Pharmacologic modulation of endometrial intracrinology and steroid receptor expression

• Main Author: Vani, Susheel Narendra
• Published: University of Edinburgh 2013
• Subjects: 612.4
• Online Access: https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.726486

Steroid hormones, acting via their cognate receptors, are key players in fundamental reproductive events: implantation and endometrial bleeding. To understand local mechanisms regulating function and the effect of pharmacologic modulation it is essential to have an understanding of factors regulating ligand availability and steroid receptor expression in the physiological state and after pharmacologic manipulations. This thesis encompasses studies analysing expression of steroid metabolising enzymes (intracrinology) and steroid receptor expression in human endometrium after three different pharmacologic manipulations. 1. Endometrium exposed to a GnRH antagonist during controlled ovarian hyperstimulation Mid-luteal phase endometrial biopsies were obtained from oocyte donors undergoing ovarian stimulation and from control women with regular periods. Immunohistochemistry and real-time quantitative polymerase chain reaction (QRT-PCR) were used to compare protein and mRNA expression of sex steroid receptors and steroid metabolising enzymes. Significant alterations in the expression of sex-steroid receptors and their metabolizing enzymes were demonstrated. These changes may lead to alterations in the activity and intracellular availability of estrogens, progestogens and androgens in endometrium of women treated with a GnRH antagonist during controlled ovarian hyperstimulation. Their impact on embryo implantation merits further evaluation. 2. Endometrium exposed to hormone replacement therapy (HRT) Endometrial biopsies from postmenopausal women not using HRT and from HRT users were collected during and outside unscheduled bleeding episodes. Immunohistochemical analysis of endometrial sex steroid receptors was performed and the relationship between expression and bleeding patterns studied. Despite the predominantly progestational effect of continuous combined HRT used in the study, the steroid receptor expression in the postmenopausal endometrium differed from that seen in the premenopausal secretory phase of menstrual cycle and after long-term progestogen-only administration, suggesting that different local mechanisms are involved in HRT-related unscheduled bleeding. 3. Endometrium exposed to intrauterine delivery of a progesterone receptor antagonist Women were randomised to intrauterine administration of either the antigestogen, ZK230211 (ZK-IUS) or Levonorgestrel (LNG-IUS) prior to hysterectomy. Endometrium was obtained from hysterectomy specimens. Bleeding patterns, endometrial morphology and content of ZK230211 were evaluated. Expression of sex steroid receptors, proliferation markers; phosphorylated Histone 3 (PH3) and Ki-67, and Insulin-like Growth Factor- Binding Protein-1 (IGFBP-1) were evaluated by immunohistochemistry (IHC). Administration of the antigestogen demonstrated novel effects such as an absence of IGFBP-1 and increase in progesterone receptor expression. These results suggest that intrauterine administration of an antigestogen is feasible and trials need to be undertaken to test clinical efficacy. These studies, in pre and postmenopausal women, demonstrate that endometrial sex steroid receptor expression and enzymes determining intracellular steroid (ligand) availability are modulated by exogenous steroid manipulation.