Aims: The present study aims at evaluating the effect of a 2-week treatment with testosterone (T), dihydrotestosterone (DHT) and estradiol valerate (E2V) on brain and plasma β-endorphin (β-END) concentrations in gonadectomized rats of both sexes. Methods: Eight groups of female and 8 groups of male Wistar rats were included. For each sex, 1 group of gonad-intact and 1 group of gonadectomized rats were employed as controls (placebo). The other groups received subcutaneous T at the doses of 10 and 100 μg/kg/day (female rats) or 1 and 5 mg/kg/day (male rats). Subcutaneous DHT was administered at the doses of 1, 10, 100 μg/kg/day (female rats) or 0.1, 1 and 5 mg/kg/day (male rats). E2V was administered subcutaneously at 0.05 mg/kg/day. β-END levels were measured in different brain areas and plasma. Results: Ovariectomy (OVX) induced a significant decrease in β-END in all brain areas analyzed as well as in plasma. Orchidectomy (OCX) reduced opioid concentration in the hypothalamus, anterior pituitary and neurointermediate lobe. In OVX rats, T replacement as well as E2V significantly increased β-END concentration in all brain areas and in plasma. In the OCX group, T and E2V did not influence β-END concentrations in different hypothalamic areas. However, they produced a significant rise in β-END levels in the hypothalamus, neurointermediate lobe, anterior pituitary and plasma. Conversely, DHT replacement did not affect β-END levels at any dose administered, either in males or females. Conclusions: The sensitivity of the endogenous opiatergic system to T administration seems to be sex-related. This effect is particularly evident in the brains of female animals where this endogenous endorphin elicits a much greater response than it does in males that have undergone gonadal steroid depletion and subsequent T replacement.

Keywords:
Testosterone, Dihydrotestosterone, β-Endorphin, Rats, Brain
1.
Wierman ME, Basson R, Davis SR, Khosla S, Miller KK, Rosner W, Santoro N: Androgen therapy in women: an Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab 2006;91:3697–3710.
2.
Driscoll I, Resnick SM: Testosterone and cognition in normal aging and Alzheimer’s disease: an update. Curr Alzheimer Res 2007;4:33–45.
3.
Nieschlag E, Swerdloff R, Behre HM, Gooren LJ, Kaufman JM, Legros JJ, Lunenfeld B, Morley JE, Schulman C, Wang C, Weidner W, Wu FC: Investigation, treatment and monitoring of late-onset hypogonadism in males. Aging Male 2005;8:56–58.
4.
Isidori AM, Giannetta E, Gianfrilli D, Greco EA, Bonifacio V, Aversa A, Isidori A, Fabbri A, Lenzi A: Effects of testosterone on sexual function in men: results of a meta-analysis. Clin Endocrinol (Oxf) 2005;63:381–394.
5.
Moncada I: Testosterone and men’s quality of life. Aging Male 2006;9:189–193.
6.
Bodnar RJ, Klein GE: Endogenous opiates and behavior: 2005. Peptides 2006;27:3391–3478.
7.
Charmandari E, Tsigos C, Chrousos G: Endocrinology of the stress response. Annu Rev Physiol 2005;67:259–284.
8.
Ribeiro C, Kennedy SE, Smith YR, Stohler CS, Zubieta JK: Interface of physical and emotional stress regulation through the endogenous opioid system and mu-opioid receptors. Prog Neuropsychopharmacol Biol Psychiatry 2005;29:1264–1280.
9.
Przewlocki R, Przewlocka B: Opioids in neuropathic pain. Curr Pharm Des 2005;11:3013–3025.
10.
Argiolas A: Neuropeptides and sexual behaviour. Neurosci Biobehav Rev 1999;23:1127–1142.
11.
Gillman MA Lichtigfield FJ: Naloxone and its analeptic effect. Anesthesiology 1983;58:287.
12.
Bancroft J: The endocrinology of sexual arousal. J Endocrinol 2005;186:411–427.
13.
Liu N, Li B, Wilson FA, Ma Y, Hu X: Gender effect on the right-left discrimination task in a sample of heroin-dependent patients. Psychopharmacology (Berl) 2005;181:735–740.
14.
Zubieta JK, Dannals RF, Frost J: Gender and age influences on human brain mu-opioid receptor binding measured by PET. Am J Psychiatry 1999;156:842–848.
15.
Smith YR, Stohler CS, Nichols TE, Bueller JA, Koeppe RA, Zubieta JK: Pronociceptive and antinociceptive effects of estradiol through endogenous opioid neurotransmission in women. J Neurosci 2006;26:5777–5785.
16.
Genazzani AR, Bernardi F, Pluchino N, Begliuomini S, Lenzi E, Casarosa E, Luisi M: Endocrinology of menopausal transition and its brain implications. CNS Spectr 2005;10:449–457.
17.
Genazzani AR, Pluchino N, Luisi S, Luisi M: Estrogen, cognition and female ageing. Hum Reprod Update 2007;13:175–187.
18.
Genazzani, AR, Petraglia F, Facchinetti F, Grasso A, Alessandrini G, Volpe A: Steroid replacement treatment increases β-endorphin and β-lipotropin plasma levels in postmenopausal women. Gynecol Obstet Invest 1988;26:153–159.
19.
Petraglia F, Penava A, Locatelli V, Cocchi D, Panerai AE, Genazzani AR, Müller EE: Effect of gonadectomy and gonadal steroid replacement on pituitary and plasma β-endorphin levels in the rat. Endocrinology 1982;111:1224–1229.
20.
Genazzani AR, Stomati M, Bernardi F, Luisi S, Casarosa E, Puccetti S, Genazzani AD, Palumbo M, Luisi M: Conjugated equine estrogens reverse the effects of aging on central and peripheral allopregnanolone and β-endorphin levels in female rats. Fertil Steril 2004;81:757–766.
21.
Stomati M, Bersi C, Rubino S, Palumbo M, Comitini G, Genazzani AD, Santuz M, Petraglia F, Genazzani AR: Neuroendocrine effects of different estradiol-progestin regimens in postmenopausal women. Maturitas 1997;28:127–135.
22.
Keja JA, Stoof JC, Kits KS: Dopamine D2 receptor stimulation differentially affects voltage-activated calcium channels in rat pituitary. J Physiol 1992;450;409–435.
23.
Roselli CE, Klosterman SA: Sexual differentiation of aromatase activity in the rat brain: effects of perinatal steroid exposure. Endocrinology 1998;139:3193–3201.
24.
Roselli CE, Abdelgadir SE, Jorgensen E, Resko JA: Sex differences in androgen regulated cytochrome P450 aromatase mRNA in the rat brain. Endocrine 1996;5:59–65.
25.
Fodor M, Delemarre-van de Waal HA: Are POMC neurons targets for sex steroids in the arcuate nucleus of the rat? Neuroreport 2001;12:3989–3991.
26.
Saland LC, Carr JA, Samora A, Tejeda D: Benzodiazepine suppression of corticotropin-releasing factor (CRF)-induced β-endorphin release from rat neurointermediate pituitary. Peptides 1992;13:913–917.
27.
Chowen JA, Argente J, Vician L, Clifton DK, Steiner RA: Pro-opiomelanocortin messenger RNA in hypothalamic neurons is increased by testosterone through aromatization to estradiol. Neuroendocrinology 1990;52:581–588.
28.
Chowen-Breed J, Fraser HM, Vician L, Damassa DA, Clifton DK, Steiner RA: Testosterone regulation of proopiomelanocortin messenger ribonucleic acid in the arcuate nucleus of the male rat. Endocrinology 1989;124:1697–1702.
29.
Chowen-Breed J, Clifton DK, Steiner RA: Regional specificity of testosterone regulation of proopiomelanocortin gene expression in the arcuate nucleus of the male rat brain. Endocrinology 1989;124:2875–2881.
30.
Roselli CE, Salisbury RL, Resko JA: Genetic evidence for androgen-dependent and independent control of aromatase activity in the rat brain. Endocrinology 1987;121:2205–2210.
31.
MacMillan SJ, Mark MA, Duggan AW: The release of β-END and the neuropeptide- receptor mismatch in the brain. Brain Res 1998;794:127–136.
32.
Forlano PM, Bass AH: Steroid regulation of brain aromatase expression in glia: female preoptic and vocal motor nuclei. J Neurobiol 2005;65:50–58.
33.
Bodnar RJ, Krzanowska EK: Analysis of sex and gonadectomy differences in β-endorphin antinociception elicited from the ventrolateral periaqueductal gray in rats. Eur J Pharmacol 2000;392:157–161.
34.
Carter DA, Williams TD, Lightman SL: A sex difference in endogenous opioid regulation of the posterior pituitary response to stress in the rat. J Endocrinol 1986;111:239–244.
© 2009 S. Karger AG, Basel
2009
Copyright / Drug Dosage / Disclaimer
Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.
You do not currently have access to this content.