Amenorrhea, Oligomenorrhea, and Hyperandrogenic Disorders

Hypogonadotropic Primary Amenorrhea and Sexual Infantilism

Patients with hypogonadotropic hypogonadism have low serum FSH levels, whereas patients with hypergonadotropic hypogonadism (e.g., gonadal dysgenesis) have elevated serum FSH levels in the menopausal range (>20 to 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 suppress gonadotropin-releasing hormone (GnRH) synthesis and release. Kallmann syndrome is an example of lesions in the hypothalamus causing hypogonadotropic hypogonadism, usually with anosmia (see Chapter 32 and Figure 32-6 ). Because patients with sexual infantilism caused by hypogonadotropic hypogonadism may have a craniopharyngioma or other central nervous system (CNS) tumor, magnetic resonance imaging (MRI) or computed tomography (CT) of the hypothalamic-pituitary area is recommended.

Hypogonadotropic hypogonadism resulting in primary amenorrhea and sexual infantilism may also be caused by lesions of the pituitary, including prolactin-secreting adenomas, or a general process of pituitary failure. These patients should be screened for other pituitary hormone 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 have elevated serum FSH levels. These patients may have gonadal agenesis (the absence or early disappearance of the normal gonad). An example in males, who may appear to be female in some cases, is 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' gestation, these individuals may have female external genitalia with or without ambiguity in addition to a lack of gonads, a hypoplastic uterus (secondary to absent secretion of anti-müllerian hormone), and rudimentary genital ducts (Swyer syndrome). Regression of the testes after 12 to 14 weeks' gestation results in variable development of male external genitalia. Anorchia or streak gonads occur with testicular regression syndrome.

Other individuals with hypergonadotropic primary amenorrhea and sexual infantilism may have gonad­al dysgenesis, or an abnormally developed gonad caused by 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 of developing a gonadoblastoma (a benign germ cell tumor of the gonad) and eventually a 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 17-hydroxylase (P450c17) deficiency, which prevents the synthesis of these sex steroids ( Figure 33-1 ). 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 Leydig cells in the testes are responsible for producing testosterone, these individuals are born with female external genitalia.

Patients with sexual infantilism may be treated to stimulate breast development by administering gradually increasing doses of estrogen. One commonly used regimen is to start with 0.3 mg of conjugated estrogen every other day and slowly increase the dose over 3- to 6-month intervals. This treatment should be guided by the presence or absence of mastalgia (breast tenderness) and the rate of breast development. The estrogen can safely be increased to 0.6 mg or more daily if necessary. Recently, skin patches that deliver 17β-estradiol (E2) in various comparable doses have been used.

Individuals with persistent hypogonadotropic hypogonadism who seek fertility require either human menopausal gonadotropin injections or pulsatile GnRH administered with 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 (IVF) using donor oocytes.

Androgen Insensitivity Syndrome

Patients with complete AIS 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, due to the location of their testes within the abdominal wall or cavity (cryptorchidism). This location, with greater body heat, typically does not allow for normal male hormone secretion. Breast development (with nipples and areolae smaller than a normal genotypical female's) is caused by the testicular secretion of estrogens and by the conversion of circulating androgen to estrogens in the liver and elsewhere. The testes of individuals with AIS secrete normal male amounts of anti-müllerian hormone (AMH); 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 of care for these patients.

Müllerian Dysgenesis or Agenesis

Patients with primary amenorrhea, breast development, and a 46,XX karyotype have serum levels of testosterone appropriate for females. This clinical diagnosis may be caused by müllerian defects that cause obstruction of the vaginal canal (e.g., an imperforate hymen or a transverse vaginal septum) or by the absence of a normal cervix and/or uterus and normal fallopian tubes. An imperforate hymen should be suspected in adolescents who report monthly dysmenorrhea in the absence of vaginal bleeding. 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, females may present with similar symptoms, but without a vaginal bulge. When ultrasonography confirms a normal uterus and ovaries, a transverse, obstructing vaginal septum or cervical agenesis should be suspected. MRI is the diagnostic procedure of choice in these patients. If an 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 women with cervical agenesis undergo hysterectomy.

Finally, rectal examination and ultrasonography may indicate the absence of a uterus, indicating müllerian agenesis or the Mayer-Rokitansky-Küster-Hauser syndrome. This syndrome is characterized by a failure of the müllerian ducts to fuse distally and form the upper genital tract. These patients may have unilateral or bilateral rudimentary uterine tissues (anlagens), fallopian tubes, and ovaries. It is uncommon for an individual 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 reveal them well above the pelvic brim. Currently, the pathophysiology leading to müllerian dysgenetic defects is not known.

Creation of a neovagina can be accomplished by 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/or 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, for these patients, an intravenous pyelogram or other diagnostic radiographic study should be obtained to confirm a normal urinary system.

Hypothalamic-Pituitary Dysfunction

Patients with hypothalamic amenorrhea include women with severe weight loss, women engaging in excessive exercise resulting in low body fat, and women experiencing severe psychological stress. Also included are those women with physical wasting caused by severe systemic diseases such as disseminated malignancies and patients with pituitary or CNS lesions. In the most severe and life-threatening form of hypothalamic amenorrhea, 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 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 above.

When hypothalamic-pituitary dysfunction cannot be resolved by identifying a modifiable underlying cause (e.g., excessive exercise), combination estrogen and progestin therapy, usually in the form of a combined oral contraceptive pill or E2 skin patches with oral progestins, should be prescribed to reduce the risk of osteoporosis. This therapy is also recommended to maintain normal vaginal and breast development. In patients with anorexia nervosa (AN), 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 should be 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 as a result of 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 [T ₄ ]), 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 hormone therapy (estrogen and a progestin) to reduce the risk of osteoporosis.