What are the possible causes of low testosterone in a man with normal follicle‑stimulating hormone (FSH), luteinizing hormone (LH), prolactin, cortisol, and thyroid‑stimulating hormone (TSH)?

Low Testosterone with Normal FSH, LH, Prolactin, Cortisol, and TSH: Diagnostic Possibilities

This presentation most likely represents functional (non-organic) hypogonadism, with obesity/metabolic syndrome, medications/substances, or chronic systemic illness as the primary culprits 1.

Understanding the Hormonal Pattern

The key diagnostic feature here is inappropriately normal gonadotropins (FSH/LH) in the setting of low testosterone. This pattern indicates secondary (hypogonadotropic) hypogonadism where the hypothalamic-pituitary-gonadal (HPG) axis is suppressed but not completely absent 1, 2. Normal prolactin, cortisol, and TSH effectively rule out most organic pituitary pathology, making functional causes far more likely.

Primary Diagnostic Considerations (in order of likelihood)

1. Functional Hypogonadism from Metabolic Disease

• Obesity/Metabolic Syndrome/Type 2 Diabetes are the most common causes 1
• These conditions suppress the HPG axis through multiple mechanisms while keeping gonadotropins in the "normal" range (inappropriately low for the degree of testosterone deficiency)
• Look for: BMI >30 kg/m², waist circumference >102 cm, insulin resistance markers, fatty liver disease 1
• Critical point: This is potentially reversible with weight loss and metabolic optimization 1

2. Drug-Induced Hypogonadism

The following medications suppress the HPG axis while maintaining "normal" gonadotropins 1:

• Opioids (most common medication cause)
• Glucocorticoids (chronic use)
• Anabolic androgenic steroids (current use or recent withdrawal) 2, 3
• GnRH agonists/antagonists
• Progestogens (including cyproterone acetate)

3. Chronic Systemic Diseases

Multiple conditions suppress testosterone production without elevating gonadotropins 1:

• HIV infection
• Chronic kidney disease
• Chronic liver disease
• Chronic inflammatory conditions (rheumatoid arthritis, inflammatory bowel disease)
• Acute or critical illness (avoid testing during acute illness) 1, 4

4. Age-Related/Late-Onset Hypogonadism (LOH)

• Increasingly common with aging, often multifactorial 1
• Typically associated with comorbidities rather than pure aging
• The HPG axis remains intact but functions at a lower set point

5. Less Common but Important Causes

Idiopathic Hypogonadotropic Hypogonadism (IHH) 1:

• Includes normosmic IHH and Kallmann syndrome variants
• Usually presents earlier in life but can be mild
• Consider if no other explanation found

Pituitary/Hypothalamic Lesions (less likely given normal other pituitary hormones) 1, 2:

• Small microadenomas
• Infiltrative diseases (sarcoidosis, hemochromatosis)
• Traumatic brain injury history
• Previous cranial radiation

Endurance Exercise/Eating Disorders 1:

• Excessive exercise suppresses the HPG axis
• Significant caloric restriction

Critical Diagnostic Algorithm

Step 1: Medication/Substance Review

• Document ALL medications, especially opioids, steroids, glucocorticoids
• Ask specifically about anabolic steroid use (often not volunteered) 3
• Consider if any can be discontinued or substituted

Step 2: Metabolic Assessment

• Calculate BMI and waist circumference
• Screen for diabetes (HbA1c, fasting glucose)
• Assess for metabolic syndrome components
• Consider liver function tests (fatty liver disease) 1

Step 3: Chronic Disease Evaluation

• Review for HIV, chronic kidney disease, liver disease
• Assess for chronic inflammatory conditions
• Evaluate sleep (obstructive sleep apnea association)

Step 4: Measure SHBG

This is crucial for interpretation 1:

• Low SHBG suggests: obesity, insulin resistance, hypothyroidism, glucocorticoid use, fatty liver
• High SHBG suggests: aging, hyperthyroidism, liver disease, HIV
• Calculate free or bioavailable testosterone if SHBG abnormal

Step 5: Consider Pituitary Imaging

Only if 1, 2:

• No functional cause identified
• Young age (<40 years) without obvious explanation
• Other pituitary hormone abnormalities develop
• Severe hypogonadism (testosterone <5.2 nmol/L or <150 ng/dL)
• Visual field defects or headaches

Common Pitfalls to Avoid

1. Testing during acute illness: Testosterone drops acutely with illness; wait until recovery 1, 4
2. Missing medication causes: Always ask about supplements, "testosterone boosters," and gym drugs 3
3. Assuming age alone: Most "age-related" hypogonadism has underlying comorbidities 1, 5
4. Ignoring obesity: Weight loss of 5-10% can significantly improve testosterone levels 1
5. Premature testosterone therapy: Address reversible causes first, especially in young men desiring fertility 2, 3

Management Priority

Address underlying conditions FIRST before considering testosterone therapy 1, 2:

• Weight loss and metabolic optimization for obesity/diabetes
• Discontinue or substitute offending medications when possible
• Treat underlying chronic diseases
• Lifestyle modifications (exercise, diet) show modest but real improvements (1-2 nmol/L increase) 1

Testosterone therapy should be reserved for: persistent symptomatic hypogonadism after addressing reversible causes, or when underlying causes cannot be modified 1, 2. In young men desiring fertility, gonadotropin therapy or selective estrogen receptor modulators are preferred over testosterone 2, 3.