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Naltrexone effect on pulsatile GnRH therapy for ovulation induction in polycystic ovary syndrome: A pilot prospective study

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Abstract

The aim of the present study was to analyze the opioid influence on LH pulsatility in polycystic ovary syndrome (PCOS) patients and to evaluate the effectiveness of a long-term opioid antagonist (naltrexone) treatment in improving the pulsatile GnRH therapy which is successful in this syndrome. Ten obese women affected by PCOS participated in the study. Patients were hospitalized during the early follicular phase and underwent an oral glucose tolerance test (OGTT) with 75 g of glucose and a pulse pattern study followed by a GnRH test (100 μg iv). All patients were then treated for ovulation induction with pulsatile administration of GnRH (5 μg/bolus every 90 min). Since pregnancies did not occurr in any patient, after spontaneous or progestin-induced menstrual cycles, all patients received naltrexone at a dose of 50 mg/day orally for 8 weeks and during treatment repeated the basal protocol study and the ovulation induction cycle with the same modalities. The naltrexone treatment significantly reduced the insulin response to OGTT and the LH response to GnRH bolus, whereas it did not affect the FSH and LH pulsatility patterns. Concerning the ovulation induction by pulsatile GnRH, naltrexone treatment was able to improve, although not significantly, the ovulation rate (60% pre-treatment vs 90% posttreatment). Furthermore, the maximum diameter of the dominant follicle and the pre-ovulatory estradiol concentration were higher after long-term opioid blockade (follicular diameter 19.5±1.76 mm pre-treatment vs 21.6±2.19 mm post-treatment, p<0.001; maximum estradiol level 728.7±288.5 pmol/l pre-treatment vs 986.4±382.1 pmol/l posttreatment, p<0.05). During the naltrexone-pulsatile GnRH co-treatment two pregnancies occurred. In conclusion, our data show that naltrexone-pulsatile GnRH co-treatment is able to improve the ovarian responsiveness to ovulation induction in obese PCOS patients when compared to pulsatile GnRH alone. This action seems to be related to a decrease of insulin secretion. Further randomized studies should be performed in order to obtain significant conclusions on the possible clinical application.

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References

  1. Ciampelli M., Lanzone A. Insulin and polycystic ovary syndrome. Gynecol. Endocrinol. 1998, 12: 277–292.

    Article  PubMed  CAS  Google Scholar 

  2. Waldstreicher J., Santoro N.F., Hall J.E., Filicori M., Crowley W.F. Hyperfunction of the hypothalamic-pituitary axis in women with polycystic ovarian disease: indirect evidence for partial gonadotroph desensitization. J. Clin. Endocrinol. Metab. 1988, 66: 165–173.

    Article  PubMed  CAS  Google Scholar 

  3. Kazer R.R., Kessel B., Yen S.S.C. Circulating luteinizing hormone pulse frequency in women with polycystic ovary syndrome. J. Clin. Endocrinol. Metab. 1987, 65: 233–236.

    Article  PubMed  CAS  Google Scholar 

  4. Ciampelli M., Fulghesu A.M., Cucinelli F., Pavone V., Ronsisvalle E., Guido M., Caruso A., Lanzone A. Impact of insulin and body mass index on metabolic and endocrine variables in polycystic ovary syndrome. Metabolism 1999, 48: 167–172.

    Article  PubMed  CAS  Google Scholar 

  5. Messinis I.E., Milingos S.D. Current and future status of ovulation induction in polycystic ovary syndrome. Hum. Reprod. Update 1997, 3: 235–253.

    Article  PubMed  CAS  Google Scholar 

  6. Franks S., Mason H.D., Polson D.W., Jacobs H.S. The mechanism and management of ovulatory failure in women with polycystic ovary syndrome. Hum. Reprod. 1988, 3: 531–534.

    PubMed  CAS  Google Scholar 

  7. Healy D.L., Kovacs G.T., Pepperell R.J., Burger H.G. A normal cumulative conception rate after human pituitary gonadotropin. Fertil. Steril. 1980, 34: 341–345.

    PubMed  CAS  Google Scholar 

  8. Filicori M., Flamigni C., Dellai P., Cognigni G., Michelacci L., Arnone R., Sambataro M., Falbo A. Treatment of ovulation with pulsatile gonadotropinreleasing hormone: prognostic factors and clinical results in 600 cycles. J. Clin. Endocrinol. Metab. 1994, 79: 1215–1220.

    PubMed  CAS  Google Scholar 

  9. Filicori M., Flamigni C., Cognigni G., Dellai P., Michelacci L., Arnone R. Increased insulin secretion in patients with multifollicular and polycystic ovaries and its impact on ovulation induction. Fertil. Steril. 1994, 62: 279–285.

    PubMed  CAS  Google Scholar 

  10. Murakawa H., Hasegawa I., Kurabayashi T., Tanaka K. Polycystic ovary syndrome: insulin resistance and ovulatory response to clomiphene cytrate. J. Reprod. Med. 1999, 44: 23–27.

    PubMed  CAS  Google Scholar 

  11. Lanzone A., Fulghesu A.M., Cucinelli F., Ciampelli M., Caruso A., Mancuso S. Evidence of a distinct derangement of opioid tone in hyperinsulinemic patients with polycystic ovary syndrome: relationship with insulin and luteinizing hormone secretion. J. Clin. Endocrinol. Metab. 1995, 80: 3501–3506.

    PubMed  CAS  Google Scholar 

  12. Fulghesu A.M., Ciampelli M., Guido M., Murgia F., Caruso A., Mancuso S., Lanzone A. Role of opioid tone in the pathophysiology of hyperinsulinemia and insulin resistance in polycystic ovary syndrome. Metabolism 1998, 47: 158–162.

    Article  PubMed  CAS  Google Scholar 

  13. Barnes R.B., Lobo R.A. Central opioid activity in polycystic ovary syndrome with and without dopaminergic modulation. J. Clin. Endocrinol. Metab. 1985, 61: 779–782.

    Article  PubMed  CAS  Google Scholar 

  14. Cumming D.C., Reid R.L., Quigley M.E., Rebar R.W., Yen S.S.C. Evidence for decreased endogenous dopamine and opioid inhibitory influence on LH secretion in polycystic ovary syndrome. Clin. Endocrinol. (Oxf.) 1984, 20: 643–648.

    Article  CAS  Google Scholar 

  15. Armeanu M.C., Berkhout G.M., Schoemaker J. Pulsatile luteinizing hormone secretion in hypothalamic amenorrhea, anorexia nervosa, and polycystic ovarian disease during naltrexone treatment. Fertil. Steril. 1992, 57: 762–770.

    PubMed  CAS  Google Scholar 

  16. Fulghesu A.M., Villa P., Pavone V., Guido M., Apa R., Caruso A., Lanzone A., Rossodivita A., Mancuso S. The impact of insulin secretion on the ovarian response to exogenous gonadotropins in polycystic ovary syndrome. J. Clin. Endocrinol. Metab. 1997, 82: 644–648.

    Article  PubMed  CAS  Google Scholar 

  17. New M.I., Lorentzen F., Lerner A.J., Kohn B., Oberfield S.E., Pollack M.S. Genotyping steroid 21-hydroxylase deficiency: hormonal reference data. J. Clin. Endocrinol. Metab. 1983, 57: 320–326.

    Article  PubMed  CAS  Google Scholar 

  18. World Health Organization. WHO laboratory manual for the examination of human semen, and semen cervical-mucus interaction, ed. 2. The Press Syndicate of the University of Cambridge, Cambridge, UK, 1987.

  19. Golan A., Ron-El R., Herman A., Soffer Y., Weinraub Z., Caspi E. Ovarian hyperstimulation syndrome: an update review. Obstet. Gynecol. Surv. 1989, 44: 430–440.

    Article  PubMed  CAS  Google Scholar 

  20. National Diabetes Data Group. Classification and diagnosis of diabetes mellitus and other categories of glucose intolerance. Diabetes 1979, 28: 1039–1057.

    Article  Google Scholar 

  21. Oerter K.E., Guardabasso V., Rodbard D. Detection and characterization of peaks and estimation of instantaneous secretory rate for episodic pulsatile hormone secretion. Comput. Biomed. Res. 1986, 19: 170–177.

    Article  PubMed  CAS  Google Scholar 

  22. Hasegawa I., Murakawa H., Suzuki M., Yamamoto Y., Kurabayashi T., Tanaka K. Effect of troglitazone on endocrine and ovulatory performance in women with insulin-resistance related polycystic ovary syndrome. Fertil. Steril. 1999, 71: 323–327.

    Article  PubMed  CAS  Google Scholar 

  23. Nestler J.E., Jakubowicz D.J., Evans W.S., Pasquali R. Effects of metformin on spontaneous and clomiphene-induced ovulation in the polycystic ovary syndrome. N. Engl. J. Med. 1998, 338: 1876–1880.

    Article  PubMed  CAS  Google Scholar 

  24. Roozenburg B.J., van Dessel H.J.H.M., Evers J.L.H., Bots R.S.G.M. Successful induction of ovulation in normogonadotrophic clomiphene resistant anovulatory women by combined naltrexone and clomiphene cytrate treatment. Hum. Reprod. 1997, 12: 1720–1722.

    Article  PubMed  CAS  Google Scholar 

  25. Wildt L., Leyendecker G., Sir-Peterman T., Waibel-Treber S. Treatment with naltrexone in hypothalamic ovarian failure: induction of ovulation and pregnancy. Hum. Reprod. 1993, 8: 350–358.

    Article  PubMed  CAS  Google Scholar 

  26. Carmina E., Ditkoff E.C., Malizia G., Vijod A.G., Janni A., Lobo R.A. Increased circulating levels of immunoreactive β-endorphin in polycystic ovary syndrome is not caused by increased pituitary secretion. Am. J. Obstet. Gynecol. 1992, 167: 1819–1824.

    Article  PubMed  CAS  Google Scholar 

  27. Lanzone A., Apa R., Fulghesu A.M., Cutillo G., Caruso A., Mancuso S. Long-term naltrexone treatment normalizes the pituitary response to gonadotropin-releasing hormone in polycystic ovarian syndrome. Fertil. Steril. 1993, 59: 734–737.

    PubMed  CAS  Google Scholar 

  28. Cagnacci A., Soldano R., Paoletti A.M., Falqui A., Melis G.B. Prolonged opioid blockade with naltrexone and luteinizing hormone modifications in women with polycystic ovarian syndrome. Fertil. Steril. 1994, 62: 269–272.

    PubMed  CAS  Google Scholar 

  29. Erickson G.F., Magoffin D.A., Cragun J.R., Chang R.J. The effects of insulin and insulin-like growth factors-I and -II on estradiol production by granulosa cells of polycystic ovaries. J. Clin. Endocrinol. Metab. 1990, 70: 894–901.

    Article  PubMed  CAS  Google Scholar 

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Authors and Affiliations

  1. Department of Obstetrics and Gynecology, Università Cattolica del Sacro Cuore, Largo Gemelli 8, 00168, Rome, Italy

    Anna Maria Fulghesu, C. Belosi, R. Apa, M. Guido, A. Caruso & S. Mancuso

  2. Division of Obstetrics and Gynecology, Ospedale G.B. Grassi, Ostia, Italy

    M. Ciampelli

  3. OASI Institute of Research, Troina, Italy

    A. Lanzoneal

Authors
  1. Anna Maria Fulghesu
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  2. M. Ciampelli
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  3. C. Belosi
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  4. R. Apa
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  5. M. Guido
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  6. A. Caruso
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  7. S. Mancuso
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  8. A. Lanzoneal
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Fulghesu, A.M., Ciampelli, M., Belosi, C. et al. Naltrexone effect on pulsatile GnRH therapy for ovulation induction in polycystic ovary syndrome: A pilot prospective study. J Endocrinol Invest 24, 483–490 (2001). https://doi.org/10.1007/BF03343880

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