Estrogen regulation of testicular function

Abstract

Evidence supporting a role for estrogen in male reproductive tract development and function has been collected from rodents and humans. These studies fall into three categories: i) localization of aromatase and the target protein for estrogen (ER-alpha and ER-beta) in tissues of the reproductive tract; ii) analysis of testicular phenotypes in transgenic mice deficient in aromatase, ER-alpha and/or ER-beta gene; and, iii) investigation of the effects of environmental chemicals on male reproduction. Estrogen is thought to have a regulatory role in the testis because estrogen biosynthesis occurs in testicular cells and the absence of ERs caused adverse effects on spermatogenesis and steroidogenesis. Moreover, several chemicals that are present in the environment, designated xenoestrogens because they have the ability to bind and activate ERs, are known to affect testicular gene expression. However, studies of estrogen action are confounded by a number of factors, including the inability to dissociate estrogen-induced activity in the hypothalamus and pituitary from action occurring directly in the testis and expression of more than one ER subtype in estrogen-sensitive tissues. Use of tissue-specific knockout animals and administration of antiestrogens and/or aromatase inhibitors in vivo may generate additional data to advance our understanding of estrogen and estrogen receptor biology in the developing and mature testis.

Figure 1

An illustration of the structure of the estrogen receptor. The NH₂ terminal consists of the A/B domains, the C domain forms the DNA-binding domain (DBD) while domains D/E/F constitute the ligand-binding domain (LBD). The AF-1 and AF-2 activation units are part of the DNA-binding and ligand-binding domains, respectively. The two ER subtypes, ERα and ERβ, are almost identical in the DNA-binding domain (~95% homology) but differ in the ligand-binding domain (about 60% homology). Differences in the ligand-binding domain are responsible in part for ligand-specificity, and the ratio of ERα and ERβ is a critical determinant of cellular response to endogenous estrogen and other ER agonists and antagonists.

Figure 2

Estrogen regulates testicular steroidogenesis, acting via ERα because administration of an estrogenic chemical, estradiol benzoate, suppressed pituitary LH secretion and serum testosterone levels in wild-type but not αERKO mice (ref. 67)(A). ERα deficiency enhanced gene expression for cytochrome P450 hydroxylase/17α lyase and 17β-hydroxysteroid dehydrogenase type III in αERKO Leydig cells compared to wildtype (WT) (B), indicating that ERα regulates androgen biosynthesis by mediating changes in steroidogenic enzyme activity (ref. 67). Copyright 2003, The Endocrine Society.

Figure 3

ER agonists regulate androgen biosynthesis in Leydig cells. Incubation of mature rat Leydig cells, from 90-day old rats, with estrogenic chemicals, i.e., bisphenol A (BPA)(A), the synthetic estrogen diethylstilbestrol DES (B) and a biologically active metabolite of the pesticide methoxychlor (HPTE)(C), caused an inhibitory effect on androgen biosynthesis albeit at different doses. Using RT-PCR, ERβ was not detected in these cells, implying that inhibitory effects were ERα-mediated (ref. 89). Copyright 2004, The Endocrine Society.

Figure 4

Endocrine regulation of the testis. Pituitary gonadotropins are the chief regulators of testicular function; FSH acts through its receptors in Sertoli cells (FSHR) to regulate spermatogenesis and LH stimulates androgen production by Leydig cells after binding to LHR. However, gonadal steroids, i.e., androgen and estrogen, and other agents that bind or prevent binding to steroid hormone receptors (androgen receptor AR, ERα, and ERβ), which are present in Sertoli cells, germ cells and Leydig cells also regulate testicular function. The pathway mediated by adenosine-3',5'-cyclic monophosphate (cAMP) appears to be the primary intracellular signaling pathway in all testicular cells. However, several growth factors e.g., insulin like growth factor-1 (IGF-1) and epidermal growth factor (EGF), acting via their receptors, IGF-1R and EGF-R, possibly modulate AR and ER-mediated pathways. Thus, testicular function is regulated by interactions between several signaling pathways, some acting locally, e.g., AR and ER-mediated pathways, and others indirectly by modulating hypothalamus-pituitary function. Hormonal activation of transcriptional gene activity results in changes in cell differentiation and function. PMC, peritubular myoid cell; CRE, cAMP-responsive elements, ARE, androgen-responsive elements; ERE, estrogen-responsive elements.