Advances in stem cell research for the treatment of primary hypogonadism

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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.
 

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madman

Super Moderator
Fig. 1 | The hypothalamus–pituitary-gonadal axis and pathophysiology of male hypogonadism. a | In humans, the hypothalamic-pituitary-gonadal (HPG) axis controls testosterone synthesis. Gonadotropin-releasing hormone (GnRH) released from the hypothalamus stimulates the anterior pituitary gland to release luteinizing hormone (LH). LH triggers Leydig cells within the testes to produce testosterone, which reversely inhibits the release of GnRH and LH. GnRH also triggers the anterior pituitary gland to release follicle-stimulating hormone (FSH), which activates Sertoli cells, thereby supporting spermatogenesis. b | In patients with primary hypogonadism, the response of Leydig cells to LH stimulation is weak, and these cells consequently produce reduced amounts of testosterone. Primary hypogonadism is caused by a malfunction at the level of the testes and is of either congenital or acquired origin. c | In patients with secondary hypogonadism, the malfunction occurs at the level of either the hypothalamus or the pituitary, thereby reducing serum levels of GnRH and LH, leading to reduced production of testosterone. Secondary hypogonadism can also be of either congenital or acquired origin
Screenshot (7829).png
 

madman

Super Moderator
Fig. 2 | The development of human Leydig cells. a | Fetal Leydig cells (FLCs) are cells that produce testosterone before birth. They originate from the mesenchymal cells present in the mesonephros, coelomic epithelial (CE) cells, neural crest cells (NCC), or cells present in the adrenogonadal primordium (AGP). The precursors of FLCs, such as mesenchymal cells expressing steroidogenic factor 1 (SF-1), migrate into the gonads and form FLCs. b| Some cells present in the mesonephros differentiate into testicular mesenchymal cells (TMCs), which continue to proliferate or are at rest until the postnatal age. At the postnatal age of 2 months, a second wave of testosterone is produced by neonatal Leydig cells (NLCs), which are derived from either non-degraded FLCs or newly formed stem Leydig cells (SLCs). After postnatal year 1, NLCs gradually regress. c | Adult Leydig cells (ALCs), which are established during puberty (10–14 years old), are the third developmental stage of human Leydig cells. The differentiation of ALCs is generally divided into four stages, namely SLCs, progenitor Leydig cells (PLCs), immature Leydig cells (ILCs), and ALCs. SLCs originate from non-degraded FLCs, TMCs, peritubular cells located on the outer face of seminiferous tubules, or perivascular cells associated with testicular blood vessels. 3β-HSD, 3β-hydroxysteroid dehydrogenase; 17β-HSD, 17β-hydroxysteroid dehydrogenase/ketosteroid reductase; CYP11A1, cholesterol side-chain cleavage enzyme, mitochondrial; CYP17A1, steroid 17α-hydroxylase/17,20 lyase.
Screenshot (7830).png
 

madman

Super Moderator
Fig. 3 | Induction of human Leydig-like cells from different cell types. Human Leydig-like cells (LLCs) can be induced through the differentiation of different types of stem cells. a | Human adult stem Leydig cells (SLCs), which reside in the testes of adult men, can be isolated using the marker p75+ and induced into LLCs with the treatment of small molecules, such as thyroid hormone, luteinizing hormone, insulin-like growth factor 1, and platelet-derived growth factor-BB. These LLCs rescued serum levels of testosterone and spermatogenesis when they were transplanted in the testes of ethane dimethane sulfonate (EDS)-treated rats71. b | Human mesenchymal stem cells (MSCs), which are isolated from bone marrow (BM-MSCs), adipose (A-MSCs), or umbilical cord blood (UCB-MSCs), can be induced into LLCs with the ectopic expression of certain genes (such as NR5A1) and treatment of small molecules, or through the transplantation of isolated cells into EDS-treated rats140,141,143,144,147,148. c | Human-induced pluripotent stem cells (iPSCs), which can be reprogrammed from somatic cells of adult men, can be induced in LLCs using small molecules with or without the forced expression of NR5A1. These LLCs rescued serum levels of testosterone when they were transplanted in the testes of EDS-treated rats163. d | Human foreskin fibroblasts collected from adult men can be induced into LLC through transdifferentiation.
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madman

Super Moderator
Table 2 | Summary of preclinical trials that derive Leydig-like cells from stem cells of humans and monkeys
Screenshot (7834).png
 

madman

Super Moderator
Fig. 4 | Applications of stem cell-derived, Leydig-like cells for the study and treatment of primary hypogonadism. a | Leydig-like cells (LLCs) derived from stem cells of healthy men can be used to study Leydig cell development in vitro. A comparison of successful induction strategies used in rodents and humans might improve understanding of why differentiation of human Leydig cells differs from that in other species. b | LLCs derived from stem cells of hypogonadal men can be used for disease modeling through the manipulation of genetic factors, environmental exposures, and lifestyle. Candidate genes that might cause primary hypogonadism can be manipulated in healthy stem cells, which are further differentiated into LLCs to provide a model for the investigation of the pathophysiology of male hypogonadism. c | LLCs derived from patient-specific stem cells could undergo gene editing to correct genetic mutations and be transplanted back to patients to ameliorate the symptoms of primary hypogonadism. d | Drugs can be tested on LLCs derived from men with primary hypogonadism. Different patients with primary hypogonadism might show different responses to the same drug. Only the patient whose stem cell-derived LLCs are responsive to the drugs will receive the treatment with these drugs. Those patients whose stem cell-derived LLCs show weak or no response to drugs will not adopt such treatment. This approach can be used to select appropriate drugs and to limit unnecessary adverse effects for individual patients.
Screenshot (7835).png

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madman

Super Moderator
Gonadotropin therapy

Alternative therapies to TRT, such as the administration of exogenous gonadotropins (hCG or LH) with or without FSH, can be used to restore fertility in patients with secondary hypogonadism72. Administration of gonadotropins is not indicated for men with primary hypogonadism, as their Leydig cells respond weakly to gonadotropins. hCG and LH share the same receptor (LHCGR) and promote the testosterone biosynthesis of Leydig cells, but hCG has a longer half-life (36h) than LH (30min), making hCG a more commonly used gonadotropin for treating secondary hypogonadism107. Notably, hCG is the only FDA-approved non-testosterone compound for the treatment of male hypogonadism108. In comparison to TRT, hCG therapy can preserve spermatogenesis. hCG is generally given by subcutaneous or intramuscular injection, with an initial dose of 1,000–1,500 IU twice or three times a week109,110. FSH alone cannot reverse infertility in hypogonadal men, but FSH can be given (via subcutaneous injection, 75–150 IU three times a week) to patients when hCG administration alone fails to restore spermatogenesis109. A study including 75 men diagnosed with secondary hypogonadism showed that 38 men became fathers after receiving 116 cycles of hCG therapy with an initial hCG dose of 1,500 or 2,000 IU given twice a week followed by 75 IU of FSH given three times a week if no sperm were detected following 6 months of hCG treatment110. The median concentration of sperm to achieve pregnancy was 8.0 million/ml (95% CI: 0.2–59.5 million/ml) after 2.3 years of treatment110. hCG administration is also used in combination with TRT to maintain fertility during treatment, or to re-establish fertility after TRT107, and has minimal adverse effects, except for gynaecomastia111. However, the required twice-per-week injections are inconvenient for the patients. Thus, hypogonadal men who do not seek to preserve fertility might choose alternative therapies111
 

madman

Super Moderator
*Administration of gonadotropins is not indicated for men with primary hypogonadism, as their Leydig cells respond weakly to gonadotropins
 

madman

Super Moderator
Key points

• Primary hypogonadism is mainly treated using testosterone replacement therapy (TRT). However, TRT has adverse effects and is unsuitable for men with hypogonadism wishing to maintain fertility

• Stem-cell-based therapy, in which a cell lineage can be re-established in human bodies to produce testosterone normally, would be the ideal choice for treating primary hypogonadism

• Stem Leydig cells, mesenchymal stromal cells, pluripotent stem cells, and fibroblasts are newly discovered sources of Leydig cells

• Stem-cell-derived Leydig cells have many potential applications, including understanding the underlying mechanisms of primary hypogonadism, treating primary hypogonadism using transplantation therapy, and discovering drugs aimed at recovering Leydig cell function

• Research is needed in the applications of Leydig cells, including constructing 3D testicular organoids, promoting in vitro culture conditions of Leydig cells, and exploring the in vivo transplantation locations of Leydig cells
 

Nelson Vergel

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