Testosterone replacement therapy (TRT) is a cornerstone treatment for men with clinically confirmed hypogonadism, yet many patients benefit from a broader therapeutic approach. Can TRT be combined with other treatments for low testosterone? Yes—combining TRT with lifestyle modifications, medications for comorbidities, and targeted interventions often yields superior outcomes compared to hormonal replacement alone. This multimodal strategy addresses underlying causes, manages associated conditions such as obesity and diabetes, and optimises symptom relief. UK guidance emphasises treating the whole patient, not just testosterone levels. Understanding safe combinations, monitoring requirements, and potential interactions is essential for clinicians and patients alike.

Understanding Testosterone Replacement Therapy and Low Testosterone

Testosterone replacement therapy (TRT) is a medical treatment prescribed for men diagnosed with hypogonadism, a condition characterised by abnormally low testosterone levels. Hypogonadism can be primary (testicular failure) or secondary (hypothalamic-pituitary dysfunction), and symptoms may include reduced libido, erectile dysfunction, fatigue, decreased muscle mass, mood disturbances, and reduced bone density. Diagnosis requires biochemical confirmation—typically two early-morning total testosterone measurements on separate days—and the presence of clinical symptoms. UK guidelines generally recommend treatment if levels are below 8 nmol/L, while levels between 8-12 nmol/L are considered borderline and require assessment of free testosterone and clinical symptoms.

TRT aims to restore testosterone levels to the normal physiological range, thereby alleviating symptoms and improving quality of life. Available formulations in the UK include transdermal gels (Testogel, Tostran, Testavan) and intramuscular injections (Sustanon, Nebido). The choice of formulation depends on patient preference, lifestyle factors, cost considerations, and individual response to treatment. TRT works by supplementing endogenous testosterone production, which may be diminished due to ageing, testicular disease, pituitary disorders, or other medical conditions.

Whilst TRT effectively addresses hormonal deficiency, it does not treat underlying causes of hypogonadism or associated conditions that may contribute to symptoms. Many men with low testosterone also present with comorbidities such as obesity, type 2 diabetes, metabolic syndrome, or cardiovascular risk factors. Additionally, lifestyle factors including poor diet, sedentary behaviour, inadequate sleep, and chronic stress can negatively impact testosterone levels and treatment outcomes. Consequently, a comprehensive approach that addresses multiple contributing factors may optimise therapeutic benefits and improve overall health outcomes for men with hypogonadism.

TRT is contraindicated in men with prostate or male breast cancer, severe heart failure, untreated severe obstructive sleep apnoea, haematocrit >0.54, or those desiring fertility. When using testosterone gel, patients must take precautions to prevent transfer to women and children by applying to clean, dry skin, allowing it to dry completely, covering the application site with clothing, and washing hands thoroughly after application.

Can TRT Be Combined with Other Treatments for Low Testosterone?

Yes, TRT can be safely combined with other treatments and interventions for low testosterone, and in many cases, a multimodal approach is recommended to optimise outcomes. The decision to combine therapies depends on the underlying cause of hypogonadism, the presence of comorbidities, treatment goals, and individual patient factors. NICE guidance emphasises the importance of addressing modifiable risk factors and treating associated conditions alongside hormonal replacement.

For men with secondary hypogonadism who wish to preserve fertility, TRT is contraindicated as it suppresses gonadotrophin production and spermatogenesis. In these cases, alternative treatments such as human chorionic gonadotrophin (hCG) or gonadotrophin therapy may be used instead of TRT. These specialist-initiated medications stimulate endogenous testosterone production whilst maintaining testicular function and fertility potential. Once fertility is no longer a concern, patients may transition to conventional TRT.

Combining TRT with treatments for erectile dysfunction is common and generally safe. Phosphodiesterase-5 (PDE5) inhibitors such as sildenafil, tadalafil, or vardenafil can be prescribed alongside TRT for men whose erectile function does not fully improve with testosterone replacement alone. However, PDE5 inhibitors are absolutely contraindicated in patients taking nitrates or riociguat due to potentially dangerous drops in blood pressure, and caution is needed with alpha-blockers. Studies suggest that combined therapy may be more effective than either treatment in isolation for men with both hypogonadism and erectile dysfunction.

Additionally, addressing underlying medical conditions that contribute to low testosterone—such as obesity, diabetes, obstructive sleep apnoea, or depression—is essential. Treating these conditions with appropriate medications, alongside TRT, can enhance treatment efficacy and improve overall health. However, careful monitoring is required to identify potential drug interactions and ensure patient safety when multiple medications are prescribed concurrently.

Lifestyle Modifications to Support TRT Effectiveness

Lifestyle modifications are fundamental components of managing low testosterone and should be implemented alongside TRT to maximise therapeutic benefits. Evidence demonstrates that certain lifestyle factors significantly influence testosterone levels, treatment response, and overall health outcomes. Weight loss is particularly important for overweight or obese men, as adipose tissue contains aromatase enzyme, which converts testosterone to oestradiol, potentially reducing the effectiveness of TRT. Studies show that losing 5-10% of body weight can significantly increase endogenous testosterone production.

Regular physical activity is strongly recommended, with both resistance training and aerobic exercise showing beneficial effects on testosterone levels and body composition. Resistance training, in particular, stimulates testosterone production and helps build muscle mass, which may be compromised in hypogonadal men. UK Chief Medical Officers' guidelines recommend at least 150 minutes of moderate-intensity aerobic activity or 75 minutes of vigorous-intensity activity weekly, combined with strength training on two or more days per week.

Sleep optimisation is crucial, as testosterone production follows a circadian rhythm with peak levels occurring during sleep. Men with obstructive sleep apnoea (OSA) frequently have low testosterone. While treating OSA with continuous positive airway pressure (CPAP) therapy is essential for cardiometabolic health and symptom improvement, its effects specifically on testosterone levels are uncertain. Aiming for 7-9 hours of quality sleep nightly supports hormonal balance and enhances TRT effectiveness.

Nutritional interventions should focus on a balanced diet rich in whole foods, adequate protein, healthy fats, and micronutrients. Supplementation with zinc, vitamin D, and magnesium should only be considered if deficiencies are confirmed through testing. Limiting alcohol consumption to no more than 14 units per week, spread over three or more days, and stopping smoking are also important, as both negatively impact testosterone levels and cardiovascular health. The NHS offers support services for smoking cessation. Stress management through mindfulness, cognitive behavioural techniques, or counselling can reduce cortisol levels, which inversely affect testosterone production. These lifestyle modifications work synergistically with TRT to improve symptoms, metabolic health, and quality of life.

Medications That May Be Used Alongside TRT

Several medications may be appropriately prescribed alongside TRT to address specific symptoms, comorbidities, or treatment-related effects. Phosphodiesterase-5 inhibitors (sildenafil, tadalafil, vardenafil) are commonly co-prescribed for erectile dysfunction that persists despite adequate testosterone replacement. These medications enhance nitric oxide-mediated vasodilation in penile tissue and are generally safe when used with TRT, though patients should be counselled about potential side effects including headache, flushing, and visual disturbances. They are absolutely contraindicated with nitrates or riociguat and require caution with alpha-blockers. Patients should seek urgent medical attention for chest pain, sudden vision or hearing loss.

Aromatase inhibitors such as anastrozole are occasionally used off-label in men on TRT who develop symptoms of oestrogen excess (gynaecomastia, fluid retention) due to peripheral conversion of testosterone to oestradiol. However, their use remains controversial and should be reserved for specific cases under specialist supervision, as excessive oestrogen suppression may adversely affect bone health and lipid profiles. Regular bone mineral density and lipid monitoring is required. Adjusting the TRT dose or formulation should be considered before adding an aromatase inhibitor.

5-alpha reductase inhibitors (finasteride, dutasteride) are sometimes prescribed for benign prostatic hyperplasia or male pattern baldness in men receiving TRT. These medications reduce the conversion of testosterone to dihydrotestosterone (DHT) and lower PSA values by approximately 50%, which must be considered when interpreting PSA results. While generally compatible with TRT, they may cause sexual side effects and require monitoring. Prostate cancer risk should still be assessed with appropriate PSA interpretation and digital rectal examination.

Medications for comorbidities—including antihypertensives, statins, metformin, and antidepressants—can be safely continued alongside TRT. However, clinicians should be aware of potential interactions and monitor treatment response. While TRT may have secondary effects on insulin sensitivity in diabetic patients, it is not indicated for glycaemic control, and antidiabetic medication adjustments should be based on standard monitoring. Human chorionic gonadotrophin (hCG) may be added to TRT regimens to maintain testicular size and function, typically administered as subcutaneous injections 1-3 times weekly. This off-label combination approach requires specialist oversight. For fertility preservation, specialist-led regimens using hCG with follicle-stimulating hormone or human menopausal gonadotrophin are typically required rather than TRT.

Safety Considerations When Combining Treatments

Combining TRT with other treatments requires careful consideration of potential interactions, contraindications, and adverse effects. Cardiovascular safety is paramount, as TRT may increase haematocrit and red blood cell mass, potentially elevating thrombotic risk. Men with pre-existing cardiovascular disease, uncontrolled hypertension, or polycythaemia require particularly careful assessment before initiating TRT. When combining TRT with antihypertensive medications or anticoagulants, regular monitoring of blood pressure, haematocrit, and coagulation parameters is essential. If haematocrit exceeds 0.54, dose reduction, formulation change, treatment pause, or venesection may be required.

Prostate health monitoring is crucial when TRT is used alongside medications for benign prostatic hyperplasia. Whilst current evidence does not support a causal relationship between TRT and prostate cancer development, testosterone can stimulate growth of existing prostate malignancies. Baseline prostate-specific antigen (PSA) measurement and digital rectal examination should be performed before initiating TRT, with regular monitoring thereafter. Referral to urology is indicated for abnormal digital rectal examination or age-specific PSA elevation per NICE guidance. Men with known or suspected prostate cancer should not receive TRT.

Drug interactions must be considered when combining treatments. TRT may enhance the effects of anticoagulants such as warfarin, necessitating more frequent INR monitoring and potential dose adjustments. Corticosteroids used concurrently with TRT may increase fluid retention risk. Some medications, including opioids and glucocorticoids, can suppress endogenous testosterone production and may reduce TRT effectiveness.

Obstructive sleep apnoea may be worsened by TRT. Screening for OSA symptoms should be performed before starting treatment, and existing OSA should be adequately treated alongside TRT. Fertility preservation is a critical consideration for men of reproductive age. TRT suppresses gonadotrophin secretion, leading to reduced or absent spermatogenesis. Men wishing to father children should be counselled about fertility preservation options, including sperm banking before TRT initiation or using specialist-prescribed alternative treatments that maintain testicular function. Polypharmacy risks increase with multiple concurrent medications, particularly in older men. Regular medication reviews help identify unnecessary treatments, potential interactions, and opportunities to optimise therapy. Patients should be advised to inform all healthcare providers about their TRT use to ensure coordinated care and safe prescribing practices.

Monitoring and Optimising Combined Treatment Approaches

Effective monitoring is essential when combining TRT with other treatments to ensure safety, optimise therapeutic outcomes, and identify potential complications early. Baseline assessments before initiating TRT should include two morning testosterone measurements, luteinising hormone (LH), follicle-stimulating hormone (FSH), sex hormone binding globulin (SHBG), prolactin, full blood count, PSA, liver function tests, lipid profile, and assessment of cardiovascular risk factors. For men receiving combined therapies, additional baseline investigations may be warranted depending on comorbidities and concurrent medications.

Follow-up monitoring should occur at 3 months after TRT initiation, then 6-12 monthly thereafter, or more frequently if clinically indicated. Key parameters include testosterone levels (measured at trough for injections or at steady-state for gels), haematocrit, PSA, liver function, and lipid profile. Men on combined treatments may require additional monitoring specific to their other medications—for example, HbA1c for diabetic patients or INR for those on warfarin. Note that 5-alpha reductase inhibitors reduce PSA by approximately 50% after 6 months of use, which must be considered when interpreting results. Symptom assessment using validated questionnaires can help evaluate treatment response and guide dose adjustments.

Dose optimisation of TRT aims to achieve testosterone levels in the mid-normal range (15-25 nmol/L) whilst minimising adverse effects. When symptoms persist despite adequate testosterone levels, clinicians should reassess for other contributing factors, consider adjusting concurrent medications, or evaluate lifestyle factors. Conversely, if testosterone levels are supraphysiological or adverse effects occur, dose reduction is warranted. If haematocrit exceeds 0.54, dose adjustment, formulation change, or temporary discontinuation may be necessary.

Patient education is fundamental to successful combined treatment approaches. Men should understand the purpose of each treatment, potential interactions, warning signs requiring medical attention (chest pain, leg swelling, breathing difficulties, urinary symptoms), and the importance of adherence to both medications and lifestyle modifications. Patients should be encouraged to report suspected side effects to the MHRA Yellow Card scheme. Shared decision-making ensures treatment plans align with patient preferences, goals, and values. Regular review appointments provide opportunities to assess treatment satisfaction, address concerns, and adjust therapeutic strategies as needed.

Red flags requiring urgent GP contact include: persistent or worsening symptoms despite treatment, signs of cardiovascular complications, urinary difficulties, mood changes, or any concerning side effects from medications. Specialist endocrinology referral may be appropriate for complex cases, treatment-resistant hypogonadism, very low testosterone levels, elevated prolactin, visual symptoms, severe headaches, testicular masses, or when fertility preservation is required. Urology referral is indicated for abnormal digital rectal examination or concerning PSA changes.

Frequently Asked Questions