Polymorphisms in PPARG implicated in previous studies of metabolic traits do not appear to influence component phenotypes of PCOS, but do affect androgens and insulin resistance in the general population.Objective-To investigate the relationship of the PPARG Pro12Ala and silent exon 6 (His447His) polymorphisms with the clinical features of polycystic ovary syndrome (PCOS).Design-PCOS and control subjects were genotyped for Pro12Ala and His447His; associations between genotype, diagnosis, and hormonal/metabolic parameters were assessed.Setting-Subjects were recruited from the reproductive endocrinology clinic at the University of Alabama at Birmingham; control subjects were recruited from the surrounding community. Genotyping was performed at Cedars-Sinai Medical Center in Los Angeles.Reprint Request: Mark O. Goodarzi, M.D., Ph.D., Cedars-Sinai Medical Center, Division of Endocrinology, Diabetes and Metabolism, 8700 Beverly Blvd., Los Angeles, CA 90048, email: mark.goodarzi@cshs.org Presented in part at the 87 th Annual Meeting of the Endocrine Society, San Diego, June 4-7, 2005 Supported by:This study was supported in part by the Helping Hand of Los Angeles, and by grants R01-HD29364 and K24-HD01346 from the National Institutes of Health (to RA). Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. Result(s)-Pro12Ala and His447His did not influence risk of PCOS or its component phenotypes in PCOS patients. In controls, Pro12Ala did not influence measures of insulin resistance or androgen production; however, carriers of the His447His T allele had significantly decreased free and total testosterone levels and HOMA-IR. Furthermore, haplotypes in controls bearing the His447His T allele were also associated with decreased testosterone. Conflict of Interest NIH Public AccessConclusion(s)-does not appear to be an important modifier gene in PCOS. In controls, however, the His447His T allele may be in linkage disequilibrium with a functional variant that influences insulin resistance and testosterone production. Keywordsperoxisome proliferator activated receptor gamma; polycystic ovary syndrome; single nucleotide polymorphism; testosterone; insulin resistance Polycystic ovary syndrome (PCOS) is a common disorder affecting 6-8% of reproductive aged women (1) and clinically manifests as menstrual irregularities, hyperandrogenism, polycystic ovaries, and often obesity. Several studies demonstrate substantial familial aggregation of PCOS with most showing significantly higher rates of PCOS among first-degree relatives when compared to the general population (2,3). Fifty to s...

The 5α-reductase enzyme converts testosterone to dihydrotestosterone, the most potent androgen in certain tissues such as the hair follicle. Increased activity of this enzyme has been seen in the ovaries of patients with polycystic ovary syndrome (PCOS), the most common endocrinopathy in reproductive-aged women. Increased activity of this enzyme may have important clinical implications in PCOS. For example, 5α-reduced androstenedione inhibits aromatase in the ovaries, reducing estrogen production, a possible cause of follicular arrest and thus polycystic ovaries. Our hypothesis is that genetic variation in the gene for 5α-reductase type 1 (SRD5A1) influences the development of PCOS and the severity of hirsutism. We studied 287 white women with PCOS and 187 controls. PCOS was diagnosed using the 1990 NIH criteria. Hirsutism was quantified using the Ferriman-Gallwey (FG) score, with a score of 6 or greater indicating presence of hirsutism. Seven single nucleotide polymorphisms (SNPs) in SRD5A1 were chosen from the International HapMap project such that they would allow efficient identification of the common SRD5A1 haplotypes (a haplotype is a collection of alleles inherited together on the same chromosome). Genotyping was performed using the 5′-exonuclease reaction. Haplotypes and haplotype blocks were constructed using the program Haploview. Association of haplotypes with PCOS risk and presence of hirsutism was assessed using logistic regression and association with FG score using ANCOVA. SNP rs3797179 (C/C versus C/T+TT) was associated with reduced risk of PCOS (OR 0.4, p = .005). We discovered two haplotype blocks in the SRD5A1 gene, block 1 comprising the first five SNPs, block 2 the last two SNPs. Haplotype T-A (block 2) was associated with a 2.5-fold increased risk of PCOS (p = .004), increased risk of hirsutism (OR 2.6, p = .015), and increased FG score (9.3 vs.8.0, p = .013). Haplotype G-G (block 2) was associated with decreased severity of hirsutism with lower FG score (7.8 vs 9.6, p = .018). Haplotype C-G-G-T-T (block 1) was associated with the presence of hirsutism (OR 2.9, p = .009). In conclusion, variation in the SRD5A1 gene not only influences the risk of developing PCOS but also affects the severity of hirsutism in affected women. This is the first report to examine SRD5A1 as a candidate gene in PCOS. Identification of such underlying genes will lead to an increased understanding of the pathophysiology of this common condition, ultimately contributing to advances in risk prediction, disease prevention, and treatment.