Background Hereditary Hemochromatosis (HH), particularly due to HFE C282Y homozygosity, leads to progressive iron overload due to increased intestinal absorption. In individuals assigned female at birth, cyclic menstrual blood loss after onset of menses may delay the clinical manifestation of hereditary hemochromatosis. In cisgender males, however, this manifests earlier and more severely due to the absence of any mechanisms of blood loss.

This case review presents the hypothetical case of Finley, a 30-year-old transmasculine patient with a history of heavy menstrual bleeding and iron supplementation, who rapidly develops clinical iron overload after initiating testosterone therapy. The case examines how the interaction between testosterone, erythropoietin, and iron metabolism can unmask a latent genetic condition. Additionally, it highlights the need for proper history taking before the initiation of gender-affirming hormone therapy, proactive iron monitoring and supplementation reassessment during gender-affirming care, especially in patients with known or potential genetic risk.

Methods Finley is homozygous for the HFE C282Y mutation but does not have a diagnosis of hemochromatosis due to lack of clinical presentation. His ongoing heavy menstrual blood loss has functioned as a natural compensatory mechanism, keeping serum iron and ferritin levels low despite his genetic predisposition to iron overload.

Finley visits an endocrinologist to initiate gender affirming care and begin testosterone therapy in his transition to a transgender man. Upon standard medical history taking, his endocrinologist inquires about any prescription medications to which Finley denies. Finley does not disclose his use of over-the-counter iron supplements as he does not perceive this information to be clinically significant.

Finley initiates medical transition through testosterone therapy of 100 mg IM administered once a week. Follow-ups are scheduled with his endocrinologist for 3, 6 and 10 months.

Results Finley’s blood panels at his 10-month follow-up visit show ferritin, TSAT, hematocrit, ALT and AST values elevated well above the reference ranges. The hepatic ultrasound early signs of hepatic steatosis. DNA analysis of the HFE gene showed HFE C282Y homozygosity, consistent with a diagnosis of HH.

Conclusion This scenario emphasizes the critical need for comprehensive pre-treatment evaluation in transgender patients initiating hormonal therapy, including detailed menstrual, supplementation, and family histories. Standard history-taking procedures may fail to elicit pertinent information, such as long-term iron supplementation, emphasizing the need for specific and directed questioning. Routine monitoring of iron indices and liver function should be considered, particularly in patients with known risk factors or suggestive clinical histories.