Central and Direct Regulation of Testicular Activity by Gonadotropin-Inhibitory Hormone and Its Receptor

Abstract

Gonadotropin-inhibitory hormone (GnIH) was first identified in Japanese quail to be an inhibitor of gonadotropin synthesis and release. GnIH peptides have since been identified in all vertebrates, and all share an LPXRFamide (X = L or Q) motif at their C-termini. The receptor for GnIH is the G protein-coupled receptor 147 (GPR147), which inhibits cAMP signaling. Cell bodies of GnIH neurons are located in the paraventricular nucleus (PVN) in birds and the dorsomedial hypothalamic area (DMH) in most mammals. GnIH neurons in the PVN or DMH project to the median eminence to control anterior pituitary function via GPR147 expressed in gonadotropes. Further, GnIH inhibits gonadotropin-releasing hormone (GnRH)-induced gonadotropin subunit gene transcription by inhibiting the adenylate cyclase/cAMP/PKA-dependent ERK pathway in an immortalized mouse gonadotrope cell line (LβT2 cells). GnIH neurons also project to GnRH neurons that express GPR147 in the preoptic area (POA) in birds and mammals. Accordingly, GnIH can inhibit gonadotropin synthesis and release by decreasing the activity of GnRH neurons as well as by directly inhibiting pituitary gonadotrope activity. GnIH and GPR147 can thus centrally suppress testosterone secretion and spermatogenesis by acting in the hypothalamic–pituitary–gonadal axis. GnIH and GPR147 are also expressed in the testis of birds and mammals, possibly acting in an autocrine/paracrine manner to suppress testosterone secretion and spermatogenesis. GnIH expression is also regulated by melatonin, stress, and social environment in birds and mammals. Accordingly, the GnIH–GPR147 system may play a role in transducing physical and social environmental information to regulate optimal testicular activity in birds and mammals. This review discusses central and direct inhibitory effects of GnIH and GPR147 on testosterone secretion and spermatogenesis in birds and mammals.

Inhibitory roles of the mammalian GnIH ortholog RFRP3 in testicular activities in adult mice

“…The inhibition of testicular activities induced by RFRP3 is not a result of generalized toxicity, as even a higher dose of RFRP3 caused no deleterious effects on the histology of liver and serum AST and ALT activity compared with control mice. The antigonadal function of GnIH/RFRP3 was demonstrated previously in male quail (Ubuka et al , 2014, Syrian Hamster (Zhao et al 2010), and female mice (Singh et al 2011b).…”

“…A hypothalamic dodecapeptide (12 amino acids) having LPXRFamide motif at its C-terminal end was isolated from quail brain in the year 2000, which inhibits gonadotropin release and thus was named as gonadotropin-inhibitory hormone (GnIH) (Tsutsui et al 2000). GnIH, acting via GPR147, can suppress the testosterone secretion and spermatogenesis by acting at all levels of the hypothalamic-pituitarygonadal axis of birds and mammals (for reviews, see Tsutsui (2009), Tsutsui et al (2010a,b), and Ubuka et al (2014)). GnIH orthologous peptides that possess LPXRFamide (XZL or Q) motif at their C-termini have been documented in mammals including primates and humans and other vertebrates (for reviews, see Tsutsui (2009) and Tsutsui et al (2010a,b)).…”

“…GnIHR can bind with a high affinity to GnIH (Yin et al 2005) and RFRPs (Hinuma et al 2000), which have LPXRFamide (XZL or Q) motif at their C-termini. Accordingly, GnIHR (GPR147) plays important roles in regulating reproductive activities in birds and mammals (for reviews, see Tsutsui (2009), Tsutsui et al (2010a,b), and Ubuka et al (2014)). …”

Behavioral and physiological traits of migrant and resident White-crowned Sparrows: a common garden approach

“…However, more recent observations pinpoint mid to late March (Krause et al, 2015b). Both gonadotropins and testosterone are required for spermatogenesis (Ubuka et al, 2014), and our results show that plasma testosterone increases in Z. l. nuttalli by week 8 and DHT increases 4 weeks later (Fig. 3B,C).…”

Effects of psychological stress on male fertility

“…89 Two forms of GnIH (RFRP-1 and RFRP-3) have been identified in the human hypothalamus and are able to regulate the HPG axis in men. 90 Hinuma et al 91 identified a specific receptor for mammalian GnIH that was identical to the previously-described receptor, GPR147. 92 The molecular details of GnIH are eloquently described elsewhere.…”