism occurs before puberty, menses and secondary sexual characteristics will not develop.
Growth hormone (GH), TSH, ACTH, and prolactin are secreted by the pituitary, and the excess production of each by pituitary tumors causes menstrual abnormalities. The menstrual abnormalities are caused by adverse effects of these hormones on the GnRH pulse generator and not by direct effects on the ovary. Prolactinomas are the most common hormone-secreting tumors in the pituitary, as described above.
Altered Hypothalamic Gonadotropin-Releasing Hormone Secretion
Abnormal secretion of GnRH accounts for one-third of patients with amenorrhea (113). Chronic disease, malnutrition, stress, psychiatric disorders, eating disorders, and exercise inhibit GnRH pulses, thus altering the menstrual cycle (Table 30.5). Other hormonal systems that produce excess or insufficient hormones can cause abnormal feedback and adversely affect GnRH secretion. In hyperprolactinemia, Cushing disease (excess ACTH), and acromegaly (excess GH), excess pituitary hormones are secreted that inhibit GnRH secretion. It is uncommon to have functional hypothalamic amenorrhea without a secondary cause. Prognosis for recovery is better if the precipitating cause of the amenorrhea can be reversed (114).
Table 30.5 Abnormalities Affecting Release of Gonadotropin-Releasing Hormone
|
Variable estrogen statusa |
|
Anorexia nervosa |
|
Exercise-induced |
|
Stress-induced |
|
Pseudocyesis |
|
Malnutrition |
|
Chronic diseases |
|
Diabetes mellitus |
|
Renal disorders |
|
Pulmonary disorders |
|
Liver disease |
|
Chronic infections |
|
Addison’s disease |
|
Hyperprolactinemia |
|
Thyroid dysfunction |
|
Euestrogenic states |
|
Obesity |
|
Hyperandrogenism |
|
Polycystic ovary syndrome |
|
Cushing syndrome |
|
Congenital adrenal hyperplasia |
|
Androgen-secreting adrenal tumors |
|
Androgen-secreting ovarian tumors |
|
Granulosa cell tumor |
|
Idiopathic |
|
aSeverity of the condition determines estrogen status—the more severe, the more likely to manifest as hypoestrogenism. |
When the decrease in GnRH pulsatility is severe, amenorrhea results. With less severe alterations in GnRH pulsatility, anovulation and oligomenorrhea can occur. The pulsatile secretion of GnRH is modulated by interactions with neurotransmitters and peripheral gonadal steroids. Endogenous opioids, corticotropin-releasing hormones (CRH), melatonin, and α-aminobutyric acid (GABA) inhibit the release of GnRH, whereas catecholamines, acetylcholine, and vasoactive intestinal peptide stimulate GnRH pulses. Dopamine and serotonin have variable effects (115).
Decreased leptin levels are associated with hypothalamic amenorrhea, regardless of whether it is caused by exercise, eating disorders, or idiopathic factors (116,117). Leptin is a hormone secreted by adipocytes that is involved in energy hemostasis. Receptors are found in the hypothalamus and bone, making it an excellent candidate for a modulator of menstrual function and bone mass. Levels correlate with nutritional changes and body mass index. Administration of leptin to women with hypothalamic amenorrhea increased levels of LH, estradiol, insulinlike growth factor-1 (IGF-1), and thyroid hormone. Ovulation and increased bone mass occurred in these patients (117). Weight loss occurring with leptin administration limits the utility of using leptin as a therapeutic agent.
Eating Disorders
Anorexia nervosa is an eating disorder that affects 5% to 10% of adolescent women in the United States. The criteria for diagnosis of anorexia nervosa are refusal to maintain body weight above 15% below normal, an intense fear of becoming fat, altered perception of one’s body image (i.e., patients see themselves as fat despite being underweight), and amenorrhea. Patients attempt to maintain their low body weight by food restriction, laxative abuse, and intense exercise. This is a life-threatening disorder with a mortality rate as high as 9%. Amenorrhea may precede, coincide, or follow the weight loss. Multiple hormonal patterns are altered. The 24-hour patterns of FSH and LH may show constantly low levels as seen in childhood or increased LH pulsatility during sleep consistent with the pattern seen in early puberty. Hypercortisolism is present despite normal ACTH levels, and the ACTH response to CRH administration is blunted. Circulating triiodothyronine (T3) is low, yet circulating inactive reverse T3 concentrations are high (118). Patients may develop cold and heat intolerance, lanugo hair, hypotension, bradycardia, and diabetes insipidus. They may have yellowish discoloration of the skin resulting from elevated levels of serum carotene caused by altered vitamin A metabolism.
Binge eating is associated with bulimia consisting of vomiting, laxative abuse, and diuretics to control weight. Signs of bulimia include tooth decay, parotid gland hypertrophy (chipmunk jowls), hypokalemia, and metabolic alkalosis (119).
Weight Loss and Dieting
Weight loss can cause amenorrhea even if weight does not decrease below normal. Loss of 10% body mass in 1 year is associated with amenorrhea. Some but not all of these women have an underlying eating disorder. Prognosis is good for the return of menses if the patients recover from the weight loss. Dieting without weight loss and changes in diet can lead to amenorrhea (114).
Exercise
In patients with exercise-induced amenorrhea, there is a decrease in the frequency of GnRH pulses, which is assessed by measuring a decreased frequency of LH pulses. These patients are usually hypoestrogenic, but less severe alterations may cause minimal menstrual dysfunction (anovulation or luteal phase defect). The decrease in GnRH pulsatility can be caused by hormonal alterations, such as low levels of leptin or high levels of ghrelin, neuropeptide Y and corticotrophin-releasing hormone (120). Runners and ballet dancers are at higher risk for amenorrhea than swimmers (121). It was previously suggested that a minimum of 17% body fat is required for the initiation of menses and 22% body fat for the maintenance of menses (122). Studies suggest that inappropriately low caloric intake during strenuous exercise is more important than body fat (123). Higher-intensity training, poor nutrition, stress of competition, and associated eating disorders increase an athlete’s risk for menstrual dysfunction (124). Osteoporosis may result in stress fractures during training and lifelong increased fracture risk.Stress fractures most commonly occur in the weight-bearing cortical bone such as the tibia, metatarsal, fibula, and femur. These athletes may fail to reach peak bone mass and have abnormal bone mineralization.
Stress
Stress-related amenorrhea can be caused by abnormalities in neuromodulation in hypothalamic GnRH secretion, similar to those that occur with exercise and anorexia nervosa. Excess endogenous opioids and elevations in CRH secretion inhibit the secretion of GnRH (115). These mechanisms are not fully understood but appear to be the common link between amenorrhea and chronic diseases, pseudocyesis, and malnutrition.
Obesity
Most obese patients have normal menstrual cycles, but the percentage of women with menstrual disorders increases for women with obesity compared with women of normal weight. The menstrual disorder is more often irregular uterine bleeding with anovulation rather than amenorrhea. Obese women have an excess number of fat cells in which extraglandular aromatization of androgen to estrogen occurs. They have lower circulating levels of sex hormone–binding globulin, which allows a larger proportion of free androgens to be converted to estrone. Excess estrogen creates a higher risk for endometrial cancer for these women. The decrease in sex hormone–binding globulin allows an increase in free androgen levels, which initially are eliminated by an increased rate of metabolic clearance. This compensatory mechanism diminishes over time, and hirsutism can develop. Frequently, these patients are classified as having PCOS. Alterations in the secretion of endorphins, cortisol, insulin, growth hormone, and IGF-1 may interact with the abnormal estrogen and androgen feedback to the GnRH pulse generator to cause menstrual abnormalities.
Other Hormonal Factors
The secretion of hypothalamic neuromodulators can be altered by feedback from abnormal levels of peripheral hormones. Excesses or deficiencies of thyroid hormone, glucocorticoids, androgens, and estrogens can cause menstrual dysfunction. Excess secretion of GH, TSH, ACTH, and prolactin from the pituitary gland can cause abnormal feedback inhibition of GnRH secretion, leading to amenorrhea. Growth hormone excess causes acromegaly, which may be associated with anovulation, hirsutism, and polycystic-appearing ovaries as a result of stimulation of the ovary by IGF-1. More commonly, GH excess is accompanied by amenorrhea, low gonadotropin levels, and elevated prolactin levels. Acromegaly is recognized by enlargement of facial features, hands, and feet; hyperhidrosis; visceral organ enlargement; and multiple skin tags. Cushing disease is caused by an ACTH-secreting pituitary tumor, which is manifested by truncal obesity, moon facies, hirsutism, proximal weakness, depression, and menstrual dysfunction.
Evaluation for Women with Amenorrhea in the Presence of Normal Pelvic Anatomy and Normal Secondary Sexual Characteristics
A pregnancy test (urine or serum human chorionic gonadotropin [hCG]) should be performed in a reproductive-age woman who has amenorrhea with normal secondary sexual characteristics and a normal pelvic examination. If the results of the pregnancy test are negative, the evaluation of amenorrhea is as follows:
1. Clinical assessment of estrogen status
2. Serum TSH
3. Serum prolactin
4. Serum FSH level
5. Vaginal ultrasound for assessment of antral follicle count in the ovaries can be considered (may help establish the diagnosis of PCOS or suggest POI)
6. Imaging of the pituitary and hypothalamic assessment if prolactin is elevated or if hypothalamic amenorrhea is suspected (particularly if CNS symptoms are present or there is no clear explanation for hypothalamic amenorrhea).
Assessment of Estrogen Status
The presence of vaginal dryness or hot flashes increases the likelihood of a diagnosis of hypoestrogenism. A sample of vaginal secretions can be obtained during the physical examination, and mucosal estrogen response can be demonstrated by the presence of superficial cells. A serum estradiol level higher than 40 pg/mL is considered indicative of significant estrogen production, but interassay discrepancies often exist and serum estrogen levels can vary greatly on a day-to-day basis for a given woman. Vaginal ultrasound demonstrating a thin endometrium suggests that a patient is hypoestrogenic, unless there is reason to suspect that the patient lacks functional endometrium. A DEXA (dual-energy x-ray absorptiometry) scan to determine bone mineral density should be considered for a patient in whom long-term hypoestrogenism is suspected.
There is little utility in routine performance of a progestogen challenge test to determine the patient’s estrogen status. False positives and false negatives are common.
Thyroid and Prolactin Disorders
Consideration should be given to thyroid disorders and hyperprolactinemia in women with amenorrhea because of the relatively common incidence of these conditions.
1. Sensitive TSH assays can be used to evaluate hypothyroidism and hyperthyroidism. Further evaluation of a thyroid disorder is required if abnormalities in TSH levels are found. Mild degrees of thyroid dysfunction are unlikely to cause amenorrhea. Given the general health implications of thyroid dysfunction and readily available treatments, routine assessment of TSH is reasonable for women with amenorrhea.
2. Prolactin is most accurately obtained in a patient who is fasting and who has not had any recent breast stimulation to avoid concluding that a patient is hyperprolactinemic on the basis of a transient prolactin elevation.If a patient still has some menstrual cycles, it is advisable to obtain the prolactin level in the follicular phase.
Follicle-Stimulating Hormone Levels
Assessment of serum FSH levels is required to determine whether the patient has hypergonadotropic, hypogonadotropic, or eugonadotropic amenorrhea. A circulating FSH level of greater than 25 to 40 mIU/mL indicated on at least two blood samples is indicative of hypergonadotropic amenorrhea. Hypergonadotropism implies that the cause of amenorrhea is ovarian insufficiency. The history should establish whether the cause of ovarian insufficiency is chemotherapy or radiation therapy.
One test that is likely to be performed increasingly frequently is serum AMH. AMH is a product of the granulosa cells. AMH levels are low in women with POI and high in women with PCOS. AMH may be used more commonly in the evaluation of amenorrhea, but its assessment is not yet part of routine evaluation.
If the diagnosis of POI is confirmed, the patient should be tested for:
1. FMR1 premutation
2. Karyotype
3. 21-hydroxylase antibody.
FMR1 premutation testing will reveal women at risk for bearing a child with fragile X syndrome, which may be important information for other family members. The goal of the peripheral blood karyotype is to identify an absent or abnormal X chromosome and to identify whether or not any portion of a Y chromosome is present. In situ hybridization studies may prove the existence of Y chromosomal material with a Y-specific probe when the karyotype is normal and should be assessed if there are clinical signs to suggest that a Y-bearing cell line is present despite normal routine peripheral blood karyotype (125). It is important to identify Y chromosomal material so it may be removed to prevent malignant degeneration. Although commonly suggested that karyotype only be performed if the patient is under age 30, it should be noted that rare patients with Turner syndrome developed amenorrhea after age 35. In addition, some patients who present over the age of 30 may have actually had the onset of POI at a younger age but were unaware because of the use of oral contraceptives. Therefore, consideration should be given to performance of karyotype, regardless of the patient’s age. Testing for 21-hydroxylase antibody will identify women at risk for adrenal crisis.
If a diagnosis of PCOS is suspected, the patient should have:
1. Documentation of hyperandrogenism (either by serum total testosterone and sex hormone binding globulin or free testosterone and/or by presence of physical findings such as acne, hirsutism, and androgenic alopecia),
2. Serum 17-hydroxyprogesterone to exclude congenital adrenal hyperplasia resulting from 21-hydroxylase deficiency, particularly if the patient is at increased risk (highest prevalence is among Ashkenazi Jews, Hispanics, Yugoslavs, Native American Inuits in Alaska, and Italians) (79),
3. If the diagnosis of PCOS is made, the patient should undergo a 2-hour oral glucose tolerance test and a fasting lipid profile.
Assessment of the Pituitary and Hypothalamus
If the patient is hypoestrogenic and the FSH level is not high, pituitary and hypothalamic lesions should be excluded.
1. A complete neurologic examination may help localize a lesion.
2. Either CT or MRI scanning should be performed to confirm the presence or absence of a tumor. MRI will identify smaller lesions than CT; if a lesion is too small for identification by CT, it may be clinically insignificant. MRI offers the advantage of avoiding exposure to x-ray.
3. The patient’s history of weight changes, exercise, eating habits, and body image is an important factor in determining whether anorexia nervosa, malnutrition, obesity, exercise, or stress may be responsible for amenorrhea.
Patients with certain specific clinical findings should undergo screening for other hormonal alterations:
1. Androgen levels should be assessed in any hirsute patient to ensure that adrenal and ovarian tumors are not present and to aid in the diagnosis of PCOS.
2. Acromegaly is suggested by coarse facial features, large doughy hands, and hyperhidrosis and may be confirmed by measuring IGF-1 levels.
3. In patients with truncal obesity, hirsutism, hypertension, and erythematous striae, Cushing syndrome should be ruled out by assessing 24-hour urinary cortisol levels or performing a 1-mg overnight dexamethasone suppression test or late night salivary cortisol (126). It is important to confirm that the patient is not taking exogenous glucocorticoid.
Treatment for Women with Amenorrhea in the Presence of Normal Pelvic Anatomy and Normal Secondary Sexual Characteristics
The treatment of nonanatomic causes of amenorrhea associated with normal secondary sexual characteristics varies widely according to the cause. The underlying disorder should be treated whenever possible. Patients who are pregnant may be counseled regarding the options for continued care. When thyroid abnormalities are detected, thyroid hormone, radioactive iodine, or antithyroid drugs may be administered as appropriate. When hyperprolactinemia is present, treatment may include discontinuation of contributing medications, treatment with dopamine agonists such as bromocriptine or cabergoline, and, rarely, surgery for particularly large pituitary tumors. When POI causes amenorrhea, hormone replacement may be considered to diminish symptoms and to prevent osteoporosis. Counseling regarding the risks and benefits of hormone replacement therapy is indicated. Gonadectomy is required when a Y cell line is present.
Surgical removal, radiation therapy, or a combination of both is advocated for treatment of CNS tumors other than prolactinomas. It may be necessary to treat individuals who have panhypopituitarism with various replacement regimens after all the deficits are elucidated. These regimens include estrogen and progestogen replacement for lack of gonadotropins, corticosteroid replacement for lack of ACTH, thyroid hormone for lack of TSH, and desmopressin acetate (1-deamino-8-D-AVP [DDAVP]) to replace vasopressin.
The treatment of amenorrhea associated with hypothalamic dysfunction depends on the underlying cause:
1. Hormonally active ovarian tumors are surgically removed (rare).
2. Obesity, malnutrition or chronic disease, Cushing syndrome, and acromegaly should be specifically treated.
3. Stress-induced amenorrhea may respond to psychotherapy.
4. Exercise-induced amenorrhea may improve with moderation of activity and weight gain, when appropriate. If hypoestrogenism persists, higher doses of estrogen may be needed in these women than in older menopausal women to maintain bone density. In addition, 1,200 to 1,500 mg of calcium and 400 to 800 IU of vitamin D daily are advised. Bisphosphonates do not improve bone density in amenorrheic athletes because it is lack of bone formation rather than increased resorption that causes the osteopenia. In addition, the use of bisphosphonates is not advised because they can be deposited into the bone, and long-term effects, especially during pregnancy, are unknown.
5. Treatment of eating disorders such as anorexia nervosa generally demands a multidisciplinary approach, with severe cases requiring hospitalization (127).
Chronic anovulation associated with PCOS may be treated after identifying the desires of the patient. Patients may be concerned about their lack of menstruation, not hirsutism, or infertility. The endometrium of these individuals should be protected from the environment of unopposed estrogen that accompanies the anovulatory state. Oral contraceptives are a good alternative for those patients who require contraception. For those patients who are not candidates for oral contraceptive use, cyclic administration of progestogen is advised. Progestogen withdrawal will occur if there is an adequate estrogenic environment to induce proliferation of the endometrium, and it is not sufficient to cause withdrawal bleeding in patients who are hypoestrogenic (e.g., those who have amenorrhea associated with anorexia nervosa). Women with PCOS may require treatment for insulin resistance, dyslipidemia, and obesity. Regular periodic screening with an oral glucose load test and lipid panel is recommended for women with PCOS. Reduction in weight in obese women with PCOS leads to improved pregnancy rates, decreases hirsutism, and improves glucose and lipid levels (79). Insulin-sensitizing medications such as metformin and cholesterol-lowering medications such as statins can be considered. Ovulation induction is performed if pregnancy is desired, as described below.
A common progestogen used to induce withdrawal bleeding and thus protect the endometrium from hyperplastic transformation is medroxyprogesterone acetate (10 mg for 12 to 14 days per month). Occasionally, ovulation may occur; therefore, patients should be made aware that pregnancy is possible, and appropriate contraceptive measures should be used. Because there is theoretical concern that medroxyprogesterone acetate used in early pregnancy may increase the incidence of pseudohermaphroditism, a pregnancy test should be obtained if a woman fails to have a withdrawal bleed (128). Alternatively, progesterone suppositories (50 to 100 mg) or oral micronized progesterone(200 mg) can be given for 12 to 14 days per month to protect the endometrium from hyperplasia and induce withdrawal bleeding. No increased incidence of birth defects is associated with the use of natural progesterone (129).
In hypoestrogenic individuals such as those with POI, estrogen replacement must be added to the progestogen for successful menstrual regulation and prevention of osteoporosis. The doses of estrogen needed for relief of symptoms in young women with POI are often higher than those that are used for older menopausal women (130). Women with POI (who would normally still be making hormone if the ovaries were functioning normally) are different from those reaching menopause at a median age of 51. Therefore, data regarding hormone therapy that were collected from women reaching menopause at the median age should not be extrapolated to younger women. Although there are no comparative data and no long-term prospectively collected data regarding hormone therapy for women with POI, the risks of hormone therapy are likely to be lower and the benefits potentially greater for younger women than for older women reaching menopause after the age of 50 (131).
When chronic anovulation is caused by congenital adrenal hyperplasia, glucocorticoid administration (i.e., dexamethasone 0.5 mg at bedtime) is sometimes successful in restoring the normal feedback mechanisms, thereby permitting regular menstruation and ovulation.
Hirsutism
Patients who have oligomenorrhea or amenorrhea resulting from chronic anovulation may have hirsutism. The most common cause of hirsutism and oligo-ovulation is PCOS. After ruling out androgen-secreting tumors and congenital adrenal hyperplasia, treatment may be aimed at decreasing coarse hair growth.
Oral Contraceptives
Oral contraceptives may be effective for hirsutism by decreasing ovarian androgen production and increasing circulating levels of sex hormone–binding globulin, leading to decreased free androgen in the circulation.
Antiandrogens
Spironolactone decreases androgen production and competes with androgens at the androgen receptor. Side effects include diuresis and dysfunctional uterine bleeding. The use of spironolactone is typically combined with oral contraceptives to avoid irregular bleeding and to prevent pregnancy from occurring while on spironolactone. Flutamide is approved by the U.S. Food and Drug Administration (FDA) for adjuvant therapy in prostatic cancer and for treatment of hirsutism. Its effects are similar to those of spironolactone (132). Liver function should be monitored because of the rare complication of hepatotoxicity. Cyproterone acetate, a strong progestin and antiandrogen, is used abroad but is not available in the United States. It is usually administered in combination with ethinyl estradiol in an oral contraceptive. By decreasing circulating androgen and LH levels, and by inducing antagonism of androgen effects at the peripheral level, cyproterone acetate is effective in treating hirsutism (133). Finasteride, a 5α-reductase inhibitor, is approved by the FDA for the treatment of benign prostatic hypertrophy (Proscar) and male pattern baldness (Propecia). It is effective in treating hirsutism, although perhaps is no more effective than other available agents (134,135). Its major advantage is that it is exceptionally well tolerated and may be used when side effects preclude the use of other therapeutic options for hirsutism.
All antiandrogens are teratogenic as they may lead to feminization of the external genitalia of a male fetus (ambiguous genitalia) if the patient should conceive while taking the medication. Therefore, antiandrogens are typically used in combination with oral contraceptives.
GnRH Agonist
Administration of GnRH agonist agents virtually eliminates ovarian steroid production, and estrogen-progestogen add-back therapy allows long-term administration and protection against osteoporosis.
Eflornithine Hydrochloride
Eflornithine hydrochloride is a topical cream that is approved by the FDA for use on the face and chin. Improvements in facial hirsutism may be seen in 4 to 8 weeks of twice-daily applications.
Ovulation Induction
A large subset of patients with amenorrhea or oligomenorrhea and chronic anovulation seek care because they are unable to conceive (see Chapter 32). Ovulation induction therapy is generally the treatment of choice for such patients, but pretreatment counseling should be provided in sufficient detail to ensure realistic expectations. The patient should be provided with information regarding the chances of a successful pregnancy (considering age of the patient and treatment modality), potential complications (hyperstimulation and multiple gestation), expense, time, and psychological impact involved in completing the course of therapy. Treatment should be individualized (136).
Earlier studies raised the possibility of a relationship between ovulation induction and the risk of ovarian cancer (137,138). Ongoing studies are attempting to address this issue conclusively, but data support an increase of approximately 2.5-fold in ovarian cancer in patients with infertility, which appears unrelated to the use of ovulation-inducing drugs (139140). There is no conclusive evidence to link fertility drug use and ovarian cancer;thus, no change in current ovulation induction practices seems warranted at present (141). Pregnancy and use of oral contraceptives before or after childbearing may protect against ovarian cancer.
Clomiphene citrate is the usual first choice for ovulation induction in most patients because of its relative safety, efficacy, route of administration (oral), and relatively low cost (142). Clomiphene citrate is indicated primarily in patients with adequate levels of estrogen and normal levels of FSH and prolactin. It is generally ineffective in hypogonadotropic patients who already have a poor estrogen supply (143). Patients with inappropriate gonadotropin release (an increased LH-to-FSH ratio), such as that which occurs in PCOS, are candidates for therapy with clomiphene citrate. As many as 80% of certain patients can be expected to ovulate after clomiphene citrate therapy. Contraindications to the use of clomiphene citrate include pregnancy, liver disease, and preexisting ovarian cysts. Side effects include hot flashes and poorly understood visual symptoms, which generally were viewed as an indication to discontinue subsequent clomiphene citrate use. The risk of multiple pregnancy is increased with clomiphene citrate compared with an overall of risk of approximately 8% (142). The majority of multiple gestations are twins; triplets and higher order multiple gestations are rare.
The most commonly recommended treatment regimen for clomiphene citrate is 50 mg daily for 5 days, beginning on the third to fifth day of menstrual or withdrawal bleeding. Cycles may be monitored by measuring midluteal progesterone levels to assess ovulation. Ovulation may be confirmed by an appropriate rise of basal body temperature and menses occurring at the ex-pected time after the temperature rise. Ultrasonographic monitoring to assess folliculogenesis may be helpful, especially when hCG is used to induce ovulation. Endometrial thinning caused by the antiestrogenic effects of clomiphene citratemay be detected with midcycle ultrasound. With these data, it is possible to immediately adjust the dose in the subsequent cycle if a given regimen is ineffective. Dosage increases of 50 mg per day are usually used, and more than 70% of conceptions occur at doses no higher than 100 mg per day for 5 days (144). Dosages higher than 150 mg per day for 5 days are usually ineffective, and patients who remain anovulatory with this dosage should undergo further evaluation accompanied by changes in the therapeutic plan. Longer courses of clomiphene citrate therapy, and adjunctive therapy with glucocorticoids, are suggested if a patient does not ovulate with standard therapy (145).
Although a large randomized trial demonstrated that clomiphene alone is superior to metformin alone in achieving live birth in women with PCOS, a meta-analysis suggests that for some patients with PCOS, metforminand clomiphene combined may increase the likelihood of ovulation compared with clomiphene alone (146,147). Thinning of the endometrium at midcycle in the face of adequate midcycle estradiol and lack of success with repeated cycles of clomiphene are generally indications to consider injectable gonadotropins. Aromatase inhibitors, such as letrozole, were suggested as an option for ovulation induction (148).
Women with PCOS who do not ovulate or become pregnant with clomiphene citrate, and women with hypogonadotropic hypoestrogenic anovulation, may be candidates for therapy with injectable gonadotropins.Available preparations include recombinant FSH and LH and products purified from the urine of menopausal women (FSH or FSH-LH combinations). Administration protocols and dosages vary widely and should be adjusted to individual needs. Safe administration requires careful monitoring of ovarian response with ultrasonography and, in some cases, serial estradiol measurements. In general, gonadotropins are administered at a dose of 50 to 150 IU per day by subcutaneous injection for 3 to 5 days, after which time estradiol and follicular monitoring commence. In most cycles, gonadotropin is administered for 7 to 12 days. Ovulation is triggered by subcutaneous or intramuscular injection of 5,000 to 10,000 IU hCG or subcutaneous injection of 250 μg of recombinant hCG once the lead follicle reaches 16 to 20 mm in diameter based on ultrasonographic assessments. Ovulation generally occurs approximately 38 to 40 hours after hCG administration. Luteal phase support is sometimes provided with the administration of progesterone supplementation or with additional injections of hCG.
The two major complications associated with induction of ovulation with gonadotropins are multiple pregnancy (10% to 30%) and ovarian hyperstimulation syndrome. The incidence of both of these complications can be reduced but not eliminated by careful monitoring. Cycles complicated by the recruitment of numerous follicles or by high estradiol levels may be canceled by withholding the ovulatory dose of hCG. Selected patients may be converted safely to in vitro fertilization. Because severe ovarian hyperstimulation syndrome is life-threatening and may lead to prolonged hospitalization, ovulation induction with gonadotropins generally is performed by experienced practitioners who devote a significant portion of their practice to the treatment of infertility.
Ovulation induction with pulsatile GnRH may be effective in patients who have chronic anovulation associated with low levels of estrogen and gonadotropins. For therapy to be successful, a functional ovary and pituitary gland must be present. Patients with ovarian or pituitary failure do not respond to GnRH therapy. To be effective, GnRH must be administered in a pulsatile fashion, either intravenously or subcutaneously by a programmable pump. Ovulation induction with GnRH, as compared with gonadotropins, is associated with a relatively low incidence of ovarian hyperstimulation and multiple births. In addition, the need for appropriate timing of the ovulatory dose of hCG is avoided because patients treated with pulsatile GnRH have an appropriately timed endogenous LH surge. Disadvantages are mainly related to maintaining the programmable pump and injection site and lack of availability of an appropriate pump in the United States. After ovulation, luteal phase support is necessary and may be provided with hCG, progesterone, or continuation of the GnRH therapy.
For women with overt POI (also known as premature ovarian failure, as noted above), there is no good evidence to suggest that any treatment can increase the chance of conception with autologous oocytes (85). Treatments that were tried include ovulation induction with clomiphene or gonadotropin, pretreatment with high-dose estrogen or gonadotropin-releasing hormone agonist followed by expectant management or gonadotropin stimulation, standard-dose hormone therapy followed by gonadotropin, and corticosteroid pretreatment followed by gonadotropin.Administration of dehydroepiandrosterone (DHEA) is suggested for women with POI (149). It is uncertain whether the benefit seen in preliminary reports will stand the test of time.
If POI is diagnosed while a patient still has a significant supply of oocytes, fertility preservation could be considered if the patient is not able to consider conception at the time of diagnosis. In most cases, patients with prolonged amenorrhea are not diagnosed at a time when significant numbers of reproductively competent oocytes are present. Fertility preservation is an option for patients about to undergo gonadotoxic chemotherapy or if a patient is known (e.g., based on family history) to be at risk for POI. Either embryos or oocytes can be cryopreserved. There is more worldwide experience with cryopreservation of embryos. Improvements are occurring in techniques of oocyte and ovarian tissue cryopreservation (150,151).
Patients with POI who desire pregnancy will in most cases have a high chance of having a child with the help of oocyte donation. Oocytes from donors may be harvested after ovulation induction, fertilized with sperm from the intended father, and transferred into the recipient’s uterus after the endometrium is appropriately prepared with estrogen and progesterone. Special concern is warranted for women with Turner syndrome who appear to have a maternal mortality of at least 2% (58). Rupture of the aorta may occur even if an echocardiogram shows no dilatation (152). It is suggested that all women with Turner syndrome undergo a full cardiac evaluation, including a cardiac MRI at a center with expertise in cardiovascular imaging, and that pregnancy be contraindicated if the patient has known congenital cardiovascular disease (e.g., bicuspid aortic valve or aortic coarctation) or with aortic size greater than 2 cm/m2 (153).
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