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.

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Recent studies suggest estradiol (E2)/natural progesterone (P) confers less breast cancer risk compared with conjugated equine estrogens (CEE)/synthetic progestogens. We investigate if differences in the regulation of breast cancer-related gene expression could provide some explanation. This study is a subset of a monocentric, 2-way, open observer-blinded, phase 4 randomized controlled trial on healthy postmenopausal women with climacteric symptoms (ClinicalTrials.gov; EUCTR-2005/001016-51). Study medication was two 28-day cycles of sequential hormone treatment with oral 0.625 mg CEE and 5 mg of oral medroxyprogesterone acetate (MPA) or 1.5 mg E2 as percutaneous gel/day with the addition of 200 mg oral micronized P. MPA and P were added days 15–28/cycle. Material from two core-needle breast biopsies in 15 women in each group was subject to quantitative PCR (Q-PCR). The primary endpoint was a change in breast carcinoma development gene expression. In the first eight consecutive women, RNA was extracted at baseline and after two months of treatment and subjected to microarray for 28856 genes and Ingenuity Pathways Analysis (IPA) to identify risk factor genes. Microarray analysis showed 3272 genes regulated with a fold-change of >±1.4. IPA showed 225 genes belonging to mammary-tumor development function: 198 for CEE/MPA vs. 34 for E2/P. Sixteen genes involved in mammary tumor inclination were subject to Q-PCR, inclining the CEE/MPA group towards an increased risk for breast carcinoma compared to the E2/P group at a very high significance level (p = 3.1 × 10−8, z-score 1.94). The combination of E2/P affected breast cancer-related genes much less than CEE/MPA.