Diagnostic criteria for polycystic ovary syndrome: A reappraisal
2005; Elsevier BV; Volume: 83; Issue: 5 Linguagem: Inglês
10.1016/j.fertnstert.2005.01.085
ISSN1556-5653
Autores Tópico(s)Ovarian cancer diagnosis and treatment
ResumoNew diagnostic criteria for polycystic ovary syndrome (PCOS) were proposed in Rotterdam in 2003, which expanded the previous definition that arose from an expert conference sponsored by the National Institutes of Health (NIH) in 1990. However, these newer criteria give rise to phenotypes that may not actually represent PCOS, and a simple modification of the 1990 NIH/National Institute of Child Health and Human Disease diagnostic criteria may be more consistent with currently available data. New diagnostic criteria for polycystic ovary syndrome (PCOS) were proposed in Rotterdam in 2003, which expanded the previous definition that arose from an expert conference sponsored by the National Institutes of Health (NIH) in 1990. However, these newer criteria give rise to phenotypes that may not actually represent PCOS, and a simple modification of the 1990 NIH/National Institute of Child Health and Human Disease diagnostic criteria may be more consistent with currently available data. Few disorders have generated as much debate, passion, and confusion in their definition as polycystic ovary (or ovarian) syndrome (PCOS), with the possible exception of insulin resistance and the metabolic syndrome, with which it is mechanistically associated. A critical issue remains the definition of the disorder, which not only has an important impact on the scientific investigation of the syndrome, but also implies significant consequences for individual patients. Diagnosing a woman as having PCOS has life-long implications for her health and well-being and suggests an increased risk for diabetes, dyslipidemia, hypertension, endometrial carcinoma, infertility, and possibly cardiovascular disease, in her, her relatives, and her offspring and has the potential of negatively impacting on her ability to access health care coverage. Consequently, the diagnosis of PCOS should not be assigned lightly, and diagnostic criteria should be based on sound data. Two principal definitions of PCOS are in widespread use today. The first arose from the proceedings of an expert conference sponsored in part by the National Institute of Child Health and Human Disease (NICHD) of the United States National Institutes of Health (NIH) on April 16–18, 1990. During the meeting, all participants were surveyed regarding their perception of what features formed part of PCOS, and Drs. Zawadski and Dunaif summarized the findings in the meeting proceedings (1Zawadski J.K. Dunaif A. Diagnostic criteria for polycystic ovary syndrome: towards a rational approach.in: Dunaif A. Givens J.R. Haseltine F. Polycystic ovary syndrome. Blackwell Scientific, Boston1992: 377-384Google Scholar). They concluded that the major criteria for PCOS "should include (in order of importance): i) hyperandrogenism and/or hyperandrogenemia, ii) oligo-ovulation, [and the] iii) exclusion of other known disorders." This survey had the clarity of identifying PCOS as an androgen excess disorder of exclusion, with ovarian consequences. Under the NIH/NICHD criteria, clinical hyperandrogenism has generally been interpreted as hirsutism, since >70% of hirsute women are hyperandrogenemic (2Azziz R. Sanchez L.A. Knochenhauer E.S. Moran C. Lazenby J. Stephens K.S. et al.Androgen excess in women: experience with over 1000 consecutive patients.J Clin Endocrinol Metab. 2004; 89: 453-462Crossref PubMed Scopus (600) Google Scholar). Consequently, three principal phenotypes are generally recognized: [1] women with hirsutism, hyperandrogenemia, and oligo-ovulation; [2] women with hirsutism and oligo-ovulation; or [3] women with hyperandrogenemia and oligo-ovulation. The NIH/NICHD criteria have proven extremely useful to begin to define and understand, among other features, the extraordinarily high prevalence of the disorder (3Diamanti-Kandarakis E. Koulie C.R. Bergiele A.T. Filandra F.A. Tsianateli T.C. Spina G.G. et al.A survey of the polycystic ovary syndrome in the Greek Island of Lesbos: a hormonal and metabolic profile.J Clin Endocrinol Metab. 1999; 84: 4006-4011Crossref PubMed Google Scholar, 4Michelmore K.F. Balen A.H. Dunger D.B. Vessey M.P. Polycystic ovaries and associated clinical and biochemical features in young women.Clin Endocrinol (Oxf). 1999; 51: 779-786Crossref PubMed Scopus (304) Google Scholar, 5Asuncion M. Calvo R.M. San Millan J.L. Sancho J. Avila S. Escobar-Morreale H.F. A prospective study of the prevalence of the polycystic ovary syndrome in unselected Caucasian women from Spain.J Clin Endocrinol Metab. 2000; 85: 2434-2438Crossref PubMed Scopus (1140) Google Scholar, 6Azziz R. Yildiz B. Woods K.S. Reyna R. Key T.J. Stephens K.C. et al.The prevalence of polycystic ovary syndrome among unselected consecutive premenopausal women.J Clin Endocrinol Metab. 2004; 89: 2745-2749Crossref PubMed Scopus (1940) Google Scholar) and the accompanying high frequency of insulin resistance (7Carmina E. Koyama T. Chang L. Stanczyk F.Z. Lobo R.A. Does ethnicity influence the prevalence of adrenal hyperandrogenism in insulin resistance in the polycystic ovary syndrome?.Am J Obstet Gynecol. 1992; 167 (1807–12)Google Scholar, 8Legro 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) and considerable risk for developing type 2 diabetes mellitus (9Ehrmann D.A. Barnes R.B. Rosenfield R.L. Cavaghan M.K. Imperial J. Prevalence of impaired glucose tolerance and diabetes in women with polycystic ovary syndrome.Diabetes Care. 1999; 22: 141-146Crossref PubMed Scopus (1035) Google Scholar, 10Legro R.S. Kunselman A.R. Dodson W.C. Dunaif A. Prevalence and predictors of risk for type 2 diabetes mellitus and impaired glucose tolerance in polycystic ovary syndrome: a prospective, controlled study in 254 affected women.J Clin Endocrinol Metab. 1999; 84: 165-169Crossref PubMed Scopus (1516) Google Scholar). At the time of the 1990 NIH/NICHD meeting, and possibly because of the relative paucity of non-U.S. speakers, most participants felt that the presence of polycystic ovaries by ultrasound was suggestive, but not diagnostic, of PCOS. However, it is now clear that many patients with PCOS do demonstrate ultrasound evidence of polycystic ovaries (7Carmina E. Koyama T. Chang L. Stanczyk F.Z. Lobo R.A. Does ethnicity influence the prevalence of adrenal hyperandrogenism in insulin resistance in the polycystic ovary syndrome?.Am J Obstet Gynecol. 1992; 167 (1807–12)Google Scholar, 11Swanson M. Sauerbrei E.E. Cooperberg P.L. Medical implications of ultrasonically detected polycystic ovaries.J Clin Ultrasound. 1981; 9: 219-222Crossref PubMed Scopus (171) Google Scholar, 12Adams J. Polson D.W. Franks S. Prevalence of polycystic ovaries in women with anovulation and idiopathic hirsutism.Br Med J. 1986; 293: 355-359Crossref PubMed Scopus (923) Google Scholar, 13Polson D.W. Adams J. Wadsworth J. Franks S. Polycystic ovaries—a common finding in normal women.Lancet. 1988; 1: 870-872Abstract PubMed Scopus (829) Google Scholar, 14O'Driscoll J.B. Mamtora H. Higginson J. Pollock A. Kane J. Anderson D.C. A prospective study of the prevalence of clear-cut endocrine disorders and polycystic ovaries in 350 patients presenting with hirsutism or androgenic alopecia.Clin Endocrinol (Oxf). 1994; 41: 231-236Crossref PubMed Scopus (146) Google Scholar, 15Pache T.D. Hop W.C. Wladimiroff J.W. Schipper J. Fauser B.C. How to discriminate between normal and polycystic ovaries.Radiol. 1992; 17: 589-593Google Scholar, 16van Santbrink E.J. Hop W.C. Fauser B.C. Classification of normogonadotropic infertility: polycystic ovaries diagnosed by ultrasound versus endocrine characteristics of polycystic ovary syndrome.Fertil Steril. 1997; 67: 452-458Abstract Full Text PDF PubMed Scopus (163) Google Scholar, 17Jonard S. Robert Y. Cortet C. Decanter C. Dewailly D. Ultrasound examination of polycystic ovaries: is it worth counting the follicles?.Hum Reprod. 2003; 18: 598-603Crossref PubMed Scopus (267) Google Scholar). Consequently, another expert conference was convened in Rotterdam, The Netherlands, on May 1–3, 2003, sponsored in part by the European Society for Human Reproduction and Embryology and the American Society for Reproductive Medicine (18Rotterdam ESHRE/ASRM-Sponsored PCOS consensus workshop groupRevised 2003 consensus on diagnostic criteria and long-term health risks related to polycystic ovary syndrome.Fertil Steril. 2004; 81: 19-25Scopus (0) Google Scholar, 19Rotterdam ESHRE/ASRM-Sponsored PCOS consensus workshop groupRevised 2003 consensus on diagnostic criteria and long-term health risks related to polycystic ovary syndrome (PCOS).Hum Reprod. 2004; 19: 41-47Crossref PubMed Scopus (4412) Google Scholar). The meeting proceedings recommended that PCOS be defined when at least two of the following three features were present: [1] oligo- and/or anovulation, [2] clinical and/or biochemical signs of hyperandrogenism, and [3] polycystic ovaries. These criteria again recognize that PCOS is a diagnosis of exclusion. Polycystic ovaries as defined by the 2003 Rotterdam criteria referred to the presence of at least one ovary exhibiting 12 or more follicles measuring 2–9 mm in diameter, regardless of location, and/or a total volume >10 mL3, as determined by transvaginal ultrasound (18Rotterdam ESHRE/ASRM-Sponsored PCOS consensus workshop groupRevised 2003 consensus on diagnostic criteria and long-term health risks related to polycystic ovary syndrome.Fertil Steril. 2004; 81: 19-25Scopus (0) Google Scholar, 19Rotterdam ESHRE/ASRM-Sponsored PCOS consensus workshop groupRevised 2003 consensus on diagnostic criteria and long-term health risks related to polycystic ovary syndrome (PCOS).Hum Reprod. 2004; 19: 41-47Crossref PubMed Scopus (4412) Google Scholar). This definition differs somewhat from that originally proposed by Adams and colleagues (20Adams J. Franks S. Polson D.W. Mason H.D. Abdulwahid N. Tucker M. et al.Multifollicular ovaries: clinical and endocrine features and response to pulsatile gonadotropin releasing hormone.Lancet. 1985; 2: 1375-1379Abstract PubMed Scopus (724) Google Scholar) using transabdominal ultrasound, where polycystic ovaries were defined as those containing at least 10 follicles between 2 and 8 mm in diameter in one plane, arranged either peripherally around a dense core of ovarian stroma or scattered throughout an increased amount of stroma. These latter investigators have more recently modified their definition to consider as polycystic those ovaries containing at least eight follicles 2–8 mm in diameter (21Adams J.M. Taylor A.E. Crowley Jr, W.F. Hall J.E. Polycystic ovarian morphology with regular ovulatory cycles: insights into the pathophysiology of polycystic ovarian syndrome.J Clin Endocrinol Metab. 2004; 89: 4343-4350Crossref PubMed Scopus (132) Google Scholar). However, preliminary data suggest that the number of women who are misclassified by using the modified Adams et al. (21Adams J.M. Taylor A.E. Crowley Jr, W.F. Hall J.E. Polycystic ovarian morphology with regular ovulatory cycles: insights into the pathophysiology of polycystic ovarian syndrome.J Clin Endocrinol Metab. 2004; 89: 4343-4350Crossref PubMed Scopus (132) Google Scholar) criteria versus the Rotterdam criteria is relatively small. It should be noted that the 2003 Rotterdam criteria define a population of patients that is inclusive of those women previously diagnosed as having PCOS according to the 1990 NIH/NICHD criteria. In other words, the 2003 Rotterdam criteria has expanded, not replaced, the NIH 1990 criteria. In essence, the population of potential patients with the disorder has increased through the creation of two new phenotypes of PCOS, namely, patients who have polycystic ovaries, hirsutism, and/or hyperandrogenemia but normal ovulation and women who have polycystic ovaries and irregular ovulation but no sign of androgen excess. A valid and critical question is whether these newer phenotypes actually represent patients with PCOS. Here we briefly examine the available data to help assess the validity of these new criteria. First, there is some, albeit limited, evidence that the sole presence of polycystic ovaries in women who otherwise are not hirsute and have normal ovulation is associated with the presence of features reminiscent of those observed in patients with PCOS. These include mild elevations in circulating LH (22Eden J.A. Place J. Carter G.D. Alaghband-Zadeh J. Pawson M. Is the polycystic ovary a cause of infertility in the ovulatory woman?.Clin Endocrinol (Oxf). 1989; 30: 77-82Crossref PubMed Scopus (24) Google Scholar, 23Kousta E. White D.M. Cela E. McCarthy M.I. Franks S. The prevalence of polycystic ovaries in women with infertility.Hum Reprod. 1999; 14: 2720-2723Crossref PubMed Scopus (80) Google Scholar), androgen (21Adams J.M. Taylor A.E. Crowley Jr, W.F. Hall J.E. Polycystic ovarian morphology with regular ovulatory cycles: insights into the pathophysiology of polycystic ovarian syndrome.J Clin Endocrinol Metab. 2004; 89: 4343-4350Crossref PubMed Scopus (132) Google Scholar, 22Eden J.A. Place J. Carter G.D. Alaghband-Zadeh J. Pawson M. Is the polycystic ovary a cause of infertility in the ovulatory woman?.Clin Endocrinol (Oxf). 1989; 30: 77-82Crossref PubMed Scopus (24) Google Scholar, 23Kousta E. White D.M. Cela E. McCarthy M.I. Franks S. The prevalence of polycystic ovaries in women with infertility.Hum Reprod. 1999; 14: 2720-2723Crossref PubMed Scopus (80) Google Scholar), and insulin levels (21Adams J.M. Taylor A.E. Crowley Jr, W.F. Hall J.E. Polycystic ovarian morphology with regular ovulatory cycles: insights into the pathophysiology of polycystic ovarian syndrome.J Clin Endocrinol Metab. 2004; 89: 4343-4350Crossref PubMed Scopus (132) Google Scholar), in insulin resistance assessed using the homeostatic assessment (HOMA-IR) calculation (21Adams J.M. Taylor A.E. Crowley Jr, W.F. Hall J.E. Polycystic ovarian morphology with regular ovulatory cycles: insights into the pathophysiology of polycystic ovarian syndrome.J Clin Endocrinol Metab. 2004; 89: 4343-4350Crossref PubMed Scopus (132) Google Scholar) or the insulin tolerance test (24Chang 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), and in the LH, 17-hydroxyprogesterone, and T response to acute long-acting GnRH-analog stimulation (24Chang 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). However, not all investigators agree, with some investigators reporting no differences in basal androgen levels (24Chang 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) or in gonadotropin dynamics (21Adams J.M. Taylor A.E. Crowley Jr, W.F. Hall J.E. Polycystic ovarian morphology with regular ovulatory cycles: insights into the pathophysiology of polycystic ovarian syndrome.J Clin Endocrinol Metab. 2004; 89: 4343-4350Crossref PubMed Scopus (132) Google Scholar) in these women. Specifically characterizing ovulatory women with polycystic ovaries who are clinically hyperandrogenic, Carmina and Lobo (25Carmina E. Lobo R.A. Polycystic ovaries in hirsute women with normal menses.Am J Med. 2001; 111: 602-606Abstract Full Text Full Text PDF PubMed Scopus (101) Google Scholar) prospectively evaluated 62 hirsute ovulatory women by determining their baseline hormonal profiles, ovarian responses to gonadotropin-releasing hormone agonist, and ovarian morphology by ultrasound. Of these women, eight had normal androgen levels and were considered to have idiopathic hirsutism, although there was no mention of their ovarian morphology. Of the remaining 54 hyperandrogenemic patients, 22 (41%) had polycystic ovaries on ultrasound. Hyperandrogenemic ovulatory women with and without polycystic ovaries did not have significantly different androgen levels and LH/FSH ratios, although the former had higher fasting insulin levels, lower glucose-insulin ratios, and a higher 17-hydroxyprogesterone response to leuprolide. Taken together, these data suggest that hirsute hyperandrogenemic ovulatory women with polycystic ovaries, whether hirsute or not, tend to have mild insulin resistance and mild evidence of ovarian dysfunction, although significantly less than women with anovulatory PCOS. There is considerably less evidence that women with polycystic ovaries and ovulatory dysfunction, but without clinical or biochemical evidence of hyperandrogenism, have features suggestive of PCOS. Norman and colleagues (26Norman R.J. Hague W.M. Masters S.C. Wang X.J. Subjects with polycystic ovaries without hyperandrogenaemia exhibit similar disturbances in insulin and lipid profiles as those with polycystic ovary syndrome.Hum Reprod. 1995; 10: 2258-2261PubMed Google Scholar) compared 21 women without clinical or biochemical signs of hyperandrogenism who demonstrated polycystic ovaries on transvaginal ultrasound with 97 women with polycystic ovaries who also had increased androgens and a clinical presentation normally associated with PCOS. These investigators found that fasting and glucose-stimulated insulin and glucose levels or gonadotropin levels were similarly altered in nonhyperandrogenic women with polycystic ovaries and in patients with PCOS. In both groups, menstrual irregularity was associated with significantly higher concentrations of serum fasting and stimulated insulin levels, independent of androgens and degree of obesity, compared with those women with normal menstrual cycles. Alternatively, Michelmore et al. (27Michelmore K. Ong K. Mason S. Bennett S. Perry L. Vessey M. et al.Clinical features in women with polycystic ovaries: relationships to insulin sensitivity, insulin gene VNTR and birth weight.Clin Endocrinol (Oxf). 2001; 55: 439-446Crossref PubMed Scopus (102) Google Scholar) studied ovarian morphology by transabdominal ultrasound in 224 young women recruited as normal volunteers and observed polycystic ovaries in 33%. Surprisingly, and in contrast to the study by Norman and colleagues (26Norman R.J. Hague W.M. Masters S.C. Wang X.J. Subjects with polycystic ovaries without hyperandrogenaemia exhibit similar disturbances in insulin and lipid profiles as those with polycystic ovary syndrome.Hum Reprod. 1995; 10: 2258-2261PubMed Google Scholar), these latter women had higher mean insulin sensitivity, as assessed by the HOMA-IR calculation (27Michelmore K. Ong K. Mason S. Bennett S. Perry L. Vessey M. et al.Clinical features in women with polycystic ovaries: relationships to insulin sensitivity, insulin gene VNTR and birth weight.Clin Endocrinol (Oxf). 2001; 55: 439-446Crossref PubMed Scopus (102) Google Scholar). Many patients with nonandrogenic disorders also demonstrate a polycystic ovarian morphology. For example, most patients with bulimia and other eating disorders demonstrate polycystic ovaries on ultrasound in addition to having menstrual and ovulatory abnormalities (28Jahanfar S. Eden J.A. Nguyent T.V. Bulimia nervosa and polycystic ovary syndrome.Gynecol Endocrinol. 1995; 9: 113-117Crossref PubMed Scopus (43) Google Scholar, 29Morgan J.F. McCluskey S.E. Brunton J.N. Hubert Lacey J. Polycystic ovarian morphology and bulimia nervosa: a 9-year follow-up study.Fertil Steril. 2002; 77: 928-931Abstract Full Text Full Text PDF PubMed Scopus (51) Google Scholar). At least 50% of patients with hyperprolactinemia or hypothalamic amenorrhea also demonstrate polycystic ovaries (30Futterweit W. Yeh H.C. Mechanick J.I. Ultrasonographic study of ovaries of 19 women with weight loss-related hypothalamic oligo-amenorrhea.Biomed Pharmacother. 1988; 42: 279-283PubMed Google Scholar, 31Ardaens Y. Robert Y. Lemaitre L. Fossati P. Dewailly D. Polycystic ovarian disease: contribution of vaginal endosonography and reassessment of ultrasonic diagnosis.Fertil Steril. 1991; 55: 1062-1068Abstract Full Text PDF PubMed Scopus (94) Google Scholar). Finally, many adolescents transiently demonstrate polycystic ovaries (32Giorlandino C. Gleicher N. Taramanni C. Vizzone A. Gentili P. Mancuso S. et al.Ovarian development of the female child and adolescent I. Morphology.Int J Gynaecol Obstet. 1989; 29: 57-63Abstract Full Text PDF PubMed Scopus (26) Google Scholar, 33Rosenfield R.L. Ghai K. Ehrmann D.A. Barnes R.B. Diagnosis of the polycystic ovary syndrome in adolescence: comparison of adolescent and adult hyperandrogenism.J Pediatr Endocrinol Metab. 2000; 13: 1285-1289PubMed Google Scholar). Overall, when the available data are critically reviewed it would appear that ovulatory women with hirsutism and/or hyperandrogenemia and polycystic ovaries may have a mild form of PCOS, although it should be recognized that differences from normal are modest at best and that additional studies are needed to confirm these findings. In addition, acceptance of this presentation as a phenotype of PCOS in turn indicates that idiopathic hirsutism must be defined more strictly and should be diagnosed only in hirsute patients who have no evidence of ovulatory dysfunction, hyperandrogenemia, or polycystic ovaries. Alternatively, there are significantly less data to support the concept that isolated polycystic ovaries in oligo-ovulatory women without clinical or biochemical evidence of hyperandrogenism represent PCOS, particularly considering that patients with other ovulatory disorders may also demonstrate this ovarian morphology. Consequently, while it is clear that polycystic ovaries are a frequent feature of PCOS, the widespread adoption of the diagnostic criteria proposed in the 2003 Rotterdam meeting proceedings should be considered premature, particularly considering available data. While undoubtedly additional research is needed to more clearly determine the entire spectrum of PCOS, the publication of these guidelines should not be interpreted as an indication that the data are already available to support the phenotypes proposed. Based on current evidence, a new set of criteria for the diagnosis of PCOS can be proposed, which take into consideration the high prevalence of polycystic ovaries observed in the disorder (Table 1). These criteria simply represent a modification of the 1990 NIH/NICHD criteria and consider the two principal features of the disorder: [1] androgen excess (clinical and/or biochemical) and [2] ovarian dysfunction (functional and/or morphologic). While ovulatory patients who have polycystic ovaries with clinical and/or biochemical evidence of androgen excess would be considered to have PCOS, oligo-ovulatory patients without evidence of hyperandrogenism would not be diagnosed with the disorder, regardless of the presence of polycystic ovaries, until further data are made available.TABLE 1Modified 1990 National Institutes of Health/National Institute of Child Health and Human Disease Criteria.CriterionDescriptionAndrogen excessClinicalaSuch as hirsutism. and/or biochemical hyperandrogenismbHyperandrogenemia, such as elevated levels of total or free T.Ovarian dysfunctionOligo-anovulation and/or polycystic ovarian morphologycDefined by either the number of intermediate follicles (>8–12 follicles each 2 to 8–9 mm in diameter) and/or an increased ovarian volume (e.g., >10 mL3).ExclusionOther androgen excess or ovulatory disordersdIncluding, but not limited to, 21-hydroxylase deficient nonclassic adrenal hyperplasia, thyroid dysfunction, hyperprolactinemia, neoplastic androgen secretion, or drug-induced androgen excess.a Such as hirsutism.b Hyperandrogenemia, such as elevated levels of total or free T.c Defined by either the number of intermediate follicles (>8–12 follicles each 2 to 8–9 mm in diameter) and/or an increased ovarian volume (e.g., >10 mL3).d Including, but not limited to, 21-hydroxylase deficient nonclassic adrenal hyperplasia, thyroid dysfunction, hyperprolactinemia, neoplastic androgen secretion, or drug-induced androgen excess. 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