Male patient with total serum testosterone 15 ng/dL (reference 240‑950 ng/dL) and free testosterone 5.49 pg/mL (reference 4.65‑18.1 pg/mL) – what does this indicate and how should the hypogonadism be evaluated and managed?

Severe Hypogonadism Requiring Immediate Evaluation and Treatment

This patient has profound hypogonadism with total testosterone of 15 ng/dL (normal 240-950 ng/dL), which is critically low and requires urgent diagnostic workup to identify the underlying cause before initiating testosterone replacement therapy. 1, 2

Immediate Diagnostic Workup Required

Confirm the Diagnosis

• Repeat morning total testosterone (8-10 AM) on a second occasion to confirm persistent severe hypogonadism, as two measurements are required despite the extremely low initial value 1, 2
• The free testosterone of 5.49 pg/mL (reference 4.65-18.1 pg/mL) is at the lower limit of normal, which is discordant with the profoundly low total testosterone and suggests possible laboratory error or SHBG abnormality 2, 3
• Measure sex hormone-binding globulin (SHBG) to calculate the free androgen index and verify the free testosterone result 2, 3

Distinguish Primary from Secondary Hypogonadism

• Measure serum LH and FSH immediately – this is mandatory to determine whether the patient has primary (testicular) or secondary (hypothalamic-pituitary) hypogonadism 1, 2, 4
• Low or inappropriately normal LH/FSH with testosterone this low indicates secondary hypogonadism and requires pituitary evaluation 1, 2
• Elevated LH/FSH indicates primary testicular failure 1, 4

Screen for Pituitary Pathology (Critical in Secondary Hypogonadism)

• If testosterone is <150 ng/dL with low or low-normal LH/FSH, order pituitary MRI immediately regardless of prolactin levels – non-secreting adenomas may be present 1, 2
• Measure serum prolactin to screen for hyperprolactinemia; if elevated, repeat to confirm and refer to endocrinology 1, 2
• Persistently elevated prolactin (>1.5× upper limit of normal) indicates possible prolactinoma requiring MRI 1, 2

Evaluate for Reversible Causes

• Check TSH to exclude thyroid dysfunction 2
• Obtain fasting glucose and HbA1c to screen for diabetes 1, 2
• Measure iron saturation and ferritin to exclude hemochromatosis 2
• Screen for chronic systemic illnesses (HIV, chronic kidney/liver disease, inflammatory conditions) that can suppress the hypothalamic-pituitary axis 2

Pre-Treatment Safety Assessment

Mandatory Baseline Tests Before Starting Testosterone

• Hematocrit/hemoglobin – absolute contraindication if >50% at baseline; withhold therapy if >54% during treatment 1, 2
• PSA and digital rectal examination in men >40 years – PSA >4.0 ng/mL requires urologic evaluation and negative prostate biopsy before initiating therapy 1, 2
• Fertility assessment – ask explicitly about desire for future children; testosterone therapy causes prolonged azoospermia and is absolutely contraindicated if fertility is desired 1, 2

Treatment Approach

If Secondary Hypogonadism and Fertility Desired

• Gonadotropin therapy (hCG plus FSH) is mandatory – testosterone replacement is absolutely contraindicated as it will cause azoospermia 1, 2
• Combined hCG and FSH therapy restores both testosterone production and spermatogenesis 2
• Refer to reproductive endocrinology for gonadotropin initiation 1, 2

If Fertility Not Desired or Primary Hypogonadism Confirmed

• Transdermal testosterone gel 1.62% at 40.5 mg daily is first-line due to stable day-to-day levels and lower erythrocytosis risk (15.4%) compared to injectable testosterone (43.8%) 2
• Intramuscular testosterone cypionate/enanthate 100-200 mg every 2 weeks is a cost-effective alternative ($156/year vs $2,135/year for gel) but carries higher erythrocytosis risk 2
• Target mid-normal testosterone levels (500-600 ng/dL) when monitoring 2

Expected Treatment Outcomes

• Small but significant improvements in sexual function and libido (standardized mean difference 0.35) 1, 2
• Little to no effect on physical functioning, energy, vitality, depressive symptoms, or cognition – set realistic expectations 2
• Modest improvements in metabolic parameters (insulin resistance, triglycerides, HDL cholesterol) may occur 2

Monitoring Protocol

Initial Follow-Up (2-3 Months)

• Measure testosterone levels (midway between injections for injectable formulations, targeting 500-600 ng/dL) 1, 2
• Check hematocrit – withhold treatment if >54% and consider phlebotomy in high-risk cases 1, 2
• Measure PSA in men >40 years 1, 2
• Assess clinical response, particularly sexual function and libido 2

Ongoing Monitoring (Every 3-6 Months First Year, Then Annually)

• Repeat testosterone, hematocrit, PSA, and digital rectal examination 1, 2
• Refer to urology if PSA rises >1.0 ng/mL within first 6 months or >0.4 ng/mL per year thereafter 1, 2
• Discontinue therapy at 12 months if no improvement in sexual function to prevent unnecessary long-term exposure without benefit 2

Critical Pitfalls to Avoid

• Never start testosterone without measuring LH/FSH – the distinction between primary and secondary hypogonadism directs treatment and fertility counseling 1, 2
• Never initiate testosterone without confirming the patient does not desire fertility – this causes prolonged, potentially irreversible azoospermia 1, 2
• Never skip pituitary imaging when testosterone is <150 ng/dL with low gonadotropins – this may miss treatable pituitary lesions 1, 2
• Do not ignore the discordant free testosterone result – verify with SHBG measurement and consider laboratory error 2, 3
• Do not prescribe testosterone for weight loss, energy enhancement, or athletic performance – these are not evidence-based indications 2