title: 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.affiliation: Department of Obstetrics and Gynecology, Morsani College of Medicine, University of South Florida, Tampa, Florida, United State of America.
authors.forename: Ozlem
authors.initials: O
authors.lastname: Guzeloglu Kayisli
authors.affiliation: Department of Obstetrics and Gynecology, Morsani College of Medicine, University of South Florida, Tampa, Florida, United State of America.
authors.forename: Umit A
authors.initials: UA
authors.lastname: Kayisli
authors.affiliation: Department of Obstetrics and Gynecology, School of Medicine, Yale University, New Haven, Connecticut, United State of America.
authors.forename: Murat
authors.initials: M
authors.lastname: Basar
authors.affiliation: Department of Obstetrics and Gynecology, Morsani College of Medicine, University of South Florida, Tampa, Florida, United State of America.
authors.forename: Nihan
authors.initials: N
authors.lastname: Semerci
authors.affiliation: Department of Obstetrics and Gynecology, Morsani College of Medicine, University of South Florida, Tampa, Florida, United State of America.
authors.forename: Frederick
authors.initials: F
authors.lastname: Schatz
authors.affiliation: Department of Obstetrics and Gynecology, Morsani College of Medicine, University of South Florida, Tampa, Florida, United State of America.
authors.forename: Charles J
authors.initials: CJ
authors.lastname: Lockwood
mesh_terms: D000818:Animals; D003271:Contraceptive Agents, Female / Q000009:adverse effects; D017135:Desogestrel / Q000494:pharmacology; D004717:Endometrium / Q000473:pathology*; D005260:Female; D005938:Glucocorticoids / Q000378:metabolism*; D006168:Guinea Pigs; D006801:Humans; D053583:Interleukin-1beta / Q000235:genetics; D017258:Medroxyprogesterone Acetate / Q000494:pharmacology; D005810:Multigene Family / Q000235:genetics; D011374:Progesterone / Q000378:metabolism*; D011372:Progestins / Q000009:adverse effects*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D017154:Stromal Cells / Q000187:drug effects / Q000378:metabolism*; D022021:Tacrolimus Binding Proteins / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation / Q000187:drug effects; D014592:Uterine Hemorrhage / Q000139:chemically induced* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D000099159:Tacrolimus Binding Protein 5
chemical_list: D003271:Contraceptive Agents, Female; D017135:Desogestrel; D005938:Glucocorticoids; D053583:Interleukin-1beta; D017258:Medroxyprogesterone Acetate; D011374:Progesterone; D011372:Progestins; D012333:RNA, Messenger; D022021:Tacrolimus Binding Proteins; D000099159:Tacrolimus Binding Protein 5; C044815:etonogestrel