Adrenal Androgen Predictive Effects on Clinical andMetabolic Abnormalities of Polycystic Ovary Syndrome

Efeitos preditivos dos androgênios adrenais nas anormalidades clínicas e metabólicas da síndrome dos ovários policísticos

Sebastião Freitas de Medeiros Bruna Barcelo Barbosa Matheus Antônio Souto de Medeiros Ana Karine Lin Winck Yamamoto Márcia Marly Winck Yamamoto About the authors

Abstract

Objective

To examine the possible effects of adrenal prohormones in the prediction of clinical and metabolic abnormalities in women with polycystic ovary syndrome (PCOS).

Methods

The present study enrolled 299 normal cycling non-PCOS, 156 normoandrogenemic, and 474 hyperandrogenemic women with PCOS. Baseline characteristics were compared using a chi-squared test or analysis of variance (ANOVA) as appropriate. The roles of adrenal prohormones and their ratios with total testosterone in predicting co-occurring morbidities in women PCOS were evaluated using univariate and multivariate logistic regression analyses.

Results

Adrenal hyperandrogenism per dehydroepiandrosterone sulfate (DHEAS) levels were found in 32% of women with PCOS. In non-PCOS women, dehydroepiandrosterone (DHEA) and its sulfate had no predictive role concerning clinical, anthropometric, and metabolic parameters. In PCOS women, mainly in the hyperandrogenemic group, DHEA showed to be a significant predictor against most anthropometric-metabolic index abnormalities (odds ratio [OR]=0.36-0.97; p<0.05), and an increase in triglycerides (TG) levels (OR=0.76; p=0.006). Dehydroepiandrosterone sulfate presented a few predictive effects regarding PCOS-associated disorders. In controls, DHEAS predicted against the increase in estimated average glucose (OR= 0.38; p=0.036). In the normoandrogenic group, it predicted against elevation in the waist/hip ratio (WHR) (OR= 0.59; p=0.042), and in hyperandrogenemic PCOS women, it predicted against abnormality in the conicity index (CI) (OR=0.31; p=0.028).

Conclusion

Dehydroepiandrosterone was shown to be a better predictor of abnormal anthropometric and biochemical parameters in women with PCOS than DHEAS. Thus, regarding adrenal prohormones, DHEA measurement, instead of DHEAS, should be preferred in PCOS management. The effects of androgen prohormones on the prediction of PCOS abnormalities are weak.

Keywords:
polycystic ovary syndrome; hyperandrogenism; obesity; hyperinsulinemia; metabolism

Resumo

Objetivo

Examinar os possíveis efeitos dos pró-hormônios adrenais na predição de alterações clínicas e metabólicas em mulheres com síndrome dos ovários policísticos (SOP).

Métodos

O presente estudo envolveu 299 mulheres com ciclos menstruais regulares e 630 mulheres com SOP, sendo 156 normoandrogenêmicas e 474 hiperandrogenêmicas. As variáveis incluídas como objeto do estudo foram comparadas entre os grupos usando o teste de qui-quadrado ou análise de variância (ANOVA, na sigla em inglês). Os impactos dos pró-hormônios adrenais e suas razões com a testosterona total na predição de comorbidades em mulheres com SOP foram determinados por regressão logística univariada e multivariada.

Resultados

Hiperandrogenismo adrenal foi encontrado em 32% das mulheres com SOP. Nos controles, a dehidroepiandrosterona e seu sulfato (DHEAS) não mostraram significância na predição das alterações clínicas, antropométricas e metabólicas. Em mulheres com SOP, principalmente no grupo de mulheres com hiperandrogenemia, a dehidroepiandrosterona (DHEA) mostrou ser um preditor significante da maioria das anormalidades nos índices antropométrico-metabólicos (odds ratio [OR]=0,36-0,97; p<0,05) e aumento nos níveis de triglicerídeos (TG) (OR=0,76; p=0,006). A DHEAS apresentou ter pouco valor na predição dos distúrbios associados à SOP; nas mulheres com androgênios elevados, restringiu-se à predição da elevação do índice de conicidade (IC) (OR=0,31; p=0,028).

Conclusão

A DHEA mostrou ser um melhor preditor na identificação das alterações dos parâmetros antropométricos e bioquímicos em mulheres com SOP do que o seu sulfato. Assim, em relação aos pró-hormônios adrenais, a dosagem de DHEA, em vez de DHEAS, parece ser mais útil no manejo da SOP. O papel dos pró-hormônios adrenais na predição de anormalidades antropométricas e metabólicas da SOP é limitado.

Palavras-chave:
síndrome dos ovários policísticos; hiperandrogenismo; obesidade; hiperinsulinemia; metabolismo

Introduction

Polycystic ovary syndrome (PCOS) is found in up to 20% of women of reproductive age.11 MarchWA, Moore VM,Willson KJ, Phillips DI, Norman RJ, Davies MJ. The prevalence of polycystic ovary syndrome in a community sample assessed under contrasting diagnostic criteria. Hum Reprod. 2010;25(02):544-551. Doi: 10.1093/humrep/dep399
https://doi.org/10.1093/humrep/dep399...
Since 1990, PCOS has been defined by the presence of oligoanovulation, clinical or biochemical hyperandrogenism, and/or polycystic ovary morphology (PCOM).22 Zawadski JK, Dunaif A. Diagnostic criteria for polycystic ovary syndrome: towards a rational approach. In: Dunaif A, Givens JR, Haseltine F, eds. Polycystic ovary syndrome. Boston: Blackwell Scientific; 1992:377-384 33 Rotterdam ESHRE/ASRM-Sponsored PCOS Consensus Workshop Group. Revised 2003 consensus on diagnostic criteria and longterm health risks related to polycystic ovary syndrome. Fertil Steril. 2004;81(01):19-25. Doi: 10.1016/j.fertnstert.2003.10.004
https://doi.org/10.1016/j.fertnstert.200...
44 Azziz R, Carmina E, Dewailly D, Diamanti-Kandarakis E, Escobar- Morreale HF, Futterweit W, 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 (11):4237-4245. Doi: 10.1210/jc.2006-0178
https://doi.org/10.1210/jc.2006-0178...
The main characteristic of PCOS appears to be hyperandrogenism because PCOS women with high levels of androgens have increased risk for the development of central obesity, dysfunctional adipocyte, impaired fasting glucose (IFG), glucose intolerance (GI), insulin resistance (IR), dyslipidemia, metabolic syndrome (MS), low-grade chronic inflammation, nonalcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis (NASH), and, in the end, cardiovascular disease (CVD).55 Jones H, Sprung VS, Pugh CJ, Daousi C, Irwin A, Aziz N, 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(10):3709-3716. Doi: 10.1210/jc.2012-1382
https://doi.org/10.1210/jc.2012-1382...
66 Baranova A, Tran TP, Afendy A, Wang L, Shamsaddini A, Mehta R, 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. Doi: 10.1186/1479-5876-11-133
https://doi.org/10.1186/1479-5876-11-133...
77 Yang R, Yang S, Li R, Liu P, Qiao J, Zhang Y. Effects of hyperandrogenism on metabolic abnormalities in patients with polycystic ovary syndrome: a meta-analysis. Reprod Biol Endocrinol. 2016;14(01):67. Doi: 10.1186/s12958-016-0203-8
https://doi.org/10.1186/s12958-016-0203-...
88 Kumarendran B, O'Reilly MW, Manolopoulos KN, Toulis KA, Gokhale KM, Sitch AJ, et al. Polycystic ovary syndrome, androgen excess, and the riskof nonalcoholic fatty liver disease inwomen: A longitudinal study based on a United Kingdom primary care database. PLoS Med. 2018;15(03):e1002542. Doi: 10.1371/journal.pmed.1002542
https://doi.org/10.1371/journal.pmed.100...
99 de Medeiros SF, de Medeiros MAS, Barbosa BB, Yamamoto MMW. Relationship of biological markers of body fat distribution and corticosteroidogenic enzyme activities in women with polycystic ovary syndrome. Horm Metab Res. 2019;51(10):639-648. Doi: 10.1055/a-0975-9207
https://doi.org/10.1055/a-0975-9207...
1010 Kahal H, Kyrou I, Uthman OA, Brown A, Johnson S,Wall PDH, et al. The prevalence of obstructive sleep apnoea in women with polycystic ovary syndrome: a systematic review and meta-analysis. Sleep Breath. 2020;24(01):339-350. Doi: 10.1007/s11325-019-01835-1
https://doi.org/10.1007/s11325-019-01835...
All these harmful co-occurring conditions, to a certain extent, are associated with hyperandrogenemia.1111 Sung YA, Oh JY, Chung H, Lee H. Hyperandrogenemia is implicated in both the metabolic and reproductive morbidities of polycystic ovary syndrome. Fertil Steril. 2014;101(03):840-845. Doi: 10.1016/j.fertnstert.2013.11.027
https://doi.org/10.1016/j.fertnstert.201...
1212 Ezeh U, Pall M, Mathur R, Azziz R. Association of fat to lean mass ratio withmetabolic dysfunction inwomen with polycystic ovary syndrome. Hum Reprod. 2014;29(07):1508-1517. Doi: 10.1093/humrep/deu096
https://doi.org/10.1093/humrep/deu096...
1313 Couto Alves A, Valcarcel B, Mäkinen VP, Morin-Papunen L, Sebert S, Kangas AJ, et al. Metabolic profiling of polycystic ovary syndrome reveals interactions with abdominal obesity. Int J Obes. 2017;41(09):1331-1340. Doi: 10.1038/ijo.2017.126
https://doi.org/10.1038/ijo.2017.126...
1414 Zhang B, Wang J, Shen S, Liu J, Sun J, Gu T, et al. Association of androgen excess with glucose intolerance in women with Polycystic Ovary Syndrome. BioMed Res Int. 2018;2018:6869705. Doi: 10.1155/2018/6869705
https://doi.org/10.1155/2018/6869705...

Strong androgens, such as testosterone (T), direct macrophages toward adipocytes, induce adipocyte hypertrophy, promote visceral obesity, decrease adipocyte sensitivity to insulin, and decrease adipocyte glucose uptake.1515 Tomlinson JW, Walker EA, Bujalska IJ, Draper N, Lavery GG, Cooper MS, et al. 11beta-hydroxysteroid dehydrogenase type 1: a tissue-specific regulator of glucocorticoid response. Endocr Rev. 2004;25(05):831-866. Doi: 10.1210/er.2003-0031
https://doi.org/10.1210/er.2003-0031...
1616 Veilleux A, Rhéaume C, Daris M, Luu-The V, Tchernof A. Omental adipose tissue type 1 11 beta-hydroxysteroid dehydrogenase oxoreductase activity, body fat distribution, and metabolic alterations in women. J Clin Endocrinol Metab. 2009;94(09):3550- -3557. Doi: 10.1210/jc.2008-2011
https://doi.org/10.1210/jc.2008-2011...
1717 Georgopoulos NA, Papadakis E, Armeni AK, Katsikis I, Roupas ND, Panidis D. Elevated serum androstenedione is associated with a more severe phenotype in women with polycystic ovary syndrome (PCOS). Hormones (Athens). 2014;13(02):213-221. Doi: 10.1007/BF03401335
https://doi.org/10.1007/BF03401335...
1818 O'Reilly MW, House PJ, Tomlinson JW. Understanding androgen action in adipose tissue. J Steroid Biochem Mol Biol. 2014; 143:277-284. Doi: 10.1016/j.jsbmb.2014.04.008
https://doi.org/10.1016/j.jsbmb.2014.04....
1919 Schiffer L, Kempegowda P, ArltW, O'Reilly MW. MECHANISMS IN ENDOCRINOLOGY: The sexually dimorphic role of androgens in human metabolic disease. Eur J Endocrinol. 2017;177(03): R125-R143. Doi: 10.1530/EJE-17-0124
https://doi.org/10.1530/EJE-17-0124...
Conversely, it appears that the adrenal prohormones dehydroepiandrosterone (DHEA) and dehydroepiandrosterone sulfate (DHEAS) have a beneficial effect by inhibiting the proliferation and differentiation of subcutaneous adipocyte and adipogenesis in omental adipocyte and enhancing adipocyte glucose uptake.2020 Hansen PA, Han DH, Nolte LA, ChenM, Holloszy JO. DHEA protects against visceral obesity and muscle insulin resistance in rats fed a high-fat diet. Am J Physiol. 1997;273(05):R1704-R1708. Doi: 10.1152/ajpregu.1997.273.5.R1704
https://doi.org/10.1152/ajpregu.1997.273...
2121 Perrini S, Natalicchio A, Laviola L, Belsanti G, Montrone C, Cignarelli A, et al. Dehydroepiandrosterone stimulates glucose uptake in human and murine adipocytes by inducing GLUT1 and GLUT4 translocation to the plasma membrane. Diabetes. 2004;53(01): 41-52. Doi: 10.2337/diabetes.53.1.41
https://doi.org/10.2337/diabetes.53.1.41...
2222 Rice SP, Zhang L, Grennan-Jones F, Agarwal N, LewisMD, Rees DA, et al. Dehydroepiandrosterone (DHEA) treatment in vitro inhibits adipogenesis in human omental but not subcutaneous adipose tissue. Mol Cell Endocrinol. 2010;320(1-2):51-57. Doi: 10.1016/j.mce.2010.02.017
https://doi.org/10.1016/j.mce.2010.02.01...
Furthermore, DHEA seems to exert antiglucocorticoid action on preadipocyte proliferation and differentiation, and DHEAS stimulates lipolysis.2323 Hernandez-Morante JJ, Milagro F, Gabaldon JA, Martinez JA, Zamora S, Garaulet M. Effect of DHEA-sulfate on adiponectin gene expression in adipose tissue from different fat depots in morbidly obese humans. Eur J Endocrinol. 2006;155(04): 593-600. Doi: 10.1530/eje.1.02256
https://doi.org/10.1530/eje.1.02256...
2424 McNelis JC, Manolopoulos KN, Gathercole LL, Bujalska IJ, Stewart PM, Tomlinson JW, et al. Dehydroepiandrosterone exerts antiglucocorticoid action on human preadipocyte proliferation, differentiation, and glucose uptake. Am J Physiol Endocrinol Metab. 2013;305(09):E1134-E1144. Doi: 10.1152/ajpendo.00314.2012
https://doi.org/10.1152/ajpendo.00314.20...

Different effects of adrenal prohormones on the development of harmful subphenotypes in PCOS, when compared with the effects of testosterone and free testosterone index, have been reported.2525 LerchbaumE, Schwetz V, Giuliani A, Pieber TR,Obermayer-Pietsch B. Opposing effects of dehydroepiandrosterone sulfate and free testosterone on metabolic phenotype in women with polycystic ovary syndrome. Fertil Steril. 2012;98(05):1318-25.e1. Doi: 10.1016/j.fertnstert.2012.07.1057
https://doi.org/10.1016/j.fertnstert.201...
2626 Goodarzi MO, Carmina E, Azziz R. DHEA, DHEAS and PCOS. J Steroid Biochem Mol Biol. 2015;145:213-225. Doi: 10.1016/j.jsbmb.2014.06.003
https://doi.org/10.1016/j.jsbmb.2014.06....
The present study expands and amplifies the initial findings by examining separately women with PCOS who were classified as normoandrogenemic (NA-PCOS) and hyperandrogenemic (HA-PCOS) and comparing them with non-PCOS normal-weight controls. Therefore, the present study proposed to examine the possible beneficial effects of adrenal prohormones in preventing clinical abnormalities in women with PCOS. The secondary objective was to verify the influence of adrenal products on carbohydrate and lipid metabolism biomarkers.

Methods

Subjects, Design, Eligibility Criterion

The present cross-sectional study enrolled 630 women with PCOS, aged 27.6 ± 5.4 years old, and 299 normal cycling nonobese controls, aged 29.9 ± 4.8 years old (p < 0.001), in whom DHEA and DHEAS were measured; all of them were attended at the outpatient clinic of the Instituto Tropical de Medicina Reprodutiva and at the Hospital Universitário Julio Muller, Cuiabá, state of Mato Grosso, Brazil, between 2003 and 2019. Women with PCOS were further divided into 156 (24.8%) NA-PCOS and 474 (75.2%) HA-PCOS. These subjects were enrolled from a previously described large sample of women with PCOS.2727 de Medeiros SF, Barbosa BB, de Medeiros AKLWY, de Medeiros MAS, Yamamoto MMW. Differential effects of various androgens on polycystic ovary syndrome. Horm Metab Res. 2021;53(05): 341-349. Doi: 10.1055/a-1422-3243
https://doi.org/10.1055/a-1422-3243...
Every patient gave full-informed written consent by signing a form approved by the local Ethics in Research Committee (decision No.093/FCM/03). Late-onset adrenal enzyme deficiencies were excluded as follows: 21-hydroxylase (17-hydroxyprogesterone [17-OHP4] levels ≤ 15 nmol/L), 3β-hydroxysteroid dehydrogenase (3β-HSD) (17-hydroxypregnenolone [17-OHPE] ≤ 13.5 nmol/L), and 11-hydroxylase (compound S ≤ 23 nmol/L). Hypothyroidism was excluded by thyroid-stimulating hormone (TSH) level ≤ 4.2 µUI/mL, free thyroxin (FT4) ≤ 9.0 pmol/L, and hyperprolactinemia by prolactin (PRL) ≤ 1.1 pmol/L.99 de Medeiros SF, de Medeiros MAS, Barbosa BB, Yamamoto MMW. Relationship of biological markers of body fat distribution and corticosteroidogenic enzyme activities in women with polycystic ovary syndrome. Horm Metab Res. 2019;51(10):639-648. Doi: 10.1055/a-0975-9207
https://doi.org/10.1055/a-0975-9207...
2828 de Medeiros SF, Ormond CM, de Medeiros MAS, de Souza Santos N, Banhara CR, Yamamoto MMW. Metabolic and endocrine connections of 17-hydroxypregnenolone in polycystic ovary syndrome women. Endocr Connect. 2017;6(07):479-488. Doi: 10.1530/EC-17-0151
https://doi.org/10.1530/EC-17-0151...
Women with PCOS who had used sex steroids, insulin-sensitizing, or dipeptidyl peptidase-4 inhibitors over the previous 6 months or those who did not fulfill the Rotterdam criteria were excluded.

Definitions

Polycystic ovary syndrome was diagnosed using the Rotterdam criteria, after exclusion of other hyperandrogenic conditions.2828 de Medeiros SF, Ormond CM, de Medeiros MAS, de Souza Santos N, Banhara CR, Yamamoto MMW. Metabolic and endocrine connections of 17-hydroxypregnenolone in polycystic ovary syndrome women. Endocr Connect. 2017;6(07):479-488. Doi: 10.1530/EC-17-0151
https://doi.org/10.1530/EC-17-0151...
The normal menstrual cycle was defined by a menstrual interval of between 24 and 35 days; amenorrhea was defined by the absence of a menstrual period for ≥ 90 days.2929 Teede HJ, Misso ML, Costello MF, Dokras A, Laven J, Moran L, et al; International PCOS Network. Recommendations from the international evidence-based guideline for the assessment and management of polycystic ovary syndrome. Fertil Steril. 2018;110 (03):364-379. Doi: 10.1016/j.fertnstert.2018.05.004
https://doi.org/10.1016/j.fertnstert.201...
Frequent menses were defined as an interval < 24 days or as > 4 menstrual episodes in 90 days, and infrequent menses were defined as a menstrual cycle ≥ 35 days or as ≤ 8 menstrual periods in the previous year.3030 Fraser IS, Critchley HO, Broder M, Munro MG. The FIGO recommendations on terminologies and definitions for normal and abnormal uterine bleeding. Semin Reprod Med. 2011;29(05): 383-390. Doi: 10.1055/s-0031-1287662
https://doi.org/10.1055/s-0031-1287662...

Because of inconsistent results due to ethnicity and inter-rater evaluation, clinical hyperandrogenism was registered as a dichotomous variable according to the complaints of the patient and the presence or lack of hirsutism in the upper lip, chin, chest, upper or lower back, upper or lower abdomen, upper arms, and thighs in the medical examination.3131 Wild RA, Vesely S, Beebe L,Whitsett T, Owen W. Ferriman Gallwey self-scoring I: performance assessment inwomen with polycystic ovary syndrome. J Clin Endocrinol Metab. 2005;90(07):4112- -4114. Doi: 10.1210/jc.2004-2243
https://doi.org/10.1210/jc.2004-2243...
3232 Kristensen SL, Ramlau-Hansen CH, Ernst E, Olsen SF, Bonde JP, Vested A, 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(12):3117-3122. Doi: 10.1093/humrep/deq273
https://doi.org/10.1093/humrep/deq273...
3333 de Medeiros SF, Yamamoto MMW, Souto de Medeiros MA, Barbosa BB, Soares JM, Baracat EC. Changes in clinical and biochemical characteristics of polycystic ovary syndrome with advancing age. Endocr Connect. 2020;9(02):74-89. Doi: 10.1530/EC-19-0496
https://doi.org/10.1530/EC-19-0496...
Biochemical hyperandrogenism was defined by at least 1 of the following criteria: total T ≥ 1.75 nmol/L, free testosterone (FT) ≥ 0.032 pmol/L, DHEAS ≥ 6.6 μmol/L, androstenedione (A4) ≥ 9.4 nmol/L, DHEA ≥34 nmol/L, and free androgen index (FAI) ≥ 5.2%. All these cutoff values were ≥ 90th percentile of 425 normal cycling, normal weight, non-PCOS women.3333 de Medeiros SF, Yamamoto MMW, Souto de Medeiros MA, Barbosa BB, Soares JM, Baracat EC. Changes in clinical and biochemical characteristics of polycystic ovary syndrome with advancing age. Endocr Connect. 2020;9(02):74-89. Doi: 10.1530/EC-19-0496
https://doi.org/10.1530/EC-19-0496...

Impaired fasting glucose (IFG) was defined by fasting plasma glucose concentration > 100 mg/dL (5.5 mmol/L) or < 126 mg/dL (7.0 mmol/L). Glucose intolerance (GI) was defined by a glucose concentration ≥ 7.8 nmol/L at 120 minutes after the ingestion of dextrose. Insulin resistance (IR) was defined by fasting insulin levels > 90 pmol/L and/or a HOMA-IR value ≥ 2.6.3333 de Medeiros SF, Yamamoto MMW, Souto de Medeiros MA, Barbosa BB, Soares JM, Baracat EC. Changes in clinical and biochemical characteristics of polycystic ovary syndrome with advancing age. Endocr Connect. 2020;9(02):74-89. Doi: 10.1530/EC-19-0496
https://doi.org/10.1530/EC-19-0496...
Type 2 diabetes mellitus (T2DM) was defined as fasting plasma glucose ≥ 126 mg/dL (7.0 mmol/L) or glucose ≥ 200 mg/dL (11.1 mmol/L) at 120 minutes after the ingestion of dextrose.3434 American Diabetes Association. Standards of medical care in diabetes-2010. Diabetes Care. 2010;33(Suppl 1):S11-S61. Doi: 10.2337/dc10-S011
https://doi.org/10.2337/dc10-S011...

Ultrasound Evaluation

Ovarian morphology was examined by ultrasonography using a vaginal transducer with a frequency of between 5 and 8 MHz (Toshiba Xario SSA-660A, Toshiba Medical do Brazil LTDA, Taboão da Serra, SP, Brazil or Voluson E8, GE Health Care, Bedford, United Kingdom). Antral follicle count ≥ 20 follicles in at least 1 ovary and ovarian volume ≥ 10 cm3 were the reference for assuming PCOM. The ovarian volume was calculated by the ellipsoid formula: π/6 × D1 × D2 × D3, where D1, D2, and D3 were taken as the maximum diameters.2929 Teede HJ, Misso ML, Costello MF, Dokras A, Laven J, Moran L, et al; International PCOS Network. Recommendations from the international evidence-based guideline for the assessment and management of polycystic ovary syndrome. Fertil Steril. 2018;110 (03):364-379. Doi: 10.1016/j.fertnstert.2018.05.004
https://doi.org/10.1016/j.fertnstert.201...

Clinical and Anthropometric Parameters

All data were registered in a template used in both institutions; however, in some participants, a few observations completely at random were not recorded. Systolic blood pressure (SBP) and diastolic blood pressure (DBP) were measured with the study participants in a sitting position after at least 5 minutes of resting. Height was measured using a harpenden stadiometer (Holtain Ltd., Crymych, Dyfed, UK). Body weight was acquired using an electronic scale, and the waist circumference (WC) was measured as the narrowest measuring midway point between the lower rib margin and the iliac crest, and the hip was measured at the widest circumference at the greater trochanters. Body mass index (BMI) was calculated from the ratio between weight and height squared, despite the limitations of indirect measurement. Lean body mass (LBM) was calculated using the James3535 James WP. Research on obesity: a report of the DHSS/MRC group HM. London: Stationery Office; 1976 equation. Fat mass (FM) was calculated as body weight minus LBM. Body shape index (BSI) was calculated according to the formula: WC(cm) / [BMI2/3 x height(cm)1/2],3636 Krakauer NY, Krakauer JC. A new body shape index predicts mortality hazard independently of body mass index. PLoS One. 2012;7(07):e39504. Doi: 10.1371/journal.pone.0039504
https://doi.org/10.1371/journal.pone.003...
and the waist circumference triglyceride index (WTI) was calculated as the product of WC (cm) multiplied by TG (mmol/L).3737 Yang RF, Liu XY, Lin Z, Zhang G. 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(01):113-118 The conicity index (CI) was calculated by the equation: WC(cm) / 10.109 × square root of BW(kg) / higher(m).3838 Valdez R. A simple model-based index of abdominal adiposity. J Clin Epidemiol. 1991;44(09):955-956. Doi: 10.1016/0895-4356(91)90059-i
https://doi.org/10.1016/0895-4356(91)900...
The VAI was calculated using the equation: WC / [36.58 + (1.89 x BMI)] x (TG / 0.81) x (1.52 / HDL-C),3939 Amato MC, Giordano C,Galia M, Criscimanna A, Vitabile S,MidiriM, et al; AlkaMeSy Study Group. Visceral Adiposity Index: a reliable indicator of visceral fat function associated with cardiometabolic risk. Diabetes Care. 2010;33(04):920-922. Doi: 10.2337/dc09-1825
https://doi.org/10.2337/dc09-1825...
and the lipid accumulation product (LAP) was calculated as (WC(cm)-58) x (TG9mmol)), as established for women.4040 Kahn HS, Valdez R. Metabolic risks identified by the combination of enlarged waist and elevated triacylglycerol concentration. Am J Clin Nutr. 2003;78(05):928-934. Doi: 10.1093/ajcn/78.5.928
https://doi.org/10.1093/ajcn/78.5.928...

Biochemical Measurements

A glucose oxidase technique (Beckman Glucose Analyses, Fullerton, CA, USA) was used to measure fasting glucose. For the oral glucose tolerance test (OGTT), blood samples were collected at 0, 30, 60, 90, 120, and 180 minutes after the ingestion of 75 g of dextrose for the measurement of plasma glucose and insulin levels.4141 Medeiros SF,Gil-JuniorAB, Barbosa JS, Isaías ED,YamamotoMM.New insights into steroidogenesis in normo- and hyperandrogenic polycystic ovary syndrome patients. Arq Bras Endocrinol Metabol. 2013; 57(06):437-444. Doi: 10.1590/s0004-27302013000600005
https://doi.org/10.1590/s0004-2730201300...
Glycated hemoglobin was measured using the turbidimetric assay (Wiener Laboratories, Rosario, Argentina). The estimated average glucose (eAG, mmol/L) was calculated using the equation eAG= 1.5944 multiplied by glycated hemoglobin minus 2.5944.4242 Nathan DM, Kuenen J, Borg R, Zheng H, Schoenfeld D, Heine RJA1c- Derived Average Glucose Study Group. Translating the A1C assay into estimated average glucose values. Diabetes Care. 2008;31 (08):1473-1478. Doi: 10.2337/dc08-0545
https://doi.org/10.2337/dc08-0545...
Homeostatic Model Assessment of Insulin Resistance (HOMA-IR), and basal insulin release (β-cell function, HOMA % B) were calculated using the free HOMA 2 calculator software (Diabetes Trials Unit, Oxford, UK).4343 Matthews DR, Hosker JP, Rudenski AS, Naylor BA, Treacher DF, Turner RC. Homeostasismodel assessment: insulin resistance and beta-cell function from fasting plasma glucose and insulin concentrations in man. Diabetologia. 1985;28(07):412-419. Doi: 10.1007/BF00280883
https://doi.org/10.1007/BF00280883...
Triglycerides (TG), high-density lipoprotein cholesterol (HDL-C), and total cholesterol (TC) were measured after a 12-hour overnight fast using an enzymatic assay (Wiener Laboratories, Rosario, Argentina). Low-density lipoprotein cholesterol (LDL-C) was calculated as TC – (HDL-C + TG/5).4444 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(06):499-502

Hormone Measurements

Without the requirement of any resting period, blood samples were taken by cubital venipuncture between 7:30 and 10:00 am, after 10 to 12 hours of fasting, between the 3rd and 5th days of spontaneous menstruation or, in the case of infrequent menses or amenorrhea, on any day regardless of the time elapsed since the last menstrual period; in this case, the progesterone (P4) level was used to certify that samples were collected in the follicular phase and the results were validated whenever the P4 level was < 6.3 nmol/L.4545 de Medeiros SF, Yamamoto MM, Bueno HB, Belizario D, Barbosa JS. Prevalence of elevated glycated hemoglobin concentrations in the polycystic ovary syndrome: anthropometrical and metabolic relationship in amazonian women. J Clin Med Res. 2014;6(04): 278-286. Doi: 10.14740/jocmr1829w
https://doi.org/10.14740/jocmr1829w...
4646 Medeiros SF, Barbosa JS, YamamotoMM. Comparison of steroidogenic pathways among normoandrogenic and hyperandrogenic polycystic ovary syndrome patients and normal cycling women. J Obstet Gynaecol Res. 2015;41(02):254-263 Thyroid-stimulating hormone, estradiol (E2), PRL, SHBG, total T, DHEA, and FT4 were measured with an electrochemiluminescence assay (Elecsys 1010, Roche Diagnostics GmbH, Mannheim, Germany). Serum P4, A4, DHEAS, cortisol (F), and insulin were measured using a chemiluminescence assay (Advia Centaur, Siemens Healthcare Diagnostics, UK or Siemens Medical Solution Diagnostics, Los Angeles, CA, USA). Free testosterone concentrations were measured using an ELISA kit (GenWay Biotech Inc., San Diego, CA, USA). 17-hydroxyprogesterone levels were verified using a coat-a-count radioimmunoassay (Siemens Health Care Diagnostics Inc., Los Angeles CA, USA). The precision of these hormone measurements was verified in a recent publication.3333 de Medeiros SF, Yamamoto MMW, Souto de Medeiros MA, Barbosa BB, Soares JM, Baracat EC. Changes in clinical and biochemical characteristics of polycystic ovary syndrome with advancing age. Endocr Connect. 2020;9(02):74-89. Doi: 10.1530/EC-19-0496
https://doi.org/10.1530/EC-19-0496...
The FAI was calculated as T (nmol/L divided by SHBG (nmol/L) × 100, and index of hyperandrogenism (IHA) was estimated as fifth root FAI x A4 X DHEA x DHEAS.4646 Medeiros SF, Barbosa JS, YamamotoMM. Comparison of steroidogenic pathways among normoandrogenic and hyperandrogenic polycystic ovary syndrome patients and normal cycling women. J Obstet Gynaecol Res. 2015;41(02):254-263

Statistical Analysis

The original data of each variable were initially submitted to the Grubs test to avoid interference of outliers. Distributions of all variables were examined using the Shapiro–Wilk test. Data with asymmetric distribution are presented as numbers and percentages (n%), and data with symmetric distribution are shown as mean (x̅) and standard deviation (SD). Proportions were compared using the chi-squared test or the Fisher exact test when appropriate. Comparisons of Gaussian variables were performed using one-way analysis of variance (ANOVA). Univariate logistic regression was applied to examine the relationship between anthropometric and metabolic parameters as dependent variables and DHEA, DHEAS, DHEA/T ratio, and DHEAS/T ratios as independent variables. The strength of independent variables in predicting anthropometric and metabolic abnormalities were controlled by age and BMI and given as odds ratio (OR) and 95% confidence interval (CI). The Kruskal-Wallis test, followed by the Bonferroni post-hoc test, was used in univariate logistic regression. For all univariate logistic regression analyses, the 90th percentile of dependent variables, taken from 425 normal-weight non-PCOS controls, was used as a cutoff.99 de Medeiros SF, de Medeiros MAS, Barbosa BB, Yamamoto MMW. Relationship of biological markers of body fat distribution and corticosteroidogenic enzyme activities in women with polycystic ovary syndrome. Horm Metab Res. 2019;51(10):639-648. Doi: 10.1055/a-0975-9207
https://doi.org/10.1055/a-0975-9207...
The explained variation in the criterion variable was given by Cox and Snell R2 and Nagelkerke R2 values. Multivariate forward stepwise logistic regression was done including DHEA, DHEAS, DHEA/T, and DHEAS/T as significant independent variables in the models. Age and BMI were also included to control for confounders. The fit of the logistic regression models was evaluated using the Hosmer–Lemeshow goodness-of-fit test. Receiver operating characteristic (ROC) analysis curves were calculated using DHEA, DHEAS, DHEA/T, and DHEAS/T as independent variables, and significant anthropometric and metabolic variables were used as dependent variables. All tests were two-sided, and p-values < 0.05 were considered statistically significant. All statistical procedures were performed using SPSS Statistics for Windows, version 17 (SPSS Inc, Chicago, IL, USA).

Results

Comparisons of age, ethnicity, clinical, and hormone parameters among groups are shown in Table 1 . Most PCOS patients were Caucasians, 72.4% NA-PCOS and 70.6% HA-PCOS (p = 0.603). African descendants were 9.6 and 12.7% NA-PCOS and HA-PCOS, respectively (p = 0.307). Women of other ethnicities were also similar in NA-PCOS and HA-PCOS (18.0 versus 16.0%, respectively, p = 0.711). Among controls, the distribution of these ethnicities was different from that of the PCOS groups: 89.3% were Caucasians, 60.0% were African descendants, and 4.7% were of other races (p < 0.05 for all comparisons). Comparisons of anthropometric, anthropometric-metabolic indexes, and metabolic characteristics of normal cycling controls, NA-PCOS, and HA-PCOS women are shown in Supplementary Table S1 (available online only).

Table 1
Comparisons of baseline clinical characteristics of normoandrogenemic, hyperandrogenemic, women with polycystic ovary syndrome, and normal cycling controls

The Predictive Role of DHEA in Clinical, Anthropometric, and Metabolic Parameters

In non-PCOS controls, DHEA had no significant predictive role but tended to predict an increase in SBP (OR = 2.47; p = 0.054; area under the curve [AUC] = 0.705; p < 0.001), and a decrease in eAG (OR = 0.69; p = 0.051; AUC = 0.700; p = 0.006) without reaching statistical significance. In NA-PCOS (Table 2), DHEA levels predicted elevation in body weight (OR = 2.58; p = 0.039), fasting glucose (OR = 4.36; p = 0.021), and against increase in HOMA %B (OR = 0.58; 0.029). In HA-PCOS, Table 3, DHEA significantly predicted against the increase in most anthropometric-metabolic indexes (OR = 0.36–0.97). Regarding biochemical markers, DHEA levels predicted against elevation of TG concentrations (OR = 0.76; p = 0.006).

Table 2
Age and body mass index controlled univariate logistic regression between clinical, anthropometric, anthropometric-metabolic indexes, and metabolic biomarkers as dependent variables, and dehydroepiandrosterone as the independent variable in normoandrogenemic women with polycystic ovary syndrome
Table 3
Age and body mass index controlled univariate logistic regression between clinical, anthropometric, anthropometric-metabolic indexes, and metabolic biomarkers as dependent variables, and dehydroepiandrosterone as the independent variable in hyperandrogenemic women with polycystic ovary syndrome

The Predictive Role of DHEAS in Clinical, Anthropometric, and Metabolic Parameters

In non-PCOS controls, DHEAS was not associated with any abnormality in anthropometric or anthropometric-metabolic index. Regarding metabolic parameters, DHEAS predicted against increase in eAG (OR = 0.38; p = 0.036; AUC = 0.706; p = 0.001). In NA-PCOS women, DHEAS only predicted against increase in WHR (OR = 0.59; p = 0.042; AUC = 0.757; p = 0.002). In HA-PCOS, DHEAS concentrations predicted against elevation in the CI (OR = 0.31; p = 0.028; AUC = 0.740; p < 0.001) (Table 3).

The Predictive Role of DHEA/total Testosterone Ratio in Clinical, Anthropometric, and Metabolic Parameters

The DHEA/total testosterone ratio (DHEA/T) was a good predictor against increase in WHR (OR = 0.44; p = 0.015; AUC = 0.662; p < 0.001) in the control group. In NA-PCOS women, the DHEA/T ratio tended to predict against increase in BW (OR = 0.95; p = 0.071; AUC = 0.974; p < 0.001), and decrease in C-pep levels (OR = 0.68; p = 0.070; AUC = 0.805; p < 0.001). This ratio predicted increase in fasting glucose (OR = 2.65; p = 0.018; AUC = 0.915; p < 0.001). In HA-PCOS women (Table 4), the DHEA/T ratio predicted against increase in WTI (OR = 0.70; p = 0.003), CI (OR = 0.79; p = 0.036), BSI (OR = 0.77; p = 0.046), VAI (OR = 0.76; p = 0.039), and LAP (OR = 0.76; p = 0.032). However, with statistical significance, the DHEA/T ratio predicted against increase in TC (OR = 0.76; p = 0.033), in VLDL-C (OR = 0.90; p = 0.049), and in TG (OR = 0.72; p = 0.006).

Table 4
Age and body mass controlled univariate logistic regression between clinical, anthropometric, and anthropometric-metabolic indexes as dependent variables, and dehydrotestosterone/testosterone ratio as the independent variable in hyperandrogenic women with polycystic ovary syndrome

The Predictive Role of DHEAS/Total Testosterone Ratio in Clinical, Anthropometric, and Metabolic Parameters

In non-PCOS controls (Table 5), the DHEAS/T ratio predicted only against the increase in WHR (OR = 0.44; p = 0.015; AUC = 0.663; p < 0.001). In NA-PCOS, the DHEAS/ T ratio did not predict any biomarker of anthropometric or metabolic abnormalities. In the HA-PCOS group, the DHEAS/T ratio predicted against increase in CI (OR = 0.29; p = 0.007; AUC = 0.738; p < 0.001), and in TC (OR = 0.37; p = 0.041; AUC = 0.655; p = 0.001). Without reaching statistical significance, this ratio also tended to predict against increase in VLDL-C (OR = 0.87; p = 0.084; AUC = 0.570; p < 0.001), and in WTI (OR = 0.64; p = 0.067; AUC = 0.719; p < 0.001).

Table 5
Final models of multivariate logistic regression analysis between anthropometric, anthropometric-metabolic, and metabolic indexes it is dependent variables and androgens as independent variables in non-polycystic ovary syndrome controls and women with polycystic ovary syndrome

Multivariate Logistic Regression Analysis

Multivariate logistic regression models, consistent with univariate regression, retained the predictive role of the DHEAS/T ratio against increase in WHR (OR = 0.44; p = 0.016) and of DHEAS against increase in eAG (OR = 0.36; p = 0.029) in the non-PCOS control group. In NA-PCOS women, the results of the univariate regression were maintained after multiple regression. Thus, DHEA maintained the predictive role favoring increase in BW (OR = 2.60; p = 0.019). In these women, DHEA also predicted against the increase in HOMA %B (OR = 0.34; p = 0.039). The DHEA/T ratio favors an increase in fasting glucose (OR = 2.60; p = 0.019). In HA-PCOS, DHEA maintained prediction against the increase in VAI (OR = 0.74; p = 0.006) and in TG (OR = 0.74; p = 0.002). The DHEAS/T ratio predicted against the increase in TC (OR = 0.30; p = 0.005); nevertheless, the DHEAS/T ratio favors an increase in CI (OR = 1.54; p = 0.004). The DHEA/T ratio predicted against an increase in WTI (OR = 0.70; p = 0.004) and in LAP (OR = 0.76; p = 0.038).

Discussion

Many studies have investigated the role of adrenal androgens in PCOS. There have been attempts to translate basic knowledge into the clinical practice. The present study evaluated the strength of adrenal androgens in predicting blood pressure, anthropometric, and metabolic abnormalities in women with PCOS, after separating PCOS women with normal from high androgens in the blood. The impact of DHEA, DHEAS, and the ratios of these prohormones and total testosterone were considered because between ∼ 70 and 95% of DHEA and DHEAS molecules have the adrenal gland as a primary source.2626 Goodarzi MO, Carmina E, Azziz R. DHEA, DHEAS and PCOS. J Steroid Biochem Mol Biol. 2015;145:213-225. Doi: 10.1016/j.jsbmb.2014.06.003
https://doi.org/10.1016/j.jsbmb.2014.06....
Either in a combination of various androgens or in the elevation of at least one androgen, biochemical hyperandrogenism is found in > 70% of women with PCOS.4646 Medeiros SF, Barbosa JS, YamamotoMM. Comparison of steroidogenic pathways among normoandrogenic and hyperandrogenic polycystic ovary syndrome patients and normal cycling women. J Obstet Gynaecol Res. 2015;41(02):254-263 4747 Huang K, Bao JP, Jennings GJ, WuLD. The disease-modifying effect of dehydroepiandrosterone in different stages of experimentally induced osteoarthritis: a histomorphometric study. BMC Musculoskelet Disord. 2015;16:178. Doi: 10.1186/s12891-015-0595-1
https://doi.org/10.1186/s12891-015-0595-...
Higher androgens of the adrenal source are reported in between 20 and 30% of PCOS women.4848 Azziz R, Woods KS, Reyna R, Key TJ, Knochenhauer ES, Yildiz BO. The prevalence and features of the polycystic ovary syndrome in an unselected population. J Clin Endocrinol Metab. 2004;89(06): 2745-2749. Doi: 10.1210/jc.2003-032046
https://doi.org/10.1210/jc.2003-032046...
4949 Gil Junior AB, Rezende AP, do Carmo AV, Duarte EI, de Medeiros MM, de Medeiros SF. [Adrenal androgen participation in the polycystic ovary syndrome]. Rev Bras Ginecol Obstet. 2010;32 (11):541-548. Doi: 10.1590/s0100-72032010001100005
https://doi.org/10.1590/s0100-7203201000...
Insulin resistance is a common comorbidity of hyperandrogenemic PCOS through decreased insulin-like growth factor 1 (IGF-BP) leading to increased free insulin-like growth factor 1 (IGF-1), which stimulates ovarian androgen production.5050 Dunaif A. Insulin resistance and the polycystic ovary syndrome: mechanismand implications for pathogenesis. Endocr Rev. 1997; 18(06):774-800. Doi: 10.1210/edrv.18.6.0318
https://doi.org/10.1210/edrv.18.6.0318...
The role of insulin resistance in the adrenal function of PCOS women is unclear.5151 Tosi F, Negri C, Brun E, Castello R, Faccini G, Bonora E, et al. Insulin enhances ACTH-stimulated androgen and glucocorticoid metabolism in hyperandrogenic women. Eur J Endocrinol. 2011;164 (02):197-203. Doi: 10.1530/EJE-10-0782
https://doi.org/10.1530/EJE-10-0782...
Conversely, the cross-talk between adrenal androgens and insulin acting in women with PCOS is of clinical relevance. Furthermore, while insulin is higher in obesity, cortisol (F), DHEA, and DHEAS appear to be lower.5252 Tock L, Carneiro G, Pereira AZ, Tufik S, Zanella MT. Adrenocortical production is associated with higher levels of luteinizing hormone in nonobese women with polycystic ovary syndrome. Int J Endocrinol. 2014;2014:620605. Doi: 10.1155/2014/620605
https://doi.org/10.1155/2014/620605...

The incidence of 75% of biochemical hyperandrogenism in women with PCOS in the present study is in agreement with other studies.5353 Lerchbaum E, Schwetz V, Rabe T, Giuliani A, Obermayer-Pietsch B. Hyperandrogenemia in polycystic ovary syndrome: exploration of the role of free testosterone and androstenedione in metabolic phenotype. PLoS One. 2014;9(10):e108263. Doi: 10.1371/journal. pone.0108263
https://doi.org/10.1371/journal...
5454 Alexiou E, Hatziagelaki E, Pergialiotis V, Chrelias C, Kassanos D, Siristatidis C, et al. Hyperandrogenemia inwomen with polycystic ovary syndrome: prevalence, characteristics and associationwith body mass index. Horm Mol Biol Clin Investig. 2017;29(03): 105-111. Doi: 10.1515/hmbci-2016-0047
https://doi.org/10.1515/hmbci-2016-0047...
5555 Yanes Cardozo LL, Romero DG, Reckelhoff JF. Cardiometabolic features of polycystic ovary syndrome: role of androgens. Physiology (Bethesda). 2017;32(05):357-366. Doi: 10.1152/physiol.00030.2016
https://doi.org/10.1152/physiol.00030.20...
As shown in Table 1, the slightly higher SBP and DBP levels in PCOS than in controls, observed mainly in the hyperandrogenemic group, found in the present study, also endorse previous findings.5656 Chen MJ, Yang WS, Yang JH, Chen CL, Ho HN, Yang YS. Relationship between androgen levels and blood pressure in young women with polycystic ovary syndrome. Hypertension. 2007;49(06): 1442-1447. Doi: 10.1161/HYPERTENSIONAHA.106.083972
https://doi.org/10.1161/HYPERTENSIONAHA....
5757 Oliveira RdoS, Redorat RG, Ziehe GH, Mansur VA, Conceição FL. Arterial hypertension and metabolic profile in patients with polycystic ovary syndrome. Rev Bras Ginecol Obstet. 2013;35 (01):21-26. Doi: 10.1590/s0100-72032013000100005
https://doi.org/10.1590/s0100-7203201300...
5858 Amiri M, Ramezani Tehrani F, Behboudi-Gandevani S, Bidhendi- Yarandi R, Carmina E. Risk of hypertension in women with polycystic ovary syndrome: a systematic review, meta-analysis and meta-regression. Reprod Biol Endocrinol. 2020;18(01):23. Doi: 10.1186/s12958-020-00576-1
https://doi.org/10.1186/s12958-020-00576...
In the same way, a higher prevalence of glucose intolerance in women with PCOS has been extensively found.77 Yang R, Yang S, Li R, Liu P, Qiao J, Zhang Y. Effects of hyperandrogenism on metabolic abnormalities in patients with polycystic ovary syndrome: a meta-analysis. Reprod Biol Endocrinol. 2016;14(01):67. Doi: 10.1186/s12958-016-0203-8
https://doi.org/10.1186/s12958-016-0203-...
1313 Couto Alves A, Valcarcel B, Mäkinen VP, Morin-Papunen L, Sebert S, Kangas AJ, et al. Metabolic profiling of polycystic ovary syndrome reveals interactions with abdominal obesity. Int J Obes. 2017;41(09):1331-1340. Doi: 10.1038/ijo.2017.126
https://doi.org/10.1038/ijo.2017.126...
4545 de Medeiros SF, Yamamoto MM, Bueno HB, Belizario D, Barbosa JS. Prevalence of elevated glycated hemoglobin concentrations in the polycystic ovary syndrome: anthropometrical and metabolic relationship in amazonian women. J Clin Med Res. 2014;6(04): 278-286. Doi: 10.14740/jocmr1829w
https://doi.org/10.14740/jocmr1829w...
5959 Carmina E, Koyama T, Chang L, Stanczyk FZ, Lobo RA. Does ethnicity influence the prevalence of adrenal hyperandrogenism and insulin resistance in polycystic ovary syndrome? Am J Obstet Gynecol. 1992;167(06):1807-1812. Doi: 10.1016/0002-9378(92)91779-a
https://doi.org/10.1016/0002-9378(92)917...
6060 Li L, Yang D, Chen X, Chen Y, Feng S,Wang L. Clinical and metabolic features of polycystic ovary syndrome. Int J Gynaecol Obstet. 2007;97(02):129-134. Doi: 10.1016/j.ijgo.2007.01.005
https://doi.org/10.1016/j.ijgo.2007.01.0...
The finding that, in NA-PCOS, DHEA was negatively correlated with body weight, fasting glucose, and β-cell activity, indicates a protective role of DHEA against adiposity and insulin resistance. In previous studies, DHEA has been shown to inhibit the proliferation and differentiation of adipocytes in the subcutaneous adipose tissue compartment (SAT) and to increase adipocyte glucose uptake in this location.2121 Perrini S, Natalicchio A, Laviola L, Belsanti G, Montrone C, Cignarelli A, et al. Dehydroepiandrosterone stimulates glucose uptake in human and murine adipocytes by inducing GLUT1 and GLUT4 translocation to the plasma membrane. Diabetes. 2004;53(01): 41-52. Doi: 10.2337/diabetes.53.1.41
https://doi.org/10.2337/diabetes.53.1.41...
6161 Fujioka K, Kajita K, Wu Z, Hanamoto T, Ikeda T, Mori I, et al. Dehydroepiandrosterone reduces preadipocyte proliferation via androgen receptor. AmJ Physiol Endocrinol Metab. 2012;302(06): E694-E704. Doi: 10.1152/ajpendo.00112.2011
https://doi.org/10.1152/ajpendo.00112.20...
Additionally, DHEA appears to inhibit adipogenesis in omental adipocytes through an increase in resistin production.2020 Hansen PA, Han DH, Nolte LA, ChenM, Holloszy JO. DHEA protects against visceral obesity and muscle insulin resistance in rats fed a high-fat diet. Am J Physiol. 1997;273(05):R1704-R1708. Doi: 10.1152/ajpregu.1997.273.5.R1704
https://doi.org/10.1152/ajpregu.1997.273...
6262 Kochan Z, Karbowska J. Dehydroepiandrosterone up-regulates resistin gene expression in white adipose tissue. Mol Cell Endocrinol. 2004;218(1-2):57-64. Doi: 10.1016/j.mce.2003.12.012
https://doi.org/10.1016/j.mce.2003.12.01...
Dehydroepiandrosterone also increases insulin signaling to its secretion and protects against omental adipogenesis.6363 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(06):693-700. Doi: 10.2337/diab.40.6.693
https://doi.org/10.2337/diab.40.6.693...
Furthermore, DHEA suppresses the activity and expression of glucose-6-phosphate and of phosphoenol carboxykinase, decreasing gluconeogenesis and increasing glucose uptake in the adipocyte and hepatocyte.6464 Yamashita R, Saito T, Satoh S, Aoki K, Kaburagi Y, Sekihara H. Effects of dehydroepiandrosterone on gluconeogenic enzymes and glucose uptake in human hepatoma cell line, HepG2. Endocr J. 2005;52(06):727-733. Doi: 10.1507/endocrj.52.727
https://doi.org/10.1507/endocrj.52.727...
Clinical biomarkers of central adiposity were not correlated with DHEA concentrations in the present study in normoandrogenemic women with PCOS.

On the other hand, in HA-PCOS women, DHEA was negatively correlated with various anthropometric-metabolic indexes and TG abnormalities. Thus, the present study supports the knowledge of the beneficial role of DHEA levels in women with PCOS, at least in those with high androgen levels.1818 O'Reilly MW, House PJ, Tomlinson JW. Understanding androgen action in adipose tissue. J Steroid Biochem Mol Biol. 2014; 143:277-284. Doi: 10.1016/j.jsbmb.2014.04.008
https://doi.org/10.1016/j.jsbmb.2014.04....
6565 De Pergola G, Zamboni M, Sciaraffia M, Turcato E, Pannacciulli N, Armellini F, et al. Body fat accumulation is possibly responsible for lower dehydroepiandrosterone circulating levels in premenopausal obese women. Int J Obes Relat Metab Disord. 1996;20 (12):1105-1110 Both in vitro and in vivo studies have shown a protective role of DHEA in the cardiovascular system.6666 Mannic T, Viguie J, Rossier MF. In vivo and in vitro evidences of dehydroepiandrosterone protective role on the cardiovascular system. Int J Endocrinol Metab. 2015;13(02):e24660. Doi: 10.5812/ijem.24660
https://doi.org/10.5812/ijem.24660...
Furthermore, lower levels of DHEA are associated with increased body fat accumulation.6767 Tchernof A, Labrie F. Dehydroepiandrosterone, obesity and cardiovascular disease risk: a review of human studies. Eur J Endocrinol. 2004;151(01):1-14. Doi: 10.1530/eje.0.1510001
https://doi.org/10.1530/eje.0.1510001...
In contrast, high levels of DHEA are associated with lower BMI,6868 Moran C, Arriaga M, Arechavaleta-Velasco F, Moran S. Adrenal androgen excess and body mass index in polycystic ovary syndrome. J Clin Endocrinol Metab. 2015;100(03):942-950. Doi: 10.1210/jc.2014-2569
https://doi.org/10.1210/jc.2014-2569...
lower body fat accumulation, and lower risk of T2DM.6969 Zerradi M, Dereumetz J, BouletMM, Tchernof A. Androgens, body fat Distribution and Adipogenesis. Curr Obes Rep. 2014;3(04): 396-403. Doi: 10.1007/s13679-014-0119-6
https://doi.org/10.1007/s13679-014-0119-...
7070 Brahimaj A, Ligthart S, IkramMA, Hofman A, Franco OH, Sijbrands EJG, et al. Serum levels of apolipoproteins and incident type 2 diabetes: a prospective cohort study. Diabetes Care. 2017;40(03): 346-351. Doi: 10.2337/dc16-1295
https://doi.org/10.2337/dc16-1295...
An antiatherogenic effect of DHEA through inhibition of fibroblast growth, improvement of lipid profile, and decrease of platelet aggregation has also been shown.7171 Nestler JE, Clore JN, Blackard WG. Dehydroepiandrosterone: the "missing link" between hyperinsulinemia and atherosclerosis? FASEB J. 1992;6(12):3073-3075. Doi: 10.1096/fasebj.6.12.1387859
https://doi.org/10.1096/fasebj.6.12.1387...
It is worthy of note that lower levels of DHEA are found in hyperinsulinemic status due to its diminished synthesis or increased metabolic clearance. Additionally, high levels of glucose and insulin might impair DHEA synthesis in the adrenal gland.7272 Farah-Eways L, Reyna R, Knochenhauer ES, Bartolucci AA, Azziz R. Glucose action and adrenocortical biosynthesis in women with polycystic ovary syndrome. Fertil Steril. 2004;81(01):120-125. Doi: 10.1016/j.fertnstert.2003.05.008
https://doi.org/10.1016/j.fertnstert.200...

In PCOS, as a whole group, high levels of DHEAS have been found in between 18 and 72%.2525 LerchbaumE, Schwetz V, Giuliani A, Pieber TR,Obermayer-Pietsch B. Opposing effects of dehydroepiandrosterone sulfate and free testosterone on metabolic phenotype in women with polycystic ovary syndrome. Fertil Steril. 2012;98(05):1318-25.e1. Doi: 10.1016/j.fertnstert.2012.07.1057
https://doi.org/10.1016/j.fertnstert.201...
5959 Carmina E, Koyama T, Chang L, Stanczyk FZ, Lobo RA. Does ethnicity influence the prevalence of adrenal hyperandrogenism and insulin resistance in polycystic ovary syndrome? Am J Obstet Gynecol. 1992;167(06):1807-1812. Doi: 10.1016/0002-9378(92)91779-a
https://doi.org/10.1016/0002-9378(92)917...
7373 Morán C, Knochenhauer E, Boots LR, Azziz R. Adrenal androgen excess in hyperandrogenism: relation to age and body mass. Fertil Steril. 1999;71(04):671-674. Doi: 10.1016/s0015-0282(98)00536-6
https://doi.org/10.1016/s0015-0282(98)00...
7474 Alpañés M, Luque-Ramírez M, Martínez-García MA, Fernández- Durán E, Álvarez-Blasco F, Escobar-Morreale HF. Influence of adrenal hyperandrogenism on the clinical and metabolic phenotype of women with polycystic ovary syndrome. Fertil Steril. 2015;103(03):795-801.e2. Doi: 10.1016/j.fertnstert.2014.12.105
https://doi.org/10.1016/j.fertnstert.201...
The high levels of DHEAS have also been associated with a favorable metabolic and cardiovascular profile.7474 Alpañés M, Luque-Ramírez M, Martínez-García MA, Fernández- Durán E, Álvarez-Blasco F, Escobar-Morreale HF. Influence of adrenal hyperandrogenism on the clinical and metabolic phenotype of women with polycystic ovary syndrome. Fertil Steril. 2015;103(03):795-801.e2. Doi: 10.1016/j.fertnstert.2014.12.105
https://doi.org/10.1016/j.fertnstert.201...
7575 Vryonidou A, Papatheodorou A, Tavridou A, Terzi T, Loi V, Vatalas I-A, et al. Association of hyperandrogenemic and metabolic phenotypewith carotid intima-media thickness in young women with polycystic ovary syndrome. J Clin EndocrinolMetab. 2005;90 (05):2740-2746. Doi: 10.1210/jc.2004-2363
https://doi.org/10.1210/jc.2004-2363...
7676 Carmina E, Lobo RA. Prevalence and metabolic characteristics of adrenal androgen excess in hyperandrogenic women with different phenotypes. J Endocrinol Invest. 2007;30(02):111-116. Doi: 10.1007/BF03347408
https://doi.org/10.1007/BF03347408...
7777 Brennan K, Huang A, Azziz R. Dehydroepiandrosterone sulfate and insulin resistance in patients with polycystic ovary syndrome. Fertil Steril. 2009;91(05):1848-1852. Doi: 10.1016/j.fertnstert.2008.02.101
https://doi.org/10.1016/j.fertnstert.200...
7878 Chen MJ, Chen CD, Yang JH, Chen C-L,Ho H-N, YangW-S, et al.High serum dehydroepiandrosterone sulfate is associated with phenotypic acne and a reduced risk of abdominal obesity inwomen with polycystic ovary syndrome. Hum Reprod. 2011;26(01):227-234. Doi: 10.1093/humrep/deq308
https://doi.org/10.1093/humrep/deq308...
DHEAS opposes T action concerning the risk of obesity, and IR.2525 LerchbaumE, Schwetz V, Giuliani A, Pieber TR,Obermayer-Pietsch B. Opposing effects of dehydroepiandrosterone sulfate and free testosterone on metabolic phenotype in women with polycystic ovary syndrome. Fertil Steril. 2012;98(05):1318-25.e1. Doi: 10.1016/j.fertnstert.2012.07.1057
https://doi.org/10.1016/j.fertnstert.201...
High levels of DHEAS are associated with lower BMI6868 Moran C, Arriaga M, Arechavaleta-Velasco F, Moran S. Adrenal androgen excess and body mass index in polycystic ovary syndrome. J Clin Endocrinol Metab. 2015;100(03):942-950. Doi: 10.1210/jc.2014-2569
https://doi.org/10.1210/jc.2014-2569...
when compound with controls and its levels decrease after weight loss after bariatric surgery.7979 Misichronis G, GeorgopoulosNA, Marioli DJ, Armeni AK, Katsikis I, Piouka AD, et al. The influence of obesity on androstenedione to testosterone ratio in women with polycystic ovary syndrome (PCOS) and hyperandrogenemia. Gynecol Endocrinol. 2012;28 (04):249-252. Doi: 10.3109/09513590.2011.613965
https://doi.org/10.3109/09513590.2011.61...
Dehydroepiandrosterone sulfate levels have been negatively correlated with WC, WHR, LDL-C, and TG concentrations, adjusted for the confounding effects of age and BMI.7474 Alpañés M, Luque-Ramírez M, Martínez-García MA, Fernández- Durán E, Álvarez-Blasco F, Escobar-Morreale HF. Influence of adrenal hyperandrogenism on the clinical and metabolic phenotype of women with polycystic ovary syndrome. Fertil Steril. 2015;103(03):795-801.e2. Doi: 10.1016/j.fertnstert.2014.12.105
https://doi.org/10.1016/j.fertnstert.201...
7878 Chen MJ, Chen CD, Yang JH, Chen C-L,Ho H-N, YangW-S, et al.High serum dehydroepiandrosterone sulfate is associated with phenotypic acne and a reduced risk of abdominal obesity inwomen with polycystic ovary syndrome. Hum Reprod. 2011;26(01):227-234. Doi: 10.1093/humrep/deq308
https://doi.org/10.1093/humrep/deq308...
Furthermore, DHEAS levels were negatively correlated with carotid intima-media thickness7575 Vryonidou A, Papatheodorou A, Tavridou A, Terzi T, Loi V, Vatalas I-A, et al. Association of hyperandrogenemic and metabolic phenotypewith carotid intima-media thickness in young women with polycystic ovary syndrome. J Clin EndocrinolMetab. 2005;90 (05):2740-2746. Doi: 10.1210/jc.2004-2363
https://doi.org/10.1210/jc.2004-2363...
and improved endothelial function.8080 Huang R, Zheng J, Li S, Tao T, Ma J, Liu W. Characteristics and contributions of hyperandrogenism to insulin resistance and other metabolic profiles in polycystic ovary syndrome. Acta Obstet Gynecol Scand. 2015;94(05):494-500. Doi: 10.1111/aogs.12612
https://doi.org/10.1111/aogs.12612...
The predictive value of DHEAS against abnormalities in WHR and in the CI of women with PCOS seen in the present study supports its beneficial effect on predicting anthropometric and metabolic derangements.2525 LerchbaumE, Schwetz V, Giuliani A, Pieber TR,Obermayer-Pietsch B. Opposing effects of dehydroepiandrosterone sulfate and free testosterone on metabolic phenotype in women with polycystic ovary syndrome. Fertil Steril. 2012;98(05):1318-25.e1. Doi: 10.1016/j.fertnstert.2012.07.1057
https://doi.org/10.1016/j.fertnstert.201...
7474 Alpañés M, Luque-Ramírez M, Martínez-García MA, Fernández- Durán E, Álvarez-Blasco F, Escobar-Morreale HF. Influence of adrenal hyperandrogenism on the clinical and metabolic phenotype of women with polycystic ovary syndrome. Fertil Steril. 2015;103(03):795-801.e2. Doi: 10.1016/j.fertnstert.2014.12.105
https://doi.org/10.1016/j.fertnstert.201...
8181 Savastano S, Belfiore A, Guida B, Angrisani L, Orio F Jr, Cascella T, et al. Role of dehydroepiandrosterone sulfate levels on body composition after laparoscopic adjustable gastric banding in pre-menopausal morbidly obese women. J Endocrinol Invest. 2005;28(06):509-515. Doi: 10.1007/BF03347238
https://doi.org/10.1007/BF03347238...
8282 Simoncini T, Mannella P, Fornari L, Varone G, Caruso A, Genazzani AR. Dehydroepiandrosterone modulates endothelial nitric oxide synthesis via direct genomic and nongenomic mechanisms. Endocrinology. 2003;144(08):3449-3455. Doi: 10.1210/en.2003-0044
https://doi.org/10.1210/en.2003-0044...

The DHEA/T ratio was reported to be strongly associated with insulin sensitivity.6363 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(06):693-700. Doi: 10.2337/diab.40.6.693
https://doi.org/10.2337/diab.40.6.693...
However, there is an inconsistent correlation between the DHEAS/T ratio, insulin levels, and insulin receptor binding.8383 Meirow D, Raz I, Yossepowitch O, Brzezinski A, Rosler A, Schenker JG, et al. Dyslipidaemia in polycystic ovarian syndrome: different groups, different aetiologies? Hum Reprod. 1996;11(09):1848- -1853. Doi: 10.1093/oxfordjournals.humrep.a019505
https://doi.org/10.1093/oxfordjournals.h...
In the clinical practice, this ratio has been used for the prediction and early diagnosis of metabolic syndrome and it appears to antagonize the effect of T in women with PCOS, which is associated with a favorable metabolic profile.2525 LerchbaumE, Schwetz V, Giuliani A, Pieber TR,Obermayer-Pietsch B. Opposing effects of dehydroepiandrosterone sulfate and free testosterone on metabolic phenotype in women with polycystic ovary syndrome. Fertil Steril. 2012;98(05):1318-25.e1. Doi: 10.1016/j.fertnstert.2012.07.1057
https://doi.org/10.1016/j.fertnstert.201...
8484 Kösüs N, Kösüs A, Kamalak Z, Hizli D, Turhan NÖ Impact of adrenal versus ovarian androgen ratio on signs and symptoms of polycystic ovarian syndrome. Gynecol Endocrinol. 2012;28(08):611-614. Doi: 10.3109/09513590.2011.650770
https://doi.org/10.3109/09513590.2011.65...
Furthermore, this ratio has been negatively correlated with lower BMI, lower WC, lower WHR, lower TG, lower LDL-C, and higher HDL-C, insulin levels, and HOMA-IR.7676 Carmina E, Lobo RA. Prevalence and metabolic characteristics of adrenal androgen excess in hyperandrogenic women with different phenotypes. J Endocrinol Invest. 2007;30(02):111-116. Doi: 10.1007/BF03347408
https://doi.org/10.1007/BF03347408...
7777 Brennan K, Huang A, Azziz R. Dehydroepiandrosterone sulfate and insulin resistance in patients with polycystic ovary syndrome. Fertil Steril. 2009;91(05):1848-1852. Doi: 10.1016/j.fertnstert.2008.02.101
https://doi.org/10.1016/j.fertnstert.200...
7878 Chen MJ, Chen CD, Yang JH, Chen C-L,Ho H-N, YangW-S, et al.High serum dehydroepiandrosterone sulfate is associated with phenotypic acne and a reduced risk of abdominal obesity inwomen with polycystic ovary syndrome. Hum Reprod. 2011;26(01):227-234. Doi: 10.1093/humrep/deq308
https://doi.org/10.1093/humrep/deq308...
It also appears that the DHEA/T ratio improves lipid metabolism.8484 Kösüs N, Kösüs A, Kamalak Z, Hizli D, Turhan NÖ Impact of adrenal versus ovarian androgen ratio on signs and symptoms of polycystic ovarian syndrome. Gynecol Endocrinol. 2012;28(08):611-614. Doi: 10.3109/09513590.2011.650770
https://doi.org/10.3109/09513590.2011.65...
8585 Schriock ED, Buffington CK, Hubert GD, Kurtz BR, Kitabchi AE, Buster JE, et al. Divergent correlations of circulating dehydroepiandrosterone sulfate and testosterone with insulin levels and insulin receptor binding. J Clin Endocrinol Metab. 1988;66(06): 1329-1331. Doi: 10.1210/jcem-66-6-1329
https://doi.org/10.1210/jcem-66-6-1329...
8686 Lea-Currie YR, Wen P, McIntosh MK. Dehydroepiandrosteronesulfate (DHEAS) reduces adipocyte hyperplasia associated with feeding rats a high-fat diet. Int J Obes RelatMetab Disord. 1997;21 (11):1058-1064. Doi: 10.1038/sj.ijo.0800516
https://doi.org/10.1038/sj.ijo.0800516...
8787 Gambineri A, Patton L, Vaccina A, CacciariM,Morselli-Labate AM, Cavazza C, et al. Treatment with flutamide, metformin, and their combination added to a hypocaloric diet in overweight-obese women with polycystic ovary syndrome: a randomized, 12- month, placebo-controlled study. J Clin Endocrinol Metab. 2006;91(10):3970-3980. Doi: 10.1210/jc.2005-2250
https://doi.org/10.1210/jc.2005-2250...
8888 Ingelsson E, Schaefer EJ, Contois JH, McNamara JR, Sullivan L, Keyes MJ, et al. Clinical utility of different lipid measures for prediction of coronary heart disease in men and women. JAMA. 2007;298(07):776-785. Doi: 10.1001/jama.298.7.776
https://doi.org/10.1001/jama.298.7.776...
The present study supports the knowledge that the DHEA/T ratio predicts various abnormalities in anthropometric-metabolic indexes in PCOS women with biochemical hyperandrogenism and against the increase in fasting glucose despite normal androgens in the blood. Nevertheless, the predictive effect of DHEAS/T against anthropometric and metabolic abnormalities in PCOS is limited.

A few limitations must be considered in the analysis of the present study. The cross-sectional design does not allow to determine causal effects; instead, it provides associations or predictions. The assays used may have some imprecision, but they have presented a good correlation with the gold-standard high-performance liquid chromatography-tandem mass spectrometry assays.8989 Legro RS, Schlaff WD, Diamond MP, Coutifaris C, Casson PR, Brzyski R, 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 (12):5305-5313. Doi: 10.1210/jc.2010-1123
https://doi.org/10.1210/jc.2010-1123...
9090 Janse F, Eijkemans MJ, Goverde AJ, Lentjes EGWM, Hoek A, Lambalk CB, Hickey TE, et al. Assessment of androgen concentration in women: liquid chromatography-tandem mass spectrometry and extraction RIA show comparable results. Eur J Endocrinol. 2011;165(06):925-933. Doi: 10.1530/EJE-11-0482
https://doi.org/10.1530/EJE-11-0482...
The sample size, a clear definition for normoandrogenemic and hyperandrogenemic groups of women with PCOS, and their analysis in separate are the principal strengths of the present study.

Conclusion

Dehydroepiandrosterone has been demonstrated to be a better predictor of abnormal anthropometric and biochemical parameters in women with PCOS than DHEAS, particularly in hyperandrogenemic women. The DHEA/T ratio has also shown increased prediction to predict against increase in anthropometric and metabolic parameters in PCOS. Dehydroepiandrosterone measurement seems to be preferred in PCOS management. In general, in the clinical practice, it must be highlighted that the predictive and protective effects of both adrenal hormones DHEA and DHEAS are mild or weak.

Acknowledgments

The authors are grateful to Philip Lindeman, MD, Ph.D., Liberty Medical Communications, for the revision of the English version of the present manuscript.

References

  • 1
    MarchWA, Moore VM,Willson KJ, Phillips DI, Norman RJ, Davies MJ. The prevalence of polycystic ovary syndrome in a community sample assessed under contrasting diagnostic criteria. Hum Reprod. 2010;25(02):544-551. Doi: 10.1093/humrep/dep399
    » https://doi.org/10.1093/humrep/dep399
  • 2
    Zawadski JK, Dunaif A. Diagnostic criteria for polycystic ovary syndrome: towards a rational approach. In: Dunaif A, Givens JR, Haseltine F, eds. Polycystic ovary syndrome. Boston: Blackwell Scientific; 1992:377-384
  • 3
    Rotterdam ESHRE/ASRM-Sponsored PCOS Consensus Workshop Group. Revised 2003 consensus on diagnostic criteria and longterm health risks related to polycystic ovary syndrome. Fertil Steril. 2004;81(01):19-25. Doi: 10.1016/j.fertnstert.2003.10.004
    » https://doi.org/10.1016/j.fertnstert.2003.10.004
  • 4
    Azziz R, Carmina E, Dewailly D, Diamanti-Kandarakis E, Escobar- Morreale HF, Futterweit W, 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 (11):4237-4245. Doi: 10.1210/jc.2006-0178
    » https://doi.org/10.1210/jc.2006-0178
  • 5
    Jones H, Sprung VS, Pugh CJ, Daousi C, Irwin A, Aziz N, 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(10):3709-3716. Doi: 10.1210/jc.2012-1382
    » https://doi.org/10.1210/jc.2012-1382
  • 6
    Baranova A, Tran TP, Afendy A, Wang L, Shamsaddini A, Mehta R, 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. Doi: 10.1186/1479-5876-11-133
    » https://doi.org/10.1186/1479-5876-11-133
  • 7
    Yang R, Yang S, Li R, Liu P, Qiao J, Zhang Y. Effects of hyperandrogenism on metabolic abnormalities in patients with polycystic ovary syndrome: a meta-analysis. Reprod Biol Endocrinol. 2016;14(01):67. Doi: 10.1186/s12958-016-0203-8
    » https://doi.org/10.1186/s12958-016-0203-8
  • 8
    Kumarendran B, O'Reilly MW, Manolopoulos KN, Toulis KA, Gokhale KM, Sitch AJ, et al. Polycystic ovary syndrome, androgen excess, and the riskof nonalcoholic fatty liver disease inwomen: A longitudinal study based on a United Kingdom primary care database. PLoS Med. 2018;15(03):e1002542. Doi: 10.1371/journal.pmed.1002542
    » https://doi.org/10.1371/journal.pmed.1002542
  • 9
    de Medeiros SF, de Medeiros MAS, Barbosa BB, Yamamoto MMW. Relationship of biological markers of body fat distribution and corticosteroidogenic enzyme activities in women with polycystic ovary syndrome. Horm Metab Res. 2019;51(10):639-648. Doi: 10.1055/a-0975-9207
    » https://doi.org/10.1055/a-0975-9207
  • 10
    Kahal H, Kyrou I, Uthman OA, Brown A, Johnson S,Wall PDH, et al. The prevalence of obstructive sleep apnoea in women with polycystic ovary syndrome: a systematic review and meta-analysis. Sleep Breath. 2020;24(01):339-350. Doi: 10.1007/s11325-019-01835-1
    » https://doi.org/10.1007/s11325-019-01835-1
  • 11
    Sung YA, Oh JY, Chung H, Lee H. Hyperandrogenemia is implicated in both the metabolic and reproductive morbidities of polycystic ovary syndrome. Fertil Steril. 2014;101(03):840-845. Doi: 10.1016/j.fertnstert.2013.11.027
    » https://doi.org/10.1016/j.fertnstert.2013.11.027
  • 12
    Ezeh U, Pall M, Mathur R, Azziz R. Association of fat to lean mass ratio withmetabolic dysfunction inwomen with polycystic ovary syndrome. Hum Reprod. 2014;29(07):1508-1517. Doi: 10.1093/humrep/deu096
    » https://doi.org/10.1093/humrep/deu096
  • 13
    Couto Alves A, Valcarcel B, Mäkinen VP, Morin-Papunen L, Sebert S, Kangas AJ, et al. Metabolic profiling of polycystic ovary syndrome reveals interactions with abdominal obesity. Int J Obes. 2017;41(09):1331-1340. Doi: 10.1038/ijo.2017.126
    » https://doi.org/10.1038/ijo.2017.126
  • 14
    Zhang B, Wang J, Shen S, Liu J, Sun J, Gu T, et al. Association of androgen excess with glucose intolerance in women with Polycystic Ovary Syndrome. BioMed Res Int. 2018;2018:6869705. Doi: 10.1155/2018/6869705
    » https://doi.org/10.1155/2018/6869705
  • 15
    Tomlinson JW, Walker EA, Bujalska IJ, Draper N, Lavery GG, Cooper MS, et al. 11beta-hydroxysteroid dehydrogenase type 1: a tissue-specific regulator of glucocorticoid response. Endocr Rev. 2004;25(05):831-866. Doi: 10.1210/er.2003-0031
    » https://doi.org/10.1210/er.2003-0031
  • 16
    Veilleux A, Rhéaume C, Daris M, Luu-The V, Tchernof A. Omental adipose tissue type 1 11 beta-hydroxysteroid dehydrogenase oxoreductase activity, body fat distribution, and metabolic alterations in women. J Clin Endocrinol Metab. 2009;94(09):3550- -3557. Doi: 10.1210/jc.2008-2011
    » https://doi.org/10.1210/jc.2008-2011
  • 17
    Georgopoulos NA, Papadakis E, Armeni AK, Katsikis I, Roupas ND, Panidis D. Elevated serum androstenedione is associated with a more severe phenotype in women with polycystic ovary syndrome (PCOS). Hormones (Athens). 2014;13(02):213-221. Doi: 10.1007/BF03401335
    » https://doi.org/10.1007/BF03401335
  • 18
    O'Reilly MW, House PJ, Tomlinson JW. Understanding androgen action in adipose tissue. J Steroid Biochem Mol Biol. 2014; 143:277-284. Doi: 10.1016/j.jsbmb.2014.04.008
    » https://doi.org/10.1016/j.jsbmb.2014.04.008
  • 19
    Schiffer L, Kempegowda P, ArltW, O'Reilly MW. MECHANISMS IN ENDOCRINOLOGY: The sexually dimorphic role of androgens in human metabolic disease. Eur J Endocrinol. 2017;177(03): R125-R143. Doi: 10.1530/EJE-17-0124
    » https://doi.org/10.1530/EJE-17-0124
  • 20
    Hansen PA, Han DH, Nolte LA, ChenM, Holloszy JO. DHEA protects against visceral obesity and muscle insulin resistance in rats fed a high-fat diet. Am J Physiol. 1997;273(05):R1704-R1708. Doi: 10.1152/ajpregu.1997.273.5.R1704
    » https://doi.org/10.1152/ajpregu.1997.273.5.R1704
  • 21
    Perrini S, Natalicchio A, Laviola L, Belsanti G, Montrone C, Cignarelli A, et al. Dehydroepiandrosterone stimulates glucose uptake in human and murine adipocytes by inducing GLUT1 and GLUT4 translocation to the plasma membrane. Diabetes. 2004;53(01): 41-52. Doi: 10.2337/diabetes.53.1.41
    » https://doi.org/10.2337/diabetes.53.1.41
  • 22
    Rice SP, Zhang L, Grennan-Jones F, Agarwal N, LewisMD, Rees DA, et al. Dehydroepiandrosterone (DHEA) treatment in vitro inhibits adipogenesis in human omental but not subcutaneous adipose tissue. Mol Cell Endocrinol. 2010;320(1-2):51-57. Doi: 10.1016/j.mce.2010.02.017
    » https://doi.org/10.1016/j.mce.2010.02.017
  • 23
    Hernandez-Morante JJ, Milagro F, Gabaldon JA, Martinez JA, Zamora S, Garaulet M. Effect of DHEA-sulfate on adiponectin gene expression in adipose tissue from different fat depots in morbidly obese humans. Eur J Endocrinol. 2006;155(04): 593-600. Doi: 10.1530/eje.1.02256
    » https://doi.org/10.1530/eje.1.02256
  • 24
    McNelis JC, Manolopoulos KN, Gathercole LL, Bujalska IJ, Stewart PM, Tomlinson JW, et al. Dehydroepiandrosterone exerts antiglucocorticoid action on human preadipocyte proliferation, differentiation, and glucose uptake. Am J Physiol Endocrinol Metab. 2013;305(09):E1134-E1144. Doi: 10.1152/ajpendo.00314.2012
    » https://doi.org/10.1152/ajpendo.00314.2012
  • 25
    LerchbaumE, Schwetz V, Giuliani A, Pieber TR,Obermayer-Pietsch B. Opposing effects of dehydroepiandrosterone sulfate and free testosterone on metabolic phenotype in women with polycystic ovary syndrome. Fertil Steril. 2012;98(05):1318-25.e1. Doi: 10.1016/j.fertnstert.2012.07.1057
    » https://doi.org/10.1016/j.fertnstert.2012.07.1057
  • 26
    Goodarzi MO, Carmina E, Azziz R. DHEA, DHEAS and PCOS. J Steroid Biochem Mol Biol. 2015;145:213-225. Doi: 10.1016/j.jsbmb.2014.06.003
    » https://doi.org/10.1016/j.jsbmb.2014.06.003
  • 27
    de Medeiros SF, Barbosa BB, de Medeiros AKLWY, de Medeiros MAS, Yamamoto MMW. Differential effects of various androgens on polycystic ovary syndrome. Horm Metab Res. 2021;53(05): 341-349. Doi: 10.1055/a-1422-3243
    » https://doi.org/10.1055/a-1422-3243
  • 28
    de Medeiros SF, Ormond CM, de Medeiros MAS, de Souza Santos N, Banhara CR, Yamamoto MMW. Metabolic and endocrine connections of 17-hydroxypregnenolone in polycystic ovary syndrome women. Endocr Connect. 2017;6(07):479-488. Doi: 10.1530/EC-17-0151
    » https://doi.org/10.1530/EC-17-0151
  • 29
    Teede HJ, Misso ML, Costello MF, Dokras A, Laven J, Moran L, et al; International PCOS Network. Recommendations from the international evidence-based guideline for the assessment and management of polycystic ovary syndrome. Fertil Steril. 2018;110 (03):364-379. Doi: 10.1016/j.fertnstert.2018.05.004
    » https://doi.org/10.1016/j.fertnstert.2018.05.004
  • 30
    Fraser IS, Critchley HO, Broder M, Munro MG. The FIGO recommendations on terminologies and definitions for normal and abnormal uterine bleeding. Semin Reprod Med. 2011;29(05): 383-390. Doi: 10.1055/s-0031-1287662
    » https://doi.org/10.1055/s-0031-1287662
  • 31
    Wild RA, Vesely S, Beebe L,Whitsett T, Owen W. Ferriman Gallwey self-scoring I: performance assessment inwomen with polycystic ovary syndrome. J Clin Endocrinol Metab. 2005;90(07):4112- -4114. Doi: 10.1210/jc.2004-2243
    » https://doi.org/10.1210/jc.2004-2243
  • 32
    Kristensen SL, Ramlau-Hansen CH, Ernst E, Olsen SF, Bonde JP, Vested A, 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(12):3117-3122. Doi: 10.1093/humrep/deq273
    » https://doi.org/10.1093/humrep/deq273
  • 33
    de Medeiros SF, Yamamoto MMW, Souto de Medeiros MA, Barbosa BB, Soares JM, Baracat EC. Changes in clinical and biochemical characteristics of polycystic ovary syndrome with advancing age. Endocr Connect. 2020;9(02):74-89. Doi: 10.1530/EC-19-0496
    » https://doi.org/10.1530/EC-19-0496
  • 34
    American Diabetes Association. Standards of medical care in diabetes-2010. Diabetes Care. 2010;33(Suppl 1):S11-S61. Doi: 10.2337/dc10-S011
    » https://doi.org/10.2337/dc10-S011
  • 35
    James WP. Research on obesity: a report of the DHSS/MRC group HM. London: Stationery Office; 1976
  • 36
    Krakauer NY, Krakauer JC. A new body shape index predicts mortality hazard independently of body mass index. PLoS One. 2012;7(07):e39504. Doi: 10.1371/journal.pone.0039504
    » https://doi.org/10.1371/journal.pone.0039504
  • 37
    Yang RF, Liu XY, Lin Z, Zhang G. 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(01):113-118
  • 38
    Valdez R. A simple model-based index of abdominal adiposity. J Clin Epidemiol. 1991;44(09):955-956. Doi: 10.1016/0895-4356(91)90059-i
    » https://doi.org/10.1016/0895-4356(91)90059-i
  • 39
    Amato MC, Giordano C,Galia M, Criscimanna A, Vitabile S,MidiriM, et al; AlkaMeSy Study Group. Visceral Adiposity Index: a reliable indicator of visceral fat function associated with cardiometabolic risk. Diabetes Care. 2010;33(04):920-922. Doi: 10.2337/dc09-1825
    » https://doi.org/10.2337/dc09-1825
  • 40
    Kahn HS, Valdez R. Metabolic risks identified by the combination of enlarged waist and elevated triacylglycerol concentration. Am J Clin Nutr. 2003;78(05):928-934. Doi: 10.1093/ajcn/78.5.928
    » https://doi.org/10.1093/ajcn/78.5.928
  • 41
    Medeiros SF,Gil-JuniorAB, Barbosa JS, Isaías ED,YamamotoMM.New insights into steroidogenesis in normo- and hyperandrogenic polycystic ovary syndrome patients. Arq Bras Endocrinol Metabol. 2013; 57(06):437-444. Doi: 10.1590/s0004-27302013000600005
    » https://doi.org/10.1590/s0004-27302013000600005
  • 42
    Nathan DM, Kuenen J, Borg R, Zheng H, Schoenfeld D, Heine RJA1c- Derived Average Glucose Study Group. Translating the A1C assay into estimated average glucose values. Diabetes Care. 2008;31 (08):1473-1478. Doi: 10.2337/dc08-0545
    » https://doi.org/10.2337/dc08-0545
  • 43
    Matthews DR, Hosker JP, Rudenski AS, Naylor BA, Treacher DF, Turner RC. Homeostasismodel assessment: insulin resistance and beta-cell function from fasting plasma glucose and insulin concentrations in man. Diabetologia. 1985;28(07):412-419. Doi: 10.1007/BF00280883
    » https://doi.org/10.1007/BF00280883
  • 44
    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(06):499-502
  • 45
    de Medeiros SF, Yamamoto MM, Bueno HB, Belizario D, Barbosa JS. Prevalence of elevated glycated hemoglobin concentrations in the polycystic ovary syndrome: anthropometrical and metabolic relationship in amazonian women. J Clin Med Res. 2014;6(04): 278-286. Doi: 10.14740/jocmr1829w
    » https://doi.org/10.14740/jocmr1829w
  • 46
    Medeiros SF, Barbosa JS, YamamotoMM. Comparison of steroidogenic pathways among normoandrogenic and hyperandrogenic polycystic ovary syndrome patients and normal cycling women. J Obstet Gynaecol Res. 2015;41(02):254-263
  • 47
    Huang K, Bao JP, Jennings GJ, WuLD. The disease-modifying effect of dehydroepiandrosterone in different stages of experimentally induced osteoarthritis: a histomorphometric study. BMC Musculoskelet Disord. 2015;16:178. Doi: 10.1186/s12891-015-0595-1
    » https://doi.org/10.1186/s12891-015-0595-1
  • 48
    Azziz R, Woods KS, Reyna R, Key TJ, Knochenhauer ES, Yildiz BO. The prevalence and features of the polycystic ovary syndrome in an unselected population. J Clin Endocrinol Metab. 2004;89(06): 2745-2749. Doi: 10.1210/jc.2003-032046
    » https://doi.org/10.1210/jc.2003-032046
  • 49
    Gil Junior AB, Rezende AP, do Carmo AV, Duarte EI, de Medeiros MM, de Medeiros SF. [Adrenal androgen participation in the polycystic ovary syndrome]. Rev Bras Ginecol Obstet. 2010;32 (11):541-548. Doi: 10.1590/s0100-72032010001100005
    » https://doi.org/10.1590/s0100-72032010001100005
  • 50
    Dunaif A. Insulin resistance and the polycystic ovary syndrome: mechanismand implications for pathogenesis. Endocr Rev. 1997; 18(06):774-800. Doi: 10.1210/edrv.18.6.0318
    » https://doi.org/10.1210/edrv.18.6.0318
  • 51
    Tosi F, Negri C, Brun E, Castello R, Faccini G, Bonora E, et al. Insulin enhances ACTH-stimulated androgen and glucocorticoid metabolism in hyperandrogenic women. Eur J Endocrinol. 2011;164 (02):197-203. Doi: 10.1530/EJE-10-0782
    » https://doi.org/10.1530/EJE-10-0782
  • 52
    Tock L, Carneiro G, Pereira AZ, Tufik S, Zanella MT. Adrenocortical production is associated with higher levels of luteinizing hormone in nonobese women with polycystic ovary syndrome. Int J Endocrinol. 2014;2014:620605. Doi: 10.1155/2014/620605
    » https://doi.org/10.1155/2014/620605
  • 53
    Lerchbaum E, Schwetz V, Rabe T, Giuliani A, Obermayer-Pietsch B. Hyperandrogenemia in polycystic ovary syndrome: exploration of the role of free testosterone and androstenedione in metabolic phenotype. PLoS One. 2014;9(10):e108263. Doi: 10.1371/journal. pone.0108263
    » https://doi.org/10.1371/journal
  • 54
    Alexiou E, Hatziagelaki E, Pergialiotis V, Chrelias C, Kassanos D, Siristatidis C, et al. Hyperandrogenemia inwomen with polycystic ovary syndrome: prevalence, characteristics and associationwith body mass index. Horm Mol Biol Clin Investig. 2017;29(03): 105-111. Doi: 10.1515/hmbci-2016-0047
    » https://doi.org/10.1515/hmbci-2016-0047
  • 55
    Yanes Cardozo LL, Romero DG, Reckelhoff JF. Cardiometabolic features of polycystic ovary syndrome: role of androgens. Physiology (Bethesda). 2017;32(05):357-366. Doi: 10.1152/physiol.00030.2016
    » https://doi.org/10.1152/physiol.00030.2016
  • 56
    Chen MJ, Yang WS, Yang JH, Chen CL, Ho HN, Yang YS. Relationship between androgen levels and blood pressure in young women with polycystic ovary syndrome. Hypertension. 2007;49(06): 1442-1447. Doi: 10.1161/HYPERTENSIONAHA.106.083972
    » https://doi.org/10.1161/HYPERTENSIONAHA.106.083972
  • 57
    Oliveira RdoS, Redorat RG, Ziehe GH, Mansur VA, Conceição FL. Arterial hypertension and metabolic profile in patients with polycystic ovary syndrome. Rev Bras Ginecol Obstet. 2013;35 (01):21-26. Doi: 10.1590/s0100-72032013000100005
    » https://doi.org/10.1590/s0100-72032013000100005
  • 58
    Amiri M, Ramezani Tehrani F, Behboudi-Gandevani S, Bidhendi- Yarandi R, Carmina E. Risk of hypertension in women with polycystic ovary syndrome: a systematic review, meta-analysis and meta-regression. Reprod Biol Endocrinol. 2020;18(01):23. Doi: 10.1186/s12958-020-00576-1
    » https://doi.org/10.1186/s12958-020-00576-1
  • 59
    Carmina E, Koyama T, Chang L, Stanczyk FZ, Lobo RA. Does ethnicity influence the prevalence of adrenal hyperandrogenism and insulin resistance in polycystic ovary syndrome? Am J Obstet Gynecol. 1992;167(06):1807-1812. Doi: 10.1016/0002-9378(92)91779-a
    » https://doi.org/10.1016/0002-9378(92)91779-a
  • 60
    Li L, Yang D, Chen X, Chen Y, Feng S,Wang L. Clinical and metabolic features of polycystic ovary syndrome. Int J Gynaecol Obstet. 2007;97(02):129-134. Doi: 10.1016/j.ijgo.2007.01.005
    » https://doi.org/10.1016/j.ijgo.2007.01.005
  • 61
    Fujioka K, Kajita K, Wu Z, Hanamoto T, Ikeda T, Mori I, et al. Dehydroepiandrosterone reduces preadipocyte proliferation via androgen receptor. AmJ Physiol Endocrinol Metab. 2012;302(06): E694-E704. Doi: 10.1152/ajpendo.00112.2011
    » https://doi.org/10.1152/ajpendo.00112.2011
  • 62
    Kochan Z, Karbowska J. Dehydroepiandrosterone up-regulates resistin gene expression in white adipose tissue. Mol Cell Endocrinol. 2004;218(1-2):57-64. Doi: 10.1016/j.mce.2003.12.012
    » https://doi.org/10.1016/j.mce.2003.12.012
  • 63
    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(06):693-700. Doi: 10.2337/diab.40.6.693
    » https://doi.org/10.2337/diab.40.6.693
  • 64
    Yamashita R, Saito T, Satoh S, Aoki K, Kaburagi Y, Sekihara H. Effects of dehydroepiandrosterone on gluconeogenic enzymes and glucose uptake in human hepatoma cell line, HepG2. Endocr J. 2005;52(06):727-733. Doi: 10.1507/endocrj.52.727
    » https://doi.org/10.1507/endocrj.52.727
  • 65
    De Pergola G, Zamboni M, Sciaraffia M, Turcato E, Pannacciulli N, Armellini F, et al. Body fat accumulation is possibly responsible for lower dehydroepiandrosterone circulating levels in premenopausal obese women. Int J Obes Relat Metab Disord. 1996;20 (12):1105-1110
  • 66
    Mannic T, Viguie J, Rossier MF. In vivo and in vitro evidences of dehydroepiandrosterone protective role on the cardiovascular system. Int J Endocrinol Metab. 2015;13(02):e24660. Doi: 10.5812/ijem.24660
    » https://doi.org/10.5812/ijem.24660
  • 67
    Tchernof A, Labrie F. Dehydroepiandrosterone, obesity and cardiovascular disease risk: a review of human studies. Eur J Endocrinol. 2004;151(01):1-14. Doi: 10.1530/eje.0.1510001
    » https://doi.org/10.1530/eje.0.1510001
  • 68
    Moran C, Arriaga M, Arechavaleta-Velasco F, Moran S. Adrenal androgen excess and body mass index in polycystic ovary syndrome. J Clin Endocrinol Metab. 2015;100(03):942-950. Doi: 10.1210/jc.2014-2569
    » https://doi.org/10.1210/jc.2014-2569
  • 69
    Zerradi M, Dereumetz J, BouletMM, Tchernof A. Androgens, body fat Distribution and Adipogenesis. Curr Obes Rep. 2014;3(04): 396-403. Doi: 10.1007/s13679-014-0119-6
    » https://doi.org/10.1007/s13679-014-0119-6
  • 70
    Brahimaj A, Ligthart S, IkramMA, Hofman A, Franco OH, Sijbrands EJG, et al. Serum levels of apolipoproteins and incident type 2 diabetes: a prospective cohort study. Diabetes Care. 2017;40(03): 346-351. Doi: 10.2337/dc16-1295
    » https://doi.org/10.2337/dc16-1295
  • 71
    Nestler JE, Clore JN, Blackard WG. Dehydroepiandrosterone: the "missing link" between hyperinsulinemia and atherosclerosis? FASEB J. 1992;6(12):3073-3075. Doi: 10.1096/fasebj.6.12.1387859
    » https://doi.org/10.1096/fasebj.6.12.1387859
  • 72
    Farah-Eways L, Reyna R, Knochenhauer ES, Bartolucci AA, Azziz R. Glucose action and adrenocortical biosynthesis in women with polycystic ovary syndrome. Fertil Steril. 2004;81(01):120-125. Doi: 10.1016/j.fertnstert.2003.05.008
    » https://doi.org/10.1016/j.fertnstert.2003.05.008
  • 73
    Morán C, Knochenhauer E, Boots LR, Azziz R. Adrenal androgen excess in hyperandrogenism: relation to age and body mass. Fertil Steril. 1999;71(04):671-674. Doi: 10.1016/s0015-0282(98)00536-6
    » https://doi.org/10.1016/s0015-0282(98)00536-6
  • 74
    Alpañés M, Luque-Ramírez M, Martínez-García MA, Fernández- Durán E, Álvarez-Blasco F, Escobar-Morreale HF. Influence of adrenal hyperandrogenism on the clinical and metabolic phenotype of women with polycystic ovary syndrome. Fertil Steril. 2015;103(03):795-801.e2. Doi: 10.1016/j.fertnstert.2014.12.105
    » https://doi.org/10.1016/j.fertnstert.2014.12.105
  • 75
    Vryonidou A, Papatheodorou A, Tavridou A, Terzi T, Loi V, Vatalas I-A, et al. Association of hyperandrogenemic and metabolic phenotypewith carotid intima-media thickness in young women with polycystic ovary syndrome. J Clin EndocrinolMetab. 2005;90 (05):2740-2746. Doi: 10.1210/jc.2004-2363
    » https://doi.org/10.1210/jc.2004-2363
  • 76
    Carmina E, Lobo RA. Prevalence and metabolic characteristics of adrenal androgen excess in hyperandrogenic women with different phenotypes. J Endocrinol Invest. 2007;30(02):111-116. Doi: 10.1007/BF03347408
    » https://doi.org/10.1007/BF03347408
  • 77
    Brennan K, Huang A, Azziz R. Dehydroepiandrosterone sulfate and insulin resistance in patients with polycystic ovary syndrome. Fertil Steril. 2009;91(05):1848-1852. Doi: 10.1016/j.fertnstert.2008.02.101
    » https://doi.org/10.1016/j.fertnstert.2008.02.101
  • 78
    Chen MJ, Chen CD, Yang JH, Chen C-L,Ho H-N, YangW-S, et al.High serum dehydroepiandrosterone sulfate is associated with phenotypic acne and a reduced risk of abdominal obesity inwomen with polycystic ovary syndrome. Hum Reprod. 2011;26(01):227-234. Doi: 10.1093/humrep/deq308
    » https://doi.org/10.1093/humrep/deq308
  • 79
    Misichronis G, GeorgopoulosNA, Marioli DJ, Armeni AK, Katsikis I, Piouka AD, et al. The influence of obesity on androstenedione to testosterone ratio in women with polycystic ovary syndrome (PCOS) and hyperandrogenemia. Gynecol Endocrinol. 2012;28 (04):249-252. Doi: 10.3109/09513590.2011.613965
    » https://doi.org/10.3109/09513590.2011.613965
  • 80
    Huang R, Zheng J, Li S, Tao T, Ma J, Liu W. Characteristics and contributions of hyperandrogenism to insulin resistance and other metabolic profiles in polycystic ovary syndrome. Acta Obstet Gynecol Scand. 2015;94(05):494-500. Doi: 10.1111/aogs.12612
    » https://doi.org/10.1111/aogs.12612
  • 81
    Savastano S, Belfiore A, Guida B, Angrisani L, Orio F Jr, Cascella T, et al. Role of dehydroepiandrosterone sulfate levels on body composition after laparoscopic adjustable gastric banding in pre-menopausal morbidly obese women. J Endocrinol Invest. 2005;28(06):509-515. Doi: 10.1007/BF03347238
    » https://doi.org/10.1007/BF03347238
  • 82
    Simoncini T, Mannella P, Fornari L, Varone G, Caruso A, Genazzani AR. Dehydroepiandrosterone modulates endothelial nitric oxide synthesis via direct genomic and nongenomic mechanisms. Endocrinology. 2003;144(08):3449-3455. Doi: 10.1210/en.2003-0044
    » https://doi.org/10.1210/en.2003-0044
  • 83
    Meirow D, Raz I, Yossepowitch O, Brzezinski A, Rosler A, Schenker JG, et al. Dyslipidaemia in polycystic ovarian syndrome: different groups, different aetiologies? Hum Reprod. 1996;11(09):1848- -1853. Doi: 10.1093/oxfordjournals.humrep.a019505
    » https://doi.org/10.1093/oxfordjournals.humrep.a019505
  • 84
    Kösüs N, Kösüs A, Kamalak Z, Hizli D, Turhan NÖ Impact of adrenal versus ovarian androgen ratio on signs and symptoms of polycystic ovarian syndrome. Gynecol Endocrinol. 2012;28(08):611-614. Doi: 10.3109/09513590.2011.650770
    » https://doi.org/10.3109/09513590.2011.650770
  • 85
    Schriock ED, Buffington CK, Hubert GD, Kurtz BR, Kitabchi AE, Buster JE, et al. Divergent correlations of circulating dehydroepiandrosterone sulfate and testosterone with insulin levels and insulin receptor binding. J Clin Endocrinol Metab. 1988;66(06): 1329-1331. Doi: 10.1210/jcem-66-6-1329
    » https://doi.org/10.1210/jcem-66-6-1329
  • 86
    Lea-Currie YR, Wen P, McIntosh MK. Dehydroepiandrosteronesulfate (DHEAS) reduces adipocyte hyperplasia associated with feeding rats a high-fat diet. Int J Obes RelatMetab Disord. 1997;21 (11):1058-1064. Doi: 10.1038/sj.ijo.0800516
    » https://doi.org/10.1038/sj.ijo.0800516
  • 87
    Gambineri A, Patton L, Vaccina A, CacciariM,Morselli-Labate AM, Cavazza C, et al. Treatment with flutamide, metformin, and their combination added to a hypocaloric diet in overweight-obese women with polycystic ovary syndrome: a randomized, 12- month, placebo-controlled study. J Clin Endocrinol Metab. 2006;91(10):3970-3980. Doi: 10.1210/jc.2005-2250
    » https://doi.org/10.1210/jc.2005-2250
  • 88
    Ingelsson E, Schaefer EJ, Contois JH, McNamara JR, Sullivan L, Keyes MJ, et al. Clinical utility of different lipid measures for prediction of coronary heart disease in men and women. JAMA. 2007;298(07):776-785. Doi: 10.1001/jama.298.7.776
    » https://doi.org/10.1001/jama.298.7.776
  • 89
    Legro RS, Schlaff WD, Diamond MP, Coutifaris C, Casson PR, Brzyski R, 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 (12):5305-5313. Doi: 10.1210/jc.2010-1123
    » https://doi.org/10.1210/jc.2010-1123
  • 90
    Janse F, Eijkemans MJ, Goverde AJ, Lentjes EGWM, Hoek A, Lambalk CB, Hickey TE, et al. Assessment of androgen concentration in women: liquid chromatography-tandem mass spectrometry and extraction RIA show comparable results. Eur J Endocrinol. 2011;165(06):925-933. Doi: 10.1530/EJE-11-0482
    » https://doi.org/10.1530/EJE-11-0482

Publication Dates

  • Publication in this collection
    08 Apr 2022
  • Date of issue
    Feb 2022

History

  • Received
    22 Jan 2021
  • Accepted
    15 Sept 2021
Federação Brasileira das Sociedades de Ginecologia e Obstetrícia Av. Brigadeiro Luís Antônio, 3421, sala 903 - Jardim Paulista, 01401-001 São Paulo SP - Brasil, Tel. (55 11) 5573-4919 - Rio de Janeiro - RJ - Brazil
E-mail: editorial.office@febrasgo.org.br