What are the implications of low hemoglobin (Hb), mean corpuscular hemoglobin (MCH), and mean corpuscular hemoglobin concentration (MCHC) in a patient on testosterone therapy with elevated testosterone levels?

Paradoxical Finding Requiring Immediate Investigation

This presentation is paradoxical and concerning—testosterone therapy typically increases hemoglobin by 15-20%, yet this patient has low hemoglobin with elevated testosterone levels, indicating an underlying pathology unrelated to the testosterone therapy that requires urgent evaluation. 1

Understanding the Expected vs. Actual Response

Normal Testosterone Effects on Erythropoiesis

• Testosterone stimulates red blood cell production through increased erythropoietin (EPO) production and improved iron utilization, typically raising hemoglobin by 15-20% in hypogonadal patients 1
• Men normally have higher hemoglobin levels than women due to testosterone's erythropoietic effects 1
• Testosterone administration increases EPO levels, decreases hepcidin (improving iron availability), and establishes a new higher hemoglobin set point 2

The Paradox in This Case

• Low hemoglobin, MCH, and MCHC in the presence of elevated testosterone is the opposite of expected physiology and signals a competing pathological process 1
• The low MCH and MCHC specifically suggest microcytic, hypochromic anemia—most commonly iron deficiency 1

Critical Differential Diagnosis

Iron Deficiency Anemia (Most Likely)

• Low MCH and MCHC are late markers of iron deficiency and indicate depleted iron stores 1
• In females not experiencing menstrual losses, iron deficiency should prompt careful assessment for gastrointestinal bleeding 1
• Testosterone increases iron utilization for erythropoiesis, which can unmask or worsen underlying iron deficiency 2
• Soluble transferrin receptor levels and sTR/log ferritin ratio increase with testosterone therapy, reflecting increased iron demand 2

Other Considerations

• Vitamin B12 or folate deficiency (though these typically cause macrocytic anemia, not microcytic) 1
• Inherited disorders of hemoglobin synthesis (thalassemia trait) 1
• Chronic kidney disease with inadequate EPO response 1, 3
• Bone marrow dysfunction if other cell lines are also affected 1

Immediate Workup Required

Essential Laboratory Tests

• Complete blood count with differential to assess all three cell lines (white cells, hemoglobin, platelets)—abnormalities in two or more cell lines warrant hematology consultation 1
• Serum ferritin (tissue iron stores) and transferrin saturation (available iron for erythropoiesis) 1
• Reticulocyte count to assess bone marrow response appropriateness 1
• Vitamin B12 and folate levels 1
• Renal function (creatinine, estimated GFR) as chronic kidney disease is associated with anemia 1, 3

Clinical Assessment

• Detailed menstrual history if premenopausal—testosterone therapy in females can cause amenorrhea, but ongoing occult bleeding must be excluded 1
• Gastrointestinal symptoms suggesting blood loss (melena, hematochezia, change in stool caliber) 1
• Dietary history for iron, B12, and folate intake 1
• Medication review for drugs causing GI bleeding (NSAIDs, anticoagulants) 1

Management Algorithm

If Iron Deficiency Confirmed

1. Investigate the source of iron loss—in non-menstruating patients, this mandates GI evaluation including upper endoscopy and colonoscopy 1
2. Initiate iron supplementation while investigating the underlying cause 1
3. Continue testosterone therapy as it is not causing the anemia; rather, the anemia exists despite testosterone's erythropoietic stimulus 1, 2
4. Monitor hemoglobin response to iron replacement—expect improvement within 4-8 weeks 1

If Other Etiology Identified

• Address the specific deficiency (B12, folate) or underlying condition 1
• Consider hematology referral if inherited hemoglobin disorder suspected or if multiple cell lines affected 1
• Evaluate for chronic kidney disease if renal function impaired 1, 3

Critical Pitfalls to Avoid

Do Not Attribute Anemia to Testosterone Therapy

• This is physiologically implausible—testosterone causes erythrocytosis (elevated hemoglobin/hematocrit >54%), not anemia 1, 4, 5
• The FDA label for testosterone products warns about polycythemia requiring monitoring, not anemia 5
• Discontinuing testosterone will not resolve the anemia and may worsen the patient's hypogonadal symptoms 1

Do Not Delay Investigation

• Low hemoglobin with microcytic indices in a female on testosterone therapy represents a failure of expected erythropoietic response and demands prompt evaluation 1
• Iron deficiency in non-menstruating patients may indicate GI malignancy requiring urgent diagnosis 1
• Testosterone deficiency itself is associated with increased anemia risk, so adequate testosterone levels should be protective—their absence of protective effect here is concerning 6, 3, 7

Monitor for Future Polycythemia Risk

• Once the underlying cause is corrected and iron stores replenished, this patient may develop testosterone-induced erythrocytosis 1, 4
• Hemoglobin and hematocrit should be monitored at 1-2 months after starting treatment for the anemia, then every 3-6 months during the first year 4
• If hematocrit exceeds 54%, therapeutic phlebotomy, dose reduction, or temporary discontinuation of testosterone is indicated to reduce cardiovascular and thromboembolic risk 4, 8