Sertoli cells and Leydig cells are the two main non-sperm-producing cell types in the testes, and they do fundamentally different jobs from fundamentally different locations. Sertoli cells sit inside the seminiferous tubules and physically support sperm development, while Leydig cells live in the tissue between the tubules and produce testosterone. Despite their separate addresses and distinct roles, the two cell types depend on each other so heavily that neither can do its job properly without signals from the other.
Where Each Cell Lives
The location difference is the easiest way to keep the two straight. Sertoli cells line the walls of the seminiferous tubules, which are the tightly coiled tubes where sperm are made. Each Sertoli cell stretches from the outer edge of the tubule wall all the way to the inner lumen, and developing sperm cells are nestled into pockets along the Sertoli cell’s surface. Think of Sertoli cells as the scaffolding of a construction site, physically holding immature sperm in place as they progress through their development stages.
Leydig cells, by contrast, sit in the interstitial tissue between the seminiferous tubules. They cluster in small groups amid blood vessels and connective tissue. This position makes sense for their primary job: they need good access to the bloodstream so the testosterone they produce can circulate throughout the body. Leydig cells are not in direct contact with developing sperm at all. Their influence on sperm production is indirect, mediated by hormones and chemical signals.
What Sertoli Cells Do
Sertoli cells are sometimes called “nurse cells,” and the nickname is apt. Their roles go well beyond structural support.
The most distinctive thing Sertoli cells do is form the blood-testis barrier. Adjacent Sertoli cells are linked by specialized tight junctions that seal off the interior of the seminiferous tubule from the general blood supply. This barrier creates a protected compartment for developing sperm cells, shielding them from immune attack.1PubMed Central. Sertoli Cell Immune Regulation: A Double-Edged Sword The reason this matters is that sperm cells first appear after puberty, long after the immune system has learned to recognize the body’s own tissues. From the immune system’s perspective, sperm look foreign. Without the blood-testis barrier walling them off, the body’s own immune cells would attack developing sperm as if they were invaders.2PubMed Central. The blood-testis and blood-epididymis barriers are more than just their tight junctions
Beyond forming a physical wall, Sertoli cells actively manage the local immune environment. They secrete factors that suppress immune responses in the surrounding tissue, creating an immunologically privileged zone. This combination of physical barrier and immune modulation is so effective that researchers have explored transplanting Sertoli cells alongside grafted tissue from other organs to protect it from rejection.3PubMed Central. Sertoli cells–immunological sentinels of spermatogenesis
Sertoli cells also feed developing sperm cells. Germ cells within the protected compartment are cut off from the body’s normal nutrient supply, so Sertoli cells convert glucose into lactate and shuttle it directly to maturing sperm, which rely on lactate as their main fuel source.4American Journal of Physiology-Endocrinology and Metabolism. Metabolic pathways and male fertility: exploring the role of Sertoli cells in energy homeostasis and spermatogenesis When sperm development is complete and the mature sperm are released, the leftover cytoplasm that gets stripped away (called residual bodies) does not just float around. Sertoli cells engulf and digest these remnants through phagocytosis, recycling the material.5PubMed. The role of the Sertoli cell in phagocytosis of the residual bodies of spermatids They perform the same cleanup on any germ cells that die during the process.6PubMed Central. Ultrastructural Studies of Germ Cell Development and the Functions of Leydig Cells and Sertoli Cells associated with Spermatogenesis
Sertoli cells also produce key hormones of their own. They secrete inhibin-B and anti-Müllerian hormone (AMH).7PubMed. The Sertoli cell hormones inhibin-B and anti Müllerian hormone have different patterns of secretion in prepubertal cryptorchid boys Inhibin-B feeds back to the pituitary gland to help regulate the release of follicle-stimulating hormone (FSH). AMH plays a crucial role during fetal development by causing the regression of female reproductive duct structures, ensuring that male anatomy develops properly.
What Leydig Cells Do
Leydig cells are the body’s testosterone factory. Their primary function is steroidogenesis, the process of building testosterone from cholesterol. When luteinizing hormone (LH) from the pituitary gland binds to receptors on Leydig cells, it triggers a chain of enzymatic steps: cholesterol is shuttled into the cell’s mitochondria, converted into an intermediate molecule called pregnenolone, and then processed through additional enzymes in the mitochondria and smooth endoplasmic reticulum until testosterone is produced.8PubMed Central. Leydig cells: formation, function, and regulation The whole system is tightly regulated by the LH signal.9Current Opinion in Endocrine and Metabolic Research. Regulation of Leydig cell steroidogenesis: intriguing network of signaling pathways and mitochondrial signalosome
Testosterone from Leydig cells does not just affect the testes. It enters the bloodstream and drives male secondary sexual characteristics: deepening of the voice, muscle growth, body hair, bone density. Locally within the testis, testosterone diffuses into the nearby seminiferous tubules, where Sertoli cells and developing germ cells need it to complete sperm production. This is one of the major ways the two cell types are linked: Leydig cells make the hormone that Sertoli cells need to keep spermatogenesis running.
Testosterone is not the only product, though. Leydig cells also produce a peptide hormone called insulin-like 3 (INSL3). During fetal development, INSL3 drives the growth of the gubernaculum, the ligament that guides the testes as they descend from the abdomen into the scrotum.10PubMed. The novel hormone INSL3 is expressed in human testicular Leydig cell tumors Without adequate INSL3, the testes may fail to descend properly, a condition called cryptorchidism. In adults, INSL3 appears to play a role in maintaining bone health and may affect other organs including the kidneys and brain, though research into its full range of functions is still expanding.11PubMed Central. Diverse functions of insulin-like 3 peptide
How the Pituitary Talks to Each Cell Type
The brain’s pituitary gland releases two hormones that target the testes, and each one has a different cellular address. LH targets Leydig cells, stimulating testosterone production. FSH targets Sertoli cells, supporting their role in sperm development. This clean division makes it straightforward to understand why problems with one pituitary hormone can affect one function more than another.
FSH drives Sertoli cell proliferation (especially before puberty, when the number of Sertoli cells a male ends up with is largely determined) and helps maintain the environment needed for spermatogenesis. Meanwhile, Sertoli cells send inhibin-B back to the pituitary to dial down FSH when sperm production is adequate. It is a feedback loop: the pituitary stimulates the testis, the testis reports back, and the pituitary adjusts. A remarkable case report highlighted just how intertwined these signals are. A man with a mutation that reduced LH activity to about one to two percent of normal still had enough testosterone from his few mature Leydig cells to support complete sperm production, suggesting that even a minimal LH signal, combined with intact FSH action on Sertoli cells, can sustain fertility.12PubMed Central. The Roles of Luteinizing Hormone, Follicle-Stimulating Hormone and Testosterone in Spermatogenesis and Folliculogenesis Revisited
Crosstalk Between the Two Cell Types
Sertoli cells and Leydig cells are not just coworkers who happen to share a building. They actively signal each other throughout life, starting before birth. During fetal development, the testis-determining gene SRY triggers the formation of Sertoli cells first. Leydig cells, which do not express SRY themselves, appear afterward, and their differentiation is guided by signals from the already-established Sertoli cells.13PubMed Central. Fetal Leydig cells: progenitor cell maintenance and differentiation Without the Sertoli cells producing those early cues, fetal Leydig cells would not properly form or begin making the testosterone needed to masculinize the developing embryo.14PubMed Central. The road to maleness: from testis to Wolffian duct
The communication continues in adulthood. Sertoli cells express androgen receptors that respond to Leydig-cell-produced testosterone, and research in animal models shows that the androgen receptor in Sertoli cells actually regulates the timing of when adult Leydig cells mature, how well they function, and how many of them the testis ends up containing. Knocking out the androgen receptor specifically in Sertoli cells disrupts Leydig cell populations and upregulates paracrine signaling pathways that normally coordinate Leydig cell differentiation.15PubMed. Sertoli cell androgen receptor expression regulates temporal fetal and adult Leydig cell differentiation, function, and population size In other words, Leydig cells produce the testosterone that Sertoli cells need, and Sertoli cells return the favor by helping regulate how many Leydig cells develop and how well they work. It is a genuinely reciprocal relationship.
What Happens When One Cell Type Fails
Clinical conditions that selectively affect Sertoli cells or Leydig cells illustrate how different their functions are.
Sertoli cell-only syndrome (also called germ cell aplasia) is a condition where the seminiferous tubules contain Sertoli cells but no germ cells at all. The tubules look structurally intact, but no sperm are being made, resulting in azoospermia (a complete absence of sperm in the semen).16PubMed Central. Sertoli cell-only syndrome: etiology and clinical management This can result from genetic abnormalities, prior radiation or chemotherapy, infections, or other insults to the germ cell population. Because Leydig cells are unaffected, testosterone levels may remain normal and the person may have no hormonal symptoms at all. The only sign may be infertility. Diagnosis requires a testicular biopsy. Microscopic examination in these cases shows varying Sertoli cell health: in one study, about half were morphologically mature, roughly a third showed signs of degeneration, and nearly a fifth were undergoing programmed cell death.17Morphology. Morphological changes in the testicle in Sertoli cell-only syndrome in men with nonobstructive azoospermia
On the other side, Leydig cell hypoplasia is a rare genetic condition caused by mutations in the LH receptor gene. In its complete form, an individual who is genetically male (46,XY) may be born with female-appearing genitalia and undescended testes because insufficient testosterone was produced during fetal development. Most reported cases come to clinical attention when an adolescent does not go through puberty on the expected timeline.18PubMed Central. Leydig cell hypoplasia type 1 diagnosed in early childhood with inactivating mutation in LHCGR gene Sertoli cells may be structurally present and somewhat functional, but without adequate testosterone, spermatogenesis cannot be completed. The contrast between these two conditions neatly demonstrates the division of labor: lose the germ cells and Sertoli cells keep the structure running but produce no sperm. Lose Leydig cell function and the hormonal environment collapses, taking both masculinization and fertility with it.
Aging Affects Leydig Cells and Sertoli Cells Differently
Testosterone levels decline gradually in most men starting around the thirties or forties. This drop is largely a Leydig cell problem. With age, two specific steps in the testosterone-production pathway become less efficient: the initial response to LH stimulation (which generates a signaling molecule called cAMP) and the transport of cholesterol into the mitochondria where steroid synthesis begins.19PubMed Central. Steroidogenesis in Leydig cells: effects of aging and environmental factors Obesity and metabolic conditions like high cholesterol can accelerate this decline by speeding up Leydig cell aging and further suppressing testosterone output.20PubMed Central. Mechanisms of Leydig Cell Aging and Obesity-Related Hypogonadism in Men: A Review The resulting testosterone deficiency, sometimes called late-onset hypogonadism, can cause fatigue, reduced libido, erectile difficulties, and bone loss.
Sertoli cells age too, but the timeline and consequences look different. The total number of Sertoli cells in a man’s testes is mostly set before adulthood. As men age, Sertoli cell efficiency declines, meaning each Sertoli cell supports fewer developing sperm cells. Sperm counts drop, but complete infertility from Sertoli cell aging alone is uncommon. The more dramatic age-related fertility effects come from the Leydig cell side, where falling testosterone eventually undermines the hormonal conditions Sertoli cells need to keep spermatogenesis going.
Environmental Chemicals Hit Both Cell Types
Endocrine-disrupting chemicals (EDCs) are increasingly recognized as contributors to declining sperm counts and rising rates of male reproductive disorders.21PubMed Central. Impact of endocrine disrupting chemicals and pharmaceuticals on Sertoli cell development and functions Both Sertoli cells and Leydig cells are vulnerable, but they tend to be harmed in different ways.
Bisphenol A (BPA), found in many plastics and can linings, damages both cell types through the estrogen receptor alpha pathway, but the specific targets differ. In Leydig cells, BPA disrupts steroidogenic enzymes and reduces testosterone output. In Sertoli cells, it weakens the anchoring junctions that help form the blood-testis barrier. Each cell type also shows different sensitivity thresholds to BPA concentration and exposure duration.22PubMed. Differential susceptibility of Leydig and Sertoli cells to bisphenol A
Phthalates, another common class of plasticizers, tell a similar story of dual harm with distinct mechanisms. Research in prepubertal mouse models found that exposure to the phthalate DEHP damaged both Leydig and Sertoli cells, triggering oxidative stress and programmed cell death, but the molecular pathways leading to that damage differed between the two cell types.23PubMed. Di-(2-ethylhexyl) phthalate induces prepubertal testicular injury through MAM-related mitochondrial calcium overload in Leydig and Sertoli cell apoptosis These findings reinforce a broader theme: Sertoli and Leydig cells are different enough in their biology that even a single toxic substance can harm them through separate mechanisms.
Tumors of Sertoli Cells and Leydig Cells
Both cell types can give rise to tumors, though these are rare compared to the germ cell tumors (like seminomas) that account for the majority of testicular cancers. Sertoli cell tumors and Leydig cell tumors are classified as sex cord-stromal tumors, and they behave quite differently from each other and from germ cell cancers. Most are benign, but a small percentage of each type can be malignant.
There are also mixed tumors called Sertoli-Leydig cell tumors, which occur most often in the ovary rather than the testis. Interestingly, research into these mixed tumors found that the Leydig cells within them were not actually neoplastic (cancerous). Their proliferation rate was extremely low, with a cell-division marker (Ki-67) positive in fewer than two percent of Leydig cells, compared to about seven percent in the clearly cancerous stromal component. Clonality analysis confirmed that while the Sertoli-type tumor cells were monoclonal (derived from a single malignant cell), the Leydig cells in several of these tumors were polyclonal, meaning they were a reactive population drawn in by the tumor rather than part of the cancer itself.24Cancer. Evidence that Leydig cells in Sertoli-Leydig cell tumors have a reactive rather than a neoplastic profile This finding has practical implications for how aggressively these tumors need to be treated.
Sertoli Cell Efficiency as a Measure of Reproductive Fitness
Because each Sertoli cell can only support a finite number of developing sperm at once, the ratio of germ cells to Sertoli cells, sometimes called Sertoli cell efficiency, is a meaningful measure of how productive the testis is. This ratio varies between species and even between individuals within a species.
A striking example of this comes from research on common eland, a large African antelope. Males with bigger horns, which serve as signals of fitness, had measurably higher Sertoli cell efficiency and more uniform sperm size. Horn size was also positively linked to testis mass, sperm concentration, and the proportion of testicular tissue devoted to the sperm-producing seminiferous epithelium.25Frontiers in Cell and Developmental Biology. Horn size is linked to Sertoli cell efficiency and sperm size homogeneity during sexual development in common eland This kind of research highlights that Sertoli cell function is not just a medical curiosity. It is a fundamental parameter of male reproductive fitness across mammals, tied to whole-body traits that signal health and vigor.
Lab-Grown Testicular Cells and Future Therapies
The growing understanding of Sertoli and Leydig cell biology is feeding into efforts to create these cells in the lab. Researchers have derived testicular somatic cell-like cells, resembling both Sertoli and Leydig cells, from embryonic stem cells. These lab-generated cells were able to induce early-stage germ cells to differentiate, suggesting they could eventually be used in assisted reproductive technology or as a therapeutic approach for certain types of male infertility.26Communications Biology. Testicular somatic cell-like cells derived from embryonic stem cells induce differentiation of epiblasts into germ cells
There is also interest in using Sertoli cells’ immune-suppressive properties for transplant medicine. Because Sertoli cells are so good at creating a local environment where the immune system stands down, co-transplanting them alongside insulin-producing pancreatic islet cells has been explored as a way to protect the islets from rejection in people with type 1 diabetes. That application is still experimental, but it is a vivid example of how understanding the specific talents of each testicular cell type can open doors well beyond reproductive medicine.
A Brief History of Discovery
The two cell types were identified decades apart by different scientists. Enrico Sertoli, an Italian physiologist, described the cells lining the seminiferous tubules in 1865. Franz Leydig, a German anatomist, actually came first: he described the interstitial cells of the testis in 1850. For decades after their discovery, Leydig cells were studied by light microscopy with little understanding of what they actually did. It was not until 1903 that researchers Pol Bouin and Paul Ancel provided the first real evidence that Leydig cells functioned as an endocrine gland controlling male secondary sexual characteristics. Direct biochemical confirmation that Leydig cells actually produced testosterone did not arrive until 1965.27SpringerLink / ResearchGate. A History of Leydig Cell Research The long gap between discovery and understanding is a reminder that knowing a cell exists is very different from knowing what it does, and the story of both cell types is still being written as new roles and interactions continue to emerge.