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Article: Jean-Patrice Baillargeon and John E. Nestler POLYCYSTIC OVARY SYNDROME: A SYNDROME OF OVARIAN HYPERSENSITIVITY TO INSULIN? J Clin Endocrinol Metab 2005; 0: jc.2005-1804v1 [Abstract]

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Letter to the Editor

L. Lester Gabrilove   (17 February 2006)

Letter to the Editor 17 February 2006
L. Lester Gabrilove, Professor of Medicine Emeritus Division of Endocrinology Diabetes and Bone Diseases, Mount Sinai School of Medicine, New York, NY Send letter to journal: Re: Letter to the Editor lgabrilove{at}mssm.edu L. Lester Gabrilove	I read with great interest the article by Baillargeon and Nester (1) and would like to suggest a different mechanism for the pathogenesis of PCO; to wit, an abnormality in the testosterone/estradiol ratio. In 2002, I marshaled the evidence for a defect in aromatase as being the underlying basis for the polycystic ovary syndrome (2). However, the reports of Franks et al. (3) and that of Urbanek et al. (4) failed to find an association linkage of aromatase with polycystic ovary syndrome. In addition, Sonderlund et al. (5) reported “No evidence of mutation in the P450 aromatase gene in patients with the polycystic ovary syndrome.” However these latter authors concluded “the findings do not preclude the possible importance of an aromatase disorder in the etiology of this syndrome”. Indeed, Petry et al. (6) suggest that common variation with the aromatase gene (and not rare loss of function mutation ) is associated with the androgen excess in girls and young woman utilizing a haplotype tag single nucleotide polymorphism genotyping approach. Other support for the concept of an aromatase defect mechanism is afforded by: The induction of polycystic ovaries in aromatase knockout mice (7). Rats treated with an aromatase inhibitor (Letrozole) develop a picture resembling polycystic ovaries (8). Estrogen receptor knockout mice exhibit polycystic ovaries (9). The presence of polycystic ovaries in patients with congenital absence of aromatase (10). Further, physiologic studies in women with polycystic ovaries reveal a higher T/E ratio as compared to normal controls with testosterone being elevated and estradiol being decreased in patients with polycystic ovary syndrome (11, 12). I would suggest that the basic defect in PCO is an abnormality in the androgen/estrogen ratio (due to a congenital abnormality in aromatase). This is somewhat analogous to the obverse alteration in the testosterone/estradiol ratio seen in gynecomastia (13, 14). This concept readily explains the beneficial effects of weight reduction, of metformin, etc. These modalities act to reduce insulin resistance and thereby reduce the effect of insulin on stimulating androgen production which is inefficiently converted to estrogen. It also explains the beneficial effects of flutamide and of agents which reduce or block androgen or increase estrogen. References 1. Bellargeon JP, Nestler JE. 2006. Polycystic ovary syndrome: a syndrome of ovarian hypersensitivity to insulin. J Clin Endocrinol Metab 91:22-24 2. Gabrilove JL. 2002. The pathogenesis of the polycystic ovary syndrome: a hypothesis. Endocrine Pract 8:127-132 3. Franks S, Gharani N, McCarthy M. 2001. Candidate genes in polycystic ovary syndrome. Hum Reprod Update 7:405-410 4. Urbanek M, Legro RS, Driscoll DA, Azziz R, Ehrmann DA, Norman RJ, Strauss JF, Spielman RS, Dunaif A. 1999. Thirty-seven candidate genes of polycystic ovary syndrome: strongest evidence for linkage is with folistatin. Proc Natl Acad Sci USA 96:8575-8578 5. Soderlund D, Canto P, Carranza-Lira S, Mendes JP. 2005. No evidence of mutations in the P450 aromatase gene in patients with polycystic ovary syndrome. Hum Reprod 20:965-969 6. Petry CJ, Ong KK, Michelmore KF, Artigas S, Wingate DL, Balen AH, de Zehgen F, Ibanez L. Dunger DB. 2005. Association of aromatase (CYP 19) gene variation with features of hyperandrogenism in two populations of young women. Hum Reprod 20:1837-1843 7. Fisher CR, Graves KH, Parlow AF, Simpson ER. 1998. Characterization of mice deficient in aromatase (ArKO) because of targeted disruption in the cyp19 gene. Proc Natl Acad Sci USA 95:6965-6970 8. Kafali H, Iriadam M, Orzardali I, Demir N. 2004. Letrazole induced polycystic ovaries in the rat: a new model of cystic ovarian disease. Arch Med Res 35:103-108 9. Emmen JMA, Korach KS. 2000. Estrogen receptor knockout mice: phenotypes in the female reproductive tract. Gyneocol Endocrinol 17:169-176 10. Belgorsky A, Pepe C, Marino R, Guercio G, Saroco N, Vaiani E, Rivarola MA. 2003. Hypothalamic-pituitary-ovarian axis during infancy, early and late puberty in an aromatase deficient girl who is a compound heteroygote for the two new point mutations of the CYP 19 gene. J Clin Endocrinol Metab 88:5127-5131 11. Vander Westhuixen S, Van Der Spuy ZM. 2003. Ovarian morphology as a predictor of hormonal values in polycystic ovary syndrome. Ultrasound Obstet Gynecol 7:335-340 12. Loverro G, Vicino M, Lorusso F, Vimercati A, Greco P, Selvaggi L. 2002. Polycystic ovary syndrome: relationship between insulin sensitivity, sex hormone levels and ovarian stromal blood flow. Gynecol Endocrinol 13:142-149 13. Gabrilove JL. 1974. Some recent advances in virilizing and feminizing syndromes and hirsutism. Mount Sinai J Med 41:636 14. Wilson JD Aiman J, MacDonald PC. 1980. The pathogenesis of gynecomastia. Advan Int Med 25:1-32