Approximately one-sixth of couples of childbearing age experience infertility, and male factor infertility accounts for about 50% of cases [1]. In recent years, the fertility rate in China has declined, and the etiological mechanisms of male infertility have received increasing attention. However, many aspects of the physiology and pathophysiology of male reproductive regulation remain to be elucidated [2]. Sertoli cells in the seminiferous tubules are regulated by follicle-stimulating hormone (FSH) and are key to maintaining the microenvironment required for spermatogenesis and regulating sperm production [3]. Sertoli cells are the only cells in the testis that express the follicle-stimulating hormone receptor (FSHR). This article reviews the role of FSHR in Sertoli cells in regulating spermatogenesis and male reproduction, summarizes research progress, and provides reference material for basic research on male reproductive regulation, the diagnosis and treatment of infertility, and the development of male contraceptive drugs [4].

FSHR is a transmembrane glycoprotein belonging to the G protein-coupled receptor family and is expressed mainly in Sertoli cells. When FSH binds to its receptor on the surface of Sertoli cells, it activates a series of intracellular signaling pathways. One key example is the cyclic adenosine monophosphate (cAMP)/protein kinase A (PKA) pathway. Activation of this pathway leads to phosphorylation of multiple target proteins, thus influencing cellular functions related to spermatogenesis [5].

FSH/FSHR signaling promotes the synthesis and secretion of androgen-binding protein (ABP) by Sertoli cells. ABP binds testosterone and helps maintain a high local testosterone concentration within the seminiferous tubules, which is essential for normal sperm development. In addition, FSHR activation via the cAMP/PKA pathway regulates the expression of genes involved in cell cycle progression, cell adhesion, and nutrient transport in Sertoli cells. These effects help establish an appropriate microenvironment for spermatogonial stem cell (SSC) proliferation and differentiation into mature sperm.

Moreover, recent studies suggest that FSHR may interact with other signaling molecules and transcription factors in Sertoli cells, forming a complex regulatory network. Certain transcription factors that regulate spermatogenesis-related genes are modulated by FSHR-mediated signaling, thereby influencing spermatogenesis at the molecular level [6].

A detailed understanding of the mechanism of FSHR in regulating spermatogenesis is important for clarifying the etiology of male infertility. Abnormalities in FSHR function or expression may disrupt spermatogenesis. For example, mutations in the gene encoding FSHR can cause a variety of male reproductive disorders, including azoospermia and oligozoospermia. Studying these mutations and their effects on FSHR signaling may help identify new diagnostic markers and therapeutic targets for male infertility [7].

In addition, research on FSHR provides insights into the development of male contraceptive drugs. Because FSHR plays a crucial role in spermatogenesis, targeting FSHR could represent a novel approach to male contraception. Agents that specifically block FSHR function may inhibit sperm production without exerting substantial effects on other endocrine functions [8]. However, developing such drugs requires a detailed understanding of FSHR structure and function, as well as the complex regulatory mechanisms involved in spermatogenesis.

Furthermore, ongoing research is exploring the potential of FSHR as a biomarker for evaluating male reproductive health [9]. Measuring the expression level or activity of FSHR in testicular tissue or semen may provide valuable information about the status of spermatogenesis and male fertility. These findings could be applied in clinical practice for early diagnosis and prognostic assessment of male infertility. The role of FSHR in Sertoli cells in regulating spermatogenesis and male reproduction remains an active area of research. Continued investigation may not only deepen our understanding of the fundamental mechanisms of male reproductive regulation but also have implications for the diagnosis, treatment, and prevention of male infertility, as well as the development of male contraceptive strategies [10].

With testicular growth and development, single-cell sequencing analyses of embryonic, infantile, prepubertal, pubertal, adult, and elderly testicular tissues have revealed transcriptionally distinct Sertoli cell subtypes. One study classified and analyzed Sertoli cells from human embryos through childhood and found that genes upregulated in Sertoli-1 (primarily found in infantile datasets) were involved in biological processes such as aerobic respiration, adenosine triphosphate (ATP) synthesis coupled to electron transport, cellular responses to steroid hormone stimulation, and male gonadal development. In contrast, upregulated biological processes in Sertoli-2 (primarily in embryonic datasets) included very low-density lipoprotein particle clearance, positive regulation of cholesteryl esterification, and phospholipid efflux, whereas upregulated biological processes in Sertoli-3 (mainly in childhood datasets) included cellular respiration, mitochondrial electron transport, and mitochondrial ATP synthesis [11]. These findings suggest that genes upregulated in Sertoli-1 are associated with energy metabolism and male gonadal development, Sertoli-2 is actively involved in cholesterol metabolism-related processes, and Sertoli-3 is linked to cellular respiration and mitochondrial function. Another study performed pseudotemporal analysis of pubertal Sertoli cell development and classified Sertoli cells from 1- and 7-year-old children into two distinct states, termed immature Sertoli-1 and immature Sertoli-2. These two states ultimately converge into a developmental trajectory leading to mature Sertoli cells, which emerge in the testis from approximately 11 years of age [12]. The two immature states show marked differences in metabolic/mitochondrial activity, translation, and cell cycle characteristics: immature Sertoli-1 cells exhibit high androgen receptor (AR) target gene expression, high mitochondrial transcription, and low expression of ribosomal protein genes, whereas immature Sertoli-2 cells show higher transcription of ribosomal protein genes, mitochondrial ATPases, and mitochondrial membrane proteins, along with a higher proportion of cells in the G1 phase of the cell cycle [13].

During late puberty, Sertoli cells undergo complex developmental changes involving morphogenesis, innate immune status, and metabolism. Genes related to the cytoskeleton, cell morphogenesis, and the extracellular matrix are upregulated during Sertoli cell maturation. In addition, genes encoding antimicrobial innate immune peptides (including defensins) and other immune-related genes are upregulated during puberty, which may help Sertoli cells protect the testis from infection, especially after sexual maturity. Mature Sertoli cells display lower expression of metabolism-related genes overall but exhibit higher expression of genes related to the glycolytic pathway. One study divided testes from elderly individuals into two groups—histologically normal testes (elderly group 1) and testes with significant spermatogenic defects (elderly group 2)—and compared both with a fertile young group. The analysis suggested that genes upregulated in elderly Sertoli cells were enriched for inflammation-related Gene Ontology (GO) terms, including ‘response to injury,’ ‘acute inflammatory response,’ and ‘interleukin signaling’ [14]. Collectively, these results indicate that Sertoli cells progress through distinct developmental stages and adapt to support testicular development, maintain male reproductive physiology, provide immune protection, and meet high energy demands.

During testicular growth and development, the interactions between Sertoli cells and spermatogenic cells also change continuously. Compared with Sertoli cells in the embryonic and infantile periods, Sertoli cells in childhood (Sertoli-3) exhibit the greatest number of ligand-receptor interactions with germ cells [6]. The previously mentioned study reported that, from the young group to elderly group 1 (histologically normal testes) and then to elderly group 2 (significant spermatogenic defects), the intensity of interactions between Sertoli cells and spermatogenic cells progressively weakens; furthermore, the number and strength of interactions between SSCs and somatic cells are significantly reduced in elderly group 2 [14]. For example, in elderly group 2, activin signaling between Sertoli cells and SSCs is significantly decreased, and the receptor tyrosine kinase encoded by the KIT proto-oncogene (KIT) signaling between Sertoli cells and differentiated spermatogonia is reduced. These two pathways contribute to the regulation of SSC self-renewal and differentiation. Germ cells rely on Sertoli cells for nutrients during spermatogenesis. Correspondingly, cholesterol synthesis is increased in aged Sertoli cells, whereas the production of precursor metabolites and energy, amino acid biosynthesis, organic phosphorus biosynthesis, positive regulation of small-molecule metabolism, and positive regulation of protein maturation are reduced. These findings suggest that metabolic changes in aging Sertoli cells may contribute to the decline in sperm function [15,16].

Human FSHR is a G protein-coupled receptor localized to the cell membrane. It contains 695 amino acids, has a relative molecular mass of approximately 75,000, and includes 3–4 potential glycosylation sites. FSHR binds FSH through a large extracellular domain [17]. G proteins exist in multiple forms, and Sertoli cells express both stimulatory Gαs and inhibitory Gαi subunits (encoded by Gαi1, Gαi2, and Gαi3). Pubertal Sertoli cells express higher levels of FSHR on the membrane surface, and dual coupling of Gαs and/or Gαi to FSHR can differentially regulate adenylyl cyclase activity, thereby modulating cAMP production in response to FSH stimulation. Alternative splicing of FSHR exons generates distinct receptor isoforms; four FSHR isoforms have been reported in mice, rats, sheep, cattle, and humans. However, research on these isoforms in relation to spermatogenic defects in infertile males remains limited. One study reported three FSHR isoforms in infertile males, but whether specific isoforms are associated with spermatogenic defects remains unclear.

FSHR is first expressed in testicular tissue during weeks 8–16 of human embryonic development and is expressed exclusively in Sertoli cells in the testis; however, receptor activation occurs after the onset of neonatal FSH secretion. Sertoli cells proliferate during the prepubertal period to establish the capacity to support germ cells, ultimately helping to determine testicular size. In FSHβ subunit knockout mice, Sertoli cell proliferation is significantly reduced early in life, and transcriptomic analyses have identified differentially regulated gene networks related to the cell cycle, cell survival, carbohydrate and lipid metabolism, and molecular transport. Before male puberty, FSH signaling through Sertoli cell FSHR activates the intracellular cAMP/PKA, mitogen-activated protein kinase 1/2, and phosphatidylinositol 3-kinase/serine/threonine protein kinase B (AKT)/mammalian target of rapamycin complex 1 (mTORC1) pathways. This activation increases the transcription of c-Myc, hypoxia-inducible factor-2α, and cyclin D1, thereby regulating Sertoli cell proliferation. At the molecular level, FSH-induced proliferation increases levels of p-AKT, p-mTOR, p-p70S6K, and phospho-proline-rich Akt substrate of 40 kDa (p-PRAS40) in Sertoli cells. Because p-PRAS40 is a substrate of AKT and a component of mTORC1, it may contribute to enhanced mTORC1 signal transduction (Figure 1) [18].

The onset of male puberty is characterized by reactivation of hypothalamic neurons that secrete gonadotropin-releasing hormone (GnRH). Pulsatile GnRH secretion stimulates the pituitary to release FSH and luteinizing hormone (LH). FSH binds to FSHR on Sertoli cells, promoting the proliferation of immature Sertoli cells and increasing testicular volume. In parallel, LH acts on Leydig cells to stimulate androgen secretion, thereby increasing intratesticular testosterone concentrations and subsequently inducing mature Sertoli cells to cease proliferation. The cessation of Sertoli cell proliferation is accompanied by maturation, including changes in gene expression, establishment of the blood-testis barrier, and acquisition of full capacity to support developing germ cells; these processes help determine adult testicular size. The post-receptor signaling mechanisms of Sertoli cell FSH/FSHR signaling have been described in detail [6]. FSH binding to FSHR in Sertoli cells triggers a tightly regulated post-receptor signaling cascade that is essential for male reproductive health. Upon ligand binding, activated FSHR couples to and stimulates G proteins, leading to activation of adenylyl cyclase and increased production of cAMP from ATP. cAMP acts as a key second messenger that activates PKA. Activated PKA phosphorylates multiple downstream targets, including transcription factors, which then translocate to the nucleus and regulate transcription of specific genes. This gene regulation alters Sertoli cell functions, including the synthesis and secretion of proteins required for spermatogenesis, such as ABP and inhibin. Additionally, FSHR signaling can engage other intracellular pathways, including PI3K/AKT and mitogen-activated protein kinase (MAPK), which further modulate cellular processes such as proliferation, differentiation, and survival of Sertoli cells and developing germ cells.

In adult testes, Sertoli cells exhibit distinct FSHR transcripts. After FSH treatment, both FSHR-1 and FSHR-3 transcripts are significantly upregulated, with FSHR-3 serving as the primary transcript mediating FSH action in testicular Sertoli cells. FSH stimulates Sertoli cells to produce ABP and inhibin; ABP binds testosterone secreted by Leydig cells. ABP-bound testosterone is transported to the lumen of the seminiferous tubules, helping to create a high intratesticular androgenic environment that supports spermatogenesis. Research has also demonstrated that germ cells do not express FSHR and AR or express them only at low levels. In contrast, Sertoli cells within the seminiferous tubules express high levels of both FSHR and AR. The FSH/FSHR pathway initiates functional responses required for spermatogenesis, while testosterone activates AR in Sertoli cells to maintain spermatogenesis. FSH activates transcription of genes involved in metabolic homeostasis in Sertoli cells, regulates the synthesis of functional factors required for germ cell proliferation and differentiation, promotes the synthesis of retinoic acid, lactate, and plasminogen activator type 2, and enhances fatty acid metabolism and mitochondrial function [19]. These signaling molecules and nutrients promote germ cell differentiation, support spermatogenesis, and contribute to sperm maturation. Fatty acid transporter (FAT)/CD36 is a membrane glycoprotein involved in cellular fatty acid uptake, and intracellular fatty acids are activated by covalent linkage to coenzyme A (CoA) to form acyl-CoA derivatives [20]. Carnitine palmitoyltransferase 1 mediates the entry of acyl-CoA into mitochondria, where β-oxidation occurs, and medium-chain acyl-CoA dehydrogenase (MCAD) is a key enzyme in fatty acid β-oxidation. FSH increases the mRNA levels of FAT/CD36, carnitine palmitoyltransferase I (CPT1), and MCAD in Sertoli cells, thereby contributing to the regulation of fatty acid transport and metabolism. Nuclear respiratory factors (NRFs) and mitochondrial transcription factor A (TFAM) are key regulators of mitochondrial biogenesis; FSH also increases the mRNA levels of NRF1, NRF2, and TFAM in Sertoli cells, supporting mitochondrial biogenesis. Overall, Sertoli cell responses to FSH and androgens regulate spermatogenesis in a superimposed and synergistic manner [21].

FSHR-mediated signal transduction is essential for the normal testicular response to FSH. The human FSHR gene is located on chromosome 2p21-p16 and is a single-copy gene approximately 54 kb in length. It contains 10 exons, nine introns, and one promoter region. Sertoli cell FSH/FSHR signaling is inherently pleiotropic, supporting multiple distinct functions and promoting the secretion of numerous cytokines that regulate germ cell proliferation, differentiation, and steroidogenesis, thereby enabling the daily production of tens of millions of sperm in the testis.

Heavy metals can disrupt male reproductive health through the FSH/FSHR pathway. Exposure to heavy metal contaminants during pregnancy can disrupt FSH/FSHR signaling in Sertoli cells of the offspring, thereby impairing male reproductive health. Prenatal exposure to hexavalent chromium reduces AR and FSHR expression by inducing oxidative stress and weakening interactions between specific transcriptional regulators and their corresponding promoters, which adversely affects the structure and function of Sertoli cells in F1 offspring [12]. Prenatal cadmium exposure also exerts toxic effects on Sertoli cells by disrupting the FSHR pathway and DNA methyltransferase activity [13]. Therefore, during the critical embryonic window of testicular differentiation and growth and throughout pregnancy, exposure to wastewater, exhaust gases, and solid waste discharged from heavy metal-related industrial sectors should be avoided to reduce contact with these toxic substances.

FSHβ subunit knockout has minimal effects on spermatogenesis in mice. FSHβ subunit knockout mice develop normally and remain fertile, but they have smaller testes and an approximately 75% reduction in sperm count [22]. In contrast, inactivating mutations in the human FSHβ subunit can lead to azoospermia. To date, only three clinical cases of male FSHβ subunit mutations have been reported. These mutations resulted in the complete loss of FSH immunoreactivity and bioactivity, and all reported cases presented with azoospermia. The first reported case (1998) involved a male with low testosterone, mildly elevated LH, and undetectable FSH; puberty onset was normal, but the testes were small and showed varying degrees of spermatogenic failure. The second reported case described a male with no evidence of pubertal onset, small testes, low testosterone, elevated LH, and low FSH levels. The third case involved a male with normal puberty onset who also had azoospermia [23].

Natural mutations in the FSHR gene are also rare. The earliest reported mutation, c.566C>T (exon 7), is a loss-of-function variant that presents in males as small testes and impaired spermatogenic function. Activating mutations that preserve receptor function have also been described, such as the mutation at amino acid position 576 (Asp567Gly), in which the receptor adopts an active conformation independent of ligand binding [24]. This individual underwent pituitary adenoma resection and received long-term postoperative testosterone replacement therapy; despite undetectable serum FSH levels, he had normal testicular volume, normal spermatogenesis and semen parameters, and was able to father healthy offspring. Another activating mutation is c.1292A>T (Asn431Ile) in exon 10. This variant is associated with reduced receptor expression on the cell surface and suppressed serum FSH levels, yet spermatogenic function remains normal [25]. Approximately 1,800 single nucleotide polymorphisms (SNPs) have been reported in the FSHR gene, with most located in introns. SNPs can influence transcription factor-mediated activation, reduce gene transcription, downregulate receptor expression, and alter post-translational modifications of the FSHR protein, thereby affecting FSHR responsiveness to exogenous FSH and the effectiveness of FSH treatment. However, conclusions regarding the relationship between FSHR SNPs and male infertility or spermatogenic function remain inconsistent. Studies of three widely investigated loci, c.2039A>G (rs6166, 680Asn/Asn), c.919A>G (rs6165, 307Thr/Ala), and c.-29G>A (rs139420), have yielded mixed results. Some studies have found no significant association with clinical indicators of male reproduction, whereas others have reported correlations of one or more of these loci with testicular volume and semen quality [25].

In assisted reproductive technology, different FSHR SNPs may also influence clinical outcomes of intracytoplasmic sperm injection (ICSI). A prospective cohort study evaluated the effects of two FSHR SNPs, p.Thr307Ala and p.Asn680Ser, on ICSI outcomes in infertile males. Sperm concentration in the p.Thr307Ala group was higher than in the p.Thr307Thr and p.Ala307Ala groups, and the fertilization rate in the p.Ala307Ala genotype was significantly lower than in the p.Thr307Thr genotype. No significant difference in embryo quality was found between groups, and the clinical pregnancy rate in the p.Thr307Thr group was slightly higher than in the p.Ala307Ala group, although the difference was not statistically significant [26].

Analyses of SNPs in infertile males across different ethnicities have yielded inconsistent findings. A Baltic study reported a significant association between the FSHR Asn680Ser variant and total testicular volume, as well as associations with higher FSH levels, lower inhibin B levels, and total testosterone levels; however, no significant associations were observed with LH, estradiol, or semen parameters [27]. In contrast, an Albanian study found no association between FSHR Asn680Ser and levels of FSH, LH, prolactin, or testosterone. After adjustment for covariates such as age, body mass index, smoking, and alcohol consumption, carriers of the heterozygous FSHR Asn680Asn/Ser genotype had a higher proportion of male infertility, with only a weak association with semen parameters [28]. Therefore, future prospective studies including multiple ethnicities and large sample sizes are needed to draw definitive conclusions.

FSH preparations are used to treat hypogonadotropic hypogonadism (HH). FSHR agonists, primarily recombinant FSH, are the main clinically established FSHR modulators used for HH. Their primary effect is to bypass defects in the hypothalamic-pituitary axis and directly stimulate gonadal function through intact FSHR signaling. In males, FSH is essential for inducing and maintaining spermatogenesis (fertility) and is typically used in combination with LH or human chorionic gonadotropin (hCG) to support testosterone production. In females, FSH is essential for inducing follicular development and estrogen production (fertility and secondary sexual characteristics) and is commonly used with an LH trigger (hCG) to induce ovulation. Novel modulators, such as partial agonists or positive allosteric modulators, may offer future improvements in safety or convenience but are not yet standard treatments for HH. In contrast, FSHR antagonists are not used to stimulate gonadal function in HH because HH is characterized by insufficient FSH signaling, and treatment therefore relies on replacing this missing signal with an agonist.

Pulsatile GnRH administration is a preferred alternative therapy for HH caused by hypothalamic GnRH deficiency, which leads to inadequate pituitary secretion of gonadotropins. Pulsatile GnRH can induce the pituitary to secrete endogenous gonadotropins [29]. LH promotes androgen secretion, and FSH/FSHR and androgens/AR jointly support spermatogenesis. However, this approach is not routinely used because it requires an external pump to deliver GnRH subcutaneously in pulses, which is costly and can be uncomfortable for patients. As a result, HH is commonly treated with exogenous gonadotropins, such as hCG alone or in combination with FSH. Typically, 150–225 U of FSH is administered two to three times weekly, and 1,000–2,500 U of hCG is administered twice weekly, with high clinical efficacy. A recent meta-analysis evaluated the impact of hCG alone or in combination with FSH on sperm concentration across clinical settings in patients with HH and found that the combination of hCG and FSH was beneficial in 75% of cases, with a final mean sperm concentration of 5.92×10⁶/mL. The authors concluded that FSH and hCG have a synergistic effect and can partially restore fertility, although sperm parameters may not reach ideal levels [30]. Notably, the effectiveness of FSH depends not only on circulating levels but also on FSH bioactivity and FSHR responsiveness, and individual genetic differences may contribute to variability [31].

FSH is also used to treat male infertility in patients with idiopathic spermatogenic disorders, with beneficial outcomes reported in approximately 50% of cases with normal gonadotropin levels. Research has shown that administering 150 U of FSH every other day to patients with idiopathic severe oligozoospermia can significantly increase sperm count and improve sperm morphology, whereas high-dose FSH (300 U/day) may more strongly stimulate Sertoli cells and provide greater support for germ cell proliferation, differentiation, and maturation [32]. However, not all published controlled studies are placebo-controlled, and few include blinding. Therefore, the effectiveness of FSH treatment in idiopathic oligozoospermia should be evaluated comprehensively in terms of FSH levels, FSH formulations, and FSHR responsiveness. Different FSHR SNPs can affect FSH-induced intracellular signal transduction [33]. In one study, daily FSH administration for 3 months improved sperm quality in idiopathic infertile males who were homozygous for the FSHR p.N680S N variant, but not in p.N680S S homozygotes, suggesting that the FSHR gene may serve as a pharmacogenetic marker; however, further clinical validation is needed.

Novel FSHR modulators are under development and can be broadly classified into three categories: small non-peptide ligands, single-chain recombinant FSH, and antibodies/antibody fragments. FSHR antibodies have been shown to inhibit the differentiation of spermatogonia into primary spermatocytes, resulting in infertility without pathological effects on reproductive organs. Research has developed an anti-FSHR single-chain variable fragment (anti-FSHR scFv) using phage display technology and evaluated its effects on testicular function and testosterone production in adult macaques. Anti-FSHR scFv significantly reduced testicular volume and sperm count without altering testosterone levels, suggesting a potential approach to male contraception.

Sertoli cells in the testis undergo diverse transitions to adapt to testicular development, maintenance of reproductive physiology, and immune protection. Pituitary-derived FSH acts on FSHR and induces the proliferation and maturation of immature Sertoli cells through multiple pathways, regulating spermatogenesis in a superimposed and synergistic manner with androgens. FSHR SNPs are associated with male infertility to some extent, but their clinical utility for diagnosing male infertility requires further validation. The therapeutic effect of FSH in male spermatogenic defects is influenced by FSH levels, FSH formulation, and FSHR responsiveness. Overall, research on FSH- and FSHR-related therapeutics holds profound significance for the future diagnosis and treatment of infertility and the development of male contraceptives.

Nevertheless, the specific molecular mechanisms underlying these associations are not yet fully understood. Further studies are needed to clarify how FSHR SNPs affect Sertoli cell function and spermatogenesis. In addition, exploring more precise methods to assess FSH levels and FSHR responsiveness could improve the accuracy of diagnosing male infertility and predicting response to FSH therapy. Moreover, the development of novel drugs targeting FSH and FSHR with higher specificity and fewer side effects remains a key direction for future research. Such advances would not only improve treatment options for male infertility but also expand the range of male contraceptive approaches, potentially enabling more effective and reversible methods. As understanding of FSH and FSHR deepens, further breakthroughs in male reproductive health are anticipated, offering new options for patients with infertility and contributing to progress in reproductive medicine.