Longitudinal Improvements in Quality of Life Following Testosterone Replacement Therapy in Men with Biochemical and Symptomatic Testosterone Deficiency: a 12 Month Retrospective Observational Study in a Remote Digital Healthcare Setting in the United Kingdom

Longitudinal Improvements in Quality of Life Following Testosterone Replacement Therapy in Men with Biochemical and Symptomatic Testosterone Deficiency: a 12 Month Retrospective Observational Study in a Remote Digital Healthcare Setting in the United Kingdom | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Article Longitudinal Improvements in Quality of Life Following Testosterone Replacement Therapy in Men with Biochemical and Symptomatic Testosterone Deficiency: a 12 Month Retrospective Observational Study in a Remote Digital Healthcare Setting in the United Kingdom Hans Johnson, Ashley Clift, David Huang, Jeff Foster, Austen El-Osta This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-6246872/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Men with borderline or low-normal total testosterone often experience androgen-deficiency symptoms. While testosterone replacement therapy (TRT) benefits overt hypogonadism, its long-term effect on quality of life (QoL) in borderline cases, particularly via remote digital care, remains unclear. We retrospectively studied 1065 men (mean age 42.9±8.8 years) with total testosterone <15 nmol/L and clinical symptoms, managed through UK digital healthcare providers. QoL was assessed over 12 months using the quantitative Androgen Deficiency in the Ageing Male (qADAM) scale (range 10-50; ≥5-point increase considered clinically meaningful). Changes in qADAM were analySed with paired t-tests; subgroup differences (e.g., BMI) used one-way ANOVA, and correlations (testosterone, free testosterone, SHBG) were evaluated via Pearson’s tests. Mean qADAM increased by 6.64 points (95% CI: 6.16, 7.11; p<0.0001), with significant improvements across libido, energy, and other domains. Obese men (BMI≥30) had larger gains (+8.03 points) than normal-weight men, and those ≥100 kg improved by 8.22 points. While total testosterone rose by 31.25 nmol/L (p<0.0001), correlations between testosterone changes and qADAM were modest. In this real-world digital setting, TRT yielded clinically meaningful, multidomain QoL benefits for men with borderline testosterone levels. Future prospective research incorporating broader demographics and confounders will help optimize individualized TRT strategies. Health sciences/Health care/Quality of life Health sciences/Signs and symptoms/Reproductive signs and symptoms Figures Figure 1 Figure 2 Figure 3 Figure 4 Introduction Testosterone deficiency (hypogonadism) in men comprises a spectrum of clinical presentations influenced by advancing age, comorbidities, and lifestyle factors ( 1 – 4 ). Biochemically, low testosterone is often defined by total testosterone concentrations falling below established reference ranges, historically around < 10.4 nmol/L in the United Kingdom, though this threshold remains subject to clinical debate ( 5 – 7 ). Men with testosterone levels in the low-to-normal or borderline range may still experience symptoms sufficiently severe to justify treatment, complicating traditional diagnostic and management paradigms ( 7 , 8 ). Recognized manifestations of testosterone deficiency include diminished libido, fatigue, mood alterations, reduced muscle mass, increased adiposity, and broader metabolic dysfunction ( 1 , 4 , 9 – 13 ). These symptoms not only impair quality of life but can also contribute to heightened cardiovascular and metabolic risk profiles if left untreated ( 4 , 12 ). Although the prevalence of testosterone deficiency increases with age, it also affects younger or middle-aged men due to obesity, chronic illnesses, medication use, and lifestyle determinants ( 3 , 8 – 12 ). Mounting evidence suggests that addressing even borderline biochemical deficits can yield meaningful symptomatic improvements. This emerging view is supported by evolving international guidelines, which endorse a more symptom driven, individualised approach rather than strict adherence to a single biochemical threshold ( 14 ). For instance, men with total testosterone levels slightly above the classical < 10.4 nmol/L cut off, but still below a functional threshold (e.g., < 15 nmol/L), may present with clear androgen deficiency related symptoms warranting intervention ( 7 , 8 , 15 ). Such men represent a growing cohort seeking evaluation and care, often driven by increased health awareness, improved access to testing, and shifting patient expectations towards self-care and remote digital care, a space that is already taking shape due to the rise of e-prescribing and telehealth ( 16 , 17 ). Therefore, the inception of private digital healthcare services provides an accessible pathway for these individuals. Platforms such as Optimale, H3Health, and Manual have lowered barriers to care by offering convenient hormone testing (at home or clinic based), virtual consultations, and prompt initiation of testosterone replacement therapy (TRT) when clinically indicated. Patients utilising these digital models may differ from those managed in conventional health systems, as they tend to be more proactive and health literate, presenting with subtler biochemical abnormalities but pronounced symptomatic burdens ( 18 , 19 ). Examining outcomes in this digitally managed population is therefore crucial. Their profiles, motivations, and adherence patterns may influence both short and long term benefits of TRT, informing how best to tailor interventions and follow-up. While randomised controlled trials and meta-analyses have demonstrated that TRT improves sexual function, mood, body composition, and certain cardiometabolic parameters ( 2 , 20 – 22 ), data remain limited regarding long term quality of life outcomes in real world, non traditional healthcare settings. Most published research focuses on older, more overtly hypogonadal men or strictly controlled trial populations, potentially overlooking the nuanced responses of those with low or borderline testosterone levels who actively seek early intervention ( 2 , 11 ). To address this knowledge gap, patient reported outcome measures (PROMs) are invaluable. The quantitative Androgen Deficiency in the Ageing Male (qADAM) scale is one such PROM, providing a multidimensional assessment of symptom severity across sexual desire, energy, erection quality, mood, sleep, sports ability, and work performance domains ( 23 ). By examining qADAM changes over a 12 month period, this study captures the durability and breadth of symptomatic improvements associated with TRT in a cohort characterised by private digital healthcare engagement. Critically, understanding these longitudinal changes in men with low or borderline testosterone levels can guide clinical practice on patient selection and management strategies. For instance, identifying which subgroups based on BMI, smoking status, lifestyle factors, or hormone response derive the greatest benefit may inform personalised approaches to therapy initiation and dose optimisation ( 8 , 16 , 24 , 25 ). Furthermore, correlating qADAM improvements with biochemical parameters (testosterone, free testosterone, and sex hormone binding globulin (SHBG)) can elucidate the extent to which symptomatic relief aligns with hormonal normalisation, or whether other psychosocial and behavioural factors contribute substantially to patient outcomes ( 20 , 26 ). Ultimately, these insights may influence guideline development and support the integration of digital health pathways into mainstream clinical practice, optimising quality of life for men living with testosterone deficiency ( 7 , 16 , 21 , 27 ). Objectives The primary objective of this study was to evaluate the 12 month longitudinal impact of TRT on qADAM derived quality of life in men with biochemical and symptomatic testosterone deficiency managed through UK based private digital healthcare platforms. Secondary objectives included: Examining differences in qADAM changes across subgroups defined by body mass index (BMI), smoking status, height, weight and alcohol intake. Assessing correlations between changes in qADAM scores and hormone levels (total testosterone, free testosterone, sex hormone-binding globulin (SHBG). Identifying potential demographic or clinical factors (e.g., treatment formulation, adherence at 12 months) that may influence the magnitude of symptomatic improvement. Subjects and Methods Study Design and Setting We conducted a retrospective observational cohort analysis using anonymized records from three UK private digital healthcare providers: Optimale, H3Health, and Manual, offering at home or clinic based testosterone testing, remote (and some face to face) consultations, and rapid TRT initiation based on biochemical and symptomatic criteria. Population and Eligibility Criteria Men aged ≥ 18 years with two morning total testosterone measurements < 12 nmol/L ( 5 , 7 , 16 ) and ≥ 3 androgen-deficiency symptoms (e.g., low libido, fatigue), who began TRT between October 2018 and October 2024 and had baseline plus ≥ 1 follow-up qADAM score over 12 months, were eligible. We excluded those with severe uncontrolled comorbidities (e.g., prostate cancer, untreated obstructive sleep apnoea), haematocrit > 54%, unstable medications, or incomplete data. A small subset transferred from other clinics; their first qADAM on joining these services was designated baseline, mirroring real-world practice. Data Sources and Variables Extracted data included age, weight, height, BMI, smoking/alcohol status, and medical history. TRT modalities: intramuscular or transdermal, possibly with hCG were recorded, alongside baseline/follow-up total testosterone, free testosterone, and SHBG, measured by accredited (non-centralised) labs. Dose adjustments followed clinical judgment and patient preference in private digital settings ( 29 ). TRT Interventions TRT formulations were prescribed according to the qualified and TRT trained treating clinicians’ clinical judgment, patient preference, symptom severity, and biochemical profiles. Dose titrations were undertaken based on follow-up hormone levels, symptomatic changes, and clinical response. This approach mirrors real world practice patterns in private digital healthcare settings, where accessibility and patient led decision making may influence treatment choice by empowering self-care practices ( 29 ). Outcome Measures Primary outcome was the 12-month change in total qADAM (range 10–50; ≥5-point improvement = clinically meaningful. The qADAM scale assesses ten symptom domains associated with androgen deficiency, each component question is scored on a five-point Likert scale (1 = terrible/weak, 3 = average, and 5 = excellent/strong), except for question 8 relating to falling asleep after dinner (1 = never to 5 = every night) and question 10 relating to perceived height loss (1 = 2″, 3 = 1-1.4″, and 5 = < 0.4″ or none), generating a total range of 10–50 ( 23 ). Secondary outcomes included subdomain changes, subgroup differences (BMI, smoking, etc.), and correlations between hormone changes (total/free testosterone, SHBG) and qADAM improvements. Statistical Analyses and Sample Size Prior work indicated ~ 5-point qADAM improvement is clinically meaningful (SD ≈ 10) (( 23 )), so ≥ 200 participants would confer ~ 80% power at p = 0.05 ( 21 , 22 ). We used paired t-tests or Wilcoxon signed-rank for within-group changes, one-way ANOVA with Tukey’s post-hoc for subgroup comparisons, and Pearson’s correlation for hormone-QoL relationships. All tests were two-sided (p < 0.05). Missing data were handled by complete-case analyses and multiple imputation for sensitivity. Effect sizes, such as Cohen’s d, were computed to aid in the interpretation of clinically meaningful changes. Ethical and Regulatory Considerations This retrospective observational study constituted a service evaluation of routine clinical care delivered by private digital healthcare providers in the United Kingdom. Ethical approval was obtained from the Imperial College London Research Ethics Committee (ICREC number: 6990009). All data were fully anonymised prior to analysis, ensuring patient confidentiality and compliance with the UK General Data Protection Regulation (GDPR). This study adhered to ethical principles outlined in the Declaration of Helsinki. No individually identifiable information was used, and all results are presented in aggregate form. The investigation adhered to established principles of good clinical practice and respected the STROBE guidelines for observational research ( 28 ). Results A total of 1,065 men with confirmed biochemical and symptomatic testosterone deficiency completed the 12-month follow-up (Table 1). They had a mean age of 42.9 ± 8.8 years, and a substantial proportion was overweight or obese. Baseline qADAM was 29.7 ± 7.3, indicating a moderate symptom burden. By 12 months, mean qADAM rose by 6.64 points (95% CI 6.16–7.11; p < 0.0001; Cohen’s d = 0.84), reflecting clinically meaningful overall improvement (Table 2, Fig. 1 ). All ten subdomains improved significantly (p < 0.0001), with notable gains in libido (+ 1.04), energy (+ 0.94), and strength (+ 0.77) (Fig. 2 ). Men perceived better mood, erection strength, sleep, and work performance, suggesting broad symptomatic relief. Total testosterone increased by + 31.25 nmol/L (p < 0.0001), though correlations between testosterone changes and qADAM were modest (r ≈ 0.10), and free testosterone/SHBG changes showed weak or nonsignificant associations (Table 3, Figs. 3 – 4 ). Sensitivity analyses using multiple imputation produced comparable results, indicating that greater hormone levels alone did not fully account for improvements in patient-reported outcomes (see Supplementary File A Table 1). Subgroup analyses showed obese men (BMI ≥ 30) had larger qADAM gains (+ 8.03 points) than those with lower BMI, and men ≥ 100 kg also derived more benefit, suggesting that higher metabolic risk may amplify symptom response (see Supplementary File B Tables 1–4 for further outcomes in detail). Smoking status affected improvement magnitude, with non-smokers outperforming smokers or ex-smokers. Together, these findings highlight robust multidomain benefits from TRT while underscoring potential influences of metabolic and lifestyle factors on QoL changes. Discussion Principal Findings This 12-month retrospective observational study, conducted via private digital healthcare platforms, demonstrates that TRT can yield pronounced, multifaceted QoL improvements for men with biochemical and symptomatic deficiency, in line with the primary goal of TRT delivery through a digital health service. The mean qADAM increase of ~ 6.6 points (CI: [6.16, 7.1], p < 0.0001) exceeds established thresholds for clinical significance, indicating that men with low or borderline testosterone, rather than only those with profound hypogonadism can experience meaningful relief. Further supporting this conclusion, we observed significant increases across all ten qADAM subdomains at 12 months. Libido rose by approximately 1.04 points and energy by 0.94, suggesting that men perceived tangible benefits in sexual desire and daily motivation. Strength and endurance also improved (by 0.77), as did mood-related measures such as happiness (0.65) and life enjoyment (0.73). Participants reported better work performance (0.71) and modest yet notable gains in sleep quality (0.50) and sports ability (0.80), underscoring the broad reach of symptom relief. These increments, often exceeding the 0.5-1.0 Likert‐scale benchmark for clinical relevance, translate into real‐world improvements that men likely noticed in day‐to‐day functioning. Total testosterone levels rose significantly (+ 31.25 nmol/L), although correlations with qADAM changes were generally modest, implying that biochemical normalization alone does not fully explain symptomatic gains. In addition, our subgroup findings show that men with obesity (BMI ≥ 30) and those weighing ≥ 100 kg often experienced even greater qADAM improvements, highlighting the potential synergy between metabolic compromise and the symptomatic response to TRT. Smoking status also impacted results, with non-smokers typically improving more than those who smoked or vaped, suggesting lifestyle or behavioral factors may influence outcomes. These findings complement emerging evidence endorsing a more symptom‐driven, individualised approach rather than a rigid biochemical cutoff [7, 8, 14, 20]. Comparison with Prior Work Our results align with prior randomised trials and meta-analyses showing improvements in sexual function, mood, and body composition with TRT (2, 20‐22), but also illuminate outcomes in a population often overlooked: men with borderline biochemical deficits but pronounced symptoms. Unlike many controlled studies focusing on older, overtly hypogonadal men, our cohort was younger, more proactive, and managed outside conventional healthcare pathways. The success of TRT here suggests earlier or more flexible intervention may be beneficial. While prior work has established TRT’s role in older or severely hypogonadal patients (9‐11, 18, 19), we highlight that symptomatic improvement can occur even when testosterone levels, though low are not far below traditional cutoffs ( 7 , 8 , 30 ). This perspective endorses a shift toward symptom‐focused care and post‐treatment total testosterone targets of 15–30 nmol/L (5‐7). Thus, TRT may be appropriate for sub‐normal total testosterone (> 10.4 nmol/L to < 15 nmol/L) in men with significant symptoms ( 8 , 30 ). Influence of Patient Characteristics and Digital Care Models Subgroup analyses show potential for tailoring interventions by demographic and lifestyle factors. Obese men achieved especially robust qADAM gains, consistent with prior evidence suggesting metabolic burdens amplify TRT benefits ( 13 , 25 , 31 , 32 ). Similarly, non-smokers improved more, implying that modifiable behaviours and baseline risk profiles shape outcomes ( 24 ). The digital healthcare model, featuring prompt testing, virtual consultations, and continuous follow‐up, may have boosted engagement, adherence, and dose optimisation ( 33 ). This accessibility could reinforce psychosocial and behavioural factors that, though not directly measured, likely influence results ( 34 ). Earlier telemedicine initiatives demonstrate that remote management enhances autonomy and adherence ( 16 , 17 , 29 ), potentially amplifying QoL gains through self‐care ( 35 ). Hormone Changes and Correlates of Symptomatic Relief Although total testosterone rose significantly, correlations with qADAM improvements were modest. Certain domains, such as libido and energy, showed weak but statistically significant associations, while most domains did not. Hence, while biochemical normalisation is important, it is not solely determinative. Psychosocial factors, enhanced patient empowerment, lifestyle changes, and other non-hormonal elements likely sustain QoL benefits. Similar complexities are noted elsewhere, where hormone levels alone fail to account fully for patient‐reported outcomes (19, 36‐38). A more holistic model, combining hormone correction with behavioural interventions, psychological support ( 39 ), and personalised follow‐up, may lead to more enduring improvements via self‐determination ( 40 ). Given that many men had low‐normal testosterone, symptom improvement cannot be attributed solely to hormone increments. Rather, psychosocial, behavioural, and adherence factors, likely strengthened by digital healthcare appear critical. This weak correlation between hormone changes and symptomatic relief aligns with growing evidence that physiological, psychological, and lifestyle factors all matter. Strengths and Limitations Strengths include the large sample size, broad demographics, and a year-long observation in real‐world settings. Using qADAM, a validated, multidimensional metric, provides insights into daily functioning, emotional well‐being, and physical capacity alongside sexual health. Observed qADAM gains (~ 6.6 points) exceed the ~ 0.5-1.0 Likert‐scale threshold often deemed clinically meaningful, suggesting palpable benefits. However, as a retrospective observational study without randomisation, selection bias and unmeasured confounding remain possible. Men opting for private digital services may differ from those in the NHS regarding literacy, resources, or motivation. Such self‐selection could limit external validity and potentially inflate estimates of benefit. Attrition bias might occur if men who perceived no benefit discontinued treatment before 12 months. Incomplete demographic data (e.g., ethnicity) and missing hormone follow‐ups, handled by complete‐case analyses, could bias results if missingness was not random. No formal confounder adjustment was performed, partly due to incomplete recording of potential mediators by the digital platforms. Moreover, not all participants had baseline and follow-up hormone values, and missing qADAM subdomain data hampered detailed exploration of hormone-symptom dynamics. Relying on complete‐case analyses might introduce bias if missingness patterns were not random. Laboratory assays were not centralised; subtle differences in methodology or timing may have affected biochemical precision. We also lacked formal adherence measures and lifestyle data, such as diet, exercise, or stress, making it difficult to separate TRT effects from concurrent behavioural changes. Additionally, we did not gather comprehensive details on comorbidities or medication interactions that might affect results. Another limitation stems from reliance on qADAM as the primary outcome measure ( 23 ). While the qADAM scale refines the original ADAM questionnaire by using 1–5 Likert scoring, it remains rooted in ADAM’s core questions ( 41 ). It may not always distinguish testosterone deficiency from overlapping conditions like hypothyroidism, type 2 diabetes, or depression ( 5 ). Also, qADAM’s sensitivity for detecting incremental clinical improvements over time is not conclusively established. Subjective judgments can introduce reporting biases if patients expect or want positive results. Without objective performance markers or biomarkers (mood, metabolic status, inflammation), it is challenging to confirm subjective gains. Finally, the retrospective design hindered consistent follow-up intervals, precise dose‐titration monitoring, and structured psychosocial support to identify optimal combined interventions. Implications for Practice and Research These findings underscore the value of a flexible, symptom oriented strategy for diagnosing and treating testosterone deficiency, highlighting digital healthcare’s potential to broaden access and reinforce patient engagement. Clinicians might consider earlier intervention in borderline biochemical cases if symptom burdens are substantial, especially through digital services supporting adherence and lifestyle adjustments. Future work should probe hormonal, psychosocial, and behavioural interplays, identify who responds best, and test combined interventions (pharmacotherapy with lifestyle coaching or mental health support). Such approaches could refine patient selection, optimally dose TRT, and produce more durable, meaningful QoL gains. Prospectively controlled trials employing wearable technologies, dietary tracking, or validated mental health tools would also strengthen causal inferences and clarify which subgroups experience the greatest long-term benefit. Conclusion In summary, our study shows that men with low or borderline testosterone managed through private digital healthcare can achieve marked, sustained improvements in multidimensional QoL over 12 months of TRT. By demonstrating clinically significant qADAM gains, elucidating responsive patient subgroups, and revealing only modest hormone to symptom correlations, these results advocate a patient-centred, symptom focused paradigm. They may inform future guidelines, shape research agendas, prospective trials and ultimately enhance care for men with testosterone deficiency. Declarations Data Availability Due to the nature of the clinical data collected and the consent provided by patients, the individual participant data used in this study is not publicly available. The statistical code used in the analyses can be made available to researchers upon request to the corresponding author. Requests for access to anonymized data for noncommercial projects should be directed to the corresponding author and will require appropriate ethical approvals. Author Contributions All authors contributed to the conception and design of the study. HJ performed data extraction and analysis. HJ,DH,AKC,JF and AO interpreted the results. All authors drafted the manuscript, critically reviewed it, and approved the final version for publication. Funding No external funding was received for this study. The research was conducted as part of routine service evaluation activities within the institution. The research was conducted as part of routine service evaluation activities within the organization. AO is supported by the National Institute for Health and Care Research (NIHR) Applied Research Collaboration (ARC) Northwest London. The views expressed are those of the authors and not necessarily those of the NHS, the NIHR or the Department of Health and Social Care. Ethical Approval This retrospective observational study constituted a service evaluation of routine clinical care delivered by private digital healthcare providers in the United Kingdom. Ethical approval was obtained from the Imperial College London Research Ethics Committee (ICREC number: 6990009). All data were fully anonymised prior to analysis, ensuring patient confidentiality and compliance with the UK General Data Protection Regulation (GDPR). This study adhered to ethical principles outlined in the Declaration of Helsinki. No individually identifiable information was used, and all results are presented in aggregate form. The investigation adhered to established principles of good clinical practice. Competing Interests The authors HJ, AKC, DH, JF are employed by Menwell TM (T/a Manual). AO declared no conflict of interest. References Handelsman DJ, Wittert GA. Testosterone and Depression Symptoms in Aging Men. The Journal of Clinical Endocrinology & Metabolism. 2024:dgae093. Yang HJ, Kim KH, Kim DS, Lee CH, Jeon YS, Shim SR, et al. The Effect of Testosterone Replacement on Sexual Function in the Elderly: A Systematic Review and Meta-Analysis. The World Journal of Men's Health. 2023;41(4):861. Nguyen Hoai B, Hoang L, Nguyen Cao T, Pham Minh Q, A. Jannini E. Testosterone and aging male, a perspective from a developing country. The Aging Male. 2023;26(1):2223712. Grossmann M, Robledo KP, Daniel M, Handelsman DJ, Inder WJ, Stuckey BG, et al. Testosterone treatment, weight loss, and health-related quality of life and psychosocial function in men: a 2-year randomized controlled trial. The Journal of Clinical Endocrinology & Metabolism. 2024;109(8):2019–28. Hackett G, Kirby M, Rees RW, Jones TH, Muneer A, Livingston M, et al. The British Society for Sexual Medicine Guidelines on Male Adult Testosterone Deficiency, with Statements for Practice. World J Mens Health. 2023;41(3):508–37. Corona G, Goulis DG, Huhtaniemi I, Zitzmann M, Toppari J, Forti G, et al. European Academy of Andrology (EAA) guidelines on investigation, treatment and monitoring of functional hypogonadism in males: Endorsing organization: European Society of Endocrinology. Andrology. 2020;8(5):970–87. Bhasin S, Brito JP, Cunningham GR, Hayes FJ, Hodis HN, Matsumoto AM, et al. Testosterone Therapy in Men With Hypogonadism: An Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab. 2018;103(5):1715–44. Ramasamy R, Golan R, Wilken N, Scovell JM, Lipshultz LI. Association of free testosterone with hypogonadal symptoms in men with near-normal total testosterone levels. Urology. 2015;86(2):287–90. Ramasamy R, Scovell JM, Lipshultz L. The Influence of Testosterone Replacement Therapy in Older Men: An Age and Comorbidity Matched Cohort Study. Journal of the American College of Surgeons. 2014;219(3):S148-S9. Tsujimura A. The Relationship between Testosterone Deficiency and Men's Health. World J Mens Health. 2013;31(2):126–35. Wu FC, Tajar A, Pye SR, Silman AJ, Finn JD, O'Neill TW, et al. Hypothalamic-pituitary-testicular axis disruptions in older men are differentially linked to age and modifiable risk factors: the European Male Aging Study. The Journal of Clinical Endocrinology & Metabolism. 2008;93(7):2737–45. Wang C, Jackson G, Jones TH, Matsumoto AM, Nehra A, Perelman MA, et al. Low testosterone associated with obesity and the metabolic syndrome contributes to sexual dysfunction and cardiovascular disease risk in men with type 2 diabetes. Diabetes care. 2011;34(7):1669–75. Allan CA, McLachlan RI. Androgens and obesity. Curr Opin Endocrinol Diabetes Obes. 2010;17(3):224–32. Reddy AV, Kesavan R, Priyadharsini R, Deva R. Unlocking the therapeutic potential and personalized therapy of testosterone: a comprehensive review. Drug Metab Pers Ther. 2024. Rivas AM, Mulkey Z, Lado-Abeal J, Yarbrough S. Diagnosing and managing low serum testosterone. Proc (Bayl Univ Med Cent). 2014;27(4):321–4. Dubin JM, Fantus RJ, Halpern JA. Testosterone replacement therapy in the era of telemedicine. International Journal of Impotence Research. 2022;34(7):663–8. Jesse E, Sellke N, Muncey W, Ghayda R, Loeb A, Thirumavalavan N. 27 Cost Analysis of Online Telehealth Platforms Offering Testosterone Therapy. The Journal of Sexual Medicine. 2022;19(Supplement_1):S14-S5. Corona G, Mannucci E, Ricca V, Lotti F, Boddi V, Bandini E, et al. The age-related decline of testosterone is associated with different specific symptoms and signs in patients with sexual dysfunction. International journal of andrology. 2009;32(6):720–8. Scovell JM, Ramasamy R, Wilken N, Kovac JR, Lipshultz LI. Hypogonadal symptoms in young men are associated with a serum total testosterone threshold of 400 ng/dL. BJU international. 2015;116(1):142–6. Corona G, Rastrelli G, Maggi M. Diagnosis and treatment of late-onset hypogonadism: systematic review and meta-analysis of TRT outcomes. Best Pract Res Clin Endocrinol Metab. 2013;27(4):557–79. Grossmann M, Robledo KP, Daniel M, Handelsman DJ, Inder WJ, Stuckey BGA, et al. Testosterone Treatment, Weight Loss, and Health-related Quality of Life and Psychosocial Function in Men: A 2-year Randomized Controlled Trial. J Clin Endocrinol Metab. 2024;109(8):2019–28. Snyder PJ, Bhasin S, Cunningham GR, Matsumoto AM, Stephens-Shields AJ, Cauley JA, et al. Effects of Testosterone Treatment in Older Men. N Engl J Med. 2016;374(7):611–24. Mohamed O, Freundlich R, Dakik H, Grober E, Najari B, Lipshultz L, et al. The quantitative ADAM questionnaire: a new tool in quantifying the severity of hypogonadism. International journal of impotence research. 2010;22(1):20–4. Svartberg J, Jorde R. Endogenous testosterone levels and smoking in men. The fifth Tromsø study. International journal of andrology. 2007;30(3):137–43. Mangolim AS, Brito LdAR, Nunes-Nogueira VdS. Effectiveness of testosterone replacement in men with obesity: a systematic review and meta-analysis. European journal of endocrinology. 2022;186(1):123–35. Shin YS, You JH, Cha JS, Park JK. The relationship between serum total testosterone and free testosterone levels with serum hemoglobin and hematocrit levels: a study in 1221 men. The Aging Male. 2016;19(4):209–14. Corona G, Goulis DG, Huhtaniemi I, Zitzmann M, Toppari J, Forti G, et al. European Academy of Andrology (EAA) guidelines on investigation, treatment and monitoring of functional hypogonadism in males: Endorsing organization: European Society of Endocrinology. Andrology. 2020;8(5):970–87. Von Elm E, Altman DG, Egger M, Pocock SJ, Gøtzsche PC, Vandenbroucke JP. The Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) statement: guidelines for reporting observational studies. The lancet. 2007;370(9596):1453–7. Náfrádi L, Nakamoto K, Schulz PJ. Is patient empowerment the key to promote adherence? A systematic review of the relationship between self-efficacy, health locus of control and medication adherence. PLoS One. 2017;12(10):e0186458. Lee T-W, Kao P-Y, Chen Y-C, Wang S-T. Effects of Testosterone Replacement Therapy on Muscle Strength in Older Men with Low to Low-Normal Testosterone Levels: A Systematic Review and Meta-Analysis. Gerontology. 2023;69(10):1157–66. Hudson J, Cruickshank M, Quinton R, Aucott L, Wu F, Grossmann M, et al. Symptomatic benefits of testosterone treatment in patient subgroups: a systematic review, individual participant data meta-analysis, and aggregate data meta-analysis. Lancet Healthy Longev. 2023;4(10):e561-e72. Braga PC, Pereira SC, Ribeiro JC, Sousa M, Monteiro MP, Oliveira PF, et al. Late-onset hypogonadism and lifestyle-related metabolic disorders. Andrology. 2020;8(6):1530–8. Milne-Ives M, Homer S, Andrade J, Meinert E. The conceptualisation and measurement of engagement in digital health. Internet Interventions. 2024;36:100735. Tan SY, Sumner J, Wang Y, Wenjun Yip A. A systematic review of the impacts of remote patient monitoring (RPM) interventions on safety, adherence, quality-of-life and cost-related outcomes. NPJ Digital Medicine. 2024;7(1):192. El-Osta A, Webber D, Gnani S, Banarsee R, Mummery D, Majeed A, et al. The self-care matrix: a unifying framework for self-Care.-Selfcare Journal. SelfCare Journal. 2019. Zitzmann M. Testosterone, mood, behaviour and quality of life. Andrology. 2020;8(6):1598–605. Shigehara K, Konaka H, Koh E, Izumi K, Kitagawa Y, Mizokami A, et al. Effects of testosterone replacement therapy on nocturia and quality of life in men with hypogonadism: a subanalysis of a previous prospective randomized controlled study in Japan. The Aging Male. 2015;18(3):169–74. Rosen RC, Wu F, Behre HM, Porst H, Meuleman EJ, Maggi M, et al. Quality of life and sexual function benefits of long-term testosterone treatment: longitudinal results from the registry of hypogonadism in men (RHYME). The journal of sexual medicine. 2017;14(9):1104–15. Jayasena CN, Anderson RA, Llahana S, Barth JH, MacKenzie F, Wilkes S, et al. Society for Endocrinology guidelines for testosterone replacement therapy in male hypogonadism. Clinical endocrinology. 2022;96(2):200–19. Ntoumanis N, Ng JY, Prestwich A, Quested E, Hancox JE, Thøgersen-Ntoumani C, et al. A meta-analysis of self-determination theory-informed intervention studies in the health domain: Effects on motivation, health behavior, physical, and psychological health. Health psychology review. 2021;15(2):214–44. Morley JE, Charlton E, Patrick P, Kaiser F, Cadeau P, McCready D, et al. Validation of a screening questionnaire for androgen deficiency in aging males. Metabolism. 2000;49(9):1239–42. Tables Tables 1 to 3 are available in the Supplementary Files section. Additional Declarations Yes there is potential conflict of interest. Supplementary Files SupplementaryFileATable1.xlsx Supplementary File A Table 1 - Sensitivity analyses SupplementaryFileBTable1.xlsx Supplementary File B Table 1 - Subgroup analyses SupplementaryFileBTable2.xlsx Supplementary File B Table 2 - Full ANOVA results SupplementaryFileBTable3.xlsx Supplementary File B Table 3 - Full Tukey HSD post-hoc results SupplementaryFileBTable4.xlsx Supplementary File B Table 4: Full Paired T-Test results by category Table1use.xlsx Table 1 Table2.qADAMScoreChange.xlsx Table 2 Table3.HormonalChanges.xlsx Table 3 Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-6246872","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":430693990,"identity":"7b316886-6e8e-494e-8f34-b026b5929423","order_by":0,"name":"Hans Johnson","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA9UlEQVRIie2RsYrCQBCGJwixidhOEPQVNqQ4RcHCF0kaUwlXbrkSWBux9jHSid0uW9jMA2gn+AIBmyuuuE26K26T8or9qvl3+OBfBsDj+YcwpUX6zVdTBoGwed6+tuPfihGfEW3TVlGAfZShqEfS5FWT+ila7yskU1wmpnzXHGF8UGF8dihrpUvGeLG7nnKJihCQsjCunMW0ZBktdxUFErS0xe4Qxk+3cvjSclAwCsq6UWY9FJHs5SazisBGYY3SUUykQNvkegwkEmGUUF4uXN9n99szBb6afUTDV83tTac3ox9HhwKofueo4yqWccfe4/F4PPAD2XJbP+uHbeMAAAAASUVORK5CYII=","orcid":"https://orcid.org/0000-0002-2001-4544","institution":"Manual","correspondingAuthor":true,"prefix":"","firstName":"Hans","middleName":"","lastName":"Johnson","suffix":""},{"id":430693991,"identity":"43e71f86-4226-4293-8889-3c993ea71cd2","order_by":1,"name":"Ashley Clift","email":"","orcid":"","institution":"","correspondingAuthor":false,"prefix":"","firstName":"Ashley","middleName":"","lastName":"Clift","suffix":""},{"id":430693992,"identity":"962853cd-08fb-48e9-b5c4-f5ba736873f5","order_by":2,"name":"David Huang","email":"","orcid":"","institution":"","correspondingAuthor":false,"prefix":"","firstName":"David","middleName":"","lastName":"Huang","suffix":""},{"id":430693993,"identity":"ce347c60-0450-4743-bb1c-8cd0b32f3266","order_by":3,"name":"Jeff Foster","email":"","orcid":"","institution":"","correspondingAuthor":false,"prefix":"","firstName":"Jeff","middleName":"","lastName":"Foster","suffix":""},{"id":430693994,"identity":"facaa832-f0db-4502-aac4-b32bb7f913ba","order_by":4,"name":"Austen El-Osta","email":"","orcid":"","institution":"","correspondingAuthor":false,"prefix":"","firstName":"Austen","middleName":"","lastName":"El-Osta","suffix":""}],"badges":[],"createdAt":"2025-03-17 17:50:19","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-6246872/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-6246872/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":79563325,"identity":"301b3764-b640-46c7-a988-58a545b56e04","added_by":"auto","created_at":"2025-03-31 09:05:15","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":35378,"visible":true,"origin":"","legend":"\u003cp\u003eDepicts a bar chart of overall qADAM changes (mean difference ± 95% CI). It illustrates a clear, clinically meaningful improvement from baseline to 12 months.\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-6246872/v1/9b2d1fc57848a6fb89ff1f85.png"},{"id":79563324,"identity":"2486b845-51c5-41d1-8908-1f1b7dbf01cf","added_by":"auto","created_at":"2025-03-31 09:05:15","extension":"jpg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":47487,"visible":true,"origin":"","legend":"\u003cp\u003eShows violin plots for each qADAM subdomain, highlighting most patients’ positive change. Subdomains such as libido, energy, and erection strength notably shifted toward better scores.\u003c/p\u003e","description":"","filename":"Picture2.jpg","url":"https://assets-eu.researchsquare.com/files/rs-6246872/v1/1bd2a1b8ea54cc11c2fc3f64.jpg"},{"id":79562523,"identity":"20fe6fe0-85bd-42b3-827f-19d4918f0aea","added_by":"auto","created_at":"2025-03-31 08:57:16","extension":"jpg","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":40763,"visible":true,"origin":"","legend":"\u003cp\u003eDisplays a contour plot showing the joint distribution of total testosterone change and total qADAM change. While higher testosterone changes tended to coincide with better qADAM outcomes, variability is evident.\u003c/p\u003e","description":"","filename":"Picture3.jpg","url":"https://assets-eu.researchsquare.com/files/rs-6246872/v1/41a34f42e772affddf174796.jpg"},{"id":79562529,"identity":"5accd39b-9758-4fa1-adf4-acdce0223f45","added_by":"auto","created_at":"2025-03-31 08:57:16","extension":"jpg","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":114058,"visible":true,"origin":"","legend":"\u003cp\u003eIllustrates correlations between total testosterone increments and specific qADAM subdomains. Most relationships were weak, underscoring the multifactorial nature of symptomatic improvement.\u003c/p\u003e","description":"","filename":"Picture4.jpg","url":"https://assets-eu.researchsquare.com/files/rs-6246872/v1/efacab51059c5b562f28c684.jpg"},{"id":86245159,"identity":"70b7bb31-8419-4af2-a314-af17fc326489","added_by":"auto","created_at":"2025-07-08 11:28:30","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":681090,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-6246872/v1/e4040996-bcee-4160-80ce-3e15e9366e04.pdf"},{"id":79562520,"identity":"d0076a1c-8187-48b5-af79-74af7357e460","added_by":"auto","created_at":"2025-03-31 08:57:15","extension":"xlsx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":10450,"visible":true,"origin":"","legend":"Supplementary File A Table 1 - Sensitivity analyses","description":"","filename":"SupplementaryFileATable1.xlsx","url":"https://assets-eu.researchsquare.com/files/rs-6246872/v1/a7303ae2f1ee1e096a4c38ff.xlsx"},{"id":79564336,"identity":"f5a3a784-4282-4f66-ae1e-ffd0497e8779","added_by":"auto","created_at":"2025-03-31 09:13:15","extension":"xlsx","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":10865,"visible":true,"origin":"","legend":"Supplementary File B Table 1 - Subgroup analyses","description":"","filename":"SupplementaryFileBTable1.xlsx","url":"https://assets-eu.researchsquare.com/files/rs-6246872/v1/6aca6c6ad47bc1337f764c86.xlsx"},{"id":79563330,"identity":"5e8b0a67-1c38-49be-9d86-a5eaabc4d062","added_by":"auto","created_at":"2025-03-31 09:05:16","extension":"xlsx","order_by":3,"title":"","display":"","copyAsset":false,"role":"supplement","size":10738,"visible":true,"origin":"","legend":"Supplementary File B Table 2 - Full ANOVA results","description":"","filename":"SupplementaryFileBTable2.xlsx","url":"https://assets-eu.researchsquare.com/files/rs-6246872/v1/1e9bb27ebaa78e67c9d9aa93.xlsx"},{"id":79562526,"identity":"f69ddbad-45f6-46db-8dcf-ac98419c7b89","added_by":"auto","created_at":"2025-03-31 08:57:16","extension":"xlsx","order_by":4,"title":"","display":"","copyAsset":false,"role":"supplement","size":11038,"visible":true,"origin":"","legend":"Supplementary File B Table 3 - Full Tukey HSD post-hoc results","description":"","filename":"SupplementaryFileBTable3.xlsx","url":"https://assets-eu.researchsquare.com/files/rs-6246872/v1/d288c701b9e247802c6c5790.xlsx"},{"id":79562532,"identity":"0b9795aa-eba5-45c9-88de-2a56f98f9ebd","added_by":"auto","created_at":"2025-03-31 08:57:16","extension":"xlsx","order_by":5,"title":"","display":"","copyAsset":false,"role":"supplement","size":12632,"visible":true,"origin":"","legend":"Supplementary File B Table 4: Full Paired T-Test results by category","description":"","filename":"SupplementaryFileBTable4.xlsx","url":"https://assets-eu.researchsquare.com/files/rs-6246872/v1/9e744590d2f3dfacf28ffc64.xlsx"},{"id":79564339,"identity":"d9caa12d-d315-4b85-8aa6-4a4d78f21f4d","added_by":"auto","created_at":"2025-03-31 09:13:16","extension":"xlsx","order_by":6,"title":"","display":"","copyAsset":false,"role":"supplement","size":11617,"visible":true,"origin":"","legend":"Table 1","description":"","filename":"Table1use.xlsx","url":"https://assets-eu.researchsquare.com/files/rs-6246872/v1/33b62a6921bcb2c763a25ec9.xlsx"},{"id":79562548,"identity":"a1e5cbf0-131b-46d7-9759-ac3f65636ec2","added_by":"auto","created_at":"2025-03-31 08:57:16","extension":"xlsx","order_by":7,"title":"","display":"","copyAsset":false,"role":"supplement","size":11362,"visible":true,"origin":"","legend":"Table 2","description":"","filename":"Table2.qADAMScoreChange.xlsx","url":"https://assets-eu.researchsquare.com/files/rs-6246872/v1/4120a9182947089f776968e2.xlsx"},{"id":79563336,"identity":"3a83baaf-1c7d-4bd9-beda-9b474f0605d6","added_by":"auto","created_at":"2025-03-31 09:05:16","extension":"xlsx","order_by":8,"title":"","display":"","copyAsset":false,"role":"supplement","size":10384,"visible":true,"origin":"","legend":"Table 3","description":"","filename":"Table3.HormonalChanges.xlsx","url":"https://assets-eu.researchsquare.com/files/rs-6246872/v1/691d66faef903138587106c9.xlsx"}],"financialInterests":"\u003cb\u003eYes\u003c/b\u003e there is potential conflict of interest.","formattedTitle":"Longitudinal Improvements in Quality of Life Following Testosterone Replacement Therapy in Men with Biochemical and Symptomatic Testosterone Deficiency: a 12 Month Retrospective Observational Study in a Remote Digital Healthcare Setting in the United Kingdom","fulltext":[{"header":"Introduction","content":"\u003cp\u003eTestosterone deficiency (hypogonadism) in men comprises a spectrum of clinical presentations influenced by advancing age, comorbidities, and lifestyle factors (\u003cspan additionalcitationids=\"CR2 CR3\" citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e). Biochemically, low testosterone is often defined by total testosterone concentrations falling below established reference ranges, historically around \u0026lt;\u0026thinsp;10.4 nmol/L in the United Kingdom, though this threshold remains subject to clinical debate (\u003cspan additionalcitationids=\"CR6\" citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e). Men with testosterone levels in the low-to-normal or borderline range may still experience symptoms sufficiently severe to justify treatment, complicating traditional diagnostic and management paradigms (\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e). Recognized manifestations of testosterone deficiency include diminished libido, fatigue, mood alterations, reduced muscle mass, increased adiposity, and broader metabolic dysfunction (\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan additionalcitationids=\"CR10 CR11 CR12\" citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e). These symptoms not only impair quality of life but can also contribute to heightened cardiovascular and metabolic risk profiles if left untreated (\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e). Although the prevalence of testosterone deficiency increases with age, it also affects younger or middle-aged men due to obesity, chronic illnesses, medication use, and lifestyle determinants (\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan additionalcitationids=\"CR9 CR10 CR11\" citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eMounting evidence suggests that addressing even borderline biochemical deficits can yield meaningful symptomatic improvements. This emerging view is supported by evolving international guidelines, which endorse a more symptom driven, individualised approach rather than strict adherence to a single biochemical threshold (\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e). For instance, men with total testosterone levels slightly above the classical\u0026thinsp;\u0026lt;\u0026thinsp;10.4 nmol/L cut off, but still below a functional threshold (e.g., \u0026lt;\u0026thinsp;15 nmol/L), may present with clear androgen deficiency related symptoms warranting intervention (\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e). Such men represent a growing cohort seeking evaluation and care, often driven by increased health awareness, improved access to testing, and shifting patient expectations towards self-care and remote digital care, a space that is already taking shape due to the rise of e-prescribing and telehealth (\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e, \u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eTherefore, the inception of private digital healthcare services provides an accessible pathway for these individuals. Platforms such as Optimale, H3Health, and Manual have lowered barriers to care by offering convenient hormone testing (at home or clinic based), virtual consultations, and prompt initiation of testosterone replacement therapy (TRT) when clinically indicated. Patients utilising these digital models may differ from those managed in conventional health systems, as they tend to be more proactive and health literate, presenting with subtler biochemical abnormalities but pronounced symptomatic burdens (\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e, \u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e). Examining outcomes in this digitally managed population is therefore crucial. Their profiles, motivations, and adherence patterns may influence both short and long term benefits of TRT, informing how best to tailor interventions and follow-up.\u003c/p\u003e \u003cp\u003eWhile randomised controlled trials and meta-analyses have demonstrated that TRT improves sexual function, mood, body composition, and certain cardiometabolic parameters (\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan additionalcitationids=\"CR21\" citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e), data remain limited regarding long term quality of life outcomes in real world, non traditional healthcare settings. Most published research focuses on older, more overtly hypogonadal men or strictly controlled trial populations, potentially overlooking the nuanced responses of those with low or borderline testosterone levels who actively seek early intervention (\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e). To address this knowledge gap, patient reported outcome measures (PROMs) are invaluable. The quantitative Androgen Deficiency in the Ageing Male (qADAM) scale is one such PROM, providing a multidimensional assessment of symptom severity across sexual desire, energy, erection quality, mood, sleep, sports ability, and work performance domains (\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e). By examining qADAM changes over a 12 month period, this study captures the durability and breadth of symptomatic improvements associated with TRT in a cohort characterised by private digital healthcare engagement.\u003c/p\u003e \u003cp\u003eCritically, understanding these longitudinal changes in men with low or borderline testosterone levels can guide clinical practice on patient selection and management strategies. For instance, identifying which subgroups based on BMI, smoking status, lifestyle factors, or hormone response derive the greatest benefit may inform personalised approaches to therapy initiation and dose optimisation (\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e, \u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e, \u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e). Furthermore, correlating qADAM improvements with biochemical parameters (testosterone, free testosterone, and sex hormone binding globulin (SHBG)) can elucidate the extent to which symptomatic relief aligns with hormonal normalisation, or whether other psychosocial and behavioural factors contribute substantially to patient outcomes (\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e, \u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e). Ultimately, these insights may influence guideline development and support the integration of digital health pathways into mainstream clinical practice, optimising quality of life for men living with testosterone deficiency (\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e, \u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e, \u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eObjectives\u003c/p\u003e \u003cp\u003eThe primary objective of this study was to evaluate the 12 month longitudinal impact of TRT on qADAM derived quality of life in men with biochemical and symptomatic testosterone deficiency managed through UK based private digital healthcare platforms. Secondary objectives included:\u003c/p\u003e \u003cp\u003e \u003col\u003e \u003cspan\u003e \u003cli\u003e \u003cp\u003eExamining differences in qADAM changes across subgroups defined by body mass index (BMI), smoking status, height, weight and alcohol intake.\u003c/p\u003e \u003c/li\u003e \u003c/span\u003e \u003cspan\u003e \u003cli\u003e \u003cp\u003eAssessing correlations between changes in qADAM scores and hormone levels (total testosterone, free testosterone, sex hormone-binding globulin (SHBG).\u003c/p\u003e \u003c/li\u003e \u003c/span\u003e \u003cspan\u003e \u003cli\u003e \u003cp\u003eIdentifying potential demographic or clinical factors (e.g., treatment formulation, adherence at 12 months) that may influence the magnitude of symptomatic improvement.\u003c/p\u003e \u003c/li\u003e \u003c/span\u003e \u003c/ol\u003e \u003c/p\u003e "},{"header":"Subjects and Methods","content":"\u003cp\u003eStudy Design and Setting\u003c/p\u003e \u003cp\u003eWe conducted a retrospective observational cohort analysis using anonymized records from three UK private digital healthcare providers: Optimale, H3Health, and Manual, offering at home or clinic based testosterone testing, remote (and some face to face) consultations, and rapid TRT initiation based on biochemical and symptomatic criteria.\u003c/p\u003e \u003cp\u003ePopulation and Eligibility Criteria\u003c/p\u003e \u003cp\u003eMen aged\u0026thinsp;\u0026ge;\u0026thinsp;18 years with two morning total testosterone measurements\u0026thinsp;\u0026lt;\u0026thinsp;12 nmol/L (\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e) and \u0026ge;\u0026thinsp;3 androgen-deficiency symptoms (e.g., low libido, fatigue), who began TRT between October 2018 and October 2024 and had baseline plus\u0026thinsp;\u0026ge;\u0026thinsp;1 follow-up qADAM score over 12 months, were eligible. We excluded those with severe uncontrolled comorbidities (e.g., prostate cancer, untreated obstructive sleep apnoea), haematocrit\u0026thinsp;\u0026gt;\u0026thinsp;54%, unstable medications, or incomplete data. A small subset transferred from other clinics; their first qADAM on joining these services was designated baseline, mirroring real-world practice.\u003c/p\u003e \u003cp\u003eData Sources and Variables\u003c/p\u003e \u003cp\u003eExtracted data included age, weight, height, BMI, smoking/alcohol status, and medical history. TRT modalities: intramuscular or transdermal, possibly with hCG were recorded, alongside baseline/follow-up total testosterone, free testosterone, and SHBG, measured by accredited (non-centralised) labs. Dose adjustments followed clinical judgment and patient preference in private digital settings (\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eTRT Interventions\u003c/p\u003e \u003cp\u003eTRT formulations were prescribed according to the qualified and TRT trained treating clinicians\u0026rsquo; clinical judgment, patient preference, symptom severity, and biochemical profiles. Dose titrations were undertaken based on follow-up hormone levels, symptomatic changes, and clinical response. This approach mirrors real world practice patterns in private digital healthcare settings, where accessibility and patient led decision making may influence treatment choice by empowering self-care practices (\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eOutcome Measures\u003c/p\u003e \u003cp\u003ePrimary outcome was the 12-month change in total qADAM (range 10\u0026ndash;50; \u0026ge;5-point improvement\u0026thinsp;=\u0026thinsp;clinically meaningful. The qADAM scale assesses ten symptom domains associated with androgen deficiency, each component question is scored on a five-point Likert scale (1\u0026thinsp;=\u0026thinsp;terrible/weak, 3\u0026thinsp;=\u0026thinsp;average, and 5\u0026thinsp;=\u0026thinsp;excellent/strong), except for question 8 relating to falling asleep after dinner (1\u0026thinsp;=\u0026thinsp;never to 5\u0026thinsp;=\u0026thinsp;every night) and question 10 relating to perceived height loss (1\u0026thinsp;=\u0026thinsp;2\u0026Prime;, 3\u0026thinsp;=\u0026thinsp;1-1.4\u0026Prime;, and 5\u0026thinsp;=\u0026thinsp;\u0026lt;\u0026thinsp;0.4\u0026Prime; or none), generating a total range of 10\u0026ndash;50 (\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e). Secondary outcomes included subdomain changes, subgroup differences (BMI, smoking, etc.), and correlations between hormone changes (total/free testosterone, SHBG) and qADAM improvements.\u003c/p\u003e \u003cp\u003eStatistical Analyses and Sample Size\u003c/p\u003e \u003cp\u003ePrior work indicated\u0026thinsp;~\u0026thinsp;5-point qADAM improvement is clinically meaningful (SD\u0026thinsp;\u0026asymp;\u0026thinsp;10) ((\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e)), so \u0026ge;\u0026thinsp;200 participants would confer\u0026thinsp;~\u0026thinsp;80% power at p\u0026thinsp;=\u0026thinsp;0.05 (\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e, \u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e). We used paired t-tests or Wilcoxon signed-rank for within-group changes, one-way ANOVA with Tukey\u0026rsquo;s post-hoc for subgroup comparisons, and Pearson\u0026rsquo;s correlation for hormone-QoL relationships. All tests were two-sided (p\u0026thinsp;\u0026lt;\u0026thinsp;0.05). Missing data were handled by complete-case analyses and multiple imputation for sensitivity. Effect sizes, such as Cohen\u0026rsquo;s d, were computed to aid in the interpretation of clinically meaningful changes.\u003c/p\u003e \u003cp\u003eEthical and Regulatory Considerations\u003c/p\u003e \u003cp\u003eThis retrospective observational study constituted a service evaluation of routine clinical care delivered by private digital healthcare providers in the United Kingdom. Ethical approval was obtained from the Imperial College London Research Ethics Committee (ICREC number: 6990009). All data were fully anonymised prior to analysis, ensuring patient confidentiality and compliance with the UK General Data Protection Regulation (GDPR). This study adhered to ethical principles outlined in the Declaration of Helsinki. No individually identifiable information was used, and all results are presented in aggregate form. The investigation adhered to established principles of good clinical practice and respected the STROBE guidelines for observational research (\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e).\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003eA total of 1,065 men with confirmed biochemical and symptomatic testosterone deficiency completed the 12-month follow-up (Table\u0026nbsp;1). They had a mean age of 42.9\u0026thinsp;\u0026plusmn;\u0026thinsp;8.8 years, and a substantial proportion was overweight or obese. Baseline qADAM was 29.7\u0026thinsp;\u0026plusmn;\u0026thinsp;7.3, indicating a moderate symptom burden.\u003c/p\u003e \u003cp\u003eBy 12 months, mean qADAM rose by 6.64 points (95% CI 6.16\u0026ndash;7.11; p\u0026thinsp;\u0026lt;\u0026thinsp;0.0001; Cohen\u0026rsquo;s d\u0026thinsp;=\u0026thinsp;0.84), reflecting clinically meaningful overall improvement (Table\u0026nbsp;2, Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). All ten subdomains improved significantly (p\u0026thinsp;\u0026lt;\u0026thinsp;0.0001), with notable gains in libido (+\u0026thinsp;1.04), energy (+\u0026thinsp;0.94), and strength (+\u0026thinsp;0.77) (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). Men perceived better mood, erection strength, sleep, and work performance, suggesting broad symptomatic relief.\u003c/p\u003e \u003cp\u003eTotal testosterone increased by +\u0026thinsp;31.25 nmol/L (p\u0026thinsp;\u0026lt;\u0026thinsp;0.0001), though correlations between testosterone changes and qADAM were modest (r\u0026thinsp;\u0026asymp;\u0026thinsp;0.10), and free testosterone/SHBG changes showed weak or nonsignificant associations (Table\u0026nbsp;3, Figs.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e\u0026ndash;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003e). Sensitivity analyses using multiple imputation produced comparable results, indicating that greater hormone levels alone did not fully account for improvements in patient-reported outcomes (see Supplementary File A Table\u0026nbsp;1).\u003c/p\u003e \u003cp\u003eSubgroup analyses showed obese men (BMI\u0026thinsp;\u0026ge;\u0026thinsp;30) had larger qADAM gains (+\u0026thinsp;8.03 points) than those with lower BMI, and men\u0026thinsp;\u0026ge;\u0026thinsp;100 kg also derived more benefit, suggesting that higher metabolic risk may amplify symptom response (see Supplementary File B Tables\u0026nbsp;1\u0026ndash;4 for further outcomes in detail). Smoking status affected improvement magnitude, with non-smokers outperforming smokers or ex-smokers. Together, these findings highlight robust multidomain benefits from TRT while underscoring potential influences of metabolic and lifestyle factors on QoL changes.\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003ePrincipal Findings\u003c/p\u003e \u003cp\u003eThis 12-month retrospective observational study, conducted via private digital healthcare platforms, demonstrates that TRT can yield pronounced, multifaceted QoL improvements for men with biochemical and symptomatic deficiency, in line with the primary goal of TRT delivery through a digital health service. The mean qADAM increase of ~\u0026thinsp;6.6 points (CI: [6.16, 7.1], p\u0026thinsp;\u0026lt;\u0026thinsp;0.0001) exceeds established thresholds for clinical significance, indicating that men with low or borderline testosterone, rather than only those with profound hypogonadism can experience meaningful relief.\u003c/p\u003e \u003cp\u003eFurther supporting this conclusion, we observed significant increases across all ten qADAM subdomains at 12 months. Libido rose by approximately 1.04 points and energy by 0.94, suggesting that men perceived tangible benefits in sexual desire and daily motivation. Strength and endurance also improved (by 0.77), as did mood-related measures such as happiness (0.65) and life enjoyment (0.73). Participants reported better work performance (0.71) and modest yet notable gains in sleep quality (0.50) and sports ability (0.80), underscoring the broad reach of symptom relief. These increments, often exceeding the 0.5-1.0 Likert‐scale benchmark for clinical relevance, translate into real‐world improvements that men likely noticed in day‐to‐day functioning. Total testosterone levels rose significantly (+\u0026thinsp;31.25 nmol/L), although correlations with qADAM changes were generally modest, implying that biochemical normalization alone does not fully explain symptomatic gains.\u003c/p\u003e \u003cp\u003eIn addition, our subgroup findings show that men with obesity (BMI\u0026thinsp;\u0026ge;\u0026thinsp;30) and those weighing\u0026thinsp;\u0026ge;\u0026thinsp;100 kg often experienced even greater qADAM improvements, highlighting the potential synergy between metabolic compromise and the symptomatic response to TRT. Smoking status also impacted results, with non-smokers typically improving more than those who smoked or vaped, suggesting lifestyle or behavioral factors may influence outcomes. These findings complement emerging evidence endorsing a more symptom‐driven, individualised approach rather than a rigid biochemical cutoff [7, 8, 14, 20].\u003c/p\u003e \u003cp\u003eComparison with Prior Work\u003c/p\u003e \u003cp\u003eOur results align with prior randomised trials and meta-analyses showing improvements in sexual function, mood, and body composition with TRT (2, 20‐22), but also illuminate outcomes in a population often overlooked: men with borderline biochemical deficits but pronounced symptoms. Unlike many controlled studies focusing on older, overtly hypogonadal men, our cohort was younger, more proactive, and managed outside conventional healthcare pathways. The success of TRT here suggests earlier or more flexible intervention may be beneficial. While prior work has established TRT\u0026rsquo;s role in older or severely hypogonadal patients (9‐11, 18, 19), we highlight that symptomatic improvement can occur even when testosterone levels, though low are not far below traditional cutoffs (\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e). This perspective endorses a shift toward symptom‐focused care and post‐treatment total testosterone targets of 15\u0026ndash;30 nmol/L (5‐7). Thus, TRT may be appropriate for sub‐normal total testosterone (\u0026gt;\u0026thinsp;10.4 nmol/L to \u0026lt;\u0026thinsp;15 nmol/L) in men with significant symptoms (\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eInfluence of Patient Characteristics and Digital Care Models\u003c/p\u003e \u003cp\u003eSubgroup analyses show potential for tailoring interventions by demographic and lifestyle factors. Obese men achieved especially robust qADAM gains, consistent with prior evidence suggesting metabolic burdens amplify TRT benefits (\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e, \u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e, \u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e, \u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e). Similarly, non-smokers improved more, implying that modifiable behaviours and baseline risk profiles shape outcomes (\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e). The digital healthcare model, featuring prompt testing, virtual consultations, and continuous follow‐up, may have boosted engagement, adherence, and dose optimisation (\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e). This accessibility could reinforce psychosocial and behavioural factors that, though not directly measured, likely influence results (\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e). Earlier telemedicine initiatives demonstrate that remote management enhances autonomy and adherence (\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e, \u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e, \u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e), potentially amplifying QoL gains through self‐care (\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eHormone Changes and Correlates of Symptomatic Relief\u003c/p\u003e \u003cp\u003eAlthough total testosterone rose significantly, correlations with qADAM improvements were modest. Certain domains, such as libido and energy, showed weak but statistically significant associations, while most domains did not. Hence, while biochemical normalisation is important, it is not solely determinative. Psychosocial factors, enhanced patient empowerment, lifestyle changes, and other non-hormonal elements likely sustain QoL benefits. Similar complexities are noted elsewhere, where hormone levels alone fail to account fully for patient‐reported outcomes (19, 36‐38). A more holistic model, combining hormone correction with behavioural interventions, psychological support (\u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e39\u003c/span\u003e), and personalised follow‐up, may lead to more enduring improvements via self‐determination (\u003cspan citationid=\"CR40\" class=\"CitationRef\"\u003e40\u003c/span\u003e). Given that many men had low‐normal testosterone, symptom improvement cannot be attributed solely to hormone increments. Rather, psychosocial, behavioural, and adherence factors, likely strengthened by digital healthcare appear critical. This weak correlation between hormone changes and symptomatic relief aligns with growing evidence that physiological, psychological, and lifestyle factors all matter.\u003c/p\u003e \u003cp\u003eStrengths and Limitations\u003c/p\u003e \u003cp\u003eStrengths include the large sample size, broad demographics, and a year-long observation in real‐world settings. Using qADAM, a validated, multidimensional metric, provides insights into daily functioning, emotional well‐being, and physical capacity alongside sexual health. Observed qADAM gains (~\u0026thinsp;6.6 points) exceed the ~\u0026thinsp;0.5-1.0 Likert‐scale threshold often deemed clinically meaningful, suggesting palpable benefits. However, as a retrospective observational study without randomisation, selection bias and unmeasured confounding remain possible. Men opting for private digital services may differ from those in the NHS regarding literacy, resources, or motivation. Such self‐selection could limit external validity and potentially inflate estimates of benefit. Attrition bias might occur if men who perceived no benefit discontinued treatment before 12 months. Incomplete demographic data (e.g., ethnicity) and missing hormone follow‐ups, handled by complete‐case analyses, could bias results if missingness was not random. No formal confounder adjustment was performed, partly due to incomplete recording of potential mediators by the digital platforms.\u003c/p\u003e \u003cp\u003eMoreover, not all participants had baseline and follow-up hormone values, and missing qADAM subdomain data hampered detailed exploration of hormone-symptom dynamics. Relying on complete‐case analyses might introduce bias if missingness patterns were not random. Laboratory assays were not centralised; subtle differences in methodology or timing may have affected biochemical precision. We also lacked formal adherence measures and lifestyle data, such as diet, exercise, or stress, making it difficult to separate TRT effects from concurrent behavioural changes. Additionally, we did not gather comprehensive details on comorbidities or medication interactions that might affect results.\u003c/p\u003e \u003cp\u003eAnother limitation stems from reliance on qADAM as the primary outcome measure (\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e). While the qADAM scale refines the original ADAM questionnaire by using 1\u0026ndash;5 Likert scoring, it remains rooted in ADAM\u0026rsquo;s core questions (\u003cspan citationid=\"CR41\" class=\"CitationRef\"\u003e41\u003c/span\u003e). It may not always distinguish testosterone deficiency from overlapping conditions like hypothyroidism, type 2 diabetes, or depression (\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e). Also, qADAM\u0026rsquo;s sensitivity for detecting incremental clinical improvements over time is not conclusively established. Subjective judgments can introduce reporting biases if patients expect or want positive results. Without objective performance markers or biomarkers (mood, metabolic status, inflammation), it is challenging to confirm subjective gains. Finally, the retrospective design hindered consistent follow-up intervals, precise dose‐titration monitoring, and structured psychosocial support to identify optimal combined interventions.\u003c/p\u003e \u003cp\u003eImplications for Practice and Research\u003c/p\u003e \u003cp\u003eThese findings underscore the value of a flexible, symptom oriented strategy for diagnosing and treating testosterone deficiency, highlighting digital healthcare\u0026rsquo;s potential to broaden access and reinforce patient engagement. Clinicians might consider earlier intervention in borderline biochemical cases if symptom burdens are substantial, especially through digital services supporting adherence and lifestyle adjustments. Future work should probe hormonal, psychosocial, and behavioural interplays, identify who responds best, and test combined interventions (pharmacotherapy with lifestyle coaching or mental health support). Such approaches could refine patient selection, optimally dose TRT, and produce more durable, meaningful QoL gains. Prospectively controlled trials employing wearable technologies, dietary tracking, or validated mental health tools would also strengthen causal inferences and clarify which subgroups experience the greatest long-term benefit.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eIn summary, our study shows that men with low or borderline testosterone managed through private digital healthcare can achieve marked, sustained improvements in multidimensional QoL over 12 months of TRT. By demonstrating clinically significant qADAM gains, elucidating responsive patient subgroups, and revealing only modest hormone to symptom correlations, these results advocate a patient-centred, symptom focused paradigm. They may inform future guidelines, shape research agendas, prospective trials and ultimately enhance care for men with testosterone deficiency.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eData Availability\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eDue to the nature of the clinical data collected and the consent provided by patients, the individual participant data used in this study is not publicly available. The statistical code used in the analyses can be made available to researchers upon request to the corresponding author. Requests for access to anonymized data for noncommercial projects should be directed to the corresponding author and will require appropriate ethical approvals.\u003c/p\u003e\n\u003cp\u003eAuthor Contributions\u003c/p\u003e\n\u003cp\u003eAll authors contributed to the conception and design of the study. HJ performed data extraction and analysis. HJ,DH,AKC,JF and AO interpreted the results. All authors drafted the manuscript, critically reviewed it, and approved the final version for publication.\u003c/p\u003e\n\u003cp\u003eFunding\u003c/p\u003e\n\u003cp\u003eNo external funding was received for this study. The research was conducted as part of routine service evaluation activities within the institution. The research was conducted as part of routine service evaluation activities within the organization. AO is supported by the National Institute for Health and Care Research (NIHR) Applied Research Collaboration (ARC) Northwest London. The views expressed are those of the authors and not necessarily those of the NHS, the NIHR or the Department of Health and Social Care.\u003c/p\u003e\n\u003cp\u003eEthical Approval\u003c/p\u003e\n\u003cp\u003eThis retrospective observational study constituted a service evaluation of routine clinical care delivered by private digital healthcare providers in the United Kingdom. Ethical approval was obtained from the Imperial College London Research Ethics Committee (ICREC number: 6990009). All data were fully anonymised prior to analysis, ensuring patient confidentiality and compliance with the UK General Data Protection Regulation (GDPR). This study adhered to ethical principles outlined in the Declaration of Helsinki. \u0026nbsp; No individually identifiable information was used, and all results are presented in aggregate form. The investigation adhered to established principles of good clinical practice.\u003c/p\u003e\n\u003cp\u003eCompeting Interests\u003c/p\u003e\n\u003cp\u003eThe authors HJ, AKC, DH, JF are employed by Menwell\u003csup\u003eTM\u003c/sup\u003e (T/a Manual). AO declared no conflict of interest.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eHandelsman DJ, Wittert GA. Testosterone and Depression Symptoms in Aging Men. The Journal of Clinical Endocrinology \u0026amp; Metabolism. 2024:dgae093.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eYang HJ, Kim KH, Kim DS, Lee CH, Jeon YS, Shim SR, et al. The Effect of Testosterone Replacement on Sexual Function in the Elderly: A Systematic Review and Meta-Analysis. The World Journal of Men's Health. 2023;41(4):861.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eNguyen Hoai B, Hoang L, Nguyen Cao T, Pham Minh Q, A. Jannini E. Testosterone and aging male, a perspective from a developing country. The Aging Male. 2023;26(1):2223712.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGrossmann M, Robledo KP, Daniel M, Handelsman DJ, Inder WJ, Stuckey BG, et al. Testosterone treatment, weight loss, and health-related quality of life and psychosocial function in men: a 2-year randomized controlled trial. The Journal of Clinical Endocrinology \u0026amp; Metabolism. 2024;109(8):2019\u0026ndash;28.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHackett G, Kirby M, Rees RW, Jones TH, Muneer A, Livingston M, et al. The British Society for Sexual Medicine Guidelines on Male Adult Testosterone Deficiency, with Statements for Practice. World J Mens Health. 2023;41(3):508\u0026ndash;37.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eCorona G, Goulis DG, Huhtaniemi I, Zitzmann M, Toppari J, Forti G, et al. European Academy of Andrology (EAA) guidelines on investigation, treatment and monitoring of functional hypogonadism in males: Endorsing organization: European Society of Endocrinology. Andrology. 2020;8(5):970\u0026ndash;87.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBhasin S, Brito JP, Cunningham GR, Hayes FJ, Hodis HN, Matsumoto AM, et al. Testosterone Therapy in Men With Hypogonadism: An Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab. 2018;103(5):1715\u0026ndash;44.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eRamasamy R, Golan R, Wilken N, Scovell JM, Lipshultz LI. Association of free testosterone with hypogonadal symptoms in men with near-normal total testosterone levels. Urology. 2015;86(2):287\u0026ndash;90.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eRamasamy R, Scovell JM, Lipshultz L. The Influence of Testosterone Replacement Therapy in Older Men: An Age and Comorbidity Matched Cohort Study. Journal of the American College of Surgeons. 2014;219(3):S148-S9.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eTsujimura A. The Relationship between Testosterone Deficiency and Men's Health. World J Mens Health. 2013;31(2):126\u0026ndash;35.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWu FC, Tajar A, Pye SR, Silman AJ, Finn JD, O'Neill TW, et al. Hypothalamic-pituitary-testicular axis disruptions in older men are differentially linked to age and modifiable risk factors: the European Male Aging Study. The Journal of Clinical Endocrinology \u0026amp; Metabolism. 2008;93(7):2737\u0026ndash;45.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWang C, Jackson G, Jones TH, Matsumoto AM, Nehra A, Perelman MA, et al. Low testosterone associated with obesity and the metabolic syndrome contributes to sexual dysfunction and cardiovascular disease risk in men with type 2 diabetes. Diabetes care. 2011;34(7):1669\u0026ndash;75.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eAllan CA, McLachlan RI. Androgens and obesity. Curr Opin Endocrinol Diabetes Obes. 2010;17(3):224\u0026ndash;32.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eReddy AV, Kesavan R, Priyadharsini R, Deva R. Unlocking the therapeutic potential and personalized therapy of testosterone: a comprehensive review. Drug Metab Pers Ther. 2024.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eRivas AM, Mulkey Z, Lado-Abeal J, Yarbrough S. Diagnosing and managing low serum testosterone. Proc (Bayl Univ Med Cent). 2014;27(4):321\u0026ndash;4.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eDubin JM, Fantus RJ, Halpern JA. Testosterone replacement therapy in the era of telemedicine. International Journal of Impotence Research. 2022;34(7):663\u0026ndash;8.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eJesse E, Sellke N, Muncey W, Ghayda R, Loeb A, Thirumavalavan N. 27 Cost Analysis of Online Telehealth Platforms Offering Testosterone Therapy. The Journal of Sexual Medicine. 2022;19(Supplement_1):S14-S5.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eCorona G, Mannucci E, Ricca V, Lotti F, Boddi V, Bandini E, et al. The age-related decline of testosterone is associated with different specific symptoms and signs in patients with sexual dysfunction. International journal of andrology. 2009;32(6):720\u0026ndash;8.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eScovell JM, Ramasamy R, Wilken N, Kovac JR, Lipshultz LI. Hypogonadal symptoms in young men are associated with a serum total testosterone threshold of 400 ng/dL. BJU international. 2015;116(1):142\u0026ndash;6.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eCorona G, Rastrelli G, Maggi M. Diagnosis and treatment of late-onset hypogonadism: systematic review and meta-analysis of TRT outcomes. Best Pract Res Clin Endocrinol Metab. 2013;27(4):557\u0026ndash;79.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGrossmann M, Robledo KP, Daniel M, Handelsman DJ, Inder WJ, Stuckey BGA, et al. Testosterone Treatment, Weight Loss, and Health-related Quality of Life and Psychosocial Function in Men: A 2-year Randomized Controlled Trial. J Clin Endocrinol Metab. 2024;109(8):2019\u0026ndash;28.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSnyder PJ, Bhasin S, Cunningham GR, Matsumoto AM, Stephens-Shields AJ, Cauley JA, et al. Effects of Testosterone Treatment in Older Men. N Engl J Med. 2016;374(7):611\u0026ndash;24.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMohamed O, Freundlich R, Dakik H, Grober E, Najari B, Lipshultz L, et al. The quantitative ADAM questionnaire: a new tool in quantifying the severity of hypogonadism. International journal of impotence research. 2010;22(1):20\u0026ndash;4.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSvartberg J, Jorde R. Endogenous testosterone levels and smoking in men. The fifth Troms\u0026oslash; study. International journal of andrology. 2007;30(3):137\u0026ndash;43.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMangolim AS, Brito LdAR, Nunes-Nogueira VdS. Effectiveness of testosterone replacement in men with obesity: a systematic review and meta-analysis. European journal of endocrinology. 2022;186(1):123\u0026ndash;35.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eShin YS, You JH, Cha JS, Park JK. The relationship between serum total testosterone and free testosterone levels with serum hemoglobin and hematocrit levels: a study in 1221 men. The Aging Male. 2016;19(4):209\u0026ndash;14.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eCorona G, Goulis DG, Huhtaniemi I, Zitzmann M, Toppari J, Forti G, et al. European Academy of Andrology (EAA) guidelines on investigation, treatment and monitoring of functional hypogonadism in males: Endorsing organization: European Society of Endocrinology. Andrology. 2020;8(5):970\u0026ndash;87.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eVon Elm E, Altman DG, Egger M, Pocock SJ, G\u0026oslash;tzsche PC, Vandenbroucke JP. The Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) statement: guidelines for reporting observational studies. The lancet. 2007;370(9596):1453\u0026ndash;7.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eN\u0026aacute;fr\u0026aacute;di L, Nakamoto K, Schulz PJ. Is patient empowerment the key to promote adherence? A systematic review of the relationship between self-efficacy, health locus of control and medication adherence. PLoS One. 2017;12(10):e0186458.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLee T-W, Kao P-Y, Chen Y-C, Wang S-T. Effects of Testosterone Replacement Therapy on Muscle Strength in Older Men with Low to Low-Normal Testosterone Levels: A Systematic Review and Meta-Analysis. Gerontology. 2023;69(10):1157\u0026ndash;66.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHudson J, Cruickshank M, Quinton R, Aucott L, Wu F, Grossmann M, et al. Symptomatic benefits of testosterone treatment in patient subgroups: a systematic review, individual participant data meta-analysis, and aggregate data meta-analysis. Lancet Healthy Longev. 2023;4(10):e561-e72.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBraga PC, Pereira SC, Ribeiro JC, Sousa M, Monteiro MP, Oliveira PF, et al. Late-onset hypogonadism and lifestyle-related metabolic disorders. Andrology. 2020;8(6):1530\u0026ndash;8.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMilne-Ives M, Homer S, Andrade J, Meinert E. The conceptualisation and measurement of engagement in digital health. Internet Interventions. 2024;36:100735.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eTan SY, Sumner J, Wang Y, Wenjun Yip A. A systematic review of the impacts of remote patient monitoring (RPM) interventions on safety, adherence, quality-of-life and cost-related outcomes. NPJ Digital Medicine. 2024;7(1):192.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eEl-Osta A, Webber D, Gnani S, Banarsee R, Mummery D, Majeed A, et al. The self-care matrix: a unifying framework for self-Care.-Selfcare Journal. SelfCare Journal. 2019.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eZitzmann M. Testosterone, mood, behaviour and quality of life. Andrology. 2020;8(6):1598\u0026ndash;605.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eShigehara K, Konaka H, Koh E, Izumi K, Kitagawa Y, Mizokami A, et al. Effects of testosterone replacement therapy on nocturia and quality of life in men with hypogonadism: a subanalysis of a previous prospective randomized controlled study in Japan. The Aging Male. 2015;18(3):169\u0026ndash;74.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eRosen RC, Wu F, Behre HM, Porst H, Meuleman EJ, Maggi M, et al. Quality of life and sexual function benefits of long-term testosterone treatment: longitudinal results from the registry of hypogonadism in men (RHYME). The journal of sexual medicine. 2017;14(9):1104\u0026ndash;15.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eJayasena CN, Anderson RA, Llahana S, Barth JH, MacKenzie F, Wilkes S, et al. Society for Endocrinology guidelines for testosterone replacement therapy in male hypogonadism. Clinical endocrinology. 2022;96(2):200\u0026ndash;19.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eNtoumanis N, Ng JY, Prestwich A, Quested E, Hancox JE, Th\u0026oslash;gersen-Ntoumani C, et al. A meta-analysis of self-determination theory-informed intervention studies in the health domain: Effects on motivation, health behavior, physical, and psychological health. Health psychology review. 2021;15(2):214\u0026ndash;44.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMorley JE, Charlton E, Patrick P, Kaiser F, Cadeau P, McCready D, et al. Validation of a screening questionnaire for androgen deficiency in aging males. Metabolism. 2000;49(9):1239\u0026ndash;42.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003eTables 1 to 3 are available in the Supplementary Files section.\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"","lastPublishedDoi":"10.21203/rs.3.rs-6246872/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-6246872/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eMen with borderline or low-normal total testosterone often experience androgen-deficiency symptoms. While testosterone replacement therapy (TRT) benefits overt hypogonadism, its long-term effect on quality of life (QoL) in borderline cases, particularly via remote digital care, remains unclear.\u003c/p\u003e\n\u003cp\u003eWe retrospectively studied 1065 men (mean age 42.9±8.8 years) with total testosterone \u0026lt;15 nmol/L and clinical symptoms, managed through UK digital healthcare providers. QoL was assessed over 12 months using the quantitative Androgen Deficiency in the Ageing Male (qADAM) scale (range 10-50; ≥5-point increase considered clinically meaningful). Changes in qADAM were analySed with paired t-tests; subgroup differences (e.g., BMI) used one-way ANOVA, and correlations (testosterone, free testosterone, SHBG) were evaluated via Pearson’s tests.\u003c/p\u003e\n\u003cp\u003eMean qADAM increased by 6.64 points (95% CI: 6.16, 7.11; p\u0026lt;0.0001), with significant improvements across libido, energy, and other domains. Obese men (BMI≥30) had larger gains (+8.03 points) than normal-weight men, and those ≥100 kg improved by 8.22 points. While total testosterone rose by 31.25 nmol/L (p\u0026lt;0.0001), correlations between testosterone changes and qADAM were modest.\u003c/p\u003e\n\u003cp\u003eIn this real-world digital setting, TRT yielded clinically meaningful, multidomain QoL benefits for men with borderline testosterone levels. Future prospective research incorporating broader demographics and confounders will help optimize individualized TRT strategies.\u003c/p\u003e","manuscriptTitle":"Longitudinal Improvements in Quality of Life Following Testosterone Replacement Therapy in Men with Biochemical and Symptomatic Testosterone Deficiency: a 12 Month Retrospective Observational Study in a Remote Digital Healthcare Setting in the United Kingdom","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-03-31 08:57:11","doi":"10.21203/rs.3.rs-6246872/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"1f627ecf-3830-4f5e-a572-713e8d644633","owner":[],"postedDate":"March 31st, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[{"id":45872790,"name":"Health sciences/Health care/Quality of life"},{"id":45872791,"name":"Health sciences/Signs and symptoms/Reproductive signs and symptoms"}],"tags":[],"updatedAt":"2025-08-29T11:26:02+00:00","versionOfRecord":[],"versionCreatedAt":"2025-03-31 08:57:11","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-6246872","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-6246872","identity":"rs-6246872","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}