madman
Super Moderator
* In HH males, the best results in terms of sperm production are achieved with the co-administration of human chorionic gonadotropin (hCG) and FSH [2, 4].
* Intratesticular testosterone (ITT) binds intracellular androgen receptors located on Sertoli cells, stimulating the secretion of paracrine stimuli necessary for germ cell development[6]. The primary function of ITT is to promote the development of round spermatids into mature sperm during spermiogenesis. Furthermore, ITT helps transition typen A to type B spermatogonia and upregulates androgen receptor expression, thereby improving Sertoli cell function [6].
* LH-driven testosterone works in synergy with FSH to increase sperm quantity. Specifically, FSH regulates structural genes responsible for cell–cell junction organization and genes implicated in transporting regulatory and nutritive molecules from Sertoli cells to germ cells [3]. FSH also controls the proliferation of Sertoli cells,supports their growth and maturation, and triggers the release of androgen-binding protein. Although not required for spermatogenesis completion in humans, FSH deficiency significantly reduces sperm production[1, 3].
Abstract
The production of spermatozoa, a process known as spermatogenesis, is primarily controlled by follicle-stimulating hormone (FSH) and luteinizing hormone (LH)-driven testosterone. LH acts on the Leydig cells, stimulating steroid production, predominantly testosterone, and activating critical inter-related spermatogenesis regulatory pathways. Despite evidence that exogenous gonadotropins containing LH activity can effectively restore spermatogenesis in males with hypogonadotropic hypogonadism, the use of these drugs to treat other forms of male infertility is the subject of an ongoing debate. In this review, we delve into the molecular properties and functions of LH activity in spermatogenesis regulation and explore available preparations for therapeutic use. We also examine the evidence regarding the effectiveness of LH-containing drugs in treating specific male infertility conditions and identify the main areas for future research. Our review highlights the critical role of LH in spermatogenesis and emphasizes the potential of LH-containing drugs in treating male infertility. However, further research is required to completely elucidate the mechanisms underlying the effects of LH activity on sperm production and to establish the most effective dosages and treatment durations.
In this narrative review, we aim to (i) provide an overview of the function of LH activity in spermatogenesis regulation, (ii) summarize the evidence for the therapeutic use of preparations containing LH activity in males with infertility, and (iii) outline the main areas for future research. By exploring the latest research in this area, we hope to clarify the potential benefits and limitations of LH-activity usage for male infertility treatment and pave the way for further advancement in this field.
Luteinizing hormone: structure and role in spermatogenesis
The molecule
LH is a glycoprotein containing two non-covalently linked subunits, α and β. Te α subunit, which is identical for LH, FSH, and hCG, consists of 92 amino acids [5]. In contrast, the β subunits of LH, FSH, and hCG are distinct, providing receptor specificity and different biological properties. Te LHβ subunit, which is made up of 121 amino acids, is produced from mRNA transcripts encoded by the LHB gene located on chromosome 19q13.32. Te biological activity and half-life of the LHβ subunit are influenced by the addition of carbohydrate molecules, leading to the formation of heterodimers [5]. Te LHβ subunit contains a sole N-linked glycosylation site at asparagine 30 and one or two sialic acid residues. Te terminal half-life of endogenous LH is brief (20–30 min).
Te LHβ gene is located in a genetic cluster that also encodes for the β subunit of hCG i [1]. Te LHβ and hCGβ genes share around 95% similarity, with the main discrepancy being an additional sequence of chorionic gonadotropin beta in hCGβ. Consequently, the hCG molecule has a 28-amino acid extension with five additional glycosylation sites [5].
Physiology
LH attaches to transmembrane receptors (LHCGR) situated on Leydig cells, initiating the process of testosterone synthesis. Specifically, LH promotes the transcription of genes that encode enzymes implicated in steroidogenic pathways. Moreover, LH-mediated downstream activities trigger the production of growth factors by Leydig cells, which are essential for spermatogonia proliferation [1].
Testosterone production, which is primarily regulated by LH, is crucial for spermatogenesis. Intratesticular testosterone (ITT) binds intracellular androgen receptors located on Sertoli cells, stimulating the secretion of paracrine stimuli necessary for germ cell development[6]. The primary function of ITT is to promote the development of round spermatids into mature sperm during spermiogenesis. Furthermore, ITT helps transition typen A to type B spermatogonia and upregulates androgen receptor expression, thereby improving Sertoli cell function [6]. Testosterone can undergo partial conversion to estradiol via aromatase or dihydrotestosterone via 5α-reductase.
LH-driven testosterone works in synergy with FSH to increase sperm quantity. Specifically, FSH regulates structural genes responsible for cell–cell junction organization and genes implicated in transporting regulatory and nutritive molecules from Sertoli cells to germ cells [3]. FSH also controls the proliferation of Sertoli cells,supports their growth and maturation, and triggers the release of androgen-binding protein. Although not required for spermatogenesis completion in humans, FSH deficiency significantly reduces sperm production[1, 3].
* Mutations in the LH and LHCGR genes
* Drugs containing LH activity
* Differential molecular action of LH and hCG in Leydig cells
* Therapeutic use of gonadotropins containing LH activity in male infertility
* Hypogonadotropic hypogonadism
* Idiopathic oligozoospermia
* Non‑obstructive azoospermia
* Sperm DNA fragmentation
Future research directions
Advancements in pharmacological therapy hold promise for mitigating infertility in men. However, several critical areas related to the use of gonadotropins in male infertility treatments require further investigation. Real world data studies and prospective clinical trials are essential to evaluate the efficacy and safety of gonadotropins in hypogonadal infertile males with idiopathic oligozoospermia or NOA. Within these categories, there is a need to identify which patients may benefit from gonadotropin treatment and determine the optimal treatment regimens and durations. Another area of interest is establishing serum testosterone thresholds that support optimal spermatogenesis, emphasizing the need for a novel classification of infertile males to stratify patients based on endocrine and semen analysis parameters. Recently, the APHRODITE criteria, a new classification system for infertile men with testicular dysfunction, was introduced [57]. The system aims to enhance patient stratification and optimize hormonal therapy, potentially improving fertility outcomes and advancing the feld’s understanding of male infertility. Lastly, given the potential impact of sperm/seminal microbiome and sperm DNA fragmentation on semen quality and reproductive outcomes [6, 49–55, 58–60], research is needed to investigate the effects of LH-containing gonadotropins on these parameters. These efforts are anticipated to improve patient care and promote the discovery of innovative pharmacological treatment options for male infertility.
Conclusions
Studies suggest that gonadotropins with LH activity have a generally positive therapeutic effect on alleviating male infertility, particularly in patients with HH and NOA. Leydig cells in the testes express LHCGRs, which both LH and hCG can bind. HCG formulations are preferred for increasing ITT production in hypogonadal men, including those with HH, idiopathic oligozoospermic,and NOA, due to their lower costs and broader availability compared with rhLH. Therapy with hCG alone or combined with hMG, urinary FSH, or rFSH has been shown to restore spermatogenesis to varying degrees in HH patients, often enabling natural conception or assisted reproduction. In NOA patients, who typically exhibit low intrinsic testicular function and decreased ITT levels, hCG treatment holds promise to improve sperm retrieval outcomes. Boosting testosterone levels by hCG helps suppress the elevated FSH levels commonly seen in NOA patients and mitigates Sertoli cell receptor desensitization caused by chronic FSH elevation. Treatment with LH-activity gonadotropins may enable oligozoospermic men to achieve biological fatherhood through intrauterine insemination or natural conception, instead of requiring in vitro fertilization. For NOA patients, it may allow ICSI treatment. However, the efficacy of LH-activity gonadotropins in treating male infertility needs further validation through large-scale, well-designed studies. Further research should focus on identifying the most suitable candidates for treatment, optimizing gonadotropin treatment protocols, and clarifying the distinct roles of LH and hCG in Leydig cell function. Additionally, exploring the clinical utility of rhLH in male infertility remains an important area of investigation.
* Intratesticular testosterone (ITT) binds intracellular androgen receptors located on Sertoli cells, stimulating the secretion of paracrine stimuli necessary for germ cell development[6]. The primary function of ITT is to promote the development of round spermatids into mature sperm during spermiogenesis. Furthermore, ITT helps transition typen A to type B spermatogonia and upregulates androgen receptor expression, thereby improving Sertoli cell function [6].
* LH-driven testosterone works in synergy with FSH to increase sperm quantity. Specifically, FSH regulates structural genes responsible for cell–cell junction organization and genes implicated in transporting regulatory and nutritive molecules from Sertoli cells to germ cells [3]. FSH also controls the proliferation of Sertoli cells,supports their growth and maturation, and triggers the release of androgen-binding protein. Although not required for spermatogenesis completion in humans, FSH deficiency significantly reduces sperm production[1, 3].
Abstract
The production of spermatozoa, a process known as spermatogenesis, is primarily controlled by follicle-stimulating hormone (FSH) and luteinizing hormone (LH)-driven testosterone. LH acts on the Leydig cells, stimulating steroid production, predominantly testosterone, and activating critical inter-related spermatogenesis regulatory pathways. Despite evidence that exogenous gonadotropins containing LH activity can effectively restore spermatogenesis in males with hypogonadotropic hypogonadism, the use of these drugs to treat other forms of male infertility is the subject of an ongoing debate. In this review, we delve into the molecular properties and functions of LH activity in spermatogenesis regulation and explore available preparations for therapeutic use. We also examine the evidence regarding the effectiveness of LH-containing drugs in treating specific male infertility conditions and identify the main areas for future research. Our review highlights the critical role of LH in spermatogenesis and emphasizes the potential of LH-containing drugs in treating male infertility. However, further research is required to completely elucidate the mechanisms underlying the effects of LH activity on sperm production and to establish the most effective dosages and treatment durations.
In this narrative review, we aim to (i) provide an overview of the function of LH activity in spermatogenesis regulation, (ii) summarize the evidence for the therapeutic use of preparations containing LH activity in males with infertility, and (iii) outline the main areas for future research. By exploring the latest research in this area, we hope to clarify the potential benefits and limitations of LH-activity usage for male infertility treatment and pave the way for further advancement in this field.
Luteinizing hormone: structure and role in spermatogenesis
The molecule
LH is a glycoprotein containing two non-covalently linked subunits, α and β. Te α subunit, which is identical for LH, FSH, and hCG, consists of 92 amino acids [5]. In contrast, the β subunits of LH, FSH, and hCG are distinct, providing receptor specificity and different biological properties. Te LHβ subunit, which is made up of 121 amino acids, is produced from mRNA transcripts encoded by the LHB gene located on chromosome 19q13.32. Te biological activity and half-life of the LHβ subunit are influenced by the addition of carbohydrate molecules, leading to the formation of heterodimers [5]. Te LHβ subunit contains a sole N-linked glycosylation site at asparagine 30 and one or two sialic acid residues. Te terminal half-life of endogenous LH is brief (20–30 min).
Te LHβ gene is located in a genetic cluster that also encodes for the β subunit of hCG i [1]. Te LHβ and hCGβ genes share around 95% similarity, with the main discrepancy being an additional sequence of chorionic gonadotropin beta in hCGβ. Consequently, the hCG molecule has a 28-amino acid extension with five additional glycosylation sites [5].
Physiology
LH attaches to transmembrane receptors (LHCGR) situated on Leydig cells, initiating the process of testosterone synthesis. Specifically, LH promotes the transcription of genes that encode enzymes implicated in steroidogenic pathways. Moreover, LH-mediated downstream activities trigger the production of growth factors by Leydig cells, which are essential for spermatogonia proliferation [1].
Testosterone production, which is primarily regulated by LH, is crucial for spermatogenesis. Intratesticular testosterone (ITT) binds intracellular androgen receptors located on Sertoli cells, stimulating the secretion of paracrine stimuli necessary for germ cell development[6]. The primary function of ITT is to promote the development of round spermatids into mature sperm during spermiogenesis. Furthermore, ITT helps transition typen A to type B spermatogonia and upregulates androgen receptor expression, thereby improving Sertoli cell function [6]. Testosterone can undergo partial conversion to estradiol via aromatase or dihydrotestosterone via 5α-reductase.
LH-driven testosterone works in synergy with FSH to increase sperm quantity. Specifically, FSH regulates structural genes responsible for cell–cell junction organization and genes implicated in transporting regulatory and nutritive molecules from Sertoli cells to germ cells [3]. FSH also controls the proliferation of Sertoli cells,supports their growth and maturation, and triggers the release of androgen-binding protein. Although not required for spermatogenesis completion in humans, FSH deficiency significantly reduces sperm production[1, 3].
* Mutations in the LH and LHCGR genes
* Drugs containing LH activity
* Differential molecular action of LH and hCG in Leydig cells
* Therapeutic use of gonadotropins containing LH activity in male infertility
* Hypogonadotropic hypogonadism
* Idiopathic oligozoospermia
* Non‑obstructive azoospermia
* Sperm DNA fragmentation
Future research directions
Advancements in pharmacological therapy hold promise for mitigating infertility in men. However, several critical areas related to the use of gonadotropins in male infertility treatments require further investigation. Real world data studies and prospective clinical trials are essential to evaluate the efficacy and safety of gonadotropins in hypogonadal infertile males with idiopathic oligozoospermia or NOA. Within these categories, there is a need to identify which patients may benefit from gonadotropin treatment and determine the optimal treatment regimens and durations. Another area of interest is establishing serum testosterone thresholds that support optimal spermatogenesis, emphasizing the need for a novel classification of infertile males to stratify patients based on endocrine and semen analysis parameters. Recently, the APHRODITE criteria, a new classification system for infertile men with testicular dysfunction, was introduced [57]. The system aims to enhance patient stratification and optimize hormonal therapy, potentially improving fertility outcomes and advancing the feld’s understanding of male infertility. Lastly, given the potential impact of sperm/seminal microbiome and sperm DNA fragmentation on semen quality and reproductive outcomes [6, 49–55, 58–60], research is needed to investigate the effects of LH-containing gonadotropins on these parameters. These efforts are anticipated to improve patient care and promote the discovery of innovative pharmacological treatment options for male infertility.
Conclusions
Studies suggest that gonadotropins with LH activity have a generally positive therapeutic effect on alleviating male infertility, particularly in patients with HH and NOA. Leydig cells in the testes express LHCGRs, which both LH and hCG can bind. HCG formulations are preferred for increasing ITT production in hypogonadal men, including those with HH, idiopathic oligozoospermic,and NOA, due to their lower costs and broader availability compared with rhLH. Therapy with hCG alone or combined with hMG, urinary FSH, or rFSH has been shown to restore spermatogenesis to varying degrees in HH patients, often enabling natural conception or assisted reproduction. In NOA patients, who typically exhibit low intrinsic testicular function and decreased ITT levels, hCG treatment holds promise to improve sperm retrieval outcomes. Boosting testosterone levels by hCG helps suppress the elevated FSH levels commonly seen in NOA patients and mitigates Sertoli cell receptor desensitization caused by chronic FSH elevation. Treatment with LH-activity gonadotropins may enable oligozoospermic men to achieve biological fatherhood through intrauterine insemination or natural conception, instead of requiring in vitro fertilization. For NOA patients, it may allow ICSI treatment. However, the efficacy of LH-activity gonadotropins in treating male infertility needs further validation through large-scale, well-designed studies. Further research should focus on identifying the most suitable candidates for treatment, optimizing gonadotropin treatment protocols, and clarifying the distinct roles of LH and hCG in Leydig cell function. Additionally, exploring the clinical utility of rhLH in male infertility remains an important area of investigation.
