Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a debilitating long-term condition characterised by profound fatigue and post-exertional malaise. Some patients and clinicians have explored testosterone cypionate treatment in the hope of alleviating symptoms, particularly when hormonal imbalances are suspected. However, testosterone cypionate is not licensed in the UK for ME/CFS, and there is no robust evidence supporting its use for this condition. This article examines the relationship between ME/CFS and testosterone, the role of testosterone cypionate, potential risks and benefits, NHS prescribing guidance, and evidence-based alternatives aligned with NICE recommendations.

Understanding ME/CFS and Hormonal Imbalances

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a complex, long-term condition characterised by profound fatigue that does not improve with rest and worsens after physical or mental exertion—a phenomenon known as post-exertional malaise (PEM). The condition affects multiple body systems, including the immune, neurological, and endocrine systems, and can significantly impair daily functioning.

Research has identified various physiological abnormalities in people with ME/CFS, including potential disruptions to the hypothalamic-pituitary-adrenal (HPA) axis and hypothalamic-pituitary-gonadal (HPG) axis. These neuroendocrine pathways regulate the production of hormones, including cortisol, thyroid hormones, and sex hormones such as testosterone. Some studies have reported lower-than-average testosterone levels in both male and female patients with ME/CFS, though findings remain inconsistent and the clinical significance is not fully established. These hormonal findings are preliminary and their role in ME/CFS pathophysiology remains uncertain.

Hormonal imbalances may contribute to symptoms such as fatigue, reduced muscle mass, cognitive difficulties, and mood disturbances. However, it is important to note that there is no established link confirming that testosterone deficiency is a primary cause of ME/CFS, nor that correcting testosterone levels will resolve the condition. The relationship between hormones and ME/CFS symptoms is likely multifactorial, involving immune dysregulation, mitochondrial dysfunction, and autonomic nervous system abnormalities.

Patients experiencing persistent fatigue alongside other symptoms—such as unrefreshing sleep, orthostatic intolerance, or cognitive impairment—should consult their GP for a thorough assessment. Diagnosis of ME/CFS follows NICE guideline NG206 (2021), which recommends a positive diagnosis based on the presence of core features for at least three months: post-exertional malaise, unrefreshing sleep, cognitive difficulties, and orthostatic intolerance. Appropriate investigations should be undertaken to exclude alternative explanations for symptoms, such as thyroid disorders, anaemia, coeliac disease, or sleep apnoea. Further information and support can be found on the NHS ME/CFS overview page and through local specialist ME/CFS services where available.

What Is Testosterone Cypionate and How Does It Work?

Testosterone cypionate is a synthetic form of testosterone, the primary male sex hormone (androgen), administered via intramuscular injection. It is classified as a long-acting ester of testosterone, typically requiring administration every one to two weeks, providing sustained hormone levels and reducing the frequency of injections compared to shorter-acting formulations.

Testosterone cypionate is not routinely licensed in the UK. Commonly used licensed testosterone preparations in the UK include testosterone undecanoate (Nebido) for intramuscular injection, mixed testosterone esters (Sustanon), and transdermal gels (e.g., Testogel, Tostran). If testosterone cypionate were to be considered, it would be as an unlicensed import, requiring strict governance under GMC and Specialist Pharmacy Service (SPS) guidance for prescribing unlicensed medicines, with appropriate documentation and informed consent.

In the body, testosterone plays crucial roles in maintaining muscle mass and strength, bone density, red blood cell production, libido, mood regulation, and cognitive function. Testosterone replacement therapy (TRT) works by supplementing endogenous (naturally produced) testosterone when levels are clinically low—a condition known as hypogonadism. Once administered, the ester is cleaved by enzymes, releasing free testosterone that binds to androgen receptors in various tissues, exerting its physiological effects.

In the UK, TRT is licensed for the treatment of male hypogonadism, where there is biochemical evidence of testosterone deficiency accompanied by relevant clinical symptoms such as reduced libido, erectile dysfunction, fatigue, and loss of muscle mass. Diagnosis requires two early-morning serum testosterone measurements (taken between 7 and 11 am on separate occasions). Total testosterone below 8 nmol/L generally indicates hypogonadism; levels between 8 and 12 nmol/L are considered borderline and require assessment of sex hormone-binding globulin (SHBG) and calculation of free or bioavailable testosterone, alongside clinical correlation. Luteinising hormone (LH) and follicle-stimulating hormone (FSH) should be measured to differentiate primary (testicular) from secondary (hypothalamic-pituitary) hypogonadism.

Testosterone cypionate is not licensed or indicated for the treatment of ME/CFS. Its use in this context would be considered off-label and should only be contemplated if there is documented hypogonadism independent of the ME/CFS diagnosis. The pharmacological action of testosterone does not address the underlying pathophysiology of ME/CFS, which involves immune, neurological, and metabolic dysfunction rather than simple hormonal deficiency. Patients considering any hormonal intervention should have a comprehensive endocrine assessment and discuss potential benefits and risks with an appropriately qualified specialist, typically an endocrinologist. Further guidance is available in NICE Clinical Knowledge Summaries (CKS) on testosterone deficiency in adult men and the British Society for Sexual Medicine (BSSM) guideline on adult testosterone deficiency.

Potential Benefits and Risks in ME/CFS Patients

The potential benefits of testosterone therapy in ME/CFS patients remain largely theoretical and unproven, with no high-quality evidence supporting its use specifically for this condition. In men with confirmed hypogonadism, testosterone replacement can improve energy levels, muscle strength, mood, and cognitive function—symptoms that overlap with ME/CFS. However, any perceived benefits are likely limited to the subset of patients with concurrent, independently diagnosed testosterone deficiency.

Some patients and clinicians have explored testosterone therapy in the hope of alleviating fatigue and improving physical function. However, post-exertional malaise (PEM), the hallmark feature of ME/CFS, is unlikely to respond to hormonal manipulation alone. Testosterone may theoretically support muscle anabolism and stamina, but without addressing the core pathophysiology—such as mitochondrial dysfunction, immune dysregulation, or autonomic abnormalities—symptomatic improvement is uncertain and may be modest at best.

Risks and adverse effects of testosterone therapy include:

• Cardiovascular and blood pressure concerns: Increased risk of hypertension, polycythaemia (elevated red blood cell count), and potential thromboembolic events. The MHRA has issued Drug Safety Updates regarding cardiovascular risk and the need for blood pressure monitoring, particularly in older men and those with pre-existing cardiovascular disease.

• Polycythaemia: Elevated haematocrit (>54%) requires dose adjustment or temporary cessation of therapy. Regular monitoring of full blood count is essential.

• Prostate health: Testosterone can stimulate prostate tissue, necessitating monitoring for benign prostatic hyperplasia (BPH) and prostate-specific antigen (PSA) levels, with digital rectal examination (DRE) where appropriate. It is contraindicated in prostate or breast cancer. Referral to urology is indicated for significant PSA rise or abnormal DRE findings.

• Common adverse effects: Acne and oily skin, gynaecomastia (breast enlargement), fluid retention and oedema, hair loss, exacerbation of obstructive sleep apnoea (OSA), and injection-site reactions.

• Mood and behavioural changes: Aggression, irritability, or mood swings may occur.

• Suppression of natural testosterone production: Exogenous testosterone suppresses the HPG axis, reducing endogenous production and potentially causing testicular atrophy and infertility. Men actively trying to conceive should avoid TRT and be referred to andrology for alternative management.

• Hepatotoxicity: Significant hepatic toxicity is mainly associated with 17-alpha-alkylated oral androgens and is uncommon with injectable testosterone esters. However, liver function should be monitored as part of routine follow-up.

In women, testosterone use (off-label and not licensed in the UK for this indication) carries additional risks, including virilisation (deepening voice, facial hair, clitoral enlargement) and menstrual irregularities. Testosterone is contraindicated in pregnancy and breastfeeding due to risk of virilisation of the foetus or infant.

Given these risks and the lack of evidence supporting efficacy in ME/CFS, testosterone therapy should only be considered when there is clear biochemical and clinical hypogonadism, and after thorough discussion of risks and benefits. Patients should be advised to report any suspected side effects via the MHRA Yellow Card scheme (yellowcard.mhra.gov.uk or the Yellow Card app). Further safety information is available in the Summaries of Product Characteristics (SmPCs) for licensed UK testosterone products such as Nebido and Sustanon, accessible via the MHRA/EMC website.

NHS Guidelines and Prescribing Considerations

NICE guideline NG206 on ME/CFS, published in 2021, provides comprehensive recommendations for diagnosis and management but does not endorse testosterone therapy as a treatment for the condition. The guideline emphasises a personalised, multidisciplinary approach focusing on energy management (pacing), symptom control, and supportive care. Hormonal interventions are not included in the evidence-based treatment pathway for ME/CFS.

For patients with suspected hypogonadism, investigation should follow standard endocrine protocols as outlined in NICE Clinical Knowledge Summaries (CKS) and the British Society for Sexual Medicine (BSSM) guideline. This includes:

• Two early-morning serum testosterone measurements (taken between 7 and 11 am on separate occasions) to confirm low levels.

• Assessment of sex hormone-binding globulin (SHBG) and calculation of free or bioavailable testosterone if total testosterone is borderline (8–12 nmol/L).

• Measurement of luteinising hormone (LH) and follicle-stimulating hormone (FSH) to differentiate primary (testicular) from secondary (hypothalamic-pituitary) hypogonadism.

• Evaluation of prolactin, thyroid function, and other pituitary hormones if secondary hypogonadism is suspected.

• Consideration of underlying causes, such as obesity, medications (e.g., opioids, corticosteroids), chronic illness, or pituitary pathology.

If hypogonadism is confirmed, referral to an endocrinologist is appropriate for specialist assessment and initiation of testosterone replacement therapy. Testosterone cypionate is not routinely licensed in the UK; NHS prescribing would generally use licensed preparations such as testosterone undecanoate (Nebido), mixed esters (Sustanon), or transdermal gels, in accordance with local Integrated Care System (ICS) formularies and shared care agreements between secondary and primary care. If an unlicensed product such as testosterone cypionate were to be considered, it would require adherence to GMC and Specialist Pharmacy Service (SPS) guidance on prescribing unlicensed medicines, including appropriate documentation, informed consent, and clinical justification.

GPs may continue prescribing under specialist guidance, with regular monitoring including:

• Baseline assessment: Testosterone, full blood count (FBC) including haematocrit, PSA and digital rectal examination (DRE) where appropriate (typically men over 40 or those at higher risk), lipid profile, liver function tests, and blood pressure.

• Follow-up monitoring: At 3, 6, and 12 months, then annually. Check testosterone levels (aiming for mid-normal range), FBC/haematocrit (action required if >54%), PSA/DRE as appropriate, lipid profile, liver function, and blood pressure.

• Action thresholds: If haematocrit exceeds 54%, consider dose reduction or temporary cessation. Significant PSA rise or abnormal DRE findings warrant referral to urology.

Prescribing testosterone solely for ME/CFS symptoms, in the absence of documented hypogonadism, is not supported by NHS guidelines and would be considered inappropriate. Patients seeking such treatment privately should be counselled about the lack of evidence, potential harms, and the importance of comprehensive medical assessment. Any off-label use must be carefully justified, documented, and monitored, with informed consent obtained after full discussion of risks and uncertainties. Further information is available in the BNF entries for testosterone preparations and MHRA/EMC Summaries of Product Characteristics for licensed UK products.

Alternative and Complementary Treatment Options for ME/CFS

Given the lack of evidence for testosterone therapy in ME/CFS, patients and clinicians should focus on evidence-based and supportive management strategies aligned with NICE guideline NG206. The cornerstone of ME/CFS management is energy management (pacing), which involves balancing activity and rest to avoid triggering post-exertional malaise. This approach is individualised, recognising that each patient's energy envelope and symptom triggers differ. Graded exercise therapy (GET) should not be offered, as per NICE NG206 recommendations.

Symptom-directed treatments may include:

• Pain management: Paracetamol, NSAIDs, or low-dose amitriptyline for neuropathic pain, under GP supervision and with consideration of individual tolerability.

• Sleep disturbance: Sleep hygiene advice, cognitive behavioural strategies for insomnia, and occasionally short-term use of hypnotics if appropriate and under medical guidance.

• Orthostatic intolerance: Increased fluid and salt intake, compression garments, and medications such as fludrocortisone or midodrine in selected cases. These pharmacological options should be specialist-initiated and are not specifically recommended by NICE NG206; they may be considered by specialists with expertise in autonomic dysfunction or postural tachycardia syndrome (PoTS). Further information is available on NHS pages for postural tachycardia syndrome and orthostatic hypotension.

• Cognitive symptoms: Environmental modifications, memory aids, and occupational therapy input to support daily functioning.

Multidisciplinary support is essential and may involve physiotherapy, occupational therapy, dietetics, and psychological support to address the impact of living with a chronic, fluctuating condition. Referral to specialist ME/CFS services, where available, can provide coordinated, holistic care tailored to individual needs.

Complementary approaches such as mindfulness, relaxation techniques, and gentle movement (within individual tolerance) may help some patients manage symptoms, though they do not cure the condition. Nutritional support, including assessment for deficiencies (e.g., vitamin D, vitamin B12, iron, folate), is important, as is addressing any comorbid conditions such as depression, anxiety, or obstructive sleep apnoea.

Patients should be advised to avoid unproven or potentially harmful interventions, including high-dose supplements, extreme diets, or aggressive exercise programmes that may worsen post-exertional malaise. Open communication with healthcare professionals, realistic goal-setting, and self-compassion are vital components of long-term management.

Red-flag symptoms requiring urgent assessment include acute chest pain, severe breathlessness, focal neurological deficit (e.g., limb weakness, visual disturbance, speech difficulty), rapidly progressive symptoms, or unexplained weight loss. If any of these features develop, patients should contact their GP promptly or seek emergency care as appropriate. Further patient-facing information and support can be found on the NHS ME/CFS overview page and through local specialist services.

Frequently Asked Questions