Reproductive performance of male mice after hypothalamic ghrelin administration

Abstract

It has been demonstrated that food intake and reproductive physiology are both simultaneously modulated to optimize reproductive success under fluctuating metabolic conditions. Ghrelin (GHRL) is an orexigenic peptide identified as the endogenous ligand of the growth hormone secretagogue receptor that is being investigated for its potential role on reproduction. Considering that data available so far are still limited and characterization of GHRL action mechanism on the reproductive system has not been fully elucidated, we studied the participation of hypothalamus in GHRL effects on sperm functional activity, plasma levels of gonadotropins and histological morphology in mice testes after hypothalamic infusion of 0.3 or 3.0 nmol/day GHRL or artificial cerebrospinal fluid (ACSF) at different treatment periods. We found that GHRL 3.0 nmol/day administration for 42 days significantly reduced sperm concentration (GHRL 3.0 nmol/day = 14.05 ± 2.44 × 10/mL vs ACSF = 20.33 ± 1.35 × 10/mL, < 0.05) and motility (GHRL 3.0 nmol/day = 59.40 ± 4.20% vs ACSF = 75.80 ± 1.40%, < 0.05). In addition, histological studies showed a significant decrease percentage of spermatogonia (GHRL 3.0 nmol/day = 6.76 ± 0.68% vs ACSF = 9.56 ± 0.41%, < 0.05) and sperm (GHRL 3.0 nmol/day = 24.24 ± 1.92% vs ACSF = 31.20 ± 3.06%, < 0.05). These results were associated with a significant reduction in luteinizing hormone and testosterone plasma levels ( < 0.05). As GHRL is an orexigenic peptide, body weight and food intake were measured. Results showed that GHRL increases both parameters; however, the effect did not last beyond the first week of treatment. Results presented in this work confirm that central GHRL administration impairs spermatogenesis and suggest that this effect is mediated by inhibition of hypothalamic-pituitary-gonadal axis.

Physiological Effect of Ghrelin on Body Systems

“…On the other hand, the level of GHSR was found low in the endometrium of infertile women [261], which implies that a balanced level of ghrelin system is important for healthy reproduction. A recent study shows that ghrelin administration significantly decreases testosterone plasma levels and impairs spermatogenesis possibly by inhibition of the hypothalamic-pituitary-gonadal axis [262]. e majority of studies report that ghrelin inhibits testosterone production and spermatogenesis.…”

“…Another study on mice showed that genetic suppression of the GHSR1a in male mice attenuates the preference for female mice, sexual motivation, and interaction, by effects on DA neurotransmission [72]. After the hypothalamic ghrelin administration, the reproductive performance of male mice was found to decrease [262].…”

The Role of the Gastric Hormones Ghrelin and Nesfatin-1 in Reproduction

“…Indeed, 10-day long daily sc ghrelin injection decreased different cell types (except for spermatogonia), seminiferous tubules diameter and their germinal epithelium thickness [126]. Additionally, 42-day long treatment with ip injected ghrelin even led to reduced sperm concentration, motility, percentage of spermatogonia and sperm [118]. On the cellular level, sc injected ghrelin increased vacuolated mitochondria, reduced endoplasmic reticulum and intracellular organelles in the testis, and caused several detachment areas between cell membrane and its basement membrane [126].…”

“…In several other studies it was observed that circulating LH concentrations were reduced due to ghrelin administration in form of chronic sc injection of acyl or desacyl ghrelin in pubertal, adult [107] or food-restricted male rats [116], acute sc injection of acyl or desacyl ghrelin [107], bolus injection into the third cerebral ventricle of female sheep [117], 42 day long hypothalamic infusion in male mice [118], acute icv injection in female mice [103], as well as acyl ghrelin infusion in healthy men [104].…”

Hypothalamic neuroendocrine integration of reproduction and metabolism in mammals

“…Unlike leptin and insulin, ghrelin exhibits inhibition of GnRH/LH release and reproductive function (Furuta et al 2001a, Kluge et al 2013. Hypothalamic ghrelin administration impairs spermatogenesis in mice by inhibiting the HPG axis, thereby inhibiting reproductive function (Poretti et al 2018). Preclinical studies reported a delayed effect of ghrelin on puberty initiation and noted the inhibition of LH secretion in vivo by ghrelin (Martini et al 2006).…”