As a metabolic hormone acting on multiple tissues and organs, T exerts significant regulatory effects on skeletal muscle, bone, and adipose tissue. Studies indicate a progressive age-related decline in T levels [31], which is associated with an increased risk of fractures, sarcopenia, and SO in older adults [32]-[34]. A study on aging in Korean men demonstrated that low free T levels were not only associated with a higher risk of sarcopenia and obesity individually but also significantly increased the risk of SO [34]. Furthermore, androgen deprivation therapy in patients with prostate cancer frequently leads to SO as an adverse outcome [35][36]. Among men living with HIV, those with SO exhibited significantly lower levels of estradiol, total T, and free T compared to those without SO [37]. Although animal studies have confirmed the beneficial effects of T on increasing muscle mass and reducing fat [38], the efficacy of exogenous testosterone supplementation for improving body composition in individuals with SO remains debatable. A small study in hypogonadal men, who underwent dietary and exercise control along with a pre-treatment androgen washout period of at least 12 weeks, found that 10 weeks of weekly 100 mg T supplementation significantly improved fat-free mass, muscle size, and strength, but did not significantly alter fat mass [39]. This aligns with findings from a US study employing 6 months of sublingual T replacement in hypogonadal men [40]. In contrast, another study using the same weekly 100 mg T regimen over 18 months reported increases in lean body mass accompanied by significant reductions in fat mass [41]. Another 3-year intervention using a scrotal patch for T delivery resulted in significant increases in fat-free mass, a non-significant trend towards fat mass reduction, and no change in grip strength [42]. Long-term T gel replacement therapy has been shown to improve lean body mass and reduce fat mass, though the effect on fat mass was observed only in younger patients, and grip strength remained unaffected [43]. A randomized double-blind trial in older men found that a group with low T levels had higher fat mass at baseline. After one year of T intervention compared to a placebo control, the treatment group exhibited significantly increased fat-free mass and reduced fat mass, yet no significant differences were observed in grip strength [44]. Collectively, these findings suggest that exogenous T supplementation can improve muscle mass. Although studies have elucidated the mechanism by which low T levels affect body composition—promoting fat accumulation through reduced β-oxidation and lipolysis, along with increased adipogenesis—increased adipose tissue mass, in turn, suppresses the hypothalamic-pituitary-testicular axis by elevating pro-inflammatory cytokines and insulin resistance, creating a bidirectional interplay [45]. On the other hand, low free T levels also lead to muscle loss by impairing myogenesis, satellite cell differentiation, and protein synthesis, while upregulating the expression of proteins associated with muscle breakdown [46]. Furthermore, inflammatory cytokines elevated by fat accumulation can promote catabolism in skeletal muscle [47]. The interaction of these multiple factors collectively contributes to the development of SO. However, a significant point of contention is that most interventional studies have been conducted in hypogonadal men. It remains unclear whether individuals with SO who do not meet the criteria for hypogonadism would similarly benefit from T therapy in terms of body composition. Furthermore, variations in administration routes and dosages, which have demonstrated distinct pharmacokinetics and clinical outcomes—as seen with T gels versus patches [48][49]—must be considered when interpreting these results.

Estrogen exerts both direct and indirect effects on bone to influence bone formation and is also a significant regulator of other body composition components [50]. Mice with aromatase deficiency or inactivated Estrogen Receptor-alpha (Erα) genes demonstrate a marked increase in fat mass [51][52]. Murine studies indicate that signaling through both the androgen receptor and ERα is crucial for maintaining muscle mass, and that activation of ERα alone is sufficient to reduce adiposity [53]. A study published in the New England Journal of Medicine, which administered varying doses of T to healthy men with or without concomitant inhibition of testosterone-to-estrogen conversion, not only underscored the relationship between T and muscle mass, size, and strength but also highlighted the correlation between estrogen deficiency and increased fat accumulation [54]. Given the close metabolic relationship between T and estrogen—where over half of the estrogen in men is derived from T conversion—a decline in androgen levels directly leads to reduced estrogen synthesis. The synergistic action of both hormones contributes to the pathogenesis of SO. This provides a plausible explanation for the observed improvements in body composition following T intervention mentioned previously: the benefits may stem not only from the direct physiological actions of T itself but also from the combined effects of increased estrogen levels resulting from its aromatization. A meta-analysis of 23 studies indicated that estrogen-based therapy can indeed improve muscle strength [55]. However, studies have also reported a range of adverse outcomes associated with estrogen supplementation in postmenopausal women, including increased risks of breast cancer, cardiovascular disease, and pulmonary embolism [56]. Consequently, estrogen replacement is not currently recommended for the prevention or treatment of declining muscle strength in postmenopausal women.

Growth Hormone (GH) is an anabolic hormone whose secretion declines with age. It plays a role in protein metabolism within skeletal muscle [57] and significantly influences lipid metabolism. GH exerts a lipolytic effect, primarily mobilizing Free Fatty Acids (FFAs) from visceral adipose tissue over subcutaneous fat by increasing the activity of Hormone-Sensitive Lipase (HSL) [58]. Research indicates that GH secretion peaks during adolescence and begins to decline in adulthood, with daily secretion in elderly men being 5 to 20 times lower than in young adults [59]-[61]. Beyond aging, increased abdominal visceral fat is strongly associated with reduced pituitary GH secretion [62]. Although obesity itself suppresses GH secretion, it has been reported that individuals with SO exhibit a more profound suppression of GH secretion compared to those with obesity alone [63]. Early studies in patients with congenital GH deficiency, characterized by markedly low levels of both GH and IGF-1, revealed that this population typically presents with increased fat mass and decreased muscle mass [64]. Several intervention studies have found that GH supplementation in individuals with obesity effectively reduces fat mass [65], although some evidence suggests this effect may be sex-dependent [66]. In one study designed to test the hypothesis that GH reduces fat mass and increases lean body mass, healthy older men received exogenous GH three times per week for six months. The intervention resulted in an 8.8% increase in lean body mass, a 14.4% reduction in adipose tissue mass, and a 7.1% increase in skin thickness, whereas no significant changes were observed in the control group. This led to the conclusion that age-related GH deficiency contributes to the decline in lean mass, expansion of adipose tissue, and thinning of the skin in the elderly [67]. Another study found that while exogenous testosterone supplementation in community-dwelling older men increased lean body mass, muscle strength, and reduced fat mass, co-administration of GH augmented these beneficial effects on body composition [68]. Current evidence suggests that GH has a significant impact on body composition. However, there is insufficient evidence to support the routine use of exogenous GH supplementation in specific populations for this purpose. Furthermore, future research must carefully consider the potential for adverse effects associated with GH therapy.

IGF-1 is an anabolic hormone whose levels decline with age. It promotes muscle repair and maintenance by enhancing cell cycle progression, proliferation, and differentiation [69], and by activating satellite cells, stimulating their proliferation and fusion [70]. Ultimately, IGF-1 exerts a beneficial effect on skeletal muscle by reducing proteolysis [71]. Animal studies have demonstrated that overexpression of IGF-1 in skeletal muscle induces hypertrophy and regeneration, while preserving muscle strength and function in both aged mouse models and those with neuromuscular disease [72][73]. Conversely, reduced IGF-1 expression in obese mice exacerbates muscle loss [74]. Epidemiological and clinical studies consistently report a strong association between circulating IGF-1 levels, muscle function, and fat mass. A cross-sectional study suggested that impairment of the Growth Hormone (GH)/IGF-1 axis is associated with an increased risk of SO and ectopic fat deposition in the liver [75]. An intervention study involving 24 healthy volunteers found that leucine supplementation revealed age-related declines in muscle strength and endurance, which were correlated with lower circulating IGF-1 levels. This was attributed to reduced myosin heavy chain synthesis and impaired mitochondrial protein synthesis [76]. Patients with heart failure exhibit significantly lower IGF-1 levels compared to matched healthy controls [77]. However, aerobic exercise in these patients can increase IGF-1 expression, downregulate catabolic factors like myostatin, and improve skeletal muscle function [78]. Similar benefits are observed in individuals with type 2 diabetes, where combined aerobic and resistance training improves muscle function, reduces fat mass, and elevates serum IGF-1 levels [79]. In breast cancer patients, 16 weeks of combined aerobic and resistance training led to increased IGF-1 levels, significant gains in lean body mass, and reduced BMI compared to baseline and control groups [80]. A randomized controlled trial in older adults with SO compared 8 weeks of resistance training, aerobic exercise, and combined training against a non-exercising control. All exercise groups showed significant improvements in muscle mass, fat mass, and serum IGF-1 levels compared to the control, with resistance training yielding particularly notable effects on IGF-1 [81]. Several meta-analyses have further substantiated that exercise training effectively improves body composition and elevates IGF-1 levels in individuals with SO [82][83]. Another exercise intervention in women with obesity and sarcopenia demonstrated that 12 weeks of circuit training improved fat-free mass, fat mass, and serum IGF-1 levels, while also reducing cardiovascular risk factors and inflammatory markers [84]. Similarly, 36 weeks of personalized resistance training improved body composition and IGF-1 levels in women with probable SO [85]. In conclusion, the influence of IGF-1 on body composition is evident. Utilizing exercise as a modality to elevate endogenous IGF-1 levels appears to be a viable strategy for improving muscle function and reducing adiposity.

Cortisol, a well-known catabolic hormone, promotes protein degradation by activating the ubiquitin-proteasome and lysosomal systems, while simultaneously inhibiting protein synthesis [86]. Furthermore, it contributes to muscle loss, dysfunction, and fat deposition by antagonizing the actions of anabolic hormones such as testosterone and IGF-1 [87][88]. An elevated cortisol-to-dehydroepiandrosterone sulfate (DHEA-S) ratio has been identified as an independent risk factor for sarcopenia, likely reflecting increased catabolic activity from cortisol coupled with diminished protective effects from DHEA-S [89]. Consistently, elevated levels of both serum and salivary cortisol have been associated with lower skeletal muscle mass and impaired muscle function [90][91]. Individuals with obesity often present with lower muscle mass, lower bone mass, higher concentrations of nocturnal salivary cortisol, and elevated circulating high-sensitivity C-reactive protein compared to lean controls [92]. Previous research has confirmed that sleep deprivation elevates cortisol levels, which are strongly associated with increased fat mass and sarcopenia. Additionally, elevated cortisol drives increased levels of multiple inflammatory factors and is additionally closely associated with insulin resistance [93]. The activation of inflammatory cytokines, reduced insulin sensitivity, and increased food intake linked to enhanced dopamine receptor activity are recognized as significant contributors to the development of both obesity and sarcopenia [94]. Although a minority of studies have reported no significant difference in salivary cortisol levels between individuals with SO and control groups [95], such discrepancies in findings may be attributed to variations in study populations and methodological differences in assessment techniques.

DHEA serves as a precursor to sex steroid hormones. It is converted to testosterone via enzymes including 17β-hydroxysteroid dehydrogenase (17β-HSD) and 3β-HSD [96]. Testosterone can subsequently be metabolized into 5α-Dihydrotestosterone (DHT) by 5α-reductase, or into estrogens via the action of aromatase cytochrome P-450 (P450arom). The presence of these multiple catalytic enzymes in skeletal muscle suggests that muscle tissue can locally synthesize and metabolize various sex steroids from DHEA [97]. As no specific receptor for DHEA has been identified to date, its effects on muscle and adipose tissue are believed to be mediated primarily through its conversion to active metabolites like testosterone and estrogen. Additionally, DHEA may indirectly influence body composition by modulating the levels of other hormones, for instance, by increasing bioavailable IGF-1 through the reduction of IGF-binding protein levels [70]. Limited interventional studies indicate that DHEA supplementation can elevate testosterone levels in women and increase IGF-1 levels in men. However, these hormonal changes have not consistently translated into significant improvements in muscle mass or function [98]. A systematic review summarizing the effects of DHEA supplementation on body composition and physical function in older adults concluded that there is currently no definitive evidence supporting its efficacy for enhancing muscle mass or function [99]. Given the limited number of studies, coupled with substantial heterogeneity in intervention duration, DHEA dosage, and participant characteristics, larger and more rigorous clinical trials are warranted to substantiate these findings.