Mechanisms of the interaction between aging of the male reproductive system and obesity, and clinical management strategies (Review)

Molecular and cellular mechanisms of testicular aging

Key temporal nodes in testicular aging

Testicular aging is a gradual process. Using single-cell transcriptomic analysis, Cui et al (1) identified two critical temporal junctures for patients, in the thirties and fifties, at which the testis undergoes ‘cliff-like aging’. In the thirties, testicular peritubular cells begin to exhibit notable changes, including thickening of the basement membrane, marking the initiation phase of testicular aging. This stage primarily affects cellular structure, establishing a foundation for subsequent functional decline. In the fifties, testicular cells display substantial functional alterations, including steroidogenic metabolic abnormalities in Leydig cells (LCs) and dysregulated immune responses in macrophages. At this stage, spermatogenesis further declines, testosterone secretion decreases and fertility is markedly reduced. These findings reveal that distinct cell types in the testis exhibit cell type-specific aging patterns at specific temporal junctures, explaining the phased decline in male fertility with advancing age (1).

Cell-specific aging alterations in testicular cells

Sertoli cells are the primary structural cells within the seminiferous tubules; they maintain tubular architecture and provide nutritional support and a physical barrier for germ cells. Aging impairs the structure and function of Sertoli cells, representing a key pathological change underlying testicular dysfunction (2). Moreover, with advancing age, the number of Sertoli cells decrease (3,4), and the cells undergo morphological alterations such as vacuolization and lipofuscin deposition (5). Additionally, thickening and fibrosis of the basement membrane, along with disruption of tight junction structures, compromise blood-testis barrier (BTB) function (4). Notably, a single-cell sequencing study identified Sertoli cells as the cell type most sensitive to aging in the testis, exhibiting the highest number of aging-associated differentially expressed genes. The transcription factor Wilms' Tumor 1 (WT1), which is critical for maintaining Sertoli cell homeostasis, and its target genes are downregulated during aging. Experimental validation demonstrated that WT1 knockdown in human Sertoli cells resulted in accelerated senescence, reduced expression of tight junction proteins and decreased levels of Sertoli cell marker molecules. These findings suggest that age-related downregulation of WT1 may be a key driver of homeostatic imbalance in Sertoli cells, manifesting as accelerated senescence, impaired tight junctions and loss of cellular identity (3). Deng et al (6) reported that the somatic microenvironment of testes from patients with LOH exhibits more pronounced aging characteristics than the germ cell compartment, with Sertoli cells showing the most prominent inflammatory secretory and aging phenotypes (6). Furthermore, Sertoli cells from LOH patients display marked dysregulation of lysosomal and lipid metabolism-related genes, accompanied by substantial accumulation of lysosomes and lipids. Functional analysis of lysosomes revealed abnormal lysosomal acidity in Sertoli cells from patients with LOH (6). Recent studies have also shown that aging leads to progressive accumulation of lipid droplets in mouse Sertoli cells (5,7). Collectively, these Sertoli cell-associated changes impair their role as coordinators of nutrition and metabolism within the testis, thereby accelerating testicular aging.

LCs

LCs play an essential role in maintaining spermatogenesis and male fertility through testosterone secretion, and their function declines markedly with age. This decline is accompanied by typical aging-related morphological changes, including mitochondrial dysfunction, reduced cell volume and loss of smooth endoplasmic reticulum (8). Moreover, studies have reported a reduction in the steroidogenic capacity of LCs with age (4). Specifically, age-related decreases in peripheral benzodiazepine receptor expression impair cholesterol transport into the mitochondria, thereby directly blocking the initial step of steroidogenesis (9). The responsiveness of LCs to luteinizing hormone (LH) stimulation is also diminished (10). In aged Brown Norway rats (21–24 months), LH stimulation resulted in reduced cyclic adenosine monophosphate production (11), downregulation of the cholesterol transporters Steroidogenic acute regulatory protein (StAR) and translocator protein (12,13), and decreased expression of steroidogenic enzymes (14), changes that are closely associated with oxidative stress (15–17). Single-cell analyses have further revealed an age-related decline in LC number (4). In addition, aging-associated ketogenic dysfunction exacerbates cellular senescence through the β-hydroxybutyrate-FOXO3a axis (18). A recent study identified cellular communication network factor 5 (CCN5) as a key biomarker of testicular aging, revealing a dual mechanism by which CCN5 contributes to testosterone synthesis impairment and cellular senescence: Extracellularly, it promotes LC fibrosis via the β-catenin/SMAD signaling pathway, whereas intracellularly, it downregulates ring finger protein 213 (RNF213), leading to lipid droplet loss and cholesterol efflux (19).

Spermatogonial stem cells (SSCs)

SSCs are essential for the sustained production of gametes. Aging affects SSCs through multiple mechanisms, including increased apoptosis, reduced self-renewal capacity, impaired differentiation and altered molecular expression profiles (20–22). In a transplantation study, the transplantation of SSCs isolated from the testes of 2-year-old aged mice into young busulfan-treated recipients resulted in reduced germ cell numbers, suggesting that aging compromises the self-renewal capacity of SSCs (23). Aging is accompanied by molecular changes in SSCs, including increased expression of BRCA1, which may affect SC stability and promote depletion of the SC pool. Multiple genes associated with SSC stemness are downregulated with age, including Hmga2 (3,24), Tcf7l1, Tcf3, Dmrt1 (3,25), Gfrα1, Itgβ1, Csf1r, Itgα1, Runx2, Fgf3, Wnt7a and Wnt5b, indicating a loss of stemness in aged SSCs (25,26). Single-cell analyses further suggest that SSC numbers may decline with advancing age (4).

At the cellular level, aged testes exhibit multinucleated spermatozoa and ultrastructural abnormalities, including acrosomal defects, redundant nuclear membranes, intranuclear inclusions, excessive cytoplasmic droplets and irregular nuclei (27,28). In aged mice, comparative analysis of epididymal tissue has revealed a reduced sperm count, curved sperm heads, absent or abnormally arranged mitochondria, impaired flagellar motility and increased DNA fragmentation (29). Collectively, these cell-intrinsic aging changes constitute the cellular basis for testicular functional decline. This process is closely intertwined with systemic factors such as obesity and chronic diseases (Fig. 1).

Figure 1. Cellular changes associated with aging testes. Testicular aging is characterized by functional and structural alterations in Sertoli cells, SSCs and Leydig cells, including impaired cellular homeostasis, reduced stemness and self-renewal, mitochondrial and lysosomal dysfunction, fibrosis and defective steroidogenesis. These age-related changes disrupt the seminiferous microenvironment and spermatogenesis, leading to increased sperm DNA fragmentation and morphological abnormalities, and reduced motility. Arrows indicate increased (↑) or decreased (↓) levels or activities. WT1, Wilms tumor 1; SSC, spermatogonial stem cell; CCN5, cellular communication network factor 5; RNF213, ring finger protein 213; SA-β-gal, senescence-associated β-galactosidase; HMGCS2, 3-hydroxy-3-methylglutaryl-CoA synthase 2; LH, luteinizing hormone; cAMP, cyclic adenosine monophosphate; StAR, steroidogenic acute regulatory protein; TSPO, translocator protein.

Changes in the testicular immune microenvironment

The testis has traditionally been regarded as an immune-privileged organ, maintaining a unique immune microenvironment. This immune tolerance is sustained by the BTB, Sertoli cells and local immunosuppressive factors, which collectively protect germ cells from autoimmune attack (30). However, recent studies have shown that this immune privilege gradually diminishes with age. Changes in immune cell populations, increased chronic local inflammation and impaired immune surveillance collectively define the process now recognized as testicular immune senescence (31,32).

Notably, single-cell RNA sequencing analysis has revealed that macrophages in the aged testis do not merely increase in number but also undergo subset reprogramming. A novel macrophage subtype (subtype 3) specifically enriched in the aged testis challenges the traditional M1/M2 classification framework. These cells not only drive monocyte proliferation and T-cell activation but also exhibit markedly elevated expression of inflammation-related genes, highlighting their unique pro-inflammatory properties (33). A recent study has shown that restoring macrophage immunological homeostasis, such as through intercellular mitochondrial transfer from stem LCs, helps switch macrophages toward an anti-inflammatory state, thereby alleviating microenvironmental inflammation and promoting testicular tissue repair (34).

At the broader tissue level, the overall proportion of testicular immune cells increases substantially from the age of 40 years onward (32). Classically, aged testicular macrophages exhibit a pronounced shift toward a pro-inflammatory phenotype, releasing elevated cytokines such as tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6), which directly impair LC steroidogenesis (32). Concurrently, the testicular T-cell compartment undergoes functional decline: While overall functional T cell numbers decrease, infiltrating CD8+ T cells exhibit increased programmed cell death protein 1 expression and reduced IL-2 secretion, indicative of age-associated immune exhaustion (32,35). Aging also leads to downregulation of key junctional proteins in the BTB, disrupting its structural integrity and thereby triggering immune infiltration and an imbalance in testicular immune homeostasis (1).

Interaction between obesity and gonadal dysfunction

Studies have shown that serum testosterone levels in men begin to decline gradually from the age of 35 years (36,37). Another study reported that in men aged 40–70 years, total serum testosterone decreases by 0.4% per year, whereas free testosterone declines more markedly, at 1.3% per year (37). In addition to age, obesity is a key factor affecting testicular function. In high-income populations, the prevalence of severe obesity is projected to double between 2020 and 2035, rising from 10 to 20%, posing a substantial threat to healthcare systems (38). Among obese individuals, circulating testosterone concentrations are further reduced. Data from the European Male Aging Study (EMAS) indicate that testosterone levels decrease by ~30% in men with a body mass index (BMI) >30 kg/m2 (37), which may represent a major contributor to the development of LOH.

The effects of age and obesity on testicular function are not simply additive but rather synergistic. Emerging computational biology approaches offer new perspectives for elucidating this complex interaction; a study combining machine learning with bioinformatics successfully identified key temporal nodes at which aging and obesity act synergistically. These findings indicate that men >45 years of age with a BMI >30 kg/m2 face a higher risk of infertility (31). The underlying mechanism involves a vicious cycle between obesity and hypogonadism. Declining testosterone levels promote the accumulation of visceral adipose tissue in men (39), which in turn suppresses hypothalamic-pituitary-gonadal (HPG) axis output and directly impairs LC function through chronic inflammation and oxidative stress (40), aromatase-mediated conversion of androgens to estrogens (41) and leptin resistance (42). Together, this bidirectional interplay drives progressive testicular functional decay and metabolic derangement (Fig. 2).

Figure 2. Diagram illustrating the vicious cycle between obesity and testosterone deficiency. Adipose tissue expansion promotes aromatase activity, insulin resistance and adipokine imbalance, which disrupt hypothalamic-pituitary-gonadal axis signaling and impair testicular steroidogenesis. In parallel, endoplasmic reticulum stress, mitochondrial dysfunction, chronic inflammation and oxidative stress contribute to testicular dysfunction and reduced testosterone production, forming a vicious cycle between testosterone deficiency and metabolic dysfunction. Arrows indicate increased (↑) or decreased (↓) levels or activities. GnRH, gonadotropin-releasing hormone; FSH, follicle-stimulating hormone; LH, luteinizing hormone; TNF-α, tumor necrosis factor-α; ROS, reactive oxygen species.

Impact of obesity and metabolic disorders on male reproduction: Mechanisms and implications

LOH is a common clinical syndrome associated with male aging, characterized by declining serum testosterone levels and reduced androgen sensitivity. According to the European Association of Urology (EAU) 2025 guidelines, LOH is clinically identified by persistent symptoms combined with total testosterone <12 nmol/l (3.5 ng/ml) confirmed on two separate morning samples, with a calculated free testosterone (cFT) <220 pmol/l suggested as an additional threshold in ambiguous cases (43). In obese individuals, markedly reduced sex hormone-binding globulin (SHBG) can lead to falsely low total testosterone levels; therefore, current guidelines recommend evaluating cFT to avoid misdiagnosing low SHBG as organic hypogonadism (44,45).

The prevalence of LOH in men aged 40–79 years ranges widely from 2.1 to 25.6% depending on the diagnostic criteria applied (46), whereas the 2025 EAU guidelines estimate a prevalence of 2–8% in European men (43). Obesity may represent a major contributing factor to the development of LOH. Obesity-induced lipotoxicity impairs male gonadal function (47); in obese individuals, serum testosterone levels are frequently reduced, although this reduction is typically reversible following weight loss (48). Data from the EMAS indicate that men with a BMI >30 kg/m2 have testosterone levels 30% lower than those with a BMI <25 kg/m2 (49). Epidemiological surveys have revealed a higher prevalence of hypogonadism among obese men, with one meta-analysis reporting a rate of up to 42.8% (50). Mechanistically, obesity may drive progressive gonadal functional decline through multiple interconnected pathways, including chronic inflammation, oxidative stress, and aromatase overexpression, as detailed in the following subsections.

Obesity-induced hypoxia exacerbates endoplasmic reticulum (ER) stress by activating the inositol-requiring enzyme 1 and protein kinase R-like endoplasmic reticulum kinase branches of the unfolded protein response (51). Our previous study in male Sprague-Dawley rats found that a high-cholesterol diet induces cholesterol accumulation in LCs, elevates expression of the ER stress-associated proteins binding immunoglobulin protein and activating transcription factor 6, and is accompanied by reduced expression of steroidogenic enzymes such as StAR, 3β-hydroxysteroid dehydrogenase (3β-HSD), cytochrome P450 side-chain cleavage enzyme (CYP11A1) and cytochrome P450 17α-hydroxylase/17,20-lyase (CYP17A1), thereby leading to decreased testosterone production (52). Furthermore, using a high fat diet-induced obesity mouse model, we previously demonstrated that p38 MAPK, a key regulator under oxidative stress, exacerbates the decline in male fertility (53).

Mitochondrial function is also affected by oxidative stress. Key proteins and enzymes involved in testosterone synthesis, including StAR and CYP11A1 (P450scc), require transport via mitochondria with intact structure and function to facilitate testosterone biosynthesis; consequently, mitochondrial dysfunction directly impairs testosterone production (54). Studies have shown that obesity may generate excessive reactive oxygen species (ROS), leading to mitochondrial dysfunction and ultimately impairing testicular function (47,55).

Obesity induces testosterone decline and hypogonadism through chronic inflammatory pathways, as comprehensively described in recent reviews (56,57). Mechanistically, obesity drives white adipose tissue expansion and M1 macrophage infiltration, releasing pro-inflammatory cytokines (TNF-α, IL-6 and IL-1β) and establishing chronic low-grade inflammation. Circulating cytokines reach the testis, activating resident macrophages and the NLRP3 inflammasome to amplify local testicular inflammation (56). TNF-α and IL-6 directly suppress LC steroidogenesis via NF-κB signaling, downregulating StAR protein and steroidogenic enzymes (CYP11A1, CYP17A1 and 3β-HSD) and reducing LH receptor expression (56,57). Meanwhile, IL-1β inhibits hypothalamic gonadotropin-releasing hormone (GnRH) and pituitary LH secretion, diminishing gonadotropic drive (40,57). Together, direct inflammatory injury of LCs and reduced gonadotropic stimulation cause testosterone deficiency and obesity-related hypogonadism.

Aromatase is the key rate-limiting enzyme in estrogen synthesis, irreversibly converting androgens (such as testosterone and androstenedione) into estrogens (such as estradiol and estrone). In obese men, this conversion occurs primarily in expanded white adipose tissue, where both the increased fat mass and the upregulated aromatase expression per adipocyte, driven by multiple factors such as TNF-α, IL-6, insulin resistance and glucocorticoids, contribute to enhanced peripheral aromatization, increasing the conversion of testosterone to estradiol and thereby elevating estrogen levels while directly reducing circulating testosterone (58,59). Moreover, reduced testosterone further promotes adipose tissue accumulation and upregulates aromatase expression, creating a self-reinforcing hypogonadal-obesity cycle (60). Clinical studies have confirmed that aromatase inhibitors reduce estradiol and increase testosterone, LH and follicle-stimulating hormone (FSH) in obese men, supporting a mechanistic contribution of aromatase to obesity-related hypogonadism (41,60).

Mechanisms of obesity-induced acceleration of testicular aging

Obesity-mediated systemic chronic low-grade inflammation and metabolic stress serve as key drivers of cellular senescence and microenvironmental dyshomeostasis in multiple organs, including the liver, skeletal muscle and the testes (61). Specifically, obesity may promote testicular inflammation and accelerate testicular senescence through the following mechanisms. Leptin, primarily produced by adipocytes, suppresses appetite and increases energy expenditure, thereby regulating energy balance (51). Although leptin normally acts on kisspeptin neurons to stimulate GnRH release, obesity-associated hyperleptinemia can lead to functional leptin resistance (42) and inhibition of kisspeptin neurons, consequently impairing hypothalamic-pituitary function and subsequent testicular function (42). Obesity and hyperleptinemia upregulate suppressor of cytokine signaling 3, attenuate JAK2/STAT3 pathway activation in LCs and directly impair steroidogenesis. Meanwhile, hyperleptinemia sustains a chronic low-grade inflammatory state. The convergence of leptin resistance, inflammatory injury and hormonal deprivation accelerates testicular dysfunction and aging. This progressive leptin resistance further disrupts metabolic and reproductive regulation, contributing to obesity-associated gonadal dysfunction (42,51).

Obesity induces white adipose tissue dysfunction and hypoadiponectinemia, linking metabolic disturbance to testicular decline (62). Adiponectin shields LCs through AdipoR1-AMPK activation, which suppresses NF-κB-driven inflammation and oxidative stress (56). In obesity, adiponectin deficiency removes this cytoprotection, causing ROS accumulation, reduced antioxidant capacity and elevated TNF-α/IL-6 in the testicular interstitium (56,62). ROS further impair LC mitochondrial function and downregulate StAR and steroidogenic enzymes, decreasing testosterone biosynthesis (62). Together, adiponectin deficiency, oxidative stress and inflammation accelerate LC senescence and premature testicular aging (63).

Insulin resistance is a key physiological mechanism in metabolic disorders and is considered an important independent predictor of testosterone deficiency (64). Studies have shown that insulin resistance markedly elevates plasma levels of the pro-inflammatory cytokines IL-6 and TNF-α, stimulating the liver to produce additional cytokines and contributing to chronic systemic inflammation (64,65). Under such inflammatory conditions, aromatase activity in adipose tissue is enhanced, promoting the conversion of testosterone to estradiol and directly reducing testosterone levels (49), thereby leading to hypogonadism.

Effects of testosterone deficiency on obesity and metabolic disorders

Testosterone deficiency not only affects sexual function but also leads to reduced muscle mass and strength, increased fatigue, mood disturbances and a marked decline in overall quality of life (48). A recent study has shown that aging-associated declines in testosterone and estrogen contribute to excessive fat accumulation in men and women, respectively (66). Mechanistically, testosterone stimulates the expression of glycoprotein hormone β5 (GPHB5) via the androgen receptor (AR); AR knockout not only induces obesity but also reduces GPHB5 expression. Conversely, after GPHB5 knockout, even elevated testosterone levels fail to exert their fat-reducing effects (66). Testosterone also prevents fat accumulation in males through combined actions mediated by the estrogen receptor (following its aromatization to estradiol) and the AR. Multiple lines of evidence suggest that the inhibitory effect of testosterone on white adipose tissue (WAT) mass in males is indirectly mediated by AR signaling in skeletal muscle (67,68). In vitro experiments have demonstrated that testosterone promotes the differentiation of multipotent mesenchymal SCs toward the myogenic lineage while inhibiting their differentiation into the adipogenic lineage (67). Testosterone deficiency and insulin resistance exhibit a bidirectional relationship. Testosterone deficiency induces insulin resistance via mitochondrial dysfunction (men with low testosterone face a two-fold increased risk of insulin resistance) whereas obesity associated with insulin resistance further reduces testosterone levels (68).

Notably, visceral fat accumulation resulting from testosterone deficiency itself exacerbates the decline in testosterone levels. The underlying mechanism involves increased adipocyte aromatase activity, which irreversibly converts testosterone to estradiol and elevates ROS production, thereby depleting circulating testosterone. Concurrently, elevated estradiol exerts negative feedback to blunt LH pulse amplitude while directly promoting adipogenesis across subcutaneous, ectopic and visceral fat depots (52). Together, this vicious cycle perpetuates peripheral fat accumulation and accelerates systemic metabolic deterioration.

Clinical management and treatment strategies

Aging and obesity are key contributors to male hypogonadism. Clinical treatment should control underlying diseases while implementing targeted interventions directed at downstream pathophysiological mechanisms, including inflammation, hyperestrogenemia and insulin resistance. Clinical management of LOH and testicular aging is gradually shifting from the conventional one-size-fits-all model centered on testosterone replacement to novel individualized therapeutic strategies based on underlying pathogenetic mechanisms (Fig. 3).

Figure 3. Comprehensive treatment strategies for hypogonadism. Potential interventions for age-related testicular dysfunction include fertility-oriented treatments, metabolic disease-related interventions, cross-etiology targeted molecular therapies, and regenerative medicine and tissue engineering approaches. These strategies range from lifestyle modification, dietary and pharmacological interventions, and hormone replacement to molecular targeting, stem cell-based therapies, hydrogels and assisted reproductive technologies. GLP-1, glucagon-like peptide-1; CCN5, cellular communication network factor 5; TRPM1, transient receptor potential mucolipin 1; HMGCS2, 3-hydroxy-3-methylglutaryl-CoA synthase 2; SLC, stem Leydig cell.

However, translating these diverse mechanistic strategies into evidence-based clinical practice requires a rigorous evaluation of their efficacy, safety and clinical maturity.

To provide an evidence-based perspective on the translational landscape, currently established clinical interventions and emerging experimental modalities for obesity- and aging-related male hypogonadism are systematically summarized and compared using evidence levels adapted from the Oxford Centre for Evidence-Based Medicine Levels of Evidence (March 2009) (69) in Table I.

Table I. Evidence-based comparison of established and emerging interventions for obesity- and aging-related male hypogonadism.

Table I.

Evidence-based comparison of established and emerging interventions for obesity- and aging-related male hypogonadism.

Therapeutic modality	Intervention	Primary target/mechanism	Target population and clinical utility	Evidence level
Lifestyle modification	Caloric restriction and exercise	Reduces visceral adiposity, attenuates aromatase activity and leptin resistance	First-line management for LOH; restores endogenous HPG axis	Level 1a (70)
Weight management	Sleeve gastrectomy/RYGB	Rapid visceral fat loss, normalization of LH/FSH pulse amplitude	Highly effective for severe obesity (BMI ≥35 kg/m2) with hypogonadism	Level 2a (71,72)
Pharmacotherapy	Testosterone replacement therapy	Replenishes circulating androgens, restores bone/muscle anabolic mass	Indicated for irreversible/established LOH; contraindicated if desiring fertility	Level 1a (74,75)
	GLP-1RAs	Enhances insulin sensitivity, promotes weight loss	Adjunctive option for obesity-related hypogonadism, not yet guideline-endorsed	Level 2b (78,79)
	Aromatase inhibitors	Blocks CYP19A1-mediated testosterone-to-estradiol conversion, relieves central feedback	Off-label strategy for obese men with hyperestrogenemia desiring fertility	Level 1b (80)
Targeted small molecules	Piezo1 inhibitors, TRPML1 agonists	Resolves matrix stiffness, ribotoxic stress and lysosomal acidity deficits	Translational candidates for delaying testicular cellular senescence	Level 5 (6,7,83)
Natural antioxidants	Icariin, Quercetin,	Nrf2 antioxidant pathway activation, free-radical neutralization	Adjunctive candidates targeting oxidative stress-induced testicular damage	Level 5 (84,85)
Regenerative medicine	SLC transplantation, TdEC hydrogels	Niche reconstruction, macrophage mitochondrial transfer, tissue repair	Frontier modalities for biological restoration of endogenous steroidogenesis	Level 5 (34,87)

[i] Evidence levels are classified according to the Oxford Centre for Evidence-Based Medicine criteria: 1a=Systematic reviews/meta-analyses of randomized controlled trials (RCTs); 1b=individual RCTs; 2a=systematic reviews of cohort studies; 2b=individual cohort studies or low-quality trials; 5=preclinical evidence (animal/in vitro/tissue engineering). GLP-1RA, glucagon-like peptide-1 receptor agonist; HPG, hypothalamic-pituitary-gonadal; LOH, late-onset hypogonadism; RCT, randomized controlled trial; RYGB, Roux-en-Y gastric bypass; SLC, stem Leydig cell; TdEC, testicular decellularized extracellular matrix; TRT, testosterone replacement therapy; LH, luteinizing hormone; FSH, follicle-stimulating hormone; BMI, body mass index; TRPML1, transient receptor potential mucolipin 1.

Lifestyle modification and weight management

Foundational strategies for obesity-associated hypogonadism include dietary control, lifestyle modification and bariatric surgery. Studies have shown that calorie restriction can increase serum testosterone concentrations in overweight or obese men (70). Bariatric surgery, in particular, is an effective intervention for hypogonadism secondary to severe obesity, achieving substantial and sustained weight loss accompanied by corresponding increases in serum testosterone, LH and FSH concentrations (71). A study of 413 men with severe obesity reported that bariatric surgery markedly ameliorated hypogonadism: Total testosterone levels increased, and the prevalence of hypogonadism decreased from 69.5% before surgery to 20.1% at 3–6 months after surgery (72).

Historically, lifestyle modifications and weight management were frequently viewed merely as conservative, transitional or adjunctive measures prior to pharmacological interventions. However, over the past decade, major international guidelines, including those from the European Academy of Andrology (EAA, 2020) (45), and iterative updates from the EAU, 2024/2025 (73), have redefined this paradigm. These consensus frameworks have firmly established and consistently maintained structured lifestyle intervention and weight loss as the fundamental, first-line therapeutic strategy for obesity-associated functional hypogonadism.

Testosterone replacement therapy (TRT)

For patients with established hypogonadism, TRT represents a direct and effective pharmacological intervention (74). Commonly used formulations include oral testosterone undecanoate, intramuscular testosterone undecanoate injections and transdermal preparations (gel and patch) (43). By restoring physiological serum testosterone levels, TRT effectively improves male sexual function and enhances bone and muscle mass; however, it confers critical clinical trade-offs and potential adverse effects (75). In particular, exogenous testosterone exerts negative feedback on the HPG axis, suppressing gonadotropin secretion and severely impairing spermatogenesis, which renders TRT unsuitable for men desiring to preserve fertility.

Consequently, contemporary international guidelines [including EAA (45) and (73) guidelines] strongly caution against the indiscriminate prescription of TRT for non-organic, age-related or adiposity-driven reductions in serum testosterone (45,73). In overweight or obese individuals (BMI ≥27 kg/m2) without structural HPG pathology, guidelines mandate prioritizing the aggressive correction of reversible secondary causes, most notably structured lifestyle modification, substantial weight loss and the cessation of interfering medications, before considering lifelong androgen replacement.

Adjuvant pharmacological interventions for metabolic dysfunction

Studies have shown that exenatide, a glucagon-like peptide-1 receptor agonist (GLP-1RA), increases serum testosterone levels in men with type 2 diabetes mellitus who have low baseline testosterone, but has no such effect in those with normal baseline levels (76). Compared with testosterone therapy, a 16-week intervention with liraglutide not only reduces body weight and improves metabolic parameters but also effectively elevates serum testosterone levels (77). By promoting weight loss and improving insulin sensitivity, these agents reverse secondary HPG axis suppression and restore endogenous testosterone production without compromising spermatogenesis, thereby serving as promising, fertility-preserving metabolic interventions for obese men with functional hypogonadism (78). A systematic review of five clinical trials presented at the Endocrine Society 2026 annual meeting reported no detrimental effect of GLP-1RAs on reproductive hormones, sexual function or sperm quality, with two trials demonstrating marked improvements compared with the baseline (79). Although GLP-1RAs are not yet incorporated into formal clinical guidelines for hypogonadism, growing evidence supports their potential inclusion in future recommendations, reshaping the therapeutic paradigm for this specific patient cohort.

Aromatase inhibitors, such as letrozole, reduce the conversion of testosterone to estradiol by inhibiting aromatase, thereby lowering estrogen levels. This may alleviate negative feedback on the pituitary, increase LH and FSH levels, and consequently stimulate testicular function (41). Nevertheless, aromatase inhibitors remain an off-label option for male hypogonadism; while contemporary guidelines acknowledge their potential to improve hormonal and seminal parameters, they emphasize the need for prospective randomized controlled trials to confirm definitive efficacy (80).

Therapeutic strategies in men desiring fertility preservation

The reproductive intent of the patient constitutes a pivotal branch point in clinical decision-making. Authoritative guidelines, including those from the EAA and the EAU, explicitly advise against TRT in hypogonadal men with active fertility desires, as exogenous testosterone suppresses endogenous gonadotropin secretion and spermatogenesis, potentially resulting in oligospermia or azoospermia (44,73). For hypogonadal men with active fertility desires, clinical practice guidelines recommend a stepwise, fertility-preserving management algorithm.

i) First-line lifestyle and weight management. Structured lifestyle interventions and weight reduction serve as the cornerstone of management, as weight loss can increase serum testosterone concentrations in overweight or obese men (44,70).

ii) Guideline-recommended pharmacological options. Aromatase inhibitors (such as letrozole) and selective estrogen receptor modulators (such as clomiphene citrate and tamoxifen) are recommended by current guidelines for hypogonadal men desiring to maintain fertility. By relieving estrogenic negative feedback, they stimulate endogenous LH/FSH and testosterone secretion while preserving spermatogenesis (80,81).

iii) GLP-1Ras. Abundant clinical data support the use of GLP-1RAs in obesity-associated hypogonadism, promoting weight loss and endogenous testosterone restoration without compromising spermatogenesis (78,79); however, they have not yet been incorporated into formal guidelines.

iv) Gonadotropin-based therapy. In patients with hypogonadotropic hypogonadism and fertility desires where lifestyle and medical measures fail, gonadotropin replacement (human chorionic gonadotropin with or without FSH/human menopausal gonadotropin) is the guideline-recommended standard of care, stimulating LCs and Sertoli cells to drive spermatogenesis and restore fertility (82).

Emerging and investigational therapeutic strategies

Emerging evidence highlights several molecular targets within the aging testis that may restore LC function and endogenous testosterone production.

i) Modulating testicular microenvironment stiffness. Recent studies have revealed that the aging testis undergoes interstitial fibrosis and extracellular matrix remodeling (19), and that the extracellular matrix of the aging testis becomes stiffer, leading to increased Piezo1-mediated calcium influx, which in turn causes mitochondrial dysfunction and excessive ROS generation. This promotes ubiquitin-proteasome-mediated degradation of the stem LCs (SLCs), impairing their proliferation and differentiation (83). The study further demonstrated that a Piezo1 inhibitor restored SLC function and elevated testosterone levels, representing a novel therapeutic strategy (83).

ii) Targeting ketone body metabolic deficits. Hmgcs2, a key enzyme in ketone body synthesis, is downregulated in aging testicular LCs, resulting in insufficient ketone body production. Enhancing ketone body production, either through genetic regulation or oral administration of β-hydroxybutyrate, alleviates LC senescence and testicular aging in aged mice, effectively elevating testosterone levels (18).

iii) Restoring lysosomal function. In a high-fat diet-induced LOH mouse model, intra-seminiferous tubule injection of a transient receptor potential mucolipin 1 agonist restored lysosomal function and reversed testosterone deficiency and associated pathological changes, such as impaired lysosomal acidification, lipid droplet accumulation and Sertoli cell senescence (6).

iv) Counteracting fibrosis and steroidogenic impairment. CCN5, a key biomarker of testicular aging, impairs steroidogenesis and accelerates LC senescence via β-catenin/SMAD-mediated fibrosis and RNF213 downregulation-induced lipid loss and cholesterol efflux. Targeted CCN5 inhibition may restore endogenous testosterone while avoiding the risks of exogenous testosterone therapy (19).

v) Targeting cellular senescence and stress. The ZAKα inhibitor nilotinib alleviates testicular atrophy in aged mice, restores testosterone levels and ameliorates Sertoli cell dysfunction (7).

Natural products and metabolic interventions

i) Flavonoids. Icariin protects spermatogonia and Sertoli cells against oxidative stress by enhancing estrogen receptor α expression and activating the nuclear factor erythroid 2-related factor 2 antioxidant pathway (84). Quercetin counteracts various reproductive toxicities, including impaired sperm function, reproductive hormone dysfunction, testicular apoptosis, oxidative stress and inflammation, primarily by inhibiting ROS generation via its cyclic antioxidant structure and modulating oxidative stress-induced apoptotic signaling (85).

ii) Other natural extracts. Morinda citrifolia extract increases serum testosterone levels, reduces SHBG and dihydrotestosterone concentrations, enhances the expression of testosterone biosynthesis-associated proteins and downregulates degradative enzymes (5α-reductase and aromatase), improving muscle performance and sperm quality (86).

Despite their antioxidant and cytoprotective effects in aging rodent models, clinical evidence in humans remains limited owing to poor oral bioavailability and the lack of large-scale standardized trials.

Regenerative medicine and tissue engineering

i) Stem cell transplantation and immune modulation. Transplantation of SLCs into damaged testes promotes endogenous LC repair, thereby restoring testicular secretory function. Transplanted SLCs form nanotubes that transfer mitochondria to testicular macrophages, shifting them from a pro-inflammatory to an anti-inflammatory phenotype, thereby supporting tissue repair, and markedly improving fertility in model mice (34).

ii) Biomaterials and organ reconstruction. Chi et al (87) developed a hydrogel derived from testicular decellularized extracellular matrix that mimics the young testicular microenvironment. When co-transplanted in situ with SLCs into aged testes, this hydrogel promotes SLC proliferation and differentiation, markedly elevating endogenous testosterone and ameliorating age-related symptoms associated with testosterone deficiency, including increased muscle mass, reduced bone loss, decreased white adipose tissue and improved cognitive function (87).

Currently, SC transplantation, niche reconstruction and tissue engineering approaches remain in the early experimental phase, primarily supported by in vitro cellular systems and rodent models. With continued preclinical optimization, these regenerative strategies hold promise as potential therapeutic modalities to restore endogenous endocrine function and alleviate hypogonadism-related cardiovascular and systemic functional decline in the future.

Conclusions and future perspectives

Aging is the intrinsic mechanism underlying the decline of gonadal function, whereas obesity accelerates this aging process through chronic inflammation, oxidative stress and hormonal imbalance. Aging and obesity reinforce each other, forming a vicious cycle that jointly drives the onset and progression of chronic hypogonadism. Accordingly, future research should focus on the interplay between obesity and testicular aging, advancing along two directions, namely, basic and clinical research.

Future basic research should focus on elucidating the molecular mechanisms underlying the interaction between obesity and testicular aging, and on identifying and validating key targetable molecular nodes, thereby breaking the vicious cycle and improving gonadal function.

Although abundant population-based evidence indicates that GLP-1RAs exert beneficial effects on weight loss and male reproductive function, larger multicenter randomized controlled trials are still required to further clarify their efficacy and long-term safety, thereby providing a robust evidence basis for their eventual incorporation into clinical practice guidelines. These efforts will ultimately support evidence-based strategies to preserve gonadal health in aging men.

Acknowledgements

Not applicable.

Funding

This review was supported by grants from the National Natural Science Foundation of China (nos. 82370849, 82270839, 82200947 and 82400928) and the Natural Science Foundation of Shandong Province (nos. ZR2023MH008 and ZR2024QH375).

Availability of data and materials

Not applicable.

Authors' contributions

DL and LZ conceived the article and drafted the manuscript. XQ, QG and FX helped to revise the manuscript critically for important intellectual content. PL and CY assisted in designing and organizing the conceptual framework. Data authentication is not applicable. All authors have read and approved the final manuscript.

Ethics approval and consent to participate

Not applicable.

Patient consent for publication

Not applicable.

Competing interests

The authors declare that they have no competing interests.

References