Progestins Upregulate FKBP51 Expression in Human Endometrial Stromal Cells to Induce Functional Progesterone and Glucocorticoid Withdrawal: Implications for Contraceptive- Associated Abnormal Uterine Bleeding.

Abstract

Use of long-acting progestin only contraceptives (LAPCs) offers a discrete and highly effective family planning method. Abnormal uterine bleeding (AUB) is the major side effect of, and cause for, discontinuation of LAPCs. The endometria of LAPC-treated women display abnormally enlarged, fragile blood vessels, decreased endometrial blood flow and oxidative stress. To understanding to mechanisms underlying AUB, we propose to identify LAPC-modulated unique gene cluster(s) in human endometrial stromal cells (HESCs). Protein and RNA isolated from cultured HESCs treated 7 days with estradiol (E2) or E2+ medroxyprogesterone acetate (MPA) or E2+ etonogestrel (ETO) or E2+ progesterone (P4) were analyzed by quantitative Real-time (q)-PCR and immunoblotting. HSCORES were determined for immunostained-paired endometria of pre-and 3 months post-Depot MPA (DMPA) treated women and ovariectomized guinea pigs (GPs) treated with placebo or E2 or MPA or E2+MPA for 21 days. In HESCs, whole genome analysis identified a 67 gene group regulated by all three progestins, whereas a 235 gene group was regulated by E2+ETO and E2+MPA, but not E2+P4. Ingenuity pathway analysis identified glucocorticoid receptor (GR) activation as one of upstream regulators of the 235 MPA and ETO-specific genes. Among these, microarray results demonstrated significant enhancement of FKBP51, a repressor of PR/GR transcriptional activity, by both MPA and ETO. q-PCR and immunoblot analysis confirmed the microarray results. In endometria of post-DMPA versus pre-DMPA administered women, FKBP51 expression was significantly increased in endometrial stromal and glandular cells. In GPs, E2+MPA or MPA significantly increased FKBP51 immunoreactivity in endometrial stromal and glandular cells versus placebo- and E2-administered groups. MPA or ETO administration activates GR signaling and increases endometrial FKBP51 expression, which could be one of the mechanisms causing AUB by inhibiting PR and GR-mediated transcription. The resultant PR and/or GR-mediated functional withdrawal may contribute to associated endometrial inflammation, aberrant angiogenesis, and bleeding.

• Authors: Ozlem Guzeloglu Kayisli, Umit A Kayisli, Murat Basar, Nihan Semerci, Frederick Schatz, Charles J Lockwood
• Journal: PloS one (PLoS One) Vol. 10 Issue 10 Pg. e0137855 ( 2015) ISSN: 1932-6203 [Electronic] United States
• PMID: 26436918 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Contraceptive Agents, Female
• Glucocorticoids
• Interleukin-1beta
• Progestins
• RNA, Messenger
• etonogestrel
• Progesterone
• Desogestrel
• Medroxyprogesterone Acetate
• Tacrolimus Binding Proteins
• tacrolimus binding protein 5

Topics

• Animals
• Contraceptive Agents, Female (adverse effects)
• Desogestrel (pharmacology)
• Endometrium (pathology)
• Female
• Glucocorticoids (metabolism)
• Guinea Pigs
• Humans
• Interleukin-1beta (genetics)
• Medroxyprogesterone Acetate (pharmacology)
• Multigene Family (genetics)
• Progesterone (metabolism)
• Progestins (adverse effects)
• RNA, Messenger (genetics, metabolism)
• Stromal Cells (drug effects, metabolism)
• Tacrolimus Binding Proteins (genetics, metabolism)
• Up-Regulation (drug effects)
• Uterine Hemorrhage (chemically induced, genetics, metabolism, pathology)