175 DISORDERS OF THE FEMALE REPRODUCTIVE SYSTEM
Harrison’s Manual of Medicine
DISORDERS OF THE FEMALE REPRODUCTIVE SYSTEM
Abnormal Uterine Bleeding
The ovary is the source of ova for reproduction and produces estrogens and progestins, the hormones that induce secondary sexual characteristics in women and control the menstrual cycle. The pituitary hormones, luteinizing hormone (LH) and follicle-stimulating hormone (FSH) stimulate ovarian follicular development and result in ovulation at about day 14 of the 28-day menstrual cycle.
ABNORMAL UTERINE BLEEDING
Etiology During the reproductive years, the menstrual cycle averages 28 ± 3 days, and the mean duration of blood flow is 4 ± 2 days. A variety of descriptive terms (such as menorrhagia, metrorrhagia, and menometrorrhagia) have been used to characterize patterns of abnormal uterine bleeding, which may be associated with ovulatory cycles or with anovulatory cycles. In the premenarchal period, abnormal uterine bleeding may result from trauma, infection, or precocious puberty. In premenopausal women, abnormal uterine bleeding may also be caused by ectopic pregnancy or threatened abortion. Vaginal bleeding after menopause is frequently due to malignancy.
Menstrual bleeding associated with normal, ovulatory cycles is spontaneous, regular in onset, predictable in duration and amount of flow, and frequently associated with discomfort (dysmenorrhea). Deviations from the established pattern of menstrual flow can result from bleeding dyscrasias, abnormalities of the outflow tract (uterine synechiae or scarring), leiomyomas, adenomyosis, or endometrial polyps. Bleeding between cyclic ovulatory menses can be due to cervical or endometrial lesions.
Anovulatory menstrual bleeding (dysfunctional uterine bleeding) is painless, irregular in occurrence, and unpredictable in amount and duration. Transient disruption of ovulatory cycles occurs most often in the peripubertal years, during the perimenopausal period, or as the consequence of a variety of stresses and intercurrent illnesses. Persistent dysfunctional uterine bleeding in reproductive years is usually due to continuous estrogen effects on the uterus uninterrupted by cyclic fluctuations in progesterone associated with ovulation, and is most commonly due to polycystic ovarian syndrome.
Diagnosis The approach to a pt with dysfunctional uterine bleeding begins with a careful history of menstrual patterns and prior hormonal therapy. Since not all urogenital tract bleeding is from the uterus, rectal, bladder, vaginal, and cervical sources must be excluded by physical exam. If the bleeding is from the uterus, a pregnancy-related disorder such as abortion or ectopic pregnancy must be ruled out.
During a first episode of dysfunctional bleeding the pt can be observed, provided the bleeding is not copious and there is no evidence of a bleeding dyscrasia. If bleeding is more severe, control can be achieved with relatively high-dose estrogen oral contraceptives for 3 weeks. Hospitalization, bed rest, and IM injections of estradiol valerate (10 mg) and hydroxyprogesterone caproate (500 mg) or IV or IM conjugated estrogens (25 mg) usually control severe bleeding. Uterine biopsy should be performed in women approaching the age of menopause, or those who are massively obese, to evaluate for endometrial cancer. After initial treatment, iron replacement should be instituted along with either cyclic oral contraceptives or medroxyprogesterone acetate 10 mg PO qd for 10 days every 2–3 months. Additional evaluation (endometrial biopsy, hysteroscopy, or dilatation and curettage) may be required for diagnosis and therapy.
Etiology Pregnancy should be excluded in women of childbearing age with amenorrhea, even when history and physical exam are not suggestive.
Primary amenorrhea is defined as failure of menarche by age 15, regardless of the presence or absence of secondary sexual characteristics; secondary amenorrhea is failure of menstruation for 6 months in a woman with previous periodic menses. The causes of primary and secondary amenorrhea overlap, and it is generally more useful to classify the disorder according to the source of dysfunction: (1) anatomic defects, (2) ovarian failure, or (3) chronic anovulation with or without estrogen present (Fig. 175-1).
FIGURE 175-1. Flow diagram for the evaluation of women with amenorrhea. The most common diagnosis for each category is shown in parentheses. The dotted lines indicate that in some instances a correct diagnosis can be reached on the basis of history and physical exam alone. (Reproduced from Carr BR, Bradshaw KD: HPIM-15, p. 2165.)
Anatomic defects of the outflow tract that prevent vaginal bleeding include absence of vagina or uterus, imperforate hymen, transverse vaginal septae, and cervical stenosis. Ovarian failure may be due to Turner’s syndrome, pure gonadal dygenesis, premature ovarian failure, the resistant-ovary syndrome, and chemotherapy or radiation therapy for malignancy. The diagnosis of premature ovarian failure is applied to women who cease menstruating before age 40. Chronic anovulation with estrogen present is usually due to polycystic ovarian syndrome (PCOS) and is characterized by amenorrhea or oligomenorrhea, infertility, and evidence of androgen excess (hirsutism, acne, male pattern balding). Features of PCOS are worsened by coexistent obesity. Additional disorders with a similar presentation include excess androgen production from adrenal or ovarian tumors, adult-onset adrenal hyperplasia due to partial 21-hydroxylase deficiency, and thyroid disorders. Women with chronic anovulation with absent estrogen usually have hypogonadotropic hypogonadism due to disease of either the hypothalamus or the pituitary. Hypothalamic causes include Kallmann’s syndrome or Sheehan’s syndrome, hypothalamic lesions (craniopharyngiomas and other tumors, tuberculosis, sarcoidosis, metastatic tumors), hypothalamic trauma or irradiation, rigorous exercise, eating disorders, stressful events, and chronic debilitating diseases (end-stage renal disease, malignancy, malabsorption). Disorders of the pituitary can lead to amenorrhea by two mechanisms: direct interference with gonadotropin secretion or inhibition of gonadotropin secretion via excess prolactin (Chap. 169).
Diagnosis The initial evaluation involves careful physical exam, serum or urine human chorionic gonadotropin (hCG), serum prolactin assay, and evaluation of estrogen status (Fig. 175-1). To determine estrogen status, medroxyprogesterone acetate (10 mg po qd-bid × 5 days) or 100 mg of progesterone in oil IM should be administered. If estrogen levels are adequate and the outflow tract is intact, menstrual bleeding should occur within 1 week of ending progestin treatment. Ovarian failure is associated with a lack of withdrawal menses to progestin challenge and elevated plasma gonadotropin levels. Anatomic defects are usually diagnosed by physical exam and failure to induce menses, though hysterosalpingography or direct visual examination by hysteroscopy may be required. Chromosomal analysis 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 hyperprolactinemia is described in Chap. 169. 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.
Disorders of the outflow tract are managed surgically. Decreased estrogen production, whether from ovarian failure or hypothalamic/pituitary disease, should be treated with cyclic estrogens, either in the form of oral contraceptives or conjugated estrogens (0.625–1.25 mg PO qd) and medroxyprogesterone acetate (2.5 mg PO qd or 5–10 mg during the last 5 days of the month). PCOS may be treated by oral contraceptive agents and weight reduction, along with treatment of hirsutism (see below). Individuals with PCOS should be screened for diabetes mellitus. Fertility may be enhanced by using insulin- sensitizing agents such as metformin.
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. Severe or incapacitating cramping with ovulatory menses in the absence of demonstrable disorders of the pelvis is termed primary dysmenorrhea. Pelvic pain due to organic causes may be classified as uterine (leiomyomas, adenomyosis, cervical stenosis, infections, cancer), adnexal (salpingo-oophoritis, cysts, neoplasms, torsion, endometriosis), vulvar or vaginal (Monilia, Trichomonas, Gardnerella, herpes, condyloma acuminatum, cysts or abscesses of Bartholin’s glands), and pregnancy-associated (threatened or incomplete abortion, ectopic pregnancy). 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 and discomfort. A symptom complex of cyclic irritability, depression, and lethargy is known as premenstrual syndrome (PMS).
Diagnosis Evaluation includes a history, pelvic exam, hCG measurement, pelvic ultrasound. Laparoscopy or laparotomy is indicated in some cases of pelvic pain of undetermined cause.
Primary dysmenorrhea is best treated with NSAIDs or oral contraceptive agents. Infections should be treated with the appropriate antibiotics. Symptoms from PMS may improve with SSRI therapy. Surgery may be required for structural abnormalities.
Etiology Hirsutism, defined as excessive male-pattern hair growth, affects approximately 10% of women of reproductive age. It may be familial or caused by PCOS, ovarian or adrenal neoplasms, congenital adrenal hyperplasia, Cushing’s syndrome, hyperprolactinemia, acromegaly, 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. 53-1 p. 299 in HPIM-15). Associated manifestations of androgen excess include acne and male-pattern balding (androgenic alopecia). Virilization, 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 suggest an ovarian or adrenal neoplasm.
Diagnosis An approach to testing for androgen excess is depicted in Fig. 175-2. The dexamethasone androgen-suppression test (0.5 mg PO q6h × 4 days, with free testosterone levels obtained before and after administration of dexamethasone) may distinguish ovarian from adrenal overproduction. PCOS is a relatively common cause of hirsutism. Incomplete suppression suggests ovarian androgen excess. Congenital adrenal hyperplasia due to 21-hydroxylase deficiency can be excluded by a 17-hydroxyprogesterone level (either in the morning during the follicular phase or 1 h after administration of 250 µg of cosyntropin) that is <6 nmol/L (<2 µg/L). CT may localize an adrenal mass, and ultrasound will identify an ovarian mass, if evaluation suggests these possibilities.
FIGURE 175-2. Algorithm for the evaluation and differential diagnosis of hirsutism. ACTH, adrenocorticotropic hormone; CAH, congenital adrenal hyperplasia; DHEAS, sulfated form of dehydroepiandrosterone; GnRH, gonadotropin-releasing hormone; PCOS, polycystic ovarian syndrome.
Nonpharmacologic treatments include (1) bleaching; (2) depilatory such as shaving and chemical treatments; and (3) epilatory such as plucking, waxing, electrolysis, and laser therapy. Pharmacologic therapy includes oral contraceptives with a low androgenic progestin and spironolactone (100–200 mg PO qd), often in combination. Glucocorticoids (dexamethasone 0.25–0.5 mg qhs or prednisone 5–10 mg qhs) are the mainstay of treatment in pts with congenital adrenal hyperplasia. Attenuation of hair growth with pharmacologic therapy is typically not evident until 4–6 months after initiation of medical treatment and therefore should be used in conjunction with nonpharmacologic treatments.
Etiology The menopause is defined as the final episode of menstrual bleeding and occurs at a median age of 50–51 years. It reflects depletion of ovarian follicles or is the consequence of oophorectomy.
Clinical Features The most common menopausal symptoms are vasomotor instability (hot flashes), mood changes (nervousness, anxiety, irritability, and depression), atrophy of the urogenital epithelium and skin, decreased size of the breasts, and osteoporosis. FSH levels are elevated to ³40 IU/L.
Estrogen therapy ameliorates vasomotor instability and atrophy of the urogenital epithelium and skin and is of benefit in prevention of osteoporosis (Chap. 177) and potentially of cardiovascular disease. However, low-dose estrogen therapy may increase the incidence of breast cancer and hypertension, as well as the risk of venous thromboembolism and gallbladder disease. For long-term use, estrogens should be given in the minimal effective doses (conjugated estrogen 0.625 mg PO qd, micronized estradiol 1.0 mg PO qd, or transdermal estradiol 0.05–1.0 mg once or twice a week). Women with an intact uterus should be given estrogen in combination with a progestin (medroxyprogesterone either cyclically, 5–10 mg PO qd for days 15–25 each month, or continuously, 2.5 mg PO qd) to avoid the increased risk of endometrial carcinoma seen with unopposed estrogen use.
The most widely used methods for fertility control include (1) rhythm and withdrawal techniques, (2) barrier methods, (3) intrauterine devices, (4) oral contraceptives, (5) sterilization, and (6) abortion.
Oral contraceptive agents are widely used for both prevention of pregnancy and control of dysmenorrhea and anovulatory bleeding. Combination oral contraceptive agents contain synthetic estrogen (ethinyl estradiol or mestranol) and synthetic progestins. Low-dose norgestimate and third-generation progestins (desogestrel, gestodene) have a less androgenic profile; levonorgestrel appears to be the most androgenic of the progestins and should be avoided in pts with hyperandrogenic symptoms. The three major formulation types include fixed- dose estrogen-progestin, phasic estrogen-progestin, and progestin only.
Despite overall safety, oral contraceptive users are at risk for venous thromboembolism, hypertension, and cholelithiasis. Risks for myocardial infarction and stroke are increased with smoking and aging. Side effects, including break- through bleeding, amenorrhea, and weight gain, are often responsive to a change in formulation.
Absolute contraindications to the use of oral contraceptives include previous thromboembolic disorders, cerebrovascular or coronary artery disease, known or suspected carcinoma of the breasts or other estrogen-dependent neoplasia, liver disease, undiagnosed genital bleeding, or known or suspected pregnancy. Relative contraindications include hypertension, migraine headaches, diabetes mellitus, uterine leiomyomas, sickle cell anemia, hyperlipidemia, and elective surgery.
Emergency contraceptive pills, containing progestin only or estrogen and progestin, can be used within 72 h of unprotected intercourse for prevention of pregnancy. Both Plan B and Preven are emergency contraceptive kits specifically designed for postcoital contraception. In addition, certain oral contraceptive pills may be dosed for emergency contraception. Progestin-only pills have a lower risk of nausea and vomiting than combination estrogen-progestin agents.
Etiology Infertility is defined as the inability to conceive after 12 months of unprotected sexual intercourse. The causes of infertility are outlined in Fig. 175-3. Male infertility is discussed in Chap. 174.
FIGURE 175-3. Causes of infertility, FSH, follicle-stimulating hormone; LH, luteinizing hormone.
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. 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. Tubal disease can be evaluated by obtaining a hysterosalpingogram or by diagnostic laparoscopy. Endometriosis may be suggested by history and exam but is often clinically silent and can only be excluded definitively by laparoscopy.
The treatment of infertility should be tailored to the problems unique to each couple. Treatment options include expectant management, clomiphene citrate with or without intrauterine insemination (IUI), gonadotropins with or without IUI, and in vitro fertilization (IVF). In specific situations, surgery, pulsatile GnRH therapy, intracytoplasmic sperm injection (ICSI), or assisted reproductive technologies with donor egg or sperm may be required.
For a more detailed discussion, see Carr BR, Bradshaw KD: Disturbances of Menstruation and Other Common Gynecologic Complaints in Women, Chap. 52, p. 295; Ehrmann DA: Hirsutism and Virilization, Chap. 53, p. 297; Hall JE: Infertility and Fertility Control, Chap. 54, p. 301; and Carr BR, Bradshaw KD: Disorders of the Ovary and Female Reproductive Tract, Chap 336, p. 2154, in HPIM-15.