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Pivagabine decreases stress-related hormone secretion in women with hypothalamic amenorrhea

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Abstract

Stress-induced neuroendocrine activities influence the regulation of endocrine glands and axes. Weight loss-related hypothalamic amenorrhea is a typical stress-induced physiopathological condition. It is characterized by increased adrenal cortex activation and by reduced GH, LH, FSH and gonadal steroid hormone levels. The aim of the present study was to investigate the effects of pivagabine, a neurotropic drug (1800 mg/day for 7 days) or placebo administration on ACTH, cortisol, GH, LH, FSH and PRL plasma levels in patients with hypothalamic amenorrhea related to weight loss. Hormonal parameters and the pulsatile release of cortisol (6-hour pulsatility, sampling every 10 minutes) were evaluated before and after 7 days of treatment. Pivagabine administration significantly reduced mean plasma ACTH (from 21.7±1.7 to 15.4±1.2 pg/ml, p<0.05) and cortisol levels (from 12.2±0.7 to 9.7±0.7 ng/ml, p<0.05) and increased GH levels (from 1.4±0.5 to 3.0±0.9 ng/ml, p<0.05). A significant reduction of cortisol pulse amplitude was observed (p<0.01) while no change in pulse frequency occurred. No changes were observed in placebo-treated subjects. LH, FSH and PRL levels were not modified by placebo or pivagabine administration. In conclusion, in patients with hypothalamic amenorrhea related to weight loss pivagabine induced a significant decrease of cortisol secretion and an increase of GH release by pivagabine administration, suggesting that this drug exerts a specific neuroendocrine modulatory role.

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References

  1. Reifenstein E.C. Psychogenic or “hypothalamic” amenorrhea. Med. Clin. North Am. 1946, 30: 1103–1114.

    PubMed  Google Scholar 

  2. Berga S.L., Mortola S.F., Girton L., Suh B., Laughlin G., Pham P., Yen S.S.C. Neuroendocrine aberrations in women with functional hypothalamic amenorrhea. J. Clin. Endocrinol. Metab. 1989, 68: 301–308.

    Article  CAS  PubMed  Google Scholar 

  3. Genazzani A.D., Gastaldi M., Volpe A., Petraglia F., Genazzani A.R. Spontaneous episodic release of adenohypophyseal hormones in hypothalamic amenorrhea. Gynecol. Endocrinol. 1995, 9: 325–334.

    CAS  Google Scholar 

  4. Genazzani A.D., Petraglia F., Volpe A., Genazzani A.R. Hypothalamic amenorrhea: neuroendocrine mechanisms/stress-induced anomalies. ARTA 1997, 9: 1–13.

    Google Scholar 

  5. Frisch R.E., McArthur J.W. Menstrual cycles: fatness as a determinant of minimum weight for height necessary for their maintenance or onset. Science 1974, 185: 949–951.

    Article  CAS  PubMed  Google Scholar 

  6. Ferin M. Stress and the reproductive cycle. J. Clin. Endocrinol. Metab. 1999, 84: 1768–1774.

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  8. Genazzani A.D., Petraglia F., Algeri I., Gastaldi M., Calvani M., Botticelli G., Genazzani A.R. Acetyl-l-carnitine as possible drug in the treatment of hypothalamic amenorrhea. Acta. Obstet. Gynecol. Scand. 1991, 70: 487–492.

    Article  CAS  PubMed  Google Scholar 

  9. Quigley M.E., Yen S.S.C. The role of endogenous opiates on LH secretion during the menstrual cycle. J. Clin. Endocr. Metab. 1980, 51: 179–181.

    Article  CAS  PubMed  Google Scholar 

  10. Petraglia F., D’Ambrogio G., Comitini G., Facchinetti F., Volpe A., Genazzani A.R. Impairment of opioid control of luteinizing hormone secretion in menstrual disorders. Fertil. Steril. 1985, 43: 535–540.

    Google Scholar 

  11. Petraglia F., Porro C., Facchinetti F., Cicoli C., Bertellini E., Volpe A., Barbieri G.C., Genazzani A.R. Opiod control of LH secretion in humans: menstrual cycle, menopause and aging reduce effect of naloxone but not of morphine. Life Sci. 1986, 38: 2103–2110.

    Article  CAS  PubMed  Google Scholar 

  12. Genazzani A.D., Petraglia F., Gastaldi M., Volpogni C., Gamba O., Genazzani A.R. Naltrexone treatment restores menstrual cycles in patients with weight loss-related amenorrhea. Fertil. Steril. 1995, 64: 951–956.

    CAS  PubMed  Google Scholar 

  13. Biggio G., Sanna E., Serra M., Costa E. GABAa receptors and anxiety. In: Biggio G. (Ed.), Advances in Biochemistry and Psychopharmacology. Raven press, New York, vol. 48, 1995.

  14. Biggio G., Concas A., Corda M.G., Giorgi O., Sanna E., Serra M. GABAergic and dopaminergic transmission in the rat cerebral cortex: effect of stress, anxiolytic and anxiogenic drugs. Pharmacol. Ther. 1990, 48: 121–142.

    Article  CAS  PubMed  Google Scholar 

  15. Concas A., Serra M., Atsoggiu T., Biggio G. Foot shock and anxiogenic beta-carbolines increase t-[35S]- butylbicyclophosphorotionate binding in the rat cerebral cortex, an effect opposite to anxiolytic and gamma-aminobutyric acid mimetics. J. Neurochem. 1988, 51: 1868–1876.

    Article  CAS  PubMed  Google Scholar 

  16. Kalogeras K.T., Calogero A.E., Kuribayiashi T., Khan I., Gallucci W.T., Kling M.A., Chrousos G.P., Gold P.W. In vitro and in vivo effects of the triazolobenzodiazepine alprazolam and hypothalamic-pituitaryadrenal function: pharmacological and clinical implications. J. Clin. Endocrinol. Metab. 1990, 70: 1462–1471.

    Article  CAS  PubMed  Google Scholar 

  17. Imaki T., Vale W. Chlordiazepoxide attenuates stress-induced accumulation of corticotropin-releasing factor mRNA in the paraventricular nucleus. Brain Res. 1993, 623: 223–228.

    Article  CAS  PubMed  Google Scholar 

  18. Imaki T., Xiao-Quan W., Shibasaki T., Harada S., Chikada N., Takahashi C., Naruse M., Demura H. Chlordiazepoxide attenuates stress-induced activation of neurons, corticotropin-releasing factor (CRF) gene trascription and CRF biosynthesis in the paraventricular necleus (PVN). Mol. Brain Res. 1995, 32: 261–270.

    Article  CAS  PubMed  Google Scholar 

  19. Galzigna L., Garbin L., Bianchi M., Marzotto A. Properties of two derivatives of gamma-aminobutyric acid (GABA) capable of abolishing Cardiazol- and bicuculline-induced convulsions in the rat. Arch. Int. Pharmacodyn. Ther. 1978, 235: 73–85.

    CAS  PubMed  Google Scholar 

  20. Esposito G., Luparini M.R. Pivagabine: a novel psychoactive drug. Arzneim Forsch Drug Res. 1997, 47: 1306–1309.

    CAS  Google Scholar 

  21. Serra M., Concas A., Mostallino M.C., Chessa M.F., Stomati M., Petraglia F., Genazzani A.R., Biggio G. Antagonism by pivagabine of stress-induced changes in GABA a receptor function and corticotropin-releasing factor concentrations in rat brain. Psychoneuroendocrinology 1999, 24: 269–284.

    Article  CAS  PubMed  Google Scholar 

  22. American Psychiatric Association. Diagnostic and statistical manual of mental disorders, 4th ed. Washington, DC, American Psychiatric Association, 1995.

    Google Scholar 

  23. Genazzani A.D., Massolo F., Ferrari E., Gandolfi A., Petraglia F., Genazzani A.R. Long-term GnRH agonist administration revealed a GnRH independent mechanism stimulating FSH discharge in humans. Eur. J. Endocrinol. 1996, 134: 77–83.

    Article  CAS  PubMed  Google Scholar 

  24. Genazzani A.D., Rodbard D. Evaluation of methods for detection of pulsatile hormone secretion: sensitivity vs. specificity. Acta Endocrinol. (Copenh.) 1991, 124: 295–306.

    CAS  Google Scholar 

  25. Oerter K.E., Guardabasso V. and Rodbard D. Detection and characterization of peaks and estimation of instantaneous secretory rate for episodic pulsatile hormone secretion. Comput. Biom. Res. 1986, 19: 170–191.

    Article  CAS  Google Scholar 

  26. Cameron J.L. Regulation of reproductive hormone secretion in primates by short-term changes in nutrition. Rev. Reprod. 1996, 1: 117–126.

    Article  CAS  PubMed  Google Scholar 

  27. Scapagnini U., Matera M. Effects of pivagabine on psychophysical performance and behavioural response in experimental models of stress. Arzneim Forsch Drug Res. 1997, 47: 1310–1317.

    CAS  Google Scholar 

  28. Gigliotti B., Multinu A., Lai V.R. Role of pivagabine in the treatment of climacteric syndrome. Arzneim Forsch Drug Res. 1997, 47: 1317–1321.

    CAS  Google Scholar 

  29. Genazzani A.D., Petraglia F., Volpogni C., Gastaldi M., Pianazzi F., Montanini V., Genazzani A.R. Modulatory role of estrogens and progestins on growth hormone episodic release in women with hypothalamic amenorrhea. Fertil. Steril. 1993, 60: 465–470.

    CAS  PubMed  Google Scholar 

  30. Nappi R.E., Petraglia F., D’Ambrogio G., Zara C., Genazzani A.R. Hypothalamic amenorrhea: evidence of a central derangement of hypothalamic-pituitary-adrenal cortex axis activity. Fertil. Steril. 1993, 59: 571–576.

    CAS  PubMed  Google Scholar 

  31. Britton K.T., Lee G., Koob G.F. Corticotropin releasing factor and amphetamine exaggerate partial agonist properties of benzodiazepine antagonist Ro 15-1788 in the conflict test. Psychopharmacology 1988, 94: 306–31132.

    Article  CAS  PubMed  Google Scholar 

  32. De Boer S.F., Slanger J.L., Van de Gutner J. Brain benzodiazepine receptor control of stress hormones. In: Kvetnasky R., Mc Carty R., Axelrod J. (Eds), Stress, neuroendocrine and molecular approaches. Gordon and Breanch, Philadelphia, 1995, 719–734.

    Google Scholar 

  33. Owens M.J., Bissette G., Nemeroff C.B. Acute effects of alprazolam and adinazolam on the concentrations of corticotropin-releasing factor in the rat brain. Synapse 1989, 4: 196–202.

    Article  CAS  PubMed  Google Scholar 

  34. Barbarino A., Corsello S.M., Della Casa S., Tofani A., Sciuto R., Rota C.A., Bollanti L., Barini A. Corticotropin-releasing hormone inhibition of growth hormone-releasing hormone-induced growth hormone release in man. J. Clin. Endocrinol. Metab. 1990, 71: 1368–1374.

    Article  CAS  PubMed  Google Scholar 

  35. Robel P., Baulieu E.E. Neurosteroids: biosynthesis and function. TEM 1994, 5: 1–8.

    CAS  PubMed  Google Scholar 

  36. Purdy R.H., Morow A.L., Moore P.H. Jr., Paul S.M. Stress-induced elevation of ?-aminobutyric acid type A receptor-active steroids in the rat brain. Proc. Natl. Acad. Sci. USA 1991, 88: 4553–4557.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  37. Facchinetti F., Fava M., Fioroni L., Genazzani A.D., Genazzani A.R. Stressful life events and affective disorders inhibit pulsatile LH secretion in hypothalamic amenorrhea. Psychoneuroendocrinology 1993, 18: 397–404.

    Article  CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. Department of Obstetrics and Gynecology, University of Modena, Via del Pozzo 71, 41100, Modena, Italy

    A. D. Genazzani M.D.

  2. Department of Obstetrics and Gynecology, University of Pisa, Italy

    M. Stomati, C. Bersi, S. Luisi & A. R. Genazzani

  3. Department of Surgical Sciences, University of Udine, Italy

    M. Fedalti (Chair of Obstetrics and Gynecology), M. Santuz (Chair of Obstetrics and Gynecology) & F. Petraglia (Chair of Obstetrics and Gynecology)

  4. ACRAF, Angelini Spa, Roma, Italy

    G. Esposito

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  1. A. D. Genazzani M.D.
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  2. M. Stomati
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  3. C. Bersi
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  4. S. Luisi
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Correspondence to A. D. Genazzani M.D..

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Genazzani, A.D., Stomati, M., Bersi, C. et al. Pivagabine decreases stress-related hormone secretion in women with hypothalamic amenorrhea. J Endocrinol Invest 23, 526–532 (2000). https://doi.org/10.1007/BF03343769

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