Androgen excess is the key element in polycystic ovary syndrome
2003; Elsevier BV; Volume: 80; Issue: 2 Linguagem: Inglês
10.1016/s0015-0282(03)00735-0
ISSN1556-5653
Autores Tópico(s)Ovarian cancer diagnosis and treatment
ResumoIn 1935, Stein and Leventhal first described the association between amenorrhea and polycystic ovaries, which we now know as polycystic ovary syndrome (PCOS). In fact, PCOS appears to be one of the more common endocrine disorders, affecting approximately 4% of reproductive-aged women (1Knochenhauer E.S. Key T.J. Kahsar-Miller M. Waggoner W. Boots L.R. Azziz R. Prevalence of the polycystic ovarian syndrome in unselected black and white women of the Southeastern United States a prospective study.J Clin Endocrinol Metab. 1998; 83: 3078-3082Crossref PubMed Scopus (1496) Google Scholar). This disorder is also associated with an increased risk of insulin resistance and hyperinsulinemia, type II diabetes mellitus, dyslipidemia, endometrial carcinoma, and psychosocial dysfunction.Although there is no widespread agreement on the definition of PCOS, useful criteria arose from a conference sponsored by the National Institute of Child Health and Human Development in April 1990 (2Zawadzki J.K. Dunaif A. Diagnostic criteria for polycystic ovary syndrome towards a rational approach.in: Dunaif A. Givens J.R. Haseltine F. Merriam G.R. Polycystic ovary syndrome. Blackwell Scientific Publications, Boston1992: 377-384Google Scholar). An informal survey of conference participants indicated that for most women, the major criteria for PCOS "included (in order of importance): (i) hyperandrogenism and/or hyperandrogenemia, (ii) oligo-ovulation, [and] (iii) exclusion of other known disorders, such as Cushing's syndrome, hyperprolactinemia, or congenital [non-classic] adrenal hyperplasia." The presence of "polycystic ovaries on ultrasound" was also noted as a possible inclusion criterion, although this was felt to be particularly controversial. In general, PCOS can be viewed as a heterogeneous disorder in which ovarian, and possibly adrenal, androgen excess is present, along with varying degrees of gonadotropic and metabolic abnormalities. We should, however, note that PCOS is a diagnosis of exclusion in which other causes of oligo-ovulation or hyperandrogenism are ruled out by the examining clinician.Insulin Resistance in the General Population and in PCOSUsing either clamp studies (3Dunaif A. Segal K.R. Futterweit W. Dobrjansky A. Profound peripheral insulin resistance, independent of obesity, in polycystic ovary syndrome.Diabetes. 1989; 38: 1165-1174Crossref PubMed Google Scholar) or frequently sampled IV glucose tolerance tests (4Legro R.S. Finegood D. Dunaif A. A fasting glucose to insulin ratio is a useful measure of insulin sensitivity in women with polycystic ovary syndrome.J Clin Endocrinol Metab. 1998; 83: 2694-2698Crossref PubMed Scopus (671) Google Scholar), investigators have observed that insulin resistance affects only between 25% and 60% of subjects studied, depending on body weight. We also should note that insulin resistance is a highly prevalent abnormality in the population, affecting 10%–25% of individuals, depending on the definition and mean population body weight (5Bonora E. Kiechl S. Willeit J. Oberhollenzer F. Egger G. Targher G. et al.Prevalence of insulin resistance in metabolic disorders. The Bruneck Study.Diabetes. 1998; 47: 1643-1649Crossref PubMed Scopus (735) Google Scholar, 6Ferrannini E. Natali A. Bell P. Cavallo-Perin P. Lalic N. Mingrone G. European Group for the Study of Insulin Resistance (EGIR)Insulin resistance and hypersecretion in obesity.J Clin Invest. 1997; 100: 1166-1173Crossref PubMed Scopus (756) Google Scholar). Overall, the prevalence of insulin resistance is roughly two- to five-fold higher than that of PCOS. Hence, many women may present with insulin resistance but without PCOS.The "resistance" to the action of insulin in PCOS generally refers to the impaired action of this hormone on glucose transport and antilipolysis in adipocytes in the presence of normal insulin binding (7Ciaraldi T.M. El-Roeiy A. Madar Z. Reichart D. Olefsky J.M. Yen S.C.C. Cellular mechanisms of insulin resistance in polycystic ovarian syndrome.J Clin Endocrinol Metab. 1992; 75: 577-583Crossref PubMed Scopus (239) Google Scholar, 8Dunaif A. Xia J. Book C.-B. Schenker E. Tang Z. Excessive insulin receptor phosphorylation in cultured fibroblasts and in skeletal muscle a potential mechanism for insulin resistance in the polycystic ovary syndrome.J Clin Invest. 1995; 96: 801-810Crossref PubMed Scopus (472) Google Scholar, 9Marsden P.J. Murdoch A. Taylor R. Severe impairment of insulin action in adipocytes from amenorrheic subjects with polycystic ovary syndrome.Metab Clin Exp. 1994; 43: 1536-1542Abstract Full Text PDF PubMed Scopus (64) Google Scholar, 10Ciaraldi T.P. Morales A.J. Hickman M.G. Odom-Ford R. Olefsky J.M. Yen S.S. Cellular insulin resistance in adipocytes from obese polycystic ovary syndrome subjects involves adenosine modulation of insulin sensitivity.J Clin Endocrinol Metab. 1997; 82: 1421-1425Crossref PubMed Scopus (89) Google Scholar). In turn, insulin resistance in PCOS leads to compensatory hyperinsulinemia with the excess insulin causing an exaggerated effect in other, less traditionally responsive, tissues. Of particular importance, elevated insulin levels appear to directly enhance LH-stimulated androgen secretion from the ovary (11Barbieri R.L. Makris A. Randall R.W. Daniels G. Kistner R.W. Ryan K.J. Insulin stimulates androgen accumulation in incubations of ovarian stroma obtained from women with hyperandrogenism.J Clin Endocrinol Metab. 1986; 62: 904-910Crossref PubMed Scopus (576) Google Scholar, 12Nestler J.E. Jakubowicz D.J. de Vargas A.F. Brik C. Quintero N. Medina F. 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.J Clin Endocrinol Metab. 1998; 83: 2001-2005Crossref PubMed Scopus (536) Google Scholar). Elevated levels of insulin in the portal circulation also serve to decrease circulating SHBG levels, thus resulting in higher levels of free androgens (13Nestler J.E. Powers L.P. Matt D.W. Steingold K.A. Plymate S.R. Rittmaster R.S. et al.A direct effect of hyperinsulinemia on serum sex hormone-binding globulin levels in obese women with the polycystic ovary syndrome.J Clin Endocrinol Metab. 1991; 72: 83-89Crossref PubMed Scopus (673) Google Scholar). That insulin resistance and its secondary hyperinsulinemia contribute to the androgen excess of PCOS in many patients is supported by the facts that androgen levels are positively correlated with hyperinsulinemia (14Burghen G.A. Givens J.R. Kitabchi A.E. Correlation of hyperandrogenism with hyperinsulinism in polycystic ovarian disease.J Clin Endocrinol Metab. 1980; 50: 113-116Crossref PubMed Scopus (803) Google Scholar, 15Chang R.J. Nakamura R.M. Judd H.L. Kaplan S.A. Insulin resistance in nonobese patients with polycystic ovarian disease.J Clin Endocrinol Metab. 1983; 57: 356-359Crossref PubMed Scopus (652) Google Scholar, 16Shoupe D. Kumar D.D. Lobo R.A. Insulin resistance in polycystic ovary syndrome.Am J Obstet Gynecol. 1983; 147: 588-592Abstract Full Text PDF PubMed Scopus (166) Google Scholar, 17dos Reis R.M. Foss M.C. de Moura M.D. Ferriani R.A. Silva de Sa M.F. Insulin secretion in obese and non-obese women with polycystic ovary syndrome and its relationship with hyperandrogenism.Gynecol Endocrinol. 1995; 9: 45-50Crossref PubMed Scopus (30) Google Scholar) and that the administration of insulin-reducing or sensitizing agents improves androgenic features in many patients (18Velazquez E.M. Mendoza S. Hamer T. Sosa F. Glueck C.J. Metformin therapy in polycystic ovary syndrome reduced hyperinsulinemia, insulin resistance, hyperandrogenemia, and systolic blood pressure, while facilitating normal menses and pregnancy.Metabolism. 1994; 43: 647-654Abstract Full Text PDF PubMed Scopus (776) Google Scholar, 19Nestler J.E. Barlascini C.O. Matt D.W. Steingold K.A. Plymate S.R. Clore J.N. et al.Suppression of serum insulin by diazoxide reduces serum testosterone levels in obese women with polycystic ovary syndrome.J Clin Endocrinol Metab. 1989; 68: 1027-1032Crossref PubMed Scopus (327) Google Scholar, 20Nestler J.E. Jakubowicz D.J. Reamer P. Gunn R.D. Allan G. Ovulatory and metabolic effects of D-chiro-inositol in the polycystic ovary syndrome.N Engl J Med. 1999; 340: 1314-1320Crossref PubMed Scopus (474) Google Scholar, 21Nestler J.E. Jakubowicz D.J. Evans W.S. Pasquali R. Effects of metformin on spontaneous and clomiphene-induced ovulation in the polycystic ovary syndrome.N Engl J Med. 1998; 338: 1876-1880Crossref PubMed Scopus (717) Google Scholar, 22Azziz R. Ehermann D. Legro R.S. Whitcomb R.W. Hanley R. Fereshettian A.G. et al.Troglitazone improves ovulation and hirsutism in the polycystic ovary syndrome a multicenter, double-blind, placebo-controlled trial.J Clin Endocrinol Metab. 2001; 86: 1626-1632Crossref PubMed Scopus (529) Google Scholar).Androgen Excess in PCOSWhile recent press announcements and research publications have suggested that most patients with PCOS have insulin resistance and secondary hyperinsulinemia, we should note that the universal and pervasive abnormality in PCOS is androgen excess. It is androgen excess, and not insulin resistance, that is directly responsible for the signs and symptoms we have come to recognize as PCOS, including hirsutism, acne, alopecia, and ovulatory dysfunction. In fact, according to the diagnostic criteria generated by the 1990 National Institutes of Health–sponsored conference on the subject, patients with PCOS must have some element of androgen excess, either clinical (as in hirsutism, acne, or androgenic alopecia) or biochemical (i.e., hyperandrogenemia) or both to be considered as suffering from the disorder. It is true that in many patients with PCOS, the excess insulin levels resulting from the insulin resistance may, in part, be responsible for the hyperinsulinemia of these women and may actually directly affect hypothalamic-pituitary function to further impair ovulatory function.The importance of androgens in producing the PCOS phenotype is highlighted by studies in female to male transsexuals, where androgen supplementation alone produces a polycystic ovarian morphology (23Futterweit W. Deligdisch L. Histopathological effects of exogenously administered testosterone in 19 female to male transsexuals.J Clin Endocrinol Metab. 1986; 62: 16-21Crossref PubMed Scopus (146) Google Scholar, 24Pache T.D. Chadha S. Gooren L.J. Hop W.C. Jaarsma K.W. Dommerholt H.B. et al.Ovarian morphology in long-term androgen-treated female to male transsexuals. A human model for the study of polycystic ovarian syndrome?.Histopathology. 1991; 19: 445-452Crossref PubMed Scopus (159) Google Scholar). Hyperandrogenemia is also a common feature among those women with normal ovulatory function but polycystic ovarian morphology, which may represent an occult form of PCOS (25Carmina E. Wong L. Chang L. Paulson R.J. Sauer M.V. Stanczyk F.Z. et al.Endocrine abnormalities in ovulatory women with polycystic ovaries on ultrasound.Hum Reprod. 1997; 12: 905-909Crossref PubMed Scopus (94) Google Scholar, 26Chang P.L. Lindheim S.R. Lowre C. Ferin M. Gonzalez F. Berglund L. et al.Normal ovulatory women with polycystic ovaries have hyperandrogenic pituitary-ovarian responses to gonadotropin-releasing hormone-agonist testing.J Clin Endocrinol Metab. 2000; 85: 995-1000Crossref PubMed Scopus (91) Google Scholar). Androgen levels have also been found to be one of the most predictable markers of inheritance in family studies of patients with PCOS (27Legro R.S. Kunselman A.R. Demers L. Wang S.C. Bentley-Lewis R. Dunaif A. Elevated dehydroepiandrosterone sulfate levels as the reproductive phenotype in the brothers of women with polycystic ovary syndrome.J Clin Endocrinol Metab. 2002; 87: 2134-2138Crossref PubMed Scopus (111) Google Scholar, 28Legro R.S. Driscoll D. Strauss III, J.F. Fox J. Dunaif A. Evidence for a genetic basis for hyperandrogenemia in polycystic ovary syndrome.Proc Natl Acad Sci USA. 1998; 95: 14956-14960Crossref PubMed Scopus (542) Google Scholar). In addition, Escobar-Morreale and colleagues have recently constructed receiver-operating curves for the diagnosis of PCOS in an unselected general population and observed that androgen measures, including free T, DHEAS, and the free androgen index ([total T in nmol/L × 100]/SHBG in nmol/L), were highly effective as single analytical procedures for the detection of PCOS (29Escobar-Morreale H.F. Asuncion M. Calvo R.M. Sancho J. San Millan J.L. Receiver operating characteristic analysis of the performance of basal serum hormone profiles for the diagnosis of polycystic ovary syndrome in epidemiological studies.Eur J Endocrinol. 2001; 145: 619-624Crossref PubMed Scopus (73) Google Scholar).Androgen levels also predict therapeutic response. Fauser and colleagues studied 182 normogonadotropic oligoamenorrheic infertile women to identify what endocrine screening characteristics could potentially predict which women would be resistant to induction of ovulation by clomiphene citrate (30Imani B. Eijkemans M.J. de Jong F.H. Payne N.N. Bouchard P. Giudice L.C. et al.Free androgen index and leptin are the most prominent endocrine predictors of ovarian response during clomiphene citrate induction of ovulation in normogonadotropic oligoamenorrheic infertility.J Clin Endocrinol Metab. 2000; 85: 676-682Crossref PubMed Scopus (105) Google Scholar). The ability of insulin to predict patients who remained anovulatory after clomiphene citrate treatment disappeared when the free androgen index was included in the model, suggesting that markers for insulin sensitivity are associated with abnormal ovarian function through their correlation with androgens. These data indicate that androgen levels are perhaps the most important determinant of clinical symptoms in PCOS.Why Are Androgen Levels "Normal" in Some Patients With PCOS?The fact that androgen excess is directly responsible for many of the symptoms of PCOS does not mean that patients with "normal" androgen levels cannot have this disorder. In fact, about 20% of patients with PCOS diagnosed by the criteria arising from the 1990 National Institutes of Health conference have normal androgen levels (31Knochenhauer E.S. Sanchez L.A. Azziz R. The different phenotypes of the polycystic ovary syndrome (PCOS).Fertil Steril. 2001; 76 ([abstract]): S208Abstract Full Text Full Text PDF Google Scholar). To understand this apparent contradiction we need to review a few peculiarities inherent in the measurement and regulation of androgens in women. First, the measurement of androgens (e.g., T, free T, and androstenedione) in blood is notoriously inexact, not surprising in view of the small size and significant similarity of many of these molecules (for example, T is a steroid that differs from E2 by only one double bound in the A ring and a methyl group on position 18). This requires that the assay used to measure androgens be very exact, almost always requiring serum extraction and chromatography to purify the steroid in question. However, most clinicians use commercial assays, which directly measure the androgen in unextracted serum. Unfortunately, when we recently tested nine different commercial assays for total T we observed significant between-kit variability, which was greatest for serum samples obtained from women (32Boots L.R. Potter S. Potter H.D. Azziz R. Measurement of total serum testosterone levels using commercially available kits high degree of between-kit variability.Fertil Steril. 1998; 69: 286-292Abstract Full Text PDF PubMed Scopus (121) Google Scholar). This study strongly suggested that the measurement of total serum T using commercial kits might have limited utility, particularly for detection of hyperandrogenemia in women. While we did not directly study assays for free T, it should be noted that the level of free T is only about 2% of the total and thus it is very unlikely that commercial kits are going to be better at detecting this even smaller amount of hormone.Second, most normal ranges for hormone levels, including androgens, are generally established by the kit manufacturers and not by the immediate commercial laboratory using the kits. To establish a normal range, the kit manufacturers usually measure the blood levels of the hormone in question using their kit in 50 or so unselected women. No effort is generally made to document whether these women are actually normal. Since the normal ranges are defined as those hormonal values observed in 95%–97.5% of the population, by definition, "excessive levels of hormones" are observed in 5%–2.5% of the normal women studied. Unfortunately, because the incidence of PCOS or hirsutism in the general population of reproductive-age women is about 4% and 7%, respectively, it is very possible that the upper normal limit established by the kit manufacturer may be excessively high if some of these women are inadvertently included in the normal population used to establish the normal range. If this range is later used to determine whether a patient actually has hyperandrogenemia, many patients with abnormal values will be classified as normal.Third, we should note that there is no tight endocrine regulation of androgen levels in women (or men for that matter). For example, as the level of free thyroxin goes up, the production of TSH goes down practically simultaneously, resulting in a lower overall production of total thyroxin by the thyroid and the maintenance of normal circulating levels of the free hormone. Alternatively, as observed in men (33Hayes F.J. DeCruz S. Seminara S.B. Boepple P.A. Crowley Jr, W.F. Differential regulation of gonadotropin secretion by testosterone in the human male absence of a negative feedback effect of testosterone on follicle-stimulating hormone secretion.J Clin Endocrinol Metab. 2001; 86: 53-58Crossref PubMed Scopus (130) Google Scholar), in menopausal women (34Floter A. Carlstrom K. von Schoultz B. Nathorst-Boos J. Administration of testosterone undecanoate in postmenopausal women effects on androgens, estradiol, and gonadotrophins.Menopause. 2000; 7: 251-256Crossref PubMed Scopus (19) Google Scholar), or in patients with PCOS (35Dunaif A. Do androgens directly regulate gonadotropin secretion in the polycystic ovary syndrome?.J Clin Endocrinol Metab. 1986; 63: 215-221Crossref PubMed Scopus (76) Google Scholar), the circulating levels of androgens can increase by 100% or more, without a significant concomitant decrease in the circulating levels of LH and FSH (the pituitary hormones controlling ovarian androgens). This loose association results in a wide range of androgen levels within both women and men and actually may explain the high prevalence of androgen excess in the general population.Androgen Excess Is the Key Element in PCOSAlthough many women with PCOS have insulin resistance and hyperinsulinemia, which may be the underlying factor in their disease process, androgen excess is the immediate culprit that determines these patients' endocrine symptoms, including their degree of irregular ovulation, hirsutism, acne, or alopecia. Androgen suppression continues to be the mainstay of treatment in patients with PCOS not desiring immediate fertility. However, because of the problems inherent in the measurement and interpretation of androgen levels clinically, androgen measurements are principally useful in the evaluation of the nonhirsute oligo-ovulatory woman. This approach will minimize the amount of confusion caused by patients with frank and obvious PCOS, but whose androgen levels are deemed normal, and avoid the classification of many women with obesity (and hyperinsulinemia) as having PCOS. In 1935, Stein and Leventhal first described the association between amenorrhea and polycystic ovaries, which we now know as polycystic ovary syndrome (PCOS). In fact, PCOS appears to be one of the more common endocrine disorders, affecting approximately 4% of reproductive-aged women (1Knochenhauer E.S. Key T.J. Kahsar-Miller M. Waggoner W. Boots L.R. Azziz R. Prevalence of the polycystic ovarian syndrome in unselected black and white women of the Southeastern United States a prospective study.J Clin Endocrinol Metab. 1998; 83: 3078-3082Crossref PubMed Scopus (1496) Google Scholar). This disorder is also associated with an increased risk of insulin resistance and hyperinsulinemia, type II diabetes mellitus, dyslipidemia, endometrial carcinoma, and psychosocial dysfunction. Although there is no widespread agreement on the definition of PCOS, useful criteria arose from a conference sponsored by the National Institute of Child Health and Human Development in April 1990 (2Zawadzki J.K. Dunaif A. Diagnostic criteria for polycystic ovary syndrome towards a rational approach.in: Dunaif A. Givens J.R. Haseltine F. Merriam G.R. Polycystic ovary syndrome. Blackwell Scientific Publications, Boston1992: 377-384Google Scholar). An informal survey of conference participants indicated that for most women, the major criteria for PCOS "included (in order of importance): (i) hyperandrogenism and/or hyperandrogenemia, (ii) oligo-ovulation, [and] (iii) exclusion of other known disorders, such as Cushing's syndrome, hyperprolactinemia, or congenital [non-classic] adrenal hyperplasia." The presence of "polycystic ovaries on ultrasound" was also noted as a possible inclusion criterion, although this was felt to be particularly controversial. In general, PCOS can be viewed as a heterogeneous disorder in which ovarian, and possibly adrenal, androgen excess is present, along with varying degrees of gonadotropic and metabolic abnormalities. We should, however, note that PCOS is a diagnosis of exclusion in which other causes of oligo-ovulation or hyperandrogenism are ruled out by the examining clinician. Insulin Resistance in the General Population and in PCOSUsing either clamp studies (3Dunaif A. Segal K.R. Futterweit W. Dobrjansky A. Profound peripheral insulin resistance, independent of obesity, in polycystic ovary syndrome.Diabetes. 1989; 38: 1165-1174Crossref PubMed Google Scholar) or frequently sampled IV glucose tolerance tests (4Legro R.S. Finegood D. Dunaif A. A fasting glucose to insulin ratio is a useful measure of insulin sensitivity in women with polycystic ovary syndrome.J Clin Endocrinol Metab. 1998; 83: 2694-2698Crossref PubMed Scopus (671) Google Scholar), investigators have observed that insulin resistance affects only between 25% and 60% of subjects studied, depending on body weight. We also should note that insulin resistance is a highly prevalent abnormality in the population, affecting 10%–25% of individuals, depending on the definition and mean population body weight (5Bonora E. Kiechl S. Willeit J. Oberhollenzer F. Egger G. Targher G. et al.Prevalence of insulin resistance in metabolic disorders. The Bruneck Study.Diabetes. 1998; 47: 1643-1649Crossref PubMed Scopus (735) Google Scholar, 6Ferrannini E. Natali A. Bell P. Cavallo-Perin P. Lalic N. Mingrone G. European Group for the Study of Insulin Resistance (EGIR)Insulin resistance and hypersecretion in obesity.J Clin Invest. 1997; 100: 1166-1173Crossref PubMed Scopus (756) Google Scholar). Overall, the prevalence of insulin resistance is roughly two- to five-fold higher than that of PCOS. Hence, many women may present with insulin resistance but without PCOS.The "resistance" to the action of insulin in PCOS generally refers to the impaired action of this hormone on glucose transport and antilipolysis in adipocytes in the presence of normal insulin binding (7Ciaraldi T.M. El-Roeiy A. Madar Z. Reichart D. Olefsky J.M. Yen S.C.C. Cellular mechanisms of insulin resistance in polycystic ovarian syndrome.J Clin Endocrinol Metab. 1992; 75: 577-583Crossref PubMed Scopus (239) Google Scholar, 8Dunaif A. Xia J. Book C.-B. Schenker E. Tang Z. Excessive insulin receptor phosphorylation in cultured fibroblasts and in skeletal muscle a potential mechanism for insulin resistance in the polycystic ovary syndrome.J Clin Invest. 1995; 96: 801-810Crossref PubMed Scopus (472) Google Scholar, 9Marsden P.J. Murdoch A. Taylor R. Severe impairment of insulin action in adipocytes from amenorrheic subjects with polycystic ovary syndrome.Metab Clin Exp. 1994; 43: 1536-1542Abstract Full Text PDF PubMed Scopus (64) Google Scholar, 10Ciaraldi T.P. Morales A.J. Hickman M.G. Odom-Ford R. Olefsky J.M. Yen S.S. Cellular insulin resistance in adipocytes from obese polycystic ovary syndrome subjects involves adenosine modulation of insulin sensitivity.J Clin Endocrinol Metab. 1997; 82: 1421-1425Crossref PubMed Scopus (89) Google Scholar). In turn, insulin resistance in PCOS leads to compensatory hyperinsulinemia with the excess insulin causing an exaggerated effect in other, less traditionally responsive, tissues. Of particular importance, elevated insulin levels appear to directly enhance LH-stimulated androgen secretion from the ovary (11Barbieri R.L. Makris A. Randall R.W. Daniels G. Kistner R.W. Ryan K.J. Insulin stimulates androgen accumulation in incubations of ovarian stroma obtained from women with hyperandrogenism.J Clin Endocrinol Metab. 1986; 62: 904-910Crossref PubMed Scopus (576) Google Scholar, 12Nestler J.E. Jakubowicz D.J. de Vargas A.F. Brik C. Quintero N. Medina F. 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.J Clin Endocrinol Metab. 1998; 83: 2001-2005Crossref PubMed Scopus (536) Google Scholar). Elevated levels of insulin in the portal circulation also serve to decrease circulating SHBG levels, thus resulting in higher levels of free androgens (13Nestler J.E. Powers L.P. Matt D.W. Steingold K.A. Plymate S.R. Rittmaster R.S. et al.A direct effect of hyperinsulinemia on serum sex hormone-binding globulin levels in obese women with the polycystic ovary syndrome.J Clin Endocrinol Metab. 1991; 72: 83-89Crossref PubMed Scopus (673) Google Scholar). That insulin resistance and its secondary hyperinsulinemia contribute to the androgen excess of PCOS in many patients is supported by the facts that androgen levels are positively correlated with hyperinsulinemia (14Burghen G.A. Givens J.R. Kitabchi A.E. Correlation of hyperandrogenism with hyperinsulinism in polycystic ovarian disease.J Clin Endocrinol Metab. 1980; 50: 113-116Crossref PubMed Scopus (803) Google Scholar, 15Chang R.J. Nakamura R.M. Judd H.L. Kaplan S.A. Insulin resistance in nonobese patients with polycystic ovarian disease.J Clin Endocrinol Metab. 1983; 57: 356-359Crossref PubMed Scopus (652) Google Scholar, 16Shoupe D. Kumar D.D. Lobo R.A. Insulin resistance in polycystic ovary syndrome.Am J Obstet Gynecol. 1983; 147: 588-592Abstract Full Text PDF PubMed Scopus (166) Google Scholar, 17dos Reis R.M. Foss M.C. de Moura M.D. Ferriani R.A. Silva de Sa M.F. Insulin secretion in obese and non-obese women with polycystic ovary syndrome and its relationship with hyperandrogenism.Gynecol Endocrinol. 1995; 9: 45-50Crossref PubMed Scopus (30) Google Scholar) and that the administration of insulin-reducing or sensitizing agents improves androgenic features in many patients (18Velazquez E.M. Mendoza S. Hamer T. Sosa F. Glueck C.J. Metformin therapy in polycystic ovary syndrome reduced hyperinsulinemia, insulin resistance, hyperandrogenemia, and systolic blood pressure, while facilitating normal menses and pregnancy.Metabolism. 1994; 43: 647-654Abstract Full Text PDF PubMed Scopus (776) Google Scholar, 19Nestler J.E. Barlascini C.O. Matt D.W. Steingold K.A. Plymate S.R. Clore J.N. et al.Suppression of serum insulin by diazoxide reduces serum testosterone levels in obese women with polycystic ovary syndrome.J Clin Endocrinol Metab. 1989; 68: 1027-1032Crossref PubMed Scopus (327) Google Scholar, 20Nestler J.E. Jakubowicz D.J. Reamer P. Gunn R.D. Allan G. Ovulatory and metabolic effects of D-chiro-inositol in the polycystic ovary syndrome.N Engl J Med. 1999; 340: 1314-1320Crossref PubMed Scopus (474) Google Scholar, 21Nestler J.E. Jakubowicz D.J. Evans W.S. Pasquali R. Effects of metformin on spontaneous and clomiphene-induced ovulation in the polycystic ovary syndrome.N Engl J Med. 1998; 338: 1876-1880Crossref PubMed Scopus (717) Google Scholar, 22Azziz R. Ehermann D. Legro R.S. Whitcomb R.W. Hanley R. Fereshettian A.G. et al.Troglitazone improves ovulation and hirsutism in the polycystic ovary syndrome a multicenter, double-blind, placebo-controlled trial.J Clin Endocrinol Metab. 2001; 86: 1626-1632Crossref PubMed Scopus (529) Google Scholar). Using either clamp studies (3Dunaif A. Segal K.R. Futterweit W. Dobrjansky A. Profound peripheral insulin resistance, independent of obesity, in polycystic ovary syndrome.Diabetes. 1989; 38: 1165-1174Crossref PubMed Google Scholar) or frequently sampled IV glucose tolerance tests (4Legro R.S. Finegood D. Dunaif A. A fasting glucose to insulin ratio is a useful measure of insulin sensitivity in women with polycystic ovary syndrome.J Clin Endocrinol Metab. 1998; 83: 2694-2698Crossref PubMed Scopus (671) Google Scholar), investigators have observed that insulin resistance affects only between 25% and 60% of subjects studied, depending on body weight. We also should note that insulin resistance is a highly prevalent abnormality in the population, affecting 10%–25% of individuals, depending on the definition and mean population body weight (5Bonora E. Kiechl S. Willeit J. Oberhollenzer F. Egger G. Targher G. et al.Prevalence of insulin resistance in metabolic disorders. The Bruneck Study.Diabetes. 1998; 47: 1643-1649Crossref PubMed Scopus (735) Google Scholar, 6Ferrannini E. Natali A. Bell P. Cavallo-Perin P. Lalic N. Mingrone G. European Group for the Study of Insulin Resistance (EGIR)Insulin resistance and hypersecretion in obe
Referência(s)