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You are watching: Which hormone promotes the final step of spermatogenesis?

Feingold KR, Anawalt B, Boyce A, et al., editors. Endotext . Southern Dartmouth (MA): MDText.com, Inc.; 2000-.


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Endocrinology of the male Reproductive System and also Spermatogenesis

Liza O"Donnell, PhD, Peter Stanton, PhD, and David M de Kretser, M.D., PhD.

Author Information
Hudson institute of medical Research, Clayton, 27 - 31 bright Street, Clayton, Victoria, Australia, 3168 liza.odonnell
Hudson academy of clinical Research, Clayton, 27 - 31 bright Street, Clayton, Victoria, Australia, 3168 liza.odonnell
Hudson institute of clinical Research, Clayton, 27 - 31 wright Street, Clayton, Victoria, Australia, 3168 liza.odonnell
hudson.org.au; room of Molecular and also Translational Sciences, Monash University; room of Anatomy and Developmental Biology, Monash University, Clayton, Victoria, Australia

ABSTRACT

The testes synthesize two vital products: testosterone, essential for the advancement and maintain of countless physiological functions; and sperm, required for masculine fertility. The synthesis of both commodities is regulated by endocrine hormones developed in the hypothalamus and also pituitary, and locally in ~ the testis. Testosterone is indispensable because that sperm production, however both testosterone and also Follicle Stimulating Hormone (FSH) are necessary for optimal testicular advance and maximal sperm production. Sperm are created via the extraordinarily complex and dynamic process of spermatogenesis that requires co-operation in between multiple testicular cabinet types. When it has actually long been known that testosterone and FSH control spermatogenesis, years of study has melted light on many of the elaborate mechanisms whereby spermatogonial stem cells construct into very specialized, motile spermatozoa. Spermatogenesis involves the concerted interaction of endocrine hormones, but additionally many paracrine and growth factors, tightly co-ordinated gene and protein expression programs as well as epigenetic modification of the genome and also different non-coding RNA species. This chapter offers a substantial overview the the fascinating process of spermatogenesis and of that regulation, and also emphasises the endocrine regulation that testicular somatic cells and also germ cells. The chapter also provides a review of the clinically far-reaching aspects that the endocrine regulation the spermatogenesis. For finish coverage of every related areas of Endocrinology, please watch our online cost-free web-book, www.endotext.org.


CLINICAL SUMMARY

The testes synthesize two essential products: testosterone, needed for the advancement and maintenance of many physiological attributes including typical testis function; and also sperm, essential for masculine fertility. The synthetic of both products is regulation by endocrine hormones developed in the hypothalamus and also pituitary, as well as locally within the testis.

The cheap of hypothalamic gonadotropin-releasing hormone (GnRH) stimulates production of luteinizing hormone (LH) and follicle stimulating hormone (FSH) by the pituitary. LH is transported in the blood stream come the testes, where it stimulates Leydig cell to develop testosterone: this deserve to act as an androgen (via interaction with androgen receptors) but can likewise be aromatized to produce estrogens. The testes, in turn, feedback top top the hypothalamus and also the pituitary via testosterone and inhibin secretion, in a negative feedback loop to border GnRH and also gonodotropin production. Both androgens and FSH action on receptors in ~ the sustaining somatic cells, the Sertoli cells, to wake up various features needed because that optimal sperm production. Spermatogenesis is the process by which immature male germ cells divide, experience meiosis and also differentiate into highly dedicated haploid spermatozoa. Optimal spermatogenesis requires the action of both testosterone (via androgen receptors) and also FSH.

Spermatogenesis takes place within the seminiferous tubules of the testis. This tubules form long convoluted loops the pass into the mediastinum of the testis and also join an anastomosing network that tubules referred to as the rete testis. Spermatozoa departure the testes via the rete and also enter the efferent ductules before their passage through, and final maturation in, the epididymis. The seminiferous tubules are made up of the seminiferous epithelium: the somatic Sertoli cells and the emerging male germ cells at various stages the development. Surrounding the seminiferous epithelium is a great of basement membrane and layers of modification myofibroblastic cell termed peritubular myoid cells. In between the tubules is the interstitial an are that includes blood and also lymphatic vessels, immune cells including macrophages and lymphocytes, and the steroidogenic Leydig cells.

Male germ cell advancement relies absolutely on the structural and nutritional assistance of the somatic Sertoli cells. Sertoli cell are large columnar cells, with their base residing on basement membrane top top the exterior of the seminiferous tubules, and their apical processes bordering germ cells together they develop into spermatozoa. Androgens (and estrogens) and also FSH action on receptors within Sertoli cells: germ cells absence both androgen and FSH receptors, as such these hormones act straight on Sertoli cells to support spermatogenesis. Sertoli cells regulate the internal atmosphere of the seminiferous tubule through secreting paracrine factors and also expressing cell surface receptors required for germ cell development. Sertoli cells kind intercellular chop junctions at your base: these occluding junctions protect against the diffusion of substances from the interstitium into the tubules and create a dedicated milieu compelled for germ cell development. These junctions room a significant component the the so-called ‘blood-testis-barrier’, wherein the passage of substances indigenous the circulation is prevented native entering the inner part of the seminiferous tubules. The many immature germ cells, consisting of germline stem cells, reside close to the basement membrane of the seminiferous tubules and thus have totally free access to determinants from the interstitium, but germ cell undergoing meiosis and haploid cabinet differentiation construct “above” the blood-testis-barrier and also thus are totally reliant ~ above the Sertoli cell microenvironment. The seminiferous tubules are likewise an immune-privileged environment. Meiotic and also post-meiotic germ cells build after the establishment of immune tolerance, and also could for this reason be recognized as “foreign” through the immune system, thus the seminiferous tubules, via a number of different mechanisms including the blood-testis-barrier, proactively exclude immune cells and also factors indigenous entering the seminiferous tubules and also being exposed to meiotic and haploid germ cells.

The variety of Sertoli cell determines the ultimate spermatogenic output of the testes. In humans, Sertoli cell proliferate throughout the fetal and early neonatal duration and again before puberty. At puberty, Sertoli cells stop proliferation and also attain a mature, terminally differentiated phenotype the is able to support spermatogenesis. Disturbances to Sertoli cabinet proliferation throughout these time can result in smaller testes with reduced sperm production. Conversely, disturbances come the cessation that proliferation can an outcome in larger testes with more Sertoli cells and a greater sperm output. The seems most likely that the fail of many men through congenital hypogonadotropic hypogonadism (HH) to attain normal testicular size and sperm output, when treated by gonadotropic stimulation, may result from deficient Sertoli cell proliferation during fetal and prepubertal life. The action of both androgens and FSH top top Sertoli cell is important for the ability of Sertoli cell to support full spermatogenesis. In addition, the expression of many genes and paracrine determinants within Sertoli cells is important for spermatogenesis.

Spermatogenesis counts on the capacity of Leydig cell to produce testosterone under the affect of LH. Fetal Leydig cells appear following gonadal sex differentiation (gestational mainly 7-8 in humans) and, under the stimulation of placental human being chorionic gonadotropin (hCG), outcomes in the manufacturing of testosterone throughout gestation. In humans, fetal cells decrease in number towards term and are shed from the interstitium at around twelve months of age. The adult population of Leydig cells in the human being arises from the department and differentiation that mesenchymal precursor cells under the influence of LH at puberty. Determinants secreted through Sertoli cells and peritubular myoid cells are additionally necessary because that Leydig cell advance and steroidogenesis. Optimal Leydig cabinet steroidogenesis additionally relies on a normal complement of macrophages within the testicular interstitium and on the visibility of androgen receptors in peritubular myoid cells, presumably due to the fact that these cells secrete components necessary for Leydig cell advancement and function.

The procedure of spermatogenesis begins in the fetal testis, once the Sertoli cell populace is specified in the embryonic testis under the affect of masculine sex determining factors, such together SRY and also SOX9. Newly-specified Sertoli cells enclose and kind seminiferous cord structures and also direct primordial germ cell to commit come the male pathway that gene expression. Fetal Sertoli cell proliferate and drive seminiferous cord elongation; this procedure is likewise dependent on determinants secreted through Leydig cells. In the neonatal testis, primordial germ cell undergo more maturation and migrate to the basement the the seminiferous tubules where they administer a swimming pool of precursor germ cells for postnatal spermatogenesis.

Spermatogonia space the many immature germ cabinet type. This heterogeneous populace includes spermatogonial stem cells, i m sorry self-renew throughout life to administer a pool of stem cells available for spermatogenesis, and also proliferating cells that differentiate and become cursed to entry right into meiosis. Spermatogonial advancement is hormonally independent and also as such they are existing even in the lack of GnRH. Spermatogonia eventually identify into spermatocytes that proceed through the process of meiosis that starts with DNA synthesis resulting in a tetraploid gamete. Throughout the long meiotic prophase, i beg your pardon lasts ~2 weeks, homologous chromosomes pair and meiotic recombination occurs; this involves the induction and repair the DNA double-strand breaks enabling the exchange of genetic information in between paired chromosomes, thereby developing genetic diversity in between gametes. At the finish of prophase, the meiotic cells continue through 2 rapid and successive reductive divisions to yield haploid spermatids. The completion of meiosis depends absolutely on androgen action in Sertoli cells; in the absence of androgen, no haploid spermatids will be produced.

Newly created haploid ring spermatids differentiate, with no additional division, right into the highly committed spermatozoan during the process of spermiogenesis. This requires many facility processes, including advance of the acrosome (an organelle top top the surface ar of the sperm head that consists of enzymes forced to penetrate the zona pellucida that the oocyte and also thus facilitate fertilization), the flagella (the motile microtubule-based structure compelled for sperm motility) and the remodelling that the spermatid’s DNA into a tightly coiled framework within a small, streamlined nucleus that will certainly not hinder motility. This remodelling of the DNA requires the cessation of gene transcription as much as 2 weeks prior to the final maturation that the sperm; as such spermiogenesis entails the translational hold-up of countless mRNA species which have to then be translated at an accurate times throughout their last development. Spermatogenesis ends with the process of spermiation. This involves removal of the spermatid’s huge cytoplasm, revealing the streamlined mature spermatozoa, and the last disengagement the sperm indigenous the Sertoli cells right into the tubule lumen, prior to their passage to the epididymis. Both the survival of spermatids throughout spermiogenesis and also their relax at the finish of spermiation is dependence on optimal levels of androgen and FSH.

Spermatogenesis is a long process, taking as much as 64 work in the human, and also its inherent intricacy demands precise timing and also spatial organization. Within the seminiferous tubules, Sertoli cells and also surrounding germ cells in miscellaneous phases of development are highly organized into a collection of cell associations, known as stages. These stages an outcome from the reality that a specific spermatogonial cabinet type, when it shows up in the epithelium, is always associated with a details stage of meiosis and also spermatid development. The stages follow one one more along the length of the seminiferous tubule, and also the perfect of a series of step is termed a “cycle”. This cycle follow me the length of tubule is obvious in rodents, however in people several cycles are intertwined in a helical pattern; hence a human seminiferous tubule viewed in cross ar will contain up to three stages. The completion of one cycle results in the relax of tires spermatozoa right into the tubule lumen; the cycles are repeated along the tubules, result in consistent “pulses” the sperm production. These pulses the sperm release enable the testes come continually create millions of sperm, with the mean normospermic male able come produce roughly 1000 sperm every heartbeat.

The an accurate timing and also co-ordination of spermatogenesis is achieved by numerous factors. Emerging evidence says that retinoic acid, metabolized in ~ the testis native circulating retinol (a product that vitamin A) is a significant driver that spermatogenesis. A precise pulse that retinoic acid activity is ceded to a certain stage the the spermatogenic cycle; this pulse is completed by the constrained expression that enzymes associated in retinoic acid synthesis, degradation and also storage, and the local expression of retinoic mountain receptors. This pulse the retinoic acid acts straight on spermatogonia to stimulate their entry right into the pathway cursed to meiosis. It likewise acts straight on Sertoli cells to manage its cyclic functions. Sertoli cell contain an inner “clock” that allows them come express genes and also proteins at an exact times. This clock appears to be set by retinoic acid, but the time of the clock can be influenced by the germ cells themselves.

The timing of spermatogenesis likewise relies on one extraordinarily complex program the gene transcription and protein translation. Different splicing the mRNA is extremely prevalent in the testis, and generates countless germ cell-specific transcripts that are essential for the bespeak procession the germ cabinet development. Noncoding RNAs, including microRNAs, tiny interfering RNAs, piRNAs and long noncoding RNAs, are very expressed in the testis, specifically by the germ cells. Indeed, research studies on male germ cells have actually revealed much of what is known around the biologic and role of non-coding RNAs. These non-coding RNAs have actually many and also varied roles and also are specifically required because that the transcriptional regime executed during meiosis and spermiogenesis.

The male germ cabinet transmits both genetic and also epigenetic info to the offspring. Epigenetic adjustments of the genome room heritable; epigenetic processes such together DNA methylation and histone adjustments regulate dyed structure and also modulate gene transcription and also silencing. The masculine germ cabinet undergoes significant epigenetic programming in the fetal testis, during the genome large de-methylation and re-methylation to develop the germline-specific epigenetic pattern the is at some point transmitted come the offspring. The sperm epigenome is then further remodelled throughout postnatal spermatogenesis by various mechanisms. It is now well-known that a man’s sperm epigenome have the right to be changed by environmental determinants (including diet and also lifestyle and exposure to environmental factors) transparent his lifetime and also this changed sperm epigenome deserve to influence both his fertility and also the wellness of his future children.

It is clean from the above summary that spermatogenesis counts on numerous intrinsic and also extrinsic factors. But spermatogenesis is absolutely dependency on androgen-secretion by the Leydig cells; androgens stimulate and also maintain germ cell advancement throughout life. Testicular testosterone level are very high, through virtue the its local production, yet they space considerably greater than those compelled for the initiation and maintenance of spermatogenesis. Androgen action on receptors in ~ Leydig cells, peritubular myoid cells and Sertoli cells is crucial for regular steroidogenesis and also spermatogenesis. If testosterone is vital for spermatogenesis, that is also important to keep in mind that exogenous testosterone management resulting in also slightly supraphysiological serum levels suppresses gonadotropin secretion via negative feedback impacts on the hypothalamus and also pituitary, bring about the cessation the sperm production.

In contrast to androgens, spermatogenesis have the right to proceed in the absence of FSH; however, testes room smaller and also sperm output is reduced. This is due to FSH’s function in the peri-pubertal proliferation and differentiation the Sertoli cells and in the maintenance of germ cabinet survival. While FSH is for this reason not important for spermatogenesis, it is generally taken into consideration that optimal spermatogenesis needs the combined actions of both androgen and FSH, through both hormones having actually independent, co-operative and synergistic effects to encourage maximal sperm output.

These components are crucial consideration in the stimulation the spermatogenesis in the setup of HH. As androgens are essential for the initiation the sperm production, the induction that spermatogenesis in HH acquired after puberty is achieved by the management of hCG (as one LH substitute). Lengthy therapy is required to produce sperm in the ejaculate, given that human spermatogenesis takes much more than 2 month to develop sperm native spermatogonia. Treatment with hCG alone might be enough for the induction of spermatogenesis in males with larger testes because of potential residual FSH action, however, for plenty of men, and an especially for those v congenital HH, the co-administration that FSH is essential for maximal stimulation that sperm output. In males with congenital HH, FSH is needed to induce Sertoli cell maturation, whereas men with got HH and smaller testes benefit from the co-administration the FSH as result of the synergistic actions of FSH and also androgens ~ above spermatogenesis.

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In summary, the testes, under the affect of gonadotropins, develop testosterone and also sperm. These procedures require the co-ordinated action of multiple cell types and the cheap of paracrine factors. Spermatogenesis is a lengthy and complex process that counts on multiple somatic cells and on the co-ordinated expression of genes, proteins and non-coding RNAs. Natural vulnerabilities exist in spermatogenesis meaning that lifestyle and environmental components can potentially affect a man’s sperm epigenome, his fertility and also the health and wellness of his future children.