Searchable abstracts of presentations at key conferences in endocrinology
Endocrine Abstracts (2015) 37 S19.1 | DOI: 10.1530/endoabs.37.S19.1

ECE2015 Symposia Metabolic dysfunction in PCOS (3 abstracts)

Genetic determinants of metabolic dysfunction in PCOS

Jerome Strauss 1 & Jan McAllister 2


1Virginia Commonwealth University, Richmond, Virginia, USA; 2Pennsylvania State Hershey College of Medicine, Hershey, Pennsylvania, USA.


PCOS is a common disorder that is reported to affect 5–7% of women of reproductive age. Although there has been debate about the diagnostic criteria for PCOS, hyperandrogenemia/hyperandrogenism, not explained by other causes, is a hallmark of the disorder, and it is included as an essential element in all ‘consensus’ diagnostic schemes. Studies on cultures of human theca cells derived from normal and PCOS women have demonstrated that PCOS theca secretes greater amounts of androgen than theca tissue or cells from regularly ovulating women. Increased CYP17A1 (P450 17α-hydroxylase/17,20-lyase) gene expression in PCOS theca cells is associated with excess androgen production. Our previous molecular characterization of PCOS theca cells and normal theca cells from multiple individuals by microarray analysis and quantitative PCR established that normal and PCOS theca cells have distinctive molecular signatures, suggesting intrinsic (genetic) differences. A major milestone was achieved with the publication of a genome-wide association studies (GWAS) on Han Chinese, which identified eleven loci, including DENND1A, a finding that was subsequently validated in European populations. DENND1A is a clathrin binding protein found in coated pits, and which positions it to modulate cell surface receptor signal transduction. Using cultured human theca cells, we have shown that an isoform of DENND1A, V2, is over-expressed in PCOS theca cells compared to theca cells derived from ovaries of normally cycling women. V2 overexpression in PCOS may be the result of alternative splicing. Forced expression of V2 increases androgen production, and CYP17A1 mRNA in normal theca cells, whereas knock-down of V2 expression reduces androgen secretion and CYP17A1 mRNA in PCOS theca cells. Both humanized monoclonal antibodies against V2, and their Fab fragments, also reduce androgen production and CYP17A1 mRNA when added to cultured PCOS theca cells. DENND1A V2 can be placed into a network of genes identified in the Chinese GWAS that can explain the hyperandrogenemia phenotype of PCOS.

Disclosure: NIH grants U54HD034449, R01HD058300, and R01HD033852.

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