Identification of a functional polymorphism of the human type 5 17beta-hydroxysteroid dehydrogenase gene associated with polycystic ovary syndrome.

CONTEXT Polycystic ovary syndrome (PCOS) is characterized by chronic hyperandrogenic anovulation and is associated with insulin resistance. Its pathogenesis is believed to be multifactorial, and abnormal gene regulation could be one contributing factor. Type 5 17beta-hydroxysteroid dehydrogenase (17beta-HSD5) appears to be the major testosterone-forming 17beta-HSD isoenzyme in females. OBJECTIVE Our objective was to investigate the role of a potentially activating 17beta-HSD5 gene (HSD17B5) variant in hyperandrogenism. DESIGN AND SETTING We conducted a case study and case-control cohort study in our General Clinical Research Center. STUDY SUBJECTS Subjects included a case of PCOS who had hyperthecosis associated with profound type B insulin resistance and an unusual, frankly male testosterone response to a GnRH agonist test, as well as 121 PCOS patients and 128 population controls. INTERVENTIONS Interventions were diagnostic. MAIN OUTCOME MEASURES Main outcome measures included sequencing of HSD17B5 5'-flanking region and nine exons, genotype/phenotype studies, and in vitro functional studies. RESULTS Our case had a previously undescribed homozygous HSD17B5 variant (G-to-A substitution) -71 bp in the promoter region. Genotyping controls showed this to be a single-nucleotide polymorphism (SNP)-71G. Luciferase activity of a SNP-71G promoter construct was significantly higher than that of the wild type, and EMSAs revealed that SNP-71G possessed significantly increased affinity to nuclear transcription factors. SNP-71G allele frequency (32.2 vs. 22.3%) and SNP-71G allele presence (53.7% vs. 38.3%) were significantly increased in PCOS (P = 0.01) [corrected] SNP-71G homozygosity tended to contribute about 20% to the plasma testosterone level. CONCLUSIONS SNP-71G is a functional polymorphism that may contribute to testosterone excess in a subset of PCOS patients.

[1]  R. Rosenfield,et al.  Characterization of the basal promoter element of the human type 5 17beta-hydroxysteroid dehydrogenase gene. , 2005, Biochimica et biophysica acta.

[2]  M. McCarthy,et al.  Analysis of multiple data sets reveals no association between the insulin gene variable number tandem repeat element and polycystic ovary syndrome or related traits. , 2005, The Journal of clinical endocrinology and metabolism.

[3]  A. Levine,et al.  A Single Nucleotide Polymorphism in the MDM2 Promoter Attenuates the p53 Tumor Suppressor Pathway and Accelerates Tumor Formation in Humans , 2004, Cell.

[4]  P. G. Quinn,et al.  Increased cytochrome P450 17alpha-hydroxylase promoter function in theca cells isolated from patients with polycystic ovary syndrome involves nuclear factor-1. , 2004, Molecular endocrinology.

[5]  P. Claman.  Men at risk: occupation and male infertility. , 2004, Fertility and sterility.

[6]  B. Fauser,et al.  Revised 2003 consensus on diagnostic criteria and long-term health risks related to polycystic ovary syndrome (PCOS). , 2004, Human reproduction.

[7]  S. Hampson,et al.  Using DNA Microarray to Identify Sp1 as a Transcriptional Regulatory Element of Insulin-Like Growth Factor 1 in Cardiac Muscle Cells , 2003, Circulation research.

[8]  F. Collins,et al.  Variation in resistin gene promoter not associated with polycystic ovary syndrome. , 2003, Diabetes.

[9]  S. Samson,et al.  Role of Sp1 in insulin regulation of gene expression. , 2002, Journal of molecular endocrinology.

[10]  R. Legro,et al.  Molecular progress in infertility: polycystic ovary syndrome. , 2002, Fertility and sterility.

[11]  Simeon I. Taylor,et al.  Clinical Course of the Syndrome of Autoantibodies to the Insulin Receptor (Type B Insulin Resistance): A 28-Year Perspective , 2002, Medicine.

[12]  J. Wood,et al.  The biochemical basis for increased testosterone production in theca cells propagated from patients with polycystic ovary syndrome. , 2001, The Journal of clinical endocrinology and metabolism.

[13]  V. Luu‐The.  Analysis and characteristics of multiple types of human 17β-hydroxysteroid dehydrogenase , 2001, The Journal of Steroid Biochemistry and Molecular Biology.

[14]  Y. Tomer,et al.  Evidence for association of polycystic ovary syndrome in caucasian women with a marker at the insulin receptor gene locus. , 2001, The Journal of clinical endocrinology and metabolism.

[15]  M. Urbanek,et al.  Allelic variants of the follistatin gene in polycystic ovary syndrome. , 2000, The Journal of clinical endocrinology and metabolism.

[16]  S. Ng,et al.  Preliminary investigation of follistatin gene mutations in women with polycystic ovary syndrome. , 2000, Molecular human reproduction.

[17]  E. Diamanti-Kandarakis,et al.  Microsatellite polymorphism (tttta)(n) at -528 base pairs of gene CYP11alpha influences hyperandrogenemia in patients with polycystic ovary syndrome. , 2000, Fertility and sterility.

[18]  R. Rosenfield,et al.  Expression of 17β-Hydroxysteroid Dehydrogenase Type 5 in Human Ovary: A Pilot Study , 2000, The Journal of the Society for Gynecologic Investigation: JSGI.

[19]  R. Rosenfield,et al.  Expression of 17β-Hydroxysteroid Dehydrogenase Type 5 in Human Ovary: A Pilot Study: , 2000 .

[20]  M. Urbanek,et al.  Thirty-seven candidate genes for polycystic ovary syndrome: strongest evidence for linkage is with follistatin. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[21]  R. Legro,et al.  Augmented androgen production is a stable steroidogenic phenotype of propagated theca cells from polycystic ovaries. , 1999, Molecular endocrinology.

[22]  D. Russell,et al.  17β-hydroxysteroid dehydrogenase 3 deficiency in women , 1999 .

[23]  P. Soucy,et al.  Characteristics of a Highly Labile Human Type 5 17β-Hydroxysteroid Dehydrogenase1. , 1999, Endocrinology.

[24]  P. Soucy,et al.  Characteristics of a highly labile human type 5 17beta-hydroxysteroid dehydrogenase. , 1999, Endocrinology.

[25]  D. Driscoll,et al.  Evidence for a genetic basis for hyperandrogenemia in polycystic ovary syndrome. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[26]  D. Waterworth,et al.  Genetics of polycystic ovary syndrome , 1998, Molecular and Cellular Endocrinology.

[27]  D. Jakubowicz,et al.  Insulin stimulates testosterone biosynthesis by human thecal cells from women with polycystic ovary syndrome by activating its own receptor and using inositolglycan mediators as the signal transduction system. , 1998, The Journal of clinical endocrinology and metabolism.

[28]  M. McCarthy,et al.  Linkage and association of insulin gene VNTR regulatory polymorphism with polycystic ovary syndrome , 1997, The Lancet.

[29]  D. Ehrmann,et al.  Acute hormonal responses to the gonadotropin releasing hormone agonist leuprolide: dose-response studies and comparison to nafarelin--a clinical research center study. , 1996, The Journal of clinical endocrinology and metabolism.

[30]  K. Cheng,et al.  Substrate Specificity, Gene Structure, and Tissue-specific Distribution of Multiple Human 3α-Hydroxysteroid Dehydrogenases (*) , 1995, The Journal of Biological Chemistry.

[31]  M. Byrne,et al.  Insulin secretory defects in polycystic ovary syndrome. Relationship to insulin sensitivity and family history of non-insulin-dependent diabetes mellitus. , 1995, The Journal of clinical investigation.

[32]  D. Ehrmann,et al.  Polycystic ovary syndrome as a form of functional ovarian hyperandrogenism due to dysregulation of androgen secretion. , 1995, Endocrine reviews.

[33]  R. Sparkes,et al.  Localization of multiple human dihydrodiol dehydrogenase (DDH1 and DDH2) and chlordecone reductase (CHDR) genes in chromosome 10 by the polymerase chain reaction and fluorescence in situ hybridization. , 1995, Genomics.

[34]  D. Ehrmann,et al.  Studies of the nature of 17-hydroxyprogesterone hyperresonsiveness to gonadotropin-releasing hormone agonist challenge in functional ovarian hyperandrogenism. , 1994, The Journal of clinical endocrinology and metabolism.

[35]  S. Andersson,et al.  17 beta-Hydroxysteroid dehydrogenase type 2: chromosomal assignment and progestin regulation of gene expression in human endometrium. , 1994, The Journal of clinical investigation.

[36]  S. Franks,et al.  Hypersecretion of androstenedione by isolated thecal cells from polycystic ovaries. , 1994, The Journal of clinical endocrinology and metabolism.

[37]  J. Little,et al.  Polycystic ovaries and premature male pattern baldness are associated with one allele of the steroid metabolism gene CYP17. , 1994, Human molecular genetics.

[38]  M. New,et al.  Molecular cloning of multiple cDNAs encoding human enzymes structurally related to 3α-hydroxysteroid dehydrogenase , 1993, The Journal of Steroid Biochemistry and Molecular Biology.

[39]  D. Ehrmann,et al.  Detection of functional ovarian hyperandrogenism in women with androgen excess. , 1992, The New England journal of medicine.

[40]  J. Azzarello,et al.  Insulin-like growth factor-I enhances luteinizing hormone binding to rat ovarian theca-interstitial cells. , 1990, The Journal of clinical investigation.

[41]  S. Reeders,et al.  FAMILIAL POLYCYSTIC OVARIES: A GENETIC DISEASE? , 1988, Clinical endocrinology.

[42]  J. Cara,et al.  Insulin-like growth factor I and insulin potentiate luteinizing hormone-induced androgen synthesis by rat ovarian thecal-interstitial cells. , 1988, Endocrinology.

[43]  R. Barbieri,et al.  The role of hyperinsulinemia in the pathogenesis of ovarian hyperandrogenism. , 1988, Fertility and sterility.

[44]  D. Magoffin,et al.  Primary culture of differentiating ovarian androgen-producing cells in defined medium. , 1982, The Journal of biological chemistry.

[45]  D. Ferriman,et al.  THE INHERITANCE OF POLYCYSTIC OVARIAN DISEASE AND A POSSIBLE RELATIONSHIP TO PREMATURE BALDING , 1979, Clinical endocrinology.

[46]  R. Rosenfield,et al.  Plasma testosterone binding globulin and indexes of the concentration of unbound plasma androgens in normal and hirsute subjects. , 1971, The Journal of clinical endocrinology and metabolism.