Introduction: Polycystic ovary syndrome (PCOS) is a common endocrine disorder, affecting 510% of women of reproductive age, and is the major cause of anovulatory infertility and hyperandrogenism. Aberrant secretion and or action of gonadotropins are implicated but, to date, we have only limited knowledge about the precise mechanisms that are involved. Recent genome wide association studies have discovered significant signals have emerged at loci close to the genes on chromosome 2 coding for the gonadotropin receptors. The functional significance of these polymorphisms is, as yet, far from clear and this represents a key area for further research.
Methods: In this study granulosa-lutein (GL) cells were obtained from women with and without PCOS undergoing IVF. RNA was extracted and quantitative real-time PCR was performed to analyse differential gene expression. Cyclic AMP production was measured after administration of luteinising hormone (LH) and follicle stimulating hormone (FSH) to cultured cells using a second messenger accumulation assay. Intracellular calcium signalling was measured in cultured cells after administering LH using calcium fluorescent indicators.
Results: Increased expression of full-length FSH (P=0.02) but not LH receptor RNA was seen in PCOS, along with increased expression of signaling and trafficking molecules including β arrestin 2 (P=0.03), PDZ protein GIPC (P=0.07) and adaptor protein containing PH domain, PTB domain and leucine zipper 1 (APPL1) (P=0.005). No significant differences were seen in expression of LH receptor splice variants. Cyclic AMP level measured after administration of LH for 5 min was higher in cells from women with PCOS than from control women (×fourfold increase). Cyclic AMP measured after administration of FSH for 5 min however was negligible in both groups, suggesting involvement of an alternative to the traditional Gs signaling pathway. Administration of LH activated a calcium signaling response in granulosa cells.
Conclusion: These provisional results reveal multiple molecular alterations of LH receptor action and downstream signaling in PCOS.
11 Jul 2016 - 11 Jul 2016