Effects of Estradiol/Micronized Progesterone vs. Conjugated Equine Estrogens/Medroxyprogesterone Acetate on Breast Cancer Gene Expression in Healthy Postmenopausal Women.

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.

Percutaneous estradiol/oral micronized progesterone has less-adverse effects and different gene regulations than oral conjugated equine estrogens/medroxyprogesterone acetate in the breasts of healthy women in vivo.

Gene expression analysis of healthy postmenopausal women in a prospective clinical study indicated that genes encoding for epithelial proliferation markers Ki-67 and progesterone receptor B mRNA are differentially expressed in women using hormone therapy (HT) with natural versus synthetic estrogens. Two 28-day cycles of daily estradiol (E2) gel 1.5 mg and oral micronized progesterone (P) 200 mg/day for the last 14 days of each cycle did not significantly increase breast epithelial proliferation (Ki-67 MIB-1 positive cells) at the cell level nor at the mRNA level (MKI-67 gene). A borderline significant beneficial reduction in anti-apoptotic protein bcl-2, favouring apoptosis, was also seen followed by a slight numeric decrease of its mRNA. By contrast, two 28-day cycles of daily oral conjugated equine estrogens (CEE) 0.625 mg and oral medroxyprogesterone acetate (MPA) 5 mg for the last 14 days of each cycle significantly increased proliferation at both the cell level and at the mRNA level, and significantly enhanced mammographic breast density, an important risk factor for breast cancer. In addition, CEE/MPA affected around 2,500 genes compared with just 600 affected by E2/P. These results suggest that HT with natural estrogens affects a much smaller number of genes and has less-adverse effects on the normal breast in vivo than conventional, synthetic therapy.

Visuospatial ability correlates with performance in simulated gynecological laparoscopy.

OBJECTIVE: To analyze the relationship between visuospatial ability and simulated laparoscopy performed by consultants in obstetrics and gynecology (OBGYN). STUDY DESIGN: This was a prospective cohort study carried out at two community hospitals in Sweden. Thirteen consultants in obstetrics and gynecology were included. They had previously independently performed 10-100 advanced laparoscopies. Participants were tested for visuospatial ability by the Mental Rotations Test version A (MRT-A). After a familiarization session and standardized instruction, all participants subsequently conducted three consecutive virtual tubal occlusions followed by three virtual salpingectomies. Performance in the simulator was measured by Total Time, Score and Ovarian Diathermy Damage. Linear regression was used to analyze the relationship between visuospatial ability and simulated laparoscopic performance. The learning curves in the simulator were assessed in order to interpret the relationship with the visuospatial ability. RESULTS: Visuospatial ability correlated with Total Time (r=-0.62; p=0.03) and Score (r=0.57; p=0.05) in the medium level of the virtual tubal occlusion. In the technically more advanced virtual salpingectomy the visuospatial ability correlated with Total Time (r=-0.64; p=0.02), Ovarian Diathermy Damage (r=-0.65; p=0.02) and with overall Score (r=0.64; p=0.02). CONCLUSIONS: Visuospatial ability appears to be related to the performance of gynecological laparoscopic procedures in a simulator. Testing visuospatial ability might be helpful when designing individual training programs.

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

In 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.