Gonadal steroids are known to influence hypothalamic functions through both genomic and non-genomic pathways. Sex hormone-binding globulin (SHBG) may act by a non-genomic mechanism independent of classical steroid receptors. Here we describe the immunocytochemical mapping of SHBG-containing neurons and nerve fibers in the human hypothalamus and infundibulum. Mass spectrometry and Western blot analysis were also used to characterize the biochemical characteristics of SHBG in the hypothalamus and cerebrospinal fluid (CSF) of humans. SHBG-immunoreactive neurons were observed in the supraoptic nucleus, the suprachiasmatic nucleus, the bed nucleus of the stria terminalis, paraventricular nucleus, arcuate nucleus, the perifornical region and the medial preoptic area in human brains. There were SHBG-immunoreactive axons in the median eminence and the infundibulum. A partial colocalization with oxytocin could be observed in the posterior pituitary lobe in consecutive semithin sections. We also found strong immunoreactivity for SHBG in epithelial cells of the choroid plexus and in a portion of the ependymal cells lining the third ventricle. Mass spectrometry showed that affinity-purified SHBG from the hypothalamus and choroid plexus is structurally similar to the SHBG identified in the CSF. The multiple localizations of SHBG suggest neurohypophyseal and neuroendocrine functions. The biochemical data suggest that CSF SHBG is of brain rather than blood origin.

Keywords:
Steroid-binding globulin, Cerebrospinal fluid, Paraventricular nucleus, Arcuate nucleus, Supraoptic nucleus, Suprachiasmatic nucleus, Bed nucleus of the stria terminalis, Clinical neuroendocrinology
1.
Joseph DR, Sullivan PM, Wang YM, Millhorn DE, Bayliss DM: Complex structure and regulation of the ABP/SHBG gene. J Steroid Biochem Mol Biol 1991;40:771–775.
2.
Hammond GL, Bocchinfuso WP: Sex hormone-binding globulin: gene organization and structure/function analyses. Horm Res 1996;45:197–201.
3.
Reventos J, Sullivan PM, Joseph DR, Gordon JW: Tissue-specific expression of the rat androgen-binding protein/sex hormone-binding globulin gene in transgenic mice. Mol Cell Endocrinol 1993;96:69–73.
4.
Selva DM, Hogeveen KN, Seguchi K, Tekpetey F, Hammond GL: A human sex hormone-binding globulin isoform accumulates in the acrosome during spermatogenesis. J Biol Chem 2002;277:45291–45298.
5.
Wang YM, Bayliss DA, Millhorn DE, Petrusz P, Joseph DR: The androgen-binding protein gene is expressed in male and female rat brain. Endocrinology 1990;127:3124–3130.
6.
Herbert Z, Jirikowski GF, Petrusz P, Englöf I, Caldwell JD: Distribution of androgen-binding protein in the rat hypothalamo-neurohypophyseal system, co-localization with oxytocin. Brain Res 2003;992:151–158.
7.
Pardridge WM: Transport of protein-bound hormones into tissues in vivo. Endocr Rev 1981;2:103–123.
8.
Forunati N: Sex hormone-binding globulin: Not only a transport protein. What news is around the corner? J Endocrinol Invest 1999;22:223–234.
9.
Rosner W, Hryb DJ, Khan MS, Nakhla AM, Romas MA: Sex hormone-binding globulin: anatomy and physiology of a new regulatory system. J Steroid Biochem Mol Biol 1991;40:813–820.
10.
Caldwell JD: Evidence of sex hormone binding globulin binding sites in the medial preoptic area and hypothalamus. Horm Metab Res 2001;33:7–9.
11.
Krupenko SA, Krupenko NI, Danzo BJ: Interaction of sex hormone-binding globulin with plasma membranes from the rat epididymis and other tissues. J Steroid Biochem Mol Biol 1994;51:115–124.
12.
Hryb DJ, Kahn MS, Rosner W: Testosterone-estradiol-binding globulin binds to human prostatic cell membranes. Biochem Biophys Res Commun 1985;128:432–440.
13.
Remington SG, Nelson JD: Secretoglobins: Sexually dimorphic expression of androgen-binding protein mRNA in mouse lacrimal glands. Invest Ophthalmol Vis Sci 2005;46:31–38.
14.
Caldwell JD, Song Y, Englöf I, Höfle S, Key M, Morris M: 5a-Reduced androgens block estradiol-BSA-stimulated release of oxytocin. Brain Res 2003;976:259–261.
15.
Caldwell JD, Moe BD: Conjugated estradiol increases female sexual receptivity in response to oxytocin infused into the medial preoptic area and medial basal hypothalamus. Horm Behav 2000;35:38–46.
16.
Caldwell JD: A sexual arousability model involving steroid effects at the plasma membrane. Neurosci Biobehav Rev 2002;26:13–30.
17.
Bonelli RM, Aschoff A, Niederwieser G, Heuberger C, Jirikowski GF: Cerebrospinal fluid tissue transglutaminase as a biochemical marker for Alzheimer’s disease. Neurobiol Dis 2002;11:106–110.
18.
Lewis JG, Longley NJ, Elder PA: Monoclonal antibodies to human sex hormone-binding globulin (SHBG): characterization and use in a simple enzyme-linked immunosorbent assay of SHBG in plasma. Steroids 1999;64:259–265.
19.
Mai JK, Assheuer J, Paxinos G: Atlas of the Human Brain. San Diego, Academic Press, 1997.
20.
Becchis M, Sullivan PM, Ordronneau P, Petrusz P, Joseph DR: Distribution of immunoreactive androgen-binding protein/sex hormone-binding globulin in tissues of the fetal rat. Steroids 1996;61:392–400.
21.
Melle C, Ernst G, Schimmel B, Bleul A, Koscielny S, Wiesner A, Bogumil R, Möller U, Osterloh D, Halbhuber KJ, von Eggeling F: Biomarker discovery and identification in laser microdissected head and neck squamous cell carcinoma with ProteinChip technology, two-dimensional gel electrophoresis, tandem mass spectrometry, and immunohistochemistry. Mol Cell Proteomics 2003;2:443–452.
22.
Herbert Z, Pollak E, Caldwel JD, Jirikowski GF: Subcellular localization of sex-hormone binding globulin/ SHBG in rat hypothalamus and pituitary. Society for Neuroscience Meeting, New Orleans 2003.
23.
Feldman M, Lea OA, Petrusz P, Tres LL, Kierszenbaum AL, French FS: Androgen-binding protein. Purification from rat epididymis, characterization, and immunocytochemical localization. J Biol Chem 1981;256:5170–5175.
24.
Gao G, Herbert Z, Kong J, Gabrielson N, Mautz A, Wu D, Jirikowski GF, Caldwell JD: Estradiol control of expression and levels of estradiol-binding proteins in the medial preoptic area, medial hypothalamus and pituitary. Neuroendocrinology 2003;78:61–71.
25.
Paoletti AM, Congia S, Lello S, Tedde D, Orru M, Pistis M, Pilloni M, Zedda P, Loddo A, Melis GB: Low androgenization index in elderly women and elderly men with Alzheimer’s disease. Neurology 2004;62:301–303.
26.
Hoskins EK, Tang MX, Manly JJ, Mayeux R: Elevated sex-hormone binding globulin in elderly women with Alzheimer’s disease. Neurobiol Aging 2004;25:141–147.
27.
Jirikowski GF, Herbert Z, Petrusz P, Sendemir E, Caldwell JD: Co-expression of vasopressin and androgen-binding protein in the rat hypothalamus. J Chem Neuroanat 2005;29:233–237.
28.
Khan MS, Knowles BB, Aden DP, Rosner W: Secretion of testosterone-estradiol-binding globulin by a human hepatoma-derived cell line. J Clin Endocrinol Metab 1981;53:448–449.
29.
Englebienne P, Doyen G: Further evidence for distinction between sex hormone-binding globulin and an androgen-binding protein in hydatidiform mole serum. J Steroid Biochem 1983;18:649–653.
30.
Vigh Teichmann I, Vigh B: The infundibular cerebrospinal-fluid contacting neurons. Adv Anat Embryol Cell Biol 1974;50:1–91.
31.
Fassler R, Schwarz S, Pohl P: Demonstration of sex hormone binding globulin in human cerebrospinal fluid. Clin Endocrinol (Oxf) 1985;23:349–359.
© 2005 S. Karger AG, Basel
2005
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.