ResearchDown-regulation of progesterone receptor membrane component 1 ( PGRMC 1 ) in peripheral nucleated blood cells associated with premature ovarian failure ( POF ) and polycystic ovary syndrome ( PCOS )

Background: Progesterone receptor membrane component 1 (PGRMC1) is a member of a progesterone-binding complex implicated in female reproduction. We aimed i) to determine the natural expression of PGRMC1 in peripheral nucleated blood cells throughout the menstrual cycle and ii) to investigate any association between PGRMC1 levels in leukocytes and conditions characterized by reduced fertility. Methods: We analyzed PGRMC1 expression in peripheral leukocytes from 15 healthy cycling women over four weeks. Additionally, we determined PGRMC1 levels in samples from patients with premature ovarian failure (POF) and polycystic ovary syndrome (PCOS) as well as in healthy postmenopausal women and male controls. The levels of PGRMC1 protein in nucleated peripheral blood cells were quantified by Western blot analysis. Results: PGRMC1 levels did not vary significantly throughout the menstrual cycle. We observed a significant downregulation of PGRMC1 in postmenopausal women and in patients with premature ovarian failure (POF) and polycystic ovary syndrome (PCOS) when compared to early follicular phase of healthy women. Conclusion: This study suggests that reduced levels of PGRMC1 in peripheral leukocytes are associated with perturbed ovulatory function. Background An important mediator of progesterone's effects is its nuclear progesterone receptor (PGR). However, it has recently become evident that, at least in the uterus, many of the actions initialized by progesterone are mediated by non-genomic progesterone receptors [1], e.g. progesterone receptor membrane component 1 (PGRMC1; [2,3]). PGRMC1 was first described in 1998 [4] as a putative progesterone-binding membrane receptor of approximately 22 kDa [2]. The protein is expressed in a variety of tissues, e.g. liver, kidney, adrenal glands, uterus and leukocytes [2,5,6]. It was recently shown that PGRMC1 is part of a membrane complex that binds progesterone [2,3]. PGRMC1 is believed to be involved in progesterone signaling in the reproductive system and it mediates progesterone's anti-apoptotic effects on granulosa cells [2,5,7,8]. PGRMC1 binds to and positively regulates several members in the microsomal cytochrome P450 family of proteins, which are key players in intracellular sterol metabolism and steroidogenesis [5,6,9,10]. We have recently shown that reduced PGRMC1 levels are associated with premature ovarian failure (POF; [5]). Furthermore, a PGRMC1 missense variant identified in a patient with POF shows perturbed interaction with the P450 member CYP7A1 [5]. Recent studies have characterized the expression of PGRMC1 in uterine and placental tissues of murine origin [8,11]. Nothing is known about the natural variation of PGRMC1's expression throughout * Correspondence: jens.schuster@genpat.uu. se 1 Department of Genetics and Pathology, Uppsala University, 751 85 Uppsala, Sweden Full list of author information is available at the end of the article © 2010 Schuster et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Schuster et al. Reproductive Biology and Endocrinology 2010, 8:58 http://www.rbej. com/content/8/1/58 Page 2 of 6 the human menstrual cycle or about the association of PGRMC1 levels to conditions with reduced fertility. The aim of this study was to determine the natural expression levels of PGRMC1 in an easy accessible tissue throughout the menstrual cycle and to assess PGRMC1 levels in conditions associated with reduced fertility and anovulation. PGRMC1 is ubiquitously expressed and we selected nucleated peripheral blood cells for the analysis.