Cholesterol Metabolism Pathways are Downregulated in Granulosa-Lutein Cells from PCOS Patients

Polycystic ovary syndrome (PCOS) is a common endocrinopathy that is associated with menstrual irregularities and anovulatory infertility. Although its aetiology and pathophysiology remain unclear, granulosa cell dysfunction is a notable feature of the syndrome. In this study, we used RNA-Sequencing and pathway analysis to identify genes in granulosa cells that may be implicated in the pathogenesis of PCOS. Granulosa-lutein (GL) cells were retrieved from women undergoing IVF with normal ovaries and regular cycles (n=12) and women with polycystic ovaries and irregular cycles (n=12). RNA was extracted and processed for RNA-Sequencing. QPCR was used to validate changes in gene expression. RNA-Sequencing identified a distinct transcriptional profile in GL cells from PCOS patients with 450 genes differentially expressed (p<0.05, after controlling for multiple comparisons). Pathway and network analyses highlighted a group of genes involved in cholesterol biosynthesis and metabolism that are highly enriched (19-fold increase, p<1.60E-16) in women with PCOS. In total, a group of 21 cholesterol metabolism genes were significantly changed, and interestingly all showed reduced expression. These include Hydroxy-3-methylglutaryl CoA synthases 1 and 2 (HMGCS1, 8-fold, P<0.007, and HMGCS2, 2.5-fold, P<5.39E-05) as well as the associated HMGCR (2-fold, P<0.0001), a reductase acting as a rate-limiting enzyme in cholesterol biosynthesis. Granulosa cells play a major role in ovarian steroid synthesis including estrogen and progesterone. The significance of reduced expression of genes involved in cholesterol metabolism remains to be determined but these results lend further support to the notion of aberrant metabolic and endocrine function in steroidogenic cells of women with PCOS.