Effects of percutaneous estradiol–oral progesterone versus oral conjugated equine estrogens–medroxyprogesterone acetate on breast cell proliferation and bcl-2 protein in healthy women

Abstract

Effects of percutaneous estradiol-oral progesterone versus oral conjugated equine estrogens-medroxyprogesterone acetate on breast cell proliferation and bcl-2 protein in healthy womenIn a prospective, randomized clinical study 77 women were assigned randomly to receive sequential hormone therapy with either conventional oral conjugated equine estrogens (0.625 mg) with the addition on 14 of the 28 days of oral medroxyprogesterone acetate (5 mg) or natural E 2 gel (1.5 mg) with oral micronized P (200 mg) on 14 of the 28 days of each cycle. Because oral conjugated equine estrogens-medroxyprogesterone acetate induced a highly significant increase in breast cell proliferation in contrast to percutaneous E 2 -oral P with a difference between therapies approaching significance, the former therapy has a marked impact on the breast whereas natural percutaneous E 2 -oral micronized P has not. (Fertil Steril Ò 2011;95:1188-91. Ó2011 by American Society for Reproductive Medicine.)Key Words: Percutaneous estradiol, micronized progesterone, HT, proliferation, bcl-2 protein, normal breast tissue Postmenopausal hormone therapy (HT) has been associated with an increased risk for breast cancer. The risk with combined estrogen-progestogen therapy is greater than with estrogen alone (1-6). Hormone therapy is not a uniform concept, and various preparations, doses, and regimens of HT may have different effects (7). Although estrogen is a known mitogen in the breast, the effects of added progestogens may vary considerably (8-15), but proliferative responses are seen within 2 months (9-11). Synthetic progestogens may differ from natural P. In the French E3N cohort, women taking estrogen in combination with micronized P were found to have no increase in breast cancer risk in contrast to women taking estrogen in combination with synthetic progestogens (16,17).In this study we used core needle biopsy to evaluate breast cell proliferation in healthy postmenopausal women during two different types of sequential HTs: oral conjugated estrogens plus synthetic progestogen versus percutaneous E 2 plus natural oral micronized P. A prospective randomized clinical study was performed at the Karolinska University Hospital, Stockholm, Sweden, between May 2006 and March 2008. Apparently healthy women, aged 44 to 66 years, postmenopausal for at least 12 months, nonsmokers, with normal mammogram results, and with a body mass index of 18 to 30 kg/m 2 , were recruited. Follicle-stimulating hormone levels at screening were >25 IU/L, and E 2 levels <90 pmol/L. The washout period for previous HT users was 3 months.Exclusion criteria were any breast disease, previous breast surgery, hepatic dysfunction, active gallbladder disease, or history of thromboembolic disease. Medication with sexual steroids, barbiturates, carbamazepines, phenytoin, glucocorticoids, rifampicin, cimetidine, diltiazem, erythromycin, ketoconazole, verapamil, and quinidine was not permitted.

Glucocorticoid receptor and breast cancer

“…Similarly, MPA enhanced E2-mediated proliferation in the terminal duct-lobular units of the breast in postmenopausal women treated with estrogens and MPA [111]. Interestingly, in a recent randomized study using post-menopausal women, E2 and progesterone did not increase the proliferation index, whereas conjugated-E2 and MPA were proliferative [113]. Similarly, in breast tissues of Cynomolgus macaques, MPA was proliferative and stimulated the expression of EGFR ligands and downstream targets with a higher efficiency than progesterone [112,114].…”

Association of Etonogestrel-Releasing Contraceptive Implant with Reduced Weight Gain in an Exclusively Breastfed Infant: Report and Literature Review

“…For example, there is evidence that formulations of estrogen and progestin differentially affect breast cell proliferation in postmenopausal women. 8 These results suggest that effects for one progestin or estrogen may not be generalizable to other formulations.…”

Evidence on the use of progesterone in menopausal hormone therapy

“…For the most part, in both studies, proliferation markers (mitotic index and proliferating cell nuclear antigen index) increased with E2 vs. placebo, decreased with P4 vs. placebo, and were comparable between E2/P4 and P4 or placebo 56,57 . In another study of postmenopausal women (n ¼ 77) taking two cycles of 0.625 mg CEE plus cyclic 5 mg MPA or 1.5 mg E2 gel plus cyclic oral 200 mg P4, breast cell proliferation significantly increased from baseline with CEE/MPA, but not with E2/P4 58,59 .…”