Is there value in measuring serum testosterone in a male with unexplained hyperferritinemia?

Measuring Serum Testosterone in Males with Unexplained Hyperferritinemia

Yes, measuring serum testosterone is valuable in males with unexplained high ferritin, as hypogonadism is a recognized endocrine manifestation of hemochromatosis and can indicate iron overload affecting the hypothalamic-pituitary-gonadal axis.

Why Testosterone Measurement Matters in Hyperferritinemia

Hemochromatosis Causes Hypogonadism

• Testicular atrophy and hypogonadism are documented physical findings in patients with hereditary hemochromatosis (HH), appearing in the table of clinical manifestations alongside hepatomegaly, arthritis, and cardiac complications 1.
• Iron deposition in the pituitary gland causes secondary (hypogonadotropic) hypogonadism, which manifests as loss of libido, impotence, and testicular atrophy 1.
• The presence of hypogonadism suggests significant iron overload with end-organ damage, potentially indicating advanced disease requiring more aggressive evaluation and treatment 1.

Diagnostic Algorithm for Unexplained Hyperferritinemia

Step 1: Confirm persistent hyperferritinemia and assess iron parameters

• Measure transferrin saturation (TS) alongside ferritin, as both are needed for proper evaluation 1.
• If TS ≥ 45% and/or ferritin is elevated, proceed to HFE mutation analysis 1.
• Ferritin can be elevated without iron overload in inflammatory conditions (chronic hepatitis, NAFLD, alcoholic liver disease), lymphomas, and chronic inflammatory conditions 1.

Step 2: Evaluate for secondary causes of hyperferritinemia

• Exclude necroinflammatory liver disease by checking ALT, AST, and hepatitis serologies 1.
• Consider metabolic syndrome, obesity, and diabetes as causes of elevated ferritin 1.
• Rule out chronic inflammatory conditions and malignancy 1.

Step 3: Assess for end-organ complications if iron overload is suspected

• Measure morning serum testosterone (between 8-10 AM) on two separate occasions to screen for hypogonadism as a marker of pituitary iron deposition 1, 2.
• Check fasting glucose and HbA1c for diabetes (pancreatic iron deposition) 1.
• Obtain ECG if cardiac symptoms present (cardiac iron deposition) 1.
• Assess for arthropathy, particularly metacarpophalangeal joint involvement 1.

When Testosterone Testing is Most Valuable

High-yield scenarios for testosterone measurement:

• Ferritin >1000 μg/L with elevated TS, suggesting significant iron overload 1.
• Presence of symptoms: decreased libido, erectile dysfunction, fatigue, or loss of body hair 1, 3.
• Confirmed C282Y homozygosity or compound heterozygosity (C282Y/H63D) 1.
• Evidence of other end-organ damage (cirrhosis, diabetes, cardiomyopathy) 1.

Lower-yield scenarios:

• Ferritin elevation clearly explained by inflammation (elevated CRP, active hepatitis) with normal TS 1.
• Mild ferritin elevation (<500 μg/L in men) with normal TS and no HFE mutations 1.

Interpreting Testosterone Results in This Context

If Testosterone is Low

• Measure LH and FSH to distinguish primary from secondary hypogonadism 1, 2.
• Low or low-normal LH with low testosterone indicates secondary (hypogonadotropic) hypogonadism, consistent with pituitary iron deposition 1.
• This finding strengthens the diagnosis of hemochromatosis with end-organ involvement and may warrant liver biopsy if ferritin >1000 μg/L 1.
• Consider pituitary MRI if testosterone <150 ng/dL with low/normal LH to evaluate for structural lesions 1.

If Testosterone is Normal

• Does not exclude iron overload, as hypogonadism develops later in disease progression 1.
• Continue evaluation based on ferritin level, TS, and HFE genotype 1.

Common Pitfalls to Avoid

• Do not assume hyperferritinemia equals iron overload without checking TS, as ferritin is an acute phase reactant and can be elevated in inflammation, obesity, metabolic syndrome, and liver disease without increased iron stores 1.
• Do not measure testosterone at random times—it must be drawn between 8-10 AM due to diurnal variation, and requires confirmation with a second measurement if low 1, 2.
• Do not overlook free testosterone in obese patients, as elevated SHBG can mask true hypogonadism when total testosterone appears borderline 1, 2.
• In the general population, iron overload is NOT the most common cause of elevated ferritin 1.
• A normal TS does not completely exclude iron overload, particularly in non-HFE-related iron overload or C282Y/H63D compound heterozygotes 1.

Clinical Significance of the Finding

If hypogonadism is confirmed in the setting of hyperferritinemia:

• This indicates advanced hemochromatosis with pituitary involvement, requiring aggressive iron removal therapy 1.
• Therapeutic phlebotomy should be initiated to prevent further end-organ damage 1.
• Testosterone replacement may be considered after iron depletion, though fertility preservation requires gonadotropin therapy instead 1, 2.
• The presence of hypogonadism with ferritin >1000 μg/L and elevated liver enzymes predicts cirrhosis in 80% of C282Y homozygotes, warranting liver biopsy 1.