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Review
. 2011 Feb;84(2):207-17.
doi: 10.1095/biolreprod.110.087353. Epub 2010 Oct 6.

Estrogen, efferent ductules, and the epididymis

Affiliations
Review

Estrogen, efferent ductules, and the epididymis

Avenel Joseph et al. Biol Reprod. 2011 Feb.

Abstract

Estrogen's presence in the male reproductive system has been known for over 60 years, but its potential function in the epididymis remains an important area of investigation. Estrogen is synthesized by germ cells, producing a relatively high concentration in rete testis fluid. There are two estrogen receptors (ESR), the presence of which in the head of the epididymis is well documented and consistent between species; however, in other regions of the epididymis, their expression appears to be isotype, species, and cell specific. ESR1 is expressed constitutively in the epididymis; however, its presence is downregulated by high doses of estrogen, making the design of experiments complicated, as the phenotype of the Cyp19a1(-/-) mouse does not resemble that of the Esr1(-/-) mouse. Ligand-independent and DNA-binding Esr1 mutant models further demonstrate the complexity and importance of both signaling pathways in maintenance of efferent ductules and epididymis. Data now reveal the presence of not only classical nuclear receptors, but also cytoplasmic ESR and rapid responding membrane receptors; however, their importance in the epididymis remains undetermined. ESR1 regulates ion transport and water reabsorption in the efferent ducts and epididymis, and its regulation of other associated genes is continually being uncovered. In the male, some genes, such as Aqp9 and Slc9a3, contain both androgen and estrogen response elements and are dually regulated by these hormones. While estrogen pathways are a necessity for fertility in the male, future studies are needed to understand the interplay between androgens and estrogens in epididymal tissues, particularly in cell types that contain both receptors and their cofactors.

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Figures

FIG. 1.
FIG. 1.
Schematic and histological representation of the male reproductive tract and excurrent ducts. Schematic (left) showing relative orientation of the efferent ducts and the proximal (IS and caput) and distal segments (corpus and cauda) of the epididymis. The cauda connects to the ejaculatory duct or vas deferens. Sagittal section (right) of the efferent ducts and epididymis depicting the convoluted nature of the duct as well as its complex and changing epithelium. eff duct, efferent ductules; IS and init segment, initial segment. Bar = 1.5 mm.
FIG. 2.
FIG. 2.
Schematic representation of epididymal cell types. Principal cells make up the majority of the epithelial layer throughout the epididymis. Clear cells are large endocytic cells present in the distal caput, corpus and cauda regions. Narrow and apical cells of the initial segment and intermediate zone have a unique morphology and function that overlaps somewhat with clear cells. Basal cells are located against the basement membrane and communicate to the luminal side of the epithelium via narrow body projections and interdigitations with the principal cells.
FIG. 3.
FIG. 3.
CYP19A1 (P450Aromatase) in mouse spermatozoa. Luminal sperm in the intermediate zone of the caput epididymis show positive immunostaining for CYP19A1 [51] in the cytoplasmic droplet (cd). It is noteworthy that cytoplasm of the apical cell (Ap) shows low intensity for the protein and the interstitial connective tissue area (In) shows intense staining. Bar = 25 μm.
FIG. 4.
FIG. 4.
ESR1 immunostaining [89, 95] in monkey, hamster, and mouse efferent ductules and epididymis. A–D) Marmoset monkey. Intense nuclear staining is found in proximal and distal efferent ductal nonciliated epithelial cells. Ciliated cells are negative to slightly positive. Caput epididymidis is negative, but cauda epithelium shows low-intensity staining in the cytoplasm of all cells. E–H) Golden hamster. Intense nuclear staining is found in proximal and distal efferent ductal nonciliated and ciliated epithelial cells. The cytoplasm also appears to be slightly positive. Intraepithelial lymphocytes are negative. Caput epididymis is negative except for the nuclei of occasional basal cells. Cauda epithelium is negative. I–M) Mouse. Intense nuclear staining is found in proximal and distal efferent ductal nonciliated and ciliated epithelial cells. The cytoplasm also appears to be slightly positive. In the initial segment epididymis, apical, and narrow cells are strongly positive, while principal and basal cells are slight positive to negative. All cells of the caput epididymal epithelium are positive, but the apical cell nuclei are more intensely stained. Some nuclei of the peritubular smooth muscle are also positive. In cauda epithelium, clear cells are strongly positive, while principal cells are slightly positive, as well as the cytoplasm. Nuclei of connective tissue and smooth muscle cells are also positive. A, apical cell nuclei; B, basal cells; C, ciliated epithelial cells; Cl, clear cells; L, lymphocytes; N (A–H), nonciliated epithelial cells; N (I–M), narrow cells; P, principal cells. Bar = 25 μm.
FIG. 5.
FIG. 5.
Summary diagram of potential estrogen action in epithelia of efferent ductules and the epididymis. At least 4 potential pathways are considered. 1) testosterone (T) can enter the cell or be converted to E2 by aromatase (Arom) found in luminal sperm [54]. Testosterone binds AR and translocates into the nucleus, where it binds to AREs, on the promoter regions of genes with or without EREs. 2) E2 will either enter the cell, as did testosterone or bind the membrane ESR (mESR1). It remains controversial whether E2 binds GPR30 in the membrane [144] or collaborates with mESR1 to mediate epidermal growth factor receptor (EGFR) activation (nonclassical) of kinases and phosphorylation [180]. It is well known that E2 binds ESR1 and translocates into the nucleus for classical mediation of transcription through EREs and recruitment of numerous cofactor proteins (C1–3). It is unknown how AR and ESR1 compete for these cofactors, or what happens when the steroid balance is altered in a cell expressing both receptors. 3) The ESR1 can also be activated through phosphorylation and mediate transcription through the ERE. 4) It is well documented in other tissues that mESR1 binds E2, resulting in very rapid cell signaling [84, 175, 178]. This rapid steroid activity through the membrane receptor involves caveolin-1, G proteins, and the phosphorylation/dephosphorylation cascades, which mediate transcription either through the ESR1/ERE or other transcription factors (TF).
FIG. 6.
FIG. 6.
Epididymal epithelium from the Esr1 knockout mouse. A) Nuclei of narrow cells (N) are protruding abnormally into the lumen of the initial segment epididymis. B) An apical cell contains multiple nuclei (1, 2) and vacuoles (v) in its apical cytoplasm. C) An apical cell in the intermediate zone of the caput epididymis contains large, periodic acid-Schiff+ (PAS+) granules or lysosomes (L). n, nucleus. D) The apical cell contains PAS+ lysosomal granules in the basal cytoplasm, and the apical cytoplasm with large vacuoles (v) protrudes into the lumen. Bar = 20 μm.

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