Spermatogenesis is the process by which the testis turns stem cells into spermatozoa. It is remarkable for its scale and its precision. One estimate puts human daily sperm production at around 45 million per testis, which works out at roughly a thousand sperm every second. To sustain this output for decades, the testis combines a reserve of stem cells, rapid multiplication of their descendants, the special cell division called meiosis, and a final transformation of round cells into streamlined sperm.
Research on the testis has a long history in the journals behind this archive, from studies of seasonal breeding in wild mammals to molecular work on the genes that switch on only in male germ cells. The sections below summarise the main ideas that run through that research.
Inside the testis: tubules and supporting cells
Sperm are made inside the seminiferous tubules, the functional units of the testis. The developing germ cells are embedded in the wall of each tubule, supported by Sertoli cells. These large supporting cells supply nutrients and regulatory signals to the germ cells around them, and they are the main targets of the hormones that drive sperm production. Between the tubules lie the Leydig cells, which make testosterone in response to luteinising hormone (LH) from the pituitary gland.
Neighbouring Sertoli cells are joined by a set of junctions that form the blood–testis barrier, one of the tightest tissue barriers in the mammalian body. It divides the tubule wall into a basal compartment, where the earliest germ cells sit, and an adluminal compartment, where meiosis and the later stages of development take place. Unusually, the barrier must open and close in a controlled way so that developing germ cells can cross it without losing its protective function. How this remodelling is regulated is an active research area.
From stem cell to spermatozoon
Spermatogenesis follows a fixed sequence. Stem cells called spermatogonia divide to maintain themselves and to produce cells that are committed to development. These multiply, enter meiosis to become haploid cells with a single set of chromosomes, and then undergo spermiogenesis, the reshaping of round spermatids into sperm with a compact head and a tail.
The process is also strictly timed. Microscopists in the 1890s noticed that the same combinations of cell types recur along the tubules. In 1952 Charles Leblond and Yves Clermont formalised this as the “cycle of the seminiferous epithelium”, dividing it into 14 stages in the rat. The length of the cycle is characteristic of each species: about 8.6 days in the mouse, 12.6 days in the rat and 16 days in humans. In men, the whole journey from committed spermatogonium to released sperm is reported to take about 74 days. Unlike most mammals studied, humans and great apes can show several stages side by side in a single tubule cross-section.
Hormonal control
Two pituitary hormones sit at the top of the system. Follicle-stimulating hormone (FSH) acts on Sertoli cells, while LH stimulates the Leydig cells to produce testosterone, which also acts on Sertoli cells. Together they control the proliferation, maturation and function of the supporting cells. Experiments in mice that lack the androgen receptor show that testosterone is needed for the later steps of sperm development and for the release of mature sperm.
The relative importance of the two hormones is still discussed. Rodents can complete spermatogenesis without FSH, although they produce fewer sperm. In men, rare inherited defects tell a different story: loss-of-function changes in the gene for FSH itself have been associated with a complete absence of sperm in the ejaculate, and defects in its receptor with reduced sperm production. Researchers have also questioned the long-held view that very high testosterone levels inside the testis are essential, as experiments suggest spermatogenesis can be completed with much lower levels.
Vitamin A and temperature
Two less obvious requirements have shaped decades of research. Vitamin A has been known to be necessary for normal sperm production since 1925. Its active form, retinoic acid, is now understood to trigger the commitment of early spermatogonia to the path that leads into meiosis. Pulses of retinoic acid move along the tubules in step with the cycle of the seminiferous epithelium. In vitamin A-deficient mouse testes only the earliest spermatogonia and the Sertoli cells remain.
Temperature is the second requirement. Spermatogenesis works best at a temperature slightly below that of the body core, and raised testicular temperature has harmful effects on sperm production and on the sperm that result. The mechanisms studied include germ cell death by apoptosis and damage to DNA.
When the testis goes wrong
In 2001 a group of Danish researchers proposed that poor semen quality, testicular cancer, undescended testes and hypospadias (an abnormal position of the urethral opening) might be symptoms of one underlying condition, which they called testicular dysgenesis syndrome. They suggested that it begins with disturbed development of the testis before birth and may be influenced by the environment. The concept has been influential in research on environmental exposures, though its causes are still under investigation.
Testicular cancer usually starts in germ cells, the cells that make sperm, and is divided into two main types, seminomas and nonseminomas. According to the US National Cancer Institute, it is rare, is most often diagnosed in men aged 20 to 34, and most cases can be cured even when diagnosed at an advanced stage.
Established knowledge and open questions
- Well established: the stages of spermatogenesis and their fixed timing; the central role of Sertoli cells and the blood–testis barrier; the need for FSH, LH and testosterone; the requirement for vitamin A and for a cooler-than-core temperature.
- Still debated: exactly how much FSH and testosterone each contribute in men; how the blood–testis barrier is opened and resealed; why human tubules are organised differently from rodent ones; and whether testicular dysgenesis syndrome is one condition with shared causes.
This page summarises peer-reviewed reviews and public health information. It is not medical advice.
Sources
- Griswold MD, Physiological Reviews, 2016 — Spermatogenesis: the commitment to meiosis (doi:10.1152/physrev.00013.2015)
- Oduwole OO, Peltoketo H, Huhtaniemi IT, Frontiers in Endocrinology, 2018 — Role of follicle-stimulating hormone in spermatogenesis (doi:10.3389/fendo.2018.00763)
- Mruk DD, Cheng CY, Endocrine Reviews, 2015 — The mammalian blood–testis barrier: its biology and regulation (doi:10.1210/er.2014-1101)
- Durairajanayagam D, Agarwal A, Ong C, Reproductive BioMedicine Online, 2015 — Causes, effects and molecular mechanisms of testicular heat stress (doi:10.1016/j.rbmo.2014.09.018)
- Skakkebaek NE, Rajpert-De Meyts E, Main KM, Human Reproduction, 2001 — Testicular dysgenesis syndrome: an increasingly common developmental disorder with environmental aspects (doi:10.1093/humrep/16.5.972)
- US National Cancer Institute, “Testicular cancer”
References from the journal archive
These articles were published in Reproduction, the Journal of Reproduction and Fertility or Reviews of Reproduction and are still cited at their old addresses on this domain. Each link leads to the publisher’s version through its DOI.
- EFFECTS ON SPERMATOGENESIS IN GUINEA-PIGS, RABBITS AND SHEEP AFTER THEIR IMMUNIZATION WITH SEXUAL ORGAN FLUIDS OF BULLS
- EARLY CHANGES IN THE GERMINAL EPITHELIUM OF RAT TESTES FOLLOWING EXPOSURE TO HEAT
- IMMUNOLOGICAL STUDIES WITH RAT TESTIS: ANTIGENIC CHARACTERIZATION
- ALTERATIONS IN SIALIC ACID IN THE EPIDIDYMIS OF THE PUBERAL RAT IN RESPONSE TO CHANGES IN FUNCTIONAL ACTIVITY OF THE TESTIS
- COMPARISON OF THE EFFECTS OF CYPROTERONE, CYPROTERONE ACETATE AND OESTRADIOL ON TESTICULAR FUNCTION, ACCESSORY SEXUAL GLANDS AND FERTILITY IN A LONG-TERM STUDY ON RATS
- CELL DIVISION KINETICS AND DNA SYNTHESIS IN THE IMMATURE SERTOLI CELLS OF THE RAT TESTIS
- REGIONAL BLOOD FLOW IN THE EPIDIDYMIS OF THE RAT AND RABBIT: EFFECT OF EFFERENT DUCT LIGATION AND ORCHIDECTOMY
- THE RÔLE OF GLYCOGEN DURING THE DEVELOPMENT OF THE RAT TESTIS AND PROSTATE
- EFFECT OF CYPROTERONE ACETATE ON SPERM CONCENTRATION, SEMINAL FLUID VOLUME, TESTICULAR CYTOLOGY AND LEVELS OF PLASMA AND URINARY ICSH, FSH AND TESTOSTERONE IN NORMAL MEN
- CARBOHYDRATES OF THE PROSTATE OF TWO AUSTRALIAN MARSUPIALS, TRICHOSURUS VULPECULA AND MEGALEIA RUFA
- SECRETORY FUNCTION OF THE PROSTATE, SEMINAL VESICLE AND OTHER MALE ACCESSORY ORGANS OF REPRODUCTION
- SYNERGISTIC ACTION OF PROLACTIN WITH HCG ON RAT VENTRAL PROSTATE
- Effect of HCG on the interstitial cells and androgen production in the immature rat testis
- The fertilizing capacity of epididymal spermatozoa in the pig
- Daily sperm production and epididymal sperm reserves of pubertal and adult rats
- Seasonal variation in the histology of the testis of the red deer, Cervus elaphus
- Ultrastructural evidence for phagocytosis of spermatozoa in the bovine rete testis and testicular straight tubules
- Antiandrogenic effect of delta-9-tetrahydrocannabinol in adult castrated rats
- Effects of carnitine and some related compounds on the motility of rat spermatozoa from the caput epididymidis
- Angiotensin I converting enzyme in rat testis, epididymis and vas deferens under different conditions
- Cellular aspects of the inhibitory actions of LH-RH on the ovary and testis
- Long-term rhythms of testicular volume and plasma prolactin concentrations in rams reared for 3 years in constant photoperiod
- Testicular FSH receptor numbers and affinity in bulls of various ages
- Variations in testicular androgen receptors and histology of the lamb testis from birth to puberty
- The distribution of carnitine and acetylcarnitine in the epididymis and epididymal spermatozoa of the boar
- Cycles of antler and testicular growth in an aseasonal tropical deer ( Axis axis )
- Dimensions and allometry of testes, epididymides and spermatozoa in the domestic dog ( Canis familiaris )
- Effect of swainsonine on rat epididymal glycosidases
- Localization of androgen receptors in ram epididymal principal cells
- A physiological increase in LH may influence vascular permeability in the rat testis
- Seasonal cycles in the blood plasma concentration of FSH, inhibin and testosterone, and testicular size in rams of wild, feral and domesticated breeds of sheep
- Proliferative activity of gonocytes, Sertoli cells and interstitial cells during testicular development in mice
- Maintenance or stimulation of steroidogenic enzymes and testosterone production in rat Leydig cells by continuous and pulsatile infusions of luteinizing hormone during passive immunization against gonadotrophin-releasing hormone
- Spermatogenesis in retinol-deficient rats maintained on retinoic acid
- Influence of season on seminal characteristics, testis size and serum testosterone in the western spotted skunk ( Spilogale gracilis )
- Effects of nutrition on testicular size and the concentrations of gonadotrophins, testosterone and inhibin in plasma of mature male sheep
- Induction of reversible infertility in male rats by oral ornidazole and its effects on sperm motility and epididymal secretions
- Uptake and release of free l -carnitine by boar epididymal spermatozoa in vitro and subsequent acetylation rate
- Genetic diversity affects testicular morphology in free-ranging lions ( Panthera leo ) of the Serengeti Plains and Ngorongoro Crater
- Seasonal changes in spermatogenesis and testicular steroidogenesis in the male black bear Ursus americanus
- Androgens and masculinization of genitalia in the spotted hyaena ( Crocuta crocuta ). 2. Effects of prenatal anti-androgens
- Molecular characterization of epididymal proteins
- The Parkes Lecture Heat and the testis
- Hormonal and genetic control of germ cell apoptosis in the testis
- Pathogenesis of testicular germ cell tumours
- Role of heat shock protein HSP70-2 in spermatogenesis
- Influence of season and low-level oestradiol immunoneutralization on episodic LH and testosterone secretion and testicular steroidogenic enzymes and steroidogenic acute regulatory protein in the adult ram
- A comparative study of sperm production in two species of Australian arid zone rodents (Pseudomys australis, Notomys alexis) with marked differences in testis size
- Effects of bilateral ganglionectomy and melatonin replacement on seasonal rhythm of testicular activity in Zembra Island wild rabbits (Oryctolagus cuniculus)
- A quantitative (stereological) study of the effects of experimental unilateral cryptorchidism and subsequent orchiopexy on spermatogenesis in adult rabbit testis
- Epididymal lithiasis in roosters and efferent ductule and testicular damage
- Isolation and purification of type A spermatogonia from the bovine testis
- Regulation and perturbation of testicular functions by vitamin A
- Role of FSH, numbers of FSH receptors and testosterone in the regulation of inhibin secretion during the seasonal testicular cycle of adult rams
- Proliferation and functional maturation of Sertoli cells, and their relevance to disorders of testis function in adulthood
- A close correlation in the expression patterns of Af-6 and Usp9x in Sertoli and granulosa cells of mouse testis and ovary
- Differential hormonal regulation of estrogen receptors ERα and ERβ and androgen receptor expression in rat efferent ductules
- Meiotic progression of isolated mouse spermatocytes under simulated microgravity
- Sequential development of flagellar defects in spermatids and epididymal spermatozoa of selenium-deficient rats
- Testis-specific transcription mechanisms promoting male germ-cell differentiation
- Estrogenic induction of spermatogenesis in the hypogonadal ( hpg ) mouse: role of androgens
- Evaluation of candidate markers for the peritubular myoid cell lineage in the developing mouse testis
- Expression of IGF-II mRNA-binding proteins (IMPs) in gonads and testicular cancer
- FSH and testosterone signaling in Sertoli cells
- OCTN2-mediated transport of carnitine in isolated Sertoli cells
- Ontogeny and cellular localization of SRY transcripts in the human testes and its detection in spermatozoa
- Stage and season effects on cell cycle and apoptotic activities of germ cells and Sertoli cells during spermatogenesis in the spiny dogfish ( Squalus acanthias )
- All in the family: TGF-β family action in testis development
- Estrogen effects on fetal and neonatal testicular development
- Gene expression profiles of Spo11 −/− mouse testes with spermatocytes arrested in meiotic prophase I
- Oestrogen receptor α and β, androgen receptor and progesterone receptor mRNA and protein localisation within the developing ovary and in small growing follicles of sheep
- Role of the N , N ′-dimethylbiguanide metformin in the treatment of female prepuberal BALB/c mice hyperandrogenized with dehydroepiandrosterone
- A microarray for microRNA profiling in mouse testis tissues
- Claudin-11 expression and localisation is regulated by androgens in rat Sertoli cells in vitro
- Cryptorchidism in common eutherian mammals
- Phosphoprotein enriched in astrocytes-15 is expressed in mouse testis and protects spermatocytes from apoptosis
- Regulation of the gonadal transcriptome during sex determination and testis morphogenesis: comparative candidate genes
- Transport of carnitine and acetylcarnitine by carnitine/organic cation transporter (OCTN) 2 and OCTN3 into epididymal spermatozoa
- Vezatin, a ubiquitous protein of adherens cell–cell junctions, is exclusively expressed in germ cells in mouse testis
- A comprehensive survey of the laminins and collagens type IV expressed in mouse Leydig cells and their regulation by LH/hCG
- Adiponectin and its receptors are expressed in the chicken testis: influence of sexual maturation on testicular ADIPOR1 and ADIPOR2 mRNA abundance
- C-kit receptor in the human vas deferens: distinction of mast cells, interstitial cells and interepithelial cells
- Effect of germ cell depletion on levels of specific mRNA transcripts in mouse Sertoli cells and Leydig cells
- Mitotic, but not meiotic, oriented cell divisions in rat spermatogenesis
- Post-translational modifications in glycosylation status during epididymal passage and significance in fertility of a 33 kDa glycoprotein (MEF3) of rhesus monkey ( Macaca mulatta )
- Regulation of testicular tight junctions by gonadotrophins in the adult Djungarian hamster in vivo
- Xenografting of sheep testis tissue and isolated cells as a model for preservation of genetic material from endangered ungulates
- A deficiency of lunatic fringe is associated with cystic dilation of the rete testis
- A-kinase anchoring protein 4 has a conserved role in mammalian spermatogenesis
- Arsenic inhibits in vitro spermatogenesis and induces germ cell apoptosis in Japanese eel ( Anguilla japonica )
- Donor Sertoli cells transplanted into irradiated rat testes stimulate partial recovery of endogenous spermatogenesis
- Functions of TAM RTKs in regulating spermatogenesis and male fertility in mice
- Identification of novel immunodominant epididymal sperm proteins using combinatorial approach
- Intracellular pH regulation in human Sertoli cells: role of membrane transporters
- Recent developments in testis tissue xenografting
- Small RNA molecules in the regulation of spermatogenesis
- Testosterone induction of prostaglandin-endoperoxide synthase 2 expression and prostaglandin F2α production in hamster Leydig cells
- Aquaporin AQP11 in the testis: molecular identity and association with the processing of residual cytoplasm of elongated spermatids
- Identification of androgen receptor phosphorylation in the primate ovary in vivo
- Immunoprotective Sertoli cells: making allogeneic and xenogeneic transplantation feasible
- Isolation of sox9 duplicates in catfish: localization, differential expression pattern during gonadal development and recrudescence, and hCG-induced up-regulation of sox9 in testicular slices
- Krüppel-like factor 4 is widely expressed in the mouse male and female reproductive tract and responds as an immediate early gene to activation of the protein kinase A in TM4 Sertoli cells
- Locally produced relaxin may affect testis and vas deferens function in rats
- NAMPT (visfatin) in the chicken testis: influence of sexual maturation on cellular localization, plasma levels and gene and protein expression
- Neutralization of vascular endothelial growth factor antiangiogenic isoforms or administration of proangiogenic isoforms stimulates vascular development in the rat testis
- Orthotopic testicular transplantation in mice
- Production of viable piglets for the first time using sperm derived from ectopic testicular xenografts
- THY1 is a conserved marker of undifferentiated spermatogonia in the pre-pubertal bull testis
- A dense network of dendritic cells populates the murine epididymis
- Cyclic GMP signaling in rat urinary bladder, prostate, and epididymis: tissue-specific changes with aging and in response to Leydig cell depletion
- Endocrinology of the mammalian fetal testis
- Good planning and serendipity: exploiting the Cre/Lox system in the testis
- Prenatal testosterone and dihydrotestosterone exposure disrupts ovine testicular development
- Regucalcin is broadly expressed in male reproductive tissues and is a new androgen-target gene in mammalian testis
- Roosters affected by epididymal lithiasis present local alteration in vitamin D3, testosterone and estradiol levels as well as estrogen receptor 2 (β) expression
- Spermatogenic and sperm quality differences in an experimental model of metabolic syndrome and hypogonadal hypogonadism
- The cholinergic system in rat testis is of non-neuronal origin
- Differential marker protein expression specifies rarefaction zone-containing human Adark spermatogonia
- Distribution of GFRA1-expressing spermatogonia in adult mouse testis
- Cell-type-specific regulation of genes involved in testicular lipid metabolism: fatty acid-binding proteins, diacylglycerol acyltransferases, and perilipin 2
- Maternal obesity disturbs the postnatal development of gonocytes in the rat without impairment of testis structure at prepubertal age
- Actin dynamics regulate subcellular localization of the F-actin-binding protein PALLD in mouse Sertoli cells
- Identification of Leydig cell-specific mRNA transcripts in the adult rat testis
- Long exposure to mature ooplasm can alter DNA methylation at imprinted loci in non-growing oocytes but not in prospermatogonia
- Mind the gap: can we explain declining male reproductive health with known antiandrogens?
- New insights into epididymal function in relation to sperm maturation
- PPP1CC2 can form a kinase/phosphatase complex with the testis-specific proteins TSSK1 and TSKS in the mouse testis
- Prostasomes: extracellular vesicles from the prostate
- Ultrastructure of spermatogenesis in Spix's yellow-toothed cavy ( Galea spixii )
- Cyclooxygenase and prostaglandins in somatic cell populations of the testis
- Effect of hyperandrogenism on ovarian function
- Mammalian gonocyte and spermatogonia differentiation: recent advances and remaining challenges
- Novel molecular mechanisms involved in hormonal regulation of lactate production in Sertoli cells
- Only a small population of adult Sertoli cells actively proliferates in culture
- A novel testis-specific protein, PRAMEY, is involved in spermatogenesis in cattle
- Cellular and molecular responses of adult testis to changes in nutrition: novel insights from the sheep model
- Probing GATA factor function in mouse Leydig cells via testicular injection of adenoviral vectors
- Disturbed spermatogenic signaling in pituitary adenylate cyclase activating polypeptide-deficient mice