Prostate-specific antigen (PSA) testing is a crucial component of safe testosterone replacement therapy (TRT) prescribing in the UK. PSA is a protein produced by prostate cells, and elevated levels may indicate benign prostatic hyperplasia, prostatitis, or prostate cancer. Whilst testosterone does not cause prostate cancer, it may stimulate pre-existing malignancies, necessitating careful monitoring. UK guidelines from the British Society for Sexual Medicine and NICE emphasise individualised risk assessment, with baseline PSA measurement before treatment initiation and regular monitoring throughout therapy. This surveillance approach balances therapeutic benefits against potential prostate-related risks, enabling early detection of concerning changes and timely urological referral when required.

Understanding PSA Testing and Testosterone Treatment

Prostate-specific antigen (PSA) blood testing is an important part of risk assessment and monitoring for men receiving testosterone replacement therapy (TRT) in the UK. PSA is a protein produced by both normal and malignant cells of the prostate gland, and elevated levels may indicate prostate conditions including benign prostatic hyperplasia (BPH), prostatitis, or prostate cancer. When prescribing testosterone therapy, clinicians must balance the therapeutic benefits against potential risks, particularly concerning prostate health.

Testosterone itself does not cause prostate cancer, but there is biological plausibility that it might stimulate the growth of pre-existing prostate malignancies. The prostate gland is an androgen-dependent organ, meaning its cellular activity responds to testosterone and its metabolite dihydrotestosterone (DHT). This relationship necessitates careful monitoring of prostate health throughout testosterone treatment. While contemporary research suggests testosterone therapy may not significantly increase prostate cancer risk, the principle of clinical vigilance remains important given the limited long-term data.

PSA testing serves as a blood test used for risk assessment and surveillance during TRT. For men considering or already receiving testosterone therapy, PSA monitoring forms part of a comprehensive safety protocol. The Summary of Product Characteristics (SmPC) for testosterone preparations (such as Nebido and Testogel) and specialist endocrinology guidelines emphasise that PSA assessment should be integrated into the pre-treatment evaluation and ongoing surveillance of men on TRT. This approach enables identification of concerning trends, allowing timely investigation and intervention when necessary, thereby optimising both the safety and efficacy of testosterone treatment.

UK Guidelines on PSA Monitoring for Testosterone Therapy

The British Society for Sexual Medicine (BSSM) and endocrinology consensus statements provide guidance on PSA monitoring for men receiving testosterone therapy. These UK-specific recommendations align broadly with European Association of Urology (EAU) guidelines whilst reflecting NHS clinical practice. Before initiating testosterone treatment, men should undergo baseline PSA testing, with digital rectal examination (DRE) where clinically indicated. For men with risk factors for prostate cancer—including family history, Black ethnicity, or lower urinary tract symptoms—PSA testing may be appropriate from an earlier age.

NICE Clinical Knowledge Summary (CKS) on testosterone deficiency emphasises individualised risk assessment rather than blanket screening protocols. Clinicians must discuss the benefits and limitations of PSA testing with patients, acknowledging that PSA is not a perfect diagnostic tool. Elevated PSA levels can occur due to benign conditions, recent ejaculation, urinary tract infections, or prostate manipulation, whilst some prostate cancers may not significantly elevate PSA. The decision to test should be informed by the patient's age, life expectancy, comorbidities, and personal preferences regarding investigation and potential treatment of prostate abnormalities.

Contraindications to testosterone therapy include known or suspected prostate cancer and male breast cancer. The SmPCs for testosterone preparations typically advise that PSA levels above age-specific thresholds require urological assessment before treatment initiation. These thresholds should be interpreted within clinical context, considering local laboratory reference ranges (reported in µg/L in the UK) and the pattern of PSA change over time. Men with a history of treated prostate cancer may occasionally be considered for testosterone therapy, but only following specialist urological consultation and with enhanced monitoring protocols.

Why PSA Levels Are Checked Before and During Treatment

Pre-treatment PSA testing serves multiple critical functions in the safe prescribing of testosterone therapy. Firstly, it establishes a baseline value against which future measurements can be compared, enabling detection of significant changes that might indicate developing prostate pathology. Secondly, it identifies men with pre-existing prostate abnormalities who require further investigation before testosterone can be safely initiated. An elevated baseline PSA necessitates urological referral for assessment, which may include repeat PSA testing, multiparametric MRI scanning (as recommended by NICE NG131), and potentially prostate biopsy to exclude malignancy.

The biological rationale for PSA monitoring relates to testosterone's role in prostate physiology. Androgens stimulate prostate epithelial cell growth and PSA production. In men with hypogonadism (low testosterone), the prostate may be relatively quiescent; restoring physiological testosterone levels can increase prostate metabolic activity and consequently PSA production. This effect is typically modest in men without underlying prostate disease, with PSA levels generally remaining within normal ranges. However, if occult prostate cancer is present, testosterone supplementation could theoretically accelerate tumour growth, leading to more rapid PSA elevation.

Ongoing PSA monitoring during testosterone treatment functions as a surveillance mechanism to detect interval development of prostate pathology. Most prostate cancers are slow-growing, and regular PSA testing may help identify concerning changes requiring investigation. Additionally, monitoring helps identify men who may be experiencing benign prostatic enlargement, which can cause bothersome lower urinary tract symptoms requiring management. The monitoring protocol provides reassurance to both patients and clinicians that testosterone therapy is not adversely affecting prostate health, whilst maintaining vigilance for the small proportion of men who may develop concerning changes requiring investigation. If urinary tract infection is suspected, this should be treated first and PSA testing repeated after approximately 6 weeks.

How Often PSA Testing Is Required on Testosterone

The frequency of PSA testing during testosterone therapy follows a structured protocol based on treatment duration and individual risk factors. UK guidelines typically recommend PSA measurement at baseline, at 3 months after initiating testosterone treatment, again at 6-12 months, and then annually thereafter for men without concerning features. The initial three-month check is important because testosterone levels should have stabilised by this point, allowing assessment of the treatment's effect on PSA. If PSA remains stable and within normal limits during the first year, the risk of significant prostate pathology is low, justifying less frequent subsequent monitoring.

For men at higher baseline risk of prostate cancer, more intensive monitoring may be appropriate. Risk factors warranting consideration of more frequent PSA testing include:

• Age over 60 years – prostate cancer incidence increases significantly with age

• Family history of prostate cancer, particularly in first-degree relatives diagnosed before age 60

• Black ethnicity – associated with higher prostate cancer risk

• Baseline PSA in the upper normal range for age

• Previous prostate biopsies showing high-grade prostatic intraepithelial neoplasia (HGPIN) or atypical small acinar proliferation (ASAP)

The annual PSA testing schedule balances clinical safety with practical considerations. More frequent testing increases healthcare costs and patient inconvenience without clear evidence of improved outcomes for men at average risk. However, men should be advised to contact their GP promptly if they develop lower urinary tract symptoms (hesitancy, poor stream, nocturia, urgency) or other concerning features between scheduled tests, as these may warrant earlier PSA assessment. Clinicians should interpret PSA results in the context of age-specific thresholds and local laboratory reference ranges, rather than focusing on fixed thresholds or PSA velocity alone. PSA results in the UK are reported in µg/L (equivalent to ng/mL), and normal ranges vary between laboratories.

What Happens If Your PSA Level Rises During Treatment

A rising PSA level during testosterone therapy requires careful clinical evaluation, but does not automatically indicate prostate cancer. The first step is to repeat the PSA test after an appropriate interval (typically 4–6 weeks) to confirm the elevation and exclude laboratory error or temporary causes such as recent sexual activity, vigorous exercise, or urinary tract infection. Men should be advised to abstain from ejaculation for 48 hours before PSA testing and to avoid cycling or other activities that might irritate the prostate.

If PSA rises above age-specific thresholds as defined in the Prostate Cancer Risk Management Programme (PCRMP), or if there are other concerning features, further investigation is needed. If confirmed elevation occurs, clinicians should consider withholding testosterone therapy whilst further investigation proceeds. The patient should be referred to urology for specialist assessment, using the urgent suspected cancer pathway as per NICE guideline NG12 where appropriate. Assessment may include digital rectal examination, repeat PSA testing, and consideration of multiparametric MRI of the prostate. NICE guideline NG131 recommends MRI as a triage tool before deciding whether prostate biopsy is necessary, reducing unnecessary invasive procedures.

If investigations exclude prostate cancer and identify benign causes for PSA elevation, testosterone therapy may be cautiously restarted with enhanced monitoring. Benign prostatic hyperplasia is common in older men and can coexist with hypogonadism; management may include alpha-blocker medications (such as tamsulosin) or 5-alpha-reductase inhibitors (such as finasteride) to control urinary symptoms. It's important to note that 5-alpha-reductase inhibitors typically reduce PSA levels by approximately 50% after 6 months of treatment, which must be considered when interpreting subsequent PSA results. Patients should be reassured that PSA elevation does not always indicate cancer, but emphasised that investigation is essential for safety. If prostate cancer is diagnosed, treatment decisions depend on tumour grade, stage, patient age, and comorbidities, with options ranging from active surveillance to radical treatment. The decision about whether to resume testosterone therapy after prostate cancer treatment requires individualised discussion with both oncology and endocrinology specialists, considering current evidence and patient preferences.

Suspected side effects of testosterone therapy should be reported via the MHRA Yellow Card Scheme.

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