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


Endocrinology the the masculine Reproductive System and 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 bright Street, Clayton, Victoria, Australia, 3168 liza.odonnell
Hudson institute 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; room of Molecular and also Translational Sciences, Monash University; department of Anatomy and Developmental Biology, Monash University, Clayton, Victoria, Australia


The testes synthesize two important products: testosterone, needed for the advancement and maintain of numerous physiological functions; and also sperm, necessary for male fertility. The synthesis of both products is regulated by endocrine hormones produced in the hypothalamus and also pituitary, and also locally within the testis. Testosterone is indispensable for sperm production, but both testosterone and Follicle Stimulating Hormone (FSH) are needed for optimal testicular advance and maximal sperm production. Sperm are produced via the extraordinarily complex and dynamic procedure of spermatogenesis that calls for co-operation between multiple testicular cabinet types. If it has actually long been recognized that testosterone and FSH regulate spermatogenesis, years of research has melted light on numerous of the detailed mechanisms by which spermatogonial stem cells develop into very specialized, motile spermatozoa. Spermatogenesis requires the concerted interaction of endocrine hormones, but additionally many paracrine and also growth factors, strictly co-ordinated gene and also protein expression programs and epigenetic modifiers of the genome and also different non-coding RNA species. This chapter offers a substantial overview the the fascinating procedure of spermatogenesis and also of that regulation, and emphasises the endocrine regulation that testicular somatic cells and also germ cells. The chapter likewise provides a review of the clinically significant aspects of the endocrine regulation that spermatogenesis. For complete coverage of every related locations of Endocrinology, please see our online cost-free web-book,


The testes synthesize two important products: testosterone, essential for the development and maintenance of plenty of physiological attributes including normal testis function; and also sperm, needed for masculine fertility. The synthetic of both assets is regulated 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 to the testes, wherein it stimulates Leydig cell to develop testosterone: this have the right to act as an androgen (via communication with androgen receptors) but can additionally be aromatized to develop estrogens. The testes, in turn, feedback ~ above the hypothalamus and also the pituitary via testosterone and inhibin secretion, in a an unfavorable feedback loop to border GnRH and gonodotropin production. Both androgens and also FSH action on receptors within the sustaining somatic cells, the Sertoli cells, to wake up various features needed for optimal sperm production. Spermatogenesis is the procedure by i m sorry immature masculine germ cells divide, undergo meiosis and differentiate into highly devoted haploid spermatozoa. Optimal spermatogenesis requires the activity of both testosterone (via androgen receptors) and also FSH.

Spermatogenesis takes location within the seminiferous tubules that the testis. These tubules form long convoluted loops the pass into the mediastinum of the testis and join an anastomosing network that tubules dubbed the rete testis. Spermatozoa departure the testes via the rete and enter the efferent ductules before their passage through, and also final mature in, the epididymis. The seminiferous tubules are made up of the seminiferous epithelium: the somatic Sertoli cells and the arising male germ cell at assorted stages that development. Neighboring the seminiferous epithelium is a class of basement membrane and also 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 the steroidogenic Leydig cells.

Male germ cell development relies certain on the structural and also nutritional assistance of the somatic Sertoli cells. Sertoli cell are huge columnar cells, through their base residing ~ above basement membrane ~ above the exterior of the seminiferous tubules, and also their apical processes bordering germ cells as they construct into spermatozoa. Androgens (and estrogens) and FSH act on receptors within Sertoli cells: germ cells absence both androgen and also FSH receptors, because of this these hormone act directly on Sertoli cell to assistance spermatogenesis. Sertoli cells control the internal atmosphere of the seminiferous tubule by secreting paracrine factors and expressing cell surface ar receptors essential for germ cell development. Sertoli cells form intercellular tight junctions at their base: this occluding junctions avoid the diffusion the substances indigenous the interstitium right into the tubules and also create a devoted milieu forced for germ cabinet development. This junctions are a major component the the so-called ‘blood-testis-barrier’, inside the i of substances native the circulation is prevented indigenous entering the inner part of the seminiferous tubules. The many immature germ cells, consisting of germline stem cells, reside close to the basement membrane the the seminiferous tubules and also thus have complimentary access to factors from the interstitium, however germ cell undergoing meiosis and haploid cell differentiation develop “above” the blood-testis-barrier and also thus are entirely reliant ~ above the Sertoli cell microenvironment. The seminiferous tubules are likewise an immune-privileged environment. Meiotic and post-meiotic germ cells build after the establishment of immune tolerance, and also could thus be known as “foreign” through the immune system, as such the seminiferous tubules, via a variety of different mechanisms consisting of the blood-testis-barrier, proactively exclude immune cells and also factors indigenous entering the seminiferous tubules and also being exposed to meiotic and also haploid germ cells.

The number of Sertoli cells determines the ultimate spermatogenic output of the testes. In humans, Sertoli cell proliferate throughout the fetal and also early neonatal period and again prior to puberty. At puberty, Sertoli cells stop proliferation and attain a mature, terminally identified phenotype the is may be to support spermatogenesis. Disturbances to Sertoli cell proliferation during these time can an outcome in smaller sized testes with lower sperm production. Conversely, disturbances come the cessation of proliferation can result in bigger testes with much more Sertoli cells and also a higher sperm output. It seems most likely that the fail of many men with congenital hypogonadotropic hypogonadism (HH) to accomplish normal testicular size and also sperm output, once treated through gonadotropic stimulation, may result from deficient Sertoli cabinet proliferation throughout fetal and also prepubertal life. The activity of both androgens and FSH ~ above Sertoli cell is crucial for the capacity of Sertoli cells to support full spermatogenesis. In addition, the expression of many genes and also paracrine components within Sertoli cell is vital for spermatogenesis.

Spermatogenesis relies on the capability of Leydig cell to develop testosterone under the affect of LH. Fetal Leydig cells show up following gonadal sex differentiation (gestational weeks 7-8 in humans) and, under the stimulation of placental human chorionic gonadotropin (hCG), results in the production of testosterone during gestation. In humans, fetal cell decrease in number towards term and are lost from the interstitium at around twelve months of age. The adult population of Leydig cell in the human being arises from the department and differentiation that mesenchymal precursor cells under the affect of LH at puberty. Determinants secreted through Sertoli cells and also peritubular myoid cells are likewise necessary because that Leydig cell development and steroidogenesis. Optimal Leydig cabinet steroidogenesis additionally relies on a normal enhance of macrophages in ~ the testicular interstitium and on the presence of androgen receptors in peritubular myoid cells, presumably due to the fact that these cells secrete components necessary because that Leydig cell development and function.

The process of spermatogenesis starts in the fetal testis, once the Sertoli cell populace is stated in the embryonic testis under the influence of male sex determining factors, such together SRY and SOX9. Newly-specified Sertoli cells enclose and kind seminiferous cord structures and also direct primordial germ cells to commit to the male pathway the gene expression. Fetal Sertoli cell proliferate and drive seminiferous cord elongation; this process is also dependent on determinants secreted through Leydig cells. In the neonatal testis, primordial germ cells undergo additional maturation and migrate come the basement of the seminiferous tubules wherein they carry out a pool of precursor germ cells because that postnatal spermatogenesis.

Spermatogonia space the most immature germ cell type. This heterogeneous population includes spermatogonial stem cells, i beg your pardon self-renew transparent life to provide a swimming pool of stem cells accessible for spermatogenesis, and proliferating cells the differentiate and also become committed to entry into meiosis. Spermatogonial advance is hormonally independent and also as together they are present even in the absence of GnRH. Spermatogonia eventually distinguish into spermatocytes that proceed through the procedure of meiosis that starts with DNA synthesis bring about a tetraploid gamete. During the long meiotic prophase, i beg your pardon lasts ~2 weeks, homologous chromosomes pair and meiotic recombination occurs; this entails the induction and also repair of DNA double-strand breaks enabling the exchange of genetic information between paired chromosomes, thereby developing genetic diversity between gametes. At the end of prophase, the meiotic cells continue through 2 rapid and successive reductive departments to yield haploid spermatids. The completion of meiosis depends absolutely on androgen action in Sertoli cells; in the lack of androgen, no haploid spermatids will be produced.

Newly developed haploid ring spermatids differentiate, v no further division, right into the highly devoted spermatozoan throughout the procedure of spermiogenesis. This requires many complex processes, including advancement of the acrosome (an organelle top top the surface of the sperm head that consists of enzymes forced to penetrate the zona pellucida of the oocyte and also thus facilitate fertilization), the flagella (the motile microtubule-based structure compelled for sperm motility) and the remodelling the the spermatid’s DNA right into a strictly coiled structure within a small, streamlined nucleus that will not hinder motility. This remodelling the the DNA involves the cessation that gene transcription as much as 2 weeks before the last maturation the the sperm; because of this spermiogenesis involves the translational delay of many mRNA types which must then be translated at an accurate times transparent their last development. Spermatogenesis ends with the process of spermiation. This requires removal the the spermatid’s huge cytoplasm, revealing the streamlined mature spermatozoa, and the last disengagement the sperm indigenous the Sertoli cells into the tubule lumen, before their passage to the epididymis. Both the survival of spermatids during spermiogenesis and also their release at the end of spermiation is dependency on optimal level of androgen and FSH.

Spermatogenesis is a lengthy process, taking approximately 64 work in the human, and also its inherent intricacy demands specific timing and also spatial organization. In ~ the seminiferous tubules, Sertoli cells and also surrounding germ cells in assorted phases of advancement are very organized right into a series of cell associations, known as stages. This stages result from the truth that a details spermatogonial cell type, when it shows up in the epithelium, is always associated v a particular stage the meiosis and also spermatid development. The stages follow one another along the length of the seminiferous tubule, and also the completion of a series of stages is termed a “cycle”. This cycle along the length of tubule is obvious in rodents, but in human beings several cycles are intertwined in a helical pattern; hence a human being seminiferous tubule viewed in cross ar will contain up to three stages. The perfect of one cycle outcomes in the release of tires spermatozoa right into the tubule lumen; the cycles are repetitive along the tubules, resulting in consistent “pulses” of sperm production. This pulses that sperm release enable the testes to continually develop millions of sperm, with the mean normospermic guy able to produce approximately 1000 sperm per heartbeat.

The specific timing and co-ordination of spermatogenesis is completed by numerous factors. Emerging evidence argues that retinoic acid, metabolized within the testis indigenous circulating retinol (a product of vitamin A) is a major driver that spermatogenesis. A an exact pulse of retinoic acid activity is ceded to a particular stage the the spermatogenic cycle; this pulse is achieved by the constrained expression of enzymes associated in retinoic mountain synthesis, degradation and also storage, as well as the neighborhood expression of retinoic acid receptors. This pulse that retinoic acid acts straight on spermatogonia to stimulate your entry into the pathway committed to meiosis. It also acts straight on Sertoli cells to regulate its cyclic functions. Sertoli cells contain an inner “clock” that allows them to express genes and proteins at an exact times. This clock appears to be collection by retinoic acid, yet the time of the clock have the right to be affected by the germ cells themselves.

The timing of spermatogenesis likewise relies on one extraordinarily complicated program of gene transcription and also protein translation. Different splicing that mRNA is extremely prevalent in the testis, and generates countless germ cell-specific transcripts that are vital for the notified procession that germ cell development. Noncoding RNAs, consisting of microRNAs, little interfering RNAs, piRNAs and also long noncoding RNAs, are very expressed in the testis, specifically by the germ cells. Indeed, researches on male germ cells have revealed lot of what is known around the biological and duty of non-coding RNAs. These non-coding RNAs have actually many and also varied roles and also are particularly required because that the transcriptional regime executed throughout meiosis and also spermiogenesis.

The masculine germ cabinet transmits both genetic and epigenetic details to the offspring. Epigenetic modifications of the genome room heritable; epigenetic processes such as DNA methylation and histone modifications regulate chromatin structure and also modulate gene transcription and also silencing. The male germ cell undergoes major epigenetic programming in the fetal testis, throughout the genome wide de-methylation and re-methylation to develop the germline-specific epigenetic pattern the is eventually transmitted come the offspring. The sperm epigenome is then additional remodelled during postnatal spermatogenesis by various mechanisms. The is now known that a man’s sperm epigenome deserve to be altered by environmental determinants (including diet and also lifestyle and exposure to ecological 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 clear from the above summary that spermatogenesis relies on many intrinsic and extrinsic factors. But spermatogenesis is absolutely dependency on androgen-secretion by the Leydig cells; androgens stimulate and also maintain germ cell development throughout life. Testicular testosterone level are really high, by virtue of its regional production, however they are considerably greater than those forced for the initiation and also maintenance of spermatogenesis. Androgen action on receptors in ~ Leydig cells, peritubular myoid cells and also Sertoli cells is necessary for normal steroidogenesis and also spermatogenesis. When testosterone is important for spermatogenesis, the is additionally important to note that exogenous testosterone management resulting in even slightly supraphysiological serum level suppresses gonadotropin cheap via negative feedback impacts on the hypothalamus and pituitary, causing the cessation of sperm production.

In contrast to androgens, spermatogenesis can proceed in the lack of FSH; however, testes are smaller and sperm output is reduced. This is as result of FSH’s duty in the peri-pubertal proliferation and also differentiation the Sertoli cells and also in the maintenance of germ cabinet survival. While FSH is for this reason not crucial for spermatogenesis, it is generally taken into consideration that optimal spermatogenesis requires the merged actions that both androgen and also FSH, through both hormones having independent, co-operative and synergistic impacts to promote maximal sperm output.

These determinants are crucial consideration in the stimulation the spermatogenesis in the setting of HH. As androgens are necessary for the initiation the sperm production, the induction of spermatogenesis in HH got after puberty is accomplished 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 much more than 2 month to create sperm indigenous spermatogonia. Treatment with hCG alone might be enough for the induction of spermatogenesis in men with larger testes because of potential residual FSH action, however, for plenty of men, and particularly for those v congenital HH, the co-administration of FSH is essential for maximal stimulation of sperm output. In males with congenital HH, FSH is needed to induce Sertoli cabinet maturation, whereas guys with gained HH and smaller testes advantage from the co-administration the FSH due to the synergistic action of FSH and also androgens top top spermatogenesis.

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In summary, the testes, under the influence of gonadotropins, develop testosterone and also sperm. These processes require the co-ordinated actions of multiple cell species and the secretion of paracrine factors. Spermatogenesis is a lengthy and facility process that depends on multiple somatic cells as well as on the co-ordinated expression of genes, proteins and non-coding RNAs. Inherent vulnerabilities exist in spermatogenesis an interpretation that lifestyle and environmental components can potentially influence a man’s sperm epigenome, his fertility and also the health and wellness of his future children.