The Hypothalamic Pituitary Testicular (HPT) Axis and Male Reproductive Physiology

Gonadotropin-releasing hormone (GNRH) is considered the primary regulator of the male reproductive system. It specifically controls the pulsatile secretion of gonadotropins, that is, luteinizing hormone (LH) and follicle-stimulating hormone (FSH), which are essential factors for proper gonadal activity. The biosynthesis and release of GNRH is under complex stimulatory and inhibitory control by a number of neurotransmitters and neurotrophic factors. In addition, a number of autocrine and paracrine drugs, including growth hormone, also known as Growth hormone (GH) or Somatotropin, and insulin-like growth factor-1 (IGF-1), can alter GNRH synthesis and action on pituitary gonadotrophs and thus affect gonadal activity. there are factors. Although the central role of GH in growth and development is well established in various tissues, the effect of GH on male reproductive functions is not fully known and therefore needs to be studied extensively.

The Effect of Growth Hormone on Testicular Growth, Development and Pobertal Maturation

Adolescence is a multifaceted process in which children mature, develop secondary sexual characteristics and gain reproductive competence. Normally, pobertal passage is initiated through central mechanisms with gonadal function driven by increased GNRH and gonadotropin secretion. In addition, adequate energy supply and nutritional balance appear necessary for central initiation of the pobertal transition. At the testicular level, GH promotes the growth and development of the gonad in childhood and adolescence, the stimulation of gametogenesis during the pobertal and reproductive maturity, and the production of steroid hormones. The rate of GH synthesis doubles during pobertal maturation, reaching a maximum peak, and the rate of production decreases with advancing age. This mechanism is also supported by IGF-1, which is produced in response to circulating GH levels. This is supported by studies that show a decrease in testicular volume in patients with growth hormone deficiency (CO-GHD) beginning in childhood and, as a result, an increase in the same patients treated with GH replacement doses. GH also supports the development and differentiation of internal testicular morphology such as seminiferous tubules (ST).
The Hypothalamic Pituitary Testicular (HPT) Axis and Male Reproductive PhysiologyIn mammals, GH plays a mandatory role in maintaining normal sexual maturation because puberty is delayed in GH-deficient or GH-resistant humans. Similarly, GH deficiency in rodents is associated with delayed sexual maturation. GNRH immunoneutralization delays sexual maturation in rats, decreases testicular mass, spermatogenesis and sensitivity to follicle stimulating hormone. The ability of GH to promote pubertal maturation in GH-deficient children and GH-filled normal male rats further demonstrates the importance of GH in pobertal development. In some species, GH acts directly on the androgen effect and thus accelerates pobertal transition because GH reduces the amount of testosterone needed to induce secondary sexual characteristics (underarm hair) in young individuals.

Effects of Growth Hormone on Germ Cell Proliferation, Survival, Spermatogenesis and Sperm Parameters

The effect of GH on testicular growth ultimately affects the proliferation of germ cells. It is a particularly complicated point as it is a balance mechanism, so the decrease in GH levels leads to a simultaneous decrease in sperm count, semen volume and sperm motility, respectively. Excess GH has been shown to produce the same results, so the correct dosage of applicable treatments is important. Local IGF-1 can mimic GH effects on germ cells, as sperm motility and morphology have been noted to be improved due to IGF-1 production.
Receptors for IGF-1 occur in more mature haploid cells of spermatogenesis, namely secondary spermatocytes, spermatids and spermatozoa. However, in some studies, testicular-level functions of these two entities exhibited decisively antagonistic effects. However, GH can act independently of IGF-1. These results demonstrate the co-localization of GH and GH-RH in chicken testis and the stimulatory function of GH-RH in testicular GH secretion and proliferation of testicular cells. Spermatogenesis, which starts with the onset of puberty, continues during reproductively active periods in men. Basically, it is a highly complex and conserved process under the control of HPG axis and intra-testicular factors produced by Leydig and Sertoli cells.
The hypothalamic decapeptide Gnrh participates in the synthesis and circulatory release of gonadotropins, LH and FSH by stimulating the anterior pituitary. These gonadotropins then bind to specific receptors located and located on Leydig and Sertoli cells, leading to the rapid production of steroids and other intra-testicular factors required for spermatogenesis. With the aid of cell-to-cell signaling, these intra-testicular factors regulate germ cell proliferation, survival, and apoptosis-inducing production of high-quality sperm. A study on chicken elucidates the co-localization of GH and GH-RH in the testes, the stimulatory roles of GH-RH in testicular GH secretion and proliferation of testicular cells.
As a primal finding, testicular GH itself promotes testicular proliferation, which reveals a precise cause of the proliferative effect of GH-RH, which is likely to occur through autocrine / paracrine induction of GH secretion. Improved sperm morphology and motility in dw / dw rats lacking GH, and extended general equine spermatozoa motility in vitro are also possibly due to GH obtained by extending sperm life. Moreover, numerous indicators of sperm quantity and quality in bulls are associated with GH gene polymorphisms. Gametogenesis is similarly supported by in vitro GH cultures of eel testicular cells. The spermatogenic effects of GH may be mediated by local production of IGF-I because it can also restore sperm motility and morphology.
The Hypothalamic Pituitary Testicular (HPT) Axis and Male Reproductive PhysiologyGH coordinately increases IGF-I production in seminal vesicle and sperm motility. However, several reports exhibit the incompatible effects of both GH and IGF-I, suggesting that GH can only act with IGF-I. Similarly, the stimulatory effect of GH on eel spermatogenesis is not dependent on IGF-I and steroids. Decreased but not eliminated fertility in GH-resistant males and GH-deficient rodents indicates that low fertility is met by adequate GH-independent local testicular IGF-I production. In chickens, this phenomenon appears to be at an acceptable level to fully restore fertility parameters. Because seminal IGF-I concentrations, sperm motility, morphology, viability and fertility do not fluctuate between GH-resistant and GH-filled chickens.

Effects of Growth Hormone on the Modulation of Testicular Steroidogenesis

Steroidogenesis requires multi-step processes that are enzyme-mediated and responsible for converting cholesterol into a biologically active steroid hormone. Regarding the hormonal nature of testicular function, GH is a potent steroidogenic factor, especially in vitro. GH stimulates androgen or estradiol production by Leydig cells isolated from rodents, ruminants, humans and fish, and the results of in vivo studies are more controversial. In a study of men with fertile GH deficiency, chronic GH treatment was found to improve chorionic gonadotropin-induced testosterone production.
It was concluded that the result observed in healthy young men treated with GH decreased total serum testosterone concentrations due to the conversion of testosterone to estradiol. In addition, GH therapy in hypopituitary or moderately obese men potentially has a stimulating effect on aromatase activity. Reports from the in vitro study show a wide variety of effects of GH, such as the change in the activity of enzymes involved in the steroidogenic pathway. Similarly, GH upregulates the formation of early steroidogenic intermediates such as dihydroprogesterone in the testicular cells of fish.
The gonadotrophic effects of GH can potentiate testicular steroidogenesis by promoting testicular LH sensitivity and increasing Leydig cell proliferation and development. Because GH-R knockout mice may be scarce in Leydig cells and LH receptors. Similarly, GH is responsible for the upregulation of LH receptors in both GH-filled (as in hamsters) and GH-deficient (dwarf mice) animals. The bioavailability of free testosterone is decreased due to sex hormone binding globulin (SHBG). Some studies confirm that GH can strengthen testosterone activity by reducing SHBG production. For example, GH therapy minimizes SHBG levels in adults with GH deficiency in some studies and in hypopituitary adolescents. Since age-related decrease in SHBG concentration is not observed in GHD adolescents, therefore, the pubertal increase in GH production may enhance male pubertal development.
The Hypothalamic Pituitary Testicular (HPT) Axis and Male Reproductive PhysiologyHowever, additional studies in healthy men have found a coordinated reduction in sex hormone-binding globulin and total serum testosterone production following GH treatment. There were also signs of decreased SHBG but unchanged total serum testosterone or increased LH-induced testosterone but unchanged SHBG. These discrepancies may reflect differences in subject’s age and GH administration protocol. Some researchers have determined the importance of IGF-I in the steroidogenic effects of GH. IGF-I can mimic the effects of GH in rat testis and partially restore testosterone synthesis in GH-resistant males. Also, in another study on rodents, GH-induced steroidogenesis required co-administration of IGF-I. However, de novo protein synthesis is unnecessary for GH-induced StAR synthesis, suggesting that at least a few testicular actions are independent of IGF-I.
Previous study observed a spontaneous correlation between testicular GH-R expression and StAR and p450 expression following exposure to nanoparticle-rich diesel exhaust (NR-DE) in rats. However, more research needs to be done to determine a causal relationship between GH and contaminant-induced androgenesis.


Writer: Ozlem Guvenc Agaoglu

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