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Reproductive Endocrinology and Infertility
The Normal Menstrual Cycle
Endometrium
The endometrium undergoes histologic and cytologic changes that culminate with menstrual bleeding when the corpus luteum ceases to secrete progesterone ( Fig. 218-1 ). The basal layer of the endometrium then regenerates the superficial layer of compact epithelial cells that line the uterine cavity and an intermediate layer of spongiosa. Endometrial glands proliferate under the influence of estrogen, and the mucosa thickens. In the luteal phase, the glands become coiled and secretory, with increased vascularity and edema of the stroma. When estradiol and progesterone decline, the stroma becomes edematous, endometrial and blood vessel necrosis occurs, both the superficial epithelial cells and the spongiosa are shed, and bleeding ensues. Local release of prostaglandins may initiate vasospasm, which results in ischemic necrosis, as well as the uterine contractions that accompany menstrual flow. Prostaglandin synthetase inhibitors can relieve menstrual cramping. The histologic changes are characteristic, so endometrial biopsies can identify the stage of the cycle and assess the endometrium’s response to gonadal steroids.
Cervix and Cervical Mucus
During the follicular phase, cervical vascularity, congestion, and edema increase as a result of estrogen. Cervical mucus increases in quantity (10- to 30-fold) and in elasticity. So-called ferning becomes prominent. Progesterone stimulates the thickening of cervical mucus, the loss of elasticity, and loss of the ability to fern.
Vagina
Low estrogen is associated with pale, thin vaginal epithelium. As estrogens rise, the number of cornified epithelial cells increases. Subsequently, progesterone decreases the percentage of cornified cells and increases the number of precornified intermediate cells, thereby resulting in increased cellular debris and clumping of shed desquamated cells. Histologic changes in the vaginal epithelium are sensitive indicators of estrogen status.
Ovary
The ovaries produce a single dominant graafian follicle that grows and develops to the preovulatory stage during the follicular phase. This process is brought about by combined action of follicle-stimulating hormone (FSH) and luteinizing hormone (LH) on the granulosa cells that comprise the follicle wall to increase estradiol biosynthesis. The LH surge acts on the preovulatory follicle to cause the secretion of the mature fertilizable oocyte. After ovulation, the follicle wall transforms into the corpus luteum, which produces progesterone and estradiol. If implantation does not occur, the corpus luteum undergoes luteolysis and stops hormone production. In the late luteal phase, another dominant follicle develops, and a new menstrual cycle begins.
Chronology of Folliculogenesis
The preovulatory follicle begins its development when a primordial follicle is recruited into the pool of growing follicles. The two major phases of folliculogenesis are the preantral (gonadotropin-independent) and the antral (gonadotropin-dependent) phases (see Fig. 218-1 ). The first phase is characterized by growth of the oocyte and proliferation of the granulosa cells. Preantral folliculogenesis, which proceeds slowly, requires at least 300 days. During the second phase, granulosa and theca cells proliferate, and the antrum enlarges. The graafian follicle increases relatively rapidly as it develops. The mature graafian follicle that will ovulate requires 40 to 50 days to complete the antral phase.
Selection
The dominant follicle is selected from a cohort at the end of the luteal phase of the previous menstrual cycle. The selected follicle requires 20 days to develop to the ovulatory stage.
Shortly after the midluteal phase of the cycle, the granulosa cells show a sharp increase in the rate of mitosis. The first indication of selection is that the granulosa cells continue dividing at a high rate. As a consequence of the high sustained mitotic rate and the progressive accumulation of follicular fluid, the dominant follicle undergoes remarkable growth. The increase in plasma FSH levels that begins at the end of luteal phase and continues through the early follicular phase evokes follicle selection. The concentration of FSH in the follicular fluid of the healthy (dominant) follicle increases but does not increase in the nondominant atretic follicles. More than 99.9% of all follicles are not selected and undergo atresia.
Ovulation
At midpoint in the menstrual cycle, the preovulatory surges of LH and FSH act on the preovulatory follicle to initiate the events leading to ovulation (see Fig. 218-1 ). The LH surge induces meiotic maturation, a process that converts the oocyte into a fertilizable egg arrested at the second meiotic metaphase. During meiotic maturation, the granulosa cells next to the oocyte are stimulated by FSH to undergo cumulus expansion ( Fig. 218-2 ). This step is a prerequisite for the oocyte’s pickup and transport by the oviduct. The LH surge also stimulates production of proteolytic enzymes in the vicinity of the presumptive stigma. This process requires the LH stimulation of progesterone and prostaglandins, which are obligatory for stigma formation. After 36 hours, the fertilizable egg and surrounding cumulus cells are secreted through the stigma (see Fig. 218-1 ). A serum progesterone level higher than 3 ng/mL at 1 week before menses is probably diagnostic of ovulation.
Luteogenesis
Ovulation changes the granulosa and theca cells of the ovulated follicle to increase their production of progesterone and estradiol during the first week of the luteal phase. This event, termed luteinization , is important for the formation and development of a secretory endometrium. Three major physiologic mechanisms are responsible for luteinization: removal of luteinization inhibitors, secretion of LH by the pituitary, and delivery of high levels of cholesterol. The induction of steroidogenic acute regulatory protein StAR, P450c22, and 3β-hydroxysteroid dehydrogenase in the granulosa lutein cells leads to the production of progesterone by the corpus luteum. The two-cell, two-gonadotropin mechanism is responsible for the production of estradiol. If implantation does not occur, the corpus luteum initiates luteolysis, thereby decreasing progesterone and estradiol and resulting in apoptosis. When luteolysis occurs, another dominant follicle is selected, and a new menstrual cycle begins.
Menstrual Symptoms
Dysmenorrhea and Endometriosis
Dysmenorrhea, defined as painful menstruation, affects about 50% of postpubertal women and can be classified as primary or secondary. Endometriosis, which affects about 10% of women of reproductive age, is the ectopic presence of endometrial tissue (glands and stroma), most commonly within the abdominal cavity but sometimes in surgical scars, on the vulva, in the umbilicus, and elsewhere. Endometriosis may result in dysmenorrhea, infertility, and dyspareunia (i.e., painful intercourse). A saliva-based micro-RNA signature appears to have a high sensitivity and specificity for the diagnosis of endometriosis.
Primary dysmenorrhea usually, but not always, occurs in ovulatory cycles. Prostaglandins produce dysmenorrhea by initiating painful, exaggerated uterine contractions and myometrial ischemia. Associated systemic symptoms include nausea, diarrhea, headache, and emotional changes. By comparison, secondary dysmenorrhea has a pathologic cause, with endometriosis being the most common. Other causes include pelvic inflammatory disease ( Chapter 264 ); congenital abnormalities, such as atresia of a portion of the distal genital tract and cystic duplication of the paramesonephric ducts; and cervical stenosis.
Treatment and Prognosis
To treat primary dysmenorrhea, over-the-counter nonsteroidal anti-inflammatory drugs (NSAIDs), which inhibit prostaglandin synthase (e.g., naproxen, ibuprofen, or prescription NSAIDs such as mefenamic acid, piroxicam, diclofenac, and meclofenamate), should be started as soon as bleeding or cramping begins and continued for up to 3 days ( Table 218-1 ). NSAIDs should not be used in women who cannot maintain adequate hydration; have underlying renal disease; are receiving anticoagulants, systemic glucocorticoids, lithium, or loop diuretics; or have a history of gastrointestinal bleeding, coagulopathy, ischemic heart disease, stroke, heart failure, liver disease, or aspirin-sensitive asthma. If the dysmenorrhea persists, addition of an oral contraceptive to inhibit ovulation and limit the release of prostaglandin is generally effective. If the pelvic pain remains intractable, additional evaluation is warranted. If thorough evaluation of the gastrointestinal and urinary tracts fails to reveal a definitive cause, examination under anesthesia and diagnostic laparoscopy may be indicated.
TABLE 218-1
SUGGESTED ORAL NONSTEROIDAL ANTI-INFLAMMATORY DRUGS TO INHIBIT PROSTAGLANDIN SYNTHASE IN PRIMARY DYSMENORRHEA
| DRUG | INITIAL DOSE | SUBSEQUENT DOSING OVER 3 DAYS IF NEEDED |
|---|---|---|
| Naproxen sodium | 550 mg | 275 mg every 6 to 8 hours up to 1375 mg total |
| Ibuprofen | 400 to 800 mg | 400 to 800 mg every 4 to 6 hours up to 2400 mg total |
| Mefenamic acid | 500 mg | 250 mg every 6 hours up to 1000 mg |
| Piroxicam | 20 mg | 10 mg to a total dose of 20 mg once daily |
| Diclofenac | 75 to 100 mg | 50 mg every 8 hours to a total dose of 150 mg |
| Meclofenamate | 100 mg | 50 mg every 4 to 6 hours up to 400 mg total |
If endometriosis is diagnosed at laparoscopy, treatment varies according to the severity of the disease and the patient’s goals regarding fertility. , Initial options include fulguration or excision of implants with lysis of adhesions. Persistent endometriosis can be treated medically, with additional surgery deferred should medical therapy fail. Medical therapy can consist of continuous suppression with oral contraceptives, progestins (e.g., norethindrone 5 mg daily), gonadotropin-releasing hormone (GnRH) analogues (e.g., leuprorelin 3.75 or 11.25 mg subcutaneously monthly), a GnRH receptor antagonist (elagolix 150 mg orally daily for up to 24 months or relugolix 40 mg orally daily), or danazol for 3 to 6 months. After a course of treatment, use of oral contraceptive agents should probably be continued until fertility is desired. Conservative surgical resection of endometriotic tissue should almost always be deferred until it is established as the cause of infertility. Surgery may be required, however, for continuing severe pain, severe endometriosis, or large ovarian cysts containing endometriosis (endometriomas).
Some patients have chronic pelvic pain that persists for more than 6 months, often related to menses or intercourse. , The cause is unknown, but patients often have coexisting fibromyalgia ( Chapter 253 ) or migraine headaches ( Chapter 367 ). If symptoms continue, medical causes have been excluded, or psychological overlay is suspected, multimodality psychosocial intervention or psychiatric evaluation may be indicated.
Prognosis
With effective treatment, quality of life improves significantly. Should initial therapy fail, however, referral to a reproductive endocrinologist is warranted.
Premenstrual Syndrome
Premenstrual syndrome (PMS), also known as premenstrual tension, is a complex of physical and emotional symptoms that occur repetitively in a cyclic fashion before menstruation and that diminish or disappear with menstruation. About 50% of menstruating women have symptoms of varying severity.
The cyclic symptoms typically are sufficiently severe to interfere with some aspects of life. More than 150 different symptoms are now thought to vary with the menstrual cycle ( Table 218-2 ). Estimates of the prevalence of premenstrual syndrome range from 25 to 100%. For most women, premenstrual syndrome is merely annoying, but severe premenstrual syndrome causes serious difficulties for 3 to 5% of women of reproductive age.
TABLE 218-2
COMMON SYMPTOMS OF CYCLIC PREMENSTRUAL SYNDROME
| SOMATIC SYMPTOMS | |
| Abdominal bloating | Constipation or diarrhea |
| Acne | Headache |
| Alcohol intolerance | Peripheral edema |
| Breast engorgement and tenderness | Weight gain |
| Clumsiness | |
| EMOTIONAL AND MENTAL SYMPTOMS | |
| Anxiety | Insomnia |
| Change in libido | Irritability |
| Depression | Lethargy |
| Fatigue | Mood swings |
| Food cravings (especially salt and sugar) | Panic attacks |
| Hostility | Paranoia |
| Inability to concentrate | Violence toward self and others |
| Increased appetite | Withdrawal from others |
Most women seek help for premenstrual syndrome in their 30s after 10 or more years of symptoms. Many report that their symptoms began at menarche; approximately half state that symptoms followed childbirth. Severity and duration of symptoms are often reported to increase after each successive pregnancy and to become more severe with advancing age. Women with severe long-standing premenstrual syndrome almost always describe associated psychological reactions, including social difficulties such as marital discord, difficulty relating to their children, difficulty maintaining friendships, and withdrawal from social activities.
The diagnosis is best established by requiring affected individuals to keep prospective daily records of symptoms during a 2- to 3-month period. Less than 50% of women who complain of premenstrual syndrome are found to have the syndrome when such records are examined.
Treatment
General Measures
The cause of premenstrual syndrome is unknown, and patients should be informed that no one therapy has been effective in all women. Women with mild premenstrual symptoms often benefit from simple changes in lifestyle, including daily mild aerobic exercise; reduction in intake of caffeine-containing beverages, salt, and refined sugar, particularly in the luteal phase; stress reduction; and adequate rest.
Medical Therapy
Women with more severe premenstrual syndrome may benefit from symptomatic treatment. Continuous oral contraceptives (see Table 220-3 ) have inconsistent but generally positive therapeutic benefit, although intermittent drospirenone/ethinyl estradiol (3 mg/20 μg) dosed on a 21-7 schedule (21 active pills followed by 7 placebo pills) has comparable efficacy to the continuous combined oral contraceptives. Off-label bromocriptine (generally 2.5 mg twice a day) or danazol (100 to 400 mg/day in two divided doses) may be given continuously for relief of mastalgia (breast pain), although its efficacy has not been documented by rigorous randomized trials. NSAIDs (see Table 218-1 ) may help reduce pain and alleviate headaches. Mild sedatives and anti-anxiety drugs ( Table 362-9 ) may help reduce insomnia and anxiety. For example, low doses of fluoxetine (10 to 20 mg) and other selective serotonin re-uptake inhibitors ( Table 362-5 ), administered either daily or for the last 2 weeks of each menstrual cycle, are highly effective in reducing the emotional symptoms associated with PMS. Mild diuretics (especially spironolactone at doses up to 100 mg each morning) may benefit cyclic edema.
GnRH agonist therapy plus exogenous estrogen and progestin (e.g., 0.625 mg oral conjugated equine estrogen, 5 mg norethindrone acetate) have been tried with variable success. Neither natural progesterone, given in the form of vaginal suppositories, nor large quantities of multiple vitamins or oil of evening primrose are of documented benefit.
Surgical Therapy
Because premenstrual syndrome requires the occurrence of cyclic ovulation, oophorectomy is occasionally considered for patients who have particularly intractable symptoms. However, oophorectomy may create new problems related to estrogen deficiency.
Prognosis
Premenstrual syndrome can cause debilitating symptoms, but intervention can frequently result in substantial improvement. In the absence of oophorectomy or menopause, however, discontinuing treatment can result in recurrence of symptoms.
Abnormal Uterine Bleeding
Epidemiology and Pathobiology
Abnormal uterine bleeding may occur in 10 to 30% of women of reproductive age but is a warning sign for endometrial cancer if it develops in postmenopausal women. Prompt and accurate diagnosis is essential.
About 20% of abnormal uterine bleeding is postmenarchal bleeding in adolescents, in whom immaturity of the hypothalamic-pituitary-ovarian axis results in anovulation. Another 50% of abnormal uterine bleeding is perimenopausal bleeding related to incipient ovarian failure and menopause ( Chapter 222 ).
Abnormal uterine bleeding with no demonstrable organic genital or extragenital cause (75% of cases) is most frequently associated with anovulation and is appropriately termed anovulatory (sometimes termed dysfunctional ) bleeding . Most anovulatory bleeding is due to either estrogen withdrawal or estrogen breakthrough bleeding. In anovulatory women, estrogen stimulates the endometrium unopposed by progesterone. The endometrium proliferates, becomes thicker, and may shed irregularly. Compared with cyclic menses, anovulatory bleeding tends to occur at less frequent intervals, whereas organic lesions tend to cause more frequent bleeding.
During the reproductive years, the causes of uterine bleeding include complications from the use of oral contraceptives; complications of pregnancy, especially threatened, incomplete, or missed miscarriages and ectopic pregnancy; coagulation disorders, most commonly idiopathic thrombocytopenic purpura ( Chapter 158 ) and von Willebrand disease ( Chapter 159 ); and pelvic disease, such as intrauterine polyps, leiomyomas (fibroids), and tumors of the vagina and cervix ( Chapter 184 ). Clear cell adenocarcinoma of the vagina or cervix may occur in women exposed to diethylstilbestrol during fetal life. Affected women may also have congenital abnormalities of the upper vagina, cervix, and uterus. Women with a history of diethylstilbestrol exposure should be reassured that the incidence of malignant change is extremely low. Trauma (coital or otherwise), foreign bodies, systemic illnesses including various endocrinopathies (such as diabetes mellitus, hypothyroidism and hyperthyroidism, Cushing syndrome, and Addison disease), leukemia, and renal disease may also be associated with abnormal bleeding as the presenting manifestation.
Clinical Manifestations
Heavy menstrual bleeding is now recognized as excessive menses that interfere with physical, social, emotional, and/or material quality of life. Abnormal bleeding may also occur independently of the menstrual cycle.
Diagnosis
All cases of abnormal bleeding should be evaluated, beginning with a thorough history emphasizing the amount and duration of blood loss. Prospective charting of the days on which bleeding occurs may be required to evaluate the bleeding pattern. Complications of pregnancy or a bleeding diathesis must always be excluded.
The findings on physical examination (including the Papanicolaou smear) are normal in anovulatory bleeding except for signs of anemia in the more severe cases. Laboratory tests should include a complete blood count, platelet count, coagulation studies (including screening for von Willebrand disease [ Chapter 159 ]), thyroid function tests ( Chapter 207 ), and fasting blood glucose concentration. Anovulatory bleeding must be a diagnosis of exclusion, with management depending on the age of the patient and the extent of the bleeding.
For all women older than age 35 years and for all patients who are at increased risk for endometrial carcinoma ( Chapter 184 ) because of prolonged anovulatory bleeding, a sample of the endometrium should be obtained by biopsy or by dilation and curettage.
Treatment
Even profuse bleeding in hemodynamically stable anovulatory women can almost always be successfully treated by the off-label administration of one combination oral contraceptive pill ( Table 220-3 ) every 6 hours for 5 to 7 days. Bleeding should cease within 24 hours, but patients should be warned to expect heavy bleeding 2 to 4 days after therapy is stopped. If anemia is profound, blood transfusion may be necessary. If the bleeding continues despite therapy, curettage can be performed. Recurrence can be prevented by giving the patient combination oral contraceptive agents cyclically if pregnancy is not desired. If pregnancy is desired, ovulation can be induced.
Acute episodes of anovulatory bleeding can also be treated with conjugated estrogens administered intravenously (25 mg every 4 hours for up to three doses) until bleeding ceases. Progestin therapy (medroxyprogesterone acetate 5 to 10 mg orally for 10 days) should be started simultaneously. Withdrawal bleeding occurs after cessation of therapy, and the patient can then be treated with oral contraceptive agents ( Table 220-3 ) for at least three cycles.
For individuals with anovulatory bleeding without an episode of profuse bleeding, treatment with cyclic oral contraceptive agents ( Table 220-3 ) or progestin (a standard oral contraceptive pill per day [see Table 220-3 ] or norethindrone 5 mg daily) can be provided unless pregnancy is desired, in which case ovulation must be induced.
Endometrial ablation by any of several methods is being used increasingly to treat persistent bleeding. However, ablation is not 100% effective, and medical management remains the first line of therapy for most women. Women suffering with uterine fibroids can be treated with oral medication (e.g., elagolix 300 mg twice daily or relugolix 40 mg daily), uterine artery embolization, or surgery ( Chapter 184 ).
Hysterectomy may be an appropriate choice for a small number of women with refractory symptoms. It is also indicated if endometrial sampling suggests malignancy.
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