Disruption of estrogen receptor signaling and similar pathways in the efferent ductules and initial segment of the epididymis

Abstract

Seminiferous tubular atrophy may involve indirectly the disruption of estrogen receptor-a (ESR1) function in efferent ductules of the testis. ESR1 helps to maintain fluid resorption by the ductal epithelium and the inhibition or stimulation of this activity in rodent species will lead to fluid accumulation in the lumen. If not resolved, the abnormal buildup of fluid in the head of the epididymis and efferent ductules becomes a serious problem for the testis, as it leads to an increase in testis weight, tubular dilation and seminiferous epithelial degeneration, as well as testicular atrophy. The same sequence of pathogenesis occurs if the efferent ductule lumen becomes occluded. This review provides an introduction to the role of estrogen in the male reproductive tract but focuses on the various overlapping mechanisms that could induce efferent ductule dysfunction and fluid backpressure histopathology. Although efferent ductules are difficult to find, their inclusion in routine histological evaluations is recommended, as morphological images of these delicate tubules may be essential for understanding the mechanism of testicular injury, especially if dilations are observed in the rete testis and/or seminiferous tubules.Signature Lesion:The rete testis and efferent ductules can appear dilated, as if the lumens were greatly expanded with excess fluid or the accumulation of sperm. Because the efferent ductules resorb most of the fluid arriving from the rete testis lumen, one of two mechanisms is likely to be involved: a) reduced fluid uptake, which has been caused by the disruption in estrogen receptor signaling or associated pathways; or b) an increased rate of fluid resorption, which results in luminal occlusion. Both mechanisms can lead to a temporary increase in testicular weight, tubular dilation and atrophy of the seminiferous tubules.

Ascorbic acid supplementation ameliorates testicular hormonal signaling, sperm production and oxidative stress in male rats exposed to rosuvastatin during pre‐puberty

“…Scale bar = 50 μm. AA, ascorbic acid isoprenylation in theca-interstitial cell culture (Ortega et al, 2012;2014). Contrary to this, AA is able to increase androgen production by augmenting luteinizing hormone receptors expression in Leydig cells and stimulating steroidogenic enzymes 3β-hydroxysteroid dehydrogenase, 17β-hydroxysteroid dehydrogenase and StAR protein in the testis (Harikrishnan et al, 2013;Radhakrishnakartha, Appu, & Indira, 2014).…”

“…Estrogens mainly play their role through binding to their cytoplasmic receptors (ERS1 or ERS2) forming hormone-receptor complexes that are translocated to the nucleus, where they modulate gene expression (Carreau et al, 2011). Previous studies have demonstrated that ERS1 knockout mice show infertility at adulthood (Shibayama et al, 2001) and fluid accumulation in the testis, an abnormal concentration of sperm and compromised sperm maturation in the caput of epididymis (Hess, 2014). Furthermore, a decreased ERS1 expression is also related to increased sperm abnormalities, decreased sperm motility (Couse & Korach, 1999;Guerra et al, 2016) and reduced sperm counts (Couse & Korach, 1999).…”

E2f4 and E2f5 are essential for the development of the male reproductive system

“…It is also possible that the stirring or mixing function of efferent ductule cilia is essential for homogenous reabsorption of fluid by the nonciliated cells, as previously predicted. [45][46][47] Additionally we speculate that the near absence of sperm from the epididymis could be caused by impaired fluid flow, an occlusion or a defect in smooth muscle contraction, which may rely upon signaling from the efferent ducts. Irrespective of the contribution of the multiciliogenesis defect, we believe that the primary problem is an accumulation of luminal fluid that reflects both impaired absorption and excess secretion.…”

Segment-specific regulation of epididymal gene expression

“…The main source of estrogen in males is the testis; however, the additional presence of P450 aromatase in spermatozoa provides a local source of estrogen in the epididymis (Reviewed in Hess 2014). As the estrogen action in the epididymis was recently reviewed (Hess et al 2011, Hess 2014, this review will focus on androgen regulation. Of note, however, is the notion that the correct balance between androgen and estrogen levels might be of importance for maintaining epididymal functions.…”

“…Inside the epididymal epithelial cells, testosterone is reduced to more potent dihydrotestosterone (DHT) by 5α-reductases (Robaire & Hamzeh 2011). The main source of estrogen in males is the testis; however, the additional presence of P450 aromatase in spermatozoa provides a local source of estrogen in the epididymis (Reviewed in Hess 2014). As the estrogen action in the epididymis was recently reviewed (Hess et al 2011, Hess 2014, this review will focus on androgen regulation.…”