The Transition

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The reproductive life span can be divided into three phases: the reproductive years, the perimenopause, and the postmenopause. The perimenopause can be further subdivided into early and late stages. The greatest stability and efficiency of ovarian function is between the ages of 25 and 34. Ovulatory variability is greatest before the age of 20 and after the age of 40 years, resulting in an increased frequency of anovulatory cycles, erratic cycle length, and abnormal uterine bleeding.

The early perimenopause is characterized by slowly declining ovarian function, increasing frequency of anovulatory cycles, irregular cycle lengths, fluctuating gonadotropin levels, and an overall increase in FSH and luteinizing hormone (LH) levels. FSH levels, in particular, may fluctuate widely, changing with each cycle, largely due to a decrease in the number of ovarian follicles. With loss of ovarian follicles as well as granulosa cells, inhibin levels, which normally provide negative feedback on the pituitary FSH secretion, decrease. This results in the loss of the negative feedback loop between inhibin and FSH, leading to an elevation of FSH levels. FSH levels trend upward starting in the late reproductive years, even before changes in the menstrual cycle, once inhibin levels fall low enough to allow a rise in FSH levels. Thus, the routine measurement of serum FSH to determine if a woman is perimenopausal can be misleading. Therefore, clinical evaluation becomes important in making the diagnosis of perimenopause. Symptoms of early perimenopause are variable but include: hot flashes, premenstrual dysphoria, breast tenderness, insomnia and the menstrual cycle changes described above.

As the transition proceeds to the late perimenopause phase, continued alterations in the production and subsequent levels of sex steroid hormones occur. Ovulation eventually ceases and the supply of ovarian follicles is eventually exhausted, resulting in permanent loss of fertility. However, the ovarian stroma continues to produce androstenedione and testosterone in significant amounts. As estrogen levels decline into the postmenopausal range, estradiol is no longer made by the follicle, but by peripheral conversion of estrone, testosterone, and, most importantly, androstenedione. The major estrogen sources throughout this period are the adrenal glands via the conversion of androstenedione to estrone in adipose tissue. In addition, the adrenals continue to secrete testosterone and small amounts of estrogen, as well as dihydroepiandrostenedione (DHEA) and dihydroepiandrostenedione-sulfate (DHEAS). However, with increasing age, the adrenals produce smaller amounts of androgen, which also results in diminished peripheral estrogen production over time.

With the menopause, significant reductions in estrogen levels are noted with a less significant decrease in androgen levels. FSH and LH levels increase markedly without change in other pituitary hormones. Finally, at the completion of the late perimenopause, now 12 months after the last menses and beginning the meno-pausal phase, gonadotropin levels have reached their final menopausal levels (usually >40 mIU/ml).

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