RFamide‐related peptide 3 and gonadotropin‐releasing hormone‐II are autocrine–paracrine regulators of testicular function in the boar

Abstract

Widespread use of artificial insemination in swine requires millions of doses of boar semen each year. Subfertility of boars remains a major constraint, which can impact the reproductive efficiency of thousands of sows, so a better understanding of testicular function is needed in order to develop methods to improve semen production. With this in mind, the effects of RFamide-related peptide 3 (RFRP3) and Gonadotropin-releasing hormone-II (GnRH-II) on gonadotropin secretion and testicular function of pigs are reviewed here. Receptors for RFRP3 are present in the pig hypothalamus, adenohypophysis, and testis. Evidence from in vitro studies indicates that RFRP3 could be a hypophysiotropic hormone in the pig by suppressing secretion of GnRH-I from the hypothalamus and luteinizing hormone (LH) from the pituitary gland; however, effects of RFRP3 on in vivo secretion of LH in pigs are minimal. Within the pig testis, RFRP3 suppresses testosterone secretion by inhibiting steroidogenic enzymes. GnRH-II and its receptor (GnRHR-II) are abundant in pig testes. Interstitial cells express GnRHR-II, and exogenous GnRH-II robustly stimulates secretion of testosterone in boars, despite minimal secretion of LH. Data illustrate that GnRH-II directly stimulates secretion of testosterone from the testes of mature boars. Thus, the primary function of RFRP3 and GnRH-II in the boar appears to be autocrine-paracrine inhibition and stimulation, respectively, of testosterone secretion within the testis. A better understanding of changes in the RFRP3 and GnRH-II systems within the testis during development will provide important clues about how to improve the testicular function of boars.

Expression and Role of Gonadotropin-Releasing Hormone 2 and Its Receptor in Mammals

“…We hypothesize that SB-75 reduced GnRH2-induced testosterone secretion by antagonizing GnRHR2 directly in the testis because the secretory pattern of LH was unaffected compared to trials where only GnRH2 treatments were administered ( 35 ). Finally, intratesticular injections of either GnRH1 or GnRH2 stimulated secretion of testosterone compared with saline-treated controls; however, GnRH2 did so without eliciting the release of LH, unlike GnRH1 ( 159 ). Together, these data support our hypothesis that GnRH2 is stimulating testosterone production directly at the testis in the absence of the classical androgen regulator, LH.…”

Functional genomics of reproduction in pigs: Are we there yet?

“…Nonneman et al, 2016) were interrogated for potential functional variants and tested for association in a validation population consisting of a portion of the original discovery composite population and animals from subsequent generations sired by commercial boars. Six nonsynonymous variants in the neuropeptide FF receptor 2 gene (NPFFR2), a putative receptor for RFamide-related peptides that negatively regulate secretion of reproductive hormones (Thorson et al, 2015;Lents et al, 2017),…”

“…Several candidate genes identified from a GWAS for age at puberty performed by our group (D. J. Nonneman et al, 2016) were interrogated for potential functional variants and tested for association in a validation population consisting of a portion of the original discovery composite population and animals from subsequent generations sired by commercial boars. Six nonsynonymous variants in the neuropeptide FF receptor 2 gene ( NPFFR2 ), a putative receptor for RFamide‐related peptides that negatively regulate secretion of reproductive hormones (Thorson et al, 2015; Lents et al, 2017), were evaluated for association with age at puberty (Thorson et al, 2017). Three of these SNP (V127M, S190R, and A429S) were found to associate.…”

Role of gonadotropin‐releasing hormone‐II and its receptor in swine reproduction

“…GnRH‐II infusion in vivo robustly elicited testosterone production similar to GnRH‐I treatment, except with minimal LH secretion compared to GnRH‐I treatment (Desaulniers et al, 2015a). Finally, intratesticular injections with either GnRH‐I or GnRH‐II enhanced testosterone production compared with saline‐treated controls; however, GnRH‐II promoted testosterone biosynthesis without increasing circulating LH levels, unlike GnRH‐I (Lents et al, 2017). Together, these data support our hypothesis that GnRH‐II and its receptor directly regulate testosterone production in the boar testis.…”

“…In contrast, GnRH‐II predominantly immunolocalized to the tubular compartment of swine testes (Desaulniers et al, 2015a). Markedly, expression of GNRHR2 increased 76‐fold following puberty, implying an important role in the adult boar (Lents et al, 2017; Voss, 2013). These results suggest autocrine/paracrine regulation of Leydig cell function by GnRHR‐II signaling in the boar.…”