Testosterone and aging male, a perspective from a developing country

Abstract

Purpose

Hypogonadism is associated with a wide range of physical and psychological symptoms that can affect the overall health of men. However, in a developing country, there are several imposing challenges in the diagnosis and treatment of hypogonadism, including a lack of awareness and understanding of the condition among healthcare providers and patients, limited resources and the high cost of treatment. This review aimed to examine the potential benefits and risks of testosterone replacement therapy (TRT) and provides a perspective of a developing country on the topic.

Materials and Methods

A comprehensive literature review was conducted to gather relevant information on the impact of testosterone deficiency on ageing males and the effectiveness of TRT for treating hypogonadism. Published peer-reviewed articles were analyzed to evaluate the benefits and risks of TRT. Additionally, the unique challenges faced in the diagnosis and treatment of hypogonadism in a developing country were considered.

Results

Testosterone replacement therapy has been shown to be an effective treatment for hypogonadism, particularly in symptomatic men with low testosterone levels. It offers potential benefits such as improvements in symptoms and overall quality of life. However, there are associated risks and side effects that need to be considered. In a developing country, challenges such as limited awareness and understanding of hypogonadism, resource constraints, and high treatment costs pose additional barriers to accessing TRT and comprehensive care.

Conclusion

In conclusion, TRT holds promise as a treatment for hypogonadism, but its implementation and accessibility face significant challenges in a developing country. Addressing these challenges, including raising awareness, allocating resources, and finding cost-effective solutions, is crucial for ensuring that men with hypogonadism in such settings receive appropriate diagnosis and treatment. Further research and efforts are needed to improve the management of hypogonadism in developing countries and optimize the potential benefits of TRT for affected individuals.

Keywords:

• Testosterone
• men’s health
• hypogonadism
• aging men
• testosterone replacement therapy

Introduction

Testosterone is a crucial factor in maintaining normal male physiological function. However, after the age of 30, testosterone levels decrease at a rate of 1–2% per year, which correlates with an increase in the incidence of diagnosed late-onset hypogonadism (LOH) in middle-aged and elderly men [1]. Previous studies have evidenced links between testosterone deficiency (TD) and age-related comorbidities. As a result, testosterone replacement therapy (TRT) is emerging as a promising solution for aging-related issues and an interesting topic in medical research worldwide. Despite being widely studied and used for managing late-onset hypogonadism (LOH), there is a lack of data from Asian countries representing 60% of the world’s population, particularly in low-middle-income nations. With the acceleration of the aging process of populations in Asia including Vietnam, managing TD for elderly men will become a burden for the healthcare system, resulting in a considerable number of undiagnosed and uncontrolled cases. In this review, we discuss the effects of testosterone on aging males and the challenges faced by developing countries.

Testosterone and sexual function

Testosterone plays a crucial role in activating all phases of the human sexual response cycle, particularly in males [2–5]. The natural relationship between testosterone and sexual functions is well-established and has been observed in patients undergoing androgen deprivation therapy (ADT) using luteinizing hormone-releasing hormone (LHRH) agonists, gonadotrophin-releasing hormone (GnRH) agonists and antagonists, or androgen receptor (AR) competitive antagonists [4,5]. Reducing testosterone levels within the therapeutic threshold for ADT of lower than 50 ng/dl (1.7 nmol/l) or even under 20 ng/dl (1 nmol/l) may increase the risks of erectile dysfunction (ED) and reduced libido threefold and five-to-sixfold, respectively [5]. Moreover, other aspects of sexuality are also affected immediately after ADT such as nocturnal erection, sexual motivation, and orgasms [4,6]. Similar situations were found in cases of hypogonadotropic/hypergonadotropic hypogonadal men [7,8]. The prevalence of all types of sexual dysfunctions significantly increases during the aging process [9–11] due to the gradual decline of androgens and their metabolites after the age of 40 [12], as well as for the increasing prevalence of other relevant comorbidities, including diabetes and other endocrine dysfunctions, metabolic conditions, and cardiovascular diseases (CVD) [13–15].

Sexual dysfunctions are often the first signs of TD in aging males [16,17]. Decreased frequencies of morning erection and sexual thought and ED are closely associated with the reduction of testosterone in men older than 40 years old but not with younger men [16]. The prevalence of desire-related disorders and ED begins to increase when the total testosterone (TT) level drops below 15 nmol/l and 8 nmol/l, respectively [17]. Interestingly, men with <10.4 nmol/l of TT and < 225 pmol/l of calculated free testosterone (FT) have a significantly higher risk of diminished morning erections, ED, and low desire, regardless of age [18]. Indeed, the relationships between testosterone and sexual dysfunction become more apparent when T downs are below a normal level [2]. However, sexual dysfunctions are typically caused by a combination of factors, and not solely by low testosterone levels. Therefore, even men with low levels of testosterone can still achieve some level of erection [2,3]. The relationship between ejaculation problems and testosterone is unclear due to limited and inconsistent evidence [2].

The direct pathophysiology of testosterone deficiency in sexual functions and behaviors has yet to be fully understood. However, observations from the functional magnetic resonance imaging (fMRI) of the brain and experiments using castrated animal models support the establishment of theories about the effects of testosterone on sexuality. In the brain, testosterone positively modulates and regulates activities of some functional regions related to sexual responses [2,3]. Testosterone plays a role in all the components of sexual excitation which have been shown to be associated with respective brain regions including (i) the temporo-occipital, superior-parietal, and orbitofrontal cortices which involve the perceptive-cognitive component of sexual arousal; (ii) the cingulate gyrus, inferior frontal regions, and the supplementary motor area which correlate with the motivational aspects of sexual behavior; and (iii) the insula, the anterior cingulate cortex, and the claustrum which control autonomic responses to sexual stimuli [3]. By these potential mechanisms, testosterone deficiency might affect sexual thought, motivation, and desire.

Moreover, testosterone is required for modulating the erection and maintaining the integrity of the penis structure [19]. In animal models, testosterone not only up-regulates the eNOS (endothelial nitric oxide synthase) and nNOS (neuronal nitric oxide synthase) but also down-regulates the activity of RhoA (Ras homolog gene family member A) and its downstream effector ROCK (-Rho-associated, coiled-coil containing protein kinase), leading to the prolonged relaxation of penile smooth muscle due to an increase in NO by the former and a change in the sensitization to calcium by the latter [2]. Lacking testosterone might suppress NO-related activities, which in turn, affect penile erection. Furthermore, studies on castrated or androgen-deprived animals show the reduction of smooth muscle and an increase in connective tissue contents, especially adipocytes, leading to fat accumulation in the corpus cavernosum. The consequences of these changes are a decrease in cavernosal compliance and restricted penile engorgement and venous occlusion [4]. As a result, the alteration of intracavernosal pressure (ICP) under stimulation is also affected by TD [4,19]. On the other hand, testosterone plays a role in regulating the expression and function of the corpus cavernosal type 5 phosphodiesterase (PDE5) gene [20]. Therefore, using PDE5 inhibitors alone is insufficient for the treatment of ED in cases of down-regulating PDE5 gene expression due to hypogonadism [4,19].

TRT has been demonstrated to be effective in managing sexual dysfunctions, particularly low libido and ED, in hypogonadal men, but not in cases of eugonadal men [21–24]. Results from previous meta-analyses on TRT consistently showed improvements in various aspects of sexual function, including libido, nocturnal erection, sexual thoughts and motivation, and erectile function in men with baseline testosterone levels less than 12 nmol/l [22,23]. Patients with testosterone levels less than 8 nmol/l derive even greater benefit from TRT, with an improvement in the erectile function domain of the International Index of Erectile Function (IIEF) of 2.95 [1.86;4.03] compared to 1.47 [0.90;2.03] in patients with testosterone levels below 12 nmol/l [20]. There are significant improvements in most of the sexual activities assessed by Psychosexual Daily Questionnaire – Question 4 (PDQ-Q4) except for “flirting by others” and “day spontaneous erections” in the treatment group of the Testosterone Trial (TTrial) [25]. However, it is important to note that the effectiveness of TRT alone is limited in the severe cases of ED that are affected by multifactorial causes, and combined treatment with a PDE5 inhibitor may be recommended [21].

Testosterone, metabolism and body composition

Metabolic syndrome (MetS) is considered to be the co-occurrence of several risk factors for CVD including central obesity, dyslipidemia, hyperglycemia, insulin resistance and hypertension [26]. Many diagnostic criteria for MetS have been proposed. However, the definition criteria of the International Diabetes Federation in 2007 are widely accepted. According to these criteria, MetS was defined as the presence of central obesity plus two of any factors including high triglycerides, low HDL cholesterol, elevated blood pressure, and elevated fasting plasma glucose [27].

In recent years, many studies have attempted to elucidate the relationship between TD and metabolic disorders [28–30], particularly in an elderly male population where the prevalence of low serum T is more common [31–37]. The results from these studies have shown a bidirectional association between T deficiency and MetS.

The Massachusetts Male Aging Study, a population-based observational study, investigated testosterone levels of men aged 40-79 years, controlling for factors such as chronic illness, anthropometric measurements, and lifestyle. TT was found to be significantly higher in healthy men compared with obese, chronically ill men [38]. More recently, Cheng et al. conducted a cross-sectional survey in China to analyze the link between TT level and multiple metabolic components in 4300 Chinese men. The results showed that men in the lowest quartile of TT level (≤12.6 nmol/L) had significantly increased parameters including body mass index (BMI), lipid profile, HbA1c, Homeostatic Model Assessment of Insulin Resistance (HOMA-IR) and diastolic blood pressure [39].

Furthermore, TD also has a predictive value for the development of MetS. In a population-based cohort study in Finland, Laaksonen et al. evaluated 702 middle-aged men who did not have MetS or diabetes at baseline. After 11 years of follow-up, 20.9% of the men (147 individuals) developed MetS. Low levels of TT, calculated FT, and sex hormone binding globulin (SHBG) were found to be independent risk factors (OR = 2.54, 95% CI 1.69-3.81; OR = 1.91, 95% CI 1.27-2.89 and OR = 2.89, 95% CI = 1.93-4.33, respectively) after adjusting for age, CVD, smoking, alcohol consumption, and socioeconomic statuses [33]. Similarly, a prospective multicenter study involving 1651 European men without MetS also reported that men with lower TT at baseline were associated with a higher incidence of MetS after a median follow-up of 4.3 years [31].

The pathophysiological mechanism of the influence of testosterone on metabolic components is complex. However, it has been proposed that testosterone promotes myocyte and inhibits adipocyte development from pluripotent stem cells [40]. Testosterone also inhibits the differentiation of preadipocytes to adipocytes by activating ARs [41]. In contrast, TD activates lipoprotein lipase, resulting in adipocyte proliferation and the formation of visceral adipose tissue [42,43]. The adipose tissue, in turn, acts as an endocrine organ and triggers several downstream mechanisms which contribute to glucose intolerance, insulin resistance and type 2 diabetes (T2D) [44]. There is also evidence that low testosterone level exacerbates insulin resistance by decreasing insulin sensitivity of muscle by alternating insulin receptor expression and cellular pathways [45]. Furthermore, the endocrine activity of adipose tissue might affect testosterone production. Leptin, a protein secreted by adipocytes that regulate food intake and energy expenditure, has been shown to be inversely correlated with luteinizing hormone (LH) - stimulated androgen in obese men [46]. Other products of visceral adipose tissue, such as the tumor necrosis factor-a (TNF-a), interleukin-6 (IL-6) can also suppress LH through blockage of LHRH secretion [47]. Lastly, the excess aromatase activity in obese men is associated with an increased conversion of testosterone to estradiol which inhibits the hypothalamic-pituitary-gonadal axis and ultimately reduces the testosterone secretion in the testes. Overall, the hypogonadal-obesity-adipocytokine cycle might explain the high prevalence of MetS-induced hypogonadism in aging men [48].

Treatment of TD has become a significant issue for aged men with MetS, as it has been shown to have numerous beneficial effects on various aspects of health. TRT has been found to improve symptoms associated with metabolic syndrome, including reducing body weight, BMI, improving insulin sensitivity and decreasing blood pressure [21,49–51]. In particular, the TIMES-2 study, an RCT specifically evaluated the effect of 12 months TRT on men with T2D or MetS, showed a reduction in HOMA-IR after 12 months by 16.4% in men treated with TRT. Glycemic control was also better in TRT group compared with placebo when patients with T2D were analyzed. In addition, mild improvement of total and LDL cholesterol and body composition was observed [52]. Similar findings are demonstrated in meta-analyses which documented a considerable reduction in fat mass, fasting glucose and insulin resistance [53,54]. More recently, the T4DM study, a large randomized double-blind placebo-controlled study, has shown the effect of 2 years of TRT in men with functional hypogonadism and MetS. A total of 1007 men aged 50-74 years, with a waist circumference of more than 94 cm, either presented with impaired glucose tolerance or newly diagnosed with T2D and a serum testosterone concentration of 14 or lower were recruited. They were all enrolled in a lifestyle program, and subsequently randomized into the intramuscular injection of testosterone undecanoate 1000 mg every 3 weeks or placebo. After 2 years, there was a significant 41% reduction in the prevalence of T2D in the TRT group compared with placebo. TRT and lifestyle intervention also prevented progression to T2D in twice as many cases compared with lifestyle intervention alone. In addition, it is evident that TRT improved several metabolic parameters such as total and visceral fat mass, waist circumference and muscle mass while they worsened in the placebo group [55].

In conclusion, the relationship between TD and MetS has been well-documented in recent studies. Low testosterone levels have been identified as independent risk factors for the development of MetS and have been linked to various parameters such as BMI, lipid profile, HbA1c, insulin resistance, and blood pressure. TRT has been found to have numerous benefits in aged men with MetS. However, in Vietnam, screening for TD in elderly men has largely been neglected despite the country’s rapidly growing economy and advancements in healthcare. A recent meta-analysis aiming to determine the prevalence of MetS and its related factors among the Vietnamese population failed to address testosterone as one of the risk factors of MetS [56]. An extensive search of the current literature was also unable to identify any article assessing TD in aged men with MetS. The underdiagnosis of low testosterone levels in elderly men is due to several factors, including a lack of awareness of the importance of testosterone levels in the development of MetS and a lack of resources dedicated to addressing men’s health issues, which prevent early intervention opportunities.

Testosterone and bone health

In men, the prevalence of osteoporosis and the incidence of new fractures at any site gradually increases after the 60s which is partly contributed by the changes in sex hormones [57]. TD, both in cases of age-related, pathological, or induced hypogonadism (in terms of ADT), is described as the cause of osteoporosis in men [58]. A study on 2447 community-dwelling men aged over 65 years old showed that hypogonadal men had a higher prevalence of osteoporosis (12.3 vs. 6.0%, p = 0.003) and a greater incidence of rapid hip bone loss (22.5 vs. 8.6%, p = 0.007) than eugonadal men [59]. Moreover, another multicenter study in elderly males also found that total and FT were both positively associated with bone mineral density (BMD) in the total body, total hip, femur trochanter, arm, and lumbar spine [60]. The role of testosterone on bone health was emphasized in the study on intermittent ADT patients whose BMD declined during therapy but recovered following the return of testosterone [61–63].

Testosterone activates estrogen receptor-α or -β (ER-α and ER-β) by converting to estradiol through aromatization, indirectly leading to well-known effects on the maturation and maintenance of bone [64]. In addition, testosterone also directly regulates the AR presented in bone cells [58,64]. While estrogens predominantly influence bone health, it is a challenge to separate the effect of androgens. Androgens play a role in prolonging the osteoblasts’ life and increasing their proliferation but suppress the formation of osteoclasts triggered by the parathyroid hormone [65,66]. Moreover, a study in secondary hypogonadal men on TRT suggested the effect of testosterone on re-modeling trabecular structure to concrete bone strength [67].

The role of TRT in maintaining bone health in men remains controversial. A recent meta-analysis of 52 RCTs by Zhang et al. failed to indicate the role of TRT in increasing the BMD or decreasing the risk of fracture at any site [68]. However, most of the studies included in the analysis were small and in short-term follow-ups that were not sufficient to investigate the change in bone density, especially when most participants were non-osteoporosis men. Indeed, larger RCTs with more than 1-year follow-up consistently showed increases in BMD and other markers for bone health in TRT compared with placebo groups [69–72]. Involving osteoporosis/osteopenia Japanese men in their RCT, Shigehara et al. found an increase in L2-L4 BMD in the TRT group more than in the placebo group after 12 months (5.0 ± 5.0 vs. 3.0 ± 3.2; p = 0.0434) but the number of men with BMD “becoming normal” was not presented [73]. Currently, there is a lack of RCTs investigating the effect of TRT used alone or in combination with standard treatment for osteoporosis. Therefore, TRT should be considered as a preventative solution for maintaining bone health in hypogonadal elderly men rather than a first-line treatment for osteoporosis.

Testosterone and cardiovascular health

TD is associated with increased cardiovascular events independently of effects on the metabolic system, particularly in a high-risk population. In the study following up 171 Japanese males aged 30-69 at risk of CVD, those with a testosterone level lower than 14.2 nmol/l had 4.61 times increased cardiovascular event risk compared with the higher testosterone tertiles after adjusting age, BMI, current smoking, systolic blood pressure, HDL cholesterol, non-HDL cholesterol, HbA1C, endothelium-dependent flow-mediated vasodilation (%FMD), using medications, estradiol, and DHEA-S (adjusted hazard ratio (HR) of 4.61; 95% CI: 1.02–21.04) [74]. Another population-based study on 3443 men over 70 years old showed an increased incidence of stroke or transient ischemic attack in those with TT < 11.7 nmol/l and FT <222 pmol/l, which were independent with age, waist-hip ratio, waist circumference, medical comorbidities (Charlson index), smoking status, diabetes, exercise history, past alcohol intake, use of aspirin or clopidogrel, hypertension, and dyslipidemia [75]. The inversed effect of testosterone and its metabolite deficiency on the cardiovascular-related mortality rate of elderly men was also reported in previous studies [76,77]. Moreover, among hypogonadal men with a TT < 10.4 nmol/l (< 300 ng/dL), those with higher testosterone levels are less likely to acquire new cardiovascular events compared with < 6.9 nmol/l (< 200 ng/dL) group (adjusted HR: 0.85; 95%CI: 0.80-0.91) [78]. This result was also highlighted in the studies on prostate cancer patients indicated for ADT, which showed an increased risk of CVD morbidities and mortality compared with the non-ADT group, but only appeared in subgroups of high cardiac risks [79–82]. Additionally, research has found patients with progressive and/or severe CVD often have significantly lower testosterone levels than others, suggesting a protective role of testosterone in such conditions [83].

The relationship between low testosterone and CVD in the general population remains a topic of debate. While some meta-analyses on community-dwelling men failed to indicate any association between lower TT and increased incidences of CVDs [84,85], Corona et al. in a meta-analysis comprising 37 observational studies, have found higher risks of cardiovascular mortality, morbidity, and incidence among hypogonadal men, regardless of other factors (adjusted odd ratio (OR) = 1.26 [95%CI: 1.17; 1.36], 1.54 [95%CI: 1.25; 1.89], and 1.17 [95%CI: 1.01; 1.36], respectively) [86]. In addition, a sub-group analysis, based on the age of participants in a study by Ruige et al. has found that testosterone may play a protective role against CVD in men over 70 years old but not in younger ones [87]. These findings suggest that testosterone may only act as a cardiac protector in specific circumstances, such as those with a high risk of developing cardiovascular events, rather than universally. Further research is needed to fully understand the complex relationship between testosterone levels and cardiovascular health. Besides the indirect effects on the metabolic system, the mechanism under the direct influence of testosterone on CVD is not yet fully understood. However, researchers have shown that TD potentially causes ultrastructural changes in the cardiovascular system by thickening the intima-media of vascular vessels and impairing the endothelium function [88]. Comparing the symptomatic LOH men with eugonadal men in their middle age, Mäkinen et al. found significant increases in maximum common carotid intima-media thickness (IMT) and IMT of the carotid bulb (1.08 ± 0.34 mm vs. 1.00 ± 0.23 mm with p = 0.045; 1.44 ± 0.48 mm vs 1.27 ± 0.35 mm, respectively) [89]. They also found an inverse correlation between testosterone levels and carotid IMT in middle-aged men after controlling for risk factors of CVD [89]. Additionally, testosterone has been negatively associated with the progression of IMT in elderly men during follow-up [90]. Low-grade inflammation is supposed to be the mechanism underlying these changes [91,92].

Endothelial function and structure are disturbed in cases with low testosterone levels in both animal models and clinical observations [88]. In rats, the vascular endothelium structure score (VESS) of the aortic after 10 weeks of the experiment was highest in the castrated group but partially recovered when administering testosterone undecanoate after castration [93]. Damage to the endothelium was also observed when dihydrotestosterone (DHT) was suspended [93]. Furthermore, TD also interrupts the NO production, regulation, expression, and activity, and in that way leads to endothelial dysfunction [94]. The number of endothelial progenitor cells was found to be decreased in hypogonadal men and this might impair endothelial repair [88]. Testosterone is directly involved in vasodilatory and smooth muscle relaxation by inhibiting the Ca²⁺ channel and activating the K⁺ channel [88]. These changes might subsequently lead to the potential risk of CVD in men with TD.

Based on the apparent relationship between testosterone and cardiovascular events in high-risk hypogonadal men, TRT might be beneficial in some cases. Although results from previous trials and longitudinal studies are not consistent regarding the effect of TRT on cardiovascular events, maintaining the testosterone concentration at the physiologically normal range is the key to fully activating its protective effects [83,95–99]. For treatment purposes, using TRT with an appropriate dose for hypogonadism in men is safe in terms of cardiovascular concerns [3,21,83,88,92]. Furthermore, there are no increased risks of erythrocytosis (in patients using transdermal or long-acting T) and venous thromboembolism in TRT men, however regular check-ups during treatment are recommended [21].

The use of TRT has also been considered to have a detrimental effect on obstructive sleep apnea syndrome (OSAS), although it remains a subject of debate [100]. While some studies have suggested that high-dose TRT could potentially worsen OSAS, these effects have primarily been observed in the short term and may normalize with longer-term follow-up [101,102]. The recent guidelines from the European Association of Urology (EAU) also highlighted the lack of evidence that TRT can result in the worsening of OSAS [103]. However, screening for OSAS and appropriate dosing adjustments should be considered in patients undergoing TRT.

Testosterone, erythropoiesis, and blood flow characteristic

Numerous studies, both in animals and humans, have highlighted a connection between testosterone and the production of red blood cells (erythropoiesis) [104,105]. As individuals reach the age of 65 and beyond, the prevalence of anemia tends to rise, particularly among men. This increase in anemia rates can have a significant impact on the health and well-being of older individuals [106–108]. Besides well-known etiologies in two-thirds of cases, TD has been identified as an independent factor contributing to unexplained anemia in the aging population [106,109,110]. A three-year follow-up study in a community-representative sample by Ferrucci et al. showed that lower TT and bioavailable testosterone (BT) levels were associated with a higher prevalence of anemia in men over 65 years old [109]. Moreover, men with a TT <354 ng/dL or a BT <68.1 ng/dL had 2.5 [95%CI: 1.0–6.0] or 5.4 [95%CI: 2.2–12.9] times higher risk of developing anemia after 3-year follow-up than others in unadjusted models [109]. The relationship between low testosterone and anemia risk is more inevitable in the case of ADT for prostate cancer [111–113]. In a large cohort of 10,364 prostate cancer patients, current and past ADT users had 2.90 [95%CI: 2.67–3.16] and 1.27 [95%CI: 1.12–1.43] times increased risk of anemia compared with non-users after controlling for other cofactors [111]. Indeed, unexplained anemia has been noted as a non-specific symptom suggesting TD for which the treatment needs to be considered according to the guidelines of the Endocrine Society in 2018 [114].

Testosterone has been involved in several steps of hematogenesis by not only increasing erythropoietin production but also decreasing the synthesis of hepcidin affecting iron bioavailability, red blood cell metabolism, and stimulating bone marrow erythropoiesis directly or indirectly through estradiol [104,115–118]. As a result, TRT has been used in treating specific types of anemia for decades [115]. However, using TRT for non-anemia individuals, especially for males with TD, might contribute to a risk of erythrocytosis, thereby increasing the blood viscosity and reducing blood flow [119].

Excessive increase in red blood cells has been reported as the most common adverse event of TRT [114,120]. Due to clinical concerns regarding the potential health consequences of erythrocytosis, it is advisable to regularly monitor hemoglobin (Hb) and hematocrit (HCT) levels in individuals undergoing TRT. Different guidelines may recommend considering cessation of TRT if HCT levels exceed 52–54%[114,115,121–123]. Testosterone effects on hematogenesis become more evident within 5–6 months with a significant peak of change in HCT after 48 months [115,124,125]. Administration of TRT results in a 1.3 to 4.0% elevation in mean HCT. Moreover, individuals undergoing TRT are approximately 3.67 to 5.07 times more likely to have HCT levels exceeding 50% [120,126]. However, the incidence of secondary erythrocytosis during TRT varies depending on the study population, ranging from 1.7–9% in individuals with hypogonadism to 22% in those with diabetes [55,125,127]. Interestingly, clinical trials indicated that using transdermal preparations of testosterone in treating hypogonadism men (TT < 12 nmol/L) did not increase the risk of erythrocytosis [21]. In most cases, a lower dose or temporary withdrawal is sufficient to revert changes in HCT and Hb. Moreover, the relationship between elevated HCT and venous thromboembolism (VET) remains controversial [128]. In hypogonadism men, those with a higher HCT at the final assessment (up to 52%) have a lower mortality rate compared with low-HCT men (≤49%) [124]. While additional research is necessary to gain a comprehensive understanding, it is suggested that TRT should be cautiously administered, with close monitoring, to assess the benefits and potential drawbacks in terms of hematogenesis and overall health.

Testosterone and the lower urinary tract

Lower urinary tract symptoms (LUTS) refer to a set of symptoms relating to storage and voiding disturbances including urinary frequency, urgency, nocturia, poor stream, hesitancy and incomplete emptying [129]. LUTS are common among aging men with a prevalence rate of more than 50% in men aged over 50 years [130]. The presence of LUTS has been associated with a significant impact on the quality of life of the elderly [131,132]. Furthermore, LUTS can lead to additional health problems, such as urinary incontinence, urinary tract infections, and bladder problems [133]. LUTS can be associated with several factors, including prostatic diseases, urinary tract infections or neurological diseases, but benign prostatic hyperplasia (BPH) is often considered to be the most common cause [133].

In the past decades, many studies have attempted to demonstrate the relationship between sex hormones and BPH, but few have investigated the effect of testosterone on LUTS [134,135]. In a cross-sectional study, Schatzl et al. reported that the prevalence of hypogonadism among men with LUTS (as defined by International Prostate Symptom Score – IPSS of more than 7) was 22.1%. However, there was no correlation between low testosterone on symptom status, prostate volume (PV) or prostate-specific antigen (PSA) [136]. Another clinical study in Korea showed that among older men, free testosterone (FT) and BT were inversely correlated with IPSS, which supports the favorable role of endogenous testosterone in lower urinary tract functions [137]. One community-based prospective study investigating serum sex hormone and the long-term risk of LUTS demonstrated a 56% decreased risk of LUTS in men with higher concentrations of BT compared with hypogonadal men [138].

On the other hand, some studies have found no association between circulating T and LUTS. One large cross-sectional study on 5506 men aged 30–79 years revealed that sex hormones are generally not significant predictors for LUTS in men after adjusting for age and there are several factors that could contribute to the pathophysiology of LUTS [139]. Data from the NHANES III study, a national wide probability sample collected in the U.S., was also unable to identify a consistent association between LUTS and testosterone, FT or SHBG concentrations [140]. These findings indicated that the relationship between sex hormone levels and LUTS is conflicting, and further studies in large populations with different severity of LUTS are required.

At present, the pathophysiological mechanism explaining the effect of T on LUTS is not fully understood; however, several theories have been proposed. AR is found in the urothelium including the bladder, prostate and the urethra of animal models [141,142]. Some studies also identified the immunoactivity of AR in non-neoplastic urothelial tissues, with a slight increase in the prostatic urethra [143,144]. Through AR, testosterone modulates the autonomic function of the smooth muscle of the lower urinary tract [145]. Other pathways of testosterone on detrusor muscle activity have also been reported. Up-regulation of the RhoA/Rho-kinase pathway, which has been shown to increase the contractile activity of the lower urinary tract smooth muscles and the development of LUTS [146], can be normalized by the administration of testosterone [147]. In addition, testosterone also activates the endothelial nitric oxide (NO) synthase/NO pathway which results in increased blood flow to the bladder [148]. NO is also one of the mediators for the relaxation of the urethra and the bladder neck which can improve the symptom of LUTS [43].

A crucial role in the cross-link between testosterone deficiency and LUTS can be attributed to MetS, which is prevalent in hypogonadal men [149–151]. Several previous studies suggested chronic inflammation induced by excess visceral fat mass can trigger cell proliferation and the remodelling of the prostate [152,153]. Insulin resistance is also a component of MetS which has been shown to be associated with a pro-inflammatory state and altered wound-healing process, collagen deposition and increased tissue stiffness [154]. In addition, hyperinsulinemia following insulin resistance is related to an increased sympathetic nerve activity which affects muscle tone and bladder outlet, even in the absence of BPH [151].

The effect of TRT on LUTS remained controversial. Early theories postulated that TRT in men with hypogonadism and BPH would worsen LUTS by increasing prostate volume. However, although testosterone has a key role in the maintenance and function of the prostate gland, its primary actions occur via binding AR. Once the AR is saturated, a higher concentration of testosterone would not produce further biochemical response [155]. In a meta-analysis involving 14 RCT, Kohn et al. reported that testosterone administration does not affect LUTS in men with late-onset hypogonadism [156]. Long-term use of TRT has also been shown to have no significant change in PSA levels or prostate volume [157]. Moreover, recent studies have found that TRT rather improves the components of LUTS in men with low testosterone levels [158–161]. However, there is a lack of data regarding the efficacy and safety of TRT on men with severe LUTS. Additional RCTs are required to provide more conclusive evidence on this population. In Vietnam, LUTS is a relatively common condition in older men and is typically diagnosed with BPH in the majority of patients by urologists. Therefore, testosterone therapy would rarely be prescribed due to the fear of worsening LUTS or the progression to prostate cancer. This caution is also mentioned in textbooks used for medical students and residents for decades. As a result, hypogonadal men with co-morbidities would have been denied access to TRT treatment.

Testosterone and mental health

Evidence on the relationship between low testosterone levels and mental disorders as well as the effects of testosterone replacement therapy on hypogonadal men with psychological symptoms has not been conclusive.

Depression

Depression is a leading cause of global disability, characterized by symptoms such as sadness, loss of interest or pleasure, guilt or low self-worth, disturbed sleep or appetite, fatigue, and poor concentration. Women have a significantly higher prevalence of depression than men [162]. This suggests that testosterone may play a protective role in the depression process in men. A subsequent presumption is that TD, particularly in older men, leads to a higher rate of depression. Male depression is substantially associated with low testosterone levels, clinical hypogonadism, ADT, AR antagonist therapy, and pharmacologically induced TD [163–165].

A prospective cohort study in the UK on participants aged 40-69 has shown that low testosterone levels were associated with major depressive disorder in men but not in women [166]. In another longitudinal study, Ford et al. reported that low serum testosterone was associated with an 86% increased hazard of depression (HR 1.86, 95%CI: 1.05-3.31). Noticeably, men with incident depression were more likely to have CVD and diabetes [167]. Although depression is more common in women after puberty, there is little gender discrepancy found in the elderly. Pirkis et al. found no gender difference between older men and women in the prevalence of clinically significant depression (8.6% vs. 7.9%) [168]. Another study reported the prevalence of depression among the Iranian elderly population was 49% in women and 48% in men [169]. Therefore, it is postulated that testosterone decline in older men may contribute to this similarity. However, other studies report conflicting results, and the relationship between TD and depression in aging men remains controversial [170,171].

Anxiety

The link between testosterone and anxiety in aging males has not been fully studied. Anxiety is often assessed with other psychological symptoms rather than alone, as in Berglund’s study. The study showed an association between men presumed to be testosterone deficient and symptoms of anxiety (p < 0.001). However, men with more pronounced symptoms indicating mental disorders did not have lower testosterone levels [172]. Other investigations found no correlation between testosterone levels and anxiety scores [173,174].

Cognition

Cognitive decline, as part of neurodegeneration, is a symptom of the aging process and increases disability in the elderly [175]. Verbal, spatial, and memory abilities are key aspects to evaluate cognitive function [176], but there are various manifestations and tools to assess the change, resulting in heterogeneous results. In older men, studies have shown a close link between low levels of testosterone and cognitive impairment. Alzheimer’s disease (AD) is a progressive condition that dismantles memory and other critical mental functions. In men, low serum testosterone levels have been implicated in the pathogenesis of AD, while a higher serum level of FT seems to be a protective factor against AD development [177]. Hsu et al. assessed global cognition with the MMSE and sex steroid hormones in a longitudinal, observational study of the epidemiology of males aged 70 years or older. After 2 years (n = 1367) and 5 years (n = 958) of follow-up, they found that levels of serum testosterone (β = 0.067), DHT (β = 0.394), calculated FT (β = 0.005) were significantly associated with cognitive decline (p < 0.05) [178]. Although the relationship between testosterone and cognitive function was found in many studies, others did not establish the same finding [179,180].

Androgens regulate many psychoneuroendocrinological functions and their receptors are expressed diversely in neuronal cells [181]. Testosterone, the primary androgen, has two mechanisms of activity in the brain: direct binding to AR and conversion to estradiol, which then binds to estrogen receptors [182]. The brain regions with a high density of AR are the hippocampus, cerebral cortex and amygdala, which play a critical role in mood and cognition. In these areas, AR is essential for the development and preservation of anatomical sex differences throughout adulthood [183]. Studies have shown that testosterone has the ability to control cerebral blood flow and neuronal activity in the amygdala, hippocampus, frontal and temporal cortex [184]. Furthermore, it has been suggested that testosterone, through AR signalling in the brain, controls mood and upregulates serotonin transporter expression as well as increases the firing rate of serotonergic dorsal raphe neurons to induce anti-stress and antidepressant effects [185]. Testosterone and other androgens have been hypothesized as having neuroprotective functions ranging from neuronal growth and regeneration to regulation of AD-related pathology such as accumulation of amyloid β protein [170]. The molecular mechanism of the neuroprotective effect can be partially explained by the activation of androgens on GABA-A and NMDA receptors, which are involved in stimulating working memory, learning performance and balancing negative moods [186].

Given the link between testosterone levels and mental health, many trials have been conducted to assess the improvement of psychological symptoms by TRT, particularly in older men. The TTrials study, a coordinated set of seven placebo-controlled, double-blind trials in 788 men with a mean age of 72 years, aimed to determine the efficacy of increasing the testosterone levels of older hypogonadal men. In the trials, psychological aspects were mainly assessed in Vitality and Cognitive Function Trials. In the Vitality Trial, testosterone only marginally improved mood and depressive symptoms while having no effect on energy levels. However, in the Cognitive Function Trial, treatment of testosterone did not improve cognitive function [127]. A random-effects meta-analysis including 27 RCT reported that TRT was associated with a significant reduction in depressive symptoms compared with placebo [187]. Another meta-analysis including 14 RCTs supported the potential of TRT as a preventative measure against cognitive decline, significantly in a cognitive composite score, psychomotor speed, and executive function, although the effect sizes were small [188].

Challenges for the management and treatment of hypogonadism in a low-middle income country

Demographic transition, aging population and aged-related disease burden

Similar to other low-middle-income countries, Vietnam is facing a demographic transition in which the elderly population increased from 8% to 10% due to a declining fertility rate, longer life expectancy and improved healthcare [189]. As a result, there is a higher prevalence of non-communicable diseases such as hypertension, T2D and CVD [190]. Together with emerging health issues such as mental health disorders and dementia, these conditions place a significant burden on the healthcare system and economy [191].

In aging men, robust data has shown that chronic diseases are often associated with TD [192]. They also share various risk factors such as smoking, alcohol consumption, unhealthy diets and physical inactivity. These lifestyle factors are becoming major concerns in a developing country such as Vietnam due to rapid urbanization [193].

The Vietnamese government has implemented various policies and programs to address the challenges of an aging population and disease burden. For example, in 2018, Vietnam launched a national action plan on the prevention and control of non-communicable diseases, which aims to reduce the prevalence of major risk factors. Additionally, the government is investing in expanding healthcare infrastructure and training healthcare professionals to address the specific needs of an aging population.

Despite these efforts, there are still significant challenges to overcome. Vietnam’s healthcare system is under-resourced and there are disparities in access to healthcare services, particularly in rural areas. Addressing these challenges will require sustained efforts from the government, healthcare professionals, and the wider community.

Culture and belief

On average, men have poorer health outcomes than women. One important factor that contributes to this discrepancy is the health-seeking behavior of men. It is well documented that men are reserved in accessing health care services and are more likely to discontinue treatment [194]. Several reasons have been attributed to this behavior among men including busy schedules, fear of bad diagnosis or just embarrassment.

In Asia, although there is significant cultural variation across the region, there are some common values to be expected in men. Traditionally, masculine characteristics are expected to be strong, unemotional and authoritative. This fact was further supported in a large multinational survey in Asia which demonstrated that Asian men associate masculinity with having a good job, being in control of their own life and being a man of honor [195]. Particularly, if testosterone deficiency is associated with sexual dysfunction, discussing this matter is considered a culturally sensitive topic [196]. Therefore, men often refrain from seeking medical attention to withholding their image and their pride. Instead, they seek alternative methods of self-medication such as medicinal liquor, herbs and supplements [197]. This might also expose users to the risk of buying counterfeit medications, which not only have reduced efficacy compared to legit treatments but also pose a significant threat to general health [198]. The risk of contamination with bacteria or other active ingredients has been documented many times in the last years [199,200]. Unsurprisingly, for the same cultural reasons presented above, drugs affecting sexual performance and physical appearance are among the world’s most counterfeited products [198].

In addition, among Asian countries, it is a belief that TD is a sign of the inevitable natural aging process. As a matter of fact, low testosterone is only considered to associate with sexual dysfunction and decreased fertility in elderly men. Furthermore, the influence of traditional Chinese medicine which characterizes the symptoms of late-onset hypogonadism as “kidney yang deficiency” also led to the assumption that testosterone deficiency is a result of impaired renal function [201]. Meanwhile, there have been numerous traditional medicine and supplements such as Eurycoma longifolia, ginseng, horny goat weed, and oyster extracts…, which are advertised to nourish the “kidney” and strengthen “yang” essence with fewer adverse effects than Western medicine [202,203]. The convenience of the aforementioned products, which are available in every pharmacy, results in fewer men seeking medical care at a hospital to avoid embarrassing visits and the potential side effect of modern medicine [204].

Lack of specialized andrology clinic and professionals

The lack of trained men’s health professionals is a significant challenge for andrology. In 2022, we conducted a national-wide survey of 370 clinicians who attended the annual Vietnam Urology and Nephrology Association congress (data not yet published). The result indicated that 50% of respondents who were seeing male patients with sexual dysfunction reported not having received any training in andrology. In addition, 32.4% of clinicians were having difficulties taking a history of male sexual problems owing to a lack of knowledge or experiences on men’s health. This results in the underdiagnosis and undertreatment of testosterone deficiency, which can have negative impacts on men’s overall health and quality of life. Similar results have been reported in Europe as well, with only a minority of physicians actively investigating their patients’ health [205].

There are also significantly fewer andrology clinics compared with their female counterpart. Among all public hospitals, only 5 hospitals have a specialized andrology clinic. The shortage of specialized andrology clinics and professionals can make it difficult for men to receive the specialized care they need for andrological issues. In addition, in the private sector, there are a growing number of unorthodox andrology clinics. They have been criticized for providing false and misleading information to men seeking advice while offering unnecessary treatment. Patients who visit these centers not only have to pay extra medical expenses but also suffer from anxiety due to misinformation.

Clearly, diagnosis and management of testosterone deficiency are challenging issues influenced by a variety of social, cultural and economic factors. However, this provides new opportunities to encourage investing more resources and funding for medical education and research in this field.

Testosterone misuse

Testosterone and other androgens misuse is defined as the medical prescription of such medication without a valid indication. One of the most frequently overprescribed conditions for testosterone is sexual dysfunction for aging men without a proven decline in testosterone concentration [206]. Although symptoms of sexual dysfunction, such as low libido and ED, are associated with TD, several other pathologies can attribute to sexual dysfunction. In addition, there is a considerable variation in testosterone between tests. Therefore, prescribing testosterone to men without a true decline in testosterone concentration is unlikely to provide any benefit. However, in clinical practice, a large number of men, especially elderly men, are given TRT without testing for testosterone levels [206,207]. In a study conducted in the US investigating the screening pattern for men treated with TRT, approximately 25% of men did not have a testosterone test before initiating treatment [208]. In Vietnam, testosterone is still widely used to treat ED by non-specialists or primary care doctors despite normal or even high baseline testosterone levels. Furthermore, men with sexual dysfunction symptoms can often obtain testosterone products from pharmacies and online markets without a prescription.

Another common misuse of TRT is the prescription for male infertility. Many physicians believe that testosterone is fundamental for spermatogenesis, and therefore prescribe TRT for astheno/oligo/teratospermia patients aiming to stimulate sperm production. However, they are unaware that exogenous androgen administration suppresses intratesticular testosterone, resulting in decreased spermatogenesis [209]. Similar findings have also been reported in the US with almost 30% of general urologists using TRT for unexplained male infertility [210]. Again, this highlights the significant challenge of lacking trained andrologist and the need for an education program for primary care doctors who are consulting men’s health conditions.

Illicit use of testosterone and anabolic steroids for nonmedical purposes has also been a threat to public health. This practice is not limited to competitive athletes and is also common among bodybuilders [211]. However, previous studies have demonstrated that Asia has a significantly lower rate of doping prevalence than Europe or Oceania [212]. Similarly, anabolic steroid abuse appears to be rare among Asian men compared with men from Western societies [213]. It is possible that Western men emphasize muscularity as the definition of “masculinity” [214], while Asian men place less value in body image [213,215]. Nevertheless, further studies are required to monitor the trend and the prevalence of anabolic steroid abuse, especially in Asia.

In short, TRT can be beneficial for men with symptomatic hypogonadism, but it should only be prescribed when there is a valid medical indication and after appropriate testing has been conducted. Avoiding the misuse of testosterone requires a deep understanding of testosterone physiology and appropriate indications for therapy. Education programs for primary care doctors and increased awareness among patients are necessary to prevent unnecessary and potentially harmful prescriptions.

Conclusion

Summing up, the present review presented evidence on the impact of testosterone deficiency on various aspects of men’s health. Treatment of testosterone deficiency improves the quality of life of men. However, there are many challenges in managing this condition in a developing country.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Data availability statement

No clinical data have been collected for the present review.

Additional information

Funding

The author(s) reported there is no funding associated with the work featured in this article.