madman
Super Moderator
Abstract
In Leydig cell dysfunction, cells respond weakly to stimulation by pituitary luteinizing hormone, and, therefore, produce less testosterone, leading to primary hypogonadism. The most widely used treatment for primary hypogonadism is testosterone replacement therapy (TRT). However, TRT causes infertility and has been associated with other adverse effects, such as causing erythrocytosis and gynecomastia, worsening obstructive sleep apnoea, and increasing cardiovascular morbidity and mortality risks. Stem-cell-based therapy that re-establishes testosterone-producing cell lineages in the body has, therefore, become a promising prospect for treating primary hypogonadism. Over the past two decades, substantial advances have been made in the identification of Leydig cell sources for use in transplantation surgery, including the artificial induction of Leydig-like cells from different types of stem cells, for example, stem Leydig cells, mesenchymal stem cells, and pluripotent stem cells (PSCs). PSC-derived Leydig-like cells have already provided a powerful in vitro model to study the molecular mechanisms underlying Leydig cell differentiation and could be used to treat men with primary hypogonadism in a more specific and personalized approach.
Reduced serum levels of testosterone, a condition known as male hypogonadism, or testosterone deficiency, affects millions of men1. Hypogonadism has been linked to a number of metabolic and quality-of-life changes that include infertility, cardiovascular disease, altered mood, fatigue, decreased lean body mass, reduced bone mineral density, increased visceral fat, metabolic syndromes, decreased libido, and impaired sexual function2–4. In male mammals, testosterone is predominantly produced by Leydig cells in the testis and is under the control of pituitary luteinizing hormone (LH; also known as lutropin)5 (Fig. 1). Small amounts of testosterone are produced by the adrenal gland and are under the control of adrenocorticotropic hormone (ACTH)5. A lack of response or a reduced response to LH that affects the ability of the testis to synthesize testosterone is referred to as primary hypogonadism, whereas a reduction in serum levels of LH that affects the production of testosterone is referred to as secondary hypogonadism6. Primary hypogonadism is frequently associated with genetic causes, ageing, the consequences of drug treatment (for example, chemotherapy), and exposure to viruses (for example, HIV), testicular trauma, or stress6.
Testosterone replacement therapy (TRT) is the first choice for treating primary hypogonadism, as exogenous administration of testosterone can largely reverse low serum levels of this hormone and ameliorate hypogonadism-associated symptoms3. However, adverse effects of TRT on fertility have been reported, mainly as a result of negative feedback in the hypothalamic-pituitary-gonadal (HPG) axis that leads to reduced levels of the gonadotropins LH and follicle-stimulating hormone (FSH), with subsequent suppression of spermatogenesis7 (Fig. 1a). Thus, owing to the suppressive effects on fertility, TRT is not suitable for patients who wish to maintain fertility during treatment. Other potential adverse effects of TRT include causing erythrocytosis and gynecomastia, worsening obstructive sleep apnoea, elevating prostate-specific antigen (PSA) and increasing cardiovascular morbidity and mortality risks8.
Owing to the adverse effects of TRT, demands for alternative therapies to TRT are noticeably increasing. Stem-cell-based therapy has, therefore, begun to gain widespread attention. The success of clinical trials of stem-cell-based therapy in other fields, such as the nervous system, bone and cardiovascular diseases9,10, suggests that stem-cell-derived Leydig cells are feasible as a new method for treating testicular failure. Moreover, these cells provide ideal tools for modelling primary hypogonadism and screening new compounds for correcting Leydig cell dysfunction, which could help to speed up the discovery of the molecular mechanisms underlying hypogonadism and the identification of new chemical entities that target mechanisms controlling testosterone production.
*In this Review, we describe the types and functions of Leydig cells and present studies in the stem-cell field, including in vitro derivation of Leydig cells, allograft and xenograft transplantation of stem-cell-derived Leydig cells in animals, models of primary hypogonadism and drug discoveries.
Development of Leydig cells
The development of Leydig cells involves cell proliferation, morphological differentiation, and functional maturation. Owing to the scarcity of human sources, our knowledge about Leydig cells is mostly obtained from non-human mammals, such as rats and mice; however, species differences are considerable1. Unlike most mammalian Leydig cells, which have a biphasic development (fetal and pubertal-to-adult stages), human and non-human primate Leydig cells undergo a triphasic development, including fetal, neonatal, and adult stages; the adult stage begins at puberty (Fig. 2).
*Fetal and neonatal Leydig cells
*Adult Leydig cells
*Male hypogonadism
*Testosterone replacement therapy
*Gonadotropin therapy
*Stem-cell-based therapy
*Inducing stem cells into Leydig cells
-Adult stem Leydig cells
-Mesenchymal stem cells
-Pluripotent stem cells
-Other types of stem cells
*Future applications of induced Leydig cells
Conclusions
In studies of hypogonadism, stem cells have been used to model the pathophysiological processes of hypogonadism and for Leydig cell transplantation. However, the efficiency and safety of Leydig-like cells derived from stem cells remain largely unknown, and more extensive and precise investigations are required before they can be applied in reproductive medicine. The successful subcutaneous transplantation of stem Leydig cells in rats is one potential ectopic location where Leydig cells could be transplanted outside the testes, but further trials of this approach are required in primates and eventually in humans.
Many obstacles still impede the use of stem cells to study Leydig cell development and to treat primary hypogonadism in men. In less than two decades, this field has seen enormous progress, including providing an in vitro system for visualizing Leydig cell differentiation and raising the possibility of treating men with hypogonadism in a highly accurate and personalized way. Stem cell-based research into primary hypogonadism is, therefore, expected to provide even more possibilities in the future for male reproductive medicine and abundant resources for transplantation therapy.
In Leydig cell dysfunction, cells respond weakly to stimulation by pituitary luteinizing hormone, and, therefore, produce less testosterone, leading to primary hypogonadism. The most widely used treatment for primary hypogonadism is testosterone replacement therapy (TRT). However, TRT causes infertility and has been associated with other adverse effects, such as causing erythrocytosis and gynecomastia, worsening obstructive sleep apnoea, and increasing cardiovascular morbidity and mortality risks. Stem-cell-based therapy that re-establishes testosterone-producing cell lineages in the body has, therefore, become a promising prospect for treating primary hypogonadism. Over the past two decades, substantial advances have been made in the identification of Leydig cell sources for use in transplantation surgery, including the artificial induction of Leydig-like cells from different types of stem cells, for example, stem Leydig cells, mesenchymal stem cells, and pluripotent stem cells (PSCs). PSC-derived Leydig-like cells have already provided a powerful in vitro model to study the molecular mechanisms underlying Leydig cell differentiation and could be used to treat men with primary hypogonadism in a more specific and personalized approach.
Reduced serum levels of testosterone, a condition known as male hypogonadism, or testosterone deficiency, affects millions of men1. Hypogonadism has been linked to a number of metabolic and quality-of-life changes that include infertility, cardiovascular disease, altered mood, fatigue, decreased lean body mass, reduced bone mineral density, increased visceral fat, metabolic syndromes, decreased libido, and impaired sexual function2–4. In male mammals, testosterone is predominantly produced by Leydig cells in the testis and is under the control of pituitary luteinizing hormone (LH; also known as lutropin)5 (Fig. 1). Small amounts of testosterone are produced by the adrenal gland and are under the control of adrenocorticotropic hormone (ACTH)5. A lack of response or a reduced response to LH that affects the ability of the testis to synthesize testosterone is referred to as primary hypogonadism, whereas a reduction in serum levels of LH that affects the production of testosterone is referred to as secondary hypogonadism6. Primary hypogonadism is frequently associated with genetic causes, ageing, the consequences of drug treatment (for example, chemotherapy), and exposure to viruses (for example, HIV), testicular trauma, or stress6.
Testosterone replacement therapy (TRT) is the first choice for treating primary hypogonadism, as exogenous administration of testosterone can largely reverse low serum levels of this hormone and ameliorate hypogonadism-associated symptoms3. However, adverse effects of TRT on fertility have been reported, mainly as a result of negative feedback in the hypothalamic-pituitary-gonadal (HPG) axis that leads to reduced levels of the gonadotropins LH and follicle-stimulating hormone (FSH), with subsequent suppression of spermatogenesis7 (Fig. 1a). Thus, owing to the suppressive effects on fertility, TRT is not suitable for patients who wish to maintain fertility during treatment. Other potential adverse effects of TRT include causing erythrocytosis and gynecomastia, worsening obstructive sleep apnoea, elevating prostate-specific antigen (PSA) and increasing cardiovascular morbidity and mortality risks8.
Owing to the adverse effects of TRT, demands for alternative therapies to TRT are noticeably increasing. Stem-cell-based therapy has, therefore, begun to gain widespread attention. The success of clinical trials of stem-cell-based therapy in other fields, such as the nervous system, bone and cardiovascular diseases9,10, suggests that stem-cell-derived Leydig cells are feasible as a new method for treating testicular failure. Moreover, these cells provide ideal tools for modelling primary hypogonadism and screening new compounds for correcting Leydig cell dysfunction, which could help to speed up the discovery of the molecular mechanisms underlying hypogonadism and the identification of new chemical entities that target mechanisms controlling testosterone production.
*In this Review, we describe the types and functions of Leydig cells and present studies in the stem-cell field, including in vitro derivation of Leydig cells, allograft and xenograft transplantation of stem-cell-derived Leydig cells in animals, models of primary hypogonadism and drug discoveries.
Development of Leydig cells
The development of Leydig cells involves cell proliferation, morphological differentiation, and functional maturation. Owing to the scarcity of human sources, our knowledge about Leydig cells is mostly obtained from non-human mammals, such as rats and mice; however, species differences are considerable1. Unlike most mammalian Leydig cells, which have a biphasic development (fetal and pubertal-to-adult stages), human and non-human primate Leydig cells undergo a triphasic development, including fetal, neonatal, and adult stages; the adult stage begins at puberty (Fig. 2).
*Fetal and neonatal Leydig cells
*Adult Leydig cells
*Male hypogonadism
*Testosterone replacement therapy
*Gonadotropin therapy
*Stem-cell-based therapy
*Inducing stem cells into Leydig cells
-Adult stem Leydig cells
-Mesenchymal stem cells
-Pluripotent stem cells
-Other types of stem cells
*Future applications of induced Leydig cells
Conclusions
In studies of hypogonadism, stem cells have been used to model the pathophysiological processes of hypogonadism and for Leydig cell transplantation. However, the efficiency and safety of Leydig-like cells derived from stem cells remain largely unknown, and more extensive and precise investigations are required before they can be applied in reproductive medicine. The successful subcutaneous transplantation of stem Leydig cells in rats is one potential ectopic location where Leydig cells could be transplanted outside the testes, but further trials of this approach are required in primates and eventually in humans.
Many obstacles still impede the use of stem cells to study Leydig cell development and to treat primary hypogonadism in men. In less than two decades, this field has seen enormous progress, including providing an in vitro system for visualizing Leydig cell differentiation and raising the possibility of treating men with hypogonadism in a highly accurate and personalized way. Stem cell-based research into primary hypogonadism is, therefore, expected to provide even more possibilities in the future for male reproductive medicine and abundant resources for transplantation therapy.
