Ovarian aging and the perimenopausal transition: the paradox of endogenous ovarian hyperstimulation

The purpose of this review is to put into a useful clinical context the changing over time of basic ovarian-pituitary-hypothalamic relationships during perimenopause. "Perimenopause" means changes in ovarian hormones, feedback relationships, and clinical experiences beginning in women ages 35-50 with regular flow and ending 1 yr after the final menstrual flow. A key observation must be explained--estradiol levels are increased in perimenopause. Inhibin B levels are lower and activin may be higher in midlife, menstruating women. These changes probably cause higher follicular phase FSH levels--"endogenous ovarian hyperstimulation" results. The positive estradiol feedback on LH is also disturbed--midcycle LH peaks and mid-luteal slow-frequency, high-amplitude LH pulses are less frequent. In addition to higher levels, estradiol receptors may increase in tissues of symptomatic women. Despite hyperstimulation of follicles, progesterone levels and luteal phase lengths are paradoxically decreased--reasons probably include LH peak disruptions and estrogen-stimulated greater corticotrophin-mediated reproductive suppression. In summary, disturbed feedback relationships causing higher and unpredictable estrogen and lower progesterone levels occur throughout perimenopause, especially during regular cycles. Prospective, population-based research is needed to systematically relate these feedback hormonal changes to clinical characteristics and to allow a diagnosis of perimenopause in regularly cycling midlife women.