Testosterone,erythrocytosis and the JAK2 V617 F mutation

Testosterone may be used in the treatment of men with primary hypogonadism or androgen deficiency, in postmenopausal women with hypoactive sexual desire disorder, and to produce physical male sex characteristics in female-to-male transgender patients. ¹ The illicit use of testosterone is also well documented. ² The characteristic haematological feature of testosterone therapy is a secondary erythrocytosis, occurring in up to two thirds of patients, though dependent on the formulation: potential mechanisms of erythrocytosis include hepcidin suppression, altered iron sequestration and turnover, increased erythropoietin production, bone marrow stimulation and genetic factors. ³ The myeloproliferative neoplasm of polycythaemia vera (PV) is characterised by primary erythrocytosis and acquisition of the specific JAK2 V617 F exon 14 mutation in 95% of patients with substitution, deletion or duplication mutations of JAK2 exon 12% in the remainder of patients. ⁴ Despite the above, erythrocytosis associated with testosterone use remains a recurrent, if infrequent, trigger for JAK2 V617 F mutation analysis. An audit was therefore performed to determine the clinical and laboratory impact of JAK2 V617 F testing in this particular scenario.

At a centre for haematological malignancy molecular diagnostics that receives greater than 2000 JAK2 V617 F diagnostic tests per annum, from January 2006 to June 2021 inclusive, 26 requests for JAK2 V617 F mutation status were identified with clinical details provided of testosterone use and erythrocytosis. All patients were male with a median age of 42 years (range 21–66 years). The JAK2 V617 F mutation was identified by an allele-specific PCR approach with a sensitivity of detection of 5% mutant alleles, unchanged throughout the audit period with JAK2 exon 12 mutations detected by next-generation sequencing. The JAK2 V617 F mutation was not detected in any of the 26 cases analysed nor were JAK2 exon 12 mutations in four of these cases when specifically requested.

Acknowledging that testosterone associated erythrocytosis might mask underlying PV, a literature search failed to reveal any such cases. Molecular investigation for the JAK2 V617 F in this scenario has minimal impact on workload. ⁵ However, on the basis of these findings, the possibility of an association between JAK2 V617 F mutations and erythrocytosis in the context of exogenous testosterone appears to be theoretical rather than actual.