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Genetics of the Polycystic Ovarian Syndrome

PCOS is a common cause of menstrual dysfunction, affecting 4-7% of women in their reproductive years. Characteristics of PCOS in women of reproductive age include hirsutism, acne, infertility, gonadotropin abnormalities, obesity and insulin resistance. Patients with PCOS may have a unique form of insulin resistance. Lean subjects with PCOS have decreased insulin sensitivity compared to weight-matched normal women. Further, obese subjects with PCOS are more insulin resistant than normal subjects matched for fat-free mass and body mass index (BMI). There is also evidence for a defect in b cell insulin secretion based on the failure of b cells to entrain to an oscillatory glucose stimulus, specifically when there was a family history of type 2 diabetes. Taken together, the data indicate that women with PCOS have insulin resistance unique to their disorder and that obese women with PCOS have evidence for b cell dysfunction, particularly when there is a family history of type 2 diabetes. Women with PCOS are at risk for impaired glucose tolerance, type 2 diabetes and possibly gestational diabetes. Two recent prospective studies examined the prevalence of IGT and type 2 diabetes in PCOS using an oral glucose tolerance test. These studies found abnormal glucose tolerance in up to 45% of patients with PCOS. The rate of IGT was 31-35% and type 2 diabetes was 7.5-10%.

The research relevant to the BADERC relates to the search for the genes in polycystic ovarian disease that account for insulin resistance. In collaboration with the Icelandic Genetics Company, deCODE Inc., we are phenotyping and genotyping a broad number of women with PCOD in Boston and in Reykjavik and doing a genetic search to track which genes in these familial studies in Iceland map to insulin resistance. This study will phenotype and genotype at least 1,200 PCOS probands in Iceland, both familial and sporadic, to isolate the PCOS genes within identified loci. In addition to the probands, we will recruit 1,000 female unaffected first degree relatives (2 for each proband in extended families) to increase the certainty of the haplotypes and for later phenotyping studies. We will also recruit 500 male first degree relatives (one for each proband in the extended families) for later phenotyping studies. For the US population, we anticipate recruiting 700 PCOS subjects and 1,000 unaffected family members (mainly sisters), i.e. 1,700 total, all of whom will undergo identical phenotyping studies. We will also make a vigorous attempt to recruit fathers and brothers wherever possible. The phenotyping of patients involves : 1) Height, weight, BMI and waist to hip ratio, 2) Blood pressure, 3) Fasting blood glucose, 4) fasting insulin, 5) G/I ratio and HOMA, 6) HbA1C, 7) total and fractionated cholesterol and triglycerides. In addition, a careful physical exam to identify signs of hyperandrogenism, gonadotropins, sex steroids and an ultrasound will be performed for additional comparison to the markers of insulin resistance and diabetes. These phenotypes will then, in turn, be mapped onto families in Iceland, and various loci and at risk haplotypes and hopefully genes will be discovered that relate to the varied phenotypic features of polycystic ovarian disease, especially insulin resistance. Since a significant number of women with polycystic ovarian disease do not have insulin resistance, the at risk haplotypes can be compared between those that do and do not have insulin resistance (and potential protected genes) will also be elucidated. . The same loci, haplotypes, and/or genes will then be examined for association in a U.S population. All of these studies are funded by the National Institutes of Health UO1 grant (The Genetics of Polycystic Ovarian Syndrome) 5UO1HD44417-03.

References

1. Welt CK, Schneyer AL, Heist K, Mantzoros CS. Leptin and soluble leptin receptor in follicular fluid. J Assist Reprod Genet. 2003;20:495-501.

2. Welt CK, Pagan YL, Smith PC, Rado KB, Hall JE. Control of follicle-stimulating hormone by estradiol and the inhibins: critical role of estradiol at the hypothalamus during the luteal-follicular transition. J Clin Endocrinol Metab. 2003;88:1766-71.

3. Seminara SB, Messager S, Chatzidaki EE, Thresher RR, Acierno JS Jr, Shagoury JK, Bo-Abbas Y, Kuohung W, Schwinof KM, Hendrick AG, Zahn D, Dixon J, Kaiser UB, Slaugenhaupt SA, Gusella JF, O'Rahilly S, Carlton MB, Crowley WF Jr, Aparicio SA, Colledge WH. The GPR54 gene as a regulator of puberty. N Engl J Med. 2003;349:1614-27.

4. Taylor AE, Stubbs C, Singer DE, Curhan G, Crowley WF Jr. An instrument for determining the amount of NIH support for clinical investigations at one academic health center. Acad Med. 2002;77:824-30.

5. Welt CK, Taylor AE, Martin KA, Hall JE. Serum inhibin B in polycystic ovary syndrome: regulation by insulin and luteinizing hormone. J Clin Endocrinol Metab. 2002;87:5559-65.

6. Welt CK. The physiology and pathophysiology of inhibin, activin and follistatin in female reproduction. Curr Opin Obstet Gynecol. 2002;14:317-23.

7. Welt CK, Smith ZA, Pauler DK, Hall JE. Differential regulation of inhibin A and inhibin B by luteinizing hormone, follicle-stimulating hormone, and stage of follicle development. J Clin Endocrinol Metab. 2001;86:2531-7.

8. Seminara SB, Crowley WF Jr. Genetic approaches to unraveling reproductive disorders: examples of bedside to bench research in the genomic era. Endocr Rev. 2002;23:382-92.


	William Crowley, M.D./ Corrine Welt, M.D Genetics of the Polycystic Ovarian Syndrome PCOS is a common cause of menstrual dysfunction, affecting 4-7% of women in their reproductive years. Characteristics of PCOS in women of reproductive age include hirsutism, acne, infertility, gonadotropin abnormalities, obesity and insulin resistance. Patients with PCOS may have a unique form of insulin resistance. Lean subjects with PCOS have decreased insulin sensitivity compared to weight-matched normal women. Further, obese subjects with PCOS are more insulin resistant than normal subjects matched for fat-free mass and body mass index (BMI). There is also evidence for a defect in b cell insulin secretion based on the failure of b cells to entrain to an oscillatory glucose stimulus, specifically when there was a family history of type 2 diabetes. Taken together, the data indicate that women with PCOS have insulin resistance unique to their disorder and that obese women with PCOS have evidence for b cell dysfunction, particularly when there is a family history of type 2 diabetes. Women with PCOS are at risk for impaired glucose tolerance, type 2 diabetes and possibly gestational diabetes. Two recent prospective studies examined the prevalence of IGT and type 2 diabetes in PCOS using an oral glucose tolerance test. These studies found abnormal glucose tolerance in up to 45% of patients with PCOS. The rate of IGT was 31-35% and type 2 diabetes was 7.5-10%. The research relevant to the BADERC relates to the search for the genes in polycystic ovarian disease that account for insulin resistance. In collaboration with the Icelandic Genetics Company, deCODE Inc., we are phenotyping and genotyping a broad number of women with PCOD in Boston and in Reykjavik and doing a genetic search to track which genes in these familial studies in Iceland map to insulin resistance. This study will phenotype and genotype at least 1,200 PCOS probands in Iceland, both familial and sporadic, to isolate the PCOS genes within identified loci. In addition to the probands, we will recruit 1,000 female unaffected first degree relatives (2 for each proband in extended families) to increase the certainty of the haplotypes and for later phenotyping studies. We will also recruit 500 male first degree relatives (one for each proband in the extended families) for later phenotyping studies. For the US population, we anticipate recruiting 700 PCOS subjects and 1,000 unaffected family members (mainly sisters), i.e. 1,700 total, all of whom will undergo identical phenotyping studies. We will also make a vigorous attempt to recruit fathers and brothers wherever possible. The phenotyping of patients involves : 1) Height, weight, BMI and waist to hip ratio, 2) Blood pressure, 3) Fasting blood glucose, 4) fasting insulin, 5) G/I ratio and HOMA, 6) HbA1C, 7) total and fractionated cholesterol and triglycerides. In addition, a careful physical exam to identify signs of hyperandrogenism, gonadotropins, sex steroids and an ultrasound will be performed for additional comparison to the markers of insulin resistance and diabetes. These phenotypes will then, in turn, be mapped onto families in Iceland, and various loci and at risk haplotypes and hopefully genes will be discovered that relate to the varied phenotypic features of polycystic ovarian disease, especially insulin resistance. Since a significant number of women with polycystic ovarian disease do not have insulin resistance, the at risk haplotypes can be compared between those that do and do not have insulin resistance (and potential protected genes) will also be elucidated. . The same loci, haplotypes, and/or genes will then be examined for association in a U.S population. All of these studies are funded by the National Institutes of Health UO1 grant (The Genetics of Polycystic Ovarian Syndrome) 5UO1HD44417-03. References 1. Welt CK, Schneyer AL, Heist K, Mantzoros CS. Leptin and soluble leptin receptor in follicular fluid. J Assist Reprod Genet. 2003;20:495-501. 2. Welt CK, Pagan YL, Smith PC, Rado KB, Hall JE. Control of follicle-stimulating hormone by estradiol and the inhibins: critical role of estradiol at the hypothalamus during the luteal-follicular transition. J Clin Endocrinol Metab. 2003;88:1766-71. 3. Seminara SB, Messager S, Chatzidaki EE, Thresher RR, Acierno JS Jr, Shagoury JK, Bo-Abbas Y, Kuohung W, Schwinof KM, Hendrick AG, Zahn D, Dixon J, Kaiser UB, Slaugenhaupt SA, Gusella JF, O'Rahilly S, Carlton MB, Crowley WF Jr, Aparicio SA, Colledge WH. The GPR54 gene as a regulator of puberty. N Engl J Med. 2003;349:1614-27. 4. Taylor AE, Stubbs C, Singer DE, Curhan G, Crowley WF Jr. An instrument for determining the amount of NIH support for clinical investigations at one academic health center. Acad Med. 2002;77:824-30. 5. Welt CK, Taylor AE, Martin KA, Hall JE. Serum inhibin B in polycystic ovary syndrome: regulation by insulin and luteinizing hormone. J Clin Endocrinol Metab. 2002;87:5559-65. 6. Welt CK. The physiology and pathophysiology of inhibin, activin and follistatin in female reproduction. Curr Opin Obstet Gynecol. 2002;14:317-23. 7. Welt CK, Smith ZA, Pauler DK, Hall JE. Differential regulation of inhibin A and inhibin B by luteinizing hormone, follicle-stimulating hormone, and stage of follicle development. J Clin Endocrinol Metab. 2001;86:2531-7. 8. Seminara SB, Crowley WF Jr. Genetic approaches to unraveling reproductive disorders: examples of bedside to bench research in the genomic era. Endocr Rev. 2002;23:382-92.