Effect of estrogen receptor-subtype-specific ligands on fertility in adult male rats

Abstract

Maintenance of normal male fertility relies on the process of spermatogenesis which is under complex endocrine control by mechanisms involving gonadotropin and steroid hormones. Although testosterone is the primary sex steroid in males, estrogen is locally produced in the testis and plays a very crucial role in male fertility. This is evident from presence of both the estrogen receptors alpha (ERa) and beta (ERb) in the testis and their absence, as in the case of knockout mice models, leads to sterility. The present study was undertaken to understand individual roles of the two ERs in spermatogenesis and their direct contribution towards the maintenance of male fertility using receptor-subtype-specific ligands. Administration of ERa and b agonists to adult male rats for 60 days results in a significant decrease in fertility, mainly due to an increase in pre-and post-implantation loss and a concomitant decrease in litter size and sperm counts. Our results indicate that ERa is mainly involved in negative feedback regulation of gonadotropin hormones, whereas both ERs are involved in regulation of prolactin and testosterone production. Histological examinations of the testis reveal that ERb could be involved in the process of spermiation since many failed spermatids were observed in stages IX-XI following ERb agonist treatment. Our results indicate that overactivation of estrogen signaling through either of its receptors can have detrimental effects on the fertility parameters and that the two ERs have both overlapping and distinct roles in maintenance of male fertility.

Revisiting the neural role of estrogen receptor beta in male sexual behavior by conditional mutagenesis

“…Whether or not these global ER knockout males exhibit altered regulation of the hypothalamus-pituitary-gonad axis, which may in turn interfere with reproductive behaviors, has not been reported. In males, ERβ is expressed in somatic and germ cells of the testis (van Pelt et al, 1999) and seems to be involved in testosterone production (Dumasia et al, 2015).…”

Of Oestrogens and Sperm: A Review of the Roles of Oestrogens and Oestrogen Receptors in Male Reproduction

“…Spermatogenesis was reported to be disrupted mainly at the spermatid stage, while there was no observed effect in Sertoli cells and early germ cells, which indicates that oestrogens are required in the later stages of spermatogenesis. This has been supported by the discovery of ERs playing an important role in spermatid differentiation and spermiation [130]. Furthermore, ArKO males are reported to have an impaired sexual behaviour, which contributes to decreased fertility in the ArKO male mice [131,132].…”

“…Artificially induced over-activation of ERα or ERβ in male rats led to a decreased litter size and sperm count, as well as to an increased pre- and post-implantation loss [130]. Moreover, both ERs played a distinct role during spermatogenesis [157].…”

“…Over-activation of ERα led to the arrest of differentiation of round to elongated spermatids as a result of decreased expression of protamine 1 ( Prm1 ), transition nucleoprotein 1 ( Tnp1 ) and 2 ( Tnp2 ), and this was accompanied with changes to the hormone level (follicle-stimulating hormone—FSH, luteinizing hormone—LH, and testosterone) [130,157]. On the other hand, over-activation of ERβ did not lead to changes in the gonadotropin level, but caused spermatocytes’ apoptosis (intrinsic pathway—via mitochondria) and spermiation failure as a result of the disruption of tubulobulbar complexes (TBCs) [130,157]. This observation is in agreement with previous studies where a high intratesticular level of oestrogens affected formation of TBCs [158] due to deregulation of actin-remodelling transcripts [102].…”

Interactions between oestrogen and 1α,25(OH)2-vitamin D3 signalling and their roles in spermatogenesis and spermatozoa functions

“…Knowing that effects of estradiol could implicate different oestrogen receptors subtypes, some studies were conducted with some oestrogen receptor subtype specific ligands [66, 67]. The over-activation of ERα or ERβ subtype had detrimental effects on the fertility parameters knowing that the two ERs had overlapping and distinct roles.…”