Journal of Endocrinological Investigation

, Volume 25, Issue 8, pp 735–747 | Cite as

Benzodiazepines and anterior pituitary function

Review Article


Benzodiazepines (BDZ) are one of the most prescribed classes of drugs because of their marked anxiolytic, anticonvulsant, muscle relaxant and hypnotic effects. The pharmacological actions of BDZ depend on the activation of 2 specific receptors. The central BDZ receptor, present in several areas of the central nervous system (CNS), is a component of the GABA-A receptor, the activation of which increases GABAergic neurotransmission and is followed by remarkable neuroendocrine effects. The peripheral benzodiazepine receptors (PBR), structurally and functionally different from the GABA-A receptor, have been shown in peripheral tissues but also in the CNS, in both neurones and glial cells, and in the pituitary gland. BDZ receptors bind to a family of natural peptides called endozepines, firstly isolated from neurons and glial cells in the brain and then in several peripheral tissues as well. Endozepines modulate several central and peripheral biological activities, including some neuroendocrine functions and synthetic BDZ are likely to mimic them, at least partially. BZD, especially alprazolam (AL), possess a clear inhibitory influence on the activity of the HPA axis in both animals and humans. This effect seems to be mediated at the hypothalamic and/or suprahypothalamic level via suppression of CRH. The strong negative influence of AL on hypothalamicpituitary-adrenal (HPA) axis agrees with its peculiar efficacy in the treatment of panic disorders and depression. BZD have also been shown to increase GH secretion via mechanisms mediated at the hypothalamic or supra-hypothalamic level, though a pituitary action cannot be ruled out. Besides the impact on HPA and somatotrope function, BDZ also significantly affect the secretion of other pituitary hormones, such as gonadotropins and PRL, probably acting through GABAergic mediation in the hypothalamus and/or in the pituitary gland. In all, BDZ are likely to represent a useful tool to investigate GABAergic activity and clarify its role in the neuroendocrine control of anterior pituitary function; their usefulness probably overrides what had been supposed before.


Benzodiazepines ACTH GH gonadotropins PRL TSH 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Benzodiazepines. In: E.E. Muller, G. Nisticò (Eds.), Brain Messengers and the pituitary. Academic Press Inc., San Diego, California, 1989, p.157.Google Scholar
  2. 2.
    Tallman J.F., Paul S.M., Skolnick P., Gallager D.W. Receptors for the age of anxiety: pharmacology of the benzodiazepines. Science 1980, 207: 274–281.PubMedGoogle Scholar
  3. 3.
    Bowery N.G., Price G.W., Hudson A.L., Hill D.R., Wilkin G.P., Turnbull M.J. GABA receptor multiplicity. Visualization of different receptor types in the mammalian CNS. Neuropharmacology 1984, 23: 219–231.PubMedGoogle Scholar
  4. 4.
    Skerritt J.H., Chow S.C., Johnston G.A. Differences in the interactions between GABA and benzodiazepine binding sites. Neurosci. Lett. 1982, 33: 173–178.PubMedGoogle Scholar
  5. 5.
    Baraldi M., Guidotti A., Schwartz J.P., Costa E. GABA receptors in clonal cell lines: a model for study of benzodiazepine action at molecular level. Science 1979, 205: 821–823.PubMedGoogle Scholar
  6. 6.
    Chen G., Trombley P.Q., van den Pol A.N. Excitatory actions of GABA in developing rat hypothalamic neurones. J. Physiol. 1996, 494: 451–464.PubMedCentralPubMedGoogle Scholar
  7. 7.
    Vijayan E., McCann S.M. The effects of intraventricular injection of gamma-aminobutyrric acid (GABA) on prolactin and gonadotropin release in conscious female rats. Brain Res. 1978, 155: 35–43.PubMedGoogle Scholar
  8. 8.
    Spergel D.J., Krsmanovic L.Z., Stojilkovic S.S., Catt K.J. Ltype Ca2+ channels mediate joint modulation by gammaamino-butyric acid and glutamate of [Ca2+]i and neuropeptide secretion in immortalized gonadodropin-releasing hormone neurons. Neuroendocrinology 1995, 61: 499–508.PubMedGoogle Scholar
  9. 9.
    Tran V., Hatalski C.G., Yan X.X., Baram T.Z. Effects of blocking GABA degradation on corticotropin-releasing hormone gene expression in selected brain regions. Epilepsia 1999, 40: 1190–1197.PubMedCentralPubMedGoogle Scholar
  10. 10.
    Lux-Lantos V., Rey E., Libertun C. Activation of GABA B receptors in the anterior pituitary inhibits prolactin and luteinizing hormone secretion. Neuroendocrinology 1992, 56: 687–693.PubMedGoogle Scholar
  11. 11.
    Virmani M.A., Stojilkovic S.S., Catt K.J. Stimulation of luteinizing hormone release by gamma-aminobutyrric acid (GABA) agonists: mediation by GABA-A-type receptors and activation of chloride and voltage-sensitive calcium channels. Endocrinology 1990, 126: 2499–2505.PubMedGoogle Scholar
  12. 12.
    Fiszer de Plazas S., Becu D., Mitridate de Novara A., Libertun C. Gamma-Aminobutyrric acid receptors in anterior pituitary and brain areas after median eminence lesions. Endocrinology 1982, 111: 1974–1978.Google Scholar
  13. 13.
    Berman J.A., Roberts J.L., Pritchett D.B. Molecular and pharmacological characterization of GABAA receptors in the rat pituitary. J. Neurochem. 1994, 63: 1948–1954.PubMedGoogle Scholar
  14. 14.
    Orth D.N. Corticotropin-releasing hormone in humans. Endocr. Rev. 1992, 13: 164–191.PubMedGoogle Scholar
  15. 15.
    Sirinathsinghji D.J., Rees L.H., Rivier J., Vale W. Corticotropin-releasing factor is a potent inhibitor of sexual receptivity in the female rat. Nature 1983, 305: 232–235.PubMedGoogle Scholar
  16. 16.
    Sutton R.E., Koob G.F., Le Moal M., Rivier J., Vale W. Corticotropin releasing factor produces behavioural activation in rats. Nature 1982, 297: 331–333.PubMedGoogle Scholar
  17. 17.
    Magiakou M.A., Mastorakos G., Webster E., Chrousos G.P. The hypothalamic-pituitary-adrenal axis and the female reproductive system. Ann. N. Y. Acad. Sci. 1997, 816: 42–56.PubMedGoogle Scholar
  18. 18.
    Gold P.W., Loriaux D.L., Roy A., et al. Responses to corticotropin-releasing hormone in the hypercortisolism of depression and Cushing’s disease. Pathophysiologic and diagnostic implications. N. Engl. J. Med. 1986, 314: 1329–1335.PubMedGoogle Scholar
  19. 19.
    Nemeroff C.B., Widerlov E., Bissette G., et al. Elevated concentrations of CSF corticotropin-releasing factor-like immunoreactivity in depressed patients. Science 1984, 226: 1342–1344.PubMedGoogle Scholar
  20. 20.
    Lopez A.L., Kathol R.G., Noyes R. Jr. Reduction in urinary free cortisol during benzodiazepine treatment of panic disorder. Psychoneuroendocrinology 1990, 15: 23–28.PubMedGoogle Scholar
  21. 21.
    Dawson G.W., Jue S.G., Brogden R.N. Alprazolam: a review of its pharmacodynamic properties and efficacy in the treatment of anxiety and depression. Drugs 1984, 27: 132–147.PubMedGoogle Scholar
  22. 22.
    Feighner J.P., Aden G.C., Fabre L.F., Rickels K., Smith W.T. Comparison of alprazolam, imipramine, and placebo in the treatment of depression. J.A.M.A. 1983, 249: 3057–3064.PubMedGoogle Scholar
  23. 23.
    Chouinard G., Annable L., Fontaine R., Solyom L. Alprazolam in the treatment of generalized anxiety and panic disorders: a double-blind placebo-controlled study. Psychopharmacology (Berl.) 1982, 77: 229–233.Google Scholar
  24. 24.
    Papadopoulos V. Peripheral-type benzodiazepine/diazepam binding inhibitor receptor: biological role in steroidogenic cell function. Endocr. Rev. 1993, 14: 222–240.PubMedGoogle Scholar
  25. ai]25.
    Whitehouse B.J. Benzodiazepines and steroidogenesis. J. Endocrinol. 1992, 134: 1–3.PubMedGoogle Scholar
  26. ai]26.
    Li S., Pelletier G. Further studies on the mechanism of action of the endogenous benzodiazepine receptor ligand octadecaneuropeptide on gonadotropin-releasing hormone gene expression in the rat brain. Neuroendocrinology 1996, 64: 79–84.PubMedGoogle Scholar
  27. 27.
    Matsumoto R.R. GABA receptors: are cellular differences reflected in function? Brain Res. Rev. 1989, 14: 203–225.PubMedGoogle Scholar
  28. 28.
    Study R.E., Barker J.L. Diazepam and (—)-pentobarbital: fluctuation analysis reveals different mechanisms for potentiation of gamma-aminobutyrric acid responses in cultured central neurons. Proc. Natl. Acad. Sci. U.S.A. 1981, 78: 7180–7184.PubMedCentralPubMedGoogle Scholar
  29. 29.
    Cowen P.J., Green A.R., Nutt D.J. Ethyl beta-carboline carboxylate lowers seizure threshold and antagonizes flurazepam-induced sedation in rats. Nature 1981, 290: 54–55.PubMedGoogle Scholar
  30. 30.
    Braestrup C., Schmiechen R., Neef G., Nielsen M., Petersen E.N. Interaction of convulsive ligands with benzodiazepine receptors. Science 1982, 216: 1241–1243.PubMedGoogle Scholar
  31. 31.
    Hunkeler W., Mohler H., Pieri L., et al. Selective antagonists of benzodiazepines. Nature 1981, 290: 514–516.PubMedGoogle Scholar
  32. 32.
    Anderson R.A., Mitchell R. Effects of gamma-aminobutyrric acid receptor agonists on the secretion of growth hormone, luteinizing hormone, adrenocorticotrophic hormone and thyroid-stimulating hormone from the rat pituitary gland in vitro. J. Endocrinol. 1986, 108: 1–8.PubMedGoogle Scholar
  33. 33.
    Racagni G., Apud J.A., Locatelli V., et al. GABA of CNS origin in the rat anterior pituitary inhibits prolactin secretion. Nature 1979, 281: 575–578.PubMedGoogle Scholar
  34. 34.
    Vincent S.R., Hokfelt T., Wu J.Y. GABA neuron systems in hypothalamus and the pituitary gland. Immunohistochemical demonstration using antibodies against glutamate decarboxylase. Neuroendocrinology 1982, 34: 117–125.PubMedGoogle Scholar
  35. 35.
    Tappaz M.L., Wassef M., Oertel W.H., Paut L., Pujol J.F. Light- and electron-microscopic immunocytochemistry of glutamic acid decarboxylase (GAD) in the basal hypothalamus: morphological evidence for neuroendocrine gamma-aminobutyrate (GABA). Neuroscience 1983, 9: 271–287.PubMedGoogle Scholar
  36. 36.
    Lehmann J., Weizman R., Pryce C.R., et al. Peripheral benzodiazepine receptors in cerebral cortex, but not in internal organs, are increased following inescapable stress and subsequent avoidance/escape shuttle-box testing. Brain Res. 1999, 851: 141–147.PubMedGoogle Scholar
  37. 37.
    Lesouhaitier O., Kodjo M.K., Cartier F., et al. The effect of the endozepine triakontatetraneuropeptide on corticosteroid secretion by the frog adrenal gland is mediated by activation of adenylyl cyclase and calcium influx through T-type calcium channels. Endocrinology 2000, 141: 197–207.PubMedGoogle Scholar
  38. 38.
    Calogero A.E., Kamilaris T.C., Bernardini R., Johnson E.O., Chrousos G.P., Gold P.W. Effects of peripheral benzodiazepine receptor ligands on hypothalamic-pituitary-adrenal axis function in the rat. J. Pharmacol. Exp. Ther. 1990, 253: 729–737.PubMedGoogle Scholar
  39. 39.
    Black K.L., Shiraishi T., Ikezak K., Tabuchi K., Becker D.P. Peripheral benzodiazepine stimulates secretion of growth hormone and mitochondrial proliferation in pituitary tumour GH3 cells. Neurol. Res. 1994, 16: 74–80.PubMedGoogle Scholar
  40. 40.
    Bruni G., Dal Pra P., Dotti M.T., Segre G. Plasma ACTH and cortisol levels in benzodiazepine treated rats. Pharmacol. Res. Commun. 1980, 12: 163–175.PubMedGoogle Scholar
  41. 41.
    Crawley J.N., Ninan P.T., Pickar D., et al. Neuropharmacological antagonism of the beta-carboline-induced “anxiety” response in rhesus monkeys. J. Neurosci. 1985, 5: 477–485.PubMedGoogle Scholar
  42. 42.
    Pivac N., Pericic D. Inhibitory effect of diazepam on the activity of the hypothalamic-pituitary-adrenal axis in female rats. J. Neural. Trans. Gen. Sect. 1993, 92: 173–186.Google Scholar
  43. 43.
    Kalman B.A., Kim P.J., Cole M.A., Chi M.S., Spencer R.L. Diazepam attenuation of restraint stress-induced corticosterone levels in enhanced by prior exposure to repeated restraint. Psychoneuroendocrinology 1997, 22: 349–360.PubMedGoogle Scholar
  44. 44.
    Barlow S., Knight A., Sullivan F. Plasma corticosterone responses to stress following chronic oral administration of diazepam in the rat. J. Pharm. Pharmacol. 1979, 31: 23–26.PubMedGoogle Scholar
  45. 45.
    Adam K., Oswald I., Shapiro C. Effects of alprazolam and triazolam on sleep and overnight urinary cortisol. Psichopharmacology 1984, 82: 389–394.Google Scholar
  46. 46.
    Torney W., Dolphin C., Darragh A. The effects of diazepam on sleep and on the nocturnal release of growth hormone, prolactin, ACTH and cortisol. Br. J. Clin. Pharmacol. 1979, 8: 90–92.Google Scholar
  47. 47.
    Havard C., Saldanha V., Bird R., Gardner R. The effect of diazepam on pituitary function in man. J. Endocrinol. 1972, 52: 79–85.PubMedGoogle Scholar
  48. 48.
    Petraglia F., Bakalakis S., Facchinetti F., Volpe A., Muller E.E., Genazzani A.R. Effects of sodium valproate and diazepam on beta-endorphin, beta-lipotropin and cortisol secretion induced by hypoglycemic stress in humans. Neuroendocrinology 1986, 44: 320–325.PubMedGoogle Scholar
  49. 49.
    Laakmann G., Wittmann M., Gugath M., et al. Effects of psychotropic drugs (desimipramine, chlorimipramine, sulpiride and diazepam) on the human HPA axis. Psychopharmacology (Berl.) 1984, 84: 66–70.Google Scholar
  50. 50.
    Brever A., Charney D.S., Heninger G.R. Intravenous diazepam fails to change growth hormone and cortisol secretion in humans. Psychiatr. Res. 1986, 18: 298–299.Google Scholar
  51. 51.
    Garland E.J., Zis A.P. Effect of codeine and oxazepam on afternoon cortisol secretion in men. Psychoneuroendocrinology 1989, 14: 397–402.PubMedGoogle Scholar
  52. 52.
    Ambrosi F., Ricci S., Quartesan R., et al. Effects of acute benzodiazepine administration on growth hormone, prolactin and cortisol release after moderate insulin-induced hypoglycemia in normal women. Psychopharmacology (Berl.) 1986, 88: 187–189.Google Scholar
  53. 53.
    Sethy V.H., Harris D.W. Determination of biological activity of alprazolam, triazolam and their metabolites. J. Pharm. Pharmacol. 1982, 34: 115–116.PubMedGoogle Scholar
  54. 54.
    Von Voigtlander P.F., Straw R.N. Alprazolam: review of pharmacological, pharmacokinetic, and clinical data. Drug Dev. Res. 1985, 6: 1–12.Google Scholar
  55. 55.
    Wamsley J.K., Longlet L.L., Hunt M.E., Mahan D.R., Alburges M.E. Characterization of the binding and comparison of the distribution of benzodiazepine receptors labeled with [3H]diazepam and [3H]alprazolam. Neuropsychopharmacology 1993, 8: 305–314.PubMedGoogle Scholar
  56. 56.
    Eberts F.S., Philopoulos jr Y., Reineke L.M., Vliek R.W. Disposition of 14-C alprazolam, a new anxiolitic-antidepressant in man. Pharmacologist 1980, 22: 279.Google Scholar
  57. 57.
    Abernethy D.R., Greenblatt D.J., Divoll M., Shader R.I. Pharmacokinetics of alprazolam. J. Clin. Psychiatry 1983, 44: 45–47.PubMedGoogle Scholar
  58. 58.
    Kalogeras K.T., Calogero A.E., Kuribayashi T., et al. In vitro and in vivo effects of the triazolobenzodiazepine alprazolam on hypothalamic-pituitary-adrenal function: pharmacological and clinical implications. J. Clin. Endocrinol. Metab. 1990, 70: 1462–1471.PubMedGoogle Scholar
  59. 59.
    Van Vugt D.A., Washburn D.L.S., Farley A.E., Reid R.L. Hypoglycemia-induced inhibition of LH and stimulation of ACTH secretion in the Rhesus Monkey is blocked by alprazolam. Neuroendocrinology 1997, 65: 344–352.PubMedGoogle Scholar
  60. 60.
    Owens M.J., Vargas M.A., Knight D.L., Nemeroff C.B. The effects of alprazolam on corticotropin-releasing factor neurons in tha rat brain: acute time course, chronic treatment and abrupt withdrawal. J. Pharmacol. Exp. Ther. 1991, 258: 349–356.PubMedGoogle Scholar
  61. 61.
    Arvat E., Maccagno B., Ramunni J., et al. The inhibitory effect of alprazolam, a benzodiazepine, overrides the stimulated effect of metyrapone-induced lack of negative cortisol feedback on corticotroph secretion in humans. J. Clin. Endocrinol. Metab. 1999, 84: 2611–2615.PubMedGoogle Scholar
  62. 62.
    Zemishlany Z., McQueeney R., Gabriel S.M., Davidson M. Neuroendocrine and monoaminergic responses to acute administration of alprazolam in normal subjects. Neuropsychobiology 1990, 23: 124–128.PubMedGoogle Scholar
  63. 63.
    Risby E.D., Hsiao J.K., Golden R.N., Potter W.Z. Intravenous alprazolam challenge in normal subjects. Biochemical, cardiovascular, and behavioral effects. Psychopharmacology 1989, 99: 508–514.PubMedGoogle Scholar
  64. 64.
    Breier A., Davis O., Buchanan R., et al. Effects of alprazolam on pituitary-adrenal and catecholaminergic responses to metabolic stress in humans. Biol. Psychiatry. 1992, 32: 880–890.PubMedGoogle Scholar
  65. 65.
    Roher T., von Richthofen V., Schulz C., Beyer J., Lehnert H. The stress, but not corticotropin-releasing hormone-induced activation of the pituitary-adrenal axis in man is blocked by alprazolam. Horm. Metab. Res. 1994, 26: 200–206.Google Scholar
  66. 66.
    Torpy D.J., Grice J.E., Hockings G.I., Walters M.W., Crosbie G.V., Jackson R.V. Alprazolam blocks the naloxone-stimulated Hyphotalam.-pituitary-adrenal axis in man. J. Clin. Endocrinol. Metab. 1993, 76: 388–391.PubMedGoogle Scholar
  67. 67.
    Torpy D.J., Grice J.E., Hockings G.I., Walters M.W., Crosbie G.V., Jackson R.V. Alprazolam attenuates vasopressin-stimulated adrenocorticotropin and cortisol release: evidence for sinergy between vasopressin and corticotropin-releasing hormone in humans. J. Clin. Endocrinol. Metab. 1994, 79: 140–144.PubMedGoogle Scholar
  68. 68.
    Arvat E., Maccagno B., Ramunni J., et al. Effects of dexametasone and alprazolam, a benzodiazepine, on the stimulatory effect of Hexarelin, a synthetic GHRP, on ACTH, cortisol and GH secretion in humans. Neuroendocrinology 1998, 67: 310–316.PubMedGoogle Scholar
  69. 69.
    Giordano R., Grottoli S., Maccagno B.,et al. Effects of alprazolam, a benzodiazepine, on the GH, ACTH, cortisol and cathecolamine responses to insulin-induced hypoglycemia in humans. J. Endocrinol. Invest., 2001, 24: P134, (Abstract).Google Scholar
  70. 70.
    Braestrup C., Nielsen M. Benzodiazepine receptors. In: Iverson L., Iverson S.D., Snyder S.M. (Eds.), Handbook of psychopharmacology. Plenum Publishing Corp., New York, 1983, p.285.Google Scholar
  71. 71.
    Givalois L., Grinevich V., Li S., Garcia-De-Yebenes E., Pelletier G. The octadecaneuropeptide-induced response of corticotropin-releasing hormone messenger RNA levels is mediated by GABA(A) receptors and modulated by endogenous steroids. Neuroscience 1998, 85:557–567.PubMedGoogle Scholar
  72. 72.
    Tappaz M., Brownstein M.J., Kopin I. Glutamate decarboxylase (GAD) and gamma-aminobutyrric acid (GABA) in discrete nuclei of hypothalamus and substantia nigra. Brain Res. 1977, 125: 109–121.PubMedGoogle Scholar
  73. 73.
    Magnusson A.M., Meyerson B.J. GABA-A agonist muscimol inhibits stimulated vasopressin release in the posterior pituitary of Sprague-Dawley, Wistar, Wistar-Kyoto and spontaneously hypertensive rats. Neuroendocrinology 1993, 58: 519–524.PubMedGoogle Scholar
  74. 74.
    Wible J.H. Jr, Zerbe R.L., DiMicco J.A. Benzodiazepine receptors modulate circulating plasma vasopressin concentration. Brain Res. 1985, 359: 368–370.PubMedGoogle Scholar
  75. 75.
    Hillhouse E.W., Milton N.G. Effect of noradrenaline and gamma-aminobutyrric acid on the secretion of corticotrophin-releasing factor-41 and arginine vasopressin from the rat hypothalamus in vitro. J. Endocrinol. 1989, 122: 719–723.PubMedGoogle Scholar
  76. 76.
    S. Grottoli, B. Maccagno, J. Ramunni, et al. Alprazolam, a benzodiazepine, does not modify the ACTH and cortisol response to CRH and AVP but blunts the cortisol response to ACTH in humans. J. Endocrinol. Invest., 2002, 25: 420–425.PubMedGoogle Scholar
  77. 77.
    Korbonits M., Trainer P.J., Edwards R., Besser G.M., Grossman A.B. Benzodiazepines attenuate the pituitaryadrenal responses to corticotrophin-releasing hormone in healthy volunteers, but not in patients with Cushing’s syndrome. Clin. Endocrinol. (Oxf.) 1995, 43: 29–35.Google Scholar
  78. 78.
    Chiodera P., Gnudi A., Volpi R., et al. Effects of the GABAergic agent sodium valproate on the arginine vasopressin responses to hypertonic stimulation and upright posture in man. Clin. Endocrinol. (Oxf.) 1989, 30: 389–395.Google Scholar
  79. 79.
    Grigoriadis D.E., Pearsall D., De Souza E.B. Effects of chronic antidepressant and benzodiazepine treatment on corticotropin-releasing-factor receptors in rat brain and pituitary. Neuropsychopharmacology 1989, 2: 53–60.PubMedGoogle Scholar
  80. 80.
    Arvat E., Maccagno B., Giordano R., et al. The stimulatory effect of canrenoate, a mineralcorticoid antagonist, on the activity of hypothalamus-pituitary-adrenal axis (HPA) is abolished by alprazolam, a benzodiazepine, in humans. Invecchiamento e Ormoni, p.85, (Abstract).Google Scholar
  81. 81.
    Jacobson L., Sapolsky R. The role of the hippocampus in feedback regulation of the hypothalamic-pituitary-adrenocortical axis. Endocr. Rev. 1991, 12: 118–134.PubMedGoogle Scholar
  82. 82.
    Corrodi H., Fuxe K., Hokfelt T. The effect of some psychoactive drugs on central monoamine neurons. Eur. J. Pharmacol. 1967, 1: 363–368.PubMedGoogle Scholar
  83. 83.
    Taylor K.M., Laverty R. The effect of chlordiazepoxide, diazepam and nitrazepam on catecholamine metabolism in regions of the rat brain. Eur. J. Pharmacol. 1969, 8: 296–301.PubMedGoogle Scholar
  84. 84.
    Sawchenko P.E., Swanson L.W. The organization of noradrenergic pathways from the brainstem to the paraventricular and supraoptic nuclei in the rat. Brain Res. 1982, 257: 275–325.PubMedGoogle Scholar
  85. 85.
    Novas M.L., Medina J.H., De Robertis E. Benzodiazepine receptors in the rat hippocampal formation: action of catecholaminergic, serotoninergic and commissural denervation. Neuroscience 1983, 8: 459–465.PubMedGoogle Scholar
  86. 86.
    Sabato U.C., Novas M.L., Lowestein P., Zieher L.M., De Robertis E. Action of 6-hydroxydopamine on benzodiazepine receptors in tha rat cerebral cortex. Eur. J. Pharmacol. 1981, 73: 381–382.Google Scholar
  87. 87.
    Charney D.S., Breier A., Jatlow P.I., Heninger G.R. Behavioural, biochemical and blood pressure responses to alprazolam in healthy subjects: interactions with yohimbine. Psychopharmacology 1986, 88: 133–140.PubMedGoogle Scholar
  88. 88.
    Williams B., Bence M., Everest H., Forrest-Owen W., Lightman S.L., McArdle C.A. GABAA receptor mediated elevation of Ca2+ and modulation of gonadotrophin-releasing hormone action in alphaT3-1 gonadotropes. J. Neuroendocrinol. 2000, 12: 159–166.PubMedGoogle Scholar
  89. 89.
    Grottoli S., Arvat E., Gauna C., et al. Effects of alprazolam, a benzodiazepine, on the ACTH-, GH- and PRL-releasing activity of Hexarelin, a synthetic peptidyl GH secretagogue (GHS), in patients with simple obesity and in patients with Cushing’s disease. Pituitary 1999, 2: 197–204.PubMedGoogle Scholar
  90. 90.
    Roy-Byrne P.P., Cowley D.S., Hommer D., Ritchie J., Greenblatt D., Nemeroff C. Neuroendocrine effects of diazepam in panic and generalized anxiety disorders. Biol. Psychiatry 1991, 30: 73–80.PubMedGoogle Scholar
  91. 91.
    Hommer D.W., Matsuo V., Wolkowitz O., et al. Benzodiazepine sensitivity in normal human subjects. Arch. Gen. Psychiatry 1986, 43: 542–551.PubMedGoogle Scholar
  92. 92.
    Syvälahti E.K., Kanto J.H. Serum growth hormone, serum immunoreactive insulin and blood glucose response to oral and intravenous diazepam in man. Int. J. Clin. Pharmacol. Biopharm. 1975, 12: 74–82.PubMedGoogle Scholar
  93. 93.
    Kangas L., Kanto J., Syvälahti E. Plasma nitrazepam concentrations after an acute intake and their correlation to sedation and serum growth hormone levels. Acta Pharmacol. Toxicol. (Copenh.) 1977, 41: 65–73.Google Scholar
  94. 94.
    Seifritz E., Hemmeter U., Trachsel L., et al. Effects of flumazenil on recovery sleep and hormonal secretion after sleep deprivation in male controls. Psychopharmacology (Berl.) 1995, 120: 449–456.Google Scholar
  95. 95.
    Guldner J., Trachsel L., Kratschmayr C., Rothe B., Holsboer F., Steiger A. Bretazenil modulates sleep EEG and nocturnal hormone secretion in normal men. Psychopharmacology (Berl.) 1995, 122: 115–121.Google Scholar
  96. 96.
    Copinschi G., Van Onderbergen A., L’Hermite-Baleriaux M., et al. Effects of the short-acting benzodiazepine triazolam, taken at bedtime, on circadian and sleep-related hormonal profiles in normal men. Sleep 1990, 13: 232–244.PubMedGoogle Scholar
  97. 97.
    Weitzman E.D., Pollak C.P. Effects of flurazepam on sleep and growth hormone release during sleep in healthy subjects. Sleep 1982, 5: 343–349.PubMedGoogle Scholar
  98. 98.
    Roy-Byrne P.P., Risch S.C., Uhde T.W. Neuroendocrine effects of diazepam in normal subjects following brief painful stress. J. Clin. Psychopharmacol. 1988, 8: 331–335.PubMedGoogle Scholar
  99. 99.
    Breier A., Charney D.S., Heninger G.R. Intravenous diazepam fails to change growth hormone and cortisol secretion in humans. Psychiatry Res. 1986, 18: 293–299.PubMedGoogle Scholar
  100. 100.
    Steiger A., Guldner J., Lauer C.J., Meschenmoser C., Pollmacher T., Holsboer F. Flumazenil exerts intrinsic activity on sleep EEG and nocturnal hormone secretion in normal controls. Psychopharmacology (Berl.) 1994, 113: 334–338.Google Scholar
  101. 101.
    Monteiro M.G., Schuckit M.A., Hauger R., Irwin M., Duthie L.A. Growth hormone response to intravenous diazepam and placebo in 82 healthy men. Biol. Psychiatry 1990, 27: 702–710.PubMedGoogle Scholar
  102. 102.
    Levin E.R., Sharp B., Carlson H.E. Failure to confirm consistent stimulation of growth hormone by diazepam. Horm. Res. 1984, 19: 86–90.PubMedGoogle Scholar
  103. 103.
    Osman O.T., Hsiao J.K., Potter W.Z. Dose-dependent effects of intravenous alprazolam on neuroendocrine, biochemical, cardiovascular, and behavioral parameters in humans. Psychopharmacology (Berl.) 1993, 111: 295–300.Google Scholar
  104. 104.
    Eriksson E., Carlsson M., Nilsson C., Soderpalm B. Does alprazolam, in contrast to diazepam, activate alpha 2-adrenoceptors involved in the regulation of rat growth hormone secretion? Life Sci. 1986, 38: 1491–1498.PubMedGoogle Scholar
  105. 105.
    Sevy S., Brown S.L., Wetzler S., et al. Effects of alprazolam on increases in hormonal and anxiety levels induced by meta-chlorophenylpiperazine. Psychiatry Res. 1994, 53: 219–229.PubMedGoogle Scholar
  106. 106.
    Koulu M., Pihlajamäki K., Huupponen R. Effect of the benzodiazepine derivative, diazepam, on the clonidine-stimulated human growth hormone secretion. J. Clin. Endocrinol. Metab. 1983, 56: 1316–1318.PubMedGoogle Scholar
  107. 107.
    Cavagnini F., Invitti C., Pinto M., et al. Effect of acute and repeated administration of gamma aminobutyrric acid (GABA) on growth hormone and prolactin secretion in man. Acta Endocrinol. (Copenh.) 1980, 93: 149–154.Google Scholar
  108. 108.
    Mannisto P.T., Laakso M.L., Järvinen A., Rago L. Effects of central and peripheral type benzodiazepine ligands on growth hormone and gonadotropin secretion in male rats. Pharmacol. Toxicol. 1992, 71: 75–80.PubMedGoogle Scholar
  109. 109.
    Harvey S. Benzodiazepine antagonism of thyrotrophin-releasing hormone receptors: biphasic actions on growth hormone secretion in domestic fowl. J. Endocrinol. 1993, 137: 35–42.PubMedGoogle Scholar
  110. 110.
    Brambilla F., Bellodi L., Arancio C., Nobile P., Perna G. Alpha 2-adrenergic receptor sensitivity in panic disorder: I. GH response to GHRH and clonidine stimulation in panic disorder. Psychoneuroendocrinology 1995, 20: 1–9.PubMedGoogle Scholar
  111. 111.
    Koulu M., Lämmintausta R., Kangas L., Dahlstrom S. The effect of methysergide, pimozide, and sodium valproate on the diazepam-stimulated growth hormone secretion in man. J. Clin. Endocrinol. Metab. 1979, 48: 119–122.PubMedGoogle Scholar
  112. 112.
    Stryker T.D., Conlin T., Reichlin S. Influence of a benzodiazepine, midazolam, and gamma-aminobutyrric acid (GABA) on basal somatostatin secretion from cerebral and diencephalic neurons in dispersed cell culture. Brain Res. 1986, 362: 339–343.PubMedGoogle Scholar
  113. 113.
    Ghigo E., Arvat E., Bellone J., Ramunni J., Camanni F. Neurotransmitter control of growth hormone secretion in humans. J. Pediatr. Endocrinol. 1993, 6: 263–266.PubMedGoogle Scholar
  114. 114.
    Duvilanski B.H., Perez R., Seilicovich A., Lasaga M., Diaz M.C., Debeljuk L. Intracellular distribution of GABA in the rat anterior pituitary. An electron microscopic autoradiographic study. Tissue Cell. 2000, 32: 284–292.PubMedGoogle Scholar
  115. 115.
    Roussel J.P., Astier H., Tapia-Arancibia L. Benzodiazepines inhibit thyrotropin (TSH)-releasing hormone-induced TSH and growth hormone release from perifused rat pituitaries. Endocrinology 1986, 119: 2519–2526.PubMedGoogle Scholar
  116. 116.
    D’Armiento M., Bisignani G., Reda G. Effect of bromazepam on growth hormone and prolactin secretion in normal subjects. Horm. Res. 1981, 15: 224–227.PubMedGoogle Scholar
  117. 117.
    Lamberts R., Vijayan E., Graf M., Mansky T., Wuttke W. Involvement of preoptic-anterior hypothalamic GABA neurons in the regulation of pituitary LH and prolactin release. Exp. Brain. Res. 1983, 52: 356–362.PubMedGoogle Scholar
  118. 118.
    Li S., Pelletier G. Chronic administration of muscimol and pentobarbital decreases gonadotropin-releasing hormone mRNA levels in the male rat hypothalamus determined by quantitative in situ hybridization. Neuroendocrinology 1993, 58: 136–139.PubMedGoogle Scholar
  119. 119.
    Li S., Pelletier G. Inhibitory effect of the potential endogenous benzodiazepine receptor ligand, octadecaneuropeptide (ODN), on gonadotropin-releasing hormone gene expression in the male rat brain. Neuroreport 1995, 6: 1354–1356.PubMedGoogle Scholar
  120. 120.
    Alleva J.J., Alleva F.R. Synergistic inhibition by benzodiazepine and barbiturate drugs of the clock control of ovulation in hamsters. Chronobiol. Int. 1995, 12: 1–7.PubMedGoogle Scholar
  121. 121.
    Gargiulo P.A., Donoso A.O. Is inhibition by diazepam and beta-carbolines of estrogen-induced luteinizing hormone secretion related to sedative effects? Pharmacol. Biochem. Behav. 1991, 40: 335–338.PubMedGoogle Scholar
  122. 122.
    Judd S.J., Wong J., Saloniklis S., et al. The effect of alprazolam on serum cortisol and luteinizing hormone pulsatility in normal women and in women with stress-related anovulation. J. Clin. Endocrinol. Metab. 1995, 80: 818–823.PubMedGoogle Scholar
  123. 123.
    Weizman R., Dagan E., Snyder S.H., Gavish M. Impact of pregnancy and lactation on GABA(A) receptor and central-type and peripheral-type benzodiazepine receptors. Brain Res. 1997, 752: 307–314.PubMedGoogle Scholar
  124. 124.
    Torner L., Toschi N., Pohlinger A., Landgraf R., Neumann I.D. Anxiolytic and anti-stress effects of brain prolactin: improved efficacy of antisense targeting of the prolactin receptor by molecular modeling. J. Neurosci. 2001, 21: 3207–3214.PubMedGoogle Scholar
  125. 125.
    Weizman A., Tyano S., Wijsenbeek H., Ben David M. High dose diazepam treatment and its effect on prolactin secretion in adolescent schizophrenic patients. Psychopharmacology (Berl.) 1984, 82: 382–385.Google Scholar
  126. 126.
    Carr D.B., Sheehan D.V., Surman O.S., et al. Neuroendocrine correlates of lactate-induced anxiety and their response to chronic alprazolam therapy. Am. J. Psychiatry 1986, 143: 483–494.PubMedGoogle Scholar
  127. 127.
    Järvinen A., Rago L., Mannisto P.T. Effects of central and peripheral type benzodiazepine ligands on thyrotropin and prolactin secretion. Neuropeptides 1992, 2: 183–191.Google Scholar
  128. 128.
    Schettini G., Cronin M.J., O’Dell S.B., MacLeod R.M. The benzodiazepine agonist diazepam inhibits basal and secretagogue-stimulated prolactin release in vitro. Brain Res. 1984, 291: 343–349.PubMedGoogle Scholar
  129. 129.
    Grandison L. Suppression of prolactin secretion by benzodiazepines in vivo. Neuroendocrinology 1982, 34: 369–373.PubMedGoogle Scholar
  130. 130.
    Humbert T., Pujalte D., Bottai T., Hue B., Pouget R., Petit P. Pilot investigation of thyrotropin-releasing hormone-induced thyrotropin and prolactin release in anxious patients treated with diazepam. Clin. Neuropharmacol. 1998, 21: 80–85.PubMedGoogle Scholar
  131. 131.
    Willoughby J.O., Jervois P.M., Menadue M.F., Blessing W.W. Activation of GABA receptors in the hypothalamus stimulates secretion of growth hormone and prolactin. Brain Res. 1986, 374: 119–125.PubMedGoogle Scholar
  132. 132.
    Ondo J.G., Dom R. The arcuate nucleus: a site for gamma-aminobutyrric acid regulation of prolactin secretion. Brain Res. 1986, 381: 43–48.PubMedGoogle Scholar
  133. 133.
    Keller H.H., Schaffner R., Haefely W. Interaction of benzodiazepines with neuroleptics at central dopamine neurons. Arch. Pharmacol. 1976, 294: 1–7.Google Scholar
  134. 134.
    Anderson R.A., Mitchell R. Benzodiazepine- and barbiturate-interactions with GABAA receptor responses on lactotrophs. Brain Res. 1986, 371: 287–292.PubMedGoogle Scholar
  135. 135.
    Zaccaria M., Giordano G., Ragazzi E., Sicolo N., Foresta C., Scandellari C. Lack of effect of im diazepam administration on hGH and hPRL secretion in normal and acromegalic subjects. J. Endocrinol. Invest. 1985, 8: 167–170.PubMedGoogle Scholar
  136. 136.
    Ajlouni K., El-Khateeb M., El-Zaheri M.M., El-Najdawi A. The response of growth hormone and prolactin to oral diazepam in diabetics. J. Endocrinol. Invest. 1982, 5: 157–159.PubMedGoogle Scholar
  137. 137.
    Ajlouni K., El-Khateeb M. Effect of glucose of growth hormone, prolactin and thyroid-stimulating hormone response to diazepam in normal subjects. Horm. Res. 1980, 13: 160–164.PubMedGoogle Scholar
  138. 138.
    Martin J.V., Williams D.B., Fitzgerald R.M., Im H.K., Vonvoigtlander P.F. Thyroid hormonal modulation of the binding and activity of the GABAA receptor complex of brain. Neuroscience 1996, 73: 705–713.PubMedGoogle Scholar

Copyright information

© Italian Society of Endocrinology (SIE) 2002

Authors and Affiliations

  1. 1.Division of Endocrinology and Metabolism, Department of Internal MedicineUniversity of TurinTorinoItaly

Personalised recommendations