Expression of functional aromatase in the epididymis: Role of androgens and LH in modulation of expression and activity

doi:10.1016/j.mce.2006.01.016

Molecular and Cellular Endocrinology

Volume 249, Issues 1–2, 25 April 2006, Pages 40-50

https://doi.org/10.1016/j.mce.2006.01.016 Get rights and content

Abstract

The primary source of 17beta-estradiol (E2) in the male is the testis, which expresses the enzyme complex aromatase that is involved in E2 biosynthesis. However, recent evidences suggest that the epididymis is also capable of E2 biosynthesis. Our results demonstrate the presence of cytochrome P450 aromatase (P450_AROM) and 17beta-hydroxysteroid dehydrogenase I messenger ribonucleic acid (mRNA) in the caput and cauda regions of rat epididymis. The androgenic substrates testosterone and androstenedione could be utilized by the rat epididymal aromatase for E2 biosynthesis as assessed by radioimmunoassay. P450_AROM expression is transcriptionally regulated in a tissue-specific manner by various factors including androgens and luteinizing hormone (LH). Androgens could positively modulate epididymal P450_AROM mRNA levels as assessed by castration studies, treatment with flutamide or in vitro incubation of tissue minces with 5alpha-dihydrotestosterone (DHT). Several extra-gonadal tissues including the epididymis are known to express LH receptors (LHR). Our study revealed a higher level of LHR mRNA expression in the cauda region compared to the caput. Caudal membrane extracts could bind human chorionic gonadotropin (hCG), which resulted in the production of cAMP. Interestingly, hCG could also regulate P450_AROM mRNA expression in vitro and enhance E2 biosynthesis. Together our results highlight the presence of a functional aromatase in the epididymis that is subject to regulation by LH and androgens.

Introduction

Epididymal development and function is governed by a complex interplay of hormones and testicular growth factors, among which testosterone is crucial for epididymal functioning (Ezer and Robaire, 2002). However, recent studies unfold compelling evidence regarding the role of the ‘female hormone’ estrogen, in modulating functions of the efferent ductules and the epididymis (Hess, 2003, Shayu et al., 2005). The epididymis and the efferent ductules express moderate to abundant amount of estrogen receptors (Hess et al., 1997, Mowa and Iwanaga, 2001) and E2 is one of the key hormones that regulates the functioning of these tissues (Hess et al., 2001, Lee et al., 2001). The source of E2 for the excurrent ducts, is mainly the testis which has three cell types capable of E2 biosynthesis. In the immature rat, the Sertoli cells are the main sites of E2 production, subsequent to which, in the adult, the Leydig cells take over the function of E2 biosynthesis (Carreau et al., 1999). Besides these two cell types, the germ cells are a unique source of E2 in the testis and synthesize E2 in measurable quantities (Janulis et al., 1998).

E2 biosynthesis is catalyzed by a microsomal enzyme complex, called aromatase that is responsible for the irreversible transformation of androgens into estrogens. The aromatase enzyme complex is comprised of two proteins, the ubiquitous NADPH cytochrome P450 reductase and cytochrome P450 aromatase (P450_AROM). The P450_AROM component contains the heme and the steroid binding pocket. Aromatase can utilize either androstenedione or testosterone as androgenic substrates, which are aromatized to estrone (E1) and E2, respectively. The further conversion of E1 to the highly potent E2 is catalyzed by the enzyme 17β-hydroxysteroid dehydrogenase (17β-HSD)-I. The 17β-HSD family consists of multiple isoforms, of which type III catalyzes the interconversion of androstenedione to testosterone, and type I catalyzes the interconversion of E1 to E2 (Luu-The et al., 1995, Mindnich et al., 2004).

The expression of P450_AROM is principally regulated at the level of transcription (Simpson et al., 1994). P450_AROM is transcribed from a single gene CYP19, which contains multiple promoters that are utilized in a tissue-specific manner. Thus, while P450_AROM expression in human adipose tissue is driven by promoter I.4 that is subject to regulation by glucocorticoids and cytokines (Mahendroo et al., 1993, Zhao et al., 1996), in the ovary and testis, a proximal promoter PII governs P450_AROM expression under the influence of the gonadotropins LH and FSH (Donadeu and Ascoli, 2005, Jenkins et al., 1993, Lanzino et al., 2001). LH mediates its functions in the target tissues by binding to LHR, resulting in increased intracellular cAMP concentration. The cAMP generated phosphorylates target proteins and activates gene transcription by binding to cAMP responsive elements present on the promoters of several genes, including aromatase (Bulun et al., 1993, Simpson, 2000). Interestingly, besides LH, androgens are also strong modulators of P450_AROM expression and influence P450_AROM expression in ovarian granulosa cells, testicular germ cells and Leydig cells (Bourguiba et al., 2003, Genissel and Carreau, 2001, Hamel et al., 2005).

Intriguingly, despite the proximity of the testicular E2 sources, the efferent ductules and the epididymis also express P450_AROM mRNA and protein (Carpino et al., 2004, Pereyra-Martinez et al., 2001, Wiszniewska, 2002). A recent report described E2 biosynthesis from epididymal cells cultured in vitro (Wiszniewska, 2002), and since cell isolations excluded the presence of sperm, which possess aromatase (Janulis et al., 1998), it was evident that the epididymal cells themselves were capable of E2 synthesis. In light of these recent reports, the study of P450_AROM expression and regulation in the epididymis gains significance. In the present investigation, the functional and regulatory aspects of epididymal P450_AROM were studied. As mentioned earlier, LH and androgens are strong modulators of P450_AROM expression (Bourguiba et al., 2003, Genissel and Carreau, 2001). Considering that androgens are crucial for the expression of several epididymal genes, the role of androgens in regulation of P450_AROM expression was examined.

Until recently, it was believed that LHR expression was confined to the gonads; however, interestingly several extra-gonadal tissues, including the epididymis have been identified to possess LHR (Lei et al., 2003). Although the epididymis expresses LHR, the segmental distribution of LHR in the epididymis or their precise biological role in the epididymis remains elusive. Hence, the expression of LHR in the caput and cauda regions of the epididymis was studied, and the ability of epididymal LHR to bind the ligand hCG and transduce downstream signaling was also assessed. Finally, the modulation of epididymal P450_AROM expression and activity by LH was examined.

Section snippets

Animals and Leydig cell isolation

Adult male rats unless indicated, were of age 40 days. Animals were obtained from the Central Animal Facility of the Institute and all the procedures carried out on the animals were approved by the Ethics Committee of Indian Institute of Science (Protocol Number 21). The anterior and posterior poles of the epididymis, namely caput and cauda regions were dissected free from fat. The caput and cauda regions were excised carefully to exclude the efferent ductules and vas deferens, respectively.

P450_AROM and 17β-HSDI mRNA are expressed in the caput and cauda regions of the epididymis

P450_AROM mRNA was expressed in both the caput and cauda regions of the epididymis. A single band of 290 base pair was obtained by RT-PCR analysis as shown in Fig. 1A. Interestingly, the level of P450_AROM expression did not differ between the two regions. The enzyme aromatase can utilize either testosterone or androstenedione as substrates. In addition to P450_AROM, the mRNA for 17β-HSDI could also be detected in the caput and cauda (Fig. 1B). Ontological analysis of P450_AROM expression revealed

Discussion

Recent literature on the diverse roles of E2 in the male reproductive tract has resulted in a renewed interest in studying the E2 source(s) for these tissues. The present study elucidates the presence of P450_AROM mRNA in both the caput and cauda regions of the epididymis and in accordance with aromatase expression, both regions were capable of E2 biosynthesis. Among the few methods available to study aromatase activity, RIA and the tritiated water based assay are perhaps the most prevalent. The

Acknowledgements

The authors would like to gratefully acknowledge DBT (Indo-U.S. Program), Mellon Foundation, CONRAD U.S.A., ICMR, ICMR Advanced Centre, CSIR, DST, Government of India and Indian Institute of Science, Bangalore for providing financial assistance. The authors thank Mr. Vijay, Ms. Deepika and Mrs. Hemalatha for technical assistance. Author AJR is thankful to CSIR for award of Emeritus Scientistship and SD is grateful for the award of CSIR-SRF fellowship.

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While the adult rat testis contributes about 21% of the blood E2 (de Jong et al., 1973), it contributes 100% to the rete testis fluid, where concentrations of E2 are reported to reach 510 pg/ml and average 249 pg/ml (Free and Jaffe, 1979). Although most of the E2 synthesis in the male reproductive system comes from the testis, the presence of aromatase has also been reported in the epithelium of efferent ductules and the epididymis (Carpino et al., 2004; Kim et al., 2008; Pereyra-Martinez et al., 2001; Rosati et al., 2020; Shayu and Rao, 2006; Swider-Al-Amawi et al., 2007). In addition, the external genitalia express aromatase (Jesmin et al., 2002).
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Both androgens and estrogens play key, albeit incompletely described, roles in the functioning of the epididymis. Because this tightly-coiled tubular structure is compartmented, precise mapping of the distribution of sex steroid’s receptors is important. Such receptors have been located in the first segments (caput, corpus), but the last part (cauda) remains poorly explored. We used immunochemistry to localize androgen (AR) and estrogen (ESR1 and ESR2) receptors in the cauda in the fat sand rat (Psammomys obesus). We compared results obtained during the breeding versus resting seasons. We also used individuals castrated, or castrated then treated with testosterone, or subjected to the ligation of their efferent ducts. During the breeding season, in principal cells, we found strong staining both for AR and ESR1 in the apical cytoplasm, and strong staining for ESR2 in the nucleus. During the resting season, principal cells were positive for AR and ESR1, but negative for ESR2. In castrated animals, staining was null for ESR2 and AR, and weak for ESR1. In castrated then treated animals, immuno-expression was restored but only for AR and ESR1. Following efferent duct ligation, AR reactivity decreased while ESR1 and ESR2 provided strong staining. Broadly similar, but not fully identical patterns were observed in basal cells. They were positive for ESR2 and AR during the breeding season, but not for ESR1. During the resting season, staining was modest for ESR1 and AR and negative for ESR2. In all experimentally treated animals, we observed weak staining for AR and ESR1, and a lack of signal for ESR2. Overall, this study provides strong evidence that androgens and estrogens are involved in the seasonal regulation of the whole epididymis in the fat sand rat, with marked differences between caput and cauda (the corpus is highly reduced in rodent).
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Sperm granuloma may develop in the epididymis following vasectomy or chemical insults. Inflammation due to sperm granuloma causes abdominal and scrotal pain. Prolonged and persistent inflammation in the epididymis due to sperm granuloma may lead to infertility. Extravasation of germ cells into the interstitium of epididymis following damage of the epididymal epithelium is one of the primary reasons for sperm granuloma-associated pathology. Since testosterone is vital for the maintenance of epididymal epithelium, we investigated the pathology of sperm granuloma and its relationship with testosterone. Adult rats were treated with a Leydig cell-specific toxicant ethylene dimethane sulfonate (EDS) to eliminate testosterone. At 7 days post-EDS, disrupted epididymal epithelium and sperm granuloma were observed in the caput epididymis. Sperm granuloma and caput were collagen-filled indicating fibrosis. Numerous round apoptotic cells were localized inside the caput lumen and dispersed through the sperm granuloma. Tnp1 (round spermatid marker) was significantly higher in the epididymis of the EDS-treated group compared to controls suggesting the apoptotic cells were round spermatids. Increases in CD68⁺ macrophages and T cells (CD4 and CD8) support an inflammatory immune infiltration in post-EDS epididymis. However, testosterone replacement following EDS prevented the sperm granuloma-associated pathology. We suggest that the immune response in the sperm granuloma may be due to the increased numbers of apoptotic round spermatids or other testicular tissue components that may be released, in addition to the regression of epididymal epithelium due to testosterone loss. Thus, testosterone replacement prevents EDS-induced sperm granuloma and ameliorates sperm granuloma-associated pathology.
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The testicular Leydig cells were major source for estrogen biosynthesis in males by locally expressed steroidogenic P450arom (Nagata et al., 1998; Banerjee et al., 2012). However, more and more collected data demonstrated that epididymis had the capacity to synthesize estrogen as well (Shayu and Rao, 2006; Wiszniewska, 2002). The cultured epididymal epithelial cells of rat displayed features of steroidogenesis by expressing P450arom to aromatise androgen to 17β-estradiol (Wiszniewska, 2002).
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Expression of functional aromatase in the epididymis: Role of androgens and LH in modulation of expression and activity

Abstract

Introduction

Section snippets

Animals and Leydig cell isolation

P450AROM and 17β-HSDI mRNA are expressed in the caput and cauda regions of the epididymis

Discussion

Acknowledgements

J. Steroid Biochem. Mol. Biol.

Mol. Cell. Endocrinol.

Mol. Cell. Endocrinol.

Meth. Enzymol.

J. Biol. Chem.

J. Steroid Biochem. Mol. Biol.

J. Biol. Chem.

Mol. Cell. Endocrinol.

J. Biol. Chem.

J. Steroid Biochem. Mol. Biol.

Mol. Cell. Endocrinol.

Lutropins appear to contact two independent sites in the extracellular domain of their receptors

Biochem. J.

Steroids control the aromatase gene expression in purified germ cells from the adult male rat

J. Mol. Endocrinol.

Use of tissue-specific promoters in the regulation of aromatase cytochrome P450 gene expression in human testicular and ovarian sex cord tumors, as well as in normal fetal and adult gonads

J. Clin. Endocrinol. Metab.

Aromatase immunolocalization in human ductuli efferentes and proximal ductus epididymis

J. Anat.

Sources of oestrogen in the testis and reproductive tract of the male

Int. J. Androl.

The promoter(s) of the aromatase gene in male testicular cells

Reprod. Biol.

Androgen ablation results in differential regulation of transforming growth factor-beta isoforms in rat male accessory sex organs and epididymis

J. Mol. Endocrinol.

The differential effects of the gonadotropin receptors on aromatase expression in primary cultures of immature rat granulosa cells are highly dependent on the density of receptors expressed and the activation of the inositol phosphate cascade

Endocrinology

Androgenic regulation of the structure and functions of the epididymis

Androstenedione increases cytochrome P450 aromatase messenger ribonucleic acid transcripts in nonluteinizing bovine granulosa cells

Mol. Reprod. Dev.

Estrogen receptor (alpha and beta) expression in the excurrent ducts of the adult male rat reproductive tract

J. Androl.

Estrogens and epididymal function

Reprod. Fertil. Dev.

Estrogen in the adult male reproductive tract: a review

Reprod. Biol. Endocrinol.

P450_AROM and 17β-HSDI mRNA are expressed in the caput and cauda regions of the epididymis