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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.

Introduction

The testis consists of two compartments: seminiferous tubules and intertubular tissue, which forms the interstitium. Seminiferous tubules are lined by layers of germ cells in various stages of development (spermatogonia, spermatocytes, spermatids, spermatozoa) and supporting Sertoli cells. The interstitium consists of loose connective tissue, blood and lymphatic vessels, and various cell types, including Leydig cells, fibroblasts, macrophages and leukocytes. Leydig cells are the predominant source of the male sex steroid hormone testosterone. However, recent observations challenge the dogma that the male phenotype is maintained solely by testosterone binding to its protein target, i.e., the androgen receptor. Growing public concerns that exposures to environmental chemicals with estrogenic activity may impact human reproductive health have focused attention on the role of estrogen in male reproductive health [1]. The aromatization of C19 androgens, i.e., testosterone and androstenedione, is a key step in estrogen (E2) biosynthesis and is catalyzed by the aromatase enzyme, which is a product of the CYP 19 gene [2]. The serum levels of E2 measure about 40 pg/mL in male rats [3], and ranges between 20 and 40 pg/mL in men [4]. Evidence from several studies indicates that aromatase, ERα and ERβ are encoded by separate genes but are co-expressed with androgen receptors in the male reproductive tract [2, 3]. In consonance with localization studies, mice which have targeted deletion of the aromatase gene, ERα and/or ERβ showed altered testicular morphology and derangements of spermatogenesis [5–7], and exposures of laboratory species and wildlife to estrogenic chemicals were found to cause abnormalities of the reproductive tract [8].

Although the present review is focused on direct estrogen action in the testis, estrogen regulation may occur indirectly by changes caused in the hypothalamus and pituitary. Gonadal steroids act on the hypothalamus to affect GnRH pulses, and at the pituitary level to regulate gonadotropin (FSH and LH) secretion. FSH and LH are the primary tropic hormones that regulate testicular function. Indeed, FSH receptors are expressed only in Sertoli cells, and Leydig cells are the only binding sites for LH in the testis. In contrast, ERs have a more diversified pattern of expression. There is conclusive evidence showing that ERα and ERβ are present in several hypothalamic nuclei and in pituitary gonadotropes, indicating that estrogen regulates the hypothalamus-pituitary axis [9, 10]. For example, E2 treatment of a mouse gonadotroph cell line (LβT2) increased LH secretion and, following co-incubation with GnRH, increased LHβ mRNA levels [11]. Furthermore, the presence of estrogen-response-elements (EREs) on the promoter region of the β-subunit of the LH gene has been reported, implying that estrogen regulation of LH secretion occurs directly at the level of the LHβ gene [12, 13]. There is also evidence that ERα can be transcriptionally activated in gonadotrope cells in an estrogen-independent manner, through the GnRH receptor and signaling via protein kinase C (PKC) and mitogen-activated protein kinase (MAPK) pathways [14]. Together, these observations demonstrate that estrogen regulation of testicular function is also mediated indirectly by changes occurring in the hypothalamus and pituitary.

Estrogen Receptors

ERs are members of the steroid/thyroid hormone super family of nuclear receptors, which share a common structural architecture, and consist of three independent but interacting functional domains: the N-terminal or A/B domains, the C or DNA-binding domain, and the D/E/F or ligand-binding domain (Fig 1). Binding of a ligand to the ER causes a series of downstream events, including receptor dimerization, receptor-DNA interactions mediated by EREs present in the promoter region of target genes, recruitment of and interaction with transcription factors, and the formation of a preinitiation complex. Ligand-receptor interactions ultimately cause changes in target gene expression [15]. The N-terminal domain of nuclear receptors encodes an activation function called AF-1, which mediates protein-protein interactions to induce transcriptional activity. It is thought that this domain is highly active in ERα-mediated stimulation of reporter gene expression from a variety of ERE-constructs but its activity in the ERβ is limited [16]. On the other hand, the C-terminal or ligand-binding domain contains the AF-2 interacting surface that mediates ligand binding and receptor dimerization to stimulate transcriptional activity [17]. Thus, AF-1 and AF-2 are both involved in mediating the transcriptional activation functions of ERs.

Figure 1
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.

Although there is a high degree of homology in the DNA-binding domains of ERα and ERβ (about 95%), only a partial homology exists in the ligand-binding domain (~60%) [18]. Differences in ligand binding, in association with other factors, have the effect of altering the pattern of ER-mediated transcriptional activity. For example, some agonists bind both ER subtypes with the same affinity while others preferentially bind to ERα or ERβ [19–21]. There is general agreement that ERs function as dimers, and co-expression of ERα and ERβ in the same cell causes the formation of homodimers (ERα/ERα and ERβ/ERβ) or heterodimers (ERα/ERβ), which affect ligand-specificity. The interactions between ERs and EREs are complicated by other factors, including the ability of ERβ to modulate ERα transcriptional activity and recruitment of several protein co-activators and repressors by both ER subtypes. Therefore, the relative amounts of ERα and ERβ in a given tissue are key determinants of cellular responses to estrogen and other ER agonists and antagonists [22]. Moreover, ER and other steroid receptors have the ability to mediate biological effects through non-transcriptional mechanisms mediated by protein-protein interactions occurring between ERs and growth factors e.g., IGF-1 and EGF [23, 24]. Furthermore, there is growing evidence for the presence of a small pool of ERs localized to the plasma membrane. For example, BSA-conjugated E2, which is unable to gain entry into the cytosol and acts at the plasma membrane, decreased testicular androgen production in vitro [25]. Membrane ER is thought to signal mainly by coupling to GTP-activating proteins and through pathways involving second messengers (e.g., calcium) and kinase cascades [26]. The integration of several pathways implies that estrogen action in any particular tissue and organ is the result of activities mediated by genomic and non-genomic pathways although the physiological significance of specific pathways in the testis remains to be elucidated [27].

I. Localization of aromatase and ERs

Data describing aromatase activity and ER expression in reproductive tissues were collected using a combination of techniques: binding assays, immunohistochemistry, in situ hybridization, reverse transcriptase-polymerase chain reaction (RT-PCR), and RNase protection assays. In spite of the large body of information derived from these studies, localization studies have shortcomings that limit data interpretation regarding ER expression in specific tissues. For example, binding assays do not distinguish between ERα and ERβ while in situ hybridization studies measure mRNA levels but do not determine whether mRNA is translated to protein. Similarly, immunocytochemistry lacked specificity for either ER subtype. However, the availability of antibodies directed against ERα, and much later for ERβ, allowing for discrimination between ER subtypes in subsequent studies has generated substantial information on ER biology.

During fetal development in the rodent, aromatase is expressed in Sertoli cells and Leydig cells but not in spermatogonia. On the other hand, aromatase has been localized to virtually all cell types in the adult testis, including Leydig cells, Sertoli cells, spermatocytes, spermatids and spermatozoa [6, 28, 29]. Cellular expression of aromatase is age-dependent in the postnatal rat, occurring predominantly in Sertoli cells and germ cells of the prepubertal testis (up to 21 days of age) and in Leydig cells after this period [30]. Taken together, the bulk of data collected from the rodent testis point to a general pattern of ERα expression in Leydig cells and peritubular myoid cells and ERβ in germ cells [10, 31–33]. However, ERβ was localized to adult Leydig cells in the mouse [34], and both ERα and ERβ were found to be present in rat fetal and adult Leydig cells [35]. Similarly, ERα and ERβ were immunolocalized to Leydig cells in pubertal rats although treatment with the pure antiestrogen ICI 182,780 abolished ERα, but not ERβ, protein [36]. Consistent with ER expression in diverse cell types in the testis, it is not surprising that administration of ER agonists and antagonists or targeted deletion of the aromatase gene and ERs caused derangements in germ cell development and testicular steroidogenesis.

Unlike in rodents, aromatase activity and estrogen biosynthesis occur mostly in adipose tissue in men, and the testis synthesizes only 10–25% of E2 in circulation [37]. Early studies showed that prenatal exposures to the synthetic estrogen diethylstilbestrol (DES) caused male reproductive tract abnormalities in mice [38] and men [39]. In agreement with these observations, ERα and ERβ were localized to the human testis, and the presence of two variants of ERβ, designated ERβ1 and ERβ2, has been clearly demonstrated [40]. Although ERβ mRNA levels were 3-fold greater than ERα, both were expressed in the testis beginning from 16 weeks of gestation [41]. ERβ1 was more widely expressed in Sertoli cells, germ cells and Leydig cells while ERβ2 mRNA and protein were restricted to spermatogonia [42]. In the adult testis, both ERα and ERβ are expressed in spermatocytes, elongating spermatids, Sertoli cells and Leydig cells [43, 44]. Other studies have demonstrated the presence of ERα in spermatids and mature spermatozoa [45], ERβ in all germ cells [46, 47], and the absence of ERα in Leydig cells [48]. ERβ1 appears to be expressed at high levels in pachytene spermatocytes and round spermatids but much less so in Sertoli cells and spermatogonia whereas expression of ERβ2 is high in Sertoli cells and spermatogonia and is reduced in spermatocytes [49, 50]. Although the physiological significance of ERβ isoforms in the human testis remains to be clarified, it has been suggested that ERβ2 forms heterodimers with ERα thereby attenuating its transcriptional activity; however, it lacks the ability to bind endogenous E2 or recruit cofactors via the AF-2 domain [51].

II. Transgenic mouse studies

Reports of testicular anomalies in men with naturally occurring mutations in the aromatase gene and in individuals lacking a functional ERα, including undescended testis, decreased sperm production, and altered endocrine profiles, reinforced the view that estrogen action is a requirement for normal testicular function [52–55]. Thus, development of knockout or transgenic mice with disruption of molecules related to reproduction and hormone action, e.g., mice with targeted deletion of the aromatase gene (ARKO), ERα (αERKO), ERβ (βERKO) and both ER subtypes (αβERKO), has contributed immensely to our understanding of reproductive endocrinology [56]. A major difference between these lines of mutant mice is that ARKO mice adequately express ERα and ERβ protein and do not make endogenous E2 whereas ER knockout mice are able to synthesize E2 but lack either ERα and/or ERβ protein. Therefore, a major caveat in these studies is the inadvertent removal of estrogen priming of extragonadal tissues during development. In this regard, there is a possibility that absence of endogenous E2 and/or ER-mediated activity during tissue differentiation in the hypothalamus and pituitary jeopardizes developmental maturation of regulatory pathways in the HPT axis.

The spectrum of testicular anomalies exhibited by transgenic mice deficient in E2 biosynthesis and ER protein is summarized in Table 1. ARKO mice have enlarged sex accessory organ weights presumably as a result of elevated serum testosterone levels and enhanced androgen action, and show disturbances of spermatogenesis, which is associated with increased apoptosis of developing germ cells [6, 7]. However, the results of fertility assessment in ARKO mice have been rather inconsistent, sexual function being impaired in one line of mice and not in the other; these differences are thought to be due to the amounts of residual aromatase gene products in mutant mice [7, 57]. In contrast to the lack of E2, overexpression of the aromatase gene and enhanced E2 production in mice induced cryptorchidism or undescended testis, spermatogenic arrest, Leydig cell hyperplasia, and decreased serum FSH and testosterone levels. Disruption of spermatogenesis was associated with decreased FSH levels while increased exposures to E2 induce Leydig cell hyperplasia [58]. Progressive degeneration of testicular tissue, dilation of the seminiferous tubules, and sexual behavioral problems are typical findings in αERKO mice [5]. Disruption of spermatogenesis has been attributed to fluid retention, which causes pressure atrophy of the seminiferous epithelium [59].

Table 1 Testicular function in mice deficient in estrogen biosynthesis or estrogen receptor protein

The obvious differences in the phenotypes of ARKO and αERKO mice, as were determined in early studies, implied that ERα is not the sole mediator of estrogen action and that another ER protein may be present in testicular cells. These speculations were confirmed by cloning of ERβ in the rat prostate and ovary [60]. Subsequently, the bulk of experimental evidence shows that ERβ regulates germ cell development. For example, ERα inactivation had no effect on the number of Sertoli cells and spermatogonia whereas ERβ inactivation increased the number of spermatogonia by more than 50% in neonatal mice [61]. However, it is surprising that in spite of the evidence for ERβ regulation of mitosis in spermatogonia, which serve as stem cells for the process of spermatogenesis, disturbances of sperm production were not evident in βERKO mice. On the other hand, the presence of ERα in Sertoli cells has not been demonstrated. Paradoxically, spermatogenic arrest occurs in αERKO mice, which have ERβ protein. These observations suggest that testicular cells regulate Sertoli cell support of germ cell development through unidentified ERα-mediated mechanisms. This line of thinking is supported by data from experiments in which germ cells were transplanted from donor males homozygous for the mutation ERα-/- to testes of wild-type ERα+/+ recipient mice depleted of germ cells. When mated to wild-type females, the recipients sired offspring heterozygous for the mutation ERα+/- but retained the coat-color marker of the ERα-/- donor mice. This finding confirmed that somatic cells in the testis, but not germ cells, have a requirement for ERα in order to support the process of spermatogenesis [62, 63]. In contrast to the αERKO, βERKO males retain full fertility but tend to show increased incidence of prostate hyperplasia with advancing age [64]. Perhaps not unexpectedly, male αβERKO mice are infertile, which is likely due to ERα deficiency because these effects are absent in βERKO mice [65, 66].

Alteration of the endocrine profile is a consistent finding in transgenic mice with targeted deletion of aromatase gene or ERs (Table 2). For example, serum LH levels were elevated in adult ARKO mice [6] while serum testosterone concentrations, though were increased at 12–14 wk of age, were comparable in wild-type and mutant mice [7]. Similarly, the concentrations of serum testosterone, LH, and FSH were increased in αERKO males compared to their wild-type littermates [5, 67]. The changes in serum gonadotropin levels presumably result from alleviation of estrogen feedback regulation on the hypothalamus-pituitary axis. The regulation of testicular steroidogenesis appears to be mediated primarily by ERα because changes in serum steroid hormone levels seen in the αERKO are absent in βERKO mice. Moreover, administration of a synthetic estrogen, estradiol benzoate, reduced serum LH and testosterone levels in wild-type but not αERKO mice (Fig. 2A), and treatment with the pure antiestrogen ICI 182,780 decreased androgen biosynthesis in wild-type but not αERKO Leydig cells [67]. The differences in androgen biosynthesis between αERKO and wild-type Leydig cells were associated with changes in steroidogenic enzyme activity because ERα deficiency enhanced gene expression for cytochrome P450 hydroxylase/17α lyase and 17β-hydroxysteroid dehydrogenase type III; these enzymes take part in reactions involved in the conversion of the steroid substrate cholesterol to testosterone (Fig. 2B). Consistent with these observations, a recent report showed that DES decreased testosterone production of wild-type fetal and neonatal testes but not ERα-/- [68].

Table 2 Endocrine profiles of mice deficient in estrogen biosynthesis or estrogen receptor protein
Figure 2
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.

III. Studies of xenoestrogens

Although there had been long standing evidence that male reproductive tract development is subject to estrogen action [39, 69], scientific attention to the role of estrogen in reproductive activity was highlighted only recently by public concerns that exposures to environmental chemicals may adversely affect the endocrine and reproductive systems. Exposures of laboratory animals and wildlife to high levels of estrogenic chemicals resulted in a number of abnormalities, including reduced gonad size, feminization of genetic males, and low sperm count and quality. In this regard, estrogenic activity has been attributed to a diverse array of steroidal and non steroidal compounds, including industrial chemicals (e.g., polychlorobiphenyls, alkyphenols, pesticides (e.g., DDT derivatives, methoxychlor, kepone), pharmaceutical agents (e.g., DES, tamoxifen, raloxifene), phthalates (e.g., di-2-ethylhexylphthalate, di-n-butyl phthalate), and phytoestrogens (e.g., genistein, daidzen) [1, 70, 71]. While there is no clear data demonstrating that environmental chemicals are the cause of reproductive anomalies in humans, the homology in organ systems between animal models and humans indicates a potential for adverse effects on sexual development and function.

Although binding affinity of xenoestrogens for ERs is low, ranging from 0.0001% to 1% of E2 levels, these chemicals have the ability to activate ERα and ERβ as agonists or prevent their binding by endogenous ligands when acting as antagonists [72, 73]. Just as diverse as the number of chemicals known to exhibit estrogenic activity, the profile of biological responses to exogenous chemicals is affected by a variety of factors in reproductive tissues: animal strain and species differences, relative amounts of ER subtypes, presence of EREs, recruitment of co-regulatory proteins (co-activators and repressors), binding to plasma proteins, chirality of chemicals, and multiple mechanisms of action (e.g., estrogenicity versus antiandrogenicity) [71, 74]. Specifically, xenoestrogens evoke estrogenic responses and cause their effects by mimicking and/or blocking the actions of endogenous E2 (agonist versus antagonist), and these effects may be result in changes in steroid hormone receptor gene expression, altered steroid hormone metabolism, cross-talk between ERs and other signaling systems (e.g., aryl hydrocarbon and EGF), and interference with serum protein binding [75–77]. It has also been suggested that the presence of xenoestrogens in the hormonal milieu of estrogen-sensitive tissues has the effect of potentiating E2 action [78]. The nature of the ERE in the promoter region of target genes may affect cellular response as indicated by the ability of ERβ to activate EREs from the vitellogene while ERα showed greater activation at the more divergent LH EREs in COS-1 cells [79]. Because ERs function as dimers, estrogen responsive genes may respond differently to ERα and ERβ homodimers or ERα/ERβ heterodimers following ER activation [80]. Furthermore, there are ligand-dependent differences in the ability of ERα and ERβ to bind co-regulatory proteins [21, 81]. Thus, the cellular response to ER agonists and antagonists is the result of interaction between several factors.

A detailed discussion of the effects of environmental chemicals on male reproduction is outside the scope of the present review and can be found elsewhere [82, 83]. However, studies of estrogenic chemicals have been conducted in laboratory species with low (physiological) and high (pharmacological) doses. Data from these investigations indicate that estrogen action is dose-dependent and may be stimulatory or inhibitory. For example, exposure to E2 restored spermatogenesis to the germ cell-depleted testis of hypogonadal mice [84], decreased the rate of apoptosis and stimulated proliferation of mouse and rat spermatogonia in vitro [43, 85], and induced renewal of spermatogonial stem cells in the testis of the Japanese eel [86]. On the other hand, incubation with E2 and DES was found to inhibit development of spermatogonia, Leydig cells and Sertoli cells in the fetal rat testis [87]. Administration of low doses of the industrial and estrogenic chemical bisphenol A (BPA) reduced spermatogenesis in mice [88], decreased DNA synthesis by immature rat Leydig cells (author's unpublished observations), and suppressed androgen biosynthesis by mature rat Leydig cells (Fig. 3). The effects of E2 and BPA on spermatogonial divisions and Leydig cell steroidogenesis were blocked by co-incubation with antiestrogens ICI 164384 and ICI 182,780, respectively, indicating that these effects were ER-mediated [1, 89]. There is also evidence showing that E2 regulates ER gene expression in a dose-dependent manner because chronic exposures of mice to 0.5 or 50 μg/ml BPA decreased ERβ and increased ERα gene expression in germ cells [90] but a single injection of estradiol benzoate at high doses (500 μg) caused the opposite effect in prepubertal rats, i.e., decreased ERα mRNA levels and increased ERβ expression [91]. Disparities in data from different laboratories are probably due to several factors, which act to moderate estrogen signaling in sensitive tissues, e.g., interaction between transcriptional and non-transcriptional signaling pathways, receptor cross-talks, unpredictable mixture effects, and changes in steroid production and action. In addition, an inverted U-shaped dose-response, in which low doses are stimulatory and high doses are inhibitory, has been proposed for estrogen action in reproductive tissues [92].

Figure 3
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.

In agreement with studies conducted in rodents, evidence supporting a direct role for estrogen in male reproductive tract development was collected from men. For example, poor semen quality has been a consistent finding in male patients with mutations in ERα [52] as well as those suffering from aromatase deficiency [53, 54]. A recent study involving a large cohort of men concluded that prenatal DES exposure is associated with testicular cancer and malformations of the genitalia although fertility was not affected [93]. Increased incidence in testicular cancer was thought to be due to early life-stage exposures to environmental estrogens and/or antiandrogens, which interfere with the ability of gonadal steroids to support tissue differentiation in the fetal period [94, 95]. Indeed, elevated blood estrogen levels in dizygotic twin pregnancies are known to increase the risk of testicular cancer in males [96]. Growing epidemiological evidence in support of these observations has led to the hypothesis, which states that a testicular dysgenesis syndrome (TDS) that is characterized by hypospadias, testicular cancer, abnormal spermatogenesis and undescended testis, is the result of interaction between genetic and environmental factors, including inappropriate exposures to endocrine-active chemicals [97, 98]. The growing incidence of TDS in the population implies that changes in steroid hormone synthesis and action cause greater effects during sexual differentiation in humans, as in rodents, but it is not clear that sperm function and fertility are affected in adulthood.

A series of data were published lately to highlight aspects of estrogen action in the testis. First, it was observed that neonatal treatment of prepubertal rats with DES alone (0.1 μg) induced only minor effects, which were amplified after suppression of androgen production and action. Thus, it was hypothesized that reduced androgen levels render the reproductive tract more sensitive to estrogen stimulation, and that the ratio between androgen and estrogen, rather than their absolute levels, is the critical determinant of E2 action [99, 100]. Curiously, this line of thinking does not explain similarities in the phenotypes of ARKO and αERKO mice, which have comparable serum androgen levels but exhibit different E2 levels (Table 2). However, there are suggestions that phenotypic similarities in ARKO and αERKO mice are possibly due to the confounding effects of growth factors that activate signaling pathways mediating E2 activity, e.g., EGF [59]. Also of interest are recent data showing that the presence of soy in the diet decreases body and testis weights, suppresses gonadotropin secretion, and retards germ cell development in the rat [101]. These findings have implications for analysis of estrogen action in the testis because: 1) The normal rat chow contains significant levels of phytoestrogens (200–300 mg/kg), potentially interfering with the action of E2 and estrogenic chemicals in reproductive tissues [102, 103]; and, 2) Putative health benefits associated with soy-based diets may be confounded by phytoestrogen signaling in the testis [104]. Although there is no evidence that consumption of soy-based diets has deleterious effects on testicular function, the possibility that such effects may occur in the prepubertal period, i.e., in infanthood, cannot be discounted as this population is not routinely examined for reproductive health. Because acquisition of adult sexual behavior is dependent on priming of sexually dimorphic hypothalamic nuclei by steroid hormones in the perinatal period [105], such evaluations seem to be warranted.

IV. Conclusion

The major source of E2 biosynthesis is the testis in rodents and adipose tissue in men but the receptor protein (ERα and ERβ) is localized to most cell types in the testis of both species in consonance with a physiological role for estrogen in testicular development and function (Fig. 4). It is therefore not surprising that targeted deletion of the aromatase gene, ERα, and/or ERβ caused a variety of testicular anomalies in mutant mice. For example, evidence for direct ER-mediated action in testicular cells is provided by disruption of spermatogenesis in ARKO and αERKO mice and the requirement for ERα for estrogen action in Leydig cells [6, 7]. Moreover, elevated serum LH levels in αERKO mice indicate that ERα deficiency jeopardizes steroid hormone negative feedback mechanisms in the hypothalamus-pituitary axis [5, 106]. These observations have clinical relevance because men with disorders of glucose metabolism and those with increased body mass index (i.e., overweight or obese) exhibit elevated serum E2 levels [107] with the potential for enhanced estrogen action in the testis. However, a number of confounding variables need resolution in order to clearly identify the mechanisms associated with the physiological actions of E2 in the testis. In this regard, new experimental approaches are needed, and may include: i) use of tissue-specific knockouts in order to remove effects of concurrent ER-mediated activity in the hypothalamus and/or pituitary [108]; ii) analysis of signaling pathways not mediated by ligand binding of ERα and/or ERβ [109, 110]; iii) investigation of the role of membrane ER signaling in the regulation of testicular function [111, 112]; iv) assessment of the influence of genetic background on estrogen action [96, 113]; v) development of methods for measuring bioavailability of estrogens in the body in order to define dose-effect relationships [114, 115]; and vi) use of techniques that maintain the normal hormonal milieu of reproductive tract tissues during investigation, i.e., as related to gonadotropin and androgen action [116]. A combination of these approaches will advance our understanding of the regulatory role of E2 in the mammalian testes.

Figure 4
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.

Abbreviations

ER:

estrogen receptor

E2:

17β-estradiol

DES:

diethylstilbestrol

HPT:

hypothalamus-pituitary-testicular axis

GnRH:

gonadotropin releasing hormone

FSH:

follicle stimulating hormone

LH:

luteinizing hormone

ERE:

estrogen response elements

IGF:

insulin growth factor

EGF:

epidermal growth factor

ARKO:

aromatase knockout mice

αERKO:

ERα knockout mice

βERKO:

ERβ knockout mice, αβERKO mice, mice deficient in both ERα and ERβ

BPA:

bisphenol A.

References

  1. Colborn T, vom Saal FS, Soto AM: Developmental effects of endocrine-disrupting chemicals in wildlife and humans. Environ Health Perspect. 1993, 101: 378-384.

    PubMed Central  CAS  PubMed  Google Scholar 

  2. Simpson ER, Mahendroo MS, Means GD, Kilgore MW, Corbin CJ, Mendelson CR: Tissue-specific promoters regulate aromatase cytochrome P450 expression. Clin Chem. 1993, 39: 317-324.

    CAS  PubMed  Google Scholar 

  3. Brewster ME, Anderson WR, Pop E: Effect of sustained estradiol release in the intact male rat: correlation of estradiol serum levels with actions on body weight, serum testosterone, and peripheral androgen-dependent tissues. Physiol Behav. 1997, 61: 225-229. 10.1016/S0031-9384(96)00364-2.

    CAS  PubMed  Google Scholar 

  4. Nagata C, Takatsuka N, Shimizu H, Hayashi H, Akamatsu T, Murase K: Effect of soymilk consumption on serum estrogen and androgen concentrations in Japanese men. Cancer Epidemiol Biomarkers Prev. 2001, 10: 179-184.

    CAS  PubMed  Google Scholar 

  5. Eddy EM, Washburn TF, Bunch DO, Goulding EH, Gladen BC, Lubahn DB, Korach KS: Targeted disruption of the estrogen receptor gene in male mice causes alteration of spermatogenesis and infertility. Endocrinology. 1996, 137: 4796-4805. 10.1210/en.137.11.4796.

    CAS  PubMed  Google Scholar 

  6. Fisher CR, Graves KH, Parlow AF, Simpson ER: Characterization of mice deficient in aromatase (ArKO) because of targeted disruption of the cyp19 gene. Proc Natl Acad Sci U S A. 1998, 95: 6965-6970. 10.1073/pnas.95.12.6965.

    PubMed Central  CAS  PubMed  Google Scholar 

  7. Robertson KM, O'Donnell L, Jones ME, Meachem SJ, Boon WC, Fisher CR, Graves KH, McLachlan RI, Simpson ER: Impairment of spermatogenesis in mice lacking a functional aromatase (cyp 19) gene. Proc Natl Acad Sci U S A. 1999, 96: 7986-7991. 10.1073/pnas.96.14.7986.

    PubMed Central  CAS  PubMed  Google Scholar 

  8. Sharpe RM, Skakkebaek NE: Are oestrogens involved in falling sperm counts and disorders of the male reproductive tract?. Lancet. 1993, 341: 1392-1395. 10.1016/0140-6736(93)90953-E.

    CAS  PubMed  Google Scholar 

  9. Shughrue PJ, Lane MV, Merchenthaler I: Comparative distribution of estrogen receptor-alpha and -beta mRNA in the rat central nervous system. J Comp Neurol. 1997, 388: 507-525. 10.1002/(SICI)1096-9861(19971201)388:4<507::AID-CNE1>3.0.CO;2-6.

    CAS  PubMed  Google Scholar 

  10. Shughrue PJ, Lane MV, Scrimo PJ, Merchenthaler I: Comparative distribution of estrogen receptor-alpha (ER-alpha) and beta (ER-beta) mRNA in the rat pituitary, gonad, and reproductive tract. Steroids. 1998, 63: 498-504. 10.1016/S0039-128X(98)00054-3.

    CAS  PubMed  Google Scholar 

  11. Nicol L, McNeilly JR, Stridsberg M, Crawford JL, McNeilly AS: Influence of steroids and GnRH on biosynthesis and secretion of secretogranin II and chromogranin A in relation to LH release in Lbeta2 gonadotroph cells. J Endocrinol. 2002, 174: 473-483. 10.1677/joe.0.1740473.

    CAS  PubMed  Google Scholar 

  12. Shupnik MA, Gharib SD, Chin WW: Estrogen suppresses rat gonadotropin gene transcription in vivo. Endocrinology. 1988, 122: 1842-1846.

    CAS  PubMed  Google Scholar 

  13. Shupnik MA, Rosenzweig BA: Identification of an estrogen-responsive element in the rat LH beta gene. DNA-estrogen receptor interactions and functional analysis. J Biol Chem. 1991, 266: 17084-17091.

    CAS  PubMed  Google Scholar 

  14. Demay F, De Monti M, Tiffoche C, Vaillant C, Thieulant ML: Steroid-independent activation of ER by GnRH in gonadotrope pituitary cells. Endocrinology. 2001, 142: 3340-3347. 10.1210/en.142.8.3340.

    CAS  PubMed  Google Scholar 

  15. Kraus WL, McInerney EM, Katzenellenbogen BS: Ligand-dependent, transcriptionally productive association of the amino- and carboxyl-terminal regions of a steroid hormone nuclear receptor. Proc Natl Acad Sci U S A. 1995, 92: 12314-12318.

    PubMed Central  CAS  PubMed  Google Scholar 

  16. McInerney EM, Tsai MJ, O'Malley BW, Katzenellenbogen BS: Analysis of estrogen receptor transcriptional enhancement by a nuclear hormone receptor coactivator. Proc Natl Acad Sci U S A. 1996, 93: 10069-10073. 10.1073/pnas.93.19.10069.

    PubMed Central  CAS  PubMed  Google Scholar 

  17. Giguere V: Orphan nuclear receptors: from gene to function. Endocr Rev. 1999, 20: 689-725. 10.1210/er.20.5.689.

    CAS  PubMed  Google Scholar 

  18. Nilsson S, Makela S, Treuter E, Tujague M, Thomsen J, Andersson G, Enmark E, Pettersson K, Warner M, Gustafsson JA: Mechanisms of estrogen action. Physiol Rev. 2001, 81: 1535-65.

    CAS  PubMed  Google Scholar 

  19. Chang WY, Prins GS: Estrogen receptor-beta: implications for the prostate gland. Prostate. 1999, 40: 115-124. 10.1002/(SICI)1097-0045(19990701)40:2<115::AID-PROS7>3.0.CO;2-3.

    CAS  PubMed  Google Scholar 

  20. Kuiper GG, Carlsson B, Grandien K, Enmark E, Haggblad J, Nilsson S, Gustafsson JA: Comparison of the ligand binding specificity and transcript tissue distribution of estrogen receptors alpha and beta. Endocrinology. 1997, 138: 863-870. 10.1210/en.138.3.863.

    CAS  PubMed  Google Scholar 

  21. Kuiper GG, Lemmen JG, Carlsson B, Corton JC, Safe SH, van der Saag PT, van der Burg B, Gustafsson JA: Interaction of estrogenic chemicals and phytoestrogens with estrogen receptor beta. Endocrinology. 1998, 139: 4252-4263. 10.1210/en.139.10.4252.

    CAS  PubMed  Google Scholar 

  22. Hall JM, McDonnell DP: The estrogen receptor beta-isoform (ERbeta) of the human estrogen receptor modulates ERalpha transcriptional activity and is a key regulator of the cellular response to estrogens and antiestrogens. Endocrinology. 1999, 140: 5566-5578. 10.1210/en.140.12.5566.

    CAS  PubMed  Google Scholar 

  23. Hewitt SC, Korach KS: Estrogen receptors: structure, mechanisms and function. Rev Endocr Metab Disord. 2002, 3: 193-200. 10.1023/A:1020068224909.

    CAS  PubMed  Google Scholar 

  24. Simoncini T, Mannella P, Fornari L, Caruso A, Varone G, Genazzani AR: In vitro effects of progesterone and progestins on vascular cells. Steroids. 2003, 68: 831-836. 10.1016/j.steroids.2003.08.006.

    CAS  PubMed  Google Scholar 

  25. Loomis AK, Thomas P: Effects of estrogens and xenoestrogens on androgen production by Atlantic Croaker testes in vitro: evidence for a non-genomic action mediated by an estrogen membrane receptor. Biol Reprod. 2000, 62: 995-1004.

    CAS  PubMed  Google Scholar 

  26. Razandi M, Pedram A, Merchenthaler I, Greene GL, Levin ER: Plasma membrane estrogen receptors exist and functions as dimers. Mol Endocrinol. 2004, 18: 2854-2865. 10.1210/me.2004-0115.

    CAS  PubMed  Google Scholar 

  27. Bjornstrom L, Sjoberg M: Mechanisms of estrogen receptor signaling: convergence of genomic and nongenomic actions on target genes. Mol Endocrinol. 2005, 19: 833-842. 10.1210/me.2004-0486.

    PubMed  Google Scholar 

  28. Nitta H, Bunick D, Hess RA, Janulis L, Newton SC, Millette CF, Osawa Y, Shizuta Y, Toda K, Bahr JM: Germ cells of the mouse testis express P450 aromatase. Endocrinology. 1993, 132: 1396-1401. 10.1210/en.132.3.1396.

    CAS  PubMed  Google Scholar 

  29. Levallet J, Bilinska B, Mittre H, Genissel C, Fresnel J, Carreau S: Expression and immunolocalization of functional cytochrome P450 aromatase in mature rat testicular cells. Biol Reprod. 1998, 58: 919-926.

    CAS  PubMed  Google Scholar 

  30. Bourguiba S, Lambard S, Carreau S: Steroids control the aromatase gene expression in purified germ cells from the adult male rat. J Mol Endocrinol. 2003, 31: 83-94. 10.1677/jme.0.0310083.

    CAS  PubMed  Google Scholar 

  31. Kuiper GG, Gustafsson JA: The novel estrogen receptor-beta subtype: potential role in the cell- and promoter-specific actions of estrogens and anti-estrogens. FEBS Lett. 1997, 410: 87-90. 10.1016/S0014-5793(97)00413-4.

    CAS  PubMed  Google Scholar 

  32. Saunders PT, Maguire SM, Gaughan J, Millar MR: Expression of oestrogen receptor beta (ER beta) in multiple rat tissues visualised by immunohistochemistry. J Endocrinol. 1997, 154: R13-16. 10.1677/joe.0.154R013.

    CAS  PubMed  Google Scholar 

  33. van Pelt AM, de Rooij DG, van der Burg B, van der Saag PT, Gustafsson JA, Kuiper GG: Ontogeny of estrogen receptor-beta expression in rat testis. Endocrinology. 1999, 140: 478-483. 10.1210/en.140.1.478.

    CAS  PubMed  Google Scholar 

  34. Rosenfeld CS, Ganjam VK, Taylor JA, Yuan X, Stiehr JR, Hardy MP, Lubahn DB: Transcription and translation of estrogen receptor-beta in the male reproductive tract of estrogen receptor-alpha knock-out and wild-type mice. Endocrinology. 1998, 139: 2982-2987. 10.1210/en.139.6.2982.

    CAS  PubMed  Google Scholar 

  35. Saunders PT, Fisher JS, Sharpe RM, Millar MR: Expression of oestrogen receptor beta (ER beta) occurs in multiple cell types, including some germ cells, in the rat testis. J Endocrinol. 1998, 156: R13-17. 10.1677/joe.0.156R013.

    CAS  PubMed  Google Scholar 

  36. Oliveira CA, Nie R, Carnes K, Franca LR, Prins GS, Saunders PT, Hess RA: The antiestrogen ICI 182,780 decreases the expression of estrogen receptor-alpha but has no effect on estrogen receptor-beta and androgen receptor in rat efferent ductules. Reprod Biol Endocrinol. 2003, 1: 75-10.1186/1477-7827-1-75.

    PubMed Central  PubMed  Google Scholar 

  37. Levine AC, Kirschenbaum A, Gabrilove JL: The role of sex steroids in the pathogenesis and maintenance of benign prostatic hyperplasia. Mt Sinai J Med. 1997, 64: 20-25.

    CAS  PubMed  Google Scholar 

  38. McLachlan JA, Newbold RR, Bullock B: Reproductive tract lesions in male mice exposed prenatally to diethylstilbestrol. Science. 1975, 190: 991-992.

    CAS  PubMed  Google Scholar 

  39. Gill WB, Schumacher GF, Bibbo M: Structural and functional abnormalities in the sex organs of male offspring of mothers treated with diethylstilbestrol (DES). J Reprod Med. 1976, 16: 147-153.

    CAS  PubMed  Google Scholar 

  40. Brand H, Kos M, Denger S, Flouriot G, Gromoll J, Gannon F, Reid G: A novel promoter is involved in the expression of estrogen receptor alpha in human testis and epididymis. Endocrinology. 2002, 143: 3397-3404. 10.1210/en.2001-210832.

    CAS  PubMed  Google Scholar 

  41. Brandenberger AW, Tee MK, Lee JY, Chao V, Jaffe RB: Tissue distribution of estrogen receptors alpha (ER-alpha) and beta (ER-beta) mRNA in the midgestational human fetus. J Clin Endocrinol Metab. 1997, 82: 3509-3512. 10.1210/jc.82.10.3509.

    CAS  PubMed  Google Scholar 

  42. Gaskell TL, Robinson LL, Groome NP, Anderson RA, Saunders PT: Differential expression of two estrogen receptor beta isoforms in the human fetal testis during the second trimester of pregnancy. J Clin Endocrinol Metab. 2003, 88: 424-432. 10.1210/jc.2002-020811.

    CAS  PubMed  Google Scholar 

  43. Pentikainen V, Erkkila K, Suomalainen L, Parvinen M, Dunkel L: Estradiol acts as a germ cell survival factor in the human testis in vitro. J Clin Endocrinol Metab. 2000, 85: 2057-2067. 10.1210/jc.85.5.2057.

    CAS  PubMed  Google Scholar 

  44. Taylor AH, Al-Azzawi F: Immunolocalisation of oestrogen receptor beta in human tissues. J Mol Endocrinol. 2000, 24: 145-155. 10.1677/jme.0.0240145.

    CAS  PubMed  Google Scholar 

  45. Lambard S, Galeraud-Denis I, Saunders PT, Carreau S: Human immature germ cells and ejaculated spermatozoa contain aromatase and oestrogen receptors. J Mol Endocrinol. 2004, 32: 279-289. 10.1677/jme.0.0320279.

    CAS  PubMed  Google Scholar 

  46. Saunders PT, Sharpe RM, Williams K, Macpherson S, Urquart H, Irvine DS, Millar MR: Differential expression of oestrogen receptor alpha and beta proteins in the testes and male reproductive system of human and non-human primates. Mol Hum Reprod. 2001, 7: 227-236. 10.1093/molehr/7.3.227.

    CAS  PubMed  Google Scholar 

  47. Makinen S, Makela S, Weihua Z, Warner M, Rosenlund B, Salmi S, Hovatta O, Gustafsson JK: Localization of oestrogen receptors alpha and beta in human testis. Mol Hum Reprod. 2001, 7: 497-503. 10.1093/molehr/7.6.497.

    CAS  PubMed  Google Scholar 

  48. Enmark E, Pelto-Huikko M, Grandien K, Lagercrantz S, Lagercrantz J, Fried G, Nordenskjold M, Gustafsson JA: Human estrogen receptor beta-gene structure, chromosomal localization, and expression pattern. J Clin Endocrinol Metab. 1997, 82: 4258-4265. 10.1210/jc.82.12.4258.

    CAS  PubMed  Google Scholar 

  49. Nilsson S, Makela S, Treuter E, Tujague M, Thomsen J, Andersson G, Enmark E, Pettersson K, Warner M, Gustafsson JA: Mechanisms of estrogen action. Physiol Rev. 2001, 81: 1535-1565.

    CAS  PubMed  Google Scholar 

  50. Saunders PT, Millar MR, Macpherson S, Irvine DS, Groome NP, Evans LR, Sharpe RM, Scobie GA: ERbeta1 and the ERbeta2 splice variant (ERbetacx/beta2) are expressed in distinct cell populations in the adult human testis. J Clin Endocrinol Metab. 2002, 87: 2706-2715. 10.1210/jc.87.6.2706.

    CAS  PubMed  Google Scholar 

  51. Ogawa S, Inoue S, Watanabe T, Orimo A, Hosoi T, Ouchi Y, Muramatsu M: Molecular cloning and characterization of human estrogen receptor betacx: a potential inhibitor of estrogen action in human. Nucleic Acids Res. 1998, 26: 3505-3512. 10.1093/nar/26.15.3505.

    PubMed Central  CAS  PubMed  Google Scholar 

  52. Smith EP, Boyd J, Frank GR, Takahashi H, Cohen RM, Specker B, Williams TC, Lubahn DB, Korach KS: Estrogen resistance caused by a mutation in the estrogen-receptor gene in a man. N Engl J Med. 1994, 331: 1056-1061. 10.1056/NEJM199410203311604.

    CAS  PubMed  Google Scholar 

  53. Morishima A, Grumbach MM, Simpson ER, Fisher C, Qin K: Aromatase deficiency in male and female siblings caused by a novel mutation and the physiological role of estrogens. J Clin Endocrinol Metab. 1995, 80: 3689-3698. 10.1210/jc.80.12.3689.

    CAS  PubMed  Google Scholar 

  54. Carani C, Qin K, Simoni M, Faustini-Fustini M, Serpente S, Boyd J, Korach KS, Simpson ER: Effect of testosterone and estradiol in a man with aromatase deficiency. N Engl J Med. 1997, 337: 91-95. 10.1056/NEJM199707103370204.

    CAS  PubMed  Google Scholar 

  55. Herrmann BL, Saller B, Janssen OE, Gocke P, Bockisch A, Sperling H, Mann K, Broecker M: Impact of estrogen replacement therapy in a male with congenital aromatase deficiency caused by a novel mutation in the CYP19 gene. J Clin Endocrinol Metab. 2002, 87: 5476-5484. 10.1210/jc.2002-020498.

    CAS  PubMed  Google Scholar 

  56. Hewitt SC, Harrell JC, Korach KS: Lessons in estrogen biology from knockout and transgenic animals. Annu Rev Physiol. 2005, 67: 285-308. 10.1146/annurev.physiol.67.040403.115914.

    CAS  PubMed  Google Scholar 

  57. Honda S, Harada N, Ito S, Takagi Y, Maeda S: Disruption of sexual behavior in male aromatase-deficient mice lacking exons 1 and 2 of the cyp19 gene. Biochem Biophys Res Commun. 1998, 252: 445-449. 10.1006/bbrc.1998.9672.

    CAS  PubMed  Google Scholar 

  58. Li X, Nokkala E, Yan W, Streng T, Saarinen N, Warri A, Huhtaniemi I, Santti R, Makela S, Poutanen M: Altered structure and function of reproductive organs in transgenic male mice overexpressing human aromatase. Endocrinology. 2001, 142: 2435-2442. 10.1210/en.142.6.2435.

    CAS  PubMed  Google Scholar 

  59. Hess RA, Bunick D, Lee KH, Bahr J, Taylor JA, Korach KS, Lubahn DB: A role for oestrogens in the male reproductive system. Nature. 1997, 390: 509-512. 10.1038/37352.

    CAS  PubMed  Google Scholar 

  60. Kuiper GG, Enmark E, Pelto-Huikko M, Nilsson S, Gustafsson JA: Cloning of a novel receptor expressed in rat prostate and ovary. Proc Natl Acad Sci U S A. 1996, 93: 5925-5930. 10.1073/pnas.93.12.5925.

    PubMed Central  CAS  PubMed  Google Scholar 

  61. Delbes G, Levacher C, Pairault C, Racine C, Duquenne C, Krust A, Habert R: Estrogen receptor beta-mediated inhibition of male germ cell line development in mice by endogenous estrogens during perinatal life. Endocrinology. 2004, 145: 3395-3403. 10.1210/en.2003-1479.

    CAS  PubMed  Google Scholar 

  62. Mahato D, Goulding EH, Korach KS, Eddy EM: Spermatogenic cells do not require estrogen receptor-alpha for development or function. Endocrinology. 2000, 141: 1273-1276. 10.1210/en.141.3.1273.

    CAS  PubMed  Google Scholar 

  63. Mahato D, Goulding EH, Korach KS, Eddy EM: Estrogen receptor-alpha is required by the supporting somatic cells for spermatogenesis. Mol Cell Endocrinol. 2001, 178: 57-63. 10.1016/S0303-7207(01)00410-5.

    CAS  PubMed  Google Scholar 

  64. Krege JH, Hodgin JB, Couse JF, Enmark E, Warner M, Mahler JF, Sar M, Korach KS, Gustafsson JA, Smithies O: Generation and reproductive phenotypes of mice lacking estrogen receptor beta. Proc Natl Acad Sci U S A. 1998, 95: 15677-15682. 10.1073/pnas.95.26.15677.

    PubMed Central  CAS  PubMed  Google Scholar 

  65. Weihua Z, Makela S, Andersson LC, Salmi S, Saji S, Webster JI, Jensen EV, Nilsson S, Warner M, Gustafsson JA: A role for estrogen receptor beta in the regulation of growth of the ventral prostate. Proc Natl Acad Sci U S A. 2001, 98: 6330-6335. 10.1073/pnas.111150898.

    PubMed Central  CAS  PubMed  Google Scholar 

  66. Ogawa S, Chan J, Chester AE, Gustafsson JA, Korach KS, Pfaff DW: Survival of reproductive behaviors in estrogen receptor beta gene-deficient (betaERKO) male and female mice. Proc Natl Acad Sci U S A. 1999, 96: 12887-12892. 10.1073/pnas.96.22.12887.

    PubMed Central  CAS  PubMed  Google Scholar 

  67. Akingbemi BT, Ge R, Rosenfeld CS, Newton LG, Hardy DO, Catterall JF, Lubahn DB, Korach KS, Hardy MP: Estrogen receptor-alpha gene deficiency enhances androgen biosynthesis in the mouse Leydig cell. Endocrinology. 2003, 144: 84-93. 10.1210/en.2002-220292.

    CAS  PubMed  Google Scholar 

  68. Delbes G, Levacher C, Duquenne C, Racine C, Pakarinen P, Habert R: Endogenous estrogens inhibit mouse fetal Leydig cell development via estrogen receptor alpha. Endocrinology. 2005, 146: 2454-2461. 10.1210/en.2004-1540.

    CAS  PubMed  Google Scholar 

  69. Henry EC, Miller RK: Comparison of the disposition of diethylstilbestrol and estradiol in the fetal rat. Correlation with teratogenic potency. Biochem Pharmacol. 1986, 35: 1993-2001. 10.1016/0006-2952(86)90732-X.

    CAS  PubMed  Google Scholar 

  70. Witorsch RJ: Low-dose in utero effects of xenoestrogens in mice and their relevance to humans: an analytical review of the literature. Food Chem Toxicol. 2002, 40: 905-912. 10.1016/S0278-6915(02)00069-8.

    CAS  PubMed  Google Scholar 

  71. Akingbemi BT, Hardy MP: Oestrogenic and antiandrogenic chemicals in the environment: effects on male reproductive health. Ann Med. 2001, 33: 391-403.

    CAS  PubMed  Google Scholar 

  72. Soto AM, Sonnenschein C, Chung KL, Fernandez MF, Olea N, Serrano FO: The E-SCREEN assay as a tool to identify estrogens: an update on estrogenic environmental pollutants. Environ Health Perspect. 1995, 103 (Suppl 7): 113-122.

    PubMed Central  CAS  PubMed  Google Scholar 

  73. Routledge EJ, Parker J, Odum J, Ashby J, Sumpter JP: Some alkyl hydroxy benzoate preservatives (parabens) are estrogenic. Toxicol Appl Pharmacol. 1998, 153: 12-19. 10.1006/taap.1998.8544.

    CAS  PubMed  Google Scholar 

  74. Boonyaratanakornkit V, Edwards DP: Receptor mechanisms of rapid extranuclear signalling initiated by steroid hormones. Essays Biochem. 2004, 40: 105-120.

    CAS  PubMed  Google Scholar 

  75. Qian YM, Sun XJ, Tong MH, Li XP, Richa J, Song WC: Targeted disruption of the mouse estrogen sulfotransferase gene reveals a role of estrogen metabolism in intracrine and paracrine estrogen regulation. Endocrinology. 2001, 142: 5342-5350. 10.1210/en.142.12.5342.

    CAS  PubMed  Google Scholar 

  76. Birnbaum LS, Fenton SE: Cancer and developmental exposure to endocrine disruptors. Environ Health Perspect. 2003, 111: 389-394.

    PubMed Central  CAS  PubMed  Google Scholar 

  77. Bradlow HL, Davis DL, Lin G, Sepkovic D, Tiwari R: Effects of pesticides on the ratio of 16 alpha/2-hydroxyestrone: a biologic marker of breast cancer risk. Environ Health Perspect. 1995, 103 (Suppl 7): 147-150.

    PubMed Central  CAS  PubMed  Google Scholar 

  78. Rajapakse N, Silva E, Kortenkamp A: Combining xenoestrogens at levels below individual no-observed-effect concentrations dramatically enhances steroid hormone action. Environ Health Perspect. 2002, 110: 917-921.

    PubMed Central  CAS  PubMed  Google Scholar 

  79. Pennie WD, Aldridge TC, Brooks AN: Differential activation by xenoestrogens of ER alpha and ER beta when linked to different response elements. J Endocrinol. 1998, 158: R11-14. 10.1677/joe.0.158R011.

    CAS  PubMed  Google Scholar 

  80. Pettersson K, Grandien K, Kuiper GG, Gustafsson JA: Mouse estrogen receptor beta forms estrogen response element-binding heterodimers with estrogen receptor alpha. Mol Endocrinol. 1997, 11: 1486-1496. 10.1210/me.11.10.1486.

    CAS  PubMed  Google Scholar 

  81. Routledge EJ, White R, Parker MG, Sumpter JP: Differential effects of xenoestrogens on coactivator recruitment by estrogen receptor (ER) alpha and ERbeta. J Biol Chem. 2000, 275: 35986-35993. 10.1074/jbc.M006777200.

    CAS  PubMed  Google Scholar 

  82. Naciff JM, Daston GP: Toxicogenomic approach to endocrine disrupters: identification of a transcript profile characteristic of chemicals with estrogenic activity. Toxicol Pathol. 2004, 32 (Suppl 2): 59-70. 10.1080/01926230490463812.

    CAS  PubMed  Google Scholar 

  83. Safe S: Clinical correlates of environmental endocrine disruptors. Trends Endocrinol Metab. 2005, 16: 139-144. 10.1016/j.tem.2005.03.004.

    CAS  PubMed  Google Scholar 

  84. Ebling FJ, Brooks AN, Cronin AS, Ford H, Kerr JB: Estrogenic induction of spermatogenesis in the hypogonadal mouse. Endocrinology. 2000, 141: 2861-9. 10.1210/en.141.8.2861.

    CAS  PubMed  Google Scholar 

  85. Li H, Papadopoulos V, Vidic B, Dym M, Culty M: Regulation of rat testis gonocyte proliferation by platelet-derived growth factor and estradiol: identification of signaling mechanisms involved. Endocrinology. 1997, 138: 1289-1298. 10.1210/en.138.3.1289.

    CAS  PubMed  Google Scholar 

  86. Miura T, Miura C, Ohta T, Nader MR, Todo T, Yamauchi K: Estradiol-17beta stimulates the renewal of spermatogonial stem cells in males. Biochem Biophys Res Commun. 1999, 264: 230-234. 10.1006/bbrc.1999.1494.

    CAS  PubMed  Google Scholar 

  87. Lassurguere J, Livera G, Habert R, Jegou B: Time- and dose-related effects of estradiol and diethylstilbestrol on the morphology and function of the fetal rat testis in culture. Toxicol Sci. 2003, 73: 160-169. 10.1093/toxsci/kfg065.

    CAS  PubMed  Google Scholar 

  88. vom Saal FS, Cooke PS, Buchanan DL, Palanza P, Thayer KA, Nagel SC, Parmigiani S, Welshons WV: A physiologically based approach to the study of bisphenol A and other estrogenic chemicals on the size of reproductive organs, daily sperm production, and behavior. Toxicol Ind Health. 1998, 14: 239-260.

    CAS  PubMed  Google Scholar 

  89. Akingbemi BT, Sottas CM, Koulova AI, Klinefelter GR, Hardy MP: 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. 2004, 145: 592-603. 10.1210/en.2003-1174.

    CAS  PubMed  Google Scholar 

  90. Takao T, Nanamiya W, Nazarloo HP, Matsumoto R, Asaba K, Hashimoto K: Exposure to the environmental estrogen bisphenol A differentially modulated estrogen receptor-alpha and -beta immunoreactivity and mRNA in male mouse testis. Life Sci. 2003, 72: 1159-1169. 10.1016/S0024-3205(02)02364-0.

    CAS  PubMed  Google Scholar 

  91. Tena-Sempere M, Navarro J, Pinilla L, Gonzalez LC, Huhtaniemi I, Aguilar E: Neonatal exposure to estrogen differentially alters estrogen receptor alpha and beta mRNA expression in rat testis during postnatal development. J Endocrinol. 2000, 165: 345-357. 10.1677/joe.0.1650345.

    CAS  PubMed  Google Scholar 

  92. vom Saal FS, Timms BG, Montano MM, Palanza P, Thayer KA, Nagel SC, Dhar MD, Ganjam VK, Parmigiani S, Welshons WV: Prostate enlargement in mice due to fetal exposure to low doses of estradiol or diethylstilbestrol and opposite effects at high doses. Proc Natl Acad Sci U S A. 1997, 94: 2056-2061. 10.1073/pnas.94.5.2056.

    CAS  PubMed  Google Scholar 

  93. Wilcox AJ, Baird DD, Weinberg CR, Hornsby PP, Herbst AL: Fertility in men exposed prenatally to diethylstilbestrol. N Engl J Med. 1995, 332: 1411-1416. 10.1056/NEJM199505253322104.

    CAS  PubMed  Google Scholar 

  94. Strohsnitter WC, Noller KL, Hoover RN, Robboy SJ, Palmer JR, Titus-Ernstoff L, Kaufman RH, Adam E, Herbst AL, Hatch EE: Cancer risk in men exposed in utero to diethylstilbestrol. J Natl Cancer Inst. 2001, 93: 545-551. 10.1093/jnci/93.7.545.

    CAS  PubMed  Google Scholar 

  95. Leffers H, Naesby M, Vendelbo B, Skakkebaek NE, Jorgensen M: Oestrogenic potencies of Zeranol, oestradiol, diethylstilboestrol, Bisphenol-A and genistein: implications for exposure assessment of potential endocrine disrupters. Hum Reprod. 2001, 16: 1037-1045. 10.1093/humrep/16.5.1037.

    CAS  PubMed  Google Scholar 

  96. Swerdlow AJ, De Stavola BL, Swanwick MA, Maconochie NE: Risks of breast and testicular cancers in young adult twins in England and Wales: evidence on prenatal and genetic aetiology. Lancet. 1997, 350: 1723-1728. 10.1016/S0140-6736(97)05526-8.

    CAS  PubMed  Google Scholar 

  97. Skakkebaek NE: Testicular dysgenesis syndrome: new epidemiological evidence. Int J Andrology. 2004, 27: 189-191. 10.1111/j.1365-2605.2004.00488.x.

    Google Scholar 

  98. Virtanen HE, Raipert-De Meyts E, Main KM, Skakkebaek NE, Toppari J: Testicular dysgenesis syndrome and the development and occurrence of male reproductive disorders. Toxicol Appl Pharmacol. 2005,

    Google Scholar 

  99. Rivas A, Fisher JS, McKinnell C, Atanassova N, Sharpe RM: Induction of reproductive tract developmental abnormalities in the male rat by lowering androgen production or action in combination with a low dose of diethylstilbestrol: evidence for importance of the androgen-estrogen balance. Endocrinology. 2002, 143: 4797-4808. 10.1210/en.2002-220531.

    CAS  PubMed  Google Scholar 

  100. Sharpe RM, Rivas A, Walker M, McKinnell C, Fisher JS: Effect of neonatal treatment of rats with potent or weak (environmental) oestrogens, or with a GnRH antagonist, on Leydig cell development and function through puberty into adulthood. Int J Androl. 2003, 26: 26-36. 10.1046/j.1365-2605.2003.00385.x.

    CAS  PubMed  Google Scholar 

  101. Atanassova N, McKinnell C, Turner KJ, Walker M, Fisher JS, Morley M, Millar MR, Groome NP, Sharpe RM: Comparative effects of neonatal exposure of male rats to potent and weak (environmental) estrogens on spermatogenesis at puberty and the relationship to adult testis size and fertility: evidence for stimulatory effects of low estrogen levels. Endocrinology. 2000, 141: 3898-3907. 10.1210/en.141.10.3898.

    CAS  PubMed  Google Scholar 

  102. Thigpen JE, Setchell KD, Ahlmark KB, Locklear J, Spahr T, Caviness GF, Goelz MF, Haseman JK, Newbold RR, Forsythe DB: Phytoestrogen content of purified, open- and closed-formula laboratory animal diets. Lab Anim Sci. 1999, 49: 530-536.

    CAS  PubMed  Google Scholar 

  103. Thigpen JE, Setchell KD, Saunders HE, Haseman JK, Grant MG, Forsythe DB: Selecting the appropriate rodent diet for endocrine disruptor research and testing studies. ILAR J. 2004, 45: 401-416.

    CAS  PubMed  Google Scholar 

  104. Munro IC, Harwood M, Hlywka JJ, Stephen AM, Doull J, Flamm WG, Adlercreutz H: Soy isoflavones: a safety review. Nutr Rev. 2003, 61: 1-33. 10.1301/nr.2003.janr.1-33.

    PubMed  Google Scholar 

  105. Cooke B, Hegstrom CD, Villeneuve LS, Breedlove SM: Sexual differentiation of the vertebrate brain: principles and mechanisms. Front Neuroendocrinol. 1998, 19: 323-362. 10.1006/frne.1998.0171.

    CAS  PubMed  Google Scholar 

  106. Lindzey J, Wetsel WC, Couse JF, Stoker T, Cooper R, Korach KS: Effects of castration and chronic steroid treatments on hypothalamic gonadotropin-releasing hormone content and pituitary gonadotropins in male wild-type and estrogen receptor-alpha knockout mice. Endocrinology. 1998, 139: 4092-4101. 10.1210/en.139.10.4092.

    CAS  PubMed  Google Scholar 

  107. Oettel M, Hubler D, Patchev V: Selected aspects of endocrine pharmacology of the aging male. Exp Gerontol. 2003, 38: 189-198. 10.1016/S0531-5565(02)00185-7.

    CAS  PubMed  Google Scholar 

  108. Zhao L, Bakke M, Hanley NA, Majdic G, Stallings NR, Jeyasuria P, Parker KL: Tissue-specific knockouts of steroidogenic factor 1. Mol Cell Endocrinol. 2004, 215: 89-94. 10.1016/j.mce.2003.11.009.

    CAS  PubMed  Google Scholar 

  109. Das SK, Tan J, Raja S, Halder J, Paria BC, Dey SK: Estrogen targets genes involved in protein processing, calcium homeostasis, and Wnt signaling in the mouse uterus independent of estrogen receptor-alpha and -beta. J Biol Chem. 2000, 275: 28834-28842. 10.1074/jbc.M003827200.

    CAS  PubMed  Google Scholar 

  110. Gaido KW, Leonard LS, Maness SC, Hall JM, McDonnell DP, Saville B, Safe S: Differential interaction of the methoxychlor metabolite 2,2-bis-(p-hydroxyphenyl)-1,1,1-trichloroethane with estrogen receptors alpha and beta. Endocrinology. 1999, 140: 5746-5753. 10.1210/en.140.12.5746.

    CAS  PubMed  Google Scholar 

  111. Marquez DC, Pietras RJ: Membrane-associated binding sites for estrogen contribute to growth regulation of human breast cancer cells. Oncogene. 2001, 20: 5420-5430. 10.1038/sj.onc.1204729.

    CAS  PubMed  Google Scholar 

  112. Razandi M, Alton G, Pedram A, Ghonshani S, Webb P, Levin ER: Identification of a structural determinant necessary for the localization and function of estrogen receptor alpha at the plasma membrane. Mol Cell Biol. 2003, 23: 1633-1646. 10.1128/MCB.23.5.1633-1646.2003.

    PubMed Central  CAS  PubMed  Google Scholar 

  113. Stokes WS: Introduction: selecting appropriate animal models and experimental designs for endocrine disruptor research and testing studies. ILAR J. 2004, 45: 387-393.

    CAS  PubMed  Google Scholar 

  114. Bigsby RM, Caperell-Grant A, Madhukar BV: Xenobiotics released from fat during fasting produce estrogenic effects in ovariectomized mice. Cancer Res. 1997, 57: 865-869.

    CAS  PubMed  Google Scholar 

  115. Nagel SC, vom Saal FS, Thayer KA, Dhar MG, Boechler M, Welshons WV: Relative binding affinity-serum modified access (RBA-SMA) assay predicts the relative in vivo bioactivity of the xenoestrogens bisphenol A and octylphenol. Environ Health Perspect. 1997, 105: 70-76.

    PubMed Central  CAS  PubMed  Google Scholar 

  116. Nagel SC, vom Saal FS, Welshons WV: The effective free fraction of estradiol and xenoestrogens in human serum measured by whole cell uptake assays: physiology of delivery modifies estrogenic activity. Proc Soc Exp Biol Med. 1998, 217: 300-309.

    CAS  PubMed  Google Scholar 

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Acknowledgements

Some of the work described in this review was performed during the author's postdoctoral training with Dr. Matthew P. Hardy at the Center for Biomedical Research, Population Council, The Rockefeller University, New York, with funding support by the Fogarty International Center, National Institutes of Health (F05 TW05350) and the National Institute of Environmental Health Sciences (ES 10233). Drs. Y. Tao and T. Braden provided helpful comments on an early draft of this paper.

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Akingbemi, B.T. Estrogen regulation of testicular function. Reprod Biol Endocrinol 3, 51 (2005). https://doi.org/10.1186/1477-7827-3-51

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