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New Treatments for Disorders of Menstruation


Secondary amenorrhea can result from dysfunction of the central nervous system, pituitary gland, thyroid gland, adrenal gland, ovary, or uterus or from disorders of peripheral metabolism (see the box). The most common cause of secondary amenorrhea is the development of chronic hypothalamic anovulation, which can be induced by stress, increased exercise levels, a precipitous decrease in body weight, or the development of an inappropriate ratio of lean body mass to fat. If pregnancy is ruled out, the patient with chronic hypothalamic anovulation is found to have normal gonadotropin levels with an appropriate ratio of LH to FSH and will respond with withdrawal bleeding to a progestogen challenge. Any of the aforementioned states carried to the extreme form, however, result in hypothalamic amenorrhea with a fall in LH and FSH levels, inversion of the LH-to-FSH ratio, and failure to respond to progestogen challenge. Other conditions may mimic these findings, including systemic illnesses that generally present as hypogonadotropism; head trauma; space-occupying lesions of the central nervous system; and the intake of numerous pharmaceutical agents--most notably minor tranquilizers, monamine oxidase inhibitors, and drugs that alter serotonin metabolism. Unusual space-occupying lesions such as fibromas from neurofibromatosis, infiltrative disorders such as histiocytosis X (Hand-Schiiller-Christian syndrome), and syphilis and tuberculosis, which can form granulomas, also result in amenorrhea. Rare causes of amenorrhea include its association with temporal arteritis or cavernous sinus thrombosis.

Pituitary dysfunction can likewise result in secondary amenorrhea. Perhaps the most common cause is functional hyperprolactinemia, which is thought by many investigators to represent a disorder of central dopamine metabolism or to indicate the presence of prolactinomas. Hyperprolactinemia is diagnosed by

Hypothyroidism can at times result in menstrual dysfunction and may or may not be associated with hyperprolactinemia. The patient with hypothyroidism may present with dry skin, lethargy, and

Disorders of adrenal metabolism likewise can result in the development of secondary amenorrhea. Dehydroepiandrosterone sulfate may be mildly elevated in patients with polycystic ovary syndrome (PCOS) 50% of the time or in patients with variations of congenital adrenal hyperplasia. Levels of DHEAS may be markedly elevated and associated with virilism in patients with adrenal adenomas and other tumors. This elevation may be corticotropin dependent or independent and is best evaluated by a 24-hour urine measurement of free cortisol. Interpretation of the 24-hour urine measurement is based on knowledge of the patient's creatinine clearance.

Obesity is associated with the development of menstrual dysfunction; however, it may not be

Premature ovarian failure (ie, the cessation of menses before age 35 years) may be hereditary, autoimmune, or of unknown cause. The diagnosis is usually established by finding FSH levels greater than 40 mIU/mL in association with amenorrhea or oligoovulation. Often patients have variable symptoms (eg, mood alteration, depression, lethargy, dysphoria) not associated with menstrual irregularities or hot flushes but with elevated FSH levels suggestive of the perimenopausal period. These patients are best treated with oral contraceptives or replacement hormonal therapy. Patients who have FSH levels greater than 40 mlU/mL are best treated

Although not frequently recognized as an ovarian cause of secondary amenorrhea, surgery with either wedge resection or resection of large endometriomas can result in ovulatory dysfunction or premature ovarian failure. These individuals, like patients with premature ovarian failure, will have an FSH level in the range of 25-40 menstruation, amenorrhea, dysfunctional uterine bleeding, hyperprolactinemia, polycystic ovary syndrome, polysistic, hirsutism, virilization mlU/mL.

Finally, disorders of the endometrium are an uncommon cause of secondary amenorrhea. Uterine synechiae may be of the unintentional or intentional (endometrial ablation) type. Asherman's syndrome is associated

Causes of Secondary Amenorrhea

Central Nervous System Thyroid

Trauma Hypothyroidism

Tumors Hyperthyroidism

Infiltrative disease Adrenal

Granulomas Tumor

Neurofibrosis Cushing's syndrome

Stress Late-onset adrenal hyperplasia

Weight loss Ovary

Exercise Premature ovarian failure (immune)

Systemic illness Surgical removal of ovaries

Pituitary Polycystic ovary syndrome

Prolactinomas Hyperthecosis

Functional hyperprolactinemia Tumors

Other tumors Uterus

Infarction (Sheehan's syndrome) Asherman's syndrome

Surgery Endometrial ablation

Stalk transection


Patients with hyperprolactinemia present with ovulatory dysfunction, galactorrhea, delayed pubescence, or signs of a polyendocrinopathy. Four principal causes of hyperprolactinemia are pituitary hyperplasia, which may be the result of dopamine dysfunction; prolactinomas, which are characterized as microadenomas (<10 mm in size) or macroadenomas (>10 mm in size); hypothyroidism; and drug intake. Other causes of hyperprolactinemia are indicated in the box.

The origin of prolactinomas has received intense study. Prolactinomas have been demonstrated to have a blood supply that may be independent from the normal hypothalamic portal anatomy. This would allow the tumor to bypass the normal regulatory effects exerted by dopamine. In addition, errors in signal transduction Causes of Hyperprolactinemia

Central Nervous System Body

Trauma Chest trauma, surgery, or burn

Tumors and cysts (all types) Herpes zoster

Infections Breast manipulation

Neurofibromas Renal failure

Granulomas (tuberculosis and syphilis) Hysterectomy/oophorectomy

Infiltrative disease (histiocytosis X) Breast reduction or augmentation

Cavernous sinus thrombosis Pregnancy

Temporal arteritis Drugs (Examples)

Pituitary Tranquilizers, major and minor

Trauma Antidepressants

Tumor Steroid hormones

Prolactinomas Oral contraceptives

Functional disease Antihypertensives

Thyroid H2 receptor antagonists

Hypothyroidism Antituberculins


Psychoneuroendocrinology is a rapidly developing field and encompasses many disorders frequently seen by the practicing gynecologist. These disorders include chronic hypothalamic anovulation, stress-related

Eating Disorders

Anorexia nervosa is generally seen in white women under age 25 years. It is a syndrome that includes a history of weight loss, amenorrhea, and behavioral changes. This classic triad of symptoms usually occurs Exercise-Induced Amenorrhea

The modem gynecologic practitioner is frequently faced with the young professional woman in a high-stress position who participates in an ambitious exercise program each week and maintains a body weight near the threshold at which menstrual dysfunction can develop. These individuals frequently have low-normal


Polycystic ovary syndrome is a heterogeneous disorder characterized by obesity, oily skin, acne, hirsutism, and frequently oligomenorrhea or amenorrhea and infertility. Other symptoms of PCOS include increased libido, clitoromegaly, and masculinization, including deepening of voice, increase in muscle mass, a male body habitus, and often oligoovulation or anovulation. This phenotypic variability probably represents the


Treatment of women with PCOS who do not desire pregnancy depends on their underlying goals. In those individuals who wish to reduce hair growth, a variety of agents are available. However, patients should be counseled that medical therapy requires a minimum of 3-6 months to achieve a reduction in hirsutism. Usually, these medical therapies only affect hirsutism by diminishing new terminal hair growth and do little for hair already present. For this reason, medical therapy is often performed in conjunction with


Many women may complain of an increase in body hair, but the term hirsutism should be used only for excessive hair involving areas that follow a male pattern of hair distribution. This hirsutism generally is central or midline in distribution (eg, chin, intermammary area, mid-line lower abdomen). Virilization is extremely rare, and this term should not be used interchangeably with hirsutism. Virilization includes defeminizing

Differential Diagnosis of Androgen Excess

Drug Exposure

Examples include exogenous testosterone, danazol

Intersex Conditions

Usually with ambiguous genitalia (eg, 46,XY with incomplete androgen resistance)


Polycystic ovary syndrome

Stromal hyperthecosis

Ovarian tumors


Adrenal tumors

Cushing's syndrome

Congenital adrenal hyperplasia




When cyclic interactions among hypothalamic, pituitary, and ovarian hormones become tonic, ovulation ceases, and the predictability of menstruation is lost. Interference with these cyclic interactions results in anovulation, irregular menstruation, or amenorrhea and is known as dysfunctional uterine bleeding. Thus, dysfunctional uterine bleeding is not related to endometrial, myometrial, or cervical pathology such as

Hypothalamic-Pituitary Dysfunction

Hypothalamic-pituitary dysfunction can result in dysfunctional uterine bleeding, oligomenorrhea, or amenorrhea. In healthy women with a previous history of regular reproductive cycles, the physician should inquire about a change in lifestyle (eg, diet, career, interpersonal relationships, finance) that could lead to

Late-Onset Adrenal Hyperplasia

An underdiagnosed cause of dysfunctional uterine bleeding is late-onset adrenal hyperplasia (21-hydroxylase deficiency). Clinical symptoms and signs may mimic those of PCOS. However, women with adrenal

A high index of suspicion is required to make the diagnosis, which is confirmed by an elevated serum DHEAS level. Appropriate treatment is administration of low-dose glucocorticoids. This dosage of prednisone will not completely suppress ACTH secretion.


Surgery should be the last choice for management of women with dysfunctional uterine bleeding. Because the problem is self-limiting and can be controlled with medication, surgery is rarely indicated. Uterine curettage may be required in women in whom menorrhagia-metrorrhagia cannot be controlled by