amenorrhea

Primary amenorrhea is defined as the failure of menses to occur by age 16 years. Secondary amenorrhea is defined as the cessation of menses once they have begun. Oligomenorrhea is defined as menses occurring at intervals longer than 35 days. No consensus has been reached regarding the point at which oligomenorrhea becomes amenorrhea. Some authors suggest the absence of menses for 6 months constitutes amenorrhea, but the basis for this recommendation is unclear. Practically speaking, a woman aged 20-40 years who experiences loss of an established regular menstrual pattern should have an evaluation to seek the cause.

This article addresses the evaluation and treatment of women with amenorrhea who have no evidence of androgen excess. Women with amenorrhea who do have evidence of androgen excess, such as hirsutism, virilization, or sexual ambiguity, should be evaluated differently from women with amenorrhea alone.

Pathophysiology: Regular and predictable menstrual cycles occur if the ovarian hormones estradiol and progesterone are secreted in an orderly fashion in response to stimulation by the hypothalamus and pituitary. Circulating estradiol stimulates growth of the endometrium. Progesterone, produced by the corpus luteum formed after ovulation, transforms proliferating endometrium into secretory endometrium. If pregnancy does not occur, this secretory endometrium breaks down and sheds during the ensuing menstrual period.

Amenorrhea occurs if the hypothalamus and pituitary fail to provide appropriate gonadotropin stimulation to the ovary, resulting in inadequate production of estradiol or in failure of ovulation and progesterone production. Amenorrhea can also occur if the ovaries fail to produce adequate amounts of estradiol despite normal and appropriate gonadotropin stimulation by the hypothalamus and pituitary. In some cases, the hypothalamus, pituitary, and ovaries all may be functioning normally, yet amenorrhea occurs because of adhesions in the endometrial cavity or an obstruction to the cervicovaginal outflow tract.

Frequency:

* In the US: Each year, approximately 5% of menstruating women experience 3 months of secondary amenorrhea.

* Internationally: No evidence indicates that the prevalence of amenorrhea varies according to national origin or ethnic group. However, local environmental factors related to nutrition and the prevalence of chronic disease undoubtedly have an effect. For instance, the age of the first menses varies by geographic location, as demonstrated by a World Health Organization study comparing 11 countries, which reported a median age of menarche of 13-16 years across centers.

Mortality/Morbidity: The regular occurrence of menses is a sign of good health. It means that the hypothalamic-pituitary-ovarian axis is functioning normally to produce ovarian hormones and support ovulation. The ovary functions as both an endocrine organ and a reproductive organ. When menstrual cycle regularity is lost, this means the ovaries are not functioning normally in either their endocrine role or their reproductive role. Loss of menstrual regularity has been associated with reduced bone density and increased fracture rates. Thus, loss of menstrual regularity has associated morbidity and may contribute to increased mortality.

* Regular menses is a sign that the ovaries are producing normal amounts of estrogen, androgens, and progesterone. These sex hormones play an important role in building and maintaining bone mass. Late menarche has been associated with a 3-fold increase in the risk of wrist fracture. Menstrual cycle duration of longer than 31 days has been associated with a 2-fold increase in wrist fracture. Similar correlations exist for the risk of hip fracture, a potentially fatal occurrence.

* Regular menses is also a sign that the ovaries support ovulation and that they contain a normal store of primordial follicles. Primordial follicles are composed of an oocyte surrounded by a single layer of granulosa cells. The number of primordial follicles in the human ovary peaks during the fifth gestational month at approximately 7 million. After this initial finite pool is in place, no additional primordial follicles are formed. In some cases, loss of menstrual regularity is an early sign of declining fertility and impending premature ovarian failure. Also in some cases, this follicle depletion progresses to cause irreversible infertility. Approximately 10% of women evaluated for amenorrhea in a tertiary center are found to have premature ovarian failure.

Race: No evidence suggests that the incidence of either primary or secondary amenorrhea is related to race.

Sex: Amenorrhea occurs only in women.

Age: A large study by Treolar et al (1967) demonstrated that by age 20 years, women have established remarkably regular and persistent patterns of menstrual cycle length with little variation on an individual basis. Relatively stable and predictable menstrual cycle length then continues until age 40 years.

According to the findings from the Treolar et al study, fewer than 2 menses in a 90-day interval (>95th percentile) in a woman aged 20-40 years is distinctly abnormal. Further, more than 3 menses in a 90-day interval in these women is also distinctly abnormal. Finally, menstrual bleeding for more than 10 days in women in this age group is also distinctly abnormal.

As women age, a remarkably steady decline occurs in mean menstrual cycle length. The shortening cycle length may be physiologically linked in some way to the well-established decline in the number of primordial follicles remaining in the pool as women age.

While the overall median menstrual cycle length is 28 days, cycle length gradually declines from age 20 years to age 40 years. At age 20 years, the median cycle length is 29 days, and by age 40 years, this has declined to 27 days. Further shortening of the menstrual cycle length is a well-recognized early sign of impending menopausal transition.

* In the first year after menarche, the fifth percentile for menstrual cycle length is 23 days and the 95th percentile is 90 days. By the fourth year after menarche, the 95th percentile for cycle length has declined from 90 days to approximately 50 days. Menstrual cycle length is certainly more variable for females in their teens than for women aged 20-40 years. However, by 7 years after menarche, cycles are more stable; the fifth percentile in cycle length is 27 days, and the 95th percentile is 38 days.

* In the year preceding menopause, the fifth percentile for cycle length is 25 days and the 95th percentile is approximately 150 days. Four years before menopause, the fifth percentile for cycle length is 23 days and the 95th percentile for cycle length is significantly more regular, at approximately 40 days. Menstrual cycle length is certainly more variable during the years preceding the menopausal transition than during the age span of 20-40 years.