Etiology

Amenorrhea refers to the absence of menstrual periods. It is classified as primary, if menstrual bleeding has never occurred by age 15 in the absence of hormonal treatment, or secondary, if menstrual periods are absent for >3 months in a woman with previous periodic menses. Pregnancy should be excluded in women of childbearing age with amenorrhea, even when history and physical examination are not suggestive. Oligomenorrhea is defined as a cycle length of >35 days or <10 menses per year. Both the frequency and amount of bleeding are irregular in oligomenorrhea. Frequent or heavy irregular bleeding is termed dysfunctional uterine bleeding if anatomic uterine lesions or a bleeding diathesis has been excluded.

The causes of primary and secondary amenorrhea overlap, and it is generally more useful to classify disorders of menstrual function into disorders of the uterus and outflow tract and different causes for abnormal ovulation (Fig. 178-1. Algorithm for Evaluation of Amenorrhea).

Anatomic defects of the outflow tract that prevent vaginal bleeding include absence of vagina or uterus, imperforate hymen, transverse vaginal septae, and cervical stenosis.

Women with amenorrhea and low FSH and LH levels have hypogonadotropic hypogonadism due to disease of either the hypothalamus or the pituitary. Hypothalamic causes include congenital idiopathic hypogonadotropic hypogonadism, hypothalamic lesions (craniopharyngiomas and other tumors, tuberculosis, sarcoidosis, metastatic tumors), hypothalamic trauma or irradiation, vigorous exercise, eating disorders, stress, and chronic debilitating diseases (end-stage renal disease, malignancy, malabsorption). The most common form of hypothalamic amenorrhea is functional, reversible gonadotropin-releasing hormone (GnRH) deficiency due to psychological or physical stress, including excess exercise, malnutrition, and anorexia nervosa. Disorders of the pituitary include rare developmental defects, pituitary adenomas, granulomas, postradiation hypopituitarism, and Sheehan's syndrome. They can lead to amenorrhea by two mechanisms: direct interference with gonadotropin production, or inhibition of GnRH secretion via excess prolactin production (Chap. 171 Disorders of the Anterior Pituitary and Hypothalamus).

Women with amenorrhea and high FSH levels have ovarian failure, which may be due to Turner's syndrome, pure gonadal dysgenesis, premature ovarian insufficiency, the resistant-ovary syndrome, and chemotherapy or radiation therapy for malignancy. The diagnosis of premature ovarian insufficiency is applied to women who cease menstruating before age 40.

Polycystic ovarian syndrome (PCOS) is characterized by the presence of clinical or biochemical hyperandrogenism (hirsutism, acne, male pattern baldness) in association with amenorrhea or oligomenorrhea. The metabolic syndrome and infertility are often present; these features are worsened with coexistent obesity. Additional disorders with a similar presentation include excess androgen production from adrenal or ovarian tumors and adult-onset congenital adrenal hyperplasia. Hyperthyroidism may be associated with oligo- or amenorrhea; hypothyroidism more typically with metrorrhagia.

Diagnosis

The initial evaluation involves careful physical examination including assessment of hyperandrogenism, serum or urine human chorionic gonadotropin (hCG), and serum FSH levels (Fig. 178-1. Algorithm for Evaluation of Amenorrhea). Anatomic defects may be diagnosed by physical examination, though hysterosalpingography or direct visual examination by hysteroscopy is often required. A karyotype should be performed when gonadal dysgenesis is suspected. The diagnosis of PCOS is based on the coexistence of chronic anovulation and androgen excess, after ruling out other etiologies for these features. The evaluation of pituitary function and hyperprolactinemia is described in Chap. 171 Disorders of the Anterior Pituitary and Hypothalamus. In the absence of a known etiology for hypogonadotropic hypogonadism, MRI of the pituitary-hypothalamic region should be performed when gonadotropins are low or inappropriately normal.

Etiology

Pelvic pain may be associated with normal or abnormal menstrual cycles and may originate in the pelvis or be referred from another region of the body. A high index of suspicion must be entertained for extrapelvic disorders that refer to the pelvis, such as appendicitis, diverticulitis, cholecystitis, intestinal obstruction, and urinary tract infections. A thorough history including the type, location, radiation, and status with respect to increasing or decreasing severity can help to identify the cause of acute pelvic pain. Associations with vaginal bleeding, sexual activity, defecation, urination, movement, or eating should be sought. Determination of whether the pain is acute versus chronic, constant versus spasmodic, and cyclic versus noncyclic will direct further investigation (Table 178-1 Causes of Pelvic Pain).

Acute Pelvic Pain

Pelvic inflammatory disease most commonly presents with bilateral lower abdominal pain. Testing for C. trachomatis and N. gonorrhea should be considered for women at increased risk. Unilateral pain suggests adnexal pathology from rupture, bleeding, or torsion of ovarian cysts, or, less commonly, neoplasms of the ovary, fallopian tubes, or paraovarian areas. Ectopic pregnancy is associated with right- or left-sided lower abdominal pain, vaginal bleeding, and menstrual cycle abnormalities, with clinical signs appearing 6-8 weeks after the last normal menstrual period. Orthostatic signs and fever may be present. Uterine pathology includes endometritis and degenerating leiomyomas.

Chronic Pelvic Pain

Many women experience lower abdominal discomfort with ovulation (mittelschmerz), characterized as a dull, aching pain at midcycle that lasts minutes to hours. In addition, ovulatory women may experience somatic symptoms during the few days prior to menses, including edema, breast engorgement, and abdominal bloating or discomfort. A symptom complex of cyclic irritability, depression, and lethargy is known as premenstrual syndrome (PMS). Severe or incapacitating cramping with ovulatory menses in the absence of demonstrable disorders of the pelvis is termed primary dysmenorrhea. Secondary dysmenorrhea is caused by underlying pelvic pathology such as endometriosis, adenomyosis, or cervical stenosis.

Diagnosis

Evaluation includes a history, pelvic examination, hCG measurement, tests for chlamydial and gonococcal infections, and pelvic ultrasound. Laparoscopy or laparotomy is indicated in some cases of pelvic pain of undetermined cause.

Etiology

Hirsutism, defined as excessive male-pattern hair growth, affects ∼10% of women. It may be familial or caused by PCOS, ovarian or adrenal neoplasms, congenital adrenal hyperplasia, Cushing's syndrome, pregnancy, and drugs (androgens, oral contraceptives containing androgenic progestins). Other drugs, such as minoxidil, phenytoin, diazoxide, and cyclosporine, can cause excessive growth of non-androgen-dependent vellus hair, leading to hypertrichosis.

Clinical Features

An objective clinical assessment of hair distribution and quantity is central to the evaluation. A commonly used method to grade hair growth is the Ferriman-Gallwey score (see Fig. 387-1, HPIM-20). Associated manifestations of androgen excess include acne and male-pattern balding (androgenic alopecia). Virilization or androgenization, on the other hand, refers to the state in which androgen levels are sufficiently high to cause deepening of the voice, breast atrophy, increased muscle bulk, clitoromegaly, and increased libido. Historic elements include menstrual history and the age of onset, rate of progression, and distribution of hair growth. Sudden development of hirsutism, rapid progression, and virilization suggests an ovarian or adrenal neoplasm.

Diagnosis

An approach to testing for androgen excess is depicted in Fig. 178-2. Algorithm for the Evaluation and Differential Diagnosis of Hirsutism. PCOS is a relatively common cause of hirsutism. The dexamethasone androgen-suppression test (0.5 mg PO every 6 h × 4 days, with free testosterone levels obtained before and after administration of dexamethasone) may distinguish ovarian from adrenal overproduction. Incomplete suppression suggests ovarian androgen excess. Congenital adrenal hyperplasia due to 21-hydroxylase deficiency can be excluded by a 17-hydroxyprogesterone level that is <6 nmol/L (<2 µg/L) either in the morning during the follicular phase or 1 h after administration of 250 µg of cosyntropin. CT may localize an adrenal mass, and ultrasound may identify an ovarian mass, if evaluation suggests these possibilities.

Etiology

Menopause is defined as the final episode of menstrual bleeding and occurs at a median age of 51 years. It is the consequence of depletion of ovarian follicles or of oophorectomy. The onset of perimenopause, when fertility wanes and menstrual irregularity increases, precedes the final menses by 2-8 years.

Clinical Features

The most common menopausal symptoms are vasomotor instability (hot flashes and night sweats), mood changes (nervousness, anxiety, irritability, and depression), insomnia, and atrophy of the urogenital epithelium and skin. FSH levels are elevated to ≥40 IU/L with estradiol levels that are <30 pg/mL.

Etiology

Infertility is defined as the inability to conceive after 12 months of unprotected sexual intercourse. The causes of infertility are outlined in Fig. 178-4. Causes of Infertility. Male infertility is discussed in Chap. 177 Disorders of the Male Reproductive System.

Clinical Features

The initial evaluation includes discussion of the appropriate timing of intercourse, semen analysis in the male, confirmation of ovulation in the female, and, in the majority of situations, documentation of tubal patency in the female. Abnormalities in menstrual function constitute the most common cause of female infertility (Fig. 178-1. Algorithm for Evaluation of Amenorrhea). A history of regular, cyclic, predictable, spontaneous menses usually indicates ovulatory cycles, which may be confirmed by urinary ovulation predictor kits, basal body temperature graphs, or plasma progesterone measurements during the luteal phase of the cycle. An FSH level <10 IU/mL on day 3 of the cycle predicts adequate ovarian oocyte reserve. Tubal disease can be evaluated by obtaining a hysterosalpingogram or by diagnostic laparoscopy. Endometriosis may be suggested by history and examination, but is often clinically silent and can only be excluded definitively by laparoscopy.