Hypogonadotropic Primary Amenorrhea and Sexual Infantilism

Patients with hypogonadotropic hypogonadism have low FSH levels, whereas patients with hypergonadotropic hypogonadism (e.g., gonadal dysgenesis) have elevated FSH levels in the menopausal range (>20 or 40 mIU/L, depending on the assay used). The measurement of serum luteinizing hormone (LH) is of limited additional diagnostic value. The absence of breast development is indicative of inadequate secretion of estrogen.

Hypogonadotropic hypogonadism may be caused by lesions of the hypothalamus or pituitary gland or by functional disorders that result in inadequate gonadotropin-releasing hormone (GnRH) synthesis and release. Because patients with sexual infantilism caused by hypogonadotropic hypogonadism may have a craniopharyngioma or other central nervous system tumor, magnetic resonance imaging (MRI) or computerized tomography (CT) of the hypothalamic-pituitary area is recommended.

Hypogonadotropic hypogonadism resulting in primary amenorrhea and sexual infantilism may also be the result of lesions of the pituitary, including prolactin-secreting adenomas, or a general process of pituitary failure. These patients should be screened for other pituitary hormonal deficiencies by testing for thyroid-stimulating hormone (TSH), growth hormone, and adrenocorticotropic hormone (ACTH).

Finally, apparent hypogonadotropic hypogonadism may actually represent constitutionally delayed puberty. This delay in the normal onset of puberty is generally attributed to undefined hereditary factors because there is commonly a history of late puberty in family members. Constitutional delay of puberty is a diagnosis of exclusion.

Hypergonadotropic Primary Amenorrhea and Sexual Infantilism

Patients with hypergonadotropic hypogonadism have some form of failed gonadal development or premature gonadal failure and will have elevated FSH levels. These patients may have gonadal agenesis (the absence or early disappearance of the normal gonad). Examples in males who may appear to be female in some cases are pure gonadal dysgenesis, or the testicular regression syndrome. These patients have an apparently normal 46 XY karyotype but lack testicular development. If fetal testicular regression occurs between 8 and 10 weeks of gestation, they may have female external genitalia with or without ambiguity in addition to a lack of gonads, a hypoplastic uterus (secondary to absent secretion of antimüllerian hormone), and rudimentary genital ducts (Swyer syndrome). Regression of the testes after 12 to 14 weeks results in variable development of male external genitalia. Anorchia, or streak gonads, occurs with testicular regression syndrome.

Other individuals with hypergonadotropic primary amenorrhea and sexual infantilism may have gonadal dysgenesis, or the presence of an abnormally developed gonad due to chromosomal defects. The differential diagnosis includes 45 XO (Turner syndrome), a structurally abnormal X chromosome, mosaicism with or without a Y chromosome, and pure gonadal dysgenesis (46 XX and 46 XY). Although most affected patients show no signs of secondary sexual characteristics, occasionally an individual with mosaicism or Turner syndrome will have sufficient ovarian follicular activity and secrete enough estrogen to cause breast development, menstruation, ovulation, and rarely even pregnancy.

In individuals with the presence of a Y chromosome, there is a risk for developing a gonadoblastoma (a benign germ cell tumor of the gonad) and eventually dysgerminoma (a malignant germ cell tumor). All patients with hypergonadotropic hypogonadism should have a karyotype performed. Because it is important to identify mosaicism, a greater number of white blood cells (>35) should be karyotyped.

Rarely, some patients with primary amenorrhea and sexual infantilism have a defect of estrogen and androgen production. One example of this is a 17-hydroxylase (P450c17) deficiency, which prevents the synthesis of these sex steroids (Figure 32-1). These individuals have hypertension and hypokalemia caused by mineralocorticoid excess. Other patients, such as those with a 46 XY karyotype and Leydig cell agenesis, may lack the cells necessary for sex steroid production. Because the Leydig cells in the testicle are responsible for producing testosterone, these individuals are born with female external genitalia.

FIGURE 32-1 Diagrammatic representation of the steroid biosynthetic pathways. The asterisk refers to specific enzyme defects that result in congenital adrenal hyperplasia. Cmpd B, corticosterone; Cmpd S, II-deoxycortisol; DHEA, dehydroepiandrosterone; DOC, desoxycorticosterone; HSD, hydroxysteroid dehydrogenase; OH, hydroxylase; P450c, cytochrome P450.

Patients with sexual infantilism may be treated to stimulate breast development by very gradually increasing estrogen doses. One commonly used regimen is to start with 0.3 mg conjugated estrogen every other day and slowly increase over 3- to 6-month intervals. This treatment should be guided by the presence or absence of mastalgia and the rate of breast development. The estrogen can be safely increased to 0.6 mg or more daily if necessary.

Individuals with persistent hypogonadotropic hypogonadism who seek fertility require either human menopausal gonadotropin injections or pulsatile GnRH administered by an infusion pump. Patients with gonadal dysgenesis and 17-hydroxylase deficiency who have a normal uterus and cervix can achieve pregnancy only by in vitro fertilization using donor oocytes.

Androgen Insensitivity Syndrome

Patients with complete androgen insensitivity syndrome have a defect in the androgen receptor. Their karyotype is 46 XY, and they demonstrate male levels of testosterone, although usually on the lower side of normal. They may also have mildly elevated FSH and LH levels because their testes are located within the abdominal wall or cavity (cryptorchic). This location, with greater body heat, typically does not allow for normal male hormonal secretion. Breast development (with smaller nipples and areolae than normal genotypical females) is caused by the testicular secretion of estrogens and by the conversion of circulating androgen to estrogens in the liver and elsewhere. The testicles of individuals with AIS secrete normal male amounts of antimüllerian hormone; therefore, patients have only a vaginal dimple and no uterus. Treatment should consist of gonadal resection to avoid neoplasia (i.e., gonadoblastomas and dysgerminomas) once puberty is complete. The creation of a neovagina when the patient is prepared for sexual activity is possible by surgical and nonsurgical methods. Psychological counseling is an important component in the care of these patients.

Müllerian Dysgenesis or Agenesis

Patients with primary amenorrhea, breast development, and a 46 XX karyotype have levels of testosterone appropriate for females. This clinical diagnosis may be caused by müllerian defects that cause obstruction of the vaginal canal (e.g., imperforate hymen or a transverse vaginal septum) or by the absence of a normal cervix or uterus and normal fallopian tubes. An imperforate hymen should be suspected in adolescents who report monthly dysmenorrhea in the absence of vaginal bleeding (see Figure 18-7, pg 237). Clinically, these patients often present with a vaginal bulge and a midline cystic mass on rectal examination. Ultrasonography confirms the presence of a normal uterus and ovaries with a hematocolpos. These patients should be treated with hymenectomy.

Alternatively, women may present with similar symptoms but without a vaginal bulge. When ultrasonography confirms a normal uterus and ovaries, a transverse, obstructing vaginal septum (see Figure 18-8, pg 237) or cervical agenesis should be suspected. MRI is the diagnostic procedure of choice in these patients. If the MRI scan confirms a transverse septum, surgical correction is indicated. Surgical construction of a functional cervix is extremely difficult. In general, it is recommended that these women undergo hysterectomy.

Finally, rectal examination and ultrasonography may be a sign of the absence of a uterus indicating müllerian agenesis or Meyer-Rokitansky-Küster-Hauser syndrome. This syndrome is characterized by a failure of the müllerian ducts to fuse distally and to form the upper genital tract. These patients may have unilateral or bilateral rudimentary uterine tissues (anlagen), fallopian tubes, and ovaries. It is uncommon to have functional endometrial tissue within the anlagen. On occasion, the ovaries are not visible on ultrasonography because they have not descended into the pelvis. In these cases, CT or MRI may identify them well above the pelvic brim. Currently, the pathophysiology leading to müllerian dysgenesis defects is not known.

Creation of a neovagina can be accomplished using one of two general approaches. The Frank method of vaginal dilation uses dilation of the vaginal pouch with vaginal forms (usually thermoplastic acrylic resin [Lucite] dilators) over the course of weeks to months. Alternatively, a McIndoe vaginoplasty, which involves the surgical creation of a neovaginal space using a split-thickness skin graft, may be performed. Both of these methods should be initiated and performed close to the time when the patient anticipates having vaginal intercourse.

Congenital anatomic abnormalities of the uterus or vagina, or both, are often associated with renal abnormalities such as a unilateral solitary kidney or a double renal collecting system, among others. Therefore, these patients should have an intravenous pyelogram or other diagnostic study to confirm a normal urinary system.

Hypothalamic-Pituitary Dysfunction

Patients with hypothalamic amenorrhea include women experiencing severe weight loss, women undergoing excessive exercise resulting in low body fat, and women experiencing severe psychological stress. Also included are women with physical wasting from severe systemic diseases such as disseminated malignancies and patients with pituitary or central nervous system lesions. In its most severe and life-threatening form, women may have pituitary failure or anorexia nervosa. All patients with hypogonadotropic hypogonadism and hypothalamic-pituitary dysfunction should be evaluated for the status of the other pituitary hormones. Evaluation should also include an MRI of the hypothalamus and pituitary gland to exclude neoplastic and other lesions if it is uncertain whether the patient has one of the functional disorders described previously.

When hypothalamic-pituitary dysfunction cannot be resolved by identifying a modifiable underlying cause (e.g., excessive exercise), estrogen and progestin therapy, usually in the form of a combined oral contraceptive pill, is prescribed to reduce the risk for osteoporosis. This therapy is also recommended to maintain normal vaginal and breast development. In patients with anorexia nervosa, ovarian hormone therapy without weight gain will not totally prevent osteoporosis.

Premature Ovarian Failure

Premature ovarian failure is defined as ovarian failure before the age of 40 years (see Chapter 35). When it occurs in patients younger than 30 years of age, ovarian failure may be caused by a chromosomal disorder. A karyotype is performed to exclude mosaicism (i.e., some cells bearing a Y chromosome). If cells with a Y chromosome are present, a gonadectomy to prevent malignant transformation is indicated.

Other causes of premature ovarian failure include ovarian injury from surgery, radiation, or chemotherapy; galactosemia; carrier status of the fragile X syndrome; and autoimmunity. When premature ovarian failure is secondary to autoimmunity, other endocrine organs may be affected as well. Because there are no specific laboratory tests available to diagnose autoimmune ovarian failure, all patients with unexplained ovarian failure should be screened for diabetes (fasting glucose), hypothyroidism (TSH and free thyroxine [T₄]), hypoparathyroidism (serum calcium and phosphorus), and hypocortisolism (fasting morning cortisol or cortisol response to ACTH stimulation). It is not unusual for patients with premature ovarian failure to have episodes of normal ovarian and menstrual function. Patients with premature ovarian failure require hormonal therapy (estrogen and a progestin) to reduce the risk for osteoporosis.

Prolactinomas

Pituitary adenomas may cause hyperprolactinemia and make up about 10% of all intracranial tumors. Their etiology is unknown. Prolactinomas can be divided into two categories: macroadenomas (≥10 mm in diameter) or microadenomas (<10 mm in diameter). This distinction is important because microadenomas are unlikely to cause new problems due to additional growth. About half of patients with hyperprolactinemia have radiographic changes in the sella turcica consistent with an adenoma. Most patients have normal or low baseline levels of FSH.

Other Central Nervous System Lesions Affecting Prolactin

About 60% of pituitary adenomas do not produce prolactin but may cause hyperprolactinemia by compression of the pituitary stalk. Another interesting lesion, the empty sella syndrome, is caused by a herniation of the subarachnoid membrane into the pituitary sella turcica through a defective or incompetent sella diaphragm. An empty sella may coexist with a prolactin-secreting pituitary adenoma. Hypothalamic tumors may also cause hyperprolactinemia by damaging the hypothalamus or by compression of the pituitary stalk, thereby interfering with the production or transport of dopamine. Craniopharyngiomas are the most common of these lesions.

Pharmacologic Agents Affecting the Secretion of Prolactin

A number of drugs may cause hyperprolactinemia and nonphysiologic galactorrhea (see Box 32-1).The mechanism of drug-induced hyperprolactinemia is secondary to reduced hypothalamic secretion of dopamine, depriving the pituitary of a natural inhibitor of prolactin release. When clinically indicated, patients with hyperprolactinemia caused by medications should be encouraged to discontinue the medication for at least 1 month. If hyperprolactinemia persists, or if the patient cannot interrupt the medication, a complete evaluation is indicated.

Miscellaneous Causes of Hyperprolactinemia

Patients with acute or chronic renal failure may have hyperprolactinemia because of delayed clearance of the hormone. These patients rarely require treatment other than for their renal failure. Patients with scars from previous chest surgery, including breast implantation, may have galactorrhea caused by peripheral nerve stimulation. Herpes zoster of the area including the breasts, as well as other forms of breast stimulation, can cause galactorrhea and sometimes hyperprolactinemia by the same mechanism. In about 3% to 5% of patients with galactorrhea and hyperprolactinemia, primary hypothyroidism is the underlying cause. These patients have a low serum free thyroxine (T₄) level. Consequently, they lack negative feedback on the hypothalamic-pituitary axis, resulting in increased secretion of thyrotropin-releasing hormone (TRH). TRH, in turn, stimulates elevated levels of TSH and prolactin. Patients with primary hypothyroidism should be given T₄replacement therapy. Rarely cancers such as bronchogenic carcinoma or hypernephroma can result in elevated prolactin levels.

Treatment of Galactorrhea and Hyperprolactinemia

The objectives of therapy include the elimination of lactation, the establishment of normal estrogen levels, and the induction of ovulation when fertility is desired. The recommended forms of management are periodic observation, medical therapy, and surgery.

Congenital Adrenal Hyperplasia

Congenital adrenal hyperplasia (CAH) is a general term used to describe an assortment of disorders that arise from inborn glandular enzyme deficiencies associated with the overproduction of steroids. The most common cause of CAH is 21-hydroxylase deficiency. CAH represents a spectrum of disorders, ranging from the severe salt-wasting form, to simple virilizing CAH, to nonclassic CAH. Both salt-wasting and simple-virilizing CAH are called classic because symptoms (e.g., salt loss or ambiguous genitalia in female newborns) are present at birth or shortly thereafter. Alternatively, the nonclassic form (also called late onset) presents later in life, generally at the time of puberty or later. These patients do not present with genital abnormalities, although they may develop hirsutism, acne, and menstrual and ovulatory irregularities.

Because 21-hydroxylase is responsible for the conversion of 17-hydroxyprogesterone to 11-deoxycortisol (compound S), a deficiency in 21-hydroxylase results in an excessive accumulation of 17-hydroxyprogesterone. As a result, this enzyme disorder is marked by an elevated serum 17-hydroxyprogesterone level as well as increases in its Δ⁴ metabolites androstenedione and testosterone (see Figure 32-1). This disease is inherited as an autosomal recessive trait.

Cushing’s Syndrome

Another major adrenal disorder leading to excessive androgen production is Cushing’s syndrome or persistent hypercortisolism. Characteristic cushingoid signs include truncal obesity, moon-like faces, hypertension, easy bruisability, impaired glucose tolerance, muscle wasting, osteoporosis, abdominal striae, and supraclavicular and cervical spinal fat pads. Other manifestations include hirsutism, acne, and irregular menses. This disorder may arise from a cortisol-producing tumor of the adrenal gland or from an ACTH-producing pituitary adenoma (Cushing’s disease). This is a rare cause of menstrual dysfunction in women.

Adrenal Neoplasms

Adrenal tumors causing hyperandrogenism without symptoms and signs of glucocorticoid excess are rare. Adenomas, which produce androgens only, generally secrete large amounts of DHEA-S. Adrenal carcinomas may produce large amounts of both glucocorticoids and androgens.

Polycystic Ovary Syndrome

Six to 10% of women of reproductive age have some form of PCOS. This syndrome is a chronic condition that has been defined as anovulation or oligo-ovulation with clinical or laboratory evidence of hyperandrogenism and without evidence of any other underlying condition. Its onset is usually at the time of puberty. There is a heritable aspect to PCOS with an increased chance that first-degree female relatives are affected.

Clinically, the most common signs of PCOS are hirsutism (90%), menstrual irregularity (90%), and infertility (75%). Hirsutism is less likely in women who have used combined hormonal contraceptives for most of their postpubertal lives and for women of East Asian ethnicity. Although many patients with PCOS demonstrate abdominal obesity, the prevalence of obesity varies widely by country of origin, with the United States having the highest prevalence of obesity in women with PCOS (about 60%).

In most patients with PCOS, the ovaries contain multiple follicular cysts that are inactive and arrested in the mid-antral stage of development. The cysts are located peripherally in the cortex of the ovary (Figure 32-3). The ovarian stroma is hyperplastic and usually contains nests of luteinized theca cells that produce androgens. About 20% of hormonally normal women may also have polycystic-appearing ovaries.

FIGURE 32-3 Transvaginal ultrasound in a woman with polycystic ovarian disease. The multiple subcapsular cysts, with their “string of pearls” appearance (arrows), are common in this syndrome.

The hyperandrogenism of PCOS results from an overproduction of male hormones by the ovary and often the adrenal gland. It is not clear what the ultimate underlying pathophysiology of PCOS is or even whether it is a single clinical entity. Patients with PCOS exhibit increased LH pulse frequency, usually resulting in higher circulating levels of LH. It is likely that these patients exhibit increased LH levels because of increased GnRH secretion from the hypothalamus and increased pituitary sensitivity to GnRH.

The increased LH level promotes androgen secretion from ovarian theca cells, leading to elevated levels of ovarian-derived androstenedione and testosterone. This then leads to atresia of many developing follicles and interferes with the normal development of a dominant or preovulatory ovarian follicle much of the time. Peripheral conversion of androgen to estrogen results in tonic estrogen levels that are higher than those found normally in the early follicular phase and that suppress FSH release from the pituitary gland. The normal pattern of stimulated estrogen rise is disrupted, and the midcycle LH surge does not occur with resulting anovulation and progesterone production. Some PCOS patients have excessive androgen production from the adrenal glands as well as the ovaries. The mechanism for the excess adrenal androgen production in PCOS is unclear.

In women with PCOS there is an association between abnormal androgen production and insulin resistance with hyperinsulinism. In about 60% to 70% of patients with PCOS, insulin sensitivity is decreased, leading to insulin hypersecretion. This hyperinsulinemia results from direct insulin stimulation of theca cells resulting in androgen secretion. Elevated androgen and insulin levels in PCOS also reduce the hepatic production and secretion of SHBG. When SHBG production is suppressed, the amount of free testosterone may be dramatically increased, even though the overall increase in total testosterone is moderate or small. Thus, the physical manifestations of hyperandrogenism in PCOS may seem dramatic in relation to the level of total testosterone.

In the long term, the insulin resistance associated with PCOS may lead to an increased risk for metabolic syndrome (diabetes and heart disease). The unopposed estrogens in women with PCOS may cause hyperplasia of the endometrium and occasionally endometrial carcinoma.

The diagnosis of PCOS continues to be somewhat controversial because of disagreement about diagnostic criteria. PCOS is a diagnosis of exclusion. It is also a syndrome, rather than a distinct and readily definable disease. The European Society for Human Reproduction and Embryology defines PCOS as being present when patients demonstrate irregular ovulation (usually with clinically evident oligomenorrhea), signs of hyperandrogenism, or polycystic ovaries, after other causes of these signs have been ruled out.

Hyperandrogenic Insulin Resistance and Acanthosis Nigricans Syndrome

Hyperandrogenic insulin resistance and acanthosis nigricans (HAIR-AN) syndrome is an inherited hyperandrogenic disorder of severe insulin resistance, distinct from PCOS. HAIR-AN syndrome is characterized by extremely high circulating levels of insulin (>80 µU/mL basally or >500 µU/mL following an oral glucose challenge) due to severe insulin resistance. Because insulin is also a mitogenic hormone, these extremely elevated insulin levels result in hyperplasia of the basal layers of the epidermal skin, leading to the development of acanthosis nigricans, a velvety, hyperpigmented change of the crease areas of the skin (Figure 32-4). In addition, because of the effect of insulin on ovarian theca cells, the ovaries of many patients with the HAIR-AN syndrome are hyperthecotic. Patients with this disorder can be severely hyperandrogenic and even present with virilization. In addition, these patients are at significant risk for dyslipidemia, type 2 diabetes mellitus, hypertension, and cardiovascular disease. These patients are particularly difficult to treat, although the use of long-acting GnRH analogues has been promising.

FIGURE 32-4 Acanthosis nigricans of the nape of the neck. These gray-brown velvety areas of the skin can be seen on the neck, groin, abdomen, or axillae and are markers of insulin resistance and hyperinsulinemia.

(Courtesy of Ricardo Azziz, MD, MPH, MBA, Cedars-Sinai Medical Center.)

Ovarian Neoplasms

Androgen-producing ovarian tumors are extremely uncommon, occurring in about 1 in 500 hirsute women and include Sertoli-Leydig, hilus, and lipoid cell tumors and virilizing conditions associated with hyperplasia of the stroma surrounding non–hormone-producing ovarian neoplasms. These tumors include cystic teratomas, Brenner’s tumors, serous cystadenomas, and Krukenberg’s tumors (see Chapter 20).