Atypical estradiol secretion and ovulation patterns caused by luteal out-of-phase (LOOP) events underlying irregular ovulatory menstrual cycles in the menopausal transition

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Abstract
Objective: The menopausal transition is characterized by irregular menstrual cycles and unpredictable hormone levels, including dramatic swings in estradiol (E-2). An increasing number of studies have found variable high E-2 and low luteal phase progesterone occur with progression of Stages of Reproductive Aging Workshop (STRAW) stage, but the cause remains unclear. To explore the causes of the erratic changes in E-2, individual within-cycle secretion patterns of E-2 progesterone, follicle-stimulating hormone, luteinizing hormone, inhibin A, and inhibin B were explored in detail. Design: Blood samples taken three times per week over 1 1/3 menstrual cycles from 77 women aged 21 to 55 classified as mid-reproductive age (STRAW stages 5 and 4; n = 21), late-reproductive age (STRAW stages 4 and 3; n = 16), early menopausal transition (STRAW stage 2; n = 17), and late menopausal transition (STRAW stage 1; n = 23) were analyzed. Results: Eleven of the 29 (37%) early and late menstrual transition ovulatory cycles exhibited a specific pattern of E-2 secretion that was characterized by a second increase in E-2 during the mid- and late luteal phases and that continued to a peak during the Subsequent menstrual phase. This second rise and fall in E-2 was typical in appearance of a normal follicular phase, except that it was superimposed on an existing ovulatory cycle (specifically during the luteal and menstrual phases). The pattern was therefore referred to as a luteal out-of-phase (LOOP) follicular event. In four of these LOOP cycles, a luteinizing hormone peak and ovulatory episode followed the second E-2 peak early in the subsequent cycle. Compared with the typical ovulatory cycles, the cycles with LOOP events exhibited lower luteal phase progesterone, higher early cycle follicle-stimulating hormone, and lower early cycle inhibin B. They were also associated with abnormally short (40 d) cycle length. Conclusions: Many of the marked increases in ovulatory cycle E-2 and cycle irregularities during the menopausal transition may be due to LOOP events and appear to be triggered by prolonged high follicular phase follicle-stimulating hormone levels.

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