Meredith B. Loveless
Shehzad Basaria
A normal menstrual cycle in a woman of reproductive age is an indicator of health. Absent or abnormal menses is not only a source of discomfort and anxiety but may also signify pathology in a wide variety of organ systems. Because there are a myriad of causes of abnormal vaginal bleeding, it is helpful to think of relevant etiologies during the various stages of a woman's reproductive life. This chapter reviews the evaluation and management of common menstrual disorders by age group to guide clinical care.
Female Reproductive Physiology
The female menstrual cycle is a complex milieu of hormonal functions that establish the normal menstrual pattern. Maturation of the hypothalamic–pituitary axis is required for normal menstrual function. The pulsatile release of gonadotropin releasing hormone (GnRH) from the hypothalamus causes the gonadotropins, luteinizing hormone (LH) and follicle-stimulating hormone (FSH), to be secreted from the pituitary. Under the influence of FSH multiple follicles in the ovary are stimulated. This stimulation causes follicular granulosa cells to increase the number of FSH receptors, and release estrogen and convert
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androgens to estradiol by aromatization, ultimately resulting in increasing levels of estradiol. A dominant follicle emerges, producing even higher levels of estrogen. Negative feedback from the rising estrogen levels halts further FSH stimulation of the nondominant follicles resulting in atresia (destruction). The estrogen secretion in this early or follicular phase of the menstrual cycle induces proliferation of the uterine endometrium. The rising estradiol levels stimulate a positive feedback, resulting in release of LH from the theca cells surrounding the dominant follicle. The LH surge causes ovulation or the release of the ovum from the dominant follicle. During the later half of the cycle or luteal phase, the corpus luteum produces both estrogen and progesterone at levels high enough to maintain an early pregnancy if fertilization occurs and suppresses GnRH release from the hypothalamus. The luteal phase is relatively constant at 14 ± 2 days. Progesterone acts on the uterus to produce a secretory endometrium that is rich in glycogen, and in concert with estrogen, causes a negative feedback effect that gradually reduces the secretion of LH and FSH. With loss of gonadotropic stimulation, the corpus luteum involutes, steroid secretion diminishes, and the endometrium, left without estrogen and progesterone support, sloughs off as the menstrual flow. Breakdown of the endometrium is orderly and progressive, providing reproducible menstrual flow. At this point, with estradiol and progesterone negative feedback at low levels, FSH and LH begin to rise, a new cohort of small follicles is recruited, and the stage is set for the next cycle.
Abnormal Bleeding Patterns
When evaluating abnormal vaginal bleeding, it is helpful to define various bleeding patterns. The normal intermenstrual interval is 28 ± 7 days (1). The normal duration of menstrual flow is 4 to 7 days, with a mean blood loss of 40 mL. Prolonged excessive bleeding of greater than 80 mL or lasting longer than 7 days is menorrhagia. Metrorrhagia is bleeding between periods. Menometrorrhagia is prolonged menses with intramenstrual bleeding. Menses less than 21 days apart is defined as polymenorrhea. Oligomenorrhea is menses greater than 35 days apart, of which the majority are anovulatory. Amenorrhea is defined as no menses for at least 6 months. Abnormal uterine bleeding (AUB) is a clinical term referring to abnormal bleeding in premenopausal women that is not caused by identifiable gynecologic pathology. Postmenopausal bleeding must be investigated (see Chapter 106).
Amenorrhea
Amenorrhea is divided into two categories: primary and secondary. Primary amenorrhea is diagnosed in young women who have developed secondary sexual characteristics but have not menstruated by age 16, or who have not developed secondary sexual characteristics or begun to menstruate by age 14 years (see Primary Amenorrhea section). Secondary amenorrhea is diagnosed in women with a previously normal cycle who have had no menses for 6 months or a length of time equivalent to a total of a least three of the previous cycle intervals. Any report of missed menses necessitates a pregnancy test because this is commonly the cause of missed menses.
Anovulatory Bleeding
Anovulatory bleeding is a diagnosis of exclusion after it has been established that there are no anatomic abnormalities. In the absence of ovulation the endometrium proliferates under the unopposed stimulation of estrogen. The endometrium becomes thickened and disorderly. Unlike the synchronized endometrial sloughing seen in the normal cycle, anovulatory bleeding is disorganized, unpredictable, and irregular. Spontaneous bleeding from the breakdown of the spiral arteries within the endometrium leads to vaginal spotting. Regions of the hyperplastic endometrium will be disrupted, then heal, while another region begins to bleed. Disruption in estrogen stimulation results in the collapse of the thickened endometrium and results in heavy and prolonged bleeding. This type of bleeding is most common at either end of the reproductive life span due to disturbances in the hypothalamic–pituitary–ovarian (HPO) axis. When ovulation is suppressed by the administration of progestins, such as medroxyprogesterone, for hormonal contraception or for induction of amenorrhea to control gynecologic disorders such as endometriosis, anovulatory bleeding may also occur.
Postcoital Bleeding
The cause of postcoital bleeding is usually mechanical trauma. The cervix in pregnant women and in women taking oral contraceptives (OCs) tends to be friable due to the exposure of the endocervix. This is visible on speculum examination and is termed an ectropion cervix. Postcoital bleeding may also occur as a result of local pathology. Lesions such as cervical polyps or vaginal or cervical malignancy may be friable and contribute to vaginal bleeding, whereas lesions such as submucous myomas may disturb the endometrium itself. Infections of the cervix may present with postcoital bleeding because of the friability and inflammation of the cervix and should be excluded.
Atrophic Bleeding
The most common form of postmenopausal bleeding is bleeding from atrophic endometrium. This bleeding often occurs after coitus or other mechanical
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trauma as a result of the thinning and subsequent fragility of non-estrogenized tissue. This diagnosis cannot be established, however, without first ruling out malignancy with endometrial sampling (see Late Reproductive Age through Postmenopause). All postmenopausal bleeding is abnormal, and gastrointestinal (GI)/urinary sources should be excluded, as should gynecologic malignancies.
Evaluation of Abnormal Bleeding
Diagnostic evaluation of a patient with abnormal bleeding is modified depending on the patient's age. A basic overview of the evaluation includes the following.
History
The history can help establish the likelihood that abnormal bleeding is associated with one of four common causes: pregnancy, bleeding because of abnormal endocrine control, bleeding because of gynecologic pathology, or menstrual disruption because of systemic disease. The key items to note are the patient's age, onset of menarche, prior menstrual cycle history, contraceptive and sexual history, and any symptoms of systemic disorders.
A chronicle of pubertal events should be recorded, including earliest budding of breast tissue (thelarche), pubic hair darkening and lengthening (pubarche), onset of menstrual flow (menarche), and time of onset and cessation of the growth spurt. A menstrual history includes the average interval between menses, their regularity, and when any irregularity developed; date of last period and previous period before that; duration of flow and its magnitude; and presence of ovulatory pain (mittelschmerz), premenstrual tension, and dysmenorrhea (the latter three findings suggest ovulatory cycles). Sexual history including contraception use and history of sexual transmitted diseases should be obtained. A pregnancy and nursing history should include number of pregnancies, miscarriages, abortions, mode of delivery and complications during the pregnancy or birth. Gynecologic history should include abnormal Pap smears and treatments, prior gynecologic procedures (including dilation and curettage), history of ovarian cyst or tumors, endometriosis, pelvic pain, or malignancy.
One should ask whether the patient is troubled by growth of excessive hair and, if so, the duration of symptoms, the location and severity of the problem, and any treatment used. Removal of unwanted hair is common, and may be missed if the history is not elicited. Symptoms of estrogen deficiency (hot flushes, vaginitis, dyspareunia, breast atrophy) are important (see Chapter 106). A careful history of medication and drug use, including use of OCs, may be helpful. A further general history should include weight gain or loss; dietary habits (especially rigorous dieting); strenuous exercise (e.g., running, ballet, gymnastics); symptoms of diabetes mellitus, adrenal disease, or thyroid disease; and a history of tuberculosis or hepatic, renal, or neurologic problems. A family history should include ethnic origin and a familial occurrence of reproductive and other endocrine dysfunctions (e.g., hirsutism, oligomenorrhea, hypothyroidism, type 1 diabetes mellitus [DM]) and a history of blood dyscrasias.
Physical Examination
Findings on the general physical examination can provide important clues to the diagnosis of anovulatory states. On inspection one should note body habitus (obese or wasted, mature or child-like, masculine or feminine) and general health of the patient. The presence or absence of pubic and axillary hair; distribution of coarse dark hair on the chest (periareolar, midsternal), abdomen, buttocks, and extremities; and the density of such hair must be noted. The skin should be evaluated for bruises, petechiae, striae and signs of androgen excess such as acne and acanthosis nigricans. Examination of breasts and pubic hair should include an estimate of their stage of maturity based on available standards. Nipples should be squeezed gently to assess for expressible galactorrhea.
Pelvic examination is of chief importance in identifying lesions of the external genitalia, vagina, or cervix and in delineating uterine size and shape. Clinically important lesions of the uterus affecting the endometrial canal are not reliably detected by physical examination, however. On pelvic examination it is important to look for clitoromegaly (greater than 2.0 cm in length), state of the vaginal mucosa (dry versus moist, thick and rugose versus thin and atrophic), abnormal discharge, and condition of the cervix (ectropion, erythema, lesions). Bimanual examination should be done to estimate the uterine size, presence of fibroids, and whether the ovaries are enlarged. In primary amenorrhea without maturation, signs of Turner syndrome (wide-set eyes, shield chest, wide-set nipples, “webbing” of neck, short fourth metacarpal, and signs of aortic coarctation) should be sought.
Laboratory Tests and Radiology
It is critical to exclude pregnancy in all women of reproductive age (Table 101.1). All women with secondary amenorrhea should be considered pregnant until proven otherwise (even if sexual activity is not admitted, as may be the case with adolescents). Specific human chorionic gonadotropin (hCG) assay is the most sensitive test for pregnancy. Screening for sexually transmitted diseases (chlamydia, gonorrhea) is important (see Chapter 37), because cervicitis may be associated with vaginal bleeding.
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TABLE 101.1 Suggested Diagnostic Studies in the Evaluation of Abnormal Vaginal Bleeding |
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The routine laboratory studies done for the evaluation of abnormal uterine bleeding are the complete blood count (CBC), thyroid-stimulating hormone (TSH), and prolactin. The hemoglobin and hematocrit may help to quantify the amount of blood loss. A normal platelet count excludes thrombocytopenia, but not platelet dysfunction. The investigation of central hypogonadism should include a serum prolactin level, especially if galactorrhea is present. Prolactin values between 30 and 100 ng/mL are elevated, but they may result from other causes such as hypothalamic (idiopathic) galactorrhea or drug effects. Values greater than 100 ng/mL almost always mean that a prolactinoma is present. In this case evaluation for visual changes and compressive symptoms must be performed. If the physical examination suggests that the patient is hyperandrogenic, testosterone, dehydroepiandrosterone-sulfate (DHEAS), serum 17-OH progesterone, cholesterol and fasting blood sugar should be determined. It is important to identify chronic anovulation in hyperandrogenic patients early in life to help reduce the incidence of future cardiovascular disease, endometrial cancer, and diabetes.
Other systemic causes of abnormal bleeding include coagulopathies (see Chapter 56). Studies have demonstrated a wide variation in the prevalence of coagulation disorders, ranging from 5% to 20% in hospitalized adolescents with menorrhagia (3). von Willebrand disease, the most common inherited bleeding disorder, has been identified in 5% to 24% of women who present with menorrhagia (4). von Willebrand disease is important to identify, since bleeding can often be managed with intranasal desmopressin acetate (DDAVP) or OC (5,6). Leukemia, idiopathic thrombocytopenic purpura, and severe liver or kidney disease can cause coagulopathy. A personal and family history of bleeding diathesis with prior surgery, trauma, or dental procedures should be elicited. Table 101.1 can be used as a guide for appropriate testing based on the history and examination findings.
Papanicolaou Smear and Endometrial Biopsy
Evaluations to exclude malignancy include a recent Papanicolaou (Pap) smear, with colposcopy and biopsy if any cervical abnormalities are seen. Visible lesions of the external genitalia, vagina, and cervix require biopsy because cytologic evaluation becomes less sensitive in the presence of inflammation and necrosis (7). High risk strains of human papilloma virus (HPV) are associated with abnormal cervical cytology. HPV testing can aid in the diagnosis and management of cervical dysplasia (see Chapter 104).
The principal use of endometrial biopsy is to exclude malignancy or premalignant states in the endometrium. Endometrial biopsy is indicated for evaluation of postmenopausal bleeding, abnormal bleeding in the perimenopausal woman, and less often, abnormal bleeding in younger women who are at risk for neoplasm because of anovulation (8). Sampling of endometrial tissue by blind transcervical biopsy accurately reflects the histologic state of the endometrium to a remarkable degree, given the small portion of endometrial surface retrieved. Chapter 104 discusses the procedure more fully. Numerous studies have validated the accuracy of histologic results achieved by biopsy using formal dilatation and curettage as a gold standard. The sensitivity of the technique in detecting endometrial carcinoma ranged from 85% to 95% in several series (8).
Imaging of the Reproductive Tract
The chief value of imaging procedures in the patient with abnormal bleeding is to identify lesions of the uterus, fallopian tubes, and ovaries and to assess the appearance of the endometrium. Transvaginal ultrasound provides high-resolution images that permit evaluation for endometrial thickness, endometrial contour, and presence of leiomyomas in the subadjacent myometrium. Simultaneous
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transcervical instillation of fluid (sonohysterography) can add sensitivity to detection of lesions affecting the endometrial canal (10,11). Transvaginal ultrasound is also a cost-effective complement to endometrial biopsy in the evaluation of abnormal bleeding (9,12). Clinicians should consider ultrasound evaluation of the endometrial thickness, particularly in older patients in whom biopsy may be difficult. Computed tomography (CT) and magnetic resonance imaging (MRI) have not been shown to be superior to these ultrasound techniques. During proliferation in the normal cycle, endometrial thickness may reach 1 cm or more and appears as distinct layers due to the stromal edema in the opposing anterior and posterior surfaces. Secretory endometrium appears homogenous and more echogenic. Excessive thickness, with or without irregularity, is consistent with hyperplasia or may reflect the presence of endometrial polyps. Leiomyomas are easily distinguishable. Those that are subadjacent to, or that distort, the uterine cavity are more likely to be associated with abnormal bleeding. Sonohysterography is a particularly helpful adjuvant to standard vaginal sonography to identify submucosal fibroids and polyps.
The significance of endometrial thickness in the evaluation of postmenopausal bleeding has received considerable study. Malignancy or other abnormal proliferation is unlikely when the endometrial thickness is less than 4 mm (12,13). If endometrial biopsy in such patients yields insufficient tissue for histologic interpretation, as may commonly occur, malignancy is adequately ruled out if the endometrium is less than 5 mm thick on ultrasound evaluation. Further investigation should be done if tissue sampling is insufficient for diagnosis and endometrial thickness is 5 mm or more, depending on the entire clinical picture, including age, symptoms, and risk factors.
Age-Specific Guidelines for Evaluation of Abnormal Vaginal Bleeding
Adolescent: 1 to 18 Years
Menorrhagia
The principal causes of menorrhagia in the young patient are anovulatory bleeding and bleeding diathesis. However, the possibility of pregnancy should never be overlooked in a young woman with bleeding complaints, even in the absence of a supporting history. The history provides important clues to the evaluation: erratic and unpredictable bleeding patterns suggest an ovulatory disturbance, whereas regular heavy menses associated with nongynecologic bleeding problems suggest a bleeding diathesis.
Anovulatory bleeding at this age is a normal physiologic event; 85% of perimenarchal cycles are anovulatory. This is especially true in the first 2 years after menarche. If the history and examination are otherwise normal, symptomatic management and observation are preferable to endocrine evaluation over the short term. If evidence of ovulatory disturbance is present more than 1 year after menarche, endocrine evaluation should be undertaken. Endocrine assessment for persistent anovulation and anovulatory bleeding in the very young woman is sufficiently investigated with assessment for thyroid dysfunction (TSH) and hyperprolactinemia (serum prolactin). A pattern consistent with chronic anovulation is commonly revealed, and if this is the case, it is likely that normal cycles will be established with further maturation. OCs may be used to regulate the menstrual cycle and help allay anxiety and possible concerns about pregnancy if the teenager is sexually active. In the young woman, it is important to rule out coagulopathy and leukemia with a complete blood count and coagulation profile. Blood dyscrasias are common in this age group with reported frequency up to 20% in young women presenting with menorrhagia (3); therefore adolescents with menorrhagia should be screened with partial thromboplastin time, prothrombin time, and assessment of platelet function. A platelet function analyzer or PFA-100 test is a useful screening test for von Willebrand disease and other platelet disorders if available (14) (see Chapter 56).
Anovulatory bleeding may be heavy and require emergency care. The risk of endometrial cancer in this group is extremely rare. Endometrial biopsy should be confined to those cases in which medical management has failed or chronic anovulation has persisted for several years, thus placing the endometrium at risk. Acute episodes of menorrhagia can usually be arrested with high doses of oral progestational agents in the form of OCs or medroxyprogesterone acetate (MPA), 10 mg daily, administered for 1 to 2 weeks, during which time bleeding tapers or ceases. After progestin treatment is stopped, “normal,” self-limited, menstrual withdrawal occurs. Further episodes of anovulatory menorrhagia can be prevented by regular progestin-induced withdrawal with OC use. If bleeding is severe, it can be managed acutely with either intravenous conjugated estrogen, 25 mg every 4 to 6 hours for up to 24 hours, or 2.5 mg conjugated oral estrogen, up to 10 mg/day; 90% to 95% of patients respond to medical therapy within 1 to 2 days. Antiemetics are often needed to control the nausea experienced with higher doses of estrogen. Once bleeding has stopped, OCs are started in a taper regimen (3 pills per day for 3 days, then 2 pills per day for 3 days, then 1 pill per day for 4 weeks). Then a withdrawal bleed is allowed, and standard cyclic OCs are started. Continuous OCs will also help restore normal hemoglobin if anemia is present. Furthermore, iron supplementation should be given (see Chapter 55). Endometrial curettage is rarely necessary; however, if the patient is hemodynamically unstable or refractory to treatment, this
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procedure can be very successful in stopping the bleeding. A coagulation panel should be drawn before hormonal agents are given as estrogen can alter the results of von Willebrand testing. Patients with chronic medical disease, such as immune thrombocytopenia, can be regulated with hormonal therapy to prevent worsening anemia from vaginal bleeding.
Primary Amenorrhea
Primary amenorrhea (defined in Amenorrhea section) is not usually idiopathic, and an underlying cause must be sought. Primary central amenorrhea with maturational failure suggests idiopathic or genetic gonadotropin deficiency of pituitary or hypothalamic origin. A patient with primary gonadal failure is most likely to have Turner syndrome (XO sex chromosomes and no ovaries). Primary amenorrhea with normal maturation may be the result of peripheral causes as simple as imperforate hymen with obstruction of menses or as serious as congenital uterine agenesis.
The first component of the evaluation is to determine the presence or absence of normal secondary sexual characteristics. The presence of breasts confirms an intact HPO axis and functional ovaries. Pubic and axillary hair indicate normal androgen and androgen-receptor function. Physical examination should include growth chart evaluation, Tanner staging (see Chapter 11), neurologic examination, galactorrhea screening, olfactory tests, and evaluation for Turner stigmata.
If the patient has normal secondary sexual characteristics but no menses, she probably has an anatomic problem, usually one that is obvious on examination. If the uterus is present, it may be abnormal (Rokitansky–Küster–Hauser syndrome) or there may be an abnormality in the outflow tract (müllerian agenesis). An MRI or pelvic ultrasound examination helps confirm the diagnosis. These patients should be referred to a pediatric gynecologist for further evaluation and treatment.
The presence of normal breast development and height but no sexual hair suggests androgen insensitivity. Serum testosterone levels in the male range and XY karyotype confirm the diagnosis (see Chapter 85).
If the patient has no secondary sexual characteristics and no menarche, then an FSH level may be diagnostic. Elevated FSH indicates ovarian dysgenesis. If the FSH is low or normal, the diagnostic possibilities include hyperprolactinemia, thyroid disease, brain tumor, and Turner syndrome.
Amenorrhea Secondary to Weight Loss, Eating Disorders, or Exercise
Functional hypothalamic dysfunction is common in younger women, and if endocrine evaluation is inconclusive, attention should be given to the possibilities of stress at home or in school, adjustment problems, substance abuse, and eating disorders (see Chapter 11). Irregular menses, delayed onset of menarche, and secondary amenorrhea are not uncommon in women who are 10% to 12% less than their ideal body weight. With excessive weight loss, amenorrhea may last longer than 1 year after dieting ceases. This phenomenon arises from hypothalamic suppression with decreased GnRH secretion. There are many theories about the exact mechanism by which the hypothalamus is suppressed; however, a significant determinant is the amount of body fat. As body fat decreases, there is a measurable decrease in LH pulsatile frequency and amplitude before onset of irregular menses. According to Speroff et al., the minimum level of body fat associated with menarche is 17%; secondary amenorrhea is associated with levels less than 22% (15).
The treatment for functional hypothalamic disorder focuses on contraception and bone protection. It is still possible to ovulate with this condition and, in the presence of irregular or absent menses, it is difficult to gauge whether the cause is pregnancy or physical activity. It must be stressed to these patients that contraception is necessary to ensure that an undesired pregnancy is avoided. Those desiring conception should be advised to decrease their level of activity with the possibility of establishing a regular menstrual cycle or at least enough GnRH secretion to result in ovulation. Another issue raised by this condition is whether the decreased amount of estrogen results in increased rates of bone demineralization. Studies have established a radiologically detectable decrease in bone mineral density in amenorrheic female athletes, despite a normal rate of bone turnover. Hetland et al. noted a 10% decrease in lumbar bone density in amenorrheic runners, with a concomitant 25% to 44% decrease in circulating progesterone and estradiol (16). Prior et al. reported increased bone mineral density after a year's treatment with cyclic progesterone, which occurred regardless of calcium supplementation and was significantly higher than with use of calcium alone (17). They also noted a significant decrease in bone mineral density in runners who were taking placebo, compared to those taking MPA. Based on this evidence, both contraception and osteopenia concerns can be addressed with hormonal contraception, preferably with combined OCs or, alternatively, with progestin-only contraceptives (see Chapter 100).
Chapter 11 discusses anorexia nervosa and bulimia. Menstrual irregularity or amenorrhea in these disorders occurs secondary to hypothalamic suppression and low GnRH secretion, similar to that of exercise-induced amenorrhea. Amenorrhea is a relatively benign symptom of the disease; other symptoms and signs that occur as the disease progresses are constipation (from low intake and laxative abuse), hypotension, hypothermia, lanugo formation, and possible cardiac arrhythmia (especially with hypokalemia and other electrolyte imbalances secondary to
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laxative abuse). Diagnosis is critical since this disease is associated with a 5% to 15% mortality rate.
Individuals with any of the risk factors listed should be asked about their behaviors with food and their family relationships, because abrupt changes may cause a tendency toward anorexia to become active disease. Patients with this type of amenorrhea should be referred to a multispecialty practice (psychiatry, behavioral therapy, nutrition, and internal medicine) that specializes in eating disorders, with hospitalization as needed. The amenorrhea resolves in up to 70% of these women after normal body weight is attained (15). Pregnancy must be ruled out; the severe self-imposed malnutrition of eating disorders confers significant risk to the fetus, and also the weight gain associated with pregnancy further intensifies feelings of fatness. Contraception should be offered to all patients who are sexually active. If hormonal contraceptives are not desired, the patient should be given hormone replacement therapy because she is at risk for bone loss due to lack of estrogen. A daily dose of conjugated estrogen 0.625 mg and progesterone 2.5 mg is adequate for bone protection but will not result in menstrual bleeding. A cyclic progesterone regimen with up to 1.25 mg daily estrogen is necessary for resumption of menstruation. Progesterone (at least 5 mg) may be given on the first 12 days of each cycle in the presence of continuous estrogen; withdrawal bleeding occurs 3 to 5 days after the progesterone is finished. Alternatively, estrogen may be given on days 1 through 25 each month, with progesterone given on days 14 and 25 in which case withdrawal bleeding occurs on day 29 to 30. Regularly menstruating women who begin strenuous exercise programs are unlikely to become amenorrheic unless significant weight loss is associated with the exercise.
Reproductive Adult: Up to 45 Years
The “reproductive adult female” (loosely, women between the ages of 18 and 45 years) fall into an age range in which many different conditions may surface. Some of the physiologic causes of irregular bleeding or amenorrhea in this age group are pregnancy (intrauterine, ectopic, or miscarriage) and lactation. Beyond these causes, there are various pathologic conditions that should be considered.
Polycystic Ovary Syndrome
Polycystic ovary syndrome (PCOS) is the most common endocrine disorder among women of reproductive age. Estimates suggest that 5% to 10% of premenopausal women have the full-blown syndrome of hirsutism, chronic anovulation, obesity, and polycystic ovaries, the original constellation known as Stein–Leventhal syndrome (18). The associated decrease in ovulation rate in patients with PCOS causes varying degrees of infertility.
Definition
Since PCOS presents with heterogenous clinical features and occurs in both obese and lean women, the diagnosis of PCOS has been somewhat difficult. The National Institutes of Health (NIH) consensus conference in 1990 established the initial criteria for the diagnosis of PCOS (19). These include 1) chronic anovulation or oligo-ovulation, 2) clinical (hirsutism) or biochemical (elevated testosterone levels) features of hyperandrogenism, and 3) exclusion of other causes of anovulation and hirsutism (e.g., nonclassic congenital adrenal hyperplasia, Cushing syndrome, hyperprolactinemia, androgen secreting tumors, acromegaly). Therefore, although PCOS is named in relation to an ovarian morphologic abnormality, it is defined by functional abnormalities and not by ovarian morphology. This is because the classic ovarian morphology of PCOS (enlarged, with numerous small subcortical follicles) is inconsistently present among patients with ovulatory dysfunction and is observed in some women without a disorder of ovulation (20,21). However, a recent international conference added the presence of polycystic ovaries (defined by ultrasound) as one of the diagnostic criteria (in addition to the NIH criteria) for the diagnosis of PCOS (22). Since some authorities find this additional criterion to be controversial, many clinicians still follow the NIH criteria.
Pathogenesis
The etiology of PCOS is multifactorial. Women with this syndrome secrete excessive quantities of androgenic steroids from the ovaries and often from the adrenal glands as well. Two potential mechanisms for increased androgen production are increased LH secretion and insulin resistance.
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lowers free testosterone and SHBG levels in patients with insulin-resistant PCOS suggests that the insulin resistance may be the underlying cause of the gonadal dysregulation (23). Indeed, a unique insulin receptor defect has been identified in approximately 50% of women with PCOS (18).
The clinical concerns with this process are anovulation and the effects of chronic androgen stimulation. Women with this disorder are classically obese with some degree of hirsutism and acne, although this is not always true. The usual presentation is a complaint of oligomenorrhea or amenorrhea (80%), primary infertility or hirsutism. The most consistent endocrine feature is ovarian hyperandrogenism. Increased LH/FSH secretion and mild hyperprolactinemia may also be present. Diagnostic evaluation should include a detailed history and physical examination with particular attention paid to the degree and distribution of hair, signs of virilization, and presence of acanthosis nigricans (a marker of insulin resistance). A history of sleep apnea should be sought since its prevalence is much higher in women with PCOS compared to age and body mass index (BMI)-matched controls (20).
Studies of patients with PCOS suggest that there are two etiologically distinct subpopulations (24). In approximately 50% of patients, hyperandrogenism is accompanied by carbohydrate intolerance and increased levels of insulin and insulin-like growth factor-1 (IGF-1) (25). These insulin-resistant patients tend to be more obese, have a greater waist-to-hip ratio, are more hirsute, and have higher levels of plasma testosterone and lower levels of SHBG. In contrast, the non–insulin resistant patients have higher LH/FSH ratios than insulin-resistant patients, suggesting that the primary problem in this group involves GnRH regulation.
Laboratory Evaluation
The goals of laboratory evaluation are to assess hyperandrogenism and insulin resistance. Screening tests should include testosterone, free testosterone, SHBG, DHEAS, prolactin, and TSH. Tests to exclude other causes of anovulation and hirsutism should include measuring 24-hour urine free cortisol, 17-OH progesterone, and serum IGF-1. These tests are performed by most commercial laboratories (see Chapter 81). To screen for metabolic complications, fasting levels of glucose, insulin, and lipid profile should be checked. In patients with a history of sleep apnea, polysomnography should be performed. These women should also be referred to gynecologists for evaluation of endometrial thickness, since both endometrial hyperplasia and carcinoma are more common in women with PCOS.
Treatment
Therapeutic options depend on the patient's symptoms and her desire for fertility.
Hirsutism
If hirsutism is mild, mechanical methods of shaving and plucking should be encouraged. For women with moderate to severe hirsutism, the choices include oral contra-ceptives and anti-androgens. Oral contraceptives suppress LH levels, hence reducing stimulation of theca cells. Furthermore, they also increase SHBG production in the liver, resulting in decreased free testosterone levels. Among anti-androgens, cyproterone acetate has been very effective. It suppresses LH levels due to its progestin component and also prevents the binding of testosterone to its receptor. Cyproterone acetate, however, is not available in the United States. In a recent study, a novel estrogen-progestin combination was used in the treatment of hirsutism in women with PCOS (26). The combination included ethinyl estradiol (30 µg) and drospirenone (3 mg) (Yasmin). Drospirenone is a progestin with a strong antimineralocorticoid activity. There was a significant decrease in the levels of both ovarian and adrenal androgens and the subjects showed a significant improvement in hirsutism scores. Spironolactone in doses of 100 to 200 mg daily also antagonizes the binding of testosterone to the androgen receptor and is commonly used in the United States. It should not be given to women with PCOS who desire fertility (because of its anti-androgen effect on the fetus). Recently, finasteride (Proscar) (a 5α-reductase inhibitor) has also shown some promise. By inhibiting this enzyme, finasteride decreases the formation of dihydrotestosterone (DHT), the active metabolite of testosterone.
Anovulation and Infertility
Life-style modification with diet and exercise is fundamental since weight loss itself may lead to spontaneous ovulation. This should always be attempted first for at least 3 to 6 months. Treatment with insulin sensitizers like metformin (Glucophage) and thiazolidinediones (Avandia, Actos) have resulted in resumption of ovulation and improvement in hirsutism scores by improving insulin sensitivity. In addition to improving insulin sensitivity, metformin also directly inhibits ovarian steroidogenesis (27). Metformin dose is gradually maximized to 1000 mg twice daily to avoid GI side effects. The patients should be counseled that at least 6 months of therapy may be needed before any benefits are noticed. If the patient remains anovulatory, clomiphene (alone or in combination with metformin) or gonadotropins may be useful to induce ovulation. Referral to a reproductive endocrinologist is indicated if the patient desires pregnancy.
Even if fertility is not immediately desired, the danger of unopposed estrogen secretion must be addressed. Women who have had an abnormal bleeding pattern for longer than 1 year should be referred to a gynecologist for endometrial biopsy to rule out endometrial hyperplasia or malignancy. Patients diagnosed in adolescence or in their
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early twenties with this disorder and those who have had 6 months or less of amenorrhea may benefit from a course of MPA (Provera), 10 mg daily for 10 to 12 days, to induce a withdrawal bleed and restore secretory endometrium. After this initial treatment, maintenance is best achieved with the use of combined OCs with low estrogen analog content for continuous ovarian suppression and also for contraception, since ovulatory cycles may occur after progesterone withdrawal (see Chapter 100).
As noted, these patients tend to have impaired glucose metabolism, increased lipid levels, and a tendency to be overweight, which puts them at increased risk for diabetes and cardiovascular disease. Combination OCs may improve lipid profile, although weight control has been demonstrated to be the most beneficial factor for preventing chronic disease. Therefore, patients should be counseled on lifestyle and cardiac risk reduction for the rest of their lives (see Chapter 79).
Secondary Amenorrhea
Secondary amenorrhea is diagnosed in women with previously normal cycles who have had no menses for a total of 6 months or have missed the equivalent of three previous cycle intervals. There are many causes for this condition, although one of the most prevalent and most easily diagnosed is pregnancy, which must be ruled out before proceeding with the workup (Fig. 101.1). Feminized patients with central secondary amenorrhea may have a brain tumor or anorexia nervosa, but most commonly they have hypothalamic amenorrhea. Although this can have an exogenous cause (see later discussion), it is often idiopathic with no explanation even after thorough examination. Pituitary amenorrhea is usually acquired and is often accompanied by deficiencies in other hormone axes (adrenal, thyroid).
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FIGURE 101.1. Approach to secondary amenorrhea. |
The term gonadal secondary amenorrhea refers to loss of function of the ovary itself after puberty. This can be caused by infection (e.g., tuberculosis), neoplasm (e.g., Krukenberg tumor—metastasis of a GI neoplasm to an ovary), trauma, surgery, or an autoimmune disorder. The latter category is often associated with a syndrome of polyglandular failure that may include disorders of the thyroid (Hashimoto thyroiditis) and adrenal (primary Addison disease), type 1 DM, and, rarely, autoimmune hypophysitis (28). Autoimmune ovarian failure is the most common cause of idiopathic premature menopause.
Exogenous amenorrhea can be caused by other systemic disease, such as hyperthyroidism or hypothyroidism, liver failure, renal failure, or other nonendocrine illness. Hypothalamic (secondary, central, acquired) amenorrhea is also often exogenous in that there is a proximate cause, such as weight loss (especially in anorexia nervosa), pathologic obesity, vigorous exercise (e.g., runners, ballet dancers), or severe stress, as in grief reactions or mental illness. Another form of exogenous interruption of menses may result from consumption of substances of abuse (opiates, alcohol) or prescribed medications (major tranquilizers, estrogens).
Serum or urinary gonadotropins are used to classify hypogonadism as gonadal (LH and FSH elevated) or central (LH and FSH low or normal). The investigation of central hypogonadism should include a serum prolactin level, especially if galactorrhea is present. Prolactin values between 30 and 100 ng/mL are elevated and are consistent with a prolactinoma, but they may be related to other causes such as hypothalamic (idiopathic) galactorrhea or drug effects. Values greater than 100 ng/mL almost always mean that a prolactinoma is present. Appropriate specialists should undertake further testing which is similar to that outlined for patients with male hypogonadism (see Chapter 85). If hirsutism is present, the serum testosterone and 17-hydroxyprogesterone (17-OHP) levels should be checked (see Hirsutism).
If TSH, FSH, and prolactin levels are normal, a progestin challenge should be done to evaluate estrogen production. A progestin challenge is done by prescribing oral MPA (Provera), 10 mg once a day for 7 days. Patients usually bleed 2 to 7 days after the last pill, although sometimes ovulation is triggered and they do not bleed until 14 days later. If the patient bleeds in response to progestin, then the diagnosis is anovulation. The underlying cause of anovulation should then be sought (e.g., stress, weight loss, anorexia, PCOS).
Patients who do not respond to progesterone challenge should be assessed for cessation of estrogen production
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with a combined estrogen plus progestin challenge (OCs). If the patient bleeds, then the problem is that she does not produce estrogen (as seen in gonadal secondary amenorrhea). The history is important in making the differential diagnosis and will implicate possible underlying causes as well as identify women in whom early menopause follows a clearly familial pattern. When the diagnosis is made in women who are younger than 30 years of age, a karyotype should be performed to exclude gonadal dysgenesis. Among the remainder, precise distinction between autoimmune and idiopathic causes is difficult. All patients with premenopausal estrogen deficiency should be screened periodically for evidence of associated autoimmune endocrinopathy affecting the adrenal, parathyroid, and thyroid glands and the gastric parietal cells (28). These patients are essentially menopausal and must be given hormone replacement therapy for bone protective effects (see Chapter 106). Future fertility is not possible from a native oocyte, although the patient may be referred to a reproductive endocrinologist to explore options of oocyte donation.
If the FSH is low or normal, then the diagnosis is hypothalamic amenorrhea. This is not common but is easily treated. Usually it is caused by stress or weight loss, although a head CT should be obtained to rule out a brain tumor, and the diagnosis of other rare central nervous system disorders should be entertained. This group is characterized by deficient gonadotropin secretion and mimics the endocrine state of the prepubertal girl. The low gonadotropin levels are not necessarily lower than those seen during parts of the normal cycle (particularly the luteal phase) and are of significance only in the context of concurrent diminished ovarian function. When fully expressed, these disorders are markedly hypoestrogenic: withdrawal bleeding does not occur after challenge with a progestational agent. Vasomotor symptoms such as hot flushes and night sweats may be present.
The differential diagnosis of hypothalamic amenorrhea includes conditions associated with destruction of hypothalamic and pituitary tissue such as ischemic necrosis (Sheehan syndrome), head trauma, and neoplasms such as craniopharyngioma and pituitary adenoma. Evaluation should consider both destructive and functional origins of hypogonadotropism through a careful history, physical examination, and, if a functional or nutritional cause is not evident, imaging of the pituitary and juxtapituitary structures. One of the more common intracranial lesions in women is a pituitary microadenoma or macroadenoma, which may be treated with bromocriptine and monitored with prolactin levels and imaging (see Chapter 81). Imaging of the sella turcica and determination of the prolactin level should be repeated annually to rule out or monitor pituitary adenoma, with the possibility of increasing this interval to every 2 to 3 years if results are stable for several years. Because all of these patients are hypoestrogenic and anovulatory, estrogen replacement must be prescribed (either combined OCs or hormone replacement therapy) and the patient reassured that ovulation induction is possible with GnRH analog injections when conception is desired. Treatment is given to remove the cause, restore normal menstrual function, or replace hormones. Patients desiring fertility will not respond to clomiphene and must be treated with gonadotropins for ovulation induction.
A history of dilatation and curettage suggests a uterine cause for secondary amenorrhea. If no bleeding occurred with the combined estrogen/progesterone challenge, a uterine problem such as Asherman syndrome is indicated. A hysterosalpingogram or hysteroscopy will show intrauterine adhesions (Asherman syndrome). This diagnosis is usually suspected with a history of postpartum hemorrhage or menorrhagia that required a dilatation and curettage. The treatment consists of resection of the adhesions, treatment with estrogens for several weeks postoperatively, and re-evaluation with a hysterosalpingogram. Successful pregnancies are achieved in 60% to 85% of patients, although they are at higher risk of abnormal placentation.
Menorrhagia or Intermenstrual Bleeding
Abnormal uterine bleeding (AUB) is a diagnosis of exclusion. Women presenting with menorrhagia or metrorrhagia need to be evaluated for organic, systemic, and iatrogenic causes for their abnormal bleeding (Table 101.2).
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TABLE 101.2 Causes of Abnormal Vaginal Bleeding in a Woman of Reproductive Age |
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Organic Causes
The most common causes for abnormal bleeding in the reproductive age group are accidents of pregnancy. Miscarriage and ectopic pregnancy should be evaluated by performing a β-hCG assay, as well as a pelvic ultrasound examination if indicated.
Prolonged excessive bleeding (menorrhagia) as a feature of otherwise normal cycles requires evaluation to exclude pathology affecting the endometrium. The most common reason is leiomyomas or “fibroids,” which are a benign overgrowth of the smooth muscle that makes up the myometrium. Leiomyomas are present in up to 40% of women at the time of death (based on autopsy studies), are stimulated by estrogen, and typically become symptomatic in the age range of 30 to 40 years. A history of heavy, prolonged menses with possible clot passage and an enlarged, irregularly shaped uterus on pelvic examination suggests leiomyomas. In this circumstance, evaluation by an experienced examiner, endometrial biopsy in every patient older than 40 years of age, and imaging (pelvic ultrasound) are warranted to exclude another neoplasm masquerading as leiomyoma. Any patient with presumed leiomyomas exhibiting rapid uterine growth should be referred to a gynecologist for evaluation and hysterectomy, because leiomyomas do rarely undergo malignant degeneration (less than 1%). Leiomyomas may also undergo other types of degeneration (cystic, hemorrhagic), typically when blood supply is outgrown, and this may result in a significant amount of abdominal and pelvic pain. Additionally, large leiomyomas may cause other symptoms such as urinary frequency, constipation, and fullness in the lower abdomen.
Abnormal bleeding caused by leiomyomas may respond to hormonal management. Options include high-dose progestins (Depo-Provera, 150 mg or more, by intramuscular injection as frequently as monthly to control symptoms), OCs, or a GnRH agonist. GnRH agonists (leuprolide, goserelin, nafarelin) provide irreversible blockade of estrogen receptors and effectively induce a temporary menopausal state. The GnRH agonists are not options for long-term therapy and may only be used for 6 months because of risks of bone depletion and adversely affected lipid profiles that result from estrogen depletion. However, these medications are useful for decreasing the size of the uterus or allowing the resolution of anemia before surgery. Surgical options are hysterectomy or myomectomy, depending on the patient's preferences for future fertility. Uterine artery embolization through interventional radiology is a nonsurgical option in select patients. Patients who are asymptomatic or who are not anemic and refuse hormonal or surgical therapy may be observed, because these tumors usually decrease in size when the menopause is reached. Leiomyomas should not be considered a contraindication to hormone replacement therapy.
The cause of menorrhagia accompanying otherwise normal cycles in the presence of a normal pelvic examination can be submucous leiomyomas or endometrial polyps, which usually are revealed by ultrasound, especially if it is performed with fluid contrast in the endometrial canal (sonohysterography) (10). The etiology of endometrial polyps is unknown. Because polyps are often associated with endometrial hyperplasia, unopposed estrogen may be the cause. These polyps rarely bleed enough to cause a clinically significant anemia. Occasionally a pedunculated endometrial polyp protrudes through the external cervical os and can cause intermenstrual or postcoital bleeding. The rate of malignant transformation in an endometrial polyp has been estimated to be as high as 0.5%. However, a case-controlled study from Sweden estimated that the increased risk of endometrial cancer in women with endometrial polyps is only twofold (29). Malignant change in an endometrial polyp, when found, is often of a low stage and grade and usually curable. The management of endometrial polyps consists of resection via the hysteroscope and examination of the endometrial lining.
Cervical lesions such as cervical polyps or cervicitis may cause irregular bleeding, particularly postcoital spotting. These lesions can be diagnosed by visualization of the cervix. In addition, traumatic vaginal lesions, severe vaginal infections, and foreign bodies have been associated with abnormal bleeding. Similarly, infections of the upper genital tract, such as endometritis, have been associated with intermenstrual spotting and may even manifest as prolonged menses. Malignancies of any portion of the genital tract may manifest as abnormal bleeding, particularly cervical and endometrial cancer. Less commonly, vaginal, fallopian tube, and ovarian cancer may produce abnormal bleeding. Careful physical examination and evaluation with cervical cytology, endometrial sampling, and ultrasound, when indicated, help to establish the diag-nosis.
Systemic Causes
Hypothyroidism is frequently associated with menorrhagia as well as with intermenstrual bleeding. The incidence of this disorder among women with menorrhagia is estimated to range between 0.3% to 2.5%. TSH should be measured and, if abnormal, appropriately treated (see Chapter 80). Although hyperthyroidism is not usually associated with menstrual abnormalities, hypomenorrhea, oligomenorrhea, and amenorrhea have been reported. Similarly, hyperprolactinemia and PCOS are most often associated with amenorrhea but can sometimes manifest as irregular menses.
Systemic disorders that produce abnormalities in coagulation or platelet abnormalities, such as von Willebrand disease, leukemia, severe sepsis, immune thrombocytopenic purpura, cirrhosis, and chronic renal disease, may all be associated with excessive or irregular bleeding (see Chapter 56).
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Iatrogenic Causes
Foreign bodies in the uterus, such as an IUD, frequently produce abnormal uterine bleeding. Several medications may interfere with the neurotransmitters responsible for releasing and inhibiting hypothalamic hormones, resulting in anovulation and abnormal bleeding. Medications typically implicated are phenothiazines, isoniazid, opiates, metoclopramide, tricyclic antidepressants, and α-blockade antihypertensives. Exogenous hormones such as danazocrine and OCs or MPA can cause irregular bleeding.
Abnormal Uterine Bleeding
After organic, systemic, and iatrogenic causes for the abnormal bleeding are ruled out, the diagnosis of AUB can be made. Treatment is age dependent and should be tailored to the patient, after reviewing all of her options. For adolescents, either expectant management or OCs may be appropriate. AUB during the reproductive years can usually be well managed with OCs, including the 20-µg pill, or with cyclic progestins (see Chapter 100). OCs offer several advantages, including ease of use, predictable menses and contraceptive benefit. Cyclic progestins are a good option for women who cannot tolerate OCs and those in whom OCs are contraindicated. A low-dose progestin, such as MPA (Provera) 2.5 mg, may be given 12 days during every second or every third month. Another option for some patients is the use of a progestin IUD. AUB in women of late reproductive age to postmenopause can be treated with cyclic progestin, low-dose OCs, or cyclic combination hormone replacement. Treatment choice depends on the patient's symptoms and her need for contraception. Medical management generally offers excellent results for AUB management and should be the first line of treatment in the majority of cases. If medical management fails, surgical options include endometrial ablation, through a variety of techniques, or hysterectomy for definitive management.
Late Reproductive Age through Postmenopause: Greater than 45 Years
Perimenopause usually commences in the fifth decade, heralded by alterations in menstrual rhythm. Although the transition to the postmenopausal state can be brief and uncomplicated, the normal perimenopause is characterized in many women by the unpredictable occurrence of both shortened and lengthened ovulatory cycles as well as anovulatory episodes commencing well before menopause (30,31). The resulting menstrual chaos is a cause for inconvenience, frustration, and fear among affected women. It is in this age group that the term AUB is most commonly applied to the menstrual history. The clinician's focus must be to distinguish those patients whose symptoms are a result of the normal dysfunction of this transition from those who harbor gynecologic pathology. The perimenopausal woman is at increased risk for endometrial hyperplasia, endometrial polyps, and leiomyomas.
Patients approaching the end of the reproductive years often exhibit symptoms long before the manifestation of menopausal symptoms. Patients note bleeding patterns consistent with an anovulatory state, resulting from the decreased number of remaining oocytes. There is also an increased perception of premenstrual symptoms, which is probably secondary to increased levels of hormones resulting from elevated GnRH concentrations required to induce ovulation with limited numbers of recruitable oocytes. In addition to exclusion of pregnancy, patients older than age 40 years with abnormal patterns require endometrial biopsy and ultrasound examination. These patients must undergo workup to exclude other causes of disordered bleeding, especially endometrial neoplasia as the incidence of endometrial carcinoma increases in this age group.
Bleeding after the menopause is the only symptom of many women with endometrial neoplasia, which must be ruled out first. In addition to endometrial hyperplasia and malignancy, there are several benign causes of bleeding that should be considered in the differential diagnosis. Unexpected bleeding is common during hormone replacement therapy, with either cyclic regimens or continuous combined estrogen–progestin regimens, but it requires the same attention given to postmenopausal bleeding in a woman not receiving hormones (8,32) (seeChapter 106). Vaginal bleeding may also occur secondary to atrophic changes occurring after the menopause, in which the mucosal tissue has thinned due to lack of estrogen. This bleeding may occur after examination or coitus, and a tear will be clinically evident. Unless bleeding occurs regularly as a result of hormonal replacement therapy, vaginal bleeding in the postmenopausal woman should be regarded as a result of genital tract malignancy until proven otherwise. Careful clinical examination and endometrial biopsy are mandatory.
Endometrial Neoplasia
Endometrial carcinoma is the most common of the gynecologic malignancies and also one of the most treatable, because it is typically diagnosed at an early stage because of the symptom of postmenopausal bleeding. Because of the possibility of carcinoma, such bleeding must be investigated further immediately. Chapter 104 fully discusses the approach to diagnosis of endometrial carcinoma.
Dysmenorrhea
Dysmenorrhea (painful menstruation) is a common problem. It is considered primary when no pathologic condition is present. The condition usually presents within 1 to
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2 years after the menarche. Secondary dysmenorrhea is a result of a specific pathologic process such as uterine myomas, endometriosis, pelvic inflammatory disease, or an intrauterine contraceptive device that causes pelvic pain in conjunction with menses. Therefore, in secondary dysmenorrhea, one should seek an initiating cause. Patients with secondary dysmenorrhea usually should be referred to a gynecologist. Typical primary dysmenorrhea consists of the development within 1 or 2 days after the onset of menstruation of either crampy or sustained lower abdominal and pelvic pain that may radiate into the legs and that can be associated with nausea, vomiting, irritability, diarrhea, back pain, or abdominal distention. In a few patients, symptoms may be so severe that performance of usual daily activities is impaired or prevented. Usually the discomfort is most severe during the initial several hours of menstrual flow, fades gradually, and disappears within 2 or 3 days. The episodes tend to become less severe with increasing age and often disappear spontaneously within 5 or 10 years after the menarche or after the first pregnancy. Occasionally, idiopathic dysmenorrhea reappears (or makes its first appearance) during the perimenopausal period. There is evidence that dysmenorrhea is caused by excess production of prostaglandins from the uterine endometrium, which results in prolonged and sustained uterine contraction during menses. The concentration of prostaglandins found in the endometrium correlates with the severity of dysmenorrhea (33). Further support for this hypothesis is found by the excellent response to nonsteroidal anti-inflammatory drugs (NSAIDs), which act to inhibit prostaglandin synthetase, in treating dysmenorrhea (34).
Mild forms of dysmenorrhea require only analgesic therapy and reassurance from the physician. First-line therapy for dysmenorrhea is NSAIDs, which have been shown to be effective for approximately 70% to 90% or patients (35). They should be taken with food to minimize GI side effects.
Ibuprofen (e.g., Motrin 400 mg four times daily for 5 to 6 days, naproxen (Naprosyn 500 mg two times daily for five doses), and mefenamic acid (Ponstel 250 mg four times daily for 5 to 6 days) have been approved by the U.S. FDA for use in dysmenorrhea. Ibuprofen has the best risk–benefit ratio in this population (36). NSAIDs are most effective if given just before menstrual flow begins and continued for 2 to 3 days thereafter. However, because of the uncertainty of the effects of these agents in early pregnancy, it is suggested that their use be delayed until the beginning of menstrual flow in those patients who are sexually active and who are not using effective means of birth control. The patient should use one agent as a trial for three cycles, then discontinue the agent if there has been inadequate control of the symptoms.
Steroidal contraceptive agents, either oral or injectable, suppress ovarian hormone production and therefore usually control dysmenorrhea; these agents occasionally may be necessary for management of the problem when it is severe. OCs should be considered first line therapy in young women who also desire contraception (see Chapter 100). The unusual patient who does not respond to any of these therapies should be seen by a gynecologist for evaluation for an undetected problem causing secondary dysmenorrhea (such as endometriosis) or to provide more experienced guidance in drug therapy for primary dys-menorrhea.
Premenstrual Dysphoric Disorder
Premenstrual dysphoric disorder (PMDD) is an ill-defined complex of signs and symptoms that occurs to some degree in approximately 20% to 50% of women of reproductive age. Symptoms include irritability and increased aggressiveness, cravings for sweet or salty foods, nervousness, depression, tearfulness, mood swings, difficulty concentrating, headaches, fullness and tenderness of the breasts, fatigue, and abdominal bloating. Any or all of the symptoms may be present, and the characteristic complaints vary among patients, but the hallmark of the syndrome is that these problems appear during the latter half (luteal phase) of the menstrual cycle, disappear with the onset of menstruation, and are absent during the first part (follicular phase) of the cycle. Approximately 1% to 9% of affected women find such symptoms severely disruptive to their lives and meet the criteria for PMDD (37). To meet the criteria for PMDD as described in theDiagnostic and Statistical Manual of Mental Disorders, 4th Edition (DSM-IV) at least five of 11 possible symptoms must be present during the premenstrual phase with resolution within the first few days of menses. Symptoms must be charted over at least two cycles to conform to luteal pattern before the diagnosis can be confirmed.
Investigations of the cause of this entity have not been rewarding. Most studies have found no typical pattern of hormone or electrolyte changes that distinguishes symptomatic from asymptomatic women. Nonetheless, although progesterone supplementation does not eliminate symptoms, the suppression of ovarian activity cyclically medically (e.g., with GnRH analogs) or surgically effectively eliminates premenstrual syndrome, and sex steroid hormone replacement in suppressed patients does not restore symptoms. It therefore seems most likely that the symptoms stem from an “abnormal” physical response to a more or less normal pattern of steroid hormone fluctuations during the menstrual cycle. Serotonin dysregulation has also been implicated in several studies (37).
Randomized controlled trails have demonstrated that treatment with selective serotonin reuptake inhibitors (SSRIs) and other serotonin modulators are effective and
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can be considered the first line of treatment for PMDD (38). Treatments with SSRIs have shown a significant improvement in premenstrual symptoms compared to placebo. Fluoxetine (Prozac) 20 mg/day has been approved by the FDA for treatment of emotional and physical symptoms of PMDD (37). A meta-analysis found that various SSRIs show equal effectiveness, ranging from 60% to 70%, compared to placebo, given in both the continuous and luteal phase dosing (7 days before menses) (38).
Galactorrhea
Galactorrhea refers to the production of milk (confirmed by demonstration of fat after staining of the fluid with Sudan stain) in a woman who is not recently postpartum or nursing a baby. Secondary central amenorrhea is often accompanied by galactorrhea (15% of cases). In approximately 40% of cases, galactorrhea/amenorrhea is caused by a prolactin-secreting pituitary adenoma that may or may not be readily detectable by imaging procedures (macroadenoma versus microadenoma). In patients with macroprolactinoma, the serum prolactin levels are generally greater than 200 ng/mL. Other causes of galactorrheic amenorrhea include medication, (phenothiazines, butyrophenones, metoclopramide, resperidol, verapamil), recent pregnancy, hypothyroidism, and idiopathic hypothalamic dysfunction. Occasionally, a woman who has nursed has mild persistent galactorrhea (without amenorrhea) for up to 5 years after weaning. In these cases, prolactin levels are usually normal (less than 30 ng/mL).
Hirsutism and Virilization
Growth of coarse dark hair (terminal hairs) in various body areas (besides the scalp and eyebrows) depends on the action of androgens. The pattern of hair growth reflects the relative sensitivity of various zones of the skin to androgen effect. Whereas pubic and axillary hair appears in both sexes, further hair growth diverges because of differing androgen levels. Although male patterns vary, maximum expression of androgen effect includes terminal hair development over the face, limbs, chest, superior pubic triangle, linea alba, and back. In those carrying genes for male-pattern baldness, high levels of androgens are also associated with loss of scalp hair, with hair receding first at the temporal hairline (“widow's peak”) and later at the crown.
Hirsutism with Virilization
Most women (80%) develop some degree of dark hair growth over the legs and forearms but not much facial hair. About one third have small amounts of hair on the chest and abdomen (extending along the linea alba). Abnormally high levels of plasma androgens can result in male distribution of hair growth, the state of hirsutism. Over time, very high levels of androgen production also lead to virilization, defined as increased muscle mass, redistribution of fat from subcutaneous depots in hips and breasts to abdominal and intra-abdominal areas (“male habitus”), clitoral enlargement (greater than 2.0 cm), deepening of the voice, male-pattern baldness, development of acne, and increased perspiration odor from activation of sebaceous glands.
Excess body hair without signs of virilization is termed “simple hirsutism.” Hirsutism with virilization is rare and is usually a result of diagnosable causes, the most common of which are adrenal or ovarian tumor, congenital adrenal hyperplasia, male pseudohermaphroditism, and use of exogenous androgen (e.g., female athletes and body builders). Truly virilized women usually should be referred directly to an endocrinologist for detailed diagnostic investigation.
Hirsutism without Virilization
Although simple hirsutism may be an early manifestation of Cushing syndrome or of an adrenal or ovarian neoplasm, most cases fall into a group termed “idiopathic” hirsutism. The prevalence of simple hirsutism has been estimated to be as high as 10% in adult North American women. It typically develops during the late teens, alth-ough progression may be so slow that troublesome amou-nts of hair do not appear for 10 or more years after onset of menses.
In one half to two thirds of hirsute women, excessive ovarian production of androgens (testosterone or androstenedione) is demonstrable and is often associated with oligomenorrhea and decreased fertility. Ovarian structure may show hyperthecosis (overgrowth of interstitial tissue) or multiple cyst formation (PCOS; see Reproductive Adult: Up to 45 Years).
In about half of all patients with simple hirsutism, elevated serum testosterone levels are not demonstrable. However, approximately half of patients with normal total testosterone have been shown to have increased plasma “free” (or unbound) testosterone due to reduced SHBG. Increased hair follicle conversion of testosterone to the more potent dihydrotestosterone has been demonstrated in some of the remaining cases, and other causes of increased sensitivity of hair follicles to androgens have been reported.
Racial and ethnic factors are also important determinants of hair growth. Women of Asian ancestry and Caucasian women of northern European origin usually have relatively little terminal hair on face, torso, or extremities. In contrast, Caucasian women of Mediterranean origin often develop mustache, beard, or sideburns
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and have dark hair on legs and arms. Constitutional hirsutism also tends to run in families. Therefore, a patient with moderate hirsutism who is of Mediterranean origin, who has a mother or other close family members with excessive facial hair, and who has normal menses is unlikely to have identifiable endocrine disease. The timing of onset of hirsutism is also important. For example, sudden development of hirsutism many years after menarche is likely to be caused by a tumor of the ovary or adrenal rather than a functional cause.
Transitory hirsutism may occur during pregnancy and occasionally during menopause. A number of pharmacologic agents, including glucocorticoids, phenytoin (Dilantin), minoxidil, diazoxide, and phenothiazines, can result in hirsutism. Drug-induced hirsutism is characterized by increased hair growth that is not limited to the androgen-sensitive areas of the skin. Rare causes include chronic local skin trauma and porphyria cutanea tarda.
Besides PCOS, the other major cause of adult-onset simple hirsutism, sometimes with disturbance of menstrual pattern, is congenital adrenal hyperplasia (CAH). CAH is produced by a deficiency of one of the several enzymes in the steroid synthetic pathway. Although such defects are usually manifested in childhood as ambiguous genitalia with salt loss (21-hydroxylase deficiency) or non–salt losing simple virilization (11-hydroxylase deficiency), patients with partial 21- or 11-hydroxylase defects can manifest hirsutism with onset in puberty or in adult life without symptomatic disturbances of salt and water balance.
Approach to the Patient
A careful ethnic and family history is essential. The temporal evolution of the problem should be noted, including the menstrual history. On physical examination, one should carefully note the distribution and density of terminal hairs in the sideburn and mustache areas, the periareolar and midsternal regions, and over the back and buttocks. Particular attention should be paid to the pattern of pubic hair. In the female, the pubic hair forms an inverted triangle in the inferior pubic region only. The male escutcheon is a rhomboid space with terminal hairs filling the superior pubic triangle and extending up the linea alba to the umbilicus. A male type escutcheon in a female is a good presumptive sign of hyperandrogenism. Physical signs of virilization (discussed earlier) should be sought. Patients with virilism require urgent referral to an endocrinologist, whereas those with severe ovarian dysfunction may require the attention of a gynecologist for treatment of abnormal menstruation or impaired fertility. Finally, symptoms and signs of Cushing syndrome (in which hirsutism and even virilization may occasionally be more prominent than the classic “cushingoid” changes) should also be sought. Obesity with acanthosis nigricans is highly suggestive of the insulin-resistant variant of PCOS.
The decision to proceed with laboratory testing depends on the history and severity of the hirsutism. Laboratory studies can be performed sequentially if financial considerations are dominant or simultaneously if speed is of the essence. Serum testosterone, which is of ovarian and rarely of adrenal origin, is measured first. A normal serum testosterone level suggests idiopathic hirsutism and excludes major ovarian disorders. Not excluded are mild cases of ovarian hyperthecosis/polycystic ovaries with abnormal androstenedione production or cases with decreased SHBG resulting in falsely normal total testosterone (these women have increased free or bioavailable androgen). The uncovering of such borderline cases usually is not worthwhile because management would be unaffected. If the testosterone level is increased to between 85 and 200 ng/dL, a diagnosis of ovarian hyperthecosis or PCOS is most likely. Increased LH and low-normal or reduced FSH are highly suggestive of PCOS but does not occur in all patients. Pelvic sonography usually reveals multiple cysts or thickening of the cortex and enlargement of the ovaries. Levels of testosterone greater than 200 ng/dL suggest a diagnosis of ovarian neoplasm, and specialists should direct further diagnostic evaluation. This may include transvaginal sonography, computerized tomography of the abdomen and pelvis, laparoscopy with ovarian biopsy, or ovarian vein catheterization. It is important to appreciate that the ranges of testosterone elevation mentioned above are a rough guide and should not be considered absolute in terms of making decisions. Hence, each patient should be treated on an individual basis.
If testosterone levels are normal, excess production of weak androgens (e.g., androstenedione, DHEAS) by the adrenal remains a consideration and can be confirmed by appropriate assays. In 21-hydroxylase deficiency, the most common type of CAH resulting in hirsutism in adults, serum 17α-OH progesterone and urinary pregnanetriol may be elevated. However, in about half the patients with this syndrome, these steroid levels are normal at baseline and increase only after stimulation with exogenous adrenocorticotropic hormone (ACTH). Therefore, if CAH is suspected, endocrine specialty referral is appropriate. Large increases in serum DHEAS or 24-hour urinary excretion of 17-ketosteroids suggests adrenal neoplasia (adenoma or carcinoma) and also should be evaluated by an endocrinologist.
Therapy
Treatment of hyperandrogenism and hirsutism includes both local and systemic measures (39). Therapy for simple hirsutism usually is local and essentially cosmetic, even if there is a hormonal abnormality, since medical reduction
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of androgen excess does not rapidly affect the presence of existing hair and is often incomplete.
Local measures include bleaching, wax stripping, shaving, plucking (tweezing), using hair removal creams (depilatories), and performing electrolysis. Contrary to popular belief, such measures do not accelerate the growth rate of remaining hair. Plucking can occasionally cause local infection. Wax applications and hair removal creams are effective but may be irritating and must be used with care. All of these procedures must be repeated at intervals. Electrolysis and thermolysis are effective procedures for permanent removal of hair, but they are expensive and uncomfortable. Effectiveness and safety (avoidance of burns, scarring, and infection) depend on the technique of the operator. Referral of the patient requires that the clinician be familiar with the electrologist's skill. Under the best of circumstances, electrolysis is generally successful in destroying approximately 50% of the follicles treated at one time. Invariably, therefore, many repetitions are required.
Patients with hyperandrogenic hirsutism (PCOS or CAH) often respond to medical therapy. Such patients should be cautioned not to expect rapid results, because dedifferentiation of androgenized follicles may require 6 to 18 months, even if androgen excess is totally eliminated. The immediate benefit to be expected is prevention of progression of the hirsutism, with variable degrees of reversal occurring only as therapy is continued. Medical therapy is directed toward suppressing androgen production, blocking peripheral androgen action, or both. Although such therapy appears more rational when androgen excess is demonstrable, patients with idiopathic hirsutism may occasionally respond. Adrenal suppression with low dosages of dexamethasone, although introduced on the erroneous assumption that adrenal androgens were responsible for most cases of hirsutism, is nonetheless effective in about one third of cases. This seems to be so because of an accompanying reduction of ovarian androgen secretion, which is either directly dependent on ACTH or indirectly dependent via ovarian conversion of circulating adrenal steroids. Adrenal suppression is, as expected, effective in cases of CAH. This form of therapy is simple and usually free from side effects. Dexamethasone can be given as a single dose of 0.1 to 0.3 mg (as a pediatric solution) orally at bedtime. At these low dosages, neither glucocorticoid excess (iatrogenic Cushing syndrome) nor chronic adrenal suppression with adrenal insufficiency is likely to occur, but levels of both plasma or urinary cortisol and adrenal androgen should be monitored, and the dosage of dexamethasone should be adjusted to keep both in the normal range. Side effects of dexamethasone therapy include occasional insomnia and appetite stimulation.
The most appropriate treatment for ovarian hyperandrogenism is suppression of ovarian androgen production. The first line of treatment is use of a cyclically administered estrogen-progestin combination (OC). This is effective in about half of the cases. Estrogens, especially when given orally, also increase the concentration of plasma SHBG, reducing the concentration of circulating free androgens. Because progestins have some intrinsic androgen-like activity on hair follicles, a combination that minimizes the content of progestational agent may be most appropriate. Agents containing 2 mg or less of norethindrone or 0.5 mg or less of norgestrel are acceptable. Recently, a novel estrogen-progestin combination pill (containing ethinyl estradiol and drospirenone (Yasmin) has also shown good results in the treatment of hirsutism in women with PCOs (26). When used, OCs should be given on the usual schedule recommended for fertility control for the particular preparation (see Chapter 100).
Disadvantages of OCs include their potential for cardiovascular, thrombogenic, and other undesirable effects. These disadvantages have probably been overstated and are less often seen with the low-dose contraceptives of today than with their high-dose predecessors; nonetheless, possible adverse effects must be weighed carefully when they are to be prescribed for an essentially benign problem. Combined adrenal–ovarian suppression may be used if neither alone is effective.
Suppression of ovarian androgen production by OCs precludes pregnancy. Therefore, therapy must be interrupted when fertility is desired and the drug withheld during pregnancy. Spironolactone (Aldactone), at a generally well-tolerated dosage of 25 to 50 mg twice daily, suppresses ovarian androgen production and antagonizes androgen action at the hair follicle. Spironolactone is a well-accepted and relatively safe drug, and the combination of spironolactone with an OC is often effective in more severe cases of hirsutism and in those that are unresponsive to ovarian and/or adrenal suppression alone. Contraindications to spironolactone include concomitant use of potassium supplements or renal insufficiency, either of which may predispose to hyperkalemia.
Cyproterone acetate and flutamide are competitive inhibitors of androgen that block peripheral androgen receptors and have been used successfully in the treatment of hirsutism. Finasteride, which inhibits the enzyme 5-α-reductase that mediates the conversion of testosterone to its active form, dihydrotestosterone (DHT), also appears to be effective in skin and hair follicles (40). Studies of finasteride in the treatment of idiopathic hirsutism (39) and PCOS (41) have shown mixed results. Although none of the latter agents is currently approved by the FDA for the treatment of hirsutism in women, it is not unreasonable to try one of them alone or in combination with ovarian or adrenal suppression in resistant cases.
Suppression of the reproductive system with the use of a GnRH antagonist such as buserelin has also been found to be effective in reducing severe ovarian hyperandrogenism with hirsutism (42). However, because of their attendant
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risks of osteoporosis or hot flushes, the usefulness of these agents is limited.
Finally, severe hirsutism and virilization can result from benign highly functional ovarian tumors such as luteomas and thecomas (43). These tumors should be removed surgically. Similarly, localized malignant ovarian and adrenal tumors also require surgical excision followed by adjuvant therapy (if needed).
Female Sexual Dysfunction (Frigidity and Dyspareunia)
Definition
As in the male, female hyposexuality can be divided into reduced sexual interest or appetite (hypoactive sexual desire), failure of arousal (inhibition of excitement), and anorgasmia. For a more complete discussion, see Chapter 6. The discussion here is limited to physical and especially to endocrine etiologies.
Etiologies
Organic causes of female hyposexuality include DM with peripheral neuropathy, hyperprolactinemia, hypogonadism with estrogen deficiency, and organic disease of the vagina, uterus, fallopian tubes, or ovaries with resultant dyspareunia. Various endocrine (e.g., hyperthyroidism, hypothyroidism) and other systemic debilitating diseases can also cause loss of interest in sexual activity. Menopausal changes by both surgical oophorectomy or natural menopause often are associated with sexual dysfunction and 40% to 80% of women report experiencing some sexual problems during this time. The loss of ovarian function results in low levels of estrogen and subsequent menopausal symptoms including vaginal dryness. Androgen levels fall with aging and studies have shown that a decrease in testosterone levels is associated with loss of libido (2).
History
Approaching sexual dysfunction requires consideration of medical, sexual, and psychological sources of the problem. Careful history will aid the provider in narrowing this broad spectrum of causes. Questions should be the same as those asked of a woman with hypogonadism (seeSecondary Amenorrhea). Additional questions should be asked about dyspareunia. If there is pain or discomfort on intercourse, it is important to know whether it occurs with attempts at penetration (suggesting local vaginal or vulvar problems) or only after deep penetration (suggesting pelvic disease, such as leiomyoma, endometriosis, or salpingitis). The physician should determine whether there was a previous history of satisfactory sexual activity and, if so, the time and circumstances of onset of its deterioration. Careful questioning should reveal to what extent the problem is one of loss of interest, excitation (lubrication and heightened pelvic blood flow), or orgasm. A history of symptoms of DM, peripheral neuropathy, or thyroid, adrenal, or other serious systemic disorders should be obtained. Knowledge of medication use (tranquilizers, OCs, antidepressants) and substance abuse (opiates, alcohol) is also important.
Physical Examination
The physical examination should be conducted in the same way as for patients with female hypogonadism (see Evaluation of Abnormal Bleeding, Physical Examination). Careful attention should be given to the genitalia, uterus, and adnexa for evidence of infection, atrophy, or neoplasia. Endometriosis, a common cause of dyspareunia, is sometimes detected on rectovaginal examination by palpation of nodules in the space between the rectum and vagina (pouch of Douglas). Postmenopausal patients often have significant vaginal atrophy leading to dyspareunia. Neurologic examination should include testing of peripheral sensation, position sense, and deep tendon reflexes.
Diagnostic Procedures
If evidence of hypogonadism exists, appropriate tests should be made (see Secondary Amenorrhea) to classify the syndrome and diagnose the underlying condition. Measurement of the serum prolactin concentration may be helpful even in patients without apparent galactorrhea or amenorrhea (see earlier discussion). Thyroid function with TSH should be considered. To evaluate for androgen deficiency serum total testosterone level can be checked. Levels are altered by SHBG so patients taking a medication that alter SHBG should have a free testosterone level. Patients with pelvic disease should be referred to a gynecologist for further evaluation and therapy.
Therapy
Therapeutic efforts should be directed at the specific organic cause whenever possible. Estrogen deficiency should be corrected, and hyperprolactinemia should be treated surgically or medically (see Secondary Amenorrhea). Vaginal atrophy frequently responds to topical estrogen (Chapter 106). There are no FDA-approved testosterone therapies for women. Testosterone is often used off label in oral, intramuscular and transdermal forms in women with low testosterone levels and hypoactive sexual desire and have shown promise in reports (44,45). Concerns about testosterone treatment in women include virilization, male pattern hair loss, and adverse affects in the lipid panel.
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Another non–FDA-approved treatment is use of sildenafil citrate in treatment of physiologic female sexual disfunction. Sildenafil 50 mg given 1 hour before intercourse and not more then once per day was shown to improve sexual arousal and lubrication in a double-blinded trail (46). If no organic cause is evident after careful examination, consideration of various modes of psychological diagnosis and treatment is appropriate (see Chapter 19). Referral to a provider with interest and expertise in sexual dysfunction should be made. A multidisciplinary approach including marital counseling, sex therapy, and mental health care all play a role in successful treatment of sexual dysfunction.
Specific References*
For annotated General References and resources related to this chapter, visit http://www.hopkinsbayview.org/PAMreferences.