Effects of Transdermal Estradiol Therapy (100 Micrograms per Day) on Gonadotropin Levels in Young Women With 46,XX Spontaneous Premature Ovarian Failure

Abstract

We previously demonstrated by histological examination that inappropriate luteinization is a major mechanism of Graafian follicle dysfunction in women with 46,XX spontaneous premature ovarian failure. Pregnancies are known to occur in women with this diagnosis, but there is little evidence available regarding the effect of estrogen therapy on gonadotropin levels in these women. Theoretically, estrogen replacement therapy might improve pregnancy rates in this condition by suppressing serum LH levels into the normal range. The purpose of this study was to determine the proportion of women with spontaneous premature ovarian failure who achieve serum LH levels in the normal range on a standardized dose of transdermal estradiol. Analysis of data collected as part of a prospective controlled study designed to evaluate bone density as the primary outcome parameter. Blood samples were drawn during the mid follicular phase (days 5-8) from healthy regularly menstruating control women (cycles between 21 and 35 days) (n=70). Women with 46,XX spontaneous premature ovarian failure (n=106) had baseline samples drawn after being off hormone therapy for 2 weeks, and again 3 months later during the estrogen-only phase of a standard replacement regimen (100 micrograms per day estradiol patch, medroxyprogesterone acetate 10 mg for 12 days each month). All women were between the ages of 18 and 42 years. We measured LH and FSH by microparticle enzyme immunoassay (Abbott Diagnostics, Abbott Park, IL) and estradiol by competitive chemiluminescence immunoassay (Diagnostic Products Corporation, Los Angeles, CA). To compare data before and after hormone therapy we used the paired t-test for continuous variables and the signed rank test for binary variables. We defined the normal limit of mid follicular phase serum LH level in our assay as 3 to14 IU/L based on the 5th and 95th centiles from 67 control samples. (We excluded 3 control samples that had predefined mid-cycle LH levels >20 IU/L.) Transdermal estradiol therapy significantly reduced mean (SEM) serum LH levels in women with spontaneous premature ovarian failure from 52.3 (2.6) IU/L while off therapy to 15.9 (1.6) IU/L while on therapy (p<0.0001). While on transdermal estradiol therapy, 58/106 (55%) of these women had serum LH levels in the normal range, as compared to 5/106 (4.7%) at baseline (p<0.0001). We defined the normal limit of mid follicular phase serum FSH level in our assay as 3 to10 IU/L based on the 5th and 95th centiles from 67 control samples. While on transdermal estradiol therapy, 29/106 (27%) patients had FSH in the normal range, as compared to 3/106 (2.8%) at baseline (p<0.0001). Only 2/106 (1.9%) of these women had FSH suppressed below normal, whereas10/106 (9.4%) had LH suppressed. On this replacement regimen, LH was significantly more likely to be in the normal range than FSH (p<0.0001). Mean (SEM) serum estradiol level on therapy was 95.6 (8.6) pg/mL compared to 40.5 pg/mL while off replacement (p<0.0001). A standard regimen of 100 microgram transdermal estradiol replacement achieved normal serum LH levels in 55% (44.8%, 64.4%) of women with 46,XX spontaneous premature ovarian failure. Theoretically this may reduce the chance of inappropriate follicle luteinization and improve ovulatory rates. Controlled studies to assess the effect of hormone replacement regimens on ovulatory rates in these women are warranted.