Hypothalamic-Pituitary-Adrenocortical Axis Hypersensitivity and Glucocorticoid Receptor Expression and Function in Women with Polycystic Ovary Syndrome

Abstract

Introduction:

Molecular mechanisms underlying pathophysiology of polycystic ovary syndrome (PCOS), especially those related to cortisol signaling, are poorly understood. We hypothesized that modulation of glucocorticoid receptor (GR) expression and function, may underlie possible PCOS-related impairment of feedback inhibition of hypothalamic-pituitary-adrenocortical (HPA) axis activity and thus contribute to increased adrenal androgen production in women with PCOS.

Materials and Methods:

24 normal-weight and 31 obese women with PCOS were compared to 25 normal-weight controls. Fasting blood samples were collected for measurements of serum concentrations of dehydroepiandrosterone sulfate, testosterone, sex hormone-binding globulin, insulin, basal cortisol and cortisol after oral administration of 0.5 mg dexamethasone. Concentrations of GR mRNA, GR protein, mineralocorticoid receptor (MR) protein and heat shock proteins (Hsps), as well as the number of GR per cell (B_max) and its equilibrium dissociation constant (K_D) were measured in isolated peripheral blood mononuclear cells.

Results:

An increase in HPA axis sensitivity to dexamethasone, an elevation of the GR protein concentration, and unaltered receptor functional status were found in both normal-weight and obese women with PCOS vs. healthy controls. Lymphocyte MR, Hsp90 and Hsp70 concentrations, and MR/GR ratio were similar in all groups. Correlation between B_max and K_D was weaker in the group of obese women with PCOS than in the other 2 groups.

Conclusions:

The results did not confirm the initial hypothesis, but imply that PCOS is associated with increased GR protein concentration and HPA axis sensitivity to dexamethasone.

Key words

glucocorticoid receptor - polycystic ovary syndrome - HPA axis

• References

• 1 Alesci S, Bornstein SR. Intraadrenal mechanisms of DHEA regulation: a hypothesis for adrenopause. Exp Clin Endocrinol Diabetes 2001; 109: 75-82
• 2 Asuncion M, Calvo RM, San Millan JL et al. A prospective study of the prevalence of the polycystic ovary syndrome in unselected Caucasian women from Spain. J Clin Endocrinol Metab 2000; 85: 2434-2438
• 3 Azziz R, Black V, Hines GA et al. Adrenal androgen excess in the polycystic ovary syndrome: sensitivity and responsivity of the hypothalamic-pituitary-adrenal axis. J Clin Endocrinol Metab 1998; 83: 2317-2323
• 4 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
• 5 Balen A, Rajkowha M. Polycystic ovary syndrome – a systemic disorder?. Best Pract Res Clin Obstet Gynaecol 2003; 17: 263-274
• 6 Bamberger CM, Schulte HM, Chrousos GP. Molecular determinants of glucocorticoid receptor function and tissue sensitivity to glucocorticoids. Endocr Rev 1996; 17: 245-261
• 7 Bjorntorp P, Rosmond R. Obesity and cortisol. Nutrition 2000; 16: 924-936
• 8 Brkljačić J, Perišić T, Dundjerski J et al. Interaction of rat renal glucocorticoid receptor with Hsp90 and Hsp70 upon stress provoked by mercury. J Appl Toxicol 2007; 27: 43-50
• 9 Carmina E, Lobo RA. Prevalence and metabolic characteristics of adrenal androgen excess in hyperandrogenic women with different phenotypes. J Endocrinol Invest 2007; 30: 111-116
• 10 De Kloet ER, Vreugdenhil E, Oitzl MS et al. Brain corticosteroid receptor balance in health and disease. Endocr Rev 1998; 19: 269-301
• 11 Diamanti-Kandarakis E, Kouli CR, Bergiele AT et al. A survey of the polycystic ovary syndrome in the Greek island of Lesbos: hormonal and metabolic profile. J Clin Endocrinol Metab 1999; 84: 4006-4011
• 12 Doi SA, Al-Zaid M, Towers PA et al. Steroidogenic alterations and adrenal androgen excess in PCOS. Steroids 2006; 71: 751-759
• 13 Elaković I, Perišić T, Čanković-Kadijević M et al. Correlation between glucocorticoid receptor binding parameters, blood pressure, and body mass index in a healthy human population. Cell Biochem Funct 2007; 25: 427-431
• 14 Ferriman D, Gallwey JD. Clinical assessment of body hair growth in women. J Clin Endocrinol Metab 1961; 21: 1440-1447
• 15 Gladkevich A, Kauffman HF, Korf J. Lymphocytes as a neural probe: potential for studying psychiatric disorders. Prog Neuropsychopharmacol Biol Psychiatry 2004; 28: 559-576
• 16 Grad I, Picard D. The glucocorticoid responses are shaped by molecular chaperones. Mol Cell Endocrinol 2007; 275: 2-12
• 17 Gross KL, Lu NZ, Cidlowski JA. Molecular mechanisms regulating glucocorticoid sensitivity and resistance. Mol Cell Endocrinol 2009; 300: 7-16
• 18 Guven M, Acbay O, Sultuybek G. Glucocorticoid receptors on mononuclear leukocytes in polycystic ovary syndrome. Int J Gynaecol Obstet 1998; 63: 33-37
• 19 Invitti C, De Martin M, Delitala G et al. Altered morning and nighttime pulsatile corticotropin and cortisol release in polycystic ovary syndrome. Metabolis 1998; 47: 143-148
• 20 Janssen I, Heymsfield SB, Allison DB et al. Body mass index and waist circumference independently contribute to the prediction of nonabdominal, abdominal subcutaneous, and visceral fat. Am J Clin Nutr 2002; 75: 683-688
• 21 Kumar A, Woods KS, Bartolucci AA et al. Prevalence of adrenal androgen excess in patients with the polycystic ovary syndrome (PCOS). Clin Endocrinol (Oxf) 2005; 62: 644-649
• 22 Laven JS, Imani B, Eijkemans MJ et al. New approach to polycystic ovary syndrome and other forms of anovulatory infertility. Obstet Gynecol Surv 2002; 57: 755-767
• 23 Livak KJ, Schmittgen TD. Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method. Methods 2001; 25: 402-408
• 24 Lowy MT. Corticosterone regulation of brain and lymphoid corticosteroid receptors. J Steroid Biochem Mol Biol 1991; 39: 147-154
• 25 Macut D, Damjanović S, Panidis D et al. Oxidised low-density lipoprotein concentration – early marker of an altered lipid metabolism in young women with PCOS. Eur J Endocrinol 2006; 155: 131-136
• 26 Markopoulos MC, Rizos D, Valsamakis G et al. Hyperandrogenism in women with polycystic ovary syndrome persists after menopause. J Clin Endocrinol Metab 2011; 96: 623-631
• 27 Mathur RS, Moody LO, Landgrebe S et al. Plasma androgens and sex hormone-binding globulin in the evaluation of hirsute females. Fertil Steril 1981; 35: 29-35
• 28 Matthews DR, Hosker JP, Rudenski AS et al. Homeostasis model assessment: insulin resistance and beta-cell function from fasting plasma glucose and insulin concentrations in man. Diabetologia 1985; 28: 412-419
• 29 Michelmore KF, Balen AH, Dunger DB et al. Polycystic ovaries and associated clinical and biochemical features in young women. Clin Endocrinol (Oxf) 1999; 51: 779-786
• 30 Moran C, Reyna R, Boots LS et al. Adrenocortical hyperresponsiveness to corticotropin in polycystic ovary syndrome patients with adrenal androgen excess. Fertil Steril 2004; 81: 126-131
• 31 Nicolaides NC, Galata Z, Kino T et al. The human glucocorticoid receptor: molecular basis of biologic function. Steroids 2010; 75: 1-12
• 32 Panarelli M, Holloway CD, Mulatero P et al. Inhibition of lysozyme synthesis by dexamethasone in human mononuclear leukocytes: an index of glucocorticoid sensitivity. J Clin Endocrinol Metab 1994; 78: 872-877
• 33 Pasquali R, Gambineri A, Pagotto U. The impact of obesity on reproduction in women with polycystic ovary syndrome. BJOG 2006; 113: 1148-1159
• 34 Pasquali R, Vicennati V. Activity of the hypothalamic-pituitary-adrenal axis in different obesity phenotypes. Int J Obes Relat Metab Disord 2000; 24 (Suppl. 02) S47-S49
• 35 Paust HJ, Loeper S, Else T et al. Expression of the glucocorticoid receptor in the human adrenal cortex. Exp Clin Endocrinol Diabetes 2006; 114: 6-10
• 36 Pratt WB, Galigniana MD, Morishima Y et al. Role of molecular chaperones in steroid receptor action. Essays Biochem 2004; 40: 41-58
• 37 Rotterdam ESHRE/ASRM-Sponsored PCOS Consensus Workshop Group. Revised 2003 consensus on diagnostic criteria and long-term health risks related to polycystic ovary syndrome (PCOS). Hum Reprod 2004; 19: 41-47
• 38 Sabuncu T, Vural H, Harma M. Oxidative stress in polycystic ovary syndrome and its contribution to the risk of cardiovascular disease. Clin Biochem 2001; 34: 407-413
• 39 Simons Jr SS, Pratt WB. Glucocorticoid receptor thiols and steroid-binding activity. Methods Enzymol 1995; 251: 406-422
• 40 Snijder MB, van Dam RM, Visser M et al. What aspects of body fat are particularly hazardous and how do we measure them?. Int J Epidemiol 2006; 35: 83-92
• 41 Spector T. Refinement of the coomassie blue method of protein quantitation. A simple and linear spectrophotometric assay for less than or equal to 0.5 to 50 microgram of protein. Anal Biochem 1978; 86: 142-146
• 42 Szuran TF, Pliska V, Pokorny J et al. Prenatal stress in rats: effects on plasma corticosterone, hippocampal glucocorticoid receptors, and maze performance. Physiol Behav 2000; 71: 353-362
• 43 Tanaka H, Makino Y, Okamoto K et al. Redox regulation of the nuclear receptor. Oncology 2000; 59 (Suppl. 01) 13-18
• 44 Tang Y, Lu A, Aronow BJ et al. Blood genomic responses differ after stroke, seizures, hypoglycemia, and hypoxia: blood genomic fingerprints of disease. Ann Neurol 2001; 50: 699-707
• 45 Tosi F, Negri C, Brun E et al. Insulin enhances ACTH-stimulated androgen and glucocorticoid metabolism in hyperandrogenic women. Eur J Endocrinol 2011; 164: 197-203
• 46 Tsilchorozidou T, Honour JW, Conway GS. Altered cortisol metabolism in polycystic ovary syndrome: insulin enhances 5alpha-reduction but not the elevated adrenal steroid production rates. J Clin Endocrinol Metab 2003; 88: 5907-5913
• 47 Vassiliadi DA, Barber TM, Hughes BA et al. Increased 5 alpha-reductase activity and adrenocortical drive in women with polycystic ovary syndrome. J Clin Endocrinol Metab 2009; 94: 3558-3566
• 48 Vettor R, Macor C, Novo F et al. Corticosteroid receptors in mononuclear leucocytes of obese subjects. J Endocrinol 1998; 156: 187-194
• 49 Yildiz BCE, Azziz R. Hypothalamic-pituitary-adrenal dysfunction in the polycystic ovary syndrome. In: Azziz RNJ, Dewailly D. ed. Androgen excess disorders in women: Polycystic ovary syndrome and other disorders.. Totowa, New Jersey: Humana Press; 2006: 213-222
• 50 Yildiz BO, Azziz R. The adrenal and polycystic ovary syndrome. Rev Endocr Metab Disord 2007; 8: 331-342
• 51 Yildiz BO, Woods KS, Stanczyk F et al. Stability of adrenocortical steroidogenesis over time in healthy women and women with polycystic ovary syndrome. J Clin Endocrinol Metab 2004; 89: 5558-5562