Estrogen in the adult male reproductive tract: A review
© Hess; licensee BioMed Central Ltd. 2003
Received: 30 May 2003
Accepted: 09 July 2003
Published: 09 July 2003
Testosterone and estrogen are no longer considered male only and female only hormones. Both hormones are important in both sexes. It was known as early as the 1930's that developmental exposure to a high dose of estrogen causes malformation of the male reproductive tract, but the early formative years of reproductive biology as a discipline did not recognize the importance of estrogen in regulating the normal function of the adult male reproductive tract. In the adult testis, estrogen is synthesized by Leydig cells and the germ cells, producing a relatively high concentration in rete testis fluid. Estrogen receptors are present in the testis, efferent ductules and epididymis of most species. However, estrogen receptor-α is reported absent in the testis of a few species, including man. Estrogen receptors are abundant in the efferent ductule epithelium, where their primary function is to regulate the expression of proteins involved in fluid reabsorption. Disruption of the α-receptor, either in the knockout (αERKO) or by treatment with a pure antiestrogen, results in dilution of cauda epididymal sperm, disruption of sperm morphology, inhibition of sodium transport and subsequent water reabsorption, increased secretion of Cl-, and eventual decreased fertility. In addition to this primary regulation of luminal fluid and ion transport, estrogen is also responsible for maintaining a differentiated epithelial morphology. Thus, we conclude that estrogen or its α-receptor is an absolute necessity for fertility in the male.
It was known as early as the 1930's that the developing testis was responsive to the "female" hormone [, also reviewed by ]. It was also known in the 1930's and 40's that developmental exposure to high doses of estrogens could induce malformation of the male reproductive tract [3–6]. Thus, during the formative years of reproductive biology as a discipline it was suggested that estrogen might be important in the male; however, even in the early 1990's many scientists considered estrogen receptor presence in the adult male reproductive tract to be a remnant from the indifferent sex stage of embryological differentiation .
Reference to estrogen production by the testis was more of a curiosity at first, as efforts were made to determine the various metabolites of testosterone being produced [8–11]. During the 1970's, the prediction of an estrogen receptor in testis and epididymis became a reality as estradiol binding was discovered [12–15]. However, it was clear from subsequent publications that most scientists did not consider estrogen to be a major steroid hormone in the male reproductive tract, in the adult [16–19]. The potential importance of estrogen during development of the male reproductive system was made popular by the report that diethylstilbestrol (DES) treatment during pregnancy induced cryptorchidism and epididymal cysts in male mice . This discovery opened the door to numerous investigations into the long-term effects of developmental exposure to estrogenic compounds on male reproduction, an inquiry that continues today [21, 22]. Although estrogen effects in the developing male are important, such studies have not actually proven that estrogen has a role in the adult male reproductive organs. At best, it was thought that an estrogen binding ability was left over from developmental processes and that estrogen played only a small role in the adult male [7, 23, 24].
Most interesting was the discovery that cytochrome P450 aromatase, which is capable of converting androgens into estrogens, is present in the testis [25–39]. During this same period of discovery, others were using the radioimmunoassay to identify steroids present in body fluids and estrogen concentrations were found to be relatively high in seminal and rete testis plasma [40–48]. Thus, up to the 1990's it appears that most scientific inquiry into estrogen's presence in the male remained a curiosity, as well as a worry that estrogen exposure during development was harmful. Then, in the decade of the 90's new discoveries in the male led to the hypothesis that estrogen not only has important functions in the adult male reproductive tract, but that estrogen and its α-receptor are "essential" for normal fertility. This new paradigm for estrogen's role in the male began with the discovery that testicular germ cells and epididymal sperm contain aromatase and synthesize estrogen . This discovery explained the presence of a high concentration of estradiol in rete testis of the rat  and provided a source of estrogen for the high concentration of receptors that were subsequently found to populate the head of the male reproductive tract [50–55]. However, an estrogen function was not uncovered until the ERα knockout (αERKO) was produced. The αERKO mouse, originally generated by Dennis Lubahn and colleagues , showed for the first time that ERα is essential for fertility in the male [56–58]. This animal model was further developed to show that estrogen provides a physiological function in regulating fluid dynamics in the male reproductive tract, a function that is "essential" for normal reproductive performance [59–66].
Estrogen in the male tract
P450 Aromatase in the adult male reproductive system.
Rainbow trout fish
The presence of P450arom in male germ cells has now been demonstrated in several species, including mouse, rat, brown bear, the bank vole, rooster, and man [49, 52, 73–80]. The enzyme is located in cytoplasmic droplets of the sperm tail, but the staining becomes less intense as sperm traverse the epididymis [73, 75]. Its presence in germ cells and spermatozoa was recently confirmed and shown to represent approximately 62% of the total testicular aromatase [69, 70, 81]. Testicular germ cells in the boar, ram and stallion have not been shown to be aromatase-positive. It is unclear whether this is due to differences in antibodies used or if some species simply do not generate estradiol by the germ cell pathway. It would be interesting to determine if aromatase is expressed in the epididymal tract of those species lacking germ cell expression. Others have shown the absence of aromatase in the mouse epididymis ; thus, the conversion of androgens to estrogens by sperm remains the primary source of estrogen in the lumen of the reproductive tract of this species. This observation raises new and exciting hypotheses regarding the potential for estrogen to regulate functions in the efferent ductules, epididymis and vas deferens.
Estrogen receptors in the male tract
It has been known for at least 25 years that an estrogen receptor-like protein exists in epididymal tissues . However, those early studies lead to the conclusion that estrogen was more important during development of the epididymis than in adult function . Estrogen binding in epididymal tissues has been noted in many species, including the dog [93, 94], human , turtle , monkey [97, 98], ram , guinea pig , and the rat . Autoradiography was also used to show estrogen binding throughout the male reproductive system [55, 102]. Schleicher and coworkers  found very strong labeling of the efferent ductules and initial segment epididymis, with lesser binding in the distal tract. However, binding assays do not differentiate between ERα and β. Therefore, other methods, such as immunocytochemistry (ICC), in situ hybridization and Northern blot analysis, have been used to separate the two ER subtypes. However, these techniques do not always provide identical results, and there are disagreements between laboratories and between species. Using ICC, ER has been localized primarily in the epithelium of efferent ductules [53, 55, 98, 103–108]. However, in the goat and monkey, only nonciliated cells of the efferent ductal epithelium stained ER positive [54, 98]. After the discovery of ER subtypes and the production of specific antibodies, ERα localization in the epididymis has also given confusing results [53, 59, 103–105, 109, 110]. In the mouse at 90 days of age, the efferent ductule epithelium was strongly positive for ERα immunostaining, using the H222 antibody . Other epithelia along the epididymis were only slightly positive. Using a different antibody, the mouse epididymis showed strong ERα staining in principal cells and other cell types, but in a region specific manner . This immunostaining is somewhat similar to the autoradiography data previously shown by Schleicher .
In the testis, ERβ is the more abundant receptor and is typically found in nearly every cell type of the interstitium and the seminiferous tubule, except for the elongated spermatids [108–121]. In contrast, ERα is found only in the interstitium of the testis in most species examined [51, 53, 109, 110, 122, 123]. In some species both Leydig and peritubular myoid cells are ERα positive but the testis of the goat, monkey and human are reportedly devoid of ERα [98, 104, 108]. The ERβ knockout mouse [124, 125] shows no testicular phenotype and the αERKO and double ERαβ knockout mice [56–58, 125, 126] show no testicular phenotype during early development, suggesting that these receptors are not essential for normal development of sperm in the testis.
Transplantation of germ cells from the αERKO mouse testis into normal testis (made devoid of sperm) results in normal spermatozoa capable of fertilization and the production of offspring , suggesting that testicular ERα has no influence on spermatogenesis. However, loss of estrogen synthesis in the aromatase knockout mouse [127, 128] results in decreased fertility with aging. Another study in the mouse also suggests that estrogen may have a testicular function, acting through the Leydig cells. It has been suggested that testosterone concentrations are elevated in the αERKO male , but it was generally concluded that this increase was due to the disruption in feedback regulation at the hypothalamus. However, a more recent study found that Leydig cells isolated from the αERKO testis had increased production of testosterone and that normal Leydig cells when treated with the pure ER inhibitor ICI 182,780 also showed increased steroidogenesis . Therefore, ER in the testis, although not necessarily essential for spermatogenesis, does appear to have a subtle function in the Leydig cells.
In the rat, ERα localization has been more controversial. In one study, using a mouse monoclonal antibody (6F11) against the A/B region of the human ERα, positive staining was found only in epithelial cells of the efferent ductules . The epididymal tissues were negative. Our laboratory repeated this study using the 6F11 antibody (Novocastra, UK) and the data are in complete agreement with the Fisher study, showing staining only in epithelia of the efferent ductules . In another study using frozen sections and the ER21 antibody, which is made against a peptide containing the first 21 amino acids of the rat and human ERα (does not cross-react with ERβ), we also found predominant staining in efferent ductules , as shown for all species examined to date. However, the initial segment epididymis was also strongly positive and the remaining regions of the epididymis were moderately positive. This study was repeated, but using antigen retrieval methods instead of frozen sections, and the results differed only slightly . The major difference was in staining that was observed in the epithelium of the vas deferens, which was negative using frozen sections. This difference in staining in the rat between the two antibodies, 6F11 and ER21, raises serious questions regarding the literature's description of ER localization in the male reproductive tract using ICC alone. Autoradiography and estradiol binding assays indicate that ER is present in the rat epididymis. RT-PCR data also show that ERα is present in epididymal tissues [59, 108]. Therefore, future studies should focus on in situ hybridization methods for localizing the mRNA in specific regions and cell types of the epididymis.
The discovery of a second form of ER (ERβ) further complicates the interpretation of earlier data from estrogen binding studies. ERβ has now been found in testis, efferent ductules, epididymis and prostate [55, 101, 108, 119, 124, 134–137]. However, a function for ERβ in the male reproductive tract awaits further investigation, as the ERβ knockout mouse has been shown to be fertile and appears to have a normal testis and epididymis . ERβ is more widely distributed in the male tract than ERα . ERβ has strong reactivity in efferent ductules, similar to ERα. In the remainder of the tract, ERβ appears to be weaker in initial segment epididymis but stronger in the corpus, cauda and vas deferens. The stromal tissue cells also stain strongly positive for ERβ throughout the male reproductive tract. Thus, there is a large potential for estrogen binding in the epididymis and vas deferens through ERβ.
Estrogen function in testis
There is limited direct evidence that estrogen has a major role in adult testicular function [see review by ], other than the recent paper by Hardy and colleagues , in which the antiestrogen ICI 182,780 inhibited in vitro Leydig cell production of testosterone. Estradiol alone was unable to stimulate Leydig cell steroidogenesis. In the developing testis, estrogen has significant activity in establishing Sertoli cell function  and potentially even in establishing Sertoli-germ cell adhesion [138, 139]. However, in the total absence of estrogen synthesis, the ArKO male shows normal spermatogenesis at the beginning of puberty and only with aging does the testis begin to develop lesions associated with the round spermatids [127, 140]. This is not entirely surprising in light of the fact that ERα is not present within the seminiferous epithelium [109, 110] and although ERβ is found in Sertoli cells and nearly all germ cells [108–110, 141, 142], the ERβ knockout (β ERKO) male testis appears normal and the males are fertile [58, 124, 125].
Indirect evidence of estrogen's influence on spermatogenesis comes from animal models such as the hpg mouse, which is deficient in gonadotropin releasing hormone (GnRH). Ebling and colleagues  found that estradiol implants in the hpg mouse stimulated a 4-5-fold increase in seminiferous tubular volume, in the absence of measurable levels of androgens. Although it is possible that this effect was due to the slightly elevated levels of FSH, an alternative hypothesis put forward was direct effects of estrogen on cells of the testis. This hypothesis appears plausible when the ArKO mouse data are taken into consideration. The ArKO testis is normal at first, but with aging shows decreases in testis weight, seminiferous epithelium, and germ cell numbers . When the ArKO male is maintained on a soy-free diet, these effects are accelerated and enhanced [127, 140]. Thus, soy based phytoestrogens likely protected the testis somewhat in the ArKO mouse, suggesting that small amounts of estrogen do have testicular effects independent of effects due to FSH or LH. This role of estrogen in the testis will most likely be found in the germ cells, as they express ERβ abundantly [108–110, 142] and genistein has a higher affinity for ERβ than for ERα . Finally, although the Sertoli cell does not express ERα, it is interesting that in the αERKO testis there is significantly less seminiferous tubular secretion than in the wild-type testis . The same effect was suggested for the ArKO testis, as seminiferous tubule luminal volume and tubular length was decreased . Thus overall, estrogen does appear to have subtle functions in the testis, not only at the Leydig cell but also possibly targeting the seminiferous epithelium, too.
Estrogen function in efferent ductules
Much of what we know about estrogen's function in efferent ductules has been derived from the study of the αERKO mouse and the use of antiestrogen treatment models. The male αERKO mouse was found to be infertile , raising the possibility that ERα is required for normal function of the male reproductive system. Although the αERKO testis appeared normal before puberty, after the onset of spermatogenesis, the testis began to degenerate and eventually became atrophic . By 150 days, cauda sperm from the αERKO male were abnormal and sperm concentrations were significantly reduced , suggesting that the reproductive tract was also abnormal. A later study by Eddy's lab showed that αERKO germ cells transplanted into a normal testis (treated with busulphan to remove native germ cells) were capable of fertilization . That study clearly pointed to extra-testicular regions, such as the efferent ductules and epididymis, being the major source of pathological alterations in αERKO males [57, 59].
The αERKO mouse provided the first strong evidence that estrogen, or more specifically, a functional ERα, is involved in the regulation of fluid transport in the male reproductive tract, and responsible for increasing the concentration of sperm as they enter the epididymis. Subsequent studies have shown that the major Na+ transporter in the efferent ductule epithelium (NHE3) is down regulated in the αERKO male reproductive tract. Both the mRNA and NHE3 protein were decreased substantially in αERKO tissue, and Na+ uptake by the epithelial cell in vitro was negligible . However, the αERKO mouse lacks a functional ERα throughout development. Therefore, the morphological and physiological abnormalities observed could represent developmental defects, rather than adult dysfunction. To test this hypothesis, adult mice were treated with a pure antiestrogen, ICI 182,780 (AstraZeneca, Macclesfield, Cheshire, UK). This collaborative study with David Bunick and Janice Bahr showed conclusively that ERα is important for adult function of the efferent ductules, as ICI induced pathological changes that were nearly identical to those seen in the αERKO mouse . A second species, the adult male rat, also responds in a similar manner to ICI treatment over a 125-day period [65, 66]. The two major response variables, dilation of efferent ductule lumen and decreased expression of NHE3, show identical responses in rats and mice [63, 65]. Although the rats became infertile, they did show greater variation in response overall than was seen in the ICI-treated mice. Long-term treatment in the rat resulted in a transient increase in testicular weight, eventual testicular atrophy at the time of infertility, whereas in the ICI-treated mouse there was no change in testicular weight. After ICI treatment, the rat efferent ductule epithelium also showed a transient increase and redistribution of PAS-positive lysosomal granules in the nonciliated cells [65, 66]. However, with continued treatment the rat epithelium showed a decrease in the number of lysosomes to nearly undetectable levels , similar to αERKO and mice treated with ICI. Lysosomes are more numerous in the rat than in the mouse efferent ductules ; therefore, this intriguing interspecies difference in response to the antiestrogen must be examined in future studies involving other species. Overall, it was shown that ICI promotes adult dysfunctional changes in rat efferent ductules similar to those of αERKO and ICI treated mice, with luminal dilation, decreases in epithelial height, loss of cytoplasmic organelles and decreases in the expression of NHE3 protein and mRNA [65, 66].
Summary and Conclusions
I would like to acknowledge recent students of my laboratory whose work has helped to shape our understanding of estrogen function in the male: Masaaki Nakai, Rong Nie, Qing Zhou and Cleida Oliveira. The excellent technical support of Kay Carnes is always appreciated. Supported by grants from NIH # HD35126 and CONRAD.
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