A RANDOMIZED, CONTROLLED TRIAL OF ESTRADIOL REPLACEMENT THERAPY IN WOMEN WITH HYPERGONADOTROPIC AMENORRHEA

Premature ovarian failure is classically defined as menopause occurrin g before age 40 and is associated with elevated serum FSH levels. If e levated FSH levels indicate lack of ovarian feedback and depletion of primordial follicles, women with prematurely elevated FSH levels shoul d have infertility. However, there are many reports of pregnancies in affected women occurring during estrogen therapy, leading to the hypot hesis that estrogen may have a salutary effect on folliculogenesis and conception. This randomized, controlled trial was designed to investi gate whether estrogen replacement therapy offered a significant therap eutic benefit in hypergonadotropic amenorrhea and to evaluate the pote ntial pathophysiologic mechanisms that would explain the reported preg nancies. Thirty seven women, aged 16 to 40, with menstrual dysfunction and documented FSH levels elevated above the 95% confidence limits of the mid-cycle gonadotropin peak of the normal menstrual cycle (>40 IU /L 2nd IRP hMG in our RIA) on at least two occasions, entered the stud y. The average duration of their amenorrhea was 15.9 months (range 2-9 6 months). Subjects were randomized to begin estradiol replacement (mi cronized estradiol [Estrace TM], 2 mg orally each day) or no therapy f or 6 weeks in a 12-week, cross-over design with weekly monitoring by b oth pelvic ultrasonography and serum hormone levels. Thirty-one women completed the entire randomized study. As expected, estradiol therapy increased mean serum estradiol levels by 98 pg/mL and was associated w ith a significant decrease ill mean LH and FSH levels (LH: 45.4 IU/L 2 nd IRP hMG vs. 37.1 IU/L; FSH: 63.4 IU/L vs. 40.6 IU/L, geometric mean s). However, there was no effect of estradiol replacement on mean ovar ian volume, the number or size of new follicles, or the ovulation rate in all subjects or in the subset with no identified cause for their h ypergonadotropic hypogonadism (n = 20). Two pregnancies occurred durin g the randomized trial, one on and one off estradiol. In both arms of the study, the majority of subjects developed cystic ovarian structure s by ultrasound that were temporally associated with increasing serum estradiol levels, indicating functional ovarian follicles. Seventy-eig ht percent of all subjects grew at least one new follicle over 10 mm i n diameter and 46% ovulated at least once, as determined by a serum pr ogesterone level more than 4 ng/mL. Although ovulations were significa ntly more common in the 10 women subjects who had less than 3 months o f amenorrhea (all of whom ovulated) than in the 27 with greater than 3 months of amenorrhea (only 7 of whom ovulated (26%), P < 0.001), ther e was no significant difference in eventual pregnancies (2 of the 10 w omen with less than 3 months of amenorrhea us. 3 of the 27 with greate r than 3 months of amenorrhea, P = 0.47). We conclude that in hypergon adotropic women with amenorrhea: 1) folliculogenesis occurs often but is less frequently followed by ovulation and rarely by pregnancy, sugg esting that elevated FSH is a marker of oocyte dysfunction occurring d istinct from and earlier than granulosa cell or follicular dysfunction ; and 2) estrogen therapy does not improve the rate of folliculogenesi s or ovulation.