Relationship of Biological Markers of Body Fat Distribution and Corticosteroidogenic Enzyme Activities in Women with Polycystic Ovary Syndrome

Abstract

The aim of the study is to determine the impact of different anthropometric measurements of fat distribution on baseline sex-steroid concentrations and corticosteroidogenic enzyme activity in women with polycystic ovary syndrome compared to those with regular menstrual cycles. The current cross-sectional study included 106 normal cycling controls and 268 polycystic ovary syndrome patients. Patients with polycystic ovary syndrome, diagnosed by Rotterdam criteria, were divided in normoandrogenemic (n=91) and hyperandrogenemic (n=177). Anthropometric, biochemical, and hormone parameters were assessed and correlated with corticosteroidogenic enzyme activities in all three groups. Corticosteroidogenic enzyme activities were calculated using product-to-precursor ratios. Regarding sex-steroids individually, anthropometric parameters correlated with the concentrations of several androgens in polycystic ovary syndrome patients, most of them in patients with biochemical hyperandrogenism. The androgen precursors androstenedione, 17-hydroxyprogesterone, and dehydroepiandrosterone were less correlated with anthropometric parameters. The 17,20 lyase activity, in both Δ4 and Δ5 pathways, correlated with several anthropometric measurements in normo- and hyperandrogenemic polycystic ovary syndrome patients. The 17,20 lyase enzyme activity (Δ4 pathway) also correlated with conicity index, visceral adiposity index, and lipid accumulation product in the control group. 17-Hydroxylase activity positively correlated with waist-height ratio in both polycystic ovary syndrome groups. In contrast, 17-hydroxilase negatively correlated with the conicity index. Anthropometric markers of adiposity are associated with androgen levels and their precursors in blood. Body fat distribution correlates with the activities of some steroidogenic enzyme in both normo-and hyperandrogenemic polycystic ovary syndrome phenotypes. The molecular mechanisms involved in these associations are largely unclear and more investigations are required.

Key words

sex steroids - hyperandrogenism - steroidogenesis

• References

• 1 Zore T, Joshi NV, Lizneva D. et al. Polycystic ovarian syndrome: Long-term health consequences. Semin Reprod Med 2017; 35: 271-281
• 2 Wabitsch M, Hauner H, Heinze E. et al. Body fat distribution and steroid hormone concentrations in obese adolescent girls before and after weight reduction. J Clin Endocrinol Metab 1995; 80: 3469-3475
• 3 Ezeh U, Pall M, Mathur R. et al. Association of fat to lean mass ratio with metabolic dysfunction in women with polycystic ovary syndrome. Hum Reprod 2014; 129: 1508-1517
• 4 Elbers JM, Asscheman H, Seidell JC. et al. Long-term testosterone administration increases visceral fat in female to male transsexuals. J Clin Endocrinol Metab 1997; 82: 2044-2047
• 5 Sung YA, Oh JY, Chung H. et al. Hyperandrogenemia is implicated in both the metabolic and reproductive morbidities of polycystic ovary syndrome. Fertil Steril 2014; 101: 840-845
• 6 Akopians AL, Madrigal V, Fisch S. et al. Hyperandrogenism is associated with preferential fat deposition of visceral versus subcutaneous (SC) abdominal fat in lean polycystic ovary syndrome (PCOS) women. Fertil Steril 2016; 106: e31. ASRM Abstracts O-79
• 7 Carmina E, Bucchieri S, Esposito A. et al. Abdominal fat quantity and distribution in women with polycystic ovary syndrome and extent of its relation to insulin resistance. J Clin Endocrinol Metab 2007; 92: 2500-2505
• 8 Bil E, Dilbaz B, Cirik DA. et al. Metabolic syndrome and metabolic risk profile according to polycystic ovary syndrome phenotype. J Obstet Gynaecol Res 2016; 4: 837-843
• 9 Knudsen KL, Blank SK, Burt Solorzano C. et al. Hyperandrogenemia in obese peripubertal girls: Correlates and potential etiological determinants. Obesity 2010; 18: 2118-2124
• 10 Nada Z. Which is more reliable in polycystic ovarian syndrome: Body mass index or waist hip ratio?. Int J Sci: Basic Appl Res 2010; 24: 283-290
• 11 Keller JL, Casson PR, Toth MJ. Relationship of androgens to body composition, energy and substrate metabolism and aerobic capacity in healthy, young women. Steroids 2011; 76: 1247-1251
• 12 Lagaly DV, Aad PY, Grado-Ahuir JA. et al. Role of Adiponectin in regulating ovarian theca and granulosa cell function. Mol Cell Endocrinol 2008; 284: 38-45
• 13 Smolinska N, Dobrzyn K, Kiezun M. et al. Effect of Adiponectin on the steroidogenic acute regulatory protein P450 side chain cleavage enzyme and 3β-hydroxysteroid dehydrogenase gene expression, progesterone and androstenedione production by the porcine uterus during early pregnancy. J Physiol Pharmacol 2016; 67: 443-456
• 14 Comim FV, Hardy K, Franks S. Adiponectin and its receptors in the ovary: further evidence for a link between obesity and hyperandrogenism in polycystic ovary syndrome. PLoS One 2013; 8: e80416
• 15 Douchi T, Huin H, Nakamura S. et al. Body fat distribution in women with polycystic ovary syndrome. Obstet Gynecol 1995; 86: 516-519
• 16 Deslypere JP, Verdonck L, Vermeulen A. Fat tissue: A steroid reservoir and site of steroid metabolism. J Clin Endocrinol Metab 1985; 61: 564-570
• 17 Bolt HM, Gobel P. Formation of estrogens from androgens by human subcutaneous adipose tissue in vitro. Horm Metab Res 1972; 4: 312-313
• 18 Bleau G, Roberts KD, Chapdelaine A. The in vitro uptake and metabolism of steroids in human adipose tissue. J Clin Endocrinol Metab 1974; 39: 236-246
• 19 Szymczak J, Milewicz A, Thijssen JHH. et al. Concentrations of sex steroids in adipose tissue after menopause. Steroids 1998; 63: 319-321
• 20 Simpson AM, Judd SJ, Rodgers RJ. Role of aromatase in sex steroid action. J Mol Endocrinol 2000; 25: 149-156
• 21 Masuzaki H, Paterson J, Shinyama H. et al. A transgenic model of visceral obesity and the metabolic syndrome. Science 2001; 294: 2166-2170
• 22 Yildiz BO, Gedik O. Insulin resistance in polycystic ovary syndrome: hyperandrogenemia versus normoandrogenemia. Eur J Obstet Gynecol Reprod Biol 2001; 100: 62-66
• 23 Azziz R, Woods KS, Reyna R. et al. The prevalence and features of the polycystic ovary syndrome in an unselected population. J Clin Endocrinol Metab 2004; 89: 2745-2749
• 24 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
• 25 de Medeiros SF, Ormond CM, de Medeiros MAS. et al. Metabolic and endocrine connections of 17-hydroxypregnenolone in polycystic ovary syndrome women. Endocr Connect 2017; 6: 479-488
• 26 James WPT. Research on obesity. A repot of the DHSS/MRC group. Her Majesty’s Stationary. Department of Health and Social Security and Medical Research Council Group. In Her Majesty’s Stationary Office. London: Office; 1976. 94
• 27 Valdez R. A simple model-based index of abdominal adiposity. J Clin Epidemiol 1991; 44: 955-956
• 28 Amato MC, Giordano C. Visceral adiposity index: An indicator of adipose tissue dysfunction. Int J Endocrinol 2014; 3: 730827
• 29 Kahn HS, Valdez R. Metabolic risks identified by the combination of enlarged waist and elevated triacylglycerol concentration. Am J Clin Nutr 2003; 78: 928-934
• 30 Friedewald WT, Levy RI, Fredrickson DS. Estimations of the concentration of low-density lipoprotein cholesterol in plasma, without use of the preparative ultracentrifuge. Clin Chem 1972; 18: 499-502
• 31 Geloneze B, Vasques AC, Stabe CF. et al. BRASMS Investigators, HOMA1-IR and HOMA2-IR indexes in identifying insulin resistance and metabolic syndrome: Brazilian Matabolic Syndrome Sudy (BRAMS). Arq Bras Endocrinol Metab 2009; 53: 281-287
• 32 http://www.dtu.ox.ac.uk/homacalculator
• 33 de Medeiros SF, Ormond CM, de Medeiros MAS. et al. Metabolic and endocrine connections of 17-hydroxypregnenolone in polycystic ovary syndrome women. Endoc Connect 2017; 6: 479-488
• 34 Sowers SM, Derby C, Jannausch ML. et al. Insulin resistance, hemostatic factors, and hormone interactions in pre- and perimenopausal women: SWAN. J Clin Endocrinol Metab 2003; 88: 4904-4910
• 35 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
• 36 Baptiste CG, Marie-Claude B, Trottier A. et al. Insulin and hyperandrogenism in women with polycystic ovary syndrome. J Steroid Biochem Mol Biol 2010; 122: 42-52
• 37 Albu A, Florea S, Fica S. The connections between androgens and adipose tissue function in polycystic ovary syndrome patients. Int J Sciences Appl Research 2014; 15: 368-378
• 38 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
• 39 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 Cond Res 2013; 27: 236-243
• 40 Hicks R, Yee JK, Mao CS. et al. Precursor-to-product ratios reflect biochemical phenotype in congenital adrenal hyperplasia. Metabolomics 2014; 10: 123-131
• 41 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 Metab 2013; 57: 437-444
• 42 Costa-Barbosa FA, Carvalho VM, Nakamura OH. et al. Zona fasciculata 21-hydroxysteroids and precursor-to-product ratios in 21- hydroxylase defiency: Further characterization of classic and non-classic patients and heterozygote carriers. J Endocrinol Invest 2011; 34: 587-592
• 43 Tieh PY, Yee JKW, Hicks RA. et al. Utility of a precursor-to-product ratio in the evaluation of presumptive positives in newborn screening of congenital adrenal hyperplasia. J Perinatol 2017; 37: 283-287
• 44 Ardawi MS, Rouzi AA. Plasma adiponectin and insulin resistance in women with polycystic ovary syndrome. Fertil Steril 2005; 83: 1708-1716
• 45 Mannerås-Holm L, Leonhardt H, Kullberg J. et al. Adipose tissue has aberrant morphology and function in PCOS: Enlarged adipocytes and low serum adiponectin, but not circulating sex steroids, are strongly associated with insulin resistance. J Clin Endocrinol Metab 2011; 96: E304-E311
• 46 Chen X, Jia X, Qiao J. et al. Adipokines in reproductive function: A link between obesity and polycystic ovary syndrome. J mol Endocrinol 2013; 50: R21-R37
• 47 Kim SH, Moon JY, Sasano H. et al. Body fat mass is associated with ratio of steroid metabolites reflecting 17, 20-lyase activity in prepubertal girls. J Clin Endocrinol Metab 2016; 101: 4653-4660
• 48 Dieudonne MN, Pecquery R, Boumediene A. Androgen receptors in human preadipocytes and adipocytes: Regional specificities and regulation by sex steroids. Am J Physiol 1998; 274: 1645-1652
• 49 Carbould A. Chronic testosterone treatment induces selective insulin resistance in subcutaneous adipocytes of women. J Endocrinol 2007; 94: 157-163
• 50 Chazenbalk G, Singh P, Irge D. et al. Androgens inhibit adipogenesis during human adipose stem cell commitment to preadipocyte formation. Steroids 2013; 78: 920-926
• 51 Barbosa-Desongles A, Hernández C, Simó R. et al. Testosterone induces cell proliferation and cell cycle gene overexpression in human visceral preadipocytes. Am J Physiol Cell Physiol 2013; 305: C355-C359
• 52 Evans DJ, Barth JH, Burke CW. Body fat topography in women with androgen excess. Int J Obes 1988; 12: 157-162
• 53 Van Anders SM, Hampson E. Waist-to-hip ratio is positively associated with bioavailable testosterone but negatively associated with sexual desire in healthy premenopausal women. Psychosom Med 2005; 67: 246-250
• 54 Judd AM, Call GB, Barney M. et al. Possible function of IL-6 and THF as intraadrenal factors in the regulation of adrenal steroid secretion. Ann NY Acad Sci 2000; 917: 628-637
• 55 Kruse M, Bornstein SR, Uhlmann K. et al. Leptin down-regulates the steroid producing system in the adrenal. Endocr Res 1998; 24: 587-590
• 56 Schrover IM, Van der Graaf Y, Spiering W. et al. The relation between body fat distribution, plasma concentrations of adipokines and the metabolic syndrome in patients with clinically manifest vascular disease. Eur J Prev Cardiol 2018; 25: 1-10
• 57 Bayoumy HA, Alothman AN. Adrenal contribution to polycystic ovary syndrome. Med Princ Prac 2001; 10: 151-155
• 58 Rask E, Walker BR, Söderberg S. et al. Tissue-specific changes in peripheral cortisol metabolism in obese women: Increased adipose 11beta-hydroxysteroid dehydrogenase type 1 activity. J Clin Endocrinol Metab 2002; 87: 3330-3336
• 59 Campos DB, Palin MF, Bordignon V. et al. The 'beneficial' adipokines in reproduction and fertility. Int J Obes (Lond) 2008; 32: 223-231
• 60 Agarwal SK, Vogel K, Weitsman SR. et al. Leptin antagonizes the insulin-like growth factor-I augmentation of steroidogensis in granulosa cells of the human ovary. J Clin Endocrinol Metab 1999; 84: 1072-1076
• 61 Brann DW, Wade MF, Dhandapani KM. et al. Leptin and reproduction. Steroids 2002; 67: 95-104
• 62 Binelli M, Murphy BD. Coordinated regulation of follicle development by germ and somatic cells. Reprod Fertil Dev 2010; 22: 1-12
• 63 Samir M, Glister C, Mattar D. et al. Follicular expression of pro-inflammatory cytokines tumour necrosis factor-α (TNFα), interleukin 6 (IL6) and their receptors in cattle: TNFα, IL6 and macrophages suppress thecal androgen production in vitro. Reproduction 2017; 154: 35-49
• 64 Cupisti S, Kajaia N, Dittrich R. et al. Body mass index and ovarian function are associated with endocrine and metabolic abnormalities in women with hyperandrogenic syndrome. Eur J Endocrinol 2008; 158: 711-719
• 65 Pangaribuan B, Yusuf I, Mansyur M. et al. Serum adiponectin and resistin in relation to insulin resistance and markers of hyperandrogenism in lean and obese women with polycystic ovary syndrome. Therap Adv Endocrinol Metab 2011; 2: 235-245
• 66 Lecke SB, Mattei F, Morsch DM, Spritzer PM. Abdominal subcutaneous fat gene expression and circulating levels of leptin and adiponectin in polycystic ovary syndrome. Fertil Steril 2011; 95: 2044-2049
• 67 Villa J, Pratley RE. Adipose tissue dysfunction in polycystic ovary syndrome. Curr Diab Rep 2011; 11: 179-184
• 68 Barber TM, Franks S. Adipocyte biology in polycystic ovary syndrome. Mol Cell Endocrinol 2013; 373: 68-76
• 69 Goossens GH. The metabolic phenotype in obesity: Fat mass, body fat distribution, and adipose tissue function. Obes Facts 2017; 10: 207-215
• 70 Ditkoff EC, Fruzzetti F, Chang L. et al. The impact of estrogen on adrenal androgen sensitivity and secretion in polycystic ovary syndrome. J Clin Endocrinol Metab 1995; 80: 603-607
• 71 Path G, Bornstein SR, Ehrhart-Bornstein M. et al. Interleukin-6 and the interleukin-6 receptor in the human adrenal gland: Expression and effects on steroidogenesis. J Clin Endocrinol Metab 1997; 82: 2343-2349
• 72 Biason-Lauber A, Zachmann M, Schoenle EJ. Effect of leptin on CYP17 enzymatic activities in human adrenal cells: new insight in the onset of adrenarche. Endocrinology 2000; 141: 1446-1454
• 73 Auchus RJ, Lee TC, Miller WL. Cytochrome b5 augments the 17,20-lyase activity of human P450c17 without direct electron transfer. J Biol Chem 1998; 273: 3158-3165
• 74 Ryan KJ, Petro Z. Steroid biosynthesis by human ovarian granulosa and thecal cells. J Clin Endocrinol Metab 1966; 26: 46-52
• 75 Munir I, Yen HW, Baruth T. et al. Resistin stimulation of 17alpha-hydroxylase activity in ovarian theca cells in vitro: relevance to polycystic ovary syndrome. J Clin Endocrinol Metab 2005; 90: 4852-4857
• 76 Yilmaz M, Bukan N, Demirci H. et al. Serum resistin and adiponectin levels in women with polycystic ovary syndrome. Gynecol Endocrinol 2009; 25: 246-252
• 77 Rosenfield RL, Barnes RB, Cara JF. et al. Dysregulation of cytochrome P450c 17 alpha as the cause of polycystic ovarian syndrome. Fertil Steril 1990; 53: 785-791
• 78 Shi L, Wudy SA, Buyken AE. et al. Body fat and animal protein intakes are associated with adrenal androgen secretion in children. Am J Clin Nutr 2009; 90: 1321-1328