Differential Effects of Various Androgens on Polycystic Ovary Syndrome

Abstract

The hyperandrogenism in polycystic ovary syndrome (PCOS) is associated with the risk for the future development of the cardiovascular disease. The objective of the study is to verify whether different androgens have the same harmful effect. This cross-sectional study enrolled 823 women with PCOS: 627 (76.2%) with biochemical hyperandrogenism and 196 (23.8%) with normal androgen levels. The role of individual androgen was evaluated using univariate and multivariate logistic regression. In normoandrogenemic PCOS (NA-PCOS), free androgen index (FAI) predicted significant abnormality in visceral adipose index (VAI, OR=9.2, p=0.002) and dehydroepiandrosterone (DHEA) predicted against alteration in β-cell function (OR=0.5, p=0.007). In hyperandrogenemic PCOS (HA-PCOS), FAI predicted derangements in waist triglyceride index (WTI), VAI, and lipid accumulation product (LAP) (OR ranging from 1.6 to 5.8, p<0.05). DHEA weakly predicted against VAI (OR 0.7, p=0.018), dehydroepiandrosterone sulfate (DHEAS) tended to predict against the conicity index (OR=0.7, p=0.037). After multiple regression, FAI retained significant strength to predict various anthropometric and metabolic abnormalities (OR ranging from 1.1 to 3.0, p<0.01), DHEA was kept as a protector factor against WTI, LAP, and VAI (OR ranging from 0.6 to 0.9; p<0.01) and DHEAS against the conicity index (OR=0.5, p<0.001). In conclusion, the free androgen index was the most powerful predictor of anthropometric and metabolic abnormalities of polycystic ovary syndrome. Conversely, DHEA and DHEAS demonstrated protective effects against disorders in some markers of obesity and abnormal metabolism.

Key words

polycystic ovary syndrome - biomarkers - metabolism - hyperandrogenism - hyperinsulinemia - anthropometry

Publication History

Received: 22 December 2020

Accepted after revision: 04 March 2021

Article published online:
20 April 2021

• References

• 1 Azziz R, Sanchez LA, Knochenhauer ES. et al. Androgen excess in women: experience with over 1000 consecutive patients. J Clin Endocrinol Metab 2004; 89: 453-462
• 2 March WA, Moore VM, Wilson KJ. et al. The prevalence of polycystic ovary syndrome in a community sample assessed under contrasting diagnostic criteria. Hum Reprod 2010; 25: 544-551
• 3 Fauser BC, Tarlatzis BC, Rebar RW. et al. Consensus on women's health aspects of polycystic ovary syndrome (PCOS): The Amsterdam ESHRE/ASRM-Sponsored 3rd PCOS Consensus Workshop Group. Fertil Steril 2012; 97: e25
• 4 Azziz R, Carmina E, Dewailly D. et al. Androgen Excess Society. Positions statement: criteria for defining polycystic ovary syndrome as a predominantly hyperandrogenic syndrome: an Androgen Excess Society guideline. J Clin Endocrinol Metab 2006; 91: 4237-4245
• 5 National Institutes of Health. Evidence-based methodology workshop on polycystic ovary syndrome 2012; 1-14
• 6 Valderhaug TG, Hertel JK, Nordstrand N. et al. The association between hyperandrogenemia and the metabolic syndrome in morbidly obese women. Diabetol Metab Syndr 2015; 7: 46
• 7 Daan NM, Jaspers L, Koster MP. et al. Androgen levels in women with various forms of ovarian dysfunction: associations with cardiometabolic features. Hum Reprod 2015; 30: 2376-2386
• 8 Yang R, Yang S, Li R. et al. Effects of hyperandrogenism on metabolic abnormalities in patients with polycystic ovary syndrome: A meta-analysis. Reprod Biol Endocrinol 2016; 14: 67
• 9 Kumarendran B, O'Reilly MW, Manolopoulos KN. et al. Polycystic ovary syndrome, androgen excess, and the risk of nonalcoholic fatty liver disease in women: A longitudinal study based on a United Kingdom primary care database. PLoS Med 2018; 15: e1002542
• 10 Cortón M, Botella-Carretero JI, Benguría A. et al. Differential gene expression profile in omental adipose tissue in women with polycystic ovary syndrome. J Clin Endocrinol Metab 2007; 92: 328-337
• 11 McInnes KJ, Corbould A, Simpson ER. et al. Regulation of adenosine 5',monophosphate-activated protein kinase and lipogenesis by androgens contributes to visceral obesity in an estrogen-deficient state. Endocrinology 2006; 147: 5907-5913
• 12 Baranova A, Tran TP, Afendy A. et al. Molecular signature of adipose tissue in patients with both non-alcoholic fatty liver disease (NAFLD) and polycystic ovarian syndrome (PCOS). J Transl Med 2013; 11: 133
• 13 Hansen PA, Han DH, Nolte LA. et al. DHEA protects against visceral obesity and muscle insulin resistance in rats fed a high-fat diet. Am J Physiol 1997; 273: R1704-R1708
• 14 Hernandez-Morante JJ, Milagro F, Gabaldon JA. et al. Effect of DHEA-sulfate on adiponectin gene expression in adipose tissue from different fat depots in morbidly obese humans. Eur J Endocrinol 2006; 155: 593-600
• 15 González F, Sia CL, Bearson DM. et al. Hyperandrogenism induces a proinflammatory TNF response to glucose ingestion in a receptor-dependent fashion. J Clin Endocrinol Metab 2014; 99: E848-E854
• 16 de Medeiros SF, Gil-Junior AB, Barbosa JS. et al. New insights into steroidogenesis in normo- and hyperandrogenic polycystic ovary syndrome patients. Arq Bras Endocrinol Metabol 2013; 57: 437-444
• 17 O'Reilly MW, Taylor AE, Crabtree NJ. et al. Hyperandrogenemia predicts metabolic phenotype in polycystic ovary syndrome: the utility of serum androstenedione. J Clin Endocrinol Metab 2014; 99: 1027-1036
• 18 de Medeiros SF, Barbosa JS, Yamamoto MMW. Comparison of steroidogenic pathways among normoandrogenic and hyperandrogenic polycystic ovary syndrome patients and normal cycling women. J Obstet Gynaecol Res 2015; 41: 254-263
• 19 de Medeiros SF, Ormond CM, de Medeiros MAS. et al. Metabolic and endocrine connections of 17-hydroxypregnenolone in polycystic ovary syndrome women. Endo Connect 2017; 6: 479-488
• 20 de Medeiros SF, de Medeiros MAS, Barbosa BB. et al. Relationship of biological markers of body fat distribution and corticosteroidogenic enzyme activities in women with polycystic ovary syndrome. Horm Metab Res 2019; 51: 639-648
• 21 Fraser IS, Critchley HO, Broder M. et al. The FIGO recommendations on terminologies and definitions for normal and abnormal uterine bleeding. Seminars Reprod Med 2011; 29: 383-390
• 22 Teede HJ, Misso ML, Costello MF. et al. Recommendations from the international evidence-based guideline for the assessment and management of polycystic ovary syndrome. Fertil Steril 2018; 110: 364-379
• 23 American Diabetes Association. Standards of Medical Care in Diabetes. Diabetes Care. 2010; 33: S11-S61
• 24 Kristensen SL, Ramlau-Hansen CH, Ernst E. et al. A very large proportion of young Danish women have polycystic ovaries: is a revision of the Rotterdam criteria needed?. Hum Reprod 2010; 25: 3117-3122
• 25 de Medeiros SF, Yamamoto MMW, Souto de Medeiros MA. et al. Changes in clinical and biochemical characteristics of polycystic ovary syndrome with advancing age. Endocr Connect 2020; 9: 74-89
• 26 Yang RF, Liu XY, Lin Z. et al. Correlation study on waist circumference-triglyceride (WT) index and coronary artery scores in patients with coronary heart disease. Eur Rev Med Pharmacol Sci 2015; 19: 113-118
• 27 Nathan DM, Kuenen J, Borg R. et al. Translating the A1C assay into estimated average glucose values. Diabetes Care 2008; 31: 1473-1478
• 28 Diabetes Trial Unit. The Oxford Centre for Diabetes, Endocrinology and Metabolism [internet]. Oxford, UK: Oxford University. 2013; May 1 Available from http://www.dtu.ox.ac.uk/homacalculator
• 29 Friedewald WT, Levy RI, Fredrickson DS. Estimation of the concentration of low-density lipoprotein cholesterol in plasma, without use of the preparative ultracentrifuge. Clin Chem 1972; 18: 499-502
• 30 Buffington CK, Givens JR, Kitabchi AE. Opposing actions of dehydroepiandrosterone and testosterone on insulin sensitivity. In vivo and in vitro studies of hyperandrogenic females Diabetes 1991; 40: 693-700
• 31 Carmina E, Lobo RA. Prevalence and metabolic characteristics of adrenal androgen excess in hyperandrogenic women with different phenotypes. J Endocrinol Invest 2007; 30: 111-116
• 32 Brennan K, Huang A, Azziz R. Dehydroepiandrosterone sulfate and insulin resistance in patients with polycystic ovary syndrome. Fertil Steril 2009; 91: 1848-1852
• 33 Jones H, Sprung VS, Pugh CJ. et al. Polycystic ovary syndrome with hyperandrogenism is characterized by an increased risk of hepatic steatosis compared to nonhyperandrogenic PCOS phenotypes and healthy controls, independent of obesity and insulin resistance. J Clin Endocrinol Metab 2012; 97: 3709-3716
• 34 Wang JG, Zhang Y, Chen HE. et al. Comparison of two bioelectrical impedance analysis devices with dual energy X-ray absorptiometry and magnetic resonance imaging in the estimation of body composition. J Strength Condition Res 2013; 27: 236-2343
• 35 Lerchbaum E, Schwetz V, Rabe T. et al. Hyperandrogenemia in polycystic ovary syndrome: exploration of the role of free testosterone and androstenedione in metabolic phenotype. PLoS One 2014; 9: e108263
• 36 Conway GS, Honour JW, Jacobs HS. Heterogeneity of the polycystic ovary syndrome: Clinical, endocrine and ultrasound features in 556 patients. Clin Endocrinol 1989; 30: 459-470
• 37 Chang WY, Knochenhauer ES, Bartolucci AA. et al. Phenotypic spectrum of polycystic ovary syndrome: clinical and biochemical characterization of the three major clinical subgroups. Fertil Steril 2005; 83: 1717-1723
• 38 Apridonidze T, Essah PA, Iuorno MJ. et al. Prevalence and characteristics of the metabolic syndrome in women with polycystic ovary syndrome. J Clin Endocrinol Metab 2005; 90: 1929-1935
• 39 Wehr E, Möller R, Horejsi R. et al. Subcutaneous adipose tissue topography and metabolic disturbances in polycystic ovary syndrome. Wien Klin Wochenschr 2009; 121: 262-269
• 40 Huang A, Brennan K, Azziz R. Prevalence of hyperandrogenemia in the polycystic ovary syndrome diagnosed by the National Institutes of Health 1990 criteria. Fertil Steril 2010; 93: 1938-1941
• 41 Lerchbaum E, Schwetz V, Giuliani A. et al. Opposing effects of dehydroepiandrosterone sulfate and free testosterone on metabolic phenotype in women with polycystic ovary syndrome. Fertil Steril 2012; 98: e1
• 42 Panidis D, Macut D, Tziomalos K. et al. Prevalence of metabolic syndrome in women with polycystic ovary syndrome. Clin Endocrinol 2013; 78: 586-592
• 43 Large V, Arner P. Regulation of lipolysis in humans. Pathophysiological modulation in obesity, diabetes, and hyperlipidaemia. Diabetes Metab 1998; 24: 409-418
• 44 Dicker A, Rydén M, Näslund EE. et al. Effect of testosterone on lipolysis in human pre-adipocytes from different fat depots. Diabetologia 2004; 47: 420-428
• 45 Jayagopal V, Kilpatrick ES, Jennings PE. et al. The biological variation of testosterone and sex hormone-binding globulin (SHBG) in polycystic ovarian syndrome: Implications for SHBG as a surrogate marker of insulin resistance. J Clin Endocrinol Metab 2003; 88: 1528-1533
• 46 Diamanti-Kandarakis E, Papavassiliou AG, Kandarakis SA. et al. Pathophysiology and types of dyslipidemia in PCOS. Trends Endocrinol Metab 2007; 18: 280-2805
• 47 Weerakiet S, Srisombut C, Bunnag P. et al. Prevalence of type 2 diabetes mellitus and impaired glucose tolerance in Asian women with polycystic ovary syndrome. Int J Gynaecol Obstet 2001; 75: 177-184
• 48 Chen X, Yang D, Li L. et al. Abnormal glucose tolerance in Chinese women with polycystic ovary syndrome. Hum Reprod 2006; 21: 2027-2032
• 49 Lee H, Oh JY, Sung YA. et al. The prevalence and risk factors for glucose intolerance in young Korean women with polycystic ovary syndrome. Endocrine 2009; 36: 326-332
• 50 Forrester-Dumont K, Galescu O, Kolesnikov A. et al. Hyperandrogenism does not influence metabolic parameters in adolescent girls with PCOS. Int J Endocrinol 2012; 434830
• 51 Yasmin E, Balen AH, Barth JH. The association of body mass index and biochemical hyperandrogenaemia in women with and without polycystic ovary syndrome. Eur J Obstet Gynecol Reprod Biol 2013; 166: 173-177
• 52 Münzker J, Hofer D, Trummer C. et al. Testosterone to dihydrotestosterone ratio as a new biomarker for an adverse metabolic phenotype in the polycystic ovary syndrome. J Clin Endocrinol Metab 2015; 100: 653-660
• 53 Ganie MA, Dhingra A, Nisar S. et al. Oral glucose tolerance test significantly impacts the prevalence of abnormal glucose tolerance among Indian women with polycystic ovary syndrome: lessons from a large database of two tertiary care centers on the Indian subcontinent. Fertil Steril 2016; 105: e1-e3
• 54 Antonio L, Pauwels S, Laurent MR. et al. Free Testosterone Reflects Metabolic as well as Ovarian Disturbances in Subfertile Oligomenorrheic Women. Int J Endocrinol 2018; 7956951
• 55 Pugeat M, Plotton I, de la Perrière AB. et al. Management of endocrine disease hyperandrogenic states in women: Pitfalls in laboratory diagnosis. Eur J Endocrinol 2018; 178: R141-R154
• 56 Chen MJ, Yang WS, Yang JH. et al. Relationship between androgen levels and blood pressure in young women with polycystic ovary syndrome. Hypertension 2007; 49: 1442-1447
• 57 Chen YF, Naftilan AJ, Oparil S. Androgen-dependent angiotensinogen and renin messenger RNA expression in hypertensive rats. Hypertension 1992; 19: 456-463
• 58 Li H, Xu X, Wang X. et al. Free androgen index and Irisin in polycystic ovary syndrome. J Endocrinol Invest 2016; 39: 549-556
• 59 Deng Y, Zhang Y, Li S. et al. Steroid hormone profiling in obese and nonobese women with polycystic ovary syndrome. Sci Rep 2017; 7: 14156
• 60 Al-Jefout M, Alnawaiseh N, Al-Qtaitat A. Insulin resistance and obesity among infertile women with different polycystic ovary syndrome phenotypes. Sci Rep 2017; 7: 5339
• 61 Ribeiro VB, Kogure GS, Lopes IP. et al. Association of measures of central fat accumulation indices with body fat distribution and metabolic, hormonal, and inflammatory parameters in women with polycystic ovary syndrome. Arch Endocrinol Metab 2019; 63: 417-426
• 62 Chernukha GE, Naidukova AA, Udovichenko MA. et al. Androgen profile in patients with polycystic ovary syndrome and its association with metabolic dysfunction. Nat Med Res Center Obestet Gynecol. 2019
• 63 Alpañés M, Luque-Ramírez M, Martínez-García MÁ. et al. Influence of adrenal hyperandrogenism on the clinical and metabolic phenotype of women with polycystic ovary syndrome. Fertil Steril 2015; 103: e2
• 64 Zhang B, Wang J, Shen S. et al. Association of androgen excess with glucose intolerance in women with polycystic ovary syndrome. Biomed Res Int 2018; 2018: 6869705
• 65 Castelo-Branco C, Steinvarcel F, Osorio A. et al. Atherogenic metabolic profile in PCOS patients: role of obesity and hyperandrogenism. Gynecol Endocrinol 2010; 26: 736-742
• 66 Azziz R, Black V, Hines GA. et al. Adrenal androgen excess in the polycystic ovary syndrome: sensitivity and responsivity of the hypothalamic-pituitary-adrenal axis. J Clin Endocrinol Metab 1998; 83: 2317-2323
• 67 Azziz R, Carmina E, Dewailly D. et al. Task Force on the Phenotype of the Polycystic Ovary Syndrome of The Androgen Excess and PCOS Society. The Androgen Excess and PCOS Society criteria for the polycystic ovary syndrome: the complete task force report. Fertil Steril 2009; 91: 456-488
• 68 Conway G, Dewailly D, Diamanti-Kandarakis E. et al. The polycystic ovary syndrome: a position statement from the European Society of Endocrinology. Eur J Endocrinol 2014; 171: P1-P29
• 69 Dunaif A, Graf M. Insulin administration alters gonadal steroid metabolism independent of changes in gonadotropin secretion in insulin-resistant women with the polycystic ovary syndrome. J Clin Invest 1989; 83: 23-29
• 70 Brennan MJ, Cantrill RC, Wylie BA. Modulation of synaptosomal GABA release by enkephalin. Life Sci 1980; 27: 1097-1101
• 71 Misichronis G, Georgopoulos NA, Marioli DJ. et al. The influence of obesity on androstenedione to testosterone ratio in women with polycystic ovary syndrome (PCOS) and hyperandrogenemia. Gynecol Endocrinol 2012; 28: 249-252
• 72 Moran C, Renteria JL, Moran S. et al. Obesity differentially affects serum levels of androstenedione and testosterone in polycystic ovary syndrome. Fertil Steril 2008; 90: 2310-2317
• 73 Dunaif A, Mandeli J, Fluhr H. et al. The impact of obesity and chronic hyperinsulinemia on gonadotropin release and gonadal steroid secretion in the polycystic ovary syndrome. J Clin Endocrinol Metab 1988; 66: 131-139
• 74 Barbieri RL. Human ovarian 17-ketosteroid oxidoreductase: unique characteristics of the granulosa-luteal cell and stromal enzyme. Am J Obstet Gynecol 1992; 166: 1117-1126
• 75 Fulghesu A, Magnini R, Portoghese E. et al. Obesity-related lipid profile and altered insulin incretion in adolescents with polycystic ovary syndrome. J Adolesc Health 2010; 46: 474-481
• 76 Georgopoulos NA, Papadakis E, Armeni AK. et al. Elevated serum androstenedione is associated with a more severe phenotype in women with polycystic ovary syndrome (PCOS). Hormones 2014; 13: 213-221
• 77 Gansler TS, Muller S, Cleary MP. Chronic administration of dehydroepiandrosterone reduces pancreatic beta-cell hyperplasia and hyperinsulinemia in genetically obese Zucker rats. Proc Soc Exp Biol Med 1985; 180: 155-162
• 78 Yamashita R, Saito T, Satoh S. et al. Effects of dehydroepiandrosterone on gluconeogenic enzymes and glucose uptake in human hepatoma cell line, HepG2. Endocr J 2005; 52: 727-733
• 79 Kameda W, Daimon M, Oizumi T. et al. Association of decrease in serum dehydroepiandrosterone sulfate levels with the progression to type 2 diabetes in men of a Japanese population: the Funagata Study. Metabolism 2005; 54: 669-676
• 80 Farah-Eways L, Reyna R, Knochenhauer ES. et al. Glucose action and adrenocortical biosynthesis in women with polycystic ovary syndrome. Fertil Steril 2004; 81: 120-125
• 81 Kumar A, Woods KS, Bartolucci AA. et al. Prevalence of adrenal androgen excess in patients with the polycystic ovary syndrome (PCOS). Clin Endocrinol 2005; 62: 644-649
• 82 Chen MJ, Chen CD, Yang JH. et al. High serum dehydroepiandrosterone sulfate is associated with phenotypic acne and a reduced risk of abdominal obesity in women with polycystic ovary syndrome. Hum Reprod 2011; 26: 227-234
• 83 Schunkert H, Hense HW, Andus T. et al. Relation between dehydroepiandrosterone sulfate and blood pressure levels in a population-based sample. Am J Hypertens 1999; 121140-121143
• 84 Meirow D, Raz I, Yossepowitch O. et al. Dyslipidaemia in polycystic ovarian syndrome: different groups, different aetiologies?. Hum Reprod 1996; 11: 1848-1853
• 85 Köşüş N, Köşüş A, Kamalak Z. et al. Impact of adrenal versus ovarian androgen ratio on signs and symptoms of polycystic ovarian syndrome. Gynecol Endocrinol 2012; 28: 611-614
• 86 Morán C, Knochenhauer E, Boots LR. et al. Adrenal androgen excess in hyperandrogenism: relation to age and body mass. Fertil Steril 1999; 71: 671-674
• 87 Chen MJ, Han DS, Yang JH. et al. Myostatin and its association with abdominal obesity, androgen and follistatin levels in women with polycystic ovary syndrome. Hum Reprod 2012; 27: 2476-2483
• 88 Moran C, Arriaga M, Arechavaleta-Velasco F. et al. Adrenal androgen excess and body mass index in polycystic ovary syndrome. J Clin Endocrinol Metab 2015; 100: 942-950
• 89 Barrett-Connor E, Khaw KT, Yen SS. A prospective study of dehydroepiandrosterone sulfate, mortality, and cardiovascular disease. N Engl J Med 1986; 315: 1519-1524
• 90 Legro RS, Schlaff WD, Diamond MP. et al. Reproductive Medicine Network. Total testosterone assays in women with polycystic ovary syndrome: precision and correlation with hirsutism. J Clin Endocrinol Metab 2010; 95: 5305-5313
• 91 Janse F, Eijkemans MJ, Goverde AJ. et al. Assessment of androgen concentration in women: liquid chromatography-tandem mass spectrometry and extraction RIA show comparable results. Eur J Endocrinol 2011; 165: 925-933
• 92 Keefe CC, Goldman MM, Zhang K. et al. Simultaneous measurement of thirteen steroid hormones in women with polycystic ovary syndrome and control women using liquid chromatography-tandem mass spectrometry. PLoS One 2014; 9: e93805