What is the physiology of menopause?

Updated: Jun 06, 2018
  • Author: PonJola Coney, MD; Chief Editor: Richard Scott Lucidi, MD, FACOG  more...
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Menopause results from loss of ovarian sensitivity to gonadotropin stimulation, which is directly related to follicular attrition. The oocytes in the ovaries undergo atresia throughout a woman’s life cycle, resulting in a decline in both the quantity and the quality of follicles. Thus, the variable menstrual cycle length during the menopausal transition (MT) is due more to a shrinking follicle cohort size than to follicle failure.

Anovulatory cycles and absence of cyclicity become common, with a highly variable pattern of gonadotropin and steroid hormone production, estrogen insensitivity, failure of the luteinizing hormone (LH) surge, the occurrence of the final menstrual period, and permanent amenorrhea. [1, 2]

Hormonal fluctuation may not be responsible for all irregular bleeding during this period; therefore, pelvic pathology (eg, uterine fibroids, uterine polyps, endometrial hyperplasia, or endometrial cancer), which becomes more prevalent during this time, must be excluded through endometrial sampling (eg, with endometrial biopsy [EMB] or dilatation and curettage [D&C]).

During the fifth decade of life, many women are lulled into a false sense of security, thinking that they are no longer fertile because they are so close to menopause. Although fertility declines, pregnancy can still occur, as demonstrated by a relatively high rate of unintended pregnancies in women aged 40-44 years. In fact, the number of unintended pregnancies in this age group has increased over the past decade, [13] which underscores the need for continued contraceptive practice in heterosexual couples.

A shorter menstrual cycle (< 25 days) is the most common change in menstrual cyclicity that occurs during the MT in women who have no pelvic pathology and who continue to be ovulatory. [14] Because functional follicles, which are stimulated by follicle-stimulating hormone (FSH) during the first part of the menstrual cycle, have declined in number, less recruitment of oocytes occurs, and the follicular phase shortens accordingly. However, once ovulation occurs, the luteal phase remains fairly constant, at 14 days.

Over time, as aging follicles become more resistant to gonadotropin stimulation, circulating FSH and LH levels increase. Elevated FSH and LH levels lead to stromal stimulation of the ovary, with a resultant increase in estrone levels and a decrease in estradiol levels. Inhibins are peptides of the transforming growth factor (TGF)-β superfamily and are produced by the granulosa cells of the ovarian follicles in the terminal stages of development. Inhibin levels also drop during this time because of the negative feedback of elevated FSH levels. [1, 2, 15]

With the commencement of menopause and a loss of functioning follicles, the most significant change in the hormonal profile is the dramatic decrease in circulating estradiol, which rapidly declines over a period of 4 years (starting 2 years before the final menstrual period and stabilizing approximately 2 years after the final period). Without a follicular source, the larger proportion of postmenopausal estrogen is derived from ovarian stromal and adrenal secretion of androstenedione, which is aromatized to estrone in the peripheral circulation.

Total serum testosterone levels do not change during the MT. Dehydroepiandrosterone (DHEAS) levels do decline with age. A trend toward higher total cholesterol, low-density lipoprotein (LDL), and apolipoprotein B levels, in conjunction with loss of the protective effect of high-density lipoprotein (HDL), is characteristic in menopause. [1, 2, 16]

With cessation of ovulation, estrogen production by the aromatization of androgens in the ovarian stroma and estrogen production in extragonadal sites (adipose tissue, muscle, liver, bone, bone marrow, fibroblasts, and hair roots) [16] continue, unopposed by progesterone production by a corpus luteum. Consequently, perimenopausal and menopausal women are often exposed to unopposed estrogen for long periods, and this exposure can lead to endometrial hyperplasia, a precursor of endometrial cancer.

Although estradiol levels decrease significantly because of the loss of follicular production with menopause and postmenopause, estrone, which is aromatized from androstenedione from nonfollicular sources, is still produced and is the major source of circulating estrogen in the postmenopausal female.

Because most conversion of androgens to estrogens occurs in adipose tissue, it is frequently assumed that obese women, who have more circulating estrogen, should have fewer complaints of vasomotor symptoms. However, this is not always the case, and vasomotor symptoms of menopause can be as frequent and severe in heavier women as they are in thinner women.

The clinical indication that menopause has occurred is a rise in the measured FSH level. The FSH level rises more than the LH level because of the reduced renal clearance of FSH in comparison with LH. A slightly elevated or borderline menopausal FSH level in the MT may not be a reliable indicator of menopause, because of the wide variation of FSH and LH levels in response to increased release of gonadotropin-releasing hormone (GnRH) by the hypothalamus and increased pituitary sensitivity to GnRH.

Repeated measurement of FSH and LH levels at 2- to 3-month intervals is helpful for establishing whether the woman is progressing through menopause. Women with elevated, but not postmenopausal, FSH levels are still at risk for pregnancy, and contraception should continue to be used until FSH levels remain in the postmenopausal range.

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