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Clinical Trial
. 2023 Feb 18;24(4):4123.
doi: 10.3390/ijms24044123.

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

Parameswaran Grace Luther Lalitkumar  1 , Eva Lundström  1 , Birgitta Byström  1 , Dorina Ujvari  1 , Daniel Murkes  1 , Edneia Tani  2 , Gunnar Söderqvist  1
Affiliations
Clinical Trial

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

Parameswaran Grace Luther Lalitkumar et al. Int J Mol Sci. .

Abstract

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.

Keywords: breast cancer gene expression; conjugated equine estrogens/medroxyprogesterone acetate; core needle biopsies; estradiol/micronized progesterone; healthy postmenopausal women; menopausal hormone treatment and breast cancer risk.

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Conflict of interest statement

P.G.L.L. Lalitkumar has received consulting fees from IVF access, India. No disclosures were reported by the other authors.

Figures

Figure 1
Figure 1
Fold change ratios (no’: s within symbols) for CEE/MPA vs. (E2)/P for thirteen genes affecting breast carcinoma. Star-shaped symbols represent genes increasing breast carcinoma when activated. Plus: +—sign represents net effect of increasing breast carcinoma inclination. Minus: −sign represents net effect decreasing breast carcinoma inclination. Rectangle represents gene with protective effect against breast carcinoma. Thick black arrows represent positive FC ratios. Thin black arrows represent negative FC ratios. Dotted arrows indicate findings inconsistent with state of downstream molecule. The biological function “breast carcinoma” was augmented more for CEE/MPA than for (E2)/P at a very high significance level (p = 3.1 × 10−8, z-score = 1.94). (Adapted information from IPA database, Ingenuity Systems).
See this image and copyright information in PMC

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