The hormones engaged in the regulation of the hypothalamic-pituitary-testis axis are depicted in Figure 1. The chemistry of GnRH, LH, and FSH was covered in detail in Chapter 3. The secretion of FSH and LH from the adenohypophysis is governed primarily by hypothalamic GnRH and the blood level of steroid hormones. A relative newcomer to our understanding of this system is kisspeptin, which plays a crucial role in the pulsatile secretion of GnRH. Inhibin B, secreted by the Sertoli cells, also plays an important role in FSH secretion.

Fig1. The Hypothalamic-Pituitary-Testis Axis. Gonadotrophin releasing hormone (GnRH) is released from hypothalamic neurons in the median eminence and stimulates gonadotrophs to release luteinizing hormone (LH) and follicle stimulating hormone (FSH). GnRH secretion is stimulated by kisspeptin (Kiss-1) from neurons of the arcuate nucleus. Leydig cells in the testis respond to LH stimulation by secreting testosterone. Sertoli cells, the target of FSH, secrete inhibin B. Testosterone exerts negative feedback at the pituitary, the hypothalamus, and on kisspeptide neurons. Inhibin B inhibits the secretion of FSH at the pituitary.

1. Kisspeptin

The gene for the peptide now known as kisspeptin and its shorter derivatives was originally identified in 1996 as a tumor suppressor gene and its product was also known as metastin. Peptides that were isolated from human placenta as ligands for the orphan receptor GPR54 were found to be products of the human KiSS1 gene. Study of the distribution of these peptides soon revealed their presence in what are now known as kisspeptin neurons. In humans these neurons are located in the arcuate nucleus and the anteroventral periventricular nucleus, both in the hypothalamic area. The axons of these neurons terminate in the GnRH secreting neurons, whose axons release GnRH into the median eminance. From there, GnRH stimulates the release of LH and FSH from pituitary gonadotrophs. Thus, kisspeptin is a crucial integrator of central and peripheral signals that ultimately control GnRH secretion.

Figure 1 shows the 145 amino acid primary transcript produced from the KiSS1 gene and its active cleavage product, kisspeptin 54. C-terminal cleavage products of kisspeptin containing 13 and 14 amino acids have been identified in tissue extracts. It has been determined that only the C-terminal 10 amino acids are required for full kisspeptin activity; these amino acids are completely conserved among primates and only slight variations occur in other mammals and in nonmammalian vertebrates.

Fig2. Kisspeptin. The primary transcript of kisspeptin is shown, with a signal peptide (yellow) and the active 5.9 kDa mature peptide, kisspeptin 54 (purple and blue). This peptide, originally isolated from human placenta and known for its metastasis suppression properties, has also been referred to as metastin. The amidated C-terminal decapeptide (blue) expresses full biological activity. These ten amino acids, along with the preceding four residues, are completely conserved across mammals and very highly conserved among vertebrates thus far studied.

Kisspeptin signals GnRH neurons through its receptor, KISS1R/GPR54, activating phospholipase C, and ultimately bringing about GnRH release. In both mice and humans, inactivating mutations of either GPR54 or kisspeptin leads to reproductive failure such as hypogonadotrophic hypogonadism and delayed or absent puberty. Although kisspeptin is thought to be an important component of the GnRH pulse generator, the exact mechanism by which this occurs and the role of other neuropeptides such as neurokinin B are still under intense study.

2. GnRH

The chemistry, biosynthesis, and control of the secretion of GnRH is covered in Chapter 3. Briefly, this decapeptide is secreted in a pulsatile fashion under the influence of input from other neurons in the central nervous system, most notably those that secrete kisspeptin. The pulsatility of GnRH release is critical to its ability to stimulate gonadotrophin secretion. The amplitude and frequency of GnRH pulses are restrained from the age of 4–6 months until the onset of puberty, at which time the increase in both amplitude and frequency of GnRH (and therefore gonadotrophin) secretion is the hallmark of the onset of reproductive maturation.

3. LH

The testicular target of LH, the Leydig cells, serve two principal functions: (a) they are the site of pro duction of testosterone, producing, in adult males, approximately 7 mg daily for systemic transport to distal target tissues; and (b) they have paracrine inter actions with the immediately adjacent seminiferous tubules to support spermatogenesis. LH-mediated stimulation of testosterone synthesis and secretion is initiated by the binding of LH to specific receptors on the outer membranes of the Leydig cell. An increased level of cAMP within the Leydig cell activates PKA (cyclic AMP-dependent protein kinase) which, through phosphorylation of specific transcription factors, induces the synthesis of the steroidogenic acute regulatory protein, StAR. This protein is essential for the movement of cholesterol into the mitochondrion where cleavage of its side chain initiates steroidogenesis. Under prolonged stimulation, the other enzymes in the pathway from pregnenolone to testosterone are increased by LH, as is the growth of the Leydig cell.

4. FSH

In the male, FSH in conjunction with testosterone acts on the Sertoli cells of the seminiferous tubule at the time of puberty to initiate sperm production. In humans FSH is required for normal spermatogenesis throughout adult life. FSH binds to its specific G protein coupled receptor on the Sertoli cell to increase, through a cAMP-dependent mechanism, the synthesis of specific proteins, among which are androgen-binding protein (ABP) and inhibin, which are discussed just following and in section IV.B, respectively.

Androgen binding protein, ABP, was initially characterized as a Sertoli cell product in rodents and other small mammals. In these species it is thought to function to concentrate androgens in the seminiferous tubules and deliver the steroid hormone to developing spermatocytes and spermatids. ABP is now known to be a homolog of sex hormone binding globulin, SHBG, the serum binding protein for androgens and estrogens. In humans, there is little evidence for the presence in FSH-dependent synthesis and secretion of SHBG/ABP by Sertoli cells, although it is abundant in sperm and its levels are positively correlated with sperm motility.

FSH has direct effects on sperm development: it impacts meiosis and the maturation of spermatogonia. In addition, FSH stimulates both the proliferation and differentiation of Sertoli cells in the fetal testis, so that the complement of functional Sertoli cells in the adult human testes is dependent upon FSH-mediated processes in the late phases of fetal development. Since each Sertoli cell can support a limited number of developing sperm, this effect of FSH on Sertoli cell development influences germ cell number.

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مواضيع ذات صلة

Sex Hormone-binding Globulin

Modification of Testosterone in Target Tissues

Clinical Aspects of Hormones of the Adrenal Medulla: Chronic Stress

Biological Responses to Epinephrine

Adrenergic Receptors

Pharmacology of Catecholamines

Regulation of Catecholamine Synthesis and Secretion

Feedback Effects of Glucocorticoids

Glucocorticoids and Stress

Transport of Glucocorticoids in the Blood (CBG)

Integrated Actions of 1α,25(OH)2D3, PTH, Calcitonin, and FGF23 on Bone Remodeling and Calcium Homeostasis

Calcitonin Receptor and Biological Actions