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Leydig cell

Leydig cells, also known as interstitial cells of Leydig, are specialized endocrine cells located in the interstitial compartment of the testis, adjacent to the seminiferous tubules, and serve as the primary site of testosterone biosynthesis in males. These cells are named after the German histologist Franz von Leydig, who first described them in 1850, and they play a crucial role in male reproductive development, puberty, and maintenance of secondary sexual characteristics by producing androgens in response to luteinizing hormone (LH) from the anterior pituitary gland. Histologically, Leydig cells are large, polygonal cells arranged in clusters within the stroma of the testis, featuring abundant cytoplasm rich in smooth and mitochondria with tubular cristae, adaptations that facilitate synthesis. Their nuclei are typically round and vesicular with prominent nucleoli, and the cells may contain droplets and Reinke crystals—intracytoplasmic inclusions unique to Leydig cells that appear as hexagonal crystals under electron microscopy. Leydig cells undergo distinct developmental phases: fetal Leydig cells emerge early in from mesenchymal precursors to produce high levels of testosterone essential for the of male internal and external genitalia, after which they largely regress postnatally. Adult Leydig cells then during from Leydig cells in the compartment, maturing under the influence of LH and other factors like (IGF-1), to sustain testosterone production necessary for and androgen-dependent functions throughout adulthood. Functionally, Leydig cells respond to pulsatile LH binding to G-protein-coupled receptors, activating adenylate cyclase to increase cyclic AMP levels, which in turn upregulates steroidogenic enzymes such as (CYP11A1) and 17α-hydroxylase () for converting to testosterone. Dysregulation of Leydig cell function can lead to conditions like , characterized by low testosterone levels, , and , while rare Leydig cell tumors may cause or due to excessive secretion.

Anatomy and Structure

Location and Morphology

Leydig cells are primarily located in the testicular , positioned between the seminiferous tubules of the testes, where they form small clusters of up to 10 cells each. In humans, these cells constitute approximately 9-16% of the total testicular volume. Morphologically, Leydig cells exhibit a polyhedral shape characterized by abundant eosinophilic and a large, round, centrally located with a prominent and distinct clumps. Under light microscopy, the appears granular due to the presence of droplets and pigment. Electron microscopy reveals numerous droplets within the , which serve as precursors for synthesis. At the ultrastructural level, Leydig cells feature extensive (SER), forming a prominent network essential for steroidogenesis, along with abundant mitochondria displaying elongated forms and tubular or tubulovesicular cristae. A distinctive feature in human Leydig cells is the presence of Reinke crystals, which are rod-like or cylindrical crystalline inclusions typically found in the , composed of parallel filaments arranged in hexagonal lattices with tubules approximately 30 nm in diameter. These crystals are for human Leydig cells and are absent in most other species. Morphological variations occur across species; for instance, in rodents such as rats, Leydig cells are more densely packed in continuous strings with higher relative volumes of SER and mitochondria, reflecting enhanced steroidogenic capacity, whereas in humans and primates, they are more loosely scattered amid connective tissue and exhibit lower organelle density.

Development and Life Cycle

Fetal Leydig cells emerge in the human testis around 8-9 weeks of gestation, originating from undifferentiated mesenchymal cells in the interstitial compartment shortly after sex determination. These cells undergo rapid proliferation and achieve peak numbers between 14 and 18 weeks of gestation, during which they produce high levels of testosterone essential for the differentiation of male internal and external genitalia as well as Wolffian duct development. Following this peak, fetal Leydig cells regress postnatally through gradual atrophy, with most being replaced by adult Leydig cells derived from mesenchymal progenitors during puberty. However, a small subset (approximately 20%) of fetal Leydig cells persists into adulthood but becomes non-steroidogenic. This results in a substantial decline in their population by infancy, thereby transitioning the testis to a prepubertal state with minimal steroidogenic activity. Leydig cell progenitors derive primarily from mesenchymal stem cells within the testicular , with their differentiation guided by key signaling pathways including steroidogenic factor-1 (SF-1, also known as NR5A1) and (DHH). SF-1 acts as a that initiates steroidogenic competence in these progenitors by promoting the expression of genes involved in transport and steroid biosynthesis, while DHH, secreted by Sertoli cells, binds to Patched receptors on progenitor cells to activate Gli-mediated signaling, upregulating SF-1 and thereby specifying the Leydig cell lineage during fetal development. This orchestrated process ensures the timely formation of a functional fetal Leydig cell population from perivascular or coelomic epithelial-derived mesenchymal precursors. Adult Leydig cells differentiate from a distinct pool of stem and progenitor cells during , driven primarily by rising levels of (LH) from the . This pubertal phase involves sequential stages where Leydig cells proliferate and mature into immature Leydig cells capable of production, culminating in fully differentiated adult cells by the end of , typically around 16-18 years of age, at which point they constitute the primary source of circulating testosterone in males. LH stimulates this progression by binding to receptors on cells, promoting and the acquisition of steroidogenic machinery, while local factors such as further refine maturation. The life cycle of Leydig cells encompasses four main stages: , , immature development, and adult maintenance, followed by age-related decline. In adulthood, these cells maintain testosterone output through sustained responsiveness to LH, but with advancing age, their numbers decrease by about 50% between 20 and 70 years due to increased , reduced , and interstitial , contributing to diminished levels and associated physiological changes. Stem Leydig cells, identified in research since the early , represent an undifferentiated subpopulation of peritubular and perivascular mesenchymal cells that retain regenerative potential throughout life. These cells, marked by expression of factors like endosialin (CD248), can be induced to differentiate into functional Leydig cells and , offering promising avenues for regenerative therapies to restore testosterone production in cases of age-related or pathological decline. Studies have demonstrated their ability to regenerate the Leydig cell population following targeted ablation, highlighting their role in maintaining testicular steroidogenesis.

Physiological Function

Androgen Biosynthesis

Leydig cells primarily synthesize through , a process that converts into testosterone via a series of enzymatic reactions occurring in the mitochondria and smooth (SER). The pathway begins with as the precursor, which is transported across the mitochondrial membranes by the (StAR), serving as the rate-limiting step by facilitating delivery to the . Once inside, undergoes side-chain cleavage by the enzyme CYP11A1 (also known as P450scc) to form , the first committed intermediate. Subsequent steps occur primarily in the SER: is converted to progesterone by (3β-HSD), followed by to via 's hydroxylase activity. then cleaves the side chain of to produce , which is finally reduced to testosterone by 17β-hydroxysteroid dehydrogenase type 3 (17β-HSD3). The overall biosynthetic pathway can be summarized as: → → progesterone → → → testosterone. In adult males, Leydig cells are the main source of circulating androgens, producing approximately 95% of testosterone, with the remainder derived from adrenal glands. Under (LH) stimulation, human Leydig cells generate about 5-7 mg of testosterone per day, which is secreted into the bloodstream to support male reproductive and secondary sexual characteristics. A portion of this testosterone is further converted to the more potent (DHT) in peripheral target tissues via enzymes.

Hormonal Regulation

The primary hormonal regulation of Leydig cells is mediated by (LH) secreted from the gland. LH binds to G-protein-coupled receptors (LHCGR) on the surface of Leydig cells, activating the stimulatory G-protein (Gs) and subsequently increasing intracellular (cAMP) levels. This activates (PKA), which phosphorylates key transcription factors and upregulates the expression of (StAR) and cytochrome P450 side-chain cleavage enzyme (CYP11A1), essential initiators of . Regulation occurs through negative feedback within the hypothalamic-pituitary-gonadal (HPG) axis. Elevated testosterone levels from Leydig cells inhibit (GnRH) release from the and LH secretion from the pituitary, maintaining in androgen production. This feedback loop ensures that testosterone output aligns with physiological demands, preventing overproduction. Paracrine influences from neighboring testicular cells further modulate Leydig cell activity. Sertoli cells secrete inhibin, which inhibits the of stem Leydig cells, thereby regulating the pool of precursor cells available for differentiation into mature androgen-producing cells. In contrast, (IGF-1), produced by peritubular myoid cells and Leydig cells themselves, promotes the and differentiation of progenitor and immature Leydig cells, supporting the development of the adult Leydig cell lineage. Additional local modulators include estrogens generated via activity within Leydig cells, which convert testosterone to and exert to fine-tune synthesis and prevent excessive local accumulation. Activins, signaling through receptors on Leydig cells, stimulate the of and progenitor Leydig cells while inhibiting their differentiation to maintain reserves; , often co-expressed, antagonizes activin signaling to balance this process during testicular development. Leydig cell function exhibits diurnal and age-related variations. Testosterone production peaks in the early morning, synchronized with circadian rhythms in LH pulsatility, reflecting the HPG axis's temporal control over Leydig responsiveness. With advancing age, testosterone levels decline due to reduced sensitivity of Leydig cells to LH stimulation, involving diminished cAMP production and impaired signaling pathways, independent of changes in LH levels.

Distribution and Variants

Testicular Leydig Cells

Testicular Leydig cells are polyhedral endocrine cells located in the compartment of the testis, comprising approximately 99 million cells per testis in adult men, with a reported range of 47 to 245 million based on stereological analysis of post-mortem samples across ages 16 to 80 years. These cells are organized in clusters within the stroma between seminiferous tubules, forming lobular arrangements that facilitate their endocrine function. Each cluster is closely associated with an extensive network of fenestrated capillaries, which surround the Leydig cells to enable rapid secretion and delivery of androgens into the bloodstream. Leydig cells maintain intimate spatial relationships with adjacent testicular somatic cells, including Sertoli cells lining the seminiferous tubules and peritubular myoid cells enveloping the tubules, allowing for essential to testicular function. Produced testosterone diffuses directly from the interstitial space into the seminiferous tubules, where it binds to androgen receptors in Sertoli cells to support without requiring vascular mediation. This proximity ensures localized hormone action, coordinating development with interstitial steroidogenesis. The distinction between fetal and adult Leydig cell populations is more pronounced in , including humans, than in , where fetal cells largely persist and contribute to the pool without a clear regressive . In , fetal Leydig cells dedifferentiate postnatally, giving way to a separate lineage that emerges during , reflecting evolutionary adaptations in reproductive timing and hormonal demands. , such as rats, exhibit a more unified developmental trajectory with overlapping fetal and adult characteristics, leading to differences in cell turnover and steroidogenic capacity across . Functional adaptations of testicular Leydig cells include their high degree of vascularization, which supports efficient export by positioning clusters along both arterial and venous microvasculature branches for swift systemic distribution. In seasonally breeding mammals, such as certain ungulates and , Leydig cell volume and number increase during breeding seasons to elevate output, with size expansions correlating positively with testosterone levels and spermatogenic activity. These cells are indispensable for male reproduction, as fetal Leydig cells drive Wolffian duct stabilization and differentiation into , , and , while adult cells sustain secondary sex characteristics like muscle mass, voice deepening, and through ongoing testosterone production.

Ovarian and Other Leydig-Like Cells

Ovarian Leydig cells, also known as hilus cells, are specialized mesenchymal-derived steroidogenic cells situated in the ovarian hilus near nonmyelinated nerves. These cells morphologically resemble testicular Leydig cells, often containing eosinophilic Reinke crystals and lipid droplets, and primarily synthesize androgens such as to provide precursors for production by cells in developing ovarian follicles. In addition to hilus cells, theca interna cells of ovarian follicles function as Leydig-like cells, differentiating from ovarian stroma under (LH) stimulation to produce androgens. These cells exhibit lower testosterone output compared to testicular Leydig cells, focusing instead on secretion that supports biosynthesis in granulosa cells via the two-cell, two-gonadotropin model. During , theca-lutein cells—transformed cells within the —demonstrate similar steroidogenic capacity, regulated by (hCG) to sustain progesterone production while capable of synthesis if stimulated. Hilus cell tumors represent rare -secreting neoplasms originating from ovarian hilus cells, histologically mimicking testicular Leydig cell adenomas through the presence of Reinke crystals and elevated testosterone levels. Ectopic Leydig-like cells occasionally appear in the adrenal gland, displaying steroidogenic features analogous to gonadal Leydig cells, including androgen production in response to appropriate stimuli. Excessive androgen output from these ovarian and ectopic Leydig-like cells can cause virilization in women, manifesting as hirsutism, acne, and menstrual irregularities.

Clinical and Pathological Aspects

Associated Disorders

Leydig cell dysfunction contributes to primary , characterized by inadequate testosterone production due to direct impairment of Leydig cells, often seen in conditions like (47,XXY), where testicular fibrosis and hyalinization lead to reduced Leydig cell function, resulting in low serum testosterone levels, , and symptoms such as and . In contrast, secondary arises from disruptions in the hypothalamic-pituitary-gonadal axis, indirectly affecting Leydig cell stimulation via low levels, though primary forms directly involve Leydig cell failure. Symptoms in both types include , reduced , and risk from . Leydig cell tumors account for 1-3% of all testicular neoplasms and are typically benign, though malignant cases occur in about 10%. In children, these tumors often present with due to excess production, while adults may experience , , or from hormonal imbalances. Histologically, they feature large polygonal cells with and are distinguished by intracytoplasmic Reinke crystals—refractile, structures for Leydig cell origin, observed in 30-40% of cases. Aging leads to a progressive decline in Leydig cell number and steroidogenic capacity, contributing to (andropause), with testosterone levels dropping by approximately 1% annually after age 30, exacerbating symptoms like reduced muscle mass and mood changes. This decline is linked to , where and accelerate Leydig cell senescence, further impairing testosterone synthesis and increasing risks for and . Environmental endocrine disruptors, such as , impair fetal Leydig cell development by interfering with steroidogenesis pathways, leading to reduced testosterone in utero and long-term outcomes like and adult , as evidenced by post-2000 studies showing dose-dependent effects on male reproductive tract malformations. These chemicals bind to receptors or dysregulate in developing testes, with prenatal exposure correlating to lower sperm counts in adulthood. Leydig cell hypoplasia, a rare autosomal recessive disorder, results from inactivating mutations in the LHCGR gene encoding the /choriogonadotropin receptor, causing severe underdevelopment of Leydig cells and presenting as 46,XY disorders of sex development with female-appearing external genitalia, absent puberty, and primary amenorrhea in affected individuals. Type I involves complete loss of receptor function, leading to undetectable testosterone, while milder type II variants allow partial androgenization but still result in .

Diagnostic and Therapeutic Implications

Diagnosis of Leydig cell dysfunction primarily involves assessing production and the hypothalamic-pituitary-gonadal through tests. total testosterone levels, measured in the early morning on at least two separate occasions, serve as the initial screening tool for , with levels below 300 ng/dL indicating deficiency related to impaired Leydig cell function. Concurrent measurement of (LH) levels helps differentiate primary , characterized by elevated LH due to Leydig cell failure, from secondary causes where LH is low or normal. The (hCG) stimulation test evaluates Leydig cell reserve by administering hCG (typically 1500 IU subcutaneously every other day for up to seven doses) and measuring the subsequent rise in testosterone; a suboptimal increase (e.g., less than 300 ng/dL in prepubertal individuals) signifies reduced steroidogenic capacity. For suspected Leydig cell tumors, is the first-line imaging modality, revealing well-defined, hypoechoic masses often with increased vascularity, while MRI provides additional characterization for equivocal cases or to assess extratesticular extension. Histological examination via testicular confirms in ambiguous scenarios, with the presence of intracytoplasmic Reinke crystals—rod-shaped, structures—being a feature of Leydig cell tumors in approximately 30-40% of cases. is recommended for congenital forms, targeting mutations in the LHCGR gene (encoding the LH/choriogonadotropin receptor) for type I Leydig cell hypoplasia, which causes severe underandrogenization, or NR5A1 (SF-1) mutations associated with and impaired Leydig cell development. Therapeutic strategies for Leydig cell-related conditions focus on restoring levels or addressing pathological growths. Testosterone replacement therapy (TRT) is the cornerstone for , utilizing transdermal gels (e.g., 1% testosterone applied daily to maintain mid-normal levels of 450-600 ng/dL) or intramuscular injections (e.g., 100 mg weekly) to alleviate symptoms like and reduced while monitoring for side effects such as erythrocytosis. For Leydig cell tumors, radical is the standard curative approach for localized disease, achieving over 90% five-year survival in benign cases, with adjuvant (e.g., platinum-based regimens like ) reserved for metastatic or malignant variants, which occur in about 10% of instances. Emerging explores cell-based regeneration, with preclinical studies demonstrating of induced pluripotent cells into functional Leydig-like cells capable of testosterone production, though clinical trials remain in early phases as of 2025. Ongoing monitoring in patients with Leydig cell dysfunction includes to evaluate impacts, as reduced testosterone can impair , and (DEXA) scans to assess bone mineral density, given the risk of from chronic . Preventive measures emphasize lifestyle modifications, such as and exercise, to mitigate age-related Leydig cell decline, alongside avoidance of endocrine disruptors like and , which can impair steroidogenesis and accelerate .

History and Nomenclature

Discovery and Historical Context

The interstitial cells of the testis, now known as , were first described in 1850 by the German anatomist , who observed them using light microscopy in the testes of rabbits and other mammals, noting their location in the interstitial tissue between seminiferous tubules. These cells were initially characterized by their polygonal shape and large nuclei, though their function remained unclear for decades. Crystalline inclusions, known as , were later identified in these cells. Complementary work by in 1865 identified the supporting cells within the seminiferous tubules, providing early context for the cellular organization of the testis. The endocrine role of Leydig cells began to emerge in the early . In , Paul Ancel and Pol Bouin provided the first substantial evidence of their hormonal function by demonstrating that surgical removal of these cells in animals led to impaired male secondary sexual characteristics, suggesting they acted as an . This was further supported in the 1920s and 1930s through experiments with testicular extracts, which induced masculinization in castrated animals, indicating the presence of an active androgenic principle derived from interstitial tissue. The identification of testosterone as the key product came in 1935, when and Leopold Ruzicka independently isolated and synthesized the hormone from bull testes, confirming Leydig cells as the primary site of ; this discovery earned them the 1939 . Mid-20th-century advances solidified the structural basis for Leydig cell function. In the , electron microscopy studies revealed their abundant smooth and mitochondria, features indicative of steroidogenic activity, providing direct morphological evidence of their endocrine capability. By 1973, specific binding sites for (LH) were identified on Leydig cell membranes, establishing the receptor-mediated regulation of testosterone production. In the late 20th and early 21st centuries, shifted toward molecular and regenerative aspects. The of the LH receptor cDNA in the late 1980s enabled detailed studies of signaling pathways in Leydig cells. Stem Leydig cell populations were identified in the 2000s, revealing undifferentiated precursors capable of self- and into steroidogenic cells, offering insights into postnatal Leydig cell renewal. Concurrently, links to environmental factors emerged, with 2010s studies highlighting how endocrine-disrupting chemicals, such as , impair Leydig cell development and function in animal models, raising concerns for reproductive health. In the , advances in have enabled the of human induced pluripotent stem cells (iPSCs) into functional Leydig-like cells capable of testosterone production, offering potential therapies for conditions like .

Etymology

The Leydig cell derives its name from Franz von Leydig (1821–1908), a anatomist and zoologist who first described these polygonal cells in the testes of various mammals as part of his seminal 1850 work, Zur Anatomie der männlichen Geschlechtsorgane und Analdrüsen der Säugethiere, published in the Zeitschrift für wissenschaftliche Zoologie. The honors his histological observations of the cells' distinctive appearance and location between seminiferous tubules, though Leydig himself did not propose the term during his lifetime. Following their initial identification, the cells were commonly designated as "" in early literature, reflecting their position in the testicular rather than any specific , a that persisted into the early as researchers like Bouin and Ancel (1903) began associating them with internal secretion. The specific term "Leydig cells" gained traction around 1900–1905 and became standardized in scientific usage by the post-1920s period, coinciding with advancing endocrine research that clarified their role in production. In archival and older texts, the full phrase "" frequently appears to denote the same population, emphasizing both location and discoverer. Related nomenclature includes "hilus cells" or "hilar Leydig cells" for analogous steroid-producing cells found in the ovarian hilum, which share morphological and functional similarities with testicular Leydig cells but were distinguished in gynecological due to their ectopic-like positioning near ovarian and vessels. The surname "Leydig" itself originates as a common family name, with no additional etymological derivations beyond this eponymous tribute to the scientist's contribution.

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