Melatonin promotes male reproductive performance and increases testosterone synthesis in mammalian Leydig cells

Abstract

Leydig cells play a critical role in male reproductive physiology, and their dysfunction is usually associated with male infertility. Melatonin has an important protective and regulatory role in these cells. However, the lack of suitable animal models impedes us from addressing the impact of endogenous melatonin on these cells. In the current study, by using AANAT overexpression transgenic sheep and AANAT knockout mice, we confirmed the regulatory effects of endogenously occurring melatonin on Leydig cells as well as its beneficial effects on male reproductive performance. The results showed that the endogenously elevated melatonin level was correlated with decreased Leydig cell apoptosis, increased testosterone production and improved quality of sperm in melatonin-enriched transgenic mammals. Signal transduction analysis indicated that melatonin targeted the mitochondrial apoptotic Bax/Bcl2 pathway and thus suppressed Leydig cell apoptosis. In addition, melatonin upregulated the expression of testosterone synthesis-related genes of StAR, SF1 and Gata4 in Leydig cells. This action was primarily mediated by the melatonin nuclear receptor RORα since blockade of this receptor suppressed the effect of melatonin on testosterone synthesis. All of these actions of melatonin cause Leydig cells to generate more testosterone, which is necessary for spermatogenesis in mammals. In contrast, AANAT knockout animals have dysfunctional Leydig cells and reduced reproductive performance.

Role of Oxidative Stress in Varicocele

“…Its treatment of varicocele rats showed antioxidant effects, improved reproductive hormone axis, CatSper expression, and fertility parameters. Endogenously elevated melatonin levels were relevant to decrease apoptosis of the Leydig cell, increase testosterone production, and improve sperm quality in melatonin-enriched transgenic mammals ( Yang et al, 2021 ). It can reduce oxidative stress and endoplasmic reticulum stress of mouse spermatocytes induced by heat stress, promote DSB repair of spermatocytes, and reduce apoptosis of spermatocytes ( Guo et al, 2020 ).…”

Melatonin Receptors: A Key Mediator in Animal Reproduction

“…Mediation of melatonin-inhibited steroid and androgen production [58,59] Mediation of melatonin-stimulated CRH production and tyrosine phosphatase activity [60] Sertoli cells MT1 and MT2…”

“…Mediation of the responsiveness to FSH during testicular development and regulation of spermatogenesis [60] Mediation of melatonin-stimulated cell growth/proliferation and SSC proliferation [63] Mediation of energy metabolism, such as lactate generation and glucose consumption [64] Sperm MT1 Mediation of melatonin-inhibited apoptosis and improved fertilization ability [65,66] In female animals, the MT1 receptor is widely distributed in the ovary and is crucial in its melatonin-regulated activities, delaying the decline in fertility in female animals [65]. The growth and development of follicles are complicated, involving five stages: primordial follicle, primary follicle, preantral follicle, antral follicle, and mature follicle [67].…”

“…Both MT1 and MT2 receptors are expressed in testicular cells. Studies have shown that, by binding MT1 receptors, melatonin exerts a direct inhibitory effect on the hCG-induced cAMP signal and testosterone synthesis in Leydig cells via reducing the expression of key steroidogenic genes, including p450scc, p450c17, and StAR [ 57 , 59 ], which are essential for testosterone synthesis [ 60 , 61 ]. Melatonin acting through the MT1 receptor located in Leydig cells stimulates corticotropin-releasing hormone (CRH) production [ 59 ], which is a negative modulator of hCG-stimulated testicular steroidogenesis.…”

“…It receives light signals from the retina and regulates the circadian rhythms of organs such as the gonads through neuromodulation and humoral regulation. The circadian clock system plays an important role in the biological activities of the gonads, including the ovary and testis, and it is involved in the regulation of steroid hormone synthesis, oocyte maturation, ovulation, and seasonal estrus [ 60 , 81 ]. A disturbance in the biological clock can have an impact on gonadal function.…”