Women’s Health

Phase I. Menstruation and the Follicular Phase

The first day of menstrual bleeding is considered day 1 of the typical 28-day menstrual cycle. Women usually menstruate for 3 to 5 days. Menstruation marks the beginning of the follicular phase of the cycle. With the beginning of menstruation, plasma concentrations of E₂, progesterone, and LH reach their lowest point (normal range of 1.8 to 2.4 ng/dL, 37 to 57 ng/dL, and 5 to 25 milli-International Units/mL, respectively).^1,2 An increase in FSH begins approximately 2 days before the onset of menstruation and continues in response to the reduction in negative feedback at the pituitary gland. Under the influence of FSH, the granulosa cells in the ovarian follicle begin to secrete E₂.

By the fourth day of the cycle, E₂ begins to rise in plasma. E₂ stimulates LH receptors on the theca cells in the ovarian follicle, further increasing secretion of androgen precursors, which are converted by aromatase to E₂ in granulosa cells. The upregulation of LH receptors and hormone production prepares the granulosa and theca cells for progesterone synthesis after ovulation.

With rising E₂ levels, there is negative feedback to the pituitary gland to decrease the release of FSH and positive feedback to the pituitary gland to increase the release of LH.

Phase II. Ovulation

As the dominant follicle secretes more and more E₂ (normal range of 16.6 to 23.2 ng/dL), there is marked positive feedback to the pituitary gland to secrete LH. By days 11 to 13 of the normal cycle, an LH surge occurs (normal range of 40 to 80 milli-International Units/mL), which triggers ovulation. Ovulation occurs within 24 to 36 hours of the LH surge, causing the oocyte to be expelled from the follicle and the follicle to be converted into corpus luteum to facilitate progesterone production during the remainder of the cycle. In addition, there is a slight increase in the basal body temperature (BBT) after ovulation.

Phase III. Luteal Phase

The luteal phase of the menstrual cycle is characterized by a change in secretion of sex steroid hormones from E₂ predominance to progesterone predominance. As FSH rises early in the cycle, stimulating production of E₂, additional LH receptors are created in the granulosa cells and then theca cells. With the LH surge at the time of ovulation, LH facilitates production of progesterone.

Production of progesterone begins approximately 24 hours before ovulation and rises rapidly thereafter. A maximum production of progesterone occurs 3 to 4 days after ovulation and is maintained for approximately 11 days after ovulation (normal range of 332 to 1,198 ng/dL). If fertilization and implantation do not occur, progesterone production diminishes rapidly, initiating events leading to the beginning of a new cycle.

Adequate progesterone production is necessary to facilitate implantation of the fertilized oocyte into the endometrium and sustain pregnancy into the early first trimester. If the initial rise in FSH is inadequate and the LH surge does not achieve maximal amplitude, an “inadequate luteal phase” can occur, resulting in progesterone production that is inadequate to facilitate implantation of a fertilized oocyte or sustain pregnancy.

Physiologic plasma levels of progesterone exert negative feedback on pituitary secretion of both FSH and LH. During the luteal phase of the cycle, both FSH and LH are suppressed to low levels (5 to 25 milli-International Units/mL). As the corpus luteum fails and progesterone secretion diminishes, FSH begins to rise to prepare a woman for the next reproductive cycle.

Follicle-Stimulating Hormone²³

Normal ranges are as follows:

• Children: 5 to 10 milli-International Units/mL (5 to 10 International Units/L)

• Adult women, follicular phase: 5 to 25 milli-International Units/mL (5 to 25 International Units/L)

• Adult women, midcycle: 20 to 30 milli-International Units/mL (20 to 30 International Units/L)

• Adult women, luteal phase: 5 to 25 milli-International Units/mL (5 to 25 International Units/L)

• Menopausal women: 40 to 250 milli-International Units/mL (40 to 250 International Units/L)

Follicle-stimulating hormone (FSH)²³ is a glycoprotein pituitary hormone produced and stored in the anterior pituitary. It is under complex regulation by hypothalamic GnRH and by the gonadal sex hormones estrogen and progesterone. Normally, FSH increases occur at earlier stages of puberty, 2 to 4 years before LH reaches comparable levels. In females, FSH stimulates follicular formation in the early stages of the menstrual cycle and then the midcycle surge of LH causes ovulation of the FSH-ripened ovarian follicle.

This test may be helpful in determining whether a gonadal deficiency is of primary origin or is secondary to insufficient stimulation by the pituitary hormones. Decreased FSH levels may occur in feminizing and masculinizing ovarian tumors (when FSH production is inhibited because of increased estrogen secretion), pituitary adenomas, neoplasm of the adrenal glands (which influences secretion of estrogen or androgens), and polycystic ovary syndrome (PCOS).⁵⁶ Increased FSH levels occur in premature ovarian failure and in menopause.⁵⁶

The date of the last menstrual period (LMP) should be considered when interpreting FSH in premenopausal women. Sometimes multiple blood specimens are necessary because of episodic releases of FSH from the pituitary gland. An isolated sample may not indicate the actual activity; therefore, multiple single blood specimens may be required.

Interfering factors include recently administered radioisotopes, hemolysis of the blood sample, pregnancy, and drugs, such as estrogens or oral contraceptives or testosterone. Table 24-1 provides a detailed list of drugs affecting plasma laboratory test values of FSH.⁵⁶

Luteinizing Hormone²³

Normal ranges are as follows:

• Children: 5 to 10 milli-International Units/mL (5 to 10 IU/L)

• Adult women, follicular phase: 5 to 25 milli-International Units/mL (5 to 25 IU/L)

• Adult women, midcycle: 40 to 80 milli-International Units/mL (40 to 80 IU/L)

• Adult women, luteal phase: 5 to 25 milli-International Units/mL (5 to 25 IU/L)

• Menopausal women: >75 milli-International Units/mL (> 75 IU/L)

Like FSH, luteinizing hormone (LH)²³ is a glycoprotein pituitary hormone produced and stored in the anterior pituitary that is under complex regulation by hypothalamic-releasing hormone and by estrogen and progesterone. The midcycle surge of LH causes ovulation. Decreased LH and FSH occur in pituitary adenomas and eating disorders, whereas elevated levels are found in ovarian failure and menopause.⁵⁶ Elevated basal LH with an LH/FSH ratio of 3 or more and some increase of ovarian androgen in an essentially anovulatory adult woman are presumptive evidence of PCOS.⁵⁶

The date of the LMP should be considered in premenopausal females. Interfering factors include recently administered radioisotopes, hemolysis of the blood sample, pregnancy, and estrogens or oral contraceptives or testosterone.⁵⁶ A detailed list of drugs that affect plasma laboratory test values of LH is shown in Table 24-2.⁵⁶

Estradiol²³

Normal ranges are as follows:

• Children: <2 ng/dL

• Adult women, follicular phase: 1.8 to 2.4 ng/dL (66 to 88 pmol/L)

• Adult women, midcycle: 16.6 to 23.2 ng/dL (609 to 852 pmol/L)

• Adult women, luteal phase: 6.3 to 7.3 ng/dL (231 to 268 pmol/L)

Together with the FSH levels, estradiol (E₂)²³ is useful in evaluating menstrual and fertility problems as well as estrogen-producing tumors. E₂ is the most active of the endogenous estrogens. Estriol (E₃) levels in both plasma and urine rise as pregnancy advances; significant amounts are produced in the third trimester. E₃ is no longer considered useful for detection of fetal distress.⁵⁶

E₂ levels are increased by estrogen-producing tumors, during menstruation, before ovulation, and during the weeks 23 to 41 of pregnancy. E₂ levels are decreased in premature ovarian failure and in menopause. Normal E₂ values vary widely between women and in the presence of pregnancy, the menopausal state, or follicular, ovulatory, or luteal stages of the menstrual cycle.

The number of weeks of gestation should be considered if the patient is pregnant when interpreting E₂ levels. The number of days into the menstrual cycle must be documented and considered for a nonpregnant woman. Interfering factors include radioactive pharmaceuticals and oral contraceptives.

Progesterone²³

Normal ranges are as follows:

• Adult women, early in cycle: 37 to 57 ng/dL (1.2 to 1.8 nmol/L)

• Adult women, midcycle: rising

• Adult women, luteal phase: 332 to 1,198 ng/dL (10.6 to 38.1 nmol/L)

• Menopausal women: 10 to 22 ng/dL (0.3 to 0.7 nmol/L)

Progesterone²³ is primarily involved in the preparation of the uterus for pregnancy and its maintenance during pregnancy. The placenta begins producing progesterone at 12 weeks of gestation. Progesterone level peaks in the midluteal phase of the menstrual cycle. In nonpregnant women, progesterone is produced by the corpus luteum. Progesterone on day 21 is the single best test to determine whether ovulation has occurred.

This test is part of a fertility evaluation to confirm ovulation, evaluate corpus luteum function, and assess risk for early spontaneous abortion. Testing of several samples during the cycle is necessary. Ovarian production of progesterone is low during the follicular (first) phase of the menstrual cycle. After ovulation, progesterone levels rise for 2 to 5 days and then fall. During pregnancy, there is a gradual increase from week 9 to week 32 of gestation, often to 100 times the level in the nonpregnant woman. Levels of progesterone in twin pregnancy are higher than in a single pregnancy.

Increased progesterone levels are associated with congenital adrenal hyperplasia (CAH) and some ovarian tumors. Decreased progesterone levels are associated with threatened spontaneous abortion and hyperprolactinemia.

The date of the LMP and length of gestation should be recorded. No radioisotopes should be administered within 1 week before the test. Drugs that affect plasma laboratory test values of progesterone are listed in Table 24-3.⁵⁶

Prolactin²³

Normal ranges are as follows:

• Children: 1 to 20 ng/mL (1 to 20 mcg/L)

• Adult women: 1 to 25 ng/mL (1 to 25 mcg/L)

• Menopausal women: 1 to 20 ng/mL (1 to 20 mcg/L)

Prolactin²³ is a pituitary hormone essential for initiating and maintaining lactation. The gender difference in prolactin does not occur until puberty, when increased estrogen production results in higher prolactin levels in females. A circadian change in prolactin concentration in adults is marked by episodic fluctuation and a sleep-induced peak in the early morning hours.⁵⁶

This test may be helpful in the diagnosis, management, and follow-up of prolactin-secreting tumors, including the effectiveness of surgery, chemotherapy, and radiation treatment. Levels >100 ng/mL in a nonlactating female indicate a prolactin-secreting tumor; however, a normal prolactin level does not rule out pituitary tumor. In addition to pituitary adenomas, increased prolactin levels are associated with hypothyroidism (primary), PCOS, and anorexia nervosa; these increased levels are helpful in the differential diagnosis of infertility.

The patient should fast for 12 hours before testing. Specimens should be procured in the morning, 3 to 4 hours after awakening. Interfering factors occur in a number of circumstances. Increased values are associated with newborns, pregnancy, the postpartum period, stress, exercise, sleep, nipple stimulation, and lactation. Drugs such as estrogens, methyldopa, phenothiazines, and opiates may increase values. Dopaminergic drugs inhibit prolactin. Administration of dopaminergic agents can normalize prolactin levels in patients with galactorrhea, hyperprolactinemia, and pituitary tumor. Table 24-4 provides a comprehensive list of drugs affecting plasma laboratory test values of prolactin.^56,57

Testosterone²³

Normal ranges are as follows:

• Children: 0.12 to 0.16 ng/mL (0.4 to 0.6 nmol/L)

• Adult women: 0.2 to 0.6 ng/mL (0.7 to 2.1 nmol/L)

• Menopausal women: 0.21 to 0.37 ng/mL (0.7 to 1.3 nmol/L)

The adrenal glands and ovaries in women secrete testosterone.²³ Excessive production virilizes women. Testosterone exists in serum as both unbound (free) fractions and fractions bound to albumin, sex hormone–binding globulin (SHBG), and testosterone-binding globulin. Unbound (free) testosterone is the active portion. Testosterone serum levels undergo large and rapid fluctuations; levels peak in early morning.⁵⁶

This test is useful in the detection of ovarian tumors and virilizing conditions in women. It also may be part of a fertility evaluation. Increased total testosterone levels occur in adrenal neoplasms, CAH, and ovarian tumors (benign or malignant). Increased free testosterone levels are associated with female hirsutism, PCOS, and virilization.

Blood should be drawn in the early morning (between 6:00 a.m. and 10:00 a.m.) to obtain the highest levels. Multiple pooled samples drawn at different times throughout the day may be necessary for more reliable results. No radioisotopes should be administered within 1 week before the test. Several drugs interfere with test results, including estrogen, androgens, and steroids, which decrease testosterone levels. Other drugs that interfere with interpretation of laboratory values of testosterone are provided in Table 24-5.^52,57

Hypothyroidism

Although other clinical signs of thyroid disease are usually noted before amenorrhea presents, abnormal thyroid hormone levels can affect prolactin levels. Treatment of hypothyroidism should restore menses, but this may take several months.⁸ Table 24-8 provides differential diagnoses of anovulatory disorders and associated serum laboratory findings.⁹

Hyperprolactinemia

A patient with markedly elevated prolactin levels, galactorrhea, headaches, or visual disturbances should receive imaging tests to rule out a pituitary tumor. Adenomas are the most common cause of anterior pituitary dysfunction.¹⁰ A prolactin level >100 ng/mL suggests a prolactinoma, and magnetic resonance imaging should be performed. If tumor is excluded as the cause, medications (eg, oral contraceptive pills, antipsychotics, antidepressants, antihypertensives, histamine blockers, and opiates) are the next most common cause of hyperprolactinemia. Medications usually increase prolactin levels to >100 ng/mL.¹⁰

In most amenorrheic women with hyperprolactinemia, prolactin levels do not decline without treatment, and the amenorrhea does not resolve as long as the prolactin levels remain elevated.¹⁰ In the absence of another organic condition, dopamine agonists (eg, bromocriptine) are the preferred treatment of hyperprolactinemia with or without a pituitary tumor.^3,11,12

Uterine Outflow Obstruction

The most common cause of outflow obstruction in secondary amenorrhea is Asherman syndrome (intrauterine scarring usually from curettage or infection).⁴ Certain gynecological procedures can help diagnose Asherman syndrome. Other causes of outflow tract obstruction include cervical stenosis and obstructive fibroids or polyps.

Functional (Hypothalamic) Amenorrhea

Functional disorders of the hypothalamus or higher centers are the most common reason for chronic anovulation. Psychogenic stress, weight changes, undernutrition, and excessive exercise are frequently associated with functional hypothalamic amenorrhea, but the pathophysiologic mechanisms are unclear. More cases of amenorrhea are associated with weight loss than with anorexia, but amenorrhea with anorexia nervosa is more severe.^11,13 Women involved in competitive sports activities have a 3-fold higher risk of primary or secondary amenorrhea than others, and the highest prevalence is among long-distance runners¹⁴ (Minicase 1).

Ovarian Failure

Approximately 1% to 5% of women have premature ovarian failure, a condition in which persistent estrogen deficiency and elevated FSH levels occur prior to the age of 40 years, resulting in amenorrhea.¹⁷ Ovarian failure is confirmed by documenting an FSH level persistently in the menopausal range (40 to 250 milli-International Units/mL).³ Iatrogenic causes of premature ovarian failure, such as chemotherapy and radiation therapy for malignancy, have a potential for recovery. Ovarian function may fluctuate, with an increasingly irregular menstrual cycle before permanent ovarian failure. The resulting fluctuations in gonadotropin levels account for the lack of accuracy associated with a single FSH value.¹⁸ Women with ovarian failure should be offered estrogen and progestin treatment to promote and maintain secondary sexual characteristics and reduce the risk of developing osteoporosis.

Menopause represents a type of “physiologic” ovarian failure, which is defined as the cessation of menses for at least 12 months. The climacteric and perimenopause are the periods of waning ovarian function before menopause (ie, the transition from the reproductive to the nonreproductive years).¹ The average age for menopause in the United States is between 50 and 52 years of age (median 51.5), with 95% of women experiencing this event between the ages of 44 and 55.¹ (Minicase 2.)

During perimenopause, the ovarian follicles diminish in number and become less sensitive to FSH.¹ The process of ovulation becomes increasingly inefficient, less regular, and less predictable than in earlier years. Initially, a woman may notice a shortening of the cycle length. With increasing inefficiency of the reproductive cycle, the follicular phase shortens, but the luteal phase is maintained at normal length. With the passing of time, some cycles become anovulatory. As menopause approaches, the remaining follicles become almost totally resistant to FSH. The process of ovulation ceases entirely, and cyclic hormone production ends with menopause.

Serum FSH levels begin to rise with diminishing ovarian function; the elevation is first detected in the follicular phase. This early follicular phase rise in FSH has been developed into an endocrine test of ovarian functional reserve in which one draws an FSH level on cycle day 3. With a further decrease in ovarian function, the FSH level is elevated consistently throughout the menstrual cycle in perimenopausal women and in women after oophorectomy. Table 24-9 depicts serum hormones according to age.²³

The postmenopausal ovary is not quiescent. Under the stimulation of LH, androgens (ie, testosterone and androstenedione) are secreted. Testosterone concentrations decline after menopause but remain two times higher in menopausal women with intact ovaries than in those with ovaries removed (oophorectomy). Estrone is the predominant endogenous estrogen in postmenopausal women and is termed extragonadal estrogen because the concentration is directly related to body weight and androstenedione is converted to estrone in adipose tissue. Table 24-10 compares concentrations of androgens and estrogens in premenopausal women, postmenopausal women, and women after oophorectomy.⁹

Polycystic Ovary Syndrome

Polycystic ovary syndrome affects approximately 6% of women of reproductive age and is the most frequent cause of anovulatory infertility.^24,25 Clinical signs include those associated with a hyperandrogenic anovulatory state, including hirsutism and acne. Approximately 70% of affected women manifest growth of coarse hair in androgen-dependent body regions (eg, sideburn area, chin, upper lip, periareolar area, chest, lower abdominal midline and thigh) as well as upper-body obesity with a waist-to-hip ratio of >0.85.⁹ Patients usually retain normal secondary sexual characteristics and rarely exhibit virilizing signs such as clitoromegaly, deepening of the voice, temporal balding, or masculinization of body habitus. Suggested diagnostic criteria for PCOS are provided in Table 24-11.⁹

Women with PCOS often develop polycystic ovaries as a function of a prolonged anovulatory state. Follicular cysts are observed on ultrasound in >90% of women with PCOS, but they also are present in up to 25% of normal women.^25–28 Although PCOS is primarily a clinical diagnosis, some debate exists about whether the diagnosis should be based on assays of circulating androgens rather than clinical signs and symptoms of hirsutism and acne as well as glucose abnormality. This is because a substantial number of women with PCOS have no overt clinical signs of androgen excess.⁹

Laboratory abnormalities in PCOS include elevated levels of testosterone and LH or an elevated LH/FSH ratio, an increased LH pulse frequency, and altered diurnal rhythm of LH secretion. The LH/FSH ratio is used to facilitate diagnosis, and many researchers consider an LH/FSH ratio of ≥3:1 diagnostic of the syndrome.^29,30 Although serum testosterone levels are mildly-to-moderately elevated in women with PCOS, testosterone levels also are measured to rule out virilizing tumors. Prolactin levels are usually measured to exclude a possible prolactinoma. Suggested laboratory and radiologic evaluation for PCOS is provided in Table 24-12.⁹

Women with PCOS also should be screened for abnormal glucose metabolism because of an association with glucose intolerance. To aid in the possible prevention of cardiovascular disease, lipid abnormalities and blood pressure should be monitored annually.

The primary treatment for PCOS is weight loss through diet and exercise. Modest weight loss can lower androgen levels, improve hirsutism, normalize menses, and decrease insulin resistance.³⁰ Use of oral contraceptive pills or cyclic progestational agents can help maintain a normal endometrium. The optimal cyclic progestin regimen to prevent endometrial cancer is unknown, but a monthly 10-day to 14-day regimen is recommended.³⁰ Insulin-sensitizing agents such as metformin can reduce insulin resistance and improve ovulatory function.^30,31

Hyperandrogenism

Significantly elevated testosterone or dehydroepiandrosterone sulfate (DHEA-S) levels also may indicate an androgen-secreting tumor (ovarian or adrenal). DHEA-S is an androgen that arises almost exclusively from the adrenal gland. Levels of 17 α-hydroxyprogesterone (17-OHP) can help diagnose adult-onset CAH.³⁰ Cushing syndrome is rare; therefore, patients should be screened only when characteristic signs and symptoms (eg, striae, buffalo hump, significant central obesity, easy bruising, hypertension, proximal muscle weakness) are present.³⁰

Estrogen Status

If TSH and prolactin levels are normal, a progesterone challenge test can help detect endogenous estrogen that is affecting the endometrium. A withdrawal bleed usually occurs 2 to 7 days after the challenge test.⁴ A negative progesterone challenge test signifies inadequate estrogenization and requires further follow-up for other underlying causes.