Testosterone Replacement Therapy in Patients with Cachexia: A Contemporary Review of the Literature

INTRODUCTION

Cachexia is a progressive metabolic wasting syndrome that accompanies and is related to long term chronic diseases. Most notably it is present in up to 70% of advanced cancers, and in 10–30% of patients with other chronic diseases including chronic heart failure, chronic kidney disease, AIDS, and chronic obstructive pulmonary disease (COPD). Cachexic patients experience significant unintended weight loss, muscle atrophy, weakness, and fatigue, causing a reduction in their quality of life^1–3. In patients with chronic diseases, weight loss is correlated with severity of other symptoms, worsening them and increasing overall mortality ⁴. The symptoms of cachexia however cannot be treated through nutritional supplementation, and nutritional interventions alone are not enough to restore patients’ lean body mass and weight^1,2. This has led to the need to identify alternative potential treatments for cachexia.

Cachexia in the context of cancer – termed cancer anorexia-cachexia syndrome - has been well-studied due to its prevalence in late-stage patients. Its pathophysiology is attributed to a mix of cytokine toxicities, long-term inflammation, and hormones^3,5. However, it has also been suggested that androgen deficiency, or hypogonadism, is a key component of this process. Androgen disorders are present in the majority of men with metastatic cancers, and are found to be correlated more closely with patients also experiencing cachexic syndrome⁶. Symptoms precipitated by these two disorders are similarly non-specific and overlap - decreased energy, anorexia, sarcopenia, weight loss, fatigue, and weakness⁵. It has thus been proposed that the addition of testosterone therapy in cachexic cancer patients whether they are ostensibly exhibiting hypogonadism or not, could lead to improved outcomes and mortality. We seek to apply this principle one step further in the study of multiple chronic diseases in which hypogonadism has been concurrently observed with cachexia – specifically, Cancer, Chronic obstructive pulmonary disease (COPD), HIV/AIDS, and Liver Cirrhosis^5,7–10.

METHODS

We performed a comprehensive literature search using Pubmed, of the literature published from 2000 to 2022 concerning Testosterone Replacement Therapy (TRT). We used the search terms: “TRT,” “testosterone,” “muscle wasting,” along with related MeSH to the diseases of interest. Our search yielded 653 results, of which 641 were excluded for involving studies on animals or children. Inclusion criteria focused on studies evaluating TRT in cancer, COPD, HIV/Aids, and liver cirrhosis.

RESULTS

From the available literature, 12 studies were selected, of which 3 focused on varying cancers, 3 on Chronic Obstructive Pulmonary Disease (COPD), 4 on HIV, and 2 on Liver Cirrhosis. For the cachexic patients with cancer, the addition of testosterone replacement therapy overall improved the lean body mass but had mixed results on quality of life (QoL) (Table 1). TRT improved exercise capacity and quality of life in COPD cachexic patients (Table 2). Testosterone supplementation also improved body composition, and increased muscle mass and strength in patients with the AIDS wasting syndrome (Table 3). Testosterone supplementation improved the muscle strength and body composition in cohorts of patients with liver cirrhosis (Table 4).

Table 1:

Summary of studies on TRT effect on cancer-induced cachexia

Authors, Year	Country	Study Design	Number of Participants	Type of Cancer	Intervention	Outcome of Interest	Study Findings
Wright et al (2018)	USA	Prospective	21	Late-stage squamous cell carcinoma	Weekly IM injection of 100 mg testosterone enanthate or placebo (saline solution) Duration: 7 weeks	% Change in Lean Body Mass (LBM); assessment of Quality of Life (QoL), tests of activity levels, resting energy expenditure, nutritional intake, overall survival	Adjunct testosterone increased lean body mass by 3.2% whereas those receiving the placebo lost 3.3%. Testosterone - treated patients maintained more favorable body condition, sustained daily activity levels, and showed meaningful improvements in quality of life and physical performance. Overall survival was similar in both treatment groups.
Izumi et al (2021)	Japan	Prospective	81	Variable with the exclusion of prostate cancer	250 mg testosterone enanthate IM every 4 weeks (baseline, week 4, and week 8) Duration: 12 weeks	Differences in QoL questionnaires, cachexia-related serum protein levels	Testosterone enanthate did not improve most of the items in health- related quality of life questionnaires. But it induced a significantly better chance in the “unhappiness” item at week 12 compared with the control.
Del Fabbro et al (2013)	USA	Prospective	29	Variable with the exclusion of prostate cancer	150 or 200 mg testosterone enanthate or placebo injected every 14 days (Baseline, Day 15, Day 29, Day 43, and Day 57) to achieved baseline testosterone levels of 70-270 ng/dl Duration: 12 weeks	FACIT-fatigue scores, Sexual Desire Inventory score, performance status, fatigue subscale scores	Four weeks of intramuscular testosterone replacement in hypogonadal male patients with advanced cancer did not significantly improve quality of life (FACIT-fatigue scores). However, after 12 weeks of therapy, there was a trend for increased sexual desire and significant improvement in fatigue scores.

IM = Intramuscular

Table 2:

Summary of studies on TRT effect on COPD

Authors, Year	Country	Study Design	Number of Participants	Intervention	Outcome of Interest	Study Findings
Baillargeon et al (2018)	USA	Retrospective	703	Comparison of middle-aged (40–63 years old) and older men (>= 66 years) before and after TRT against non-users Duration: 24 months	Pre- vs. post TRT respiratory hospitalization rates in TRT users vs. TRT nonusers	TRT significantly reduced respiratory hospitalization in the middle-aged cohort following therapy as compared to prior but did not significantly reduced hospitalization in the older cohort. However, overall TRT users experienced a 4–9% decrease in respiratory hospitalizations as compared to non-users.
Atlantis et al (2013)	New South Wales	Review/meta-analysis	287	Comparison of TRT users vs. TRT nonusers	Peak muscle strength, peak cardiorespiratory fitness outcomes (peak oxygen uptake VO2 and workload), health-related quality of life (HRQoL)	Testosterone therapy is associated with improved exercise capacity outcomes, namely peak muscle strength and peak workload.
Daga et al (2014)	India	Prospective	32	25 mg of nandrolone decanoate or placebo intramuscularly in the gluteal muscle weekly Duration: 6 weeks	Anthropometric and spirometric measurements, peak respiratory flow rate, partial pressure of O2 in arterial blood, 6-minute walk test (6MWT), hand grip test, and HRQL index scores at baseline and end of treatment	Weekly administration of anabolic steroids during 6 weeks increased exercise capacity and quality of life in patients with COPD.

RCT = Randomized Control Trial

Table 3:

Summary of studies on TRT effect on HIV/AIDS

Authors, Year	Country	Study Design	Number of Participants	Intervention	Outcome of Interest	Study Findings
Blick et al (2013)	USA	Prospective	849	Administration of 5 mg or 10 mg of 1% testosterone gel per day topically; in cohorts with and without HIV Duration: 12 months	Total testosterone, free testosterone levels, symptoms of depression, sexual function, body composition profiles, and prostate-specific antigen levels	Both men with and without HIV experienced elevations in total testosterone, and free testosterone levels to within normal ranges. For both cohorts, sexual function and depression scores improved and antidepressant medication use decreased. Body composition profiles improved significantly in men without HIV/AIDS and remained stable in men with HIV/AIDS during the 12 months of follow up.
Bhasin et al (2000)	USA	Prospective RCT	61	100 mg testosterone enanthate/week intramuscularly with exercise Duration: 16 weeks	Changes in muscle strength, body weight, thigh muscle volume, and lean body mass	Testosterone and resistance exercise increased body weight, muscle mass, muscle strength, and lean body mass. Testosterone and exercise together did not produce greater gains than either intervention alone.
Grinspoon et al (2000)	USA	Prospective RCT	54	200 mg testosterone enanthate/week or placebo and progressive resistance training 3 times/week or no training Duration: 12 weeks	Cross-sectional muscle area and other indices of muscle mass	Cross-sectional muscle area increased in response to training compared with non-training and in response to testosterone therapy compared with placebo.
Kong and Edmonds (2002)	USA	Review/meta-analysis	417	Review of randomized, placebo-controlled trails that compared the effects of TRT vs. placebo	Lean body mass, total body weight, overall exercise functional capacity, and perceived quality of life	The meta-analysis of the six trials showed a difference in the lean body mass between the testosterone group and placebo group of 1.22 kg in the random effect model, 0.51 kg in the fixed effect model, and 3.34 kg for trials that used the intramuscular route.

RCT = Randomized Control Trial

Table 4:

Summary of studies on TRT effect on Liver Cirrhosis

Authors, Year	Country	Study Design	Number of Participants	Intervention	Outcome of Interest	Study Findings
Yurci et al (2011)	Turkey	Prospective	12	50 mg Testogel/day Duration: 6 months	Muscle strength, hormones, profiles, and liver enzymes evaluated monthly; body composition parameters evaluated before and after 6 months	Testosterone treatment increased muscle strength and subscapular site subcutaneous fat tissue and decreased subareolar breast tissue without adverse effects
Sinclair et al (2016)	Australia	Prospective RCT	101	1000 mg testosterone undecanoate intramuscularly at 0, 6, 18, 20, and 42 weeks (Double-blinded, placebo – controlled trial) Duration: 12 months	Body composition assessed with dual-energy X-ray absorptiometry (DEXA) at baseline, 6 months, and 12 months	Testosterone increased appendicular lean mass; Testosterone therapy increased muscle mass, bone mass, and hemoglobin, and reduced fat mass and HbA1c

RCT = Randomized Control Trial

Cancer

In a 2018 study by Wright et al., males and females diagnosed with cervical or head and neck squamous cell carcinoma were selected to undergo a 7-week long randomized clinical trial to observe the effect of TRT as an adjunct to the established chemotherapeutic regimen. The treatment arm was composed of 9 patients receiving 100mg of weekly intramuscular testosterone enanthate versus 12 patients receiving placebo. The participants were matched based on gender, race, chemotherapy regimen, BMI, and body composition. Moreover, men with testosterone levels under 300 ng/dl and women with levels less than 30 ng/dl were not excluded from the study. Results indicated that the testosterone arm experienced a meaningful surge in average lean body mass by 3.2% (95% CI, 0%–7%), while the placebo group had a 3.3% decline (95% CI, −7%−1%). In addition, results showed that TRT did not significantly affect the life span (Hazard ratio for death: 0.97). However, this study was limited by a small study population and lack of control on factors pertinent to body weight during the course of study such as glucocorticoid therapy, chemotherapy, and rate of disease progression. The authors concluded that TRT had a clinically positive impact on physical performance and quality of life from baseline parameters based on the short physical battery questionnaire (SPPB) and the General Functional Assessment of Cancer Therapy (FACT-G) questionnaire, respectively ¹¹.

In a 2021 non-placebo controlled trial by Izumi et al. on TRT and cachexia-related outcomes in male patients with non-prostatic cancer and low T levels (total T<2.31 ng/ml, free T<11.8 pg/ml). Testosterone enanthate 250mg IM was administered every 4 weeks at baseline, weeks 4 and week 8. A review of outcomes at week 12 showed that TRT did not significantly affect the overall quality of life compared to control based on subjective data, other than a slight decrease in self-reported “unhappiness”. The overall survival between the two groups did not differ significantly. This study also measured the levels of the so-called cachexia biomarkers such as IL-6 and TNF. A comparison of these biomarkers on weeks 4 and 12 showed that there was no significant difference regarding IL-6 levels between the two groups, but the TRT group had significantly lower levels of TNF at the end of the study. Several factors influence the mentioned outcomes such as using a subtherapeutic dosage of T, varying malignancy etiologies, and a homogenous population of ill Japanese men. The outcomes were only measured based on questionnaires such as the Edmonton Symptom Assessment System (ESAS), and the Functional Assessment of Anorexia/Cachexia Treatment (FAACT), rather than a thorough investigation using data such as changes in lean mass composition and physical performance ¹².

TRT effect on hypogonadal men with advanced (metastatic or locally recurrent) non-prostatic cancers was also studied in a placebo-controlled trial by Del Fabbro et al. One parameter for inclusion was a baseline of moderate to severe fatigue in participants before the intervention using the ESAS scale (pre-intervention score>3). In a more personalized approach than other studies, the investigators titrated the T level before each administration with a target bioavailable T of 70–270 ng/dL. IM testosterone enanthate was administered at baseline and then every 14 days until day 57 for a total of 5 doses to the TRT group.

Analysis after 4 weeks did not show any statistically significant change in the FAACT and Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) scores between the TRT and placebo groups despite improvement in both scores. With regards to sexual desire using the Sexual Desire Inventory (SDI) scale on week 4, an overall improvement was observed in the TRT group but with statistical insignificance (p-value: 0.54). Anthropometric indicators, psychological impact assessed through the Hospital Anxiety and Depression Scale system, measurements of physical activity, and scores derived from the International Prostate Symptom Score (IPSS) likewise demonstrated no statistically significant change following TRT. Other than the small study population, factors limiting the results include a low minimum preintervention Hb level of 9 which may have been related to the emergence of fatigue in the study group. Also, using bioimpedance instead of superior methods such as the DEXA scan for calculating the effect on lean body mass may have contributed to the observance of no significant change with intervention. Despite titration of T before administration, the difference in T levels after 4 weeks was not significant ¹³.

COPD

Using available patient databases in the United States, Baillaregeon et al. retrospectively chart-reviewed patients with COPD who had received a form of TRT for a minimum of 60 days over the course of one year. They stratified the outcomes based on the age group (old-aged and middle-aged men) and duration of TRT. To study the effect of TRT on COPD morbidity, they chose patients who had COPD for at least a year before starting TRT. They then compared respiratory-related morbidity of the pre-TRT year with a year after initiating therapy. Their results indicated that both middle-aged and old-aged patients experienced fewer hospitalizations after being commenced on TRT with varying significance. Compilation of data showed that both middle-aged and old-aged men receiving therapy for 60 days experienced significantly lower respiratory-related hospitalizations in the following year. A higher degree of statistical significance was observed when high-complexity COPD patients were excluded from the study. Despite the implied overall positive clinical effect on the patients, the effect on quality of life, body composition, or rationale for starting TRT was not mentioned in this study ¹⁴.

These results were also confirmed in a 2013 meta-analysis. After evaluating the data of approximately 3000 men with COPD, it was concluded that men with COPD had lower T levels than controls. Further review of 6 randomized clinical trials in this meta-analysis which was composed of a total of 287 patients, revealed a significant improvement in physical performance parameters in those receiving TRT. These results warrant further review of comorbidities that could decrease T levels in these patients ¹⁵.

An RCT study from India was also conducted to evaluate the effect of anabolic steroids plus a high-calorie diet versus a high-calorie diet alone on moderate to severe COPD patients. The patients were given injections of nandrolone decanoate 25 mg per week for a total of 6 injections and were then followed up for 6 weeks. One questionable aspect of this study is that the patients were not allowed to use glucocorticoids, which are a mainstay of moderate to severe COPD, during the course of this study. Limitations in this study included a low study population (32 participants; 20 TRT, 12 controls) and questionable matching due to significant differences in Hemoglobin levels between the treatment and control groups. Anthropometric measurements were also not based on more advanced procedures such as DEXA scan or calculating the amount of lean mass and was instead focused on a simplistic approach using BMI and arm circumference measurements. Intervention, regardless of TRT, resulted in significantly improved pulmonary function tests and anthropometric measures. Pre-intervention BMI of both groups was less than 21; therefore, it could be implied that the common intervention between the two groups, a high-calorie diet, may have had a significant impact in overturning the pulmonary and anthropometric shortcomings. After 6 weeks, statistically significant disparities in exercise capacity (measured by a 6-minute walk test) and Health-Related Quality of Life (HRQL) scores were observed between the treatment group and the control group, with a p-value less than 0.001 ¹⁶.

HIV

A prospective cohort study was conducted on a registry of patients with hypogonadism receiving testosterone 1% gel by Blick et al. The registry was composed of 82 patients with HIV/AIDS and 767 non-HIV/AIDS individuals. Daily application of testosterone 1% gel did not significantly affect the BMI, waist circumference, hip circumference, and weight in the HIV/AIDS patients. These parameters also showed no significant difference when compared to the non-HIV/AIDS group. All body composition parameters except for hip circumference improved in the non-HIV/AIDS group when evaluated separately. Improvements in psychological and sexual function were observed in both groups. Nevertheless, it is essential to exercise caution in drawing statistical inferences from this study, as the two groups differed significantly in numerous baseline characteristics. Matching was not the intended approach in this registry ¹⁷.

Bhasin et al. did a randomized controlled trial to investigate the effects of physical activity and TRT (100 mg testosterone enthanate IM weekly) on patients with HIV/AIDS and T levels less than 349 ng/dL. The study was composed of four arms. One group received TRT+physical activity, the second group received TRT-physical activity, the third group had physical ativity+placebo, and the final group underwent placebo therapy only. By using the Deuterium Oxide Dilution Method, lean mass in the group receiving T only increased from 62.9±3.3 at baseline to 66.9±2.9 after 16 weeks (p-value=0.05). The lean mass in the T+exercise group before intervention was 55.7±2.8 and increased to 57.3±2.9 at week 16 (p-value<0.09). Nevertheless, employing the DEXA scan technique revealed that testosterone led to a 2.3 kg rise in the group without physical activity and a significant 2.6 kg increase when physical activity was added to TRT. Testosterone also showed a significant effect in improving leg curls and latissimus pulls regardless of exercise status ¹⁸.

Using a similar methodology to the Bhasin trial, Grinspoon et al. assigned 54 patients to 4 different groups based on TRT and progressive resistance exercise status. The patients were HIV/AIDS positive with muscle wasting and no signs of hypogonadism. Testosterone enanthate 200mg IM weekly for 12 weeks resulted in a mean increase of 318 mm² in arm muscle surface area (p-value<0.001) and a 837 mm² increase in leg muscle surface area after 12 weeks. Testosterone without training led to a 2.7±2.6 kg increase in weight and testosterone plus training resulted in 2.5 ± 2.5 kg increase. Both values were considered statistically significant when compared to baseline. The majority of the patients were receiving antiretroviral therapy in this study. However, there was no information regarding the specific type of drug that the patients were receiving nor was there any information about the matching based on antiretroviral therapy between the groups ¹⁹.

A 2002 meta-analysis from pooled data of 417 patients showed favorable results regarding TRT in HIV/AIDS patients. The meta-analysis revealed that testosterone therapy increased lean body mass compared to placebo, with a more significant effect observed in trials using intramuscular administration. Total body weight also showed a modest increase with testosterone therapy. Adverse effects were similar between the testosterone and placebo groups. However, the study’s limitations, such as small sample sizes and population heterogeneity, may introduce bias ²⁰.

Liver Cirrhosis

In a small-scale study conducted by Yurci et al. on 12 patients with liver cirrhosis, it was shown that daily treatment with testosterone patches was favorable in attaining muscle mass and decreasing the burden of gynecomastia. All patients were diagnosed with low testosterone levels (20.13 ± 10.06 pmol/L) before intervention. The muscle strength was calculated using a dynamometer from the dominant hand which showed significant improvement compared to the baseline from the 3^rd month onwards. Upon review at 6 months, it was indicated that anthropometric measures such as BMI, waist circumference, and bone mass densitometry studies all improved although statistically non-significant. Significant improvement was observed in subareolar tissue (p-value =0.007), subscapular (p-value =0.012), and subdermal adipose tissue (p-value= 0.04). Despite having a meticulous measurement protocol, the authors did not provide any information regarding quality of life measures in this study ²¹.

Results from a 2016 study by Sinclair et al. showed favorable results in treating cirrhosis sarcopenia symptoms. In this study, cirrhotic patients with hypogonadism were randomized to TRT and placebo groups for a duration of 1 year. Five doses of testosterone undecanoate were administered over the course of 42 weeks to the TRT arm and the appendicular lean mass (APLM) was then compared to placebo. The mean adjusted difference in APLM was +1.13 kg at 6 months and +1.69 kg at 12 months which was statistically significant. Secondary outcomes such as total lean mass, total bone mass, and femoral T-score were also significantly increased compared to baseline. Despite observing an increase in the APLM, the authors mentioned that the target number was not reached. Overall they concluded that TRT should be used as means of treatment in cirrhotic patients with sarcopenia and hypogonadism ²².

DISCUSSION

Although cachexia is a rather evident symptom in patients with a broad range of chronic diseases, it is often challenging to define the actual criteria for such a diagnosis. Some have defined this condition as a complex metabolic manifestation of a pre-existing etiology with depleted muscle mass regardless of the change in adipose tissue percentage. Weight loss may also be a more pronounced feature of cachexia ²³. More recently, attempts have been made to quantify the symptoms of cachexia in certain populations to provide a better stratification. For instance, the cachexia score (CaSco) is a measuring scale developed for staging cachexia in cancer patients on a scale from 0 to 100 ²⁴.

Given that a substantial proportion of individuals afflicted with cancer, irrespective of the organ of origin, experience the onset of cachexia, the primary focus of scholarly investigation on cachexia is directed towards the cancer-induced etiologies ^25,26. Other conditions that fall in line with the cachexia/anorexia spectrum include congestive heart failure, chronic kidney disease, COPD, and HIV/AIDS ^27–30.

The complex pathophysiological pathways in which cachexia develops fall out of the scope of this review, but it is important to acknowledge that this could be discussed on multiple levels. Cachexia could occur in the setting of energy requirement/expenditure imbalance in diseased states with an ensuing response by decreased muscle mass, decline in white adipose tissue, and a multiorgan response in the brain, liver, and gastrointestinal system ²⁴. The activation of the ubiquitin-proteasome pathway and upregulation of chemokines such as TNF, IL-1, IL-6, and IFNγ have widely been regarded as the inflammatory component of cachexia pathogenesis ^31,32.

The advances in translational research regarding cachexia biomarkers and immunological factors have led to interest in developing new pharmacotherapeutic agents or off-label use of pre-existing drugs for tackling this issue. As of now, however, the FDA has not approved any form of drug for cachexia ³³. The current treatment strategies may include modulating the immune system, reducing energy expenditure, nutrition enhancement, and appetite promotion ³⁴. Examples of this approach include trials on drugs such as espindolol, a newly developed beta-blocker that also possesses anabolic properties. Promising results were seen when patients with non-small cell lung cancer and colorectal cancer were commenced on this drug ³⁵. Hormonal therapies such as megestrol acetate have been used with variable success in cancer and HIV patients to increase appetite by releasing neuropeptide Y, an orexigenic peptide, in the hypothalamus ^34,36.

From a biochemical and molecular perspective, testosterone appears to be at the confluence of many of the pathways involved in the development of cachexia. The immunomodulatory role of testosterone and possible decrease in inflammatory chemokine secretion following exogenous administration, render testosterone an exciting target for the treatment of muscle wasting and cachexia in various settings ³⁷. The anabolic effects on muscle mass are also another reason to consider a potential therapeutic role for TRT in chronic diseases. Even side effects such as increased erythropoietin secretion could be helpful in the setting of concurrent anemia and decreased energy in diseases associated with anorexia.

In a study of 467 men aged 65 and older, Maggio et al. demonstrated that testosterone levels were inversely related to soluble IL-6 (P < 0.001) levels. However, no such relationship was observed when other markers of inflammation were studied ³⁸. Bobjer et al. also conducted a nested cross-sectional study that compared the testosterone levels between eugonadal and hypogonadal men. The results revealed that there was a significant inverse relationship between free testosterone levels and inflammatory markers such as TNF-alpha, macrophage inflammatory protein-1 alpha (MIP1a), and macrophage inflammatory protein-1 beta (MIP1b). In-vitro studies have shown that MIP1a is expressed by pre-adipocytes rather than mature adipose tissue and is increased when cells are exposed to higher levels of TNF-alpha, one of the hallmarks of cachexia ³⁹.

Studies on castrated rats have also shown the potential for testosterone to increase neuropeptide Y levels in the hypothalamus ⁴⁰. This effect may be beneficial in cachectic patients as neuropeptide Y is considered an orexigenic peptide. Megestrol acetate has also been used based on this rationale ⁴¹.

Our review indicated that TRT in cancer as a means for alleviating cachexia symptoms is associated with mixed outcomes. The 2018 study by Wright et al. was the only study on cancer patients that advocated for TRT despite including both women and men regardless of initial testosterone level status ¹¹. The 2021 Izumi et al. study had a much larger population but relied heavily on patient-reported outcomes and questionnaires rather than anthropometric measurements. One common feature in both studies is that testosterone was not associated with a higher survival. The Izumi study is also one of the few studies that attempted to investigate the correlation of cachexia immunological markers after TRT in men with low testosterone levels. Similar to in-vitro studies, TNF was decreased after intervention but there was no statistically significant decline in IL-6 ¹². Further studies on human subjects must investigate the association of clinical improvement with immunological biomarkers to elucidate the possible beneficiary effects of TRT. The 2013 Del Fabbro study also showed fatigue and sexual desire improvement in hypogonadal cancer patients albeit in a statistically non-significant manner ¹³.

The small number of enrolled individuals in the mentioned studies and the application of different methods to assess patient-based outcomes limit our ability to give a reliable answer to whether TRT should be widely tested on cancer patients. The preliminary results at least favor TRT in improving the clinical picture rather than a statistically significant effect on the population. Another reason that physicians may be reluctant to test TRT on cancer patients is due to the worries about cardiovascular outcomes on these individuals given the hypercoagulable state they already have. After the TRAVERSE trial results, more physicians may be open to conducting such studies due to less concern regarding the cardiovascular side effects of TRT ⁴².

Regarding COPD, the original reports and metanalyses have shown a more positive stance when compared to cancer cachexia. Although retrospective studies have shown less hospitalization in COPD patients with TRT, further studies are required to evaluate more robust patient-centered outcomes ^14,15. Future studies should determine the initial testosterone status when reporting outcomes. However, we are still lacking high-quality studies on respiratory features of sarcopenia and COPD-related cachexia.

HIV/AIDS is unique in that the disease itself and the associated therapeutic agents could impose lipodystrophy and muscular weakness on the patients ⁴³. Given the very broad diagnostic criteria for cachexia diagnosis, it is important to stratify patient outcomes based on the type of retroviral therapy they are receiving. Furthermore, the introduction of newer drugs with fewer effects on muscle and adipose tissue necessitates the use of TRT in the setting of up-to-date therapeutic regimens ⁴⁴. The prospective RCTs that we have mentioned are all in favor of TRT in hypogonadal individuals compared to placebo despite belonging to more than 20 years ago ^18,19. Newer studies may be able to provide more favorable results due to the safer drug profiles that we currently have at our disposal.

An overwhelming majority of cirrhotic men experience falling levels of testosterone over the course of their disease ⁴⁵. In our review, the reports showed positive results when TRT was used for enhancing physical performance, lean mass, and alleviating known features of cirrhosis such as gynecomastia^21,22. Despite this fact, researchers may be hesitant to start patients on TRT due to concerns regarding the increased risk of hepatocellular carcinoma ⁴⁵. This may be a contributing factor to the scarcity of data regarding trials on TRT in cirrhotic patients. This also may hinder the possibility of new research being available on younger populations given the ethical issues that may arise when life expectancy is considered.

In our view, research on cachexia and TRT requires more robust standardized reporting systems for patient-based outcomes such as anthropometric measures and quality of life. A suggested improvement for any future study could be to include both hypogonadal patients and those with normal testosterone levels. Another area of interest which is rather understudied is the effect of TRT and cachexia outcomes for CKD patients. Despite being a major cause of cachexia in the population, we were unable to identify articles that met our criteria. The overall findings have promising results when the clinical picture is considered as the outcome of interest. The cost/benefit of TRT and the economic burden of TRT are also a factor which is often overlooked in the available body of literature. Despite the improved performance, TRT does not come without risk and should not be overlooked especially in younger populations. Research on the effect of chronic disease-related cachexia and TRT is also rather rare in the assigned-female-on-birth (AFAB) population.

CONCLUSIONS

Testosterone holds anti-inflammatory and anabolic properties that justify its application in the setting of chronic disease sarcopenia and cachexia when viewed from a molecular perspective. Given the limited available therapeutic options for cachexia treatment, TRT could be an important target for improving the patients’ physical profile and quality of life on an experimental level. The available body of literature has shown mixed results when different disease states are evaluated. The overall trend shows clinical improvement with or without statistical significance. Given the broad range of symptoms that a cachectic patient may exhibit and the different courses of each disease entity, further systematic reviews and meta-analyses focusing on specific diseases may provide an answer to the applicability of TRT for cachexia in chronic disease states. Clinical reasoning and weighing the benefits of TRT against its inherent risks is also a matter of debate when this form of therapy is administered to different patients.