Caso et al.  recently reported three cases of anatomopathologically confirmed gynaecomastia without evidence of lipodystrophy syndrome in HIV-infected male patients treated with efavirenz. Although some cases of breast hypertrophy had been reported on efavirenz therapy, some with the lipodystrophy syndrome, none had anatomopathological confirmation . We have previously shown that true gynaecomastia could be effectively differentiated from breast hypertrophy secondary to lipodystrophy syndrome (lipomastia) by breast ultrasonography , and that true gynaecomastia could occur with the use of all currently available classes of antiretroviral medications, including efavirenz and nevirapine and not just protease inhibitors and nucleoside reverse transcriptase inhibitors, as other authors have previously reported. Breast ultrasonography was furthermore shown to be a sensitive method of differentiating true gynaecomastia, in which there is an increase in ductal tissue and periductal stroma, from lipomastia (pseudogynacomastia) associated with the lipodystrophy syndrome [2,3].
A total of 11 HIV-1-infected patients with true gynaecomastia treated with different antiretroviral combinations including efavirenz  were investigated for other causes of gynaecomastia by complete hormone profiles, biochemical profiles, serum cholesterol, triglyceride and tumour markers. A complete drug history excluded concomitant medications as a potential cause of gynaecomastia . All patients achieved an HIV-1-RNA load of less than 50 copies/ml with the current antiretroviral regimen, as found in the cohort described by Caso et al. , and achieved an excellent increase in CD4 cell counts. Since then we have extended our original cohort to 15 patients with true gynaecomastia, which developed after the initiation of effective highly active antiretroviral therapy, with similar overall findings . In addition, 12 out of the 15 patients described had complete resolution of the gynaecomastia after a mean period of 2 months without any specific therapy. We believe that in view of the rapid increase in the CD4 cell count, the reduction in HIV-1-RNA load to less than 50 copies/ml, the absence of other pathological conditions, and the rapid resolution with no specific treatment, the true gynaecomastia described by Caso et al.  was a manifestation of immune restoration disease and not just a specific effect of efavirenz-containing antiretroviral regimens.
The mechanism underlying the development of true gynaecomastia is unclear. However, after the commencement of highly active antiretroviral therapy, there is an improvement in the T helper cell cytokine response, specifically an increased production of IL-2 . IL-2 has been shown to increase the proliferation of human breast carcinoma cells in vitro . In addition, IL-6 has been shown to increase aromatase activity in breast tissue , with a consequent increase in oestrogen available to stimulate breast growth. This evidence suggests that cytokine perturbations occurring with immune restoration may result in altered breast tissue oestrogen availability, which ultimately causes true gynaecomastia. Once immune restoration has occurred, the levels of these cytokines fall leading to restoration of the oestrogen : testosterone ratio, with the resolution of gynaecomastia without therapy.
We believe that immune restoration is a plausible unifying mechanism to explain the development of true gynaecomastia that occurs in patients treated with different classes of antiretroviral medications. Clearly, this hypothesis needs further investigation.
Nadeem A. Qazia
John F. Morlesea
D. Michael Kingb
Rizvana S. Ahmadb
Brian G. Gazzarda
Mark R. Nelsona
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