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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.




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