help button home button Endocrine Society Endocrinology
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow Purchase Article
Right arrow View Shopping Cart
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow Request Copyright Permission
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Akingbemi, B. T.
Right arrow Articles by Hardy, M. P.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Akingbemi, B. T.
Right arrow Articles by Hardy, M. P.
Endocrinology Vol. 144, No. 1 84-93
Copyright © 2003 by The Endocrine Society

ARTICLE

Estrogen Receptor-{alpha} Gene Deficiency Enhances Androgen Biosynthesis in the Mouse Leydig Cell

Benson T. Akingbemi, Renshan Ge, Cheryl S. Rosenfeld, Leslie G. Newton, Dianne O. Hardy, James F. Catterall, Dennis B. Lubahn, Kenneth S. Korach and Matthew P. Hardy

Center for Biomedical Research, Population Council (B.T.A., R.G., D.O.H., J.F.C., M.P.H.), New York, New York 10021; Departments of Animal Sciences (C.S.R., L.G.N., D.B.L.), Veterinary Biomedical Sciences (C.S.R.), and Biochemistry and Child Health (D.B.L.), University of Missouri, Columbia, Missouri 65211; and Receptor Biology Section, Laboratory of Reproductive and Developmental Toxicology, National Institute of Environmental Health Sciences, National Institutes of Health (K.S.K.), Research Triangle Park, North Carolina 27709

Address all correspondence and requests for reprints to: Matthew P. Hardy, Ph.D., Population Council, 1230 York Avenue, New York, New York 10021. E-mail: m-hardy{at}popcbr.rockefeller.edu.

Leydig cells, which produce the primary male steroid hormone testosterone (T), express the two estrogen receptor (ER) subtypes, ER{alpha} and ERß, and have the capacity to convert testosterone to the natural estrogen 17ß-estradiol. Thus, Leydig cells are subject to estrogen action. The development of transgenic mice that are homozygous for targeted deletion of genes encoding the ER subtypes provides an opportunity to examine the role of estrogen in Leydig cell function. In this study androgen biosynthesis was analyzed in Leydig cells from mice that were homozygous for targeted deletion of the ER{alpha} gene ({alpha}ERKO). T production by {alpha}ERKO Leydig cells was 2-fold higher than that in wild-type (WT) cells. Serum T levels were accordingly higher in {alpha}ERKO compared with WT mice (5.1 ± 1.1 vs. 2.2 ± 0.4 ng/ml; P <= 0.01) as were serum LH levels (1.31 ± 0.3 vs. 0.45 ± 0.08 ng/ml; P <= 0.01). Mice that were treated with the pure antiestrogen ICI 182,780 at 100 µg/kg·d for 7 d, effectively abrogating ER-mediated activity, also had 2-fold elevations in the serum levels of LH (1.15 ± 0.3 vs. 0.45 ± 0.2 ng/ml) and T (4.3 ± 1.1 vs. 2.2 ± 0.2 ng/ml; P <= 0.01). Increased androgen biosynthesis by {alpha}ERKO Leydig cells was associated with higher steroidogenic enzyme activity, especially of cytochrome P450 17{alpha}-hydroxylase/17–20 lyase (P45017{alpha}) and 17ß-hydroxysteroid dehydrogenase (17ß-HSD), as measured by conversion of radiolabeled steroid substrates to T or its precursors. The largest increases in enzymatic activity were observed for P45017{alpha} (423 ± 45 pmol/min·106 cells in {alpha}ERKO Leydig cells vs. 295 ± 27 pmol/min·106 cells in WT cells; P < 0.01). Consistent with steroidogenic enzyme activity, the testis of {alpha}ERKO mice expressed higher steady state mRNA levels for steroidogenic acute regulatory protein and two enzymes involved in androgen biosynthesis, P45017{alpha} and 17ß-HSD type III, as determined by semiquantitative RT-PCR. Compared with the controls, higher steady state mRNA levels for steroidogenic acute regulatory protein and P45017{alpha} were also measured in the testis of ICI 182,780-treated mice. In a second set of experiments estrogen administration reduced serum LH and T levels in WT controls, whereas {alpha}ERKO mice were unaffected. Although exposure of WT and {alpha}ERKO Leydig cells to estrogen in vitro did not affect androgen biosynthesis, incubation with ICI 182,780 reduced T production by WT, but not {alpha}ERKO, Leydig cells. These observations indicate that abrogation of the ER{alpha} gene by targeted deletion or treatment with an antiestrogen increases Leydig cell steroidogenesis in association with elevations in the serum levels of LH, which presumably is the result of estrogen insensitivity at the level of the hypothalamus and/or pituitary gonadotropes. Furthermore, the decrease in T production by WT Leydig cells and not {alpha}ERKO Leydig cells occasioned by incubation with ICI 182,780 suggests that of the ER subtypes, ER{alpha} has a regulatory role in Leydig cell steroidogenic function.




This article has been cited by other articles:


Home page
 EndocrinologyHome page
M. Chen, I. Hsu, A. Wolfe, S. Radovick, K. Huang, S. Yu, C. Chang, E. M. Messing, and S. Yeh
Defects of Prostate Development and Reproductive System in the Estrogen Receptor-{alpha} Null Male Mice
Endocrinology, January 1, 2009; 150(1): 251 - 259.
[Abstract] [Full Text] [PDF]

Home page
 FASEB J.Home page
F. Callewaert, K. Venken, J. Ophoff, K. De Gendt, A. Torcasio, G. H. van Lenthe, H. Van Oosterwyck, S. Boonen, R. Bouillon, G. Verhoeven, et al.
Differential regulation of bone and body composition in male mice with combined inactivation of androgen and estrogen receptor-{alpha}
FASEB J, January 1, 2009; 23(1): 232 - 240.
[Abstract] [Full Text] [PDF]

Home page
 EndocrinologyHome page
J. Weiss, M. L. Bernhardt, M. M. Laronda, L. A. Hurley, C. Glidewell-Kenney, S. Pillai, M. Tong, K. S. Korach, and J. L. Jameson
Estrogen Actions in the Male Reproductive System Involve Estrogen Response Element-Independent Pathways
Endocrinology, December 1, 2008; 149(12): 6198 - 6206.
[Abstract] [Full Text] [PDF]

Home page
 EndocrinologyHome page
M. A. McDevitt, C. Glidewell-Kenney, J. Weiss, P. Chambon, J. L. Jameson, and J. E. Levine
Estrogen Response Element-Independent Estrogen Receptor (ER)-{alpha} Signaling Does Not Rescue Sexual Behavior but Restores Normal Testosterone Secretion in Male ER{alpha} Knockout Mice
Endocrinology, November 1, 2007; 148(11): 5288 - 5294.
[Abstract] [Full Text] [PDF]

Home page
 ReproductionHome page
M L Gould, P R Hurst, and H D Nicholson
The effects of oestrogen receptors {alpha} and {beta} on testicular cell number and steroidogenesis in mice
Reproduction, August 1, 2007; 134(2): 271 - 279.
[Abstract] [Full Text] [PDF]

Home page
 ReproductionHome page
H O Goyal, T D Braden, P S Cooke, M A Szewczykowski, C S Williams, P Dalvi, and J W Williams
Estrogen receptor-{alpha} mediates estrogen-inducible abnormalities in the developing penis
Reproduction, May 1, 2007; 133(5): 1057 - 1067.
[Abstract] [Full Text] [PDF]

Home page
 J EndocrinolHome page
Y.-C. Chen, M. L Nagpal, D. M Stocco, and T. Lin
Effects of genistein, resveratrol, and quercetin on steroidogenesis and proliferation of MA-10 mouse Leydig tumor cells
J. Endocrinol., March 1, 2007; 192(3): 527 - 537.
[Abstract] [Full Text] [PDF]

Home page
 FASEB J.Home page
F. Taniguchi, J. F. Couse, K. F. Rodriguez, J. M. A. Emmen, D. Poirier, and K. S. Korach
Estrogen receptor-{alpha} mediates an intraovarian negative feedback loop on thecal cell steroidogenesis via modulation of Cyp17a1 (cytochrome P450, steroid 17{alpha}-hydroxylase/17,20 lyase) expression
FASEB J, February 1, 2007; 21(2): 586 - 595.
[Abstract] [Full Text] [PDF]

Home page
 ReproductionHome page
G. Delbes, C. Levacher, and R. Habert
Estrogen effects on fetal and neonatal testicular development.
Reproduction, October 1, 2006; 132(4): 527 - 538.
[Abstract] [Full Text] [PDF]

Home page
 EndocrinologyHome page
M. Poutanen
Toward understanding the endocrine regulation of gonadal somatic cells.
Endocrinology, August 1, 2006; 147(8): 3662 - 3665.
[Full Text] [PDF]

Home page
 EndocrinologyHome page
J. F. Couse, M. M. Yates, K. F. Rodriguez, J. A. Johnson, D. Poirier, and K. S. Korach
The Intraovarian Actions of Estrogen Receptor-{alpha} Are Necessary to Repress the Formation of Morphological and Functional Leydig-Like Cells in the Female Gonad
Endocrinology, August 1, 2006; 147(8): 3666 - 3678.
[Abstract] [Full Text] [PDF]

Home page
 EndocrinologyHome page
K. De Gendt, N. Atanassova, K. A. L. Tan, L. R. de Franca, G. G. Parreira, C. McKinnell, R. M. Sharpe, P. T. K. Saunders, J. I. Mason, S. Hartung, et al.
Development and Function of the Adult Generation of Leydig Cells in Mice with Sertoli Cell-Selective or Total Ablation of the Androgen Receptor
Endocrinology, September 1, 2005; 146(9): 4117 - 4126.
[Abstract] [Full Text] [PDF]

Home page
 Toxicol SciHome page
J. M. Naciff, K. A. Hess, G. J. Overmann, S. M. Torontali, G. J. Carr, J. P. Tiesman, L. M. Foertsch, B. D. Richardson, J. E. Martinez, and G. P. Daston
Gene Expression Changes Induced in the Testis by Transplacental Exposure to High and Low Doses of 17{alpha}-Ethynyl Estradiol, Genistein, or Bisphenol A
Toxicol. Sci., August 1, 2005; 86(2): 396 - 416.
[Abstract] [Full Text] [PDF]

Home page
 EndocrinologyHome page
G. Delbes, C. Levacher, C. Duquenne, C. Racine, P. Pakarinen, and R. Habert
Endogenous Estrogens Inhibit Mouse Fetal Leydig Cell Development via Estrogen Receptor {alpha}
Endocrinology, May 1, 2005; 146(5): 2454 - 2461.
[Abstract] [Full Text] [PDF]

Home page
 J. Clin. Endocrinol. Metab.Home page
C. E. Wood, J. M. Cline, M. S. Anthony, T. C. Register, and J. R. Kaplan
Adrenocortical Effects of Oral Estrogens and Soy Isoflavones in Female Monkeys
J. Clin. Endocrinol. Metab., May 1, 2004; 89(5): 2319 - 2325.
[Abstract] [Full Text] [PDF]

Home page
 EndocrinologyHome page
B. T. Akingbemi, C. M. Sottas, A. I. Koulova, G. R. Klinefelter, and M. P. Hardy
Inhibition of Testicular Steroidogenesis by the Xenoestrogen Bisphenol A Is Associated with Reduced Pituitary Luteinizing Hormone Secretion and Decreased Steroidogenic Enzyme Gene Expression in Rat Leydig Cells
Endocrinology, February 1, 2004; 145(2): 592 - 603.
[Abstract] [Full Text] [PDF]


HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Endocrinology Endocrine Reviews J. Clin. End. & Metab.
Molecular Endocrinology Recent Prog. Horm. Res. All Endocrine Journals
Copyright © 2003 by The Endocrine Society