Amenorrhea

AMENORRHEA

Amenorrhea (the  absence  of  menstruation)  andA abnormal uterine bleeding are the most commongynecologic disorders of reproductive-age women. Amenorrhea and abnormal uterine bleeding are discussed as separate topics. However, the pathophysiol-ogy underlying amenorrhea and abnormal uterine bleeding is often the same.

If a young woman has never menstruated by age 13 with-out secondary sexual development or by age 15 with sec-ondary sexual development, she is classified as having primary amenorrhea. If a menstruating woman has notmenstruated for 3 to 6 months or for the duration of three typical menstrual cycles for the patient with oligomenor-rhea, she is classified as having secondary amenorrhea. The designation of primary or secondary amenorrhea has no bearing on the severity of the underlying disorder or on the prognosis for restoring cyclic ovulation. Terms often confused with these include oligomenorrhea, defined as a reduction of the frequency of menses, with cycle lengths of greater than 35 days but less than 6 months, and hypomenorrhea, defined as a reduction in the number of days or the amount of menstrual flow.

Amenorrhea not caused by pregnancy occurs in 5% or less of all women during their menstrual lives.

Causes of Amenorrhea

When endocrine function along the hypothalamic– pituitary–ovarian axis is disrupted or an abnormality devel-ops in the genital outflow tract (obstruction of the uterus, cervix, or vagina or scarring of the endometrium), menstru-ation ceases. Causes of amenorrhea are divided into those arising from (1) pregnancy, (2) hypothalamic–pituitary dys-function, (3) ovarian dysfunction, and (4) alteration of the genital outflow tract.

PREGNANCY

Because pregnancy is the most common cause of amenorrhea, it is essential to exclude pregnancy in the evaluation of amenorrhea.

A history of breast fullness, weight gain, and nausea suggest the diagnosis of pregnancy, which is confirmed by a positive human chorionic gonadotropin (hCG) assay. It is important to rule out pregnancy to allay the patient’s anxiety and to avoid unnecessary testing. Also, some treatments for other causes of amenorrhea can be harmful to an ongoing pregnancy. Lastly, the diag-nosis of ectopic pregnancy should be entertained in the presence of abnormal menses and a positive preg-nancy test, as this would necessitate medical or surgical intervention.

Box 35.1

Types of Abnormal Uterine Bleeding

Polymenorrhea—frequent menstrual bleeding

(frequency, 21 days or less) Menorrhagia—prolonged or excessive uterine

bleeding that occurs at regular intervals (the loss of 80 mL or more of blood that lasts for more than 7 days)

Metrorrhagia—irregular menstrual bleeding or bleeding between periods

Menometrorrhagia—frequent menstrual bleeding that is excessive and irregular in amount and duration

American College of Obstetricians and Gynecologists. Manage-ment of anovulatory bleeding. ACOG Practice Bulletin 14. Washington, DC: American College of Obstetricians and Gyne-cologists; 2000.

HYPOTHALAMIC–PITUITARY DYSFUNCTION

Release of hypothalamic gonadotropin-releasing hor-mone (GnRH) occurs in a pulsatile fashion, modulated by catecholamine secretion from the central nervous system and by feedback of sex steroids from the ovaries. When this pulsatile secretion of GnRH is disrupted or altered, the anterior pituitary gland is not stimulated to secrete follicle-stimulating hormone (FSH) and luteinizing hor-mone (LH). The result is an absence of folliculogenesis despite estrogen production, no ovulation, and lack of corpus luteum with its usual production of estrogen and progesterone. Because of the lack of sex hormone produc-tion with no stimulation of the endometrium, there is no menstruation.

Alterations in catecholamine secretion and metabo-lism in sex steroid hormone feedback or an alteration of blood flow through the hypothalamic–pituitary portal plexus can disrupt the signaling process that leads to ovu-lation. This latter disruption can be caused by tumors or infiltrative processes that impinge on the pituitary stalk and alter blood flow.

The most common causes of hypothalamic–pituitary dysfunction are presented in Box 35.2. Most hypothalamic– pituitary amenorrhea is of functional origin and can be corrected by modifying causal behavior, by stimulating gonadotropin secretion, or by giving exogenous human menopausal gonadotropins.

The physician cannot differentiate hypothalamic– pituitary causes of amenorrhea from ovarian or genital outflow causes by medical history or even physical exam-ination alone. However, there are some clues in the med-ical history and physical examination that would suggest a hypothalamic–pituitary etiology for amenorrhea. A his tory of any condition listed in Box 35.2 should cause the physician to consider hypothalamic–pituitary dysfunction.

Box 35.2

Causes of Hypothalamic–Pituitary Amenorrhea

Functional Causes

Weight loss

Excessive exercise

Obesity

Drug-Induced Causes

Marijuana

Psychoactive drugs, including antidepressants

Neoplastic Causes

Prolactin-secreting pituitary adenomas Craniopharyngioma Hypothalamic hamartoma

Psychogenic Causes

Chronic anxiety

Pseudocyesis

Anorexia nervosa

Other Causes

Head injury

Chronic medical illness

The definitive method to identify hypothalamic–pituitary dysfunction is to measure FSH, LH, and prolactin levels in the blood. In these conditions, FSH and LH levels are in the low range. The prolactin level is normal in most conditions, but is elevated in prolactin-secreting pituitary adenomas. 

OVARIAN DYSFUNCTION

In ovarian failure, the ovarian follicles are either exhausted or are resistant to stimulation by pituitary FSH and LH. Asthe ovaries cease functioning, blood concentrations of FSH and LH increase. Women with ovarian failure experience thesymptoms and signs of estrogen deficiency. A summary of causes is presented in Box 35.3.

ALTERATION OF THE GENITAL OUTFLOW TRACT

Obstruction of the genital outflow tract prevents overt menstrual bleeding even if ovulation occurs.

Box 35.3

Causes of Ovarian Failure

Chromosomal Causes

Turner syndrome (45,X gonadal dysgenesis)

X chromosome long-arm deletion (46,XX q5)

Other Causes

Gonadotropin-resistant ovary syndrome (Savage syndrome)

Premature natural menopause

Autoimmune ovarian failure (Blizzard syndrome)

Most cases ofoutflow obstruction result from congenital abnormalities in the  development and canalization of the müllerian ducts. Imperforatehymen and no uterus or vagina are the most common anomalies that result in primary amenorrhea. Surgical cor-rection of an imperforate hymen allows for menstruation and fertility. Less-commonly encountered anomalies, such as a transverse vaginal septum, are more difficult to correct, and even with attempted surgical correction, menstruation and fertility are often not restored.

Scarring of the uterine cavity (Asherman syndrome) is the most frequent anatomic cause of secondary amenorrhea (Fig. 35.1). Women who undergo dilation and curettage (D&C) for retained products of pregnancy (especially when infection is present) are at risk for developing scar-ring of the endometrium. Cases of mild scarring can be corrected by surgical lysis of the adhesions performed by hysteroscopy and D&C. However, severe cases are often refractory to therapy. Estrogen therapy should be added to the surgical treatment postoperatively to stimulate endometrial regeneration of the denuded areas. In some cases, a balloon or intrauterine (contraceptive) device may be placed in the uterine cavity to help keep the uterine walls apart during healing.

Treatment of Amenorrhea

The first step is to establish a cause for the amenorrhea. The progesterone “challenge test” is commonly used to deter-mine whether or not the patient has adequate estrogen, a competent endometrium, and a patent outflow tract. An injection of 100 mg of progesterone in oil or a 5-day to 14-day course of oral medroxyprogesterone acetate or micronized progesterone is expected to induce proges-terone withdrawal bleeding within a few days after com-pleting the oral course. If bleeding does occur, the patient is likely to be anovulatory or oligo-ovulatory. If withdrawal bleeding does not occur, the patient may be hypoestro-genic or have an anatomic condition such as Asherman syndrome or outflow tract obstruction. 

Hyperprolactinemia associated with some pituitary adeno-mas (or other medical conditions) results in amenorrhea and galactorrhea (a milky discharge from the breast).Approxi-mately 80% of all pituitary tumors secrete prolactin, causing galactorrhea, and these patients are treated with either cabergoline (Dostinex) or the dopamine agonist bromocriptine (Parlodel). In approximately 5% of patients with hyperprolactinemia and galactorrhea, the underlying etiology is hypothyroidism. A low serum thy-roxine (T4) level eliminates negative feedback signaling to the hypothalamic–pituitary axis. As a result, TRH (thyrotropin-releasing hormone) levels increase. Positive feedback signaling that stimulates dopamine secretion is also absent, causing a decrease in dopamine levels. Elevated TRH stimulates release of prolactin from the pituitary gland. The reduced dopamine secretion results in elevated levels of TSH (thyroid-stimulating hormone) and prolactin.

In patients who desire pregnancy, ovulation can be induced through the use of clomiphene citrate, human menopausal gonadotropins, pulsatile GnRH, or aromatase inhibitors. In patients who are oligo-ovulatory or anovula-tory (polycystic ovary syndrome), ovulation can usually be induced with clomiphene citrate. In patients with hypogo-nadotropic hypogonadism, ovulation can be induced with pulsatile GnRH or human menopausal gonadotropins. Women with genital tract obstruction require surgery to create a vagina or to restore genital tract integrity. Menstruation will never be established if the uterus is absent. Women with premature menopause may require exogenous estrogen therapy.