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You are watching: Which of the following is the main hormone that regulates spermatogenesis?

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


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Endocrinology the the masculine Reproductive System and also Spermatogenesis

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

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

ABSTRACT

The testes synthesize two essential products: testosterone, necessary for the advancement and maintain of many physiological functions; and sperm, necessary for male fertility. The synthetic of both products is regulation by endocrine hormones produced in the hypothalamus and pituitary, as well as locally within the testis. Testosterone is indispensable because that sperm production, however both testosterone and also Follicle Stimulating Hormone (FSH) are required for optimal testicular advance and maximal sperm production. Sperm are developed via the extraordinarily facility and dynamic procedure of spermatogenesis that needs co-operation in between multiple testicular cell types. While it has long been well-known that testosterone and also FSH control spermatogenesis, year of research study has shed light on countless of the complex mechanisms whereby spermatogonial stem cells develop into highly specialized, motile spermatozoa. Spermatogenesis requires the concerted interactions of endocrine hormones, but additionally many paracrine and also growth factors, strictly co-ordinated gene and also protein expression programs and epigenetic amendment of the genome and also different non-coding RNA species. This chapter provides a an extensive overview that the fascinating procedure of spermatogenesis and of the regulation, and emphasises the endocrine regulation the testicular somatic cells and also germ cells. The chapter also provides a an introduction of the clinically far-ranging aspects of the endocrine regulation of spermatogenesis. For complete coverage of all related locations of Endocrinology, please see our online cost-free web-book, www.endotext.org.


CLINICAL SUMMARY

The testes synthesize two crucial products: testosterone, essential for the development and maintenance of countless physiological attributes including regular testis function; and also sperm, needed for male fertility. The synthetic of both products is regulated by endocrine hormones created in the hypothalamus and pituitary, and also locally within the testis.

The secretion of hypothalamic gonadotropin-releasing hormone (GnRH) stimulates manufacturing of luteinizing hormone (LH) and follicle stimulating hormone (FSH) by the pituitary. LH is transported in the blood stream come the testes, wherein it stimulates Leydig cells to create testosterone: this have the right to act together an androgen (via interaction with androgen receptors) however can also be aromatized to produce estrogens. The testes, in turn, feedback on the hypothalamus and the pituitary via testosterone and also inhibin secretion, in a an unfavorable feedback loop to border GnRH and also gonodotropin production. Both androgens and also FSH act on receptors within the sustaining somatic cells, the Sertoli cells, to wake up various features needed because that optimal sperm production. Spermatogenesis is the procedure by i beg your pardon immature masculine germ cells divide, undergo meiosis and also differentiate right into highly specialized haploid spermatozoa. Optimal spermatogenesis needs the activity of both testosterone (via androgen receptors) and also FSH.

Spermatogenesis takes location within the seminiferous tubules the the testis. These tubules form long convoluted loops that pass right into the mediastinum that the testis and 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 prior to their i through, and also final tires in, the epididymis. The seminiferous tubules are made up of the seminiferous epithelium: the somatic Sertoli cells and also the emerging male germ cells at various stages the development. Neighboring the seminiferous epithelium is a class of basement membrane and layers of modified myofibroblastic cell termed peritubular myoid cells. Between the tubules is the interstitial space that contains blood and lymphatic vessels, immune cells including macrophages and lymphocytes, and also the steroidogenic Leydig cells.

Male germ cell breakthrough relies absolutely on the structural and nutritional assistance of the somatic Sertoli cells. Sertoli cells are huge columnar cells, with their base residing top top basement membrane ~ above the external of the seminiferous tubules, and their apical processes neighboring germ cells together they construct into spermatozoa. Androgens (and estrogens) and FSH plot on receptors in ~ Sertoli cells: germ cells lack both androgen and FSH receptors, as such these hormones act straight on Sertoli cells to assistance spermatogenesis. Sertoli cells control the internal environment of the seminiferous tubule by secreting paracrine factors and expressing cell surface ar receptors required for germ cabinet development. Sertoli cells type intercellular chop junctions at your base: this occluding junctions avoid the diffusion the substances indigenous the interstitium into the tubules and create a committed milieu required for germ cell development. These junctions room a significant component the the so-called ‘blood-testis-barrier’, inside the i of substances indigenous the circulation is prevented from entering the inner part of the seminiferous tubules. The many immature germ cells, including germline stem cells, reside near the basement membrane of the seminiferous tubules and also thus have cost-free access to factors from the interstitium, however germ cells undergoing meiosis and haploid cabinet differentiation build “above” the blood-testis-barrier and also thus are totally reliant top top the Sertoli cell microenvironment. The seminiferous tubules are also an immune-privileged environment. Meiotic and also post-meiotic germ cells develop after the facility of immune tolerance, and could therefore be known as “foreign” by the immune system, as such the seminiferous tubules, via a number of different mechanisms consisting of the blood-testis-barrier, proactively exclude immune cells and factors indigenous entering the seminiferous tubules and being exposed to meiotic and haploid germ cells.

The variety of Sertoli cell determines the can be fried spermatogenic calculation of the testes. In humans, Sertoli cells proliferate during the fetal and also early neonatal period and again prior to puberty. At puberty, Sertoli cells cease proliferation and also attain a mature, terminally identified phenotype the is able to assistance spermatogenesis. Disturbances come Sertoli cabinet proliferation during these time can an outcome in smaller testes with reduced sperm production. Conversely, disturbances come the cessation of proliferation can result in bigger testes with an ext Sertoli cells and also a higher sperm output. That seems most likely that the fail of numerous men with congenital hypogonadotropic hypogonadism (HH) to achieve normal testicular size and also sperm output, when treated by gonadotropic stimulation, may an outcome from deficient Sertoli cell proliferation during fetal and also prepubertal life. The activity of both androgens and also FSH on Sertoli cell is vital for the capability of Sertoli cells to support complete spermatogenesis. In addition, the expression of many genes and also paracrine factors within Sertoli cells is crucial for spermatogenesis.

Spermatogenesis depends on the ability of Leydig cell to create testosterone under the affect of LH. Fetal Leydig cells show up following gonadal sex differentiation (gestational mainly 7-8 in humans) and, under the stimulation the placental person chorionic gonadotropin (hCG), results in the production of testosterone throughout gestation. In humans, fetal cells decrease in number towards term and also are shed from the interstitium at about twelve months of age. The adult population of Leydig cell in the person arises indigenous the division and differentiation the mesenchymal precursor cell under the affect of LH at puberty. Components secreted by Sertoli cells and peritubular myoid cell are likewise necessary because that Leydig cell breakthrough and steroidogenesis. Optimal Leydig cabinet steroidogenesis additionally relies top top a normal match of macrophages in ~ the testicular interstitium as well as on the existence of androgen receptor in peritubular myoid cells, presumably due to the fact that these cell secrete factors necessary because that Leydig cell breakthrough and function.

The process of spermatogenesis starts in the fetal testis, as soon as the Sertoli cell population is mentioned in the embryonic testis under the affect of male sex identify factors, such together SRY and SOX9. Newly-specified Sertoli cells enclose and form seminiferous cord structures and direct primordial germ cells to commit come the masculine pathway of gene expression. Fetal Sertoli cells proliferate and drive seminiferous cord elongation; this procedure is additionally dependent on components secreted by Leydig cells. In the neonatal testis, primordial germ cell undergo further maturation and also migrate to the basement the the seminiferous tubules whereby they carry out a pool of precursor germ cells for postnatal spermatogenesis.

Spermatogonia space the many immature germ cell type. This heterogeneous populace includes spermatogonial stem cells, i m sorry self-renew transparent life to administer a pool of stem cells easily accessible for spermatogenesis, and also proliferating cells that differentiate and become cursed to entry into meiosis. Spermatogonial advancement is hormonally independent and also as together they are present even in the lack of GnRH. Spermatogonia eventually differentiate into spermatocytes that proceed through the process of meiosis that starts with DNA synthesis bring about a tetraploid gamete. Throughout the lengthy meiotic prophase, i m sorry lasts ~2 weeks, homologous chromosomes pair and also meiotic recombination occurs; this involves the induction and also repair that DNA double-strand breaks permitting the exchange of genetic information in between paired chromosomes, thereby creating genetic diversity in between gametes. At the finish of prophase, the meiotic cells proceed through 2 rapid and also successive reductive departments to productivity haploid spermatids. The completion of meiosis relies absolutely ~ above androgen activity in Sertoli cells; in the lack of androgen, no haploid spermatids will certainly be produced.

Newly created haploid ring spermatids differentiate, with no further division, right into the highly specialized spermatozoan throughout the procedure of spermiogenesis. This requires many complicated processes, including advancement of the acrosome (an organelle ~ above the surface ar of the sperm head that consists of enzymes required to permeate the zona pellucida the the oocyte and also thus facilitate fertilization), the flagella (the motile microtubule-based structure compelled for sperm motility) and also the remodelling that the spermatid’s DNA right into a strict coiled framework within a small, streamlined nucleus that will not hinder motility. This remodelling of the DNA entails the cessation the gene transcription up to 2 weeks prior to the last maturation that the sperm; thus spermiogenesis entails the translational hold-up of plenty of mRNA types which need to then be interpreted at precise times transparent their final development. Spermatogenesis ends v the process of spermiation. This requires removal the the spermatid’s huge cytoplasm, revealing the streamlined mature spermatozoa, and the last disengagement of sperm from the Sertoli cells right into the tubule lumen, before their i to the epididymis. Both the survive of spermatids throughout spermiogenesis and also their release at the finish of spermiation is dependency on optimal level of androgen and also FSH.

Spermatogenesis is a lengthy process, taking as much as 64 job in the human, and also its inherent complexity demands an exact timing and also spatial organization. In ~ the seminiferous tubules, Sertoli cells and also surrounding germ cell in assorted phases of advancement are very organized into a collection of cabinet associations, known as stages. This stages result from the truth that a particular spermatogonial cabinet type, as soon as it appears in the epithelium, is constantly associated v a certain stage that meiosis and spermatid development. The stages monitor one another along the size of the seminiferous tubule, and the perfect of a series of stages is termed a “cycle”. This cycle along the length of tubule is evident in rodents, but in people several cycles are intertwined in a helical pattern; therefore a human seminiferous tubule regarded in cross section will contain up to three stages. The completion of one cycle outcomes in the release of maturation spermatozoa right into the tubule lumen; the cycles are repeated along the tubules, resulting in consistent “pulses” that sperm production. This pulses that sperm release enable the testes come continually create millions that sperm, through the median normospermic guy able to produce approximately 1000 sperm every heartbeat.

The an exact timing and also co-ordination of spermatogenesis is completed by countless factors. Arising evidence suggests that retinoic acid, metabolized within the testis native circulating retinol (a product of vitamin A) is a major driver of spermatogenesis. A specific pulse that retinoic acid activity is delivered to a details stage the the spermatogenic cycle; this pulse is accomplished by the constrained expression that enzymes affiliated in retinoic acid synthesis, degradation and storage, as well as the neighborhood expression the retinoic mountain receptors. This pulse of retinoic mountain acts directly on spermatogonia to stimulate your entry into the pathway committed to meiosis. It likewise acts directly on Sertoli cell to manage its cyclic functions. Sertoli cell contain an interior “clock” that permits them come express genes and proteins at an exact times. This clock shows up to be collection by retinoic acid, however the timing of the clock can be affected by the germ cells themselves.

The time of spermatogenesis additionally relies on an extraordinarily complicated program the gene transcription and protein translation. Different splicing of mRNA is extremely prevalent in the testis, and also generates countless germ cell-specific transcripts that are vital for the notified procession the germ cell development. Noncoding RNAs, including microRNAs, tiny interfering RNAs, piRNAs and also long noncoding RNAs, are very expressed in the testis, specifically by the germ cells. Indeed, studies on male germ cells have revealed lot of what is known around the biologic and role of non-coding RNAs. These non-coding RNAs have many and varied roles and are particularly required because that the transcriptional routine executed throughout meiosis and also spermiogenesis.

The masculine germ cabinet transmits both genetic and also epigenetic details to the offspring. Epigenetic changes of the genome space heritable; epigenetic procedures such together DNA methylation and histone adjustments regulate chromatin structure and modulate gene transcription and also silencing. The male germ cabinet undergoes major epigenetic programming in the fetal testis, throughout the genome broad de-methylation and also re-methylation to create 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. That is now recognized that a man’s sperm epigenome can be transformed by environmental determinants (including diet and also lifestyle as well as exposure to environmental factors) throughout his lifetime and also this altered sperm epigenome can influence both his fertility and also the health of his future children.

It is clean from the over summary the spermatogenesis counts on countless intrinsic and extrinsic factors. Yet spermatogenesis is absolutely dependency on androgen-secretion by the Leydig cells; androgens stimulate and maintain germ cell advancement throughout life. Testicular testosterone levels are an extremely high, by virtue of its neighborhood production, however they space considerably greater than those required for the initiation and maintenance the spermatogenesis. Androgen activity on receptors within Leydig cells, peritubular myoid cells and also Sertoli cell is necessary for normal steroidogenesis and also spermatogenesis. When testosterone is vital for spermatogenesis, that is also important to note that exogenous testosterone administration resulting in also slightly supraphysiological serum level suppresses gonadotropin cheap via negative feedback impacts on the hypothalamus and pituitary, causing the cessation that sperm production.

In comparison to androgens, spermatogenesis have the right to proceed in the absence of FSH; however, testes space smaller and also sperm output is reduced. This is because of FSH’s duty in the peri-pubertal proliferation and also differentiation of Sertoli cells and also in the maintain of germ cabinet survival. When FSH is hence not essential for spermatogenesis, the is generally taken into consideration that optimal spermatogenesis requires the merged actions of both androgen and FSH, with both hormones having actually independent, co-operative and also synergistic results to encourage maximal sperm output.

These determinants are vital consideration in the stimulation the spermatogenesis in the setting of HH. As androgens are necessary for the initiation that sperm production, the induction that spermatogenesis in HH acquired after puberty is completed by the administration of hCG (as one LH substitute). Lengthy therapy is required to develop sperm in the ejaculate, provided that human being spermatogenesis takes more than 2 month to create sperm from spermatogonia. Treatment through hCG alone may be adequate for the induction the spermatogenesis in guys with bigger testes due to potential residual FSH action, however, for many men, and an especially for those with congenital HH, the co-administration of FSH is essential for maximal stimulation of sperm output. In men with congenital HH, FSH is essential to induce Sertoli cabinet maturation, whereas males with gained HH and also smaller testes benefit from the co-administration of FSH because of the synergistic action of FSH and also androgens ~ above spermatogenesis.

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In summary, the testes, under the affect of gonadotropins, produce testosterone and sperm. These procedures require the co-ordinated action of many cell varieties and the cheap of paracrine factors. Spermatogenesis is a long and facility process that relies on multiple somatic cells and on the co-ordinated expression the genes, proteins and also non-coding RNAs. Inherent vulnerabilities exist in spermatogenesis an interpretation 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.