OBJECTIVES

After completing this chapter, the reader should be able to

  • Understand the reproductive cycle and recognize normal ranges for follicle-stimulating hormone, luteinizing hormone, estradiol, and progesterone and how they differ in premenopausal women, postmenopausal women, and women after oophorectomy

  • Describe clinical symptoms, physical findings, and accompanying laboratory abnormalities in women with secondary amenorrhea

  • Describe proposed diagnostic criteria, physical and radiologic findings, and accompanying laboratory abnormalities in women with polycystic ovary syndrome

  • Describe signs of virilization, causes of hirsutism, and associated laboratory abnormalities

  • Describe pertinent medical history, physical examination findings, and laboratory and gynecologic procedures to determine causes of infertility in women

  • List and describe how drugs interfere with laboratory values of follicle-stimulating hormone, luteinizing hormone, progesterone, prolactin, and testosterone

ANATOMY AND PHYSIOLOGY

The reproductive cycle depends on the complex cyclic interactions between hypothalamic gonadotropin-releasing hormone (GnRH), the pituitary gonadotropins follicle-stimulating hormone (FSH), and luteinizing hormone (LH) and the ovarian sex steroid hormones estradiol (E2) and progesterone.1 Feedback loops between the hypothalamus, pituitary gland, and ovaries are depicted in Figure 24-1. If the levels or relationship of any one (or more) of these hormones become altered, the reproductive cycle becomes disrupted, and ovulation and menstruation cease.

FIGURE 24-1.
FIGURE 24-1.

Hypothalamic-pituitary-ovarian axis. GnRH = gonadotropin-releasing hormone; LH = luteinizing hormone; FSH = follicle-stimulating hormone; (+) = stimulation of hormone secretion; (-) = inhibition of hormone secretion.

MENSTRUAL CYCLE

The reproductive cycle is divided into three phases: menstruation and the follicular phase, ovulation, and the luteal phase.1,2 These three phases, which refer to the status of the ovary during the reproductive cycle, are depicted in Figure 24-2.

FIGURE 24-2.

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.

LABORATORY TESTS

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

TABLE 24-1.

Drugs Affecting Plasma Laboratory Test Values of FSH

INCREASE FSH (OR CAUSE FALSE-POSITIVE VALUES)

DECREASE FSH (OR CAUSE FALSE-NEGATIVE VALUES)

Phenytoin

Anabolic steroids (eg, danazol)

Dopamine agonists (bromocriptine, levodopa)

Carbamazepine

Cimetidine

Diethylstilbestrol

GnRH agonists

Digoxin

Growth hormone-releasing hormone antagonists

Estrogen/oral contraceptives

Ketoconazole

Megestrol

Naloxone

Phenothiazines (eg, promethazine)

Pravastatin

Pravastatin

Spironolactone

Tamoxifen

Tamoxifen

Testosterone

Source: Adapted with permission from Fischbach F. Chemistry studies. In: A Manual of Laboratory and Diagnostic Tests. 6th ed. Philadelphia, PA: Lippincott, Williams & Wilkins; 2000:418–449.

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

TABLE 24-2.

Drugs Affecting Plasma Laboratory Test Values of LH

INCREASE LH (OR CAUSE FALSE-POSITIVE VALUES)

DECREASE LH (OR CAUSE FALSE-NEGATIVE VALUES)

Anticonvulsants (eg, phenytoin)

Anabolic steroids (eg, danazol)

Dopamine agonists (bromocriptine)

Anticonvulsants (eg, carbamazepine)

Clomiphene

Corticotropin-releasing hormone

GnRH agonists

Diethylstilbestrol

Growth hormone-releasing hormone antagonists

Digoxin

Ketoconazole

Dopamine agonists

Mestranol

Estrogen/oral contraceptives

Spironolactone

Megestrol

Phenothiazines (eg, thioridazine)

Pravastatin

Progesterone

Tamoxifen

Testosterone

Source: Adapted with permission from Fischbach F. Chemistry studies. In: A Manual of Laboratory and Diagnostic Tests. 6th ed. Philadelphia, PA: Lippincott, Williams & Wilkins; 2000:418–449.

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

TABLE 24-3.

Drugs Affecting Plasma Laboratory Test Values of Progesterone

INCREASE PROGESTERONE (OR CAUSE FALSE-POSITIVE VALUES)

DECREASE PROGESTERONE (OR CAUSE FALSE-NEGATIVE VALUES)

Valproic acid

Ampicillin

Clomiphene

Anticonvulsants (carbamazepine, phenytoin)

Corticotropin

Danazol

Ketoconazole

GnRH agonists (eg, leuprolide)

Progesterone

Oral contraceptives

Tamoxifen

Pravastatin

Source: Adapted with permission from Fischbach F. Chemistry studies. In: A Manual of Laboratory and Diagnostic Tests. 6th ed. Philadelphia, PA: Lippincott, Williams & Wilkins; 2000:418–449.

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

TABLE 24-4.

Drugs Affecting Plasma Laboratory Test Values of Prolactin

INCREASE PROLACTIN (OR CAUSE FALSE-POSITIVE VALUES)

DECREASE PROLACTIN (OR CAUSE FALSE-NEGATIVE VALUES)

Antihistamines

Calcitonin

Antipsychotics (AP) (eg, Typical AP haloperidol)

Carbamazepine

Antipsychotics (AP) (eg, Atypical AP aripiprazole)

Clonidine

Calcitonin

Cyclosporin A

Cimetidine

Dexamethasone

Danazol

Dopamine agonists (apomorphine, bromocriptine, levodopa)

Diethylstilbestrol

Ergot alkaloid derivatives

Estrogens/oral contraceptives

Nifedipine

Fenfluramine

Opiates (morphine)

Furosemide

Pergolide

GnRH agonists

Ranitidine

Growth hormone-releasing hormone antagonists

Rifampin

Histamine antagonists

Secretin

Insulin

Tamoxifen

Interferon

Labetalol

Loxapine

Megestrol

Methyldopa

Metoclopramide

Monoamine oxidase inhibitors

Molindone

Nitrous oxide

Opiates (eg, morphine)

Parathyroid hormone

Pentagastrin

Phenothiazines (eg, chlorpromazine)

Phenytoin

Ranitidine

Reserpine

SNRIs (eg, venlafaxine)

SSRIs (eg, sertraline) Thiothixene

Thyrotropin-releasing hormone

Tumor necrosis factor

Verapamil

SNRIs = serotonin-norepinephrine reuptake inhibitors; SSRIs = selective serotonin reuptake inhibitors.

Source: Adapted with permission from references 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

TABLE 24-5.

Drugs Affecting Plasma Laboratory Test Values of Testosterone

INCREASE TESTOSTERONE (OR CAUSE FALSE-POSITIVE VALUES)

DECREASE TESTOSTERONE (OR CAUSE FALSE-NEGATIVE VALUES)

Anabolic steroids (eg, danazol)

Alcohol

Anticonvulsants (eg, phenytoin, barbiturates, rifampin)

Anticonvulsants (eg, carbamazepine)

Cimetidine

Androgens

Clomiphene

Cimetidine

Dopamine agonists (eg, bromocriptine)

Corticosteroids (eg, dexamethasone)

Gonadotropin

Cyclophosphamide

Pravastatin

Diazoxide

Tamoxifen

Diethylstilbestrol

Digoxin

Estrogens/oral contraceptives

Ketoconazole

GnRH agonists (eg, leuprolide)

Magnesium sulfate

Medroxyprogesterone

Phenothiazines (eg, thioridazine)

Pravastatin

Spironolactone

Tetracycline

Source: Adapted with permission from Fischbach F. Chemistry studies. In: A Manual of Laboratory and Diagnostic Tests. 6th ed. Philadelphia, PA: Lippincott, Williams & Wilkins; 2000:418–449.

AMENORRHEA

Amenorrhea is the absence or abnormal cessation of the menses.3 Primary and secondary amenorrhea describe the occurrence of amenorrhea before and after menarche, respectively. Primary amenorrhea can be diagnosed if a patient has normal secondary sexual characteristics but no menarche by 16 years of age.4 Secondary amenorrhea is the absence of menses for 3 months in women with previously normal menstruation and for 9 months in women with previous oligomenorrhea (scant menses). Secondary amenorrhea is more common than primary amenorrhea.5 The reader is referred to other texts for the evaluation of primary amenorrhea.

The prevalence of amenorrhea not due to pregnancy, lactation, or menopause is ~3% to 4%.3,5 History, physical examination, and measurement of FSH, thyroid-stimulating hormone (TSH), and prolactin identify the most common causes of amenorrhea. Table 24-6 illustrates how symptoms elicited from a patient history assist in diagnosing the cause of amenorrhea.4,6

TABLE 24-6.

Medical History Associated with Amenorrhea

PATIENT HISTORY

ASSOCIATIONS

Acne, greasy or oily skin, hirsutism, obesity

PCOS

History of chemotherapy

Ovarian failure

History of radiation therapy

Ovarian failure

History of diabetes mellitus, Addison disease, or thyroid disease

Ovarian failure (autoimmune etiology)

Galactorrhea

Hyperprolactinemia

Weight loss, excessive exercise, severe dieting

Functional amenorrhea

Sexual activity

Pregnancy

Cessation of menstruation followed by hot flashes, vaginal dryness, dyspareunia, or mood swings

Menopause

Rapid progression of hirsutism

Adrenal or ovarian androgen-secreting tumor

Bodybuilder

Exogenous androgen use

Medication history

Amenorrhea secondary to medication use (eg, danazol, medroxyprogesterone [Depo-Provera], LHRH agonists, LHRH antagonists, oral contraceptives)

Constipation, hoarseness, loss of hair, memory impairment, sensation of cold, weakness, weight gain

Hypothyroidism

Headache, neurologic symptoms, visual field defect

CNS lesion (hypothalamic or pituitary)

History of PID, endometriosis, or D&C

Asherman syndrome

History of cautery for cervical intraepithelial neoplasia or obstructive cervical malignancy

Cervical stenosis

Debilitating illness

Functional amenorrhea

CNS = central nervous system; D&C = dilation and curettage; LHRH = luteinizing hormone-releasing hormone; PID = pelvic inflammatory disease.

Source: Adapted with permission from references 4 and 6.

During the physical examination, the clinician should note the presence of galactorrhea, thyromegaly, or other evidence of hypothyroidism or hyperthyroidism, hirsutism, acne, or signs of virilization.7 In addition, the patient’s body mass index (BMI) should be calculated. A BMI <20 kg/m2 may indicate hypothalamic ovulatory dysfunction, such as occurs with anorexia or other eating disorders. The presence of breast development suggests there has been previous estrogen activity. Excessive testosterone secretion is suggested most often by hirsutism and rarely by increased muscle mass or signs of virilization. The combination of amenorrhea and galactorrhea strongly correlates with hyperprolactinemia and not virilization. The history and physical examination should include a thorough assessment of the external and internal genitalia. Table 24-7 illustrates how physical examination findings assist in diagnosing the cause of amenorrhea.4,6

TABLE 24-7.

Physical Examination Findings Associated with Amenorrhea

FINDINGS

ASSOCIATIONS

Bradycardia

Hypothyroidism, physical or nutritional stress

Coarse skin, coarseness of hair, dry skin, edema of the eyelids, weight gain

Hypothyroidism

Galactorrhea

Hyperprolactinemia

Bradycardia, cold extremities, dry skin with lanugo hair, hypotension, hypothermia, minimum of body fat, orange discoloration of skin (hypercarotenemia)

Anorexia nervosa

Painless enlargement of parotid glands, ulcers or calluses on skin of dorsum of fingers or hands

Bulimia

Signs of virilization: clitoromegaly, frontal balding, increased muscle bulk, severe hirsutism

Adrenal or ovarian androgen-secreting tumor

Centripetal obesity, hirsutism, hypertension, proximal muscle weakness, striae

Cushing syndrome

Increased BMI, hirsutism, acne

PCOS

Transverse vaginal septum, imperforate hymen

Uterine outflow tract obstruction

BMI = body mass index.

Source: Adapted with permission from references 4 and 6.

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

TABLE 24-8.

Differential Diagnosis of Amenorrhea and Associated Serum Laboratory Findingsa

CONDITION

FSH

LH

PROLACTIN

TESTOSTERONE

Functional amenorrhea secondary to extreme exertion or rapid weight changes

Premature ovarian failure

↑↑↑

↑↑↑

Pituitary adenoma

↑↑

Use of progestational agents

Hypothyroidism

↔/↑

Eating disorders

↓↓

↓↓

PCOS

↔/↓

↑↑

↔/↑

↔/↑↑

CAH

↔/↑

anormal = ↔; mildly reduced = ↓; moderately reduced = ↓↓; significantly reduced = ↓↓↓; mildly elevated = ↑; moderately elevated = ↑↑; significantly elevated = ↑↑↑.

Source: Adapted with permission from Hunter MH, Sterrett JJ. Polycystic ovary syndrome: it’s not just infertility. Am Fam Physician. 2000;62(5):1079–1088.

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.

Amenorrhea Secondary to Intense Exercise and Weight Loss

Tonya W., a 34-year-old woman, sees her doctor for a urine pregnancy test due to no menses for about 2 months. Tonya W. has no significant past medical history. Further questioning reveals she has lost a total of 28 lb over the past 4 months and complains of recent acne. Tonya W.’s vital signs include blood pressure (BP) 105/70 mm Hg, heart rate (HR) 55 beats/min, temperature 98.8°F, and weight 112 lb. Laboratory tests are as follows:

  • urine human chorionic gonadotropin (hCG), negative

  • FSH, 6 milli-International Units/mL

  • LH 3, milli-International Units/mL,

  • prolactin 20 ng/mL

  • testosterone, 20 ng/dL

She also reports heavy exercise for the past year and a decreased appetite over the past 6 months.

QUESTION: What is the most likely diagnosis?

DISCUSSION: This patient reports amenorrhea. Pregnancy is not a cause of amenorrhea because her urine hCG is negative. Laboratory tests fall within normal range, and she has decreased appetite, bradycardia, and reports heavy exercise over an extended period of time—all indicative of a functional disorder. The combination of heavy exercise along with nutritional changes such as decreased appetite may contribute to functional amenorrhea.

Treatment of functional amenorrhea depends on the etiology, and it is important to encourage the patient to decrease the intensity of exercise and increase caloric intake. Women with excessive weight loss should be screened for eating disorders and treated if anorexia nervosa or bulimia nervosa is diagnosed. Menses usually will return after a healthy body weight is achieved.15 With young athletes, menses may return after a modest increase in caloric intake or a decrease in athletic training. Women with amenorrhea also are susceptible to the development of osteoporosis.16 In the athletic population, this is significant as these women are at an increased risk for stress fractures.14 Diagnosis is one of exclusion, and the patient should be monitored for improvement before initiating other therapies.

Perimenopause

Fiona S., a 51-year-old woman, returns for further testing due to reports of irregular menses over the past 7 months, loss of sexual desire, vaginal dryness, and episodes of warmth and sweating throughout the day. Her past medical history includes breast cancer, for which she underwent chemotherapy and radiation. On examination, her BP is 120/68 mm Hg, her HR is 90 beats/min, and her temperature is 100°F. The thyroid gland is normal to palpation. Cardiac and lung examinations are unremarkable. Breast examination reveals symmetrical breasts, without masses or discharge. Examination of the external genitalia does not reveal any masses. Laboratory values are obtained on day 3 of menses and are as follows:

  • FSH, 34 milli-International Units/mL

  • LH, 39 milli-International Units/mL

QUESTION: What is the most likely diagnosis?

DISCUSSION: This patient complains of irregular menses, vaginal dryness, and intermittent sensations of warmth and sweating. This constellation of symptoms is consistent with perimenopause. Elevated FSH and LH levels confirm the diagnosis. Due to this woman’s age and medical history, it is likely she is in the perimenopausal period. However, even when gonadotropins are in the menopausal range, as in this case, ovulation can still be occurring, albeit irregularly and unpredictably. Thus, it is best to draw FSH and LH levels during the follicular phase because they reach their lowest point during this phase. Hot flashes, which are typical vasomotor changes caused by decreasing estrogen levels, are associated with skin temperature elevation and sweating lasting for 2 to 4 minutes. The low estrogen concentration also decreases epithelial thickness of the vagina, leading to atrophy and dryness. Although her estradiol level would mostly likely be low, it is not a reliable indicator of menopausal transition because estradiol levels are prone to cyclical fluctuations, as shown in Figure 24-2. Thus, it is not necessary to draw an estradiol level.

Treatment for hot flashes includes hormone therapy with estrogen. Certain antidepressants, such as venlafaxine, can help with vasomotor symptoms as well, and paroxetine (Brisdelle) has been recently approved for the treatment of hot flashes in menopause.19,20 When a woman still has her uterus, the addition of progestin to estrogen replacement is important for preventing endometrial cancer. Because significant increased risks of breast cancer, heart disease, pulmonary embolism, and stroke are associated with hormone therapy, estrogens are not the best treatment for vasomotor symptoms for this patient.21,22

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

TABLE 24-9.

Reference Ranges for Serum Hormones According to Age

CATEGORY

FSH (mIU/mL)

LH (mIU/mL)

ESTRADIOL (ng/dL)

PROGESTERONE (ng/dL)

Children

5–10

5–10

<2

Adult women

Follicular phase

5–25

5–25

1.8–2.4

37–57

Midcycle

20–30

40–80

16.6–23.2

Rising

Luteal phase

5–25

5–25

6.3–7.3

332–1198

Menopausal women

40–250

>75

<1.5

10–22

mIU = milli-International Unit.

Source: Adapted with permission from Sacher R, McPherson RA, Campos J. Reproductive, endocrinology. In: Sacher R, McPherson RA, Campos J, eds. Widman’s Clinical Interpretation of Laboratory Tests. 11th ed. Philadelphia, PA: FA Davis Co; 2000:825–870.

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

TABLE 24-10.

Steroid Hormone Serum Concentrations in Premenopausal Women, Postmenopausal Women, and Women After Oophorectomy

HORMONE

PREMENOPAUSAL (NORMAL RANGE)

POSTMENOPAUSAL

POSTOOPHORECTOMY

Testosterone (ng/dL)

32 (20–60)

23

11

Androstenedione (ng/dL)

150 (50–300)

80–90

80–90

Estrone (pg/mL)

30–200

25–30

30

Estradiol (pg/mL)

35–500

10–15

15–20

Source: Adapted with permission from Hunter MH, Sterrett JJ. Polycystic ovary syndrome: it’s not just infertility. Am Fam Physician. 2000;62(5):1079–1088.

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

TABLE 24-11.

Suggested Diagnostic Criteria for PCOS

CLINICAL FEATURES

 Amenorrhea, oligomenorrhea, or dysfunctional uterine bleeding

 Anovulatory infertility

 Centripetal obesity

 Hirsutism, acne

ENDOCRINE ABNORMALITIES ON LABORATORY TESTS

 Elevated androgen (ie, testosterone) levels

 Elevated LH

 Insulin resistance with hyperinsulinemia

 LH-to-FSH ratio >3

 Decreased FSH

RADIOLOGIC ABNORMALITIES ON ULTRASOUND EXAMINATION

 Increased ovarian stromal density and volume

 Multiple (nine or more) subcortical follicular cysts

EXCLUSION OF OTHER ETIOLOGIES

 CAH

 Cushing syndrome

 Prolactinoma

 Virilizing adrenal or ovarian tumors

Source: Adapted with permission from Hunter MH, Sterrett JJ. Polycystic ovary syndrome: it’s not just infertility. Am Fam Physician. 2000;62(5):1079–1088.

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.2528 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

TABLE 24-12.

Suggested Laboratory and Radiologic Evaluation of PCOS

17-OHP levela

DHEA-S levela

Dexamethasone suppression testa

Fasting glucose level

FSH level

Lipid profile (total, low-density and high-density lipoproteins)

LH level

Pelvic ultrasound examinationa

Prolactin level

Testosterone level

hCG level

aSuggested only in selected patients.

Source: Adapted with permission from Hunter MH, Sterrett JJ. Polycystic ovary syndrome: it’s not just infertility. Am Fam Physician. 2000;62(5):1079–1088.

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.

HIRSUTISM AND VIRILIZATION

Hirsutism is defined as the presence of excess terminal hair in androgen-dependent areas of a woman’s body and occurs in up to 8% of women.3234 The disorder is a sign of increased androgen action on hair follicles from increased circulating levels of androgens (endogenous or exogenous) or increased sensitivity of hair follicles to normal levels of circulating androgens. Infrequently, hirsutism may signal more serious pathology, and clinical evaluation should differentiate benign causes from tumors or other conditions that require specific treatment. Hair growth varies widely among women, and distinguishing normal variations of hair growth from true hirsutism is important.

Although 60% to 80% of women with hirsutism have increased levels of circulating androgens, degrees of hirsutism correlate poorly with androgen levels.35 DHEA-S is an uncommon cause of hirsutism. The ovary is the major source of increased levels of testosterone in women who have hirsutism.32 Nearly all circulating testosterone is bound to SHBG and albumin, with free testosterone being the most biologically active form. When elevated insulin levels are present, SHBG levels decrease whereas free testosterone levels increase (Minicase 3).

When evaluating hirsutism, it is important to remember that it is only one sign of hyperandrogenism. Other abnormalities associated with excessive levels of androgen include acne, alopecia, android obesity, cardiovascular disease, and dyslipidemia, glucose intolerance/insulin resistance.32 There are several causes of hirsutism. Table 24-13 lists the causes of hirsutism according to diagnosis and the associated laboratory findings.32

TABLE 24-13.

Causes of Hirsutism and Associated Laboratory Findingsa

DIAGNOSIS

TESTOSTERONE

17-OHP

LH/FSH

PROLACTIN

DHEA-S

CORTISOL

CAH

↔/↑

↔/↑

↔/↓

PCOS

↔/↑

↔/↑ LH

↔/↑

↔/↑

↔/↓ FSH

Ovarian tumor

Adrenal tumor

↔/↑

Pharmacologic agentsb

Idiopathic

Familial

aNormal = ↔; decreased = ↓; increased = ↑.

bPharmacologic agents: androgens (eg, testosterone, danazol), anabolic steroids (eg, oxymetholone), metoclopramide, methyldopa, phenothiazines (eg, prochlorperazine), progestins (eg, medroxyprogesterone).

Source: Adapted with permission from Hunter MH, Carek PJ. Evaluation and treatment of women with hirsutism. Am Fam Physician. 2003;67(12):2565–2572.

Medications that may cause hirsutism include anabolic steroids (eg, oxymetholone), danazol, metoclopramide, methyldopa, phenothiazines, and progestins.32 Increased androgen effect that results in hirsutism can be familial; idiopathic; or caused by excess androgen secretion by the ovary (eg, tumors, PCOS), excess secretion of androgens by adrenal glands (eg, CAH, Cushing syndrome, tumor), or exogenous pharmacologic sources of androgens.

Idiopathic hirsutism is common and often familial.32 It is a diagnosis of exclusion and thought to be related to disorders in peripheral androgen activity. Onset occurs shortly after puberty with slow progression. Patients with idiopathic hirsutism generally have normal menses and normal levels of testosterone, 17-OHP, and DHEA-S.

As mentioned previously, PCOS is represented by chronic anovulation and hyperandrogenemia. Patients often report menstrual irregularities, infertility, obesity, and symptoms associated with androgen excess, and diagnosis usually is based on clinical rather than laboratory findings. Up to 70% of patients with PCOS have signs of hyperandrogenism.32

CAH is a spectrum of inherited disorders of adrenal steroidogenesis, with decreased cortisol production resulting in overproduction of androgenic steroids.32,36 The serum 17-OHP measurement is a screening test for adult-onset CAH. Common signs in postadolescent women with adult-onset CAH are hirsutism, acne, and menstrual irregularity. As many as 25% of women with adult-onset CAH also exhibit LH hypersecretion. Serum levels of 17-OHP should be drawn at 8:00 a.m. when concentrations peak. Basal follicular-phase serum 17-OHP levels >5 ng/mL suggest adult-onset CAH caused by 21-hydroxylase deficiency. In contrast, serum 17-OHP levels are normal in women with PCOS.37

Hirsutism Secondary to Adnexal Tumor

Vivian R., a 45-year-old parous woman, has noticed increasing hair growth on her face and abdomen over the past 8 months. She denies using steroid medications, weight change, or a family history of hirsutism. Her menses has been monthly with the exception of the past 3 months. Her past medical and surgical histories are unremarkable. On examination, her thyroid is normal to palpation. She has excess facial hair and male pattern hair on her abdomen. Acne is noted on her face. She also notes increased sweating and some thinning of her hair. Cardiac and pulmonary examinations are normal. Abdominal examination reveals no masses or tenderness. Examination of the external genitalia reveals possible clitoromegaly. Pelvic examination shows a normal uterus and cervix and an 8-cm, right adnexal mass. Her laboratory values obtained on the fourth day of her menstrual cycle are as follows:

  • LH, 10 milli-International Units/mL

  • FSH, 6 milli-International Units/mL

  • total testosterone, 72 ng/dL

  • prolactin, 13 ng/mL

QUESTION: What is the mostly likely diagnosis?

DISCUSSION: This patient has onset of excess male-pattern hair over the past 6 months as well as features of virilism (clitoromegaly). The patient has an elevated testosterone and other lab results are within normal range, so adrenal or ovarian tumors are possibilities. PCOS may be ruled out because she does not have an elevated LH or an LH/FSH ratio >3. This excess of androgens and the rapid onset suggests a tumor. She has a large adnexal mass, so the diagnosis is straightforward. Such tumors are normally of low malignant potential and are slow growing.32 Surgical treatment may be warranted. She has irregular menses because of an inhibition of ovulation by androgens. She does not have the presentation of Cushing syndrome, such as hypertension, buffalo hump, abdominal striae, and central obesity. Likewise, she does not take any medications containing anabolic steroids (eg, oxymetholone). Although PCOS is probably the most common cause of hyperandrogenism, it does not fit her clinical presentation because it usually presents with a gradual onset of hirsutism and irregular menses since menarche.

Hirsutism may result from use of exogenous pharmacologic agents, including danazol, anabolic steroids (eg, oxymetholone), and testosterone. Oral contraceptives containing levonorgestrel, norethindrone, and norgestrel tend to have stronger androgen effects whereas those with ethynodiol diacetate, norgestimate, drospirenone, and desogestrel are less androgenic.32

Androgen-secreting tumors of the ovary or adrenal gland are usually heralded by virilization (eg, development of male characteristics in women) and rapid progression of hirsutism and cessation of menses. Androgen-secreting ovarian tumors are more common than adrenal tumors and are associated with a better prognosis.32 Virilization occurs in >1% of patients with hirsutism. Signs of virilization are shown in Table 24-14.32

TABLE 24-14.

Signs of Virilization

Acne

Clitoromegaly

Deepening of voice

Hirsutism

Increased libido

Increased muscle mass

Infrequent/absent menses

Loss of breast tissue or normal female body contour

Malodorous perspiration

Temporal hair recession/balding

Source: Adapted with permission from Hunter MH, Carek PJ. Evaluation and treatment of women with hirsutism. Am Fam Physician. 2003;67(12):2565–2572.

A thorough history and physical examination are essential to evaluate women with hirsutism to determine which patients need additional diagnostic testing. Family history is important because 50% of women with hirsutism have a positive family history of the disorder.32 Physical examination should distinguish normal amounts of hair growth from hirsutism. Diagnosis often can be made on clinical assessment alone or by limited laboratory testing. Virilization should be noted and abdominal and pelvic examinations should be performed to exclude any masses.

Identification of serious underlying disorders is the primary purpose of laboratory testing and should be individualized. Approximately 95% of these patients have PCOS or idiopathic hirsutism.38 History and physical examination can exclude most underlying disorders, and full hormonal investigation is usually warranted only in patients with rapid progression of hirsutism, abrupt symptom onset, or virilization.

In patients with hirsutism of peripubertal onset and slow progression, regular menses, otherwise normal physical examination, and no virilization, the likelihood of an underlying neoplasm is small. Whether laboratory investigation in these patients is warranted is controversial; however, some experts recommend routine testing to exclude underlying ovarian and adrenal tumors and adult-onset adrenal hyperplasia.34 For diagnostic purposes, serum levels of testosterone and 17-OHP are usually sufficient.32

For patients with irregular menses, anovulation, PCOS, late-onset adrenal hyperplasia, and idiopathic hirsutism, prolactin levels and thyroid function tests are suggested to identify thyroid dysfunction and pituitary tumors. Testing of glucose, testosterone, and 17-OHP levels should be considered, along with careful breast examination to rule out galactorrhea.

Hirsutism outside of the perimenarchal period, rapid progression of hirsutism, or signs of Cushing syndrome or virilization should indicate the possibility of an ovarian or adrenal neoplasm. Diagnostic testing should examine levels of serum testosterone, 17-OHP, and dehydroepiandrosterone sulfate (DHEA-S). Levels of serum testosterone >200 ng/dL and DHEA-S >700 ng/mL are strongly indicative of virilizing tumors.39 For patients with this degree of hormonal elevation or those whose history suggests a neoplasm, additional diagnostic imaging, including abdominal computed tomography to assess the adrenal glands, should be performed.

Pharmacologic treatment for hirsutism aims at blocking androgen action at hair follicles or suppression of androgen production. Classes of pharmacologic agents used include oral contraceptives, antiandrogens (eg, cyproterone), glucocorticoids, GnRH agonists (eg, leuprolide), antifungal agents (eg, ketoconazole), topical hair growth retardants (eg, depilatory agents), and insulin sensitizing agents (eg, metformin). Other options include spironolactone and drospirenone-containing contraceptives. Response to pharmacologic agents is slow, occurring over many months.

INFERTILITY

Infertility, occurring in 10% to 15% of couples in the United States, is defined as 1 year of frequent, unprotected intercourse during which pregnancy has not occurred or 6 months for those other than 35 years of age.7,40 Many of these couples present first to their primary care clinician, who may initiate evaluation and treatment. Infertility can be attributed to any abnormality in the female or male reproductive system and is distributed fairly equally among male factors, ovarian dysfunction, and tubal factors. A smaller percentage of cases is attributed to endometriosis, uterine or cervical factors, or other causes. In approximately one-fourth of couples, the cause is uncertain, and the etiology is multifactorial for some couples. Laboratory testing may include serum inhibin b and serum antimuellerian hormone collection. Serum antimuellerian hormone has been shown to be associated with fertility.41 The reader is referred to other texts for the evaluation of male infertility (Minicase 4).

The medical history should include details of the menstrual cycle to determine whether the cycles are ovulatory or anovulatory. A menstrual cycle length of 22 to 35 days suggests ovulatory cycles, as does the presence of mittelschmerz and premenstrual symptoms.44 During review of the woman’s substance use history, caffeine intake should be assessed because high levels have been associated with lower fertility rates.44 Table 24-15 describes important elements in obtaining a medical history and performing a physical examination in women with infertility.44

TABLE 24-15.

Medical History and Physical Examination in Women with Infertility

HISTORY

PHYSICAL EXAMINATION

Coital practices

Breast formation

Medical history (eg, genetic disorders, endocrine disorders, PID)

Galactorrhea

Genitalia (eg, patency, masses, tenderness, discharge)

Medications (eg, hormone therapy)

Hyperandrogenism (eg, hirsutism, acne, clitoromegaly)

Menstrual history

Sexually transmitted diseases, genital inflammation (eg, vaginal discharge, dysuria, abdominal pain, fever)

Previous fertility

Substance abuse, including caffeine

Surgical history (eg, genitourinary surgery)

Toxin exposure

Source: Adapted with permission from Jose-Miller AB, Boyden JW, Frey KA. Infertility. Am Fam Physician. 2007;75(6):849–858.

Basal body temperature charting is a simple and inexpensive means of documenting ovulation.45 In recent years, BBT charting for documentation of ovulation has largely been replaced by use of the less cumbersome urinary LH prediction kit. During ovulatory cycles, an LH surge can be detected in the urine 14 to 48 hours before ovulation.46 Additionally, a single midluteal progesterone level, measured at the midpoint between ovulation and the start of the next menstrual cycle, can provide further confirmation as well as information about the adequacy of the luteal phase. A level >6 ng/mL implies ovulation and normal corpus luteal production of progesterone.47 Of the three tests, the urinary LH kit provides the greatest accuracy in predicting ovulation.47

If ovulatory dysfunction is suspected based on the results of initial evaluation, focused laboratory investigation and other testing can help determine the underlying cause. Testing in patients with amenorrhea, irregular menses, or galactorrhea should involve checking FSH, prolactin, and TSH levels.43,48 Low or normal FSH levels are most common in patients with PCOS and hypothalamic amenorrhea.43 The presence or absence of obesity and androgenization, generally occurring in women with PCOS, can be used to distinguish between the two disorders.43 A high FSH level suggests possible ovarian failure.43 Evaluation of a prolactin level is useful to rule out pituitary tumor, and measurement of TSH is necessary to rule out hypothyroidism.43 Measurement of 17-OHP and serum testosterone levels is helpful in evaluating patients with hyperandrogenism or late-onset CAH and androgen-secreting tumors.49 Table 24-16 describes the key laboratory evaluations and specialized tests that should be performed in a woman with infertility.44

TABLE 24-16.

Laboratory Evaluation in Women with Infertility

DOCUMENT OVULATION

 Measurement of midluteal progesterone level

 Urinary LH using home prediction kit

 BBT charting

DETERMINE ETIOLOGY IF OVULATORY DYSFUNCTION SUSPECTED

 Measurement of FSH, prolactin, TSH, 17-OHP, and testosterone (if hyperandrogenism suspected)

ASSESS OVARIAN RESERVE (WOMEN >35 YR OLD)

 Measurement of FSH and estradiol levels on day 3 of the menstrual cycle

 Clomiphene citrate (Clomid) challenge test

Source: Adapted with permission from Jose-Miller AB, Boyden JW, Frey KA. Infertility. Am Fam Physician. 2007;75(6):849–858.

Infertility Secondary to the Male Factor

Beatrice W., a 38-year-old woman, presents with a 3-year history of infertility. She states that her menses began at age 14 years and cycles occur at 28-day intervals. A biphasic BBT chart is recorded. She denies any history of smoking, illicit drug use, or sexually transmitted infection. A hysterosalpingogram (HSG) shows patent tubes and a normal uterine cavity. Labs tested on day 3 of her menstrual cycle include FSH 12 milli-International Units/mL and E2 122 pg/mL. Her husband is 37 years old, and they have been actively trying to conceive for the past 3 years.

QUESTION: What is the most likely etiology?

DISCUSSION: This patient has secondary infertility. In approaching infertility, there are five basic factors to examine: (1) ovulatory, (2) uterine, (3) tubal, (4) male factor, and (5) peritoneal. She has regular monthly menses, which argues strongly for regular ovulation; the biphasic BBT chart is further evidence for regular ovulation. Uterine and tubal factors are normal based on the normal HSG. Laboratory testing showed FSH and E2 levels favorable for follicular potential. If she had prior cryotherapy to the cervix, an examiner might consider cervical factor (rare).42 Similarly, if she has symptoms of endometriosis (eg, dysmenorrhea, dyspareunia), then the examiner would focus on the peritoneal factor. For this patient, neither of these are likely, and there is no evidence of a past sexually transmitted disease or potential for pelvic inflammatory disease.

In general, an infertility evaluation is initiated after 12 months of unprotected intercourse during which pregnancy has not been achieved.43 Because there are no hints favoring one factor over the other for this patient, the clinician should consider evaluation of the male factor. Causes of infertility are fairly equal among male and female reproductive abnormalities.43 A semen analysis would be recommended for her male partner.

Women older than 35 years may benefit from testing of FSH and E2 levels on day 3 of their menstrual cycle to assess ovarian reserve.50 An FSH level of >10 milli-International Units/mL, combined with E2 level of >80 pg/mL, suggests favorable follicular potential.50 The clomiphene citrate challenge test—in which the FSH level is obtained on day 3 of the cycle and then again on day 10 after administration of clomiphene citrate 100 mg/day on days 5 to 9—also can be helpful in assessing ovarian reserve.50 Normal and abnormal values vary by laboratory.

If the initial history and physical examination suggest tubal dysfunction or a uterine abnormality or if other testing has failed to reveal an etiology, hysterosalpingography, a radiologic study in which dye is placed into the uterine cavity via a transcervical catheter, is indicated.43,48 The contour of the uterine cavity, including the presence or absence of any abnormalities, as well as tubal patency, can be assessed. Other gynecologic procedures can be performed to further detect tubal or uterine abnormalities.

Management of infertility involves treating the couple, treating the male partner (if infertile), and treating the female partner (if infertile). Couple management includes reviewing coital frequency, the “fertile window,” use of ovulation kits, and emotional support. Men should be referred to a fertility specialist for evaluation of possible semen abnormalities. Women should be treated according to the underlying etiology, whether it is ovulatory dysfunction, tubal/uterine/pelvic disease, or unexplained infertility.

In women with anovulation resulting from a specific condition such as thyroid dysfunction, the underlying cause should be corrected if possible.43 Women with hyperprolactinemia can be treated with dopaminergic agents (eg, bromocriptine), which may restore ovulation.51 Insulin-sensitizing agents, such as metformin, have been shown to increase ovulation and pregnancy rates in patients with PCOS.52 In other women with ovulatory dysfunction without evident cause or not otherwise correctable, the condition can be managed with the use of oral ovulation-inducing agents such as clomiphene citrate and aromatase inhibitors such as letrozole.53 Tubal disease may be treated with tubal reparative surgery or with in vitro fertilization.44,54 Patients with endometriosis may benefit from laparoscopic ablation or ovulation induction with or without in vitro fertilization.55

SUMMARY

Knowledge of the normal reproductive cycle throughout a woman’s lifespan, including pubertal development, menstruation, pregnancy, and menopause, helps understand related laboratory values. Monitoring changes in the gonadotrophic hormones FSH and LH and the ovarian steroid hormones E2 and progesterone is essential in identifying underlying causes of conditions such as amenorrhea, hirsutism, and infertility. Moreover, pharmacologic treatments are often based on laboratory abnormalities of these hormones.

LEARNING POINTS

1. What laboratory abnormalities are useful in the differential diagnosis of secondary amenorrhea?

ANSWER: In addition to history and physical examination, FSH, TSH, and prolactin levels identify the most common causes of amenorrhea.3 When the physical examination is normal, the initial investigations should exclude pregnancy. When FSH values are normal or low, the problem is most often PCOS or functional (hypothalamic) amenorrhea due to anorexia or extreme exercise. Conversely, an elevated FSH would indicate premature ovarian failure or menopause. Measurement of TSH is useful to rule out subclinical hypothyroidism, even in the absence of thyroid-related symptoms. If the serum prolactin is persistently elevated and there is no history of medication or drug use that may elevate prolactin, a pituitary tumor should be considered.

2. What laboratory evaluations can be performed to confirm if patient symptoms are related to the perimenopausal period?

ANSWER: A history and physical examination are helpful when evaluating women who may be in the perimenopausal period. Women often present with a triad of symptoms, including irregular menses, feelings of inadequacy, and sensations of warmth and sweating. In the United States, 95% of women experience perimenopause between the ages of 44 and 55.1 FSH and LH levels can be drawn to confirm diagnosis; however, it is important to draw the levels during the follicular phase because they are lowest during this time. E2 levels are not reliable indicators of menopausal transition because they fluctuate over time.23

3. What laboratory evaluations can be done to detect ovulatory infertility in women?

ANSWER: Ovulation disorders constitute 40% of cases of female infertility.44 To document ovulation, midluteal progesterone levels can be obtained in addition to urinary LH using home prediction kits and BBT charting. If ovulatory dysfunction is suspected based on results of initial evaluations, focused laboratory investigation can help determine the underlying cause. FSH, prolactin, TSH, and testosterone levels can help identify functional (hypothalamic) amenorrhea, pituitary tumor, thyroid disease, and adrenal disease. Low or normal FSH levels are most common in patients with PCOS and hypothalamic amenorrhea, such as occurs with extreme exertion or in eating disorders. Elevated FSH can identify premature ovarian failure. To assess ovarian reserve, measurement of FSH and E2 levels on day 3 of the menstrual cycle or the clomiphene citrate challenge test may be done.

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QUICKVIEW | Follicle-Stimulating Hormone

PARAMETER

DESCRIPTION

COMMENTS

Reference range

Children

5–10 mIU/mL (5–10 IU/L)

Sometimes multiple blood specimens are necessary because of episodic increases of FSH

Adult women, follicular phase

5–25 mIU/mL (5–25 IU/L)

Adult women, midcycle

20–30 mIU/mL (20–30 IU/L)

Document date of LMP

Adult women, luteal phase

5–25 mIU/mL (5–25 IU/L)

Menopausal women

40–250 mIU/mL (40–250 IU/L)

Critical values

Not established

Extremely high or low values should be reported quickly

Natural substance?

Yes

Inherent action?

Yes

Major causes of…

High results

Associated signs and symptoms

Premature ovarian failure

Hot flashes/night sweats

Menopause

Hot flashes/night sweats

Low results

Associated signs and symptoms

Ovarian tumors

Virilization

Pituitary adenoma

Galactorrhea/visual change

Adrenal tumors

Virilization

PCOS

Hirsutism/acne/obesity

Eating disorders

Cachectic/decreased BMI

After insult, time to…

Not applicable

Initial evaluation

Peak values

Normalization

Diseases monitored with test

Infertility

FSH >10 mIU/mL on day 3 of the menstrual cycle suggests normal ovarian reserve

Drugs monitored with the test

Clomiphene challenge test

Compares FSH before and after clomiphene administration to determine ovarian reserve

Significant interferences with laboratory tests

Recently administered radioisotopes

Hemolysis of blood sample

Estrogens, oral contraceptives, testosterone, progestational agents (Table 24-1)

Pregnancy

QUICKVIEW | Leutinizing Hormone

PARAMETER

DESCRIPTION

COMMENTS

Reference range

Children

5–10 mIU/mL (5–10 IU/L)

Often measured with FSH to determine hormonally related functions/disorders

Adult women, follicular phase

5–25 mIU/mL (5–25 IU/L)

Adult women, midcycle

40–80 mIU/mL (40–80 IU/L)

Document date of LMP

Adult women, luteal phase

5–25 mIU/mL (5–25 IU/L)

Menopausal women

>75 mIU/mL (7–75 IU/L)

Critical values

Not established

Extremely high or low values should be reported quickly

Natural substance?

Yes

Inherent action?

Yes

Major causes of…

High results

Associated signs and symptoms

Premature ovarian failure

Hot flashes/night sweats

Menopause

Hot flashes/night sweats

PCOS

Hirsutism/acne/obesity

Low results

Associated signs and symptoms

Pituitary adenoma

Galactorrhea/visual changes

Eating disorders

Cachectic/low BMI

After insult, time to…

Initial evaluation

Not applicable

Peak values

Normalization

Diseases monitored with test

None

Drugs monitored with the test

None

Significant interferences with laboratory tests

Recently administered radioisotopes

Hemolysis of blood sample

Estrogens or oral contraceptives

Progestational agents, testosterone (Table 24-2)

Pregnancy

QUICKVIEW | Estradiol (E2)

PARAMETER

DESCRIPTION

COMMENTS

Reference range

Children

<2 ng/dL

Estradiol is most active of endogenous estrogens

Adult women, early cycle

1.8–2.4 ng/dL

Adult women, midcycle

16.6–23.2 ng/dL

Document date of LMP and length of gestation

Adult women, luteal phase

6.3–7.3 ng/dL

Critical values

Not established

Extremely high or low values should be reported quickly

Natural substance?

Yes

Inherent action?

Yes

Major causes of…

High results

Associated signs and symptoms

Estrogen-producing tumors

Menstruation/preovulatory

weeks 23–41 of pregnancy

Low results

Associated signs and symptoms

Menopause

Hot flashes/night sweats

Premature ovarian failure

Hot flashes/night sweats

After insult, time to…

Not applicable

Initial evaluation

Peak values

Normalization

Diseases monitored with test

Fertility

Estradiol >8 ng/dL on day 3 suggests adequate ovarian reserve

Drugs monitored with the test

None

Significant interferences with laboratory tests

Radioactive pharmaceuticals and oral contraceptives

QUICKVIEW | Progesterone

PARAMETER

DESCRIPTION

COMMENTS

Reference range

Adult women, early cycle

37–57 ng/dL (1.2–1.8 nmol/L)

Document LMP and length of gestation

Adult women, midcycle

Rising

Adult women, luteal phase

332–1198 ng/dL (10.6–38.1 nmol/L)

Menopausal women

10–22 ng/dL (0.3–0.7 nmol/L)

Critical values

Not established

Extremely high or low values should be reported quickly

Natural substance?

Yes

Inherent action?

Yes

Major causes of…

High results

Associated signs and symptoms

CAH

↑17-OHP, ↑DHEA-S, ↓cortisol, hirsutism/acne

Ovarian tumor

Virilization, rapid progression of symptoms

Low results

Associated signs and symptoms

Spontaneous abortion

Vaginal bleeding

After insult, time to…

Not applicable

Initial evaluation

Peak values

Normalization

Diseases monitored with test

Infertility

Midluteal progesterone >6 ng/mL suggests ovulation

Drugs monitored with the test

None

Significant interferences with laboratory tests

Drugs may affect test outcome (Table 24-3)

QUICKVIEW | Prolactin

PARAMETER

DESCRIPTION

COMMENTS

Reference range

Children

1–20 ng/mL (1–20 mcg/L)

Obtain 12-hr fasting samples in the morning

Adult women

1–25 ng/mL (1–25 mcg/L)

Menopausal women

1–20 ng/mL (1–20 mcg/L)

Critical values

Levels >100 ng/mL in nonlactating female may indicate a prolactin-secreting tumor

Extremely high or low values should be reported quickly

Natural substance?

Yes

Inherent action?

Yes

Major causes of…

High results

Associated signs and symptoms

Pituitary adenoma

Galactorrhea/visual changes

Hypothyroidism (primary)

Coarse skin and hair

PCOS

Hirsutism/acne/obesity

Anorexia nervosa

Cachectic/low BMI

Low results

Associated signs and symptoms

No common disorders

After insult, time to…

Not applicable

Initial evaluation

Peak values

Normalization

Diseases monitored with test

Pituitary adenoma

Drugs monitored with the test

Dopaminergic drugs

To monitor effect on prolactin levels in pituitary adenoma

Significant interferences with laboratory tests

Increased values are associated with newborns, pregnancy, postpartum period, stress, exercise, sleep, nipple stimulation, and lactation

Drugs (estrogens, methyldopa, phenothiazines, opiates) may increase values (Table 24-4)

QUICKVIEW | Testosterone

PARAMETER

DESCRIPTION

COMMENTS

Reference range

Children

0.12–0.16 ng/mL (0.4–0.6 nmol/L)

Unbound (free) testosterone is active form

Adult women

0.2–0.6 ng/mL (0.7–2.1 nmol/L)

Draw levels between 6:00 a.m. and 10:00 a.m

Menopausal women

0.21–0.37 ng/mL (0.7–1.3 nmol/L)

Critical values

Testosterone >200 ng/dL indicates virilizing tumor

Extremely high or low values should be reported quickly

Natural substance?

Yes

Inherent action?

Yes

Major causes of…

High results

Associated signs and symptoms

Adrenal neoplasms

CAH

Ovarian tumors

PCOS

Cushing syndrome

Virilization, ↑DHEA-S, ↑cortisol, rapid progression of symptoms

↑17-OHP, ↑DHEA-S, ↓cortisol, hirsutism

Virilization, rapid progression of symptoms

Hirsutism/acne/obesity, ↑DHEA-S

Buffalo hump/obesity/striae

Low results

Associated signs and symptoms

No common disorders

After insult, time to…

Not applicable

Initial evaluation

Peak values

Normalization

Rapid progression of symptoms indicative of ovarian or adrenal tumor

Diseases monitored with test

None

Drugs monitored with the test

None

Significant interferences with laboratory tests

Estrogen therapy increases testosterone levels (Table 24-5)

Many drugs, including androgens and steroids, decrease testosterone levels (Table 24-5)

Source: Adapted with permission from references 23 and 56.