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.
Highlights
Long-acting progestin-only contraceptives (LAPCs) are safe, effective and inexpensive making them ideal for use by women in underdeveloped countries with limited access to medical care [1]
The contraceptive action of LAPCs results from inhibition of ovulation, thickening of the cervical mucus and impaired cyclic changes in the functional endometrium that impede implantation [21]
Several of the highly regulated genes (Tables 2–4) identified by microarray analysis responded to either medroxyprogesterone acetate (MPA) or ETO, but not to P4. This observation suggested that modulation of these genes by MPA and ETO may reflect a glucocorticoid action. This observation was supported by use of the web-based programs i.e. MatInspector and GeneCards which identified the presence of GREs in the promoter of the insulin-like growth factor binding protein 2 (IGFBP2), ADAMTS1, F2RL2 and FKBP51 genes, but not in the four jointed box 1 (FJX1) gene promoter (S1 Fig)
Summary
Long-acting progestin-only contraceptives (LAPCs) are safe, effective and inexpensive making them ideal for use by women in underdeveloped countries with limited access to medical care [1]. Microscopic examination of endometrial biopsies from adjacent bleeding (BL) and non-bleeding (NBL) sites in LAPC users revealed that only BL sites displayed these abnormal microvessels enmeshed in a compromised extracellular matrix (ECM). These damaged microvessels are contiguous with decidualized human endometrial stromal cells (HESCs) expressing high levels of tissue factor (TF), the primary initiator of hemostasis via factor VIIa and factor Xa/Va generated thrombin [11, 12]. Thrombin induces HESC-derived matrix metalloproteinase (MMP)-1, which preferentially degrades interstitial collagens, and MMP–3, which, in turn, degrades several other ECM proteins and activates secreted MMP zymogens [13] These proteolytic and inflammatory processes markedly contribute to LAPC-induced AUB
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