What could be causing low serum testosterone in a 28‑year‑old man with only a past history of hypertension and a total testosterone of 4.35 nmol/L (reference range 5.80–28.00)?

Causes of Low Testosterone in a 28-Year-Old Man

In a 28-year-old man with testosterone 4.35 nmol/L (approximately 125 ng/dL) and only a history of hypertension, the most likely causes are secondary (hypogonadotropic) hypogonadism—potentially obesity-related, medication-induced, or due to an underlying pituitary disorder—or primary testicular failure. 1

Immediate Diagnostic Steps Required

Confirm the Diagnosis

• Repeat morning total testosterone (8–10 AM) on a second occasion to confirm persistent hypogonadism, as two separate measurements below the reference range are mandatory before proceeding. 1, 2 Single measurements are insufficient due to diurnal variation and assay variability. 1

Differentiate Primary from Secondary Hypogonadism

• Measure serum LH and FSH immediately after confirming low testosterone. 1, 2 This distinction is critical because:
  • Elevated LH/FSH with low testosterone indicates primary (testicular) hypogonadism. 1
  • Low or low-normal LH/FSH with low testosterone indicates secondary (hypothalamic-pituitary) hypogonadism. 1
  • The differentiation has profound treatment implications, including fertility preservation and treatment selection. 1

Assess Free Testosterone and SHBG

• Measure free testosterone by equilibrium dialysis and SHBG, especially given the borderline-low total testosterone. 1, 2 This helps distinguish true hypogonadism from SHBG-related alterations. 1

Most Likely Causes in This Age Group

Secondary (Hypogonadotropic) Hypogonadism

Obesity-Related Hypogonadism

• Excess adipose tissue increases aromatization of testosterone to estradiol, which causes estradiol-mediated negative feedback suppressing pituitary LH secretion. 1 This is the most common reversible cause in young men. 1
• Body mass index (BMI) is strongly associated with testosterone deficiency; testosterone declines by approximately 8.44 ng/dL for each one-unit increase in BMI. 3
• Weight loss through low-calorie diets and regular exercise can reverse this condition by improving testosterone levels and normalizing gonadotropins. 1

Medication-Induced Hypogonadism

• Chronic use of opiates, corticosteroids, or certain antihypertensive medications (particularly spironolactone) can suppress the hypothalamic-pituitary-gonadal axis. 4
• Although one study found no association between spironolactone use and testosterone deficiency 3, other antihypertensive agents or combinations may contribute. 4

Stress and Mental Health

• Mental stress can suppress the hypothalamic-pituitary-gonadal axis, decreasing testosterone levels. 5 In one study, psychotherapy ameliorated mild hypertension in climacteric men with low testosterone, suggesting a bidirectional relationship. 5
• Depression and chronic stress are recognized contributors to secondary hypogonadism. 4

Pituitary Pathology

• With testosterone this low (125 ng/dL) and if LH/FSH are <1.5 IU/L, pituitary MRI is mandatory to exclude non-functioning adenomas or prolactinomas, even in the absence of hyperprolactinemia. 1
• Measure serum prolactin; if elevated (>1.5× upper limit of normal), repeat the test and obtain pituitary MRI. 1

Primary (Hypergonadotropic) Hypogonadism

Testicular Failure

• Congenital conditions (e.g., Klinefelter syndrome, cryptorchidism) or acquired testicular damage (trauma, infection, chemotherapy, radiation) can cause primary hypogonadism. 4
• Elevated LH/FSH with low testosterone confirms primary testicular failure. 1

Metabolic and Systemic Conditions

Metabolic Syndrome and Type 2 Diabetes

• Metabolic syndrome, type 2 diabetes, and chronic inflammatory conditions are associated with high prevalence of hypogonadism. 4
• Screen for diabetes with fasting glucose and HbA1c, as testosterone should be measured even in the absence of hypogonadal symptoms in men with type 2 diabetes. 1

Chronic Systemic Illnesses

• HIV infection, chronic kidney disease, chronic liver disease, COPD, and cardiovascular disease are all associated with secondary hypogonadism. 4

Complete Diagnostic Workup

Essential Laboratory Tests

• Two separate morning total testosterone measurements (8–10 AM) 1, 2
• LH and FSH to differentiate primary from secondary hypogonadism 1, 2
• Prolactin (if LH/FSH are low or low-normal) 1
• Free testosterone by equilibrium dialysis and SHBG 1, 2
• Fasting glucose and HbA1c to screen for diabetes 1
• TSH to exclude thyroid dysfunction 1
• Iron saturation and ferritin if hemochromatosis is suspected 1
• Lipid profile as part of metabolic assessment 1

Imaging

• Pituitary MRI is indicated if:
  • Total testosterone <150 ng/dL with LH/FSH <1.5 IU/L 1
  • Prolactin >1.5× upper limit of normal 1
  • Visual field defects or anosmia are present 1

Clinical Assessment

• Document BMI and waist circumference to assess for obesity-related hypogonadism 1
• Review all medications, particularly opiates, corticosteroids, and antihypertensives 4
• Assess for symptoms of depression and chronic stress 5
• Evaluate for chronic systemic illnesses (HIV, chronic kidney disease, liver disease, inflammatory conditions) 4

Treatment Implications

If Secondary Hypogonadism and Fertility Desired

• Gonadotropin therapy (hCG ± FSH) is mandatory; testosterone replacement is absolutely contraindicated as it causes prolonged azoospermia. 1

If Obesity-Related Secondary Hypogonadism

• First-line treatment is weight loss through hypocaloric diet (500–750 kcal/day deficit) and structured exercise (≥150 min/week moderate-intensity aerobic activity plus resistance training 2–3 times/week); a 5–10% weight loss can significantly increase endogenous testosterone. 1

If Testosterone Replacement Indicated

• Transdermal testosterone gel 1.62% (≈40 mg daily) is first-line due to stable serum levels and lower erythrocytosis risk. 1
• Target mid-normal testosterone levels (450–600 ng/dL) during monitoring. 1

Critical Pitfalls to Avoid

• Do not diagnose hypogonadism on a single testosterone measurement; two morning values are required. 1, 2
• Do not omit LH/FSH testing after confirming low testosterone, as the distinction between primary and secondary hypogonadism directs therapy and fertility counseling. 1
• Do not skip pituitary imaging when testosterone <150 ng/dL with low gonadotropins, as treatable pituitary lesions may be missed. 1
• Never initiate testosterone without confirming the patient does not desire fertility, as exogenous testosterone can cause prolonged azoospermia. 1
• Do not assume age-related decline in a 28-year-old man; always investigate for secondary causes of hypogonadism, as reversible conditions must be addressed first. 1