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Hormones

, Volume 14, Issue 1, pp 109–117 | Cite as

The influence of combined oral contraceptives containing drospirenone on hypothalamic-pituitary-adrenocortical axis activity and glucocorticoid receptor expression and function in women with polycystic ovary syndrome

  • Djuro Macut
  • Ivana Božić Antić
  • Jelena Nestorov
  • Vladanka Topalović
  • Jelica Bjekić Macut
  • Dimitrios Panidis
  • Biljana Kastratović Kotlica
  • Efstathios Papadakis
  • Gordana Matić
  • Danijela Vojnović Milutinović
Research paper

Abstract

OBJECTIVE: Most women with PCOS have increased adrenal androgen production, enhanced peripheral metabolism of Cortisol and elevation in urinary excretion of its metabolites. Increased Cortisol clearance in PCOS is followed by a compensatory overdrive of the hypothalamic-pituitary-adrenocortical (HPA) axis. We hypothesized that oral contraceptives containing ethinylestradiol and drospirenone (EE-DRSP) could modulate glucocorticoid receptor (GR) expression and function and thus affect HPA axis activity in PCOS patients. DESIGN: We analyzed 12 women with PCOS (age 24.17±4.88 years; body mass index 22.05±3.97 kg/m2) treated for 12 months with EE-DRSP and 20 BMI-matched controls. In all subjects testosterone, dehydroepiandrosterone sulfate (DHEAS), sex hormone-binding globulin (SHBG), Cortisol (basal and after dexamethasone), concentrations of GR protein, phospo-GR211 protein, number of GR per cell (Bmax) and its equilibrium dissociation constant (KD) were measured. RESULTS: Before treatment, increased concentrations of testosterone and DHEAS (p<0.001, respectively), unaltered basal Cortisol and an increased sensitivity (p<0.05) of the HPA axis to dexamethasone were observed in PCOS women in comparison to controls. After treatment, testosterone (p<0.01), DHEAS (p<0.05) and Cortisol suppression after dexamethasone (p<0.01) were decreased in PCOS women. There were no changes in GR protein concentration, GR phosphorylation nor in the receptor functional parameters Bmax and KD in women with PCOS before and after the therapy, and in comparison to controls. CONCLUSIONS: Prolonged treatment with EE-DRSP in PCOS women decreased serum androgens and increased Cortisol in the presence of decreased sensitivity of the HPA axis and did not exert changes in GR expression and function.

Key terms

Combined oral contraceptives Cortisol Drospirenone Glucocorticoid receptor HPA axis Polycystic ovary syndrome 

References

  1. 1.
    Azziz R, Woods KS, Reyna R, Key TJ, Knochenhauer ES, Yildiz BO, 2004 The prevalence and features of the polycystic ovary syndrome in an unselected population. J Clin Endocrinol Metab 89: 2745–2749.CrossRefGoogle Scholar
  2. 2.
    Azziz R, Carmina E, Dewailly D, et al, 2009 The Androgen Excess and PCOS Society criteria for the polycystic ovary syndrome: the complete task force report. Fertil Steril 91: 456–488.Google Scholar
  3. 3.
    Diamanti-Kandarakis E, Papailiou J, Palimeri S, 2006 Hyperandrogenemia: pathophysiology and its role in ovulatory dysfunction in PCOS. Pediatr Endocrinol Rev 3: Suppl 1: 198–204.PubMedGoogle Scholar
  4. 4.
    Diamanti-Kandarakis E, 2008 Polycystic ovarian syndrome: pathophysiology, molecular aspects and clinical implications. Expert Rev Mol Med 10: e3.CrossRefGoogle Scholar
  5. 5.
    Kumar A, Woods KS, Bartolucci AA, Azziz R, 2005 Prevalence of adrenal androgen excess in patients with the polycystic ovary syndrome (PCOS). Clin Endocrinol (Oxf) 62: 644–649.CrossRefGoogle Scholar
  6. 6.
    Vassiliadi DA, Barber TM, Hughes BA, et al, 2009 Increased 5 alpha-reductase activity and adrenocortical drive in women with polycystic ovary syndrome. J Clin Endocrinol Metab 94: 3558–3566.CrossRefGoogle Scholar
  7. 7.
    Yildiz BO, Azziz R, 2007 The adrenal and polycystic ovary syndrome. Rev Endocr Metab Disord 8: 331–342.CrossRefGoogle Scholar
  8. 8.
    Ratka A, Sutanto W, Bloemers M, de Kloet ER, 1989 On the role of brain mineralocorticoid (type I) and glucocorticoid (type II) receptors in neuroendocrine regulation. Neuroendocrinology 50: 117–123.CrossRefGoogle Scholar
  9. 9.
    Nicolaides NC, Galata Z, Kino T, Chrousos GP, Charmandari E, 2010 The human glucocorticoid receptor: molecular basis of biologic function. Steroids 75: 1–12.CrossRefGoogle Scholar
  10. 10.
    Gross KL, Lu NZ, Cidlowski JA, 2009 Molecular mechanisms regulating glucocorticoid sensitivity and resistance. Mol Cell Endocrinol 300: 7–16.CrossRefGoogle Scholar
  11. 11.
    Ismaili N, Garabedian MJ, 2004 Modulation of glucocorticoid receptor function via phosphorylation. Ann N Y Acad Sci 1024: 86–101.CrossRefGoogle Scholar
  12. 12.
    Kino T, Ichijo T, Amin ND, et al, 2007 Cyclin-dependent kinase 5 differentially regulates the transcriptional activity of the glucocorticoid receptor through phosphorylation: clinical implications for the nervous system response to glucocorticoids and stress. Mol Endocrinol 21: 1552–1568.CrossRefGoogle Scholar
  13. 13.
    Chen W, Dang T, Blind RD, et al, 2008 Glucocorticoid receptor phosphorylation differentially affects target gene expression. Mol Endocrinol 22: 1754–1766.CrossRefGoogle Scholar
  14. 14.
    Mathur R, Levin O, Azziz R, 2008 Use of ethinylestradiol/drospirenone combination in patients with the polycystic ovary syndrome. Ther Clin Risk Manag 4: 487–492.CrossRefGoogle Scholar
  15. 15.
    Vojnović Milutinović D, Macut D, Božić I, Nestorov J, Damjanović S, Matić G, 2011 Hypothalamic-pituitary-adrenocortical axis hypersensitivity and glucocorticoid receptor expression and function in women with polycystic ovary syndrome. Exp Clin Endocrinol Diabetes 119: 636–643.CrossRefGoogle Scholar
  16. 16.
    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). 2004 Fertil Steril 81: 19–25.Google Scholar
  17. 17.
    Laven JS, Imani B, Eijkemans MJ, Fauser BC, 2002 New approach to polycystic ovary syndrome and other forms of anovulatory infertility. Obstet Gynecol Surv 57: 755–767.CrossRefGoogle Scholar
  18. 18.
    Ferriman D, Gallwey JD, 1961 Clinical assessment of body hair growth in women. J Clin Endocrinol Metab 21: 1440–1447.CrossRefGoogle Scholar
  19. 19.
    Macut D, Damjanović S, Panidis D, et al, 2006 Oxidised low-density lipoprotein concentration — early marker of an altered lipid metabolism in young women with PCOS. Eur J Endocrinol 155: 131–136.CrossRefGoogle Scholar
  20. 20.
    Balen A, Rajkowha M, 2003 Polycystic ovary syndrome—a systemic disorder? Best Pract Res Clin Obstet Gynaecol 17: 263–274.CrossRefGoogle Scholar
  21. 21.
    Mathur RS, Moody LO, Landgrebe S, Williamson HO, 1981 Plasma androgens and sex hormone-binding globulin in the evaluation of hirsute females. Fertil Steril 35: 29–35.CrossRefGoogle Scholar
  22. 22.
    Matthews DR, Hosker JP, Rudenski AS, Naylor BA, Treacher DF, Turner RC, 1985 Homeostasis model assessment: insulin resistance and beta-cell function from fasting plasma glucose and insulin concentrations in man. Diabetologia 28: 412–419.CrossRefGoogle Scholar
  23. 23.
    Spector T, 1978 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 86: 142–146.CrossRefGoogle Scholar
  24. 24.
    Cinar N, Harmanci A, Bayraktar M, Yildiz BO, 2013 Ethinyl estradiol-drospirenone vs ethinyl estradioldrospirenone plus metformin in the treatment of lean women with polycystic ovary syndrome. Clin Endocrinol (Oxf) 78: 379–384.CrossRefGoogle Scholar
  25. 25.
    De Kloet ER, Vreugdenhil E, Oitzl MS, Joëls M, 1998 Brain corticosteroid receptor balance in health and disease. Endocr Rev 19: 269–301.Google Scholar
  26. 26.
    DeRijk RH, de Kloet ER, Zitman FG, van Leeuwen N, 2010 Mineralocorticoid receptor gene variants as determinants of HPA axis regulation and behavior. Endocr Dev 20: 137–148.CrossRefGoogle Scholar
  27. 27.
    Simons SS Jr, Pratt WB, 1995 Glucocorticoid receptor thiols and steroid-binding activity. Methods Enzymol 251: 406–422.CrossRefGoogle Scholar
  28. 28.
    Guido M, Romualdi D, Giuliani M, et al, 2004 Drospirenone for the treatment of hirsute women with polycystic ovary syndrome: a clinical, endocrinological, metabolic pilot study. J Clin Endocrinol Metab 89: 2817–2823.CrossRefGoogle Scholar
  29. 29.
    Westhoff CL, Petrie KA, Cremers S, 2013 Using changes in binding globulins to assess oral contraceptive compliance. Contraception 87: 176–181.CrossRefGoogle Scholar
  30. 30.
    Weiser MJ, Handa RJ, 2009 Estrogen impairs glucocorticoid dependent negative feedback on the hypothalamic-pituitary-adrenal axis via estrogen receptor alpha within the hypothalamus. Neuro science 159: 883–895.Google Scholar
  31. 31.
    Elger W, Beier S, Pollow K, Garfield R, Shi SQ, Hillisch A, 2003 Conception and pharmacodynamic profile of drospirenone. Steroids 68: 891–905.CrossRefGoogle Scholar
  32. 32.
    Arvat E, Maccagno B, Giordano R, et al, 2001 Mineralocorticoid receptor blockade by canrenoate increases both spontaneous and stimulated adrenal function in humans. J Clin Endocrinol Metab 86: 3176–3181.PubMedGoogle Scholar
  33. 33.
    Wellhoener P, Born J, Fehm HL, Dodt C, 2004 Elevated resting and exercise-induced Cortisol levels after mineralocorticoid receptor blockade with canrenoate in healthy humans. J Clin Endocrinol Metab 89: 5048–5052.CrossRefGoogle Scholar
  34. 34.
    Mendel CM, 1989 The free hormone hypothesis: a physiologically based mathematical model. Endocr Rev 10: 232–274.CrossRefGoogle Scholar
  35. 35.
    Heuser I, Deuschle M, Weber B, Stalla GK, Holsboer F, 2000 Increased activity of the hypothalamus-pituitary-adrenal system after treatment with the mineralocorticoid receptor antagonist spironolactone. Psychoneuroendocrinology 25: 513–518.CrossRefGoogle Scholar
  36. 36.
    Grossmann C, Scholz T, Rochel M, et al, 2004 Transactivation via the human glucocorticoid and mineralocorticoid receptor by therapeutically used steroids in CV-1 cells: a comparison of their glucocorticoid and mineralocorticoid properties. Eur J Endocrinol 151: 397–406.CrossRefGoogle Scholar
  37. 37.
    van Leeuwen N, Kumsta R, Entringer S, et al, 2010 Functional mineralocorticoid receptor (MR) gene variation influences the Cortisol awakening response after dexamethasone. Psychoneuroendocrinology 35: 339–349.CrossRefGoogle Scholar
  38. 38.
    Berardelli R, Karamouzis I, Marinazzo E, et al, 2010 Effect of acute and prolonged mineralocorticoid receptor blockade on spontaneous and stimulated hypothalamic-pituitary-adrenal axis in humans. Eur J Endocrinol 162: 1067–1074.CrossRefGoogle Scholar
  39. 39.
    Mancini F, Cianciosi A, Persico N, Facchinetti F, Busacchi P, Battaglia C, 2010 Drospirenone and cardiovascular risk in lean and obese polycystic ovary syndrome patients: a pilot study. Am J Obstet Gynecol 202: 169 e1–8.CrossRefGoogle Scholar

Copyright information

© Hellenic Endocrine Society 2015

Authors and Affiliations

  • Djuro Macut
    • 1
  • Ivana Božić Antić
    • 1
  • Jelena Nestorov
    • 2
  • Vladanka Topalović
    • 2
  • Jelica Bjekić Macut
    • 3
  • Dimitrios Panidis
    • 4
  • Biljana Kastratović Kotlica
    • 5
  • Efstathios Papadakis
    • 4
  • Gordana Matić
    • 2
  • Danijela Vojnović Milutinović
    • 2
  1. 1.Institute of Endocrinology, Diabetes and Metabolic Diseases, Clinical Center of Serbia and School of MedicineUniversity of BelgradeBelgradeSerbia
  2. 2.Department of Biochemistry, Institute for Biological Research “Siniša Stanković”University of BelgradeBelgradeSerbia
  3. 3.CHC Bežanijska kosaBelgradeSerbia
  4. 4.Division of Endocrinology and Human Reproduction, 2nd Department of Obstetrics and GynecologyAristotle University of ThessalonikiThessalonikiGreece
  5. 5.Clinic of Obstetrics and Gynecology, Faculty of MedicineUniversity of BelgradeBelgradeSerbia

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