Advertisement

Neurosteroids

  • Andrea Riccardo Genazzani
  • Francesca Bernardi
  • Martina Liut
  • M. Stomati
  • M. Pieri
  • M. Luisi
Part of the Medical Science Symposia Series book series (MSSS, volume 17)

Abstract

Neurosteroids are steroids de novo synthesized in the brain or metabolized in situ by blood borne precursors. Neurosteroids influence brain function via both genomic and nongenomic mechanisms [1]; the first include the induction of progesterone receptors in cultured oligodendrocytes, the latter include the modulation of calcium channel and of chloride channel opening. Some neurosteroids act as GABA-A agonists, such as allopregnanolone and tetrahydrodesoxycorticosterone; others are GABA-A antagonists, such as DHEA and pregnanolone sulfate (Figure 1). Brain is the first known source of neurosteroids. Bixo et al. have evaluated women post-mortem concentrations of allopregnanolone in brain cortex, amygdala, hippocampus, caudate nucleus, putamen, thalamus, and the highest levels were observed in the substantia nigra and basal hypothalamus [2]. The regional differences in brain steroid levels imply different local mechanisms for steroid uptake and binding. Brain concentrations of allopregnanolone were significantly higher in fertile women at luteal phase than in postmenopausal controls; this may depend on ovarian steroid production, indicating that the secretion pattern during the menstrual cycle is reflected in the brain [2]. A5 androgens have also been measured in specific regions of cadaver brains and the central/plasmatic ratio of DHEA demonstrated a higher concentration of the steroid within the brain [1,3].

Keywords

Anorexia Nervosa Luteal Phase Premenstrual Syndrome Neuroactive Steroid Fertile Woman 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. 1.
    Mellon SH. Neurosteroids: Biochemistry, modes of action, and clinical relevance. J Clin Endocrinol Metab 1994:78:1003–8.PubMedCrossRefGoogle Scholar
  2. 2.
    Bixo M, Andersson A, Winblad B, Purdy RH, Backstrom T. Progesterone, 5alpha-pregnane-3,20-dione and 3alpha-hydroxy-5alpha-pregnane-20-one in specific regions of the human female brain in different endocrine states. Brain Res 1997 Aug 1; 764(1–2): 173–78.PubMedCrossRefGoogle Scholar
  3. 3.
    Majewska MD, Demirgoren S, Spivak CE, London ED. The neurosteroid DHEA is an allosteric antagonist of the GABAA receptor. Brain Res 1990; 526:143–46.PubMedCrossRefGoogle Scholar
  4. 4.
    Uzunova V, Sheline Y, Davis JM, et al. Increase in the cerebrospinal fluid content of neurosteroids in patients with unipolar major depression who are receiving fluoxetine or fluvoxamine. Proc Natl Acad Sci USA 1998 Mar 17; 95(6):3239–44.PubMedCrossRefGoogle Scholar
  5. 5.
    Genazzani AR, Petraglia F, Bernardi F, et al. Circulating levels of allopregnanolone in humans: Gender, age and endocrine influences. J Clin Endocrinol Metab 1998; 83:2099–210.PubMedCrossRefGoogle Scholar
  6. 6.
    Hoist J., Backstrom T., Hammerbsck S., von Schoultz B. Progestogen addition during estrogen replacement therapy-effects opn vasomotor symptoms and mood. Maturitas 1989; 11:13–19.CrossRefGoogle Scholar
  7. 7.
    Hopper BR, Yen SC. Circulating concentrations of dehydroepiandrosterone and dehydroepiandrosterone sulfate during puberty. J Clin Endocrinol Metab 1975; 40:458–61.PubMedCrossRefGoogle Scholar
  8. 8.
    Reiter EO, Fuldauer VG, Root AW. Secretion of the adrenal androgen, dehydroepiandrosterone sulfate, during normal infancy, childhood, and adolescence, in sick infants, and in children with endocrinologic abnormalities. J Pediatr 1977; 90:766–70.PubMedCrossRefGoogle Scholar
  9. 9.
    Xiaojia G, Conger RD, Elder GH. Coming of age too early: Pubertal influences on girls’ vulnerability to psychological distress. Child Develop 1996; 67:3386–3400.CrossRefGoogle Scholar
  10. 10.
    Parker CR Jr. Dehydroepiandrosterone and dehydroepiandrosterone sulfate production in the human adrenal during development and aging. Steroids. 1999 Sep; 64(9):640–47.PubMedCrossRefGoogle Scholar
  11. 11.
    Liu CH, Laughlin GA, Fischer UG, Yen SSC. Marked attenuation of ultradian and circadian rhythms of dehydroepiandrosterone in postmenopausal women: Evidence for a reduced 17,20-Desmolase enzymatic activity. J Clin Endocrinol Metab 1990;71(4):900–906.PubMedCrossRefGoogle Scholar
  12. 12.
    Barret-Connor E, Khaw K, Yen SSC. A prospective study of DS mortality and cardiovascular disease. N Engl J Med 1986; 315:1519–24.CrossRefGoogle Scholar
  13. 13.
    Helzlsouer KJ, Gordon GB, Alberg A, Bush TL, Comstock GW. Relationship of prediagnostic serum levels of DHEA and DS to the risk of developing premenopausal breast cancer. Cancer Res 1992; 52:1–4.PubMedGoogle Scholar
  14. 14.
    Thoman ML, Weigle WO. The cellular and subcellular bases of immunosenescence. Adv Immunol 1989; 46:221–61.PubMedCrossRefGoogle Scholar
  15. 15.
    Mortola JF, Yen SSC. The effects of oral dehydroepiandrosterone on endocrine-metabolic parameters in postmenopausal women. J Clin Endocrinol Metab 1990; 71:696–704.PubMedCrossRefGoogle Scholar
  16. 16.
    Morales AJ, Nolan JJ, Nelson JC, Yen SSC. Effects of replacement dose of dehydroepiandrosterone in men and women of advancing age. J Clin Endocrinol Metab 1994; 78:1360–770.PubMedCrossRefGoogle Scholar
  17. 17.
    Stomati M, Rubino S, Spinetti A, et al. Endocrine, neuroendocrine and behavioural effects of oral dehydroepiandrosterone sulphate supplementation in postmenopausal women. Gynecol Endocrinol 1999; 13:15–25.PubMedCrossRefGoogle Scholar
  18. 18.
    Thijssen JHH, Nieuwenhuyse H. DHEA: A comprehensive review. New York: The Parthenon Publishing Group, 1999.Google Scholar
  19. 19.
    Wolf OT, Neumenn O, Helhammer DH, et al. Effects of a two-week physiological dehydroepiandrosterone substitution on cognitive performance and well-being in healthy elderly women and men. J Clin Endocrinol Metab 1997; 82:2363–67.PubMedCrossRefGoogle Scholar
  20. 20.
    Genazzani AR, Palombo MA, de Micheroux AA, et al. Evidence for a role for the neurosteroid allopregnanolone in the modulation of reproductive function in female rats. Eur J Endocrinol 1995; 133:375–80.PubMedCrossRefGoogle Scholar
  21. 21.
    Genazzani AR, Petraglia F, Bernardi F, et al. Circulating levels of allopregnanolone in humans: Gender, age, and endocrine influences. J Clin Endocrinol Metab 1998; 83:2099–2103.PubMedCrossRefGoogle Scholar
  22. 22.
    Vermeulen A, Verdonck L. Plasma androgen levels during the menstrual cycle. Am J Obstet Gynecol 1976; 125:491–94.PubMedGoogle Scholar
  23. 23.
    Monteleone P, Luisi S, Tonetti A, et al. Allopregnanolone concentrations and premenstrual syndrome. Eur J Endocrinol 2000;142; 269–73.PubMedCrossRefGoogle Scholar
  24. 24.
    Schmidt PJ, Purdy RH, Moore PH, et al. Circulating levels of anxiolytic steroids in the luteal phase in women with premenstrual syndrome and in control subjects. J Clin Endocrinol Metab 1994; 79:1256–60.PubMedCrossRefGoogle Scholar
  25. 25.
    Monteleone P, Luisi S, Tonetti A, et al. Allopregnanolone concentrations and premenstrual syndrome. Eur J Endocrinol. 2000 Mar; 142(3):269–73.PubMedCrossRefGoogle Scholar
  26. 26.
    Smith SS, Gong QH, Hsu F-C, et al. GABAA receptor a4 subunit suppression prevents withdrawal properties of an endogenous steroid. Nature 1998; 392:926–30.PubMedCrossRefGoogle Scholar
  27. 27.
    Berga SL. Understanding premenstrual syndrome. Lancet 1998; 351:465–66.PubMedCrossRefGoogle Scholar
  28. 28.
    Eriksson E, Sundblad C, Lisjo P, Modigh K, Andersch B. Serum levels of androgens are higher in women with premenstrual irritability and dysphoria than in controls. Psychoneuroendocrinology. 1992 May-Jul; 17(2–3): 195–204.PubMedCrossRefGoogle Scholar
  29. 29.
    Meczekalski B, Tonetti A, Monteleone P, et al. Hypothalamic amenorrhea with normal body weight: ACTH, allopregnanolone and Cortisol responses to corticotropin-releasing hormone test. Eur J Endocrinol. 2000 Mar; 142(3):280–85.PubMedCrossRefGoogle Scholar
  30. 30.
    Petraglia F, Sutton S, Vale W, Plotsky P. Corticotropin releasing factor decreases plasma luteinizing hormone levels in female rats by inhibiting GnRH release into hypophysealportal circulation. Endocrinology 1987; 120:1083–88.PubMedCrossRefGoogle Scholar
  31. 31.
    Monteleone P, Luisi M, Colurcio B, et al. Plasma levels of neuroactive steroids are increased in untreated women with anorexia nervosa or bulimia nervosa. Psycosomatic Medicine 2001; 63:62–68.Google Scholar
  32. 32.
    Chen SW, Rodriguez L, Davies MF, Loew GH. The hyperphagic effect of 3 alpha-hydroxylated pregnane steroids in male rats. Pharmacol Biochem Behav 1996 Apr; 53(4):777–82.PubMedCrossRefGoogle Scholar
  33. 33.
    Luisi S, Petraglia F, Benedetto C, et al. Serum allopregnanolone levels in pregnant women: Changes during pregnancy, at delivery and in hypertensive patients. J Clin Endorinol Metab 2000; 83:2733–49.Google Scholar
  34. 34.
    Putnam CD, Brann DW, Kolbeck RC, Mahesh VB. Inhibition of uterine contractility by progesterone and progesterone metabolites: Mediation by progesterone and gamma amino butyric acidA recpetor systems. Biol Reprod 1991; 45:266–72.PubMedCrossRefGoogle Scholar
  35. 35.
    Majewska MD, Vaupel DB. Steroid control of uterine motility via gamma-aminobutyric acidA receptors in the rabbit: A novel mechanism? J Endocrinol 1991; 13:427–34.CrossRefGoogle Scholar
  36. 36.
    Bitran D, Shiekh M, MacLeod M. Anxiolytic effect of progesterone is mediated by the neurosteroid allopregnanoloneregnanolone at brain GABAa receptors. J Neuroendo 1995; 7:171–77.CrossRefGoogle Scholar
  37. 37.
    Buckwalter JG, Stanczyk FZ, McCleary CA, et al. Pregnancy, the postpartum, and steroid hormones: effects on cognition and mood. Psychoneuroendocrinology. 1999 Jan; 24(1):69–84.PubMedCrossRefGoogle Scholar
  38. 38.
    Peter M, Dorr HG, Sippell WG. Changes in the concentrations of dehydroepiandrosterone sulfate and estriol in maternal plasma during pregnancy: A longitudinal study in healthy women throughout gestation and at term. Horm Res 1994; 42(6):278–81.PubMedCrossRefGoogle Scholar
  39. 39.
    Parker CR Jr, Favor JK, Carden LG, Brown CH. Effects of intrapartum stress on fetal adrenal function. Am J Obstet Gynecol 1993 Dec; 169(6): 1407–11.PubMedGoogle Scholar
  40. 40.
    Stomati M, Bersi C, Rubino S, et al. Neuroendocrine effectsof different estradiol-progestin regimens in postmenopausal women. Maturitas 1997; 28:127–35.PubMedCrossRefGoogle Scholar
  41. 41.
    Purdy RH, Morrow AL, Moore PH, et al. Stress-induced elevations of y-aminobutyric acid type A receptor-active steroids in the rat brain. Proc Natl Acad Sci USA 1991; 8:4553–57.CrossRefGoogle Scholar
  42. 42.
    Patchev VK, Shoaib M, Holsboer F, et al. The neurosteroid tetrahydroprogesterone counteracts corticotropin-releasing hormone induced anxiety and alters the release and gene expression of corticotropin-releasing hormone in the rat hypothalamus. Neuroscience 1994; 62:265–71.PubMedCrossRefGoogle Scholar
  43. 43.
    Vallee M, Rivera JD, Koob GF, Purdy RH, Fitzgerald RL. Quantification of neurosteroids in rat plasma and brain following swim stress and allopregnanolone administration using negative chemical ionization gas chromatography/ mass spectrometry. Anal Biochem 2000 Dec l; 287(l):153–66.PubMedCrossRefGoogle Scholar
  44. 44.
    Serra M, Pisu MG, Lettera M, et al. Social isolation-induced decreases in both the abundance of neuroactive steroids and GABA(A) receptor function in rat brain. J Neurochem 2000 Aug; 75(2):732–40.PubMedCrossRefGoogle Scholar
  45. 45.
    Galli R, Luisi M, Pizzanelli C, et al. Circulating levels of allopregnanolone, an anticonvulsant metabolite of progesterone, in women with partial epilepsy in the postcritical phase. Epilepsia 2001;42(2):216–219.PubMedCrossRefGoogle Scholar
  46. 46.
    Berretini WH, Post RM. Gaba in affective illness. In: Post RM, Ballanger JC, editors. Ineurobilogy of mood disorders. Williams and Wilkins, Baltimore; 1984, 673–685.Google Scholar
  47. 47.
    Strohle A, Romeo E, Hermann B, et al. Concentrations of 3a-reduced neuroactive steroids and their precursors in plasma of patients with major depression and after clinical recovery. Biol Psychiatry 1999; 45:274–77.PubMedCrossRefGoogle Scholar
  48. 48.
    van Goozen SHM, Matthys W, Cohen-Kettenis PT, Thijssen JHH, van Engeland II. Adrenal androgens and aggression in conduct disorder prepubertal boys and normal controls. Biol Psychiatry 1998; 43:145–53.Google Scholar
  49. 49.
    Roberts E. Dehydroepiandrosterone (DHEA) and its sulphate (DHEAS) as neural facilitators: effects on brain tissue in culture and on memory in young and old mice: A cyclic GMP hypothesis of action of DHEA and DHEAS in nervous system and other tissues. In: Kalimi M, Regelson W, editors. The biologic role of dehydroepiandrosterone. Berlin, Walter de Gruyter; 1990, 13–42.Google Scholar
  50. 50.
    Sapolsky RM, Krey LC, McEwen BS. The neuroendocrinology of stress and aging: the glucocorticoid cascade hypothesis. Endocr Rev 1986; 7:284–301.PubMedCrossRefGoogle Scholar
  51. 51.
    Wolkowitz OM, Reus VI, Manfredi F, Roberts E. Antiglucocorticoid effects in Alzheimer’s disease (reply). Am J Psychiatry 1992; 149:1126.Google Scholar
  52. 52.
    Svec F, Lopez A. Antiglucocorticoid actions of DHEA and low concentrations in Alzheimer’s disease (letter). Lancet 1989; 2:1335–36.PubMedCrossRefGoogle Scholar
  53. 53.
    Majewska MD.Neurosteroids: Endogenous bimodal modulators of the GABA-A receptor.Mechanism of action and physiological significance. Progress in Neurobiology 1992,38: 379–95.PubMedCrossRefGoogle Scholar
  54. 54.
    Bernardi F, Lanzone A, et al. Allopregnanolone and dehydroepiandrosterone response to corticotropin-releasing factor in patients suffering from Alzheimer’s disease and vascular dementia. Eur J Endocrinol 2000; 142:466–71.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2002

Authors and Affiliations

  • Andrea Riccardo Genazzani
  • Francesca Bernardi
  • Martina Liut
  • M. Stomati
  • M. Pieri
  • M. Luisi

There are no affiliations available

Personalised recommendations