Effects of naloxone and yohimbine in polycystic ovary syndrome: a rabbit model study

Effects of naloxone and yohimbine in polycystic ovary syndrome: a rabbit model study

Background/aim: To assess the therapeutic effects of naloxone and yohimbine on polycystic ovary syndrome (PCOS) in a rabbit model in terms of body weight and endocrinological parameters (luteinizing hormone, insulin, and estradiol). Materials and methods: A total of 50 adult, reproductively mature female rabbits (Oryctolagus cuniculus) were divided into five groups (n = 10/group). In the control group PCOS was not induced (negative control group), whereas in the remaining four groups (n = 40) PCOS was induced with a single i.m. injection of testosterone daily and were designated as follows: positive control, naloxone-treated (NalT), yohimbine-treated (YohT), and naloxone+yohimbine-treated (NalYT) groups. Results: A steadily ascending trend was noted in all of the studied parameters in the PCOS-induced group as compared to the negative control group. All the parameters showed a descending trend in the NalT group as compared to the positive control. Regarding the YohT and NalYT groups, all parameters showed a descending trend as compared to the positive control group except for estradiol. Conclusion: Naloxone therapy either alone or combined with yohimbine improves a wide range of the clinical manifestations of PCOS. Furthermore, we suggest this therapy as an alternative to the conventional therapy with insulin-lowering agents in vogue.

___

  • 1. Blank SK, McCartney CR, Marshall JC. The origins of sequelae of abnormal neuroendocrine function in polycystic ovary syndrome. Human Reprod Update 2006; 12: 351-361.
  • 2. Carmina E, Rosalo F, Janni M, Lonngo RA. Relative prevalence of different androgen excess disorders in 950 women referred because of clinical hyperandrogenism. Endocrinol Metabol 2006; 91: 2-6.
  • 3. Sverrisdottir YB, Mogren T, Kataoka J, Janson PO, StenerVictorin E. Is polycystic ovary syndrome associated with high sympathetic nerve activity and size at birth? Am J Physiol Endocrinol Metab 2008; 294: E576-E581.
  • 4. Pastore LM, Dougherty PL, Bailey AP, Li A, Goldfarb AH. Beta endorphin levels in PCOS women: relationship with insulin secretion. J Endocrinol Metab 2012; 2: 11-20.
  • 5. Hadziomerovic D, Rabenbauer B, Wildt L. Normalization of hyperinsulinemia by chronic opioid receptor blockade in hyperandrogenemic women. Fertil Steril 2006; 86: 651-657.
  • 6. Hoffman LK, Ehrmann DA. Cardiometabolic features of polycystic ovary syndrome. Nat Clin Pract Endocrinol Metab 2008; 4: 215-222.
  • 7. Baqai Z, Khanam M, Parveen S. Prevalence of PCOS in infertile patients. Med Channel 2010; 16: 437-440.
  • 8. Yasin M, Yasmeen F. Polycystic ovarian syndrome; pattern of disease in patients. Professional Med J 2014; 21: 179-184.
  • 9. Williamson K, Gunn A, Johnson N, Milsom SR. The impact of ethnicity on the presentation of polycystic ovarian syndrome. Aust NZJ Obstet Gynaecol 2001; 41: 202-206.
  • 10. Kauffman RP, Baker VM, Dimarino P, Gimpel T, Castracane VD. Polycystic ovarian syndrome and insulin resistance in white and Mexican American women: a comparison of two distinct populations. Am J Obstet Gynecol 2002; 187: 1362- 1369.
  • 11. Nazir F, Saeed S, Malik M, Aziz H, Aliya S, Rana S. Polycystic ovary syndrome diagnosis and management in fertility deprivation. Pak J Obstet Gynecol 199; 12: 59-70.
  • 12. Rasul S, Dar LR, Hameed A. Prevalence of polycystic ovaries among patients with hirsutism and menstrual abnormalities. J Pak Assoc Dermatol 2011; 21: 174-178.
  • 13. Mathur R, Alexander CJ, Yano J, Trivax B, Azziz R. Use of metformin in polycystic ovary syndrome. Am J Obstet Gynecol 2008; 199: 596-609.
  • 14. Iwamoto K, Mason JI, Manaligod J, Pau KF, Spies HG, Pang S. Steroidogenic enzyme gene expression in androgen induced polycystic ovaries in the rabbit.  Clin Pediatr Endocrinol 2001; 10: 17-28.
  • 15. Yassin A, Haffeje M. Testosterone depot injection in male hypogonadism: a critical appraisal. Clin Interv Aging 2007; 2: 577-590.
  • 16. Gillett CS. The Biology of the Laboratory Rabbit. 2nd ed. San Diego, CA, USA: Academic Press; 1994.
  • 17. Pasquali R, Casimirri F, Vicennati V. Weight control and its beneficial effect on fertility in women with obesity and polycystic ovary syndrome. Hum Reprod 1997; 12: S82-S87.
  • 18. Dissen GA, Garcia-Ruda C, Paredes A. Excessive ovarian production of nerve growth factor facilitates development of cystic ovarian morphology in mice and is a feature of polycystic ovarian syndrome in humans. Endocrinol 2009; 150: 2906- 2914.
  • 19. Guido M, Romualdi D, Lanzone A. Role of opioid antagonists in the treatment of women with glucoregulation abnormalities. Curr Pharm Des 2006; 12: 1001-1012.
  • 20. Ahmed MI, Duleba AJ, Shahat OE, Ibrahim ME, Salem E. Naltrexone treatment in clomiphene resistant women with polycystic ovary syndrome. Hum Reprod 2008; 23: 2564-2569.
  • 21. Fassnacht M, Schlenz N, Schneider SB, Wudy SA, Allolio B, Arlt W. Beyond adrenal and ovarian androgen generation: increased peripheral 5 α- reductase activity in women with polycystic ovary syndrome. J Clin Endocrinol Metabol 2003; 88: 2760- 2766.
  • 22. Zang H, Rydén M, Wåhlen K, Dahlman-Wrigth K, Arner P, Hirschberg AL. Effects of testosterone and estrogen treatment on lipolysis signaling pathways in subcutaneous adipose tissue of postmenopausal women. Fertil Steril 2007; 88: 100-106.
  • 23. Zang H, Carlstrom K, Arner P, Hirschberg AL. Effects of treatment with testosterone alone or in combination with estrogen on insulin sensitivity in postmenopausal women. Fertil Steril 2006; 86: 136-144.
  • 24. Baptiste CG, Battista MC, Trottier A, Baillargeon JP. Insulin and hyperandrogenism in women with polycystic ovary syndrome. J Steroid Biochem Mol Biol 2010; 122: 42-52.
  • 25. Fruzzetti F, Bersi C, Parrini D, Ricci C, Genazzani AR. Effect of long-term naltrexone treatment on endocrine profile, clinical features, and insulin sensitivity in obese women with polycystic ovary syndrome. Fertil Steril 2002; 77: 936-944.
  • 26. Eyvazzadeh AD, Pennington KP, Pop-Busui R, Sowers M, Zubieta JK, Smith YR. The role of the endogenous opioid system in polycystic ovary syndrome. Fertil Steril 2009; 92: 1-12.
  • 27. Harwood K, Vuguin P, Dimartino-Nardi J. Current approaches to the diagnosis and treatment of polycystic ovarian syndrome in youth. Horm Res 2007; 68: 209-217.
  • 28. Nelson SM, Fleming R. Obesity and reproduction: impact and interventions. Curr Opin Obstet Gynecol 2007; 19: 384-389.
  • 29. Fulghesu AM, Ciampelli M, Belosi C, Apa R, Guido M, Caruso A, Mancuso S, Lanzone A. Naltrexone effect on pulsatile GnRH therapy for ovulation induction in polycystic ovary syndrome: a pilot prospective study. J Endocrinol Invest 2001; 24: 483-490.
  • 30. Stener-Victorin E, Jedel E, Janson PO, Sverrisdottir YB. Low frequency electroacupuncture and physical exercise decrease high muscle sympathetic nerve activity in polycystic ovary syndrome. Am J Physiol Regul Integr Comp Physiol 2009; 297: R387-R395.
  • 31. Zangeneh FZ, Mohammadi A, Ejtemaeimehr S, Naghizadeh NM, Fatemeh A. The role of opioid system and its interaction with sympathetic nervous system in the processing of polycystic ovary syndrome modeling in rat. Arch Gynecol Obstet 2011; 283: 885-892.
  • 32. Stener-Victorin E, Ploj K, Larsson BM, Holmang A. Rats with steroid-induced polycystic ovaries develop hypertension and increased sympathetic nervous system activity. Reprod Biol Endocrinol 2005; 3: 44-50.
  • 33. Naghadeh MM, Moghadam H, Ibrahimi H. Effect of yohimbine on plasma levels of leptin in normal and streptozotocin induced diabetic rats. Acta Medica Iranica 2006; 44: 77-82.
  • 34. Stener-Victorin E, Jedel E, Manneras L. Acupuncture in polycystic ovary syndrome: current experimental and clinical evidence. J Neuro Endo 2008; 20: 290-298.
  • 35. Patel K, Coffler M, Dahan M, Malcom P, Deutsch A, Chang R. Relationship of GnRH-stimulated LH release to episodic LH secretion and baseline endocrine metabolic measures in women with polycystic ovary syndrome. Clin Endocrinol 2004; 60: 67-74.
  • 36. Anjaneyulu M, Chopra K. Possible involvement of cholinergic and opioid receptor mechanisms in fluoxetine mediated antinociception response in streptozotocin-induced diabetic mice. Eur J Pharmacol 2006; 538: 80-84.