Comparison of the impact of transdermal versus oral estrogens on biliary markers of gallstone formation in postmenopausal women.

This prospective, randomized, double blind, parallel study was undertaken to elucidate further the potential mechanisms through which estrogens could promote the formation of cholesterol gallstones and to compare the impact of nonoral (transdermal) and oral estrogens on serum, hepatic, and biliary markers of estrogen action. Ninety-seven postmenopausal women were randomized to receive either transdermal estradiol (E2; 0.1 mg every 3.5 days; n = 48) or oral conjugated equine estrogens (1.25 mg every day; n = 49) for 8 weeks. Blood samples were drawn, and bile samples were obtained by cholecystokinin-stimulated duodenal drainage before and after 8 weeks of estrogen administration. The main outcome measures included serum FSH, LH, E2, estrone, estrone sulfate, sex hormone-binding globulin, lipid profiles, biliary cholesterol saturation index, cholesterol nucleation time, presence of cholesterol crystals in bile, as well as biliary arachidonate, PGE2, and mucous glycoproteins. Estrogens administered by both routes increased circulating estrogens and resulted in similar suppression of both gonadotropins. Sex hormone-binding globulin was clearly increased, and the changes in serum lipids were more pronounced with oral conjugated equine estrogens than with transdermal E2. The biliary cholesterol saturation index was significantly increased compared to the baseline values with both transdermal E2 (1.08 +/- 0.04 vs. 1.00 +/- 0.03; mean change, 8%) and oral conjugated equine estrogens (1.04 +/- 0.03 vs. 0.99 +/- 0.03; mean change, 6%); however, there was no difference between the treatments. The number of patients with cholesterol crystals detected in bile was similar after both estrogen regimens. Transdermal and oral estrogens decreased nucleation time in vitro, increased arachidonate and PGE2 levels, and minimally raised total glycoprotein concentrations. In conclusion, transdermal and oral estrogens exerted comparable nonhepatic effects, as evidenced by similar reductions of gonadotropin levels, but oral therapy exhibited substantially greater actions on hepatic markers of estrogen action. Both transdermal E2 and oral conjugated equine estrogens significantly elevated the biliary cholesterol saturation index and reduced the nucleation time. These results suggest that estrogens at the doses studied could promote gallstone formation by alteration of biliary lipids and cholesterol nucleation time that have been incriminated in this process.

Assessment of less than monthly progestin therapy in postmenopausal women given estrogen replacement.

OBJECTIVE: To study progestin administration at less than monthly intervals in postmenopausal women given continuous estrogen replacement. METHODS: Eighty postmenopausal women received 0.625 mg/day of conjugated equine estrogens for 48 weeks. Using a double-masked design, the subjects were randomized to medroxyprogesterone acetate 10 mg/day for 14 days every 28 or 84 days, or the same dosage for 28 of 84 days. Bleeding patterns, endometrial histology, and serum lipids were assessed. RESULTS: The total days of bleeding during the 48-week study were significantly reduced (P < .05) in the women given the progestin for 14 days every 3 months (mean +/- standard deviation 29 +/- 16 days) than with the other two regimens. In all groups, secretory endometrium was reported in 17-39%. At 24 but not 48 weeks, simple hyperplasia was observed in one subject in each of the less than monthly progestin groups. Significant increases (P < .05) of high-density lipoprotein cholesterol were observed before but not after medroxyprogesterone acetate in the women receiving it less than monthly. No change was seen with monthly progestin. CONCLUSIONS: In this direct comparison, medroxyprogesterone acetate given for 14 days every 3 months elicited less vaginal bleeding than standard monthly administration. Only a single woman had simple hyperplasia with each regimen of progestin given every 84 days. Medroxyprogesterone acetate given for 14 days every 3 months represents a possible alternative to standard monthly therapy if coupled with regular assessment of the endometrium.