Key Points

• Amenorrhea is categorized as primary or secondary, although this distinction may be misleading in certain patients.

• Primary amenorrhea can be caused by obstruction of the outflow tract, androgen insensitivity, gonadal dysgenesis, hyperprolactinemia, and dysfunction of the hypothalamus, pituitary, or thyroid.

• Pregnancy is the most common cause of secondary amenorrhea.

Primary Amenorrhea

Menses is a normal, physiologic function in a sexually mature female. Amenorrhea is the absence of menses in a sexually mature female. Amenorrhea is divided into two large categories, primary and secondary, depending on whether the female has ever had menarche, with attendant menstrual flow. Primary amenorrhea is defined as failure of menarche

Table 35-6 Causes of Pathologic Gynecomastia

Estradiol Excess

Estradiol Secretion

Other Causes

Local Trauma

Adrenal tumors

Sporadic testicular tumors (sex cord, Sertoli, germ, Leydig cells) Testicular tumors associated with familial syndromes (Peutz-Jeghers, Carney complex)

Exogenous Estrogens or Estrogenic Substances

Drug therapy with estrogens Estrogen creams and lotions Embalming fluid exposure Delousing powder Hair oil Marijuana

Estrogen analogues: digitoxin

Elevated Estrogen Precursors: Aromatizable Androgens

Human chorionic gonadotropin (hCG) excess (eutopic or ectopic)

Exogenous hormones

Testosterone enanthate Testosterone propionate Anabolic steroids hCG administration

Testosterone Deficiency

Anorchia

Hypogonadotropic syndromes

Drugs or exogenous substances

Ketoconazole

Heroin

Methadone

Alcohol

Estradiol/Testosterone Imbalance

Hypergonadotropic syndromes Hypogonadotropic hypogonadism syndromes Primary gonadal diseases Drugs

Regulatory Hormone Excess

Hyperthyroidism Acromegaly Prolactin excess Hypothyroidism Pituitary tumor

Drug therapy with:

Catecholamine antagonists or depleters

Domperidone

Haloperidol

Methyldopa

Metoclopramide

Phenothiazines

Reserpine

Sulpiride

Tricyclic antidepressants Administration of growth hormone Cushing's syndrome

Hip spica cast Chest injury

Herpes zoster of chest wall Post thoracotomy Spinal cord injury Primary breast tumor

Uncertain Causes

Other Chronic Illnesses

Renal failure Pulmonary tuberculosis HIV

Diabetes mellitus Leprosy

Refeeding gynecomastia Persistent pubertal macromastia Idiopathic

Drugs associated with gynecomastia with uncertain mechanisms:

Cytotoxic drug-induced hypogonadism from:

Busulfan

Nitrosourea

Vincristine

Combination chemotherapy Steroid synthesis inhibitory drugs Androgen resistance Complete testicular feminization

Partial: Reifenstein, Lubs, Rosewater, and Dreyfus syndromes

Androgen antagonistic drugs

Bicalutamide

Cimetidine

Cyproterone acetate

Flutamide

Spironolactone

Blockers of 5a-reductase

Finasteride

Tumor-related: hCG-producing tumors (testis, lung, gastrointestinal tract, etc.)

Hypogonadotropic syndromes

Isolated gonadotropin deficiency, particularly fertile eunuch syndrome

Panhypopituitarism

Systemic illnesses

Renal disease

Severe liver disease

Amiodarone

Amphetamines

Auranofin

Beta blockers

Calcium channel blockers

Captopril

Cyclosporin

Diazepam

Diethylpropion

Continued

Table 35-7 Menopausal Symptoms* and Treatment

Table 35-6 Causes of Pathologic Gynecomastia—cont'd

Enalapril

Narcotic analgesics

Ethionamide

Nitrates

Etretinate

Omeprazole

Griseofulvin

Penicillamine

Heparin

Phenytoin

Indinavir

Quinidine

Isoniazid

Sulindac

Methotrexate

Theophylline

Metronidazole

Thiacetazone

Vitamin E

From Santen RJ. Gynecomastia. In DeGroot LJ, Jameson, JL (eds). Endocrinology, 5th ed, vol

3. Philadelphia, Elsevier-Saunders, 2006.

Table 35-7 Menopausal Symptoms* and Treatment

Symptoms

Pre (%)

Peri (%)

Post (%)

Treatment

Vasomotor symptoms

14-51

35-50

30-80

ET/EPT (SOR A)

Vaginal dryness and painful intercourse

4-22

7-39

Vaginal ET preferred (SOR A)

Mood symptoms

8-37

11-21

8-38

ET may be beneficial (SOR A).

Urinary symptoms

10-36

17-39

15-36

Vaginal estrogens (SOR B)

Sleep disturbances

16-42

39-47

35-60

Sleep hygiene; other agents

Modified from http://consensus.mh.gov/2005/2005MenopausalSymptomsSOS025html.htm. incidence of premenopausal, per/menopausal, and postmenopausal symptoms.

ET, Estrogen therapy; EPT, cyclic combined estrogen-progestogen therapy; SOR, strength of recommendation.

by age 16 in a female with apparently normal sexual development or in a female age 14 who does not demonstrate evidence of developing secondary sexual characteristics. Secondary amenorrhea is failure of menstruation after normal menses are established, with the caveat that at least 3 months have passed with apparently normal menses or 9 months have passed in a woman with oligomenorrhea.

Menstruation is a complex process with many interacting and co-dependent processes that must occur in specific chronologic order. Dysfunction of any organ or system involved with these processes has the potential to disrupt the menstrual cycle and cause amenorrhea. The organs and systems involved in the menstrual cycle are CNS (influenced by environment, stress), hypothalamus (through GnRH), anterior pituitary (FSH, LH), thyroid gland, adrenals, ovary (estrogen, progesterone), and uterus. Secondary amenorrhea is more common than primary amenorrhea, with the most common cause being pregnancy. The distinction between etiologies of primary and secondary amenorrhea may be misleading, as in the woman with PCOS who presents with primary amenorrhea, or the woman with partial gonadal dysgenesis who has rudimentary ovarian development and may initially ovulate, thus presenting with secondary amenorrhea (Box 35-9).

The more common causes of primary amenorrhea fall into congenital or anatomic abnormalities. Congenital absence of the uterus and vagina, known as mullerian agenesis or Mayer-Rokitansky-Kuster-Hauser (MRKH) syndrome, is a significant cause of amenorrhea. Other congenital causes of primary amenorrhea include chromosomal abnormalities, prenatal adrenal hyperplasia, and female virilization syndrome. An anatomic cause of primary amenorrhea, usually discovered at menarche, is imperforate hymen.

To evaluate a patient with primary amenorrhea, after a thorough clinical history, the physical examination must focus on development of secondary sexual characteristics (breast development, pubic/axillary hair). Pregnancy as a cause of primary amenorrhea is less common than in secondary amenorrhea, although it should be excluded before any testing or imaging is initiated. Laboratory testing includes FSH, LH, TSH, and prolactin. If FSH is normal or reduced, this may mean the patient has chronic anovulation, functional hypothalamic amenorrhea, or PCOS. Increased FSH with breast development is likely secondary to ovarian failure. Increased FSH without secondary sexual characteristics may be caused by congenital agenesis of the ovaries. In the patient without a uterus, serum testosterone level and karyotype should be determined. In the presence of a uterus and normal secondary sexual characteristics, serum TSH levels should be evaluated (Sybert and McCauley, 2004) (Box 35-10).

Secondary Amenorrhea

Pregnancy is the most common cause of secondary amenor-rhea and must always be ruled out at the initial clinical visit. Structural changes may cause amenorrhea, such as adhesions

Box 35-9 Causes of Amenorrhea*

Hyperprolactinemia

Prolactin-secreting tumor

Centrally acting medications, including dopamine antagonists Pituitary disease

Non-prolactin-secreting pituitary tumor Generalized pituitary insufficiency, including previous pituitary surgery Hypothalamic amenorrhea Nutrition/exercise disorders Idiopathic hypogonadotropic hypogonadism

From Illingworth P. Amenorrhea, anovulation, and dysfunctional uterine bleeding. In DeGroot LJ, Jameson, JL (eds). Endocrinology, 5th ed, vol 3. Philadelphia, Elsevier-Saunders, 2006.

^Resulting from disorders of the hypothalamus and pituitary.

after instrumentation (Asherman's syndrome) or infection in the form of TB or endometritis. Patients with PCOS present with irregular or absent menses, hirsutism, acne, subfertility secondary to a hyperandrogenic state, or a combination. Adrenal or ovarian tumors, hyperthecosis, and late-onset or mild congenital adrenal hyperplasia may also result in secondary amenorrhea and hyperandrogenism. Hypergonadotropic hypogonadism (premature ovarian failure), hypogonado-tropic hypogonadism, thyroid disease, menopause, extreme exercise, anorexia nervosa, bulimia, and hyperprolactinemia are all potential causes of secondary amenorrhea.

A thorough history and physical examination will provide the diagnosis, with laboratory studies and imaging serving as collaborative evidence. Particular attention should be paid to menstrual history, diet, exercise, medications, pubertal development, hirsutism, acne, galactorrhea, and other medical conditions. Initial laboratory evaluation includes pregnancy test and TSH and prolactin levels. If these are normal, and there are no signs of hyperandrogenism (e.g., hirsutism, acne, voice change), proceed with progesterone challenge by using medroxyprogesterone (Provera), 10 to 20 mg daily for 5 to 10 days. In the presence of a uterus, the progesterone withdrawal test will induce withdrawal bleeding within 10 days in a woman with adequate estrogen production. If there is no withdrawal bleed, consider repeating the test with progesterone in oil (100-200 mg IM) or with noreth-indrone or micronized progesterone. If this test is also negative, a 21-day course of conjugated estrogen (1.25 mg/day) or a cycle of combined oral contraceptives (OCs) should provide adequate stimulation of the endometrium to support a withdrawal bleed. If all these measures fail to result in menstrual flow, additional tests may be ordered, beginning with FSH and, if there are clinical signs of hyperandrogen-ism, DHEA-S and testosterone levels. Elevated FSH indicates ovarian failure (including gonadal dysgenesis and secondary ovarian failure or menopause); normal or low values indicate hypogonadotropic hypogonadism or uterine abnormality (Asherman's syndrome). Proceed with a workup for PCOS (discussed later), late-onset congenital adrenal hyper-plasia, or Cushing's syndrome if there are features consistent with these illnesses. Features of hyperandrogenemia or substantially increased serum testosterone levels should prompt appropriate studies to rule out a neoplastic source of

Box 35-10 Causes of Primary Ovarian Failure

Iatrogenic

Surgery

Chemotherapy

Radiotherapy

Environmental

Smoking Viral infections

Autoimmune

Association with other autoimmune disease Abnormal karyotypes

46,XY 45,XO

Genetic disorders with normal karyotype

Fragile X permutations Galactosemia

Carbohydrate-deficient glycoprotein syndrome type 1 (CDG-1) Inhibin a-gene mutations

Follicle-stimulating hormone (FSH) receptor gene mutations

From Peter Illingworth. Amenorrhea, anovulation, and dysfunctional uterine bleeding. In DeGroot LJ, Jameson, JL (eds). Endocrinology, 5th ed, vol 3. Philadelphia, Elsevier-Saunders, 2006.

androgen. Figure 35-7 is a diagnostic algorithm for evaluating a patient with primary and secondary amenorrhea. Hir-sutism can be subjective.

Management of amenorrhea depends on establishing a diagnosis, specific treatment directed to the underlying cause, restoration of ovulatory cycles, and treating infertility, if desired. Also, appropriate treatment is provided for hypoestrogenemia and hyperandrogenemia (medical and surgical).

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