Gynecomastia in the Swiss HIV Cohort Study: An Association with Potent Antiretroviral Therapy

By Ronald Baker, PhD
Publisher and editor-in-chief, HIV and Hepatitis.com

Gynecomastia is defined as benign, excessive enlargement of the male mammary gland (breast). HIV-related gynecomastia develops mainly in men with preserved immunological status after years of HAART. Photographs of men affected by this syndrome are posted on the Internet at www.gynecomastia.org.

In a recently published Spanish study, researchers describe the clinical features and treatment of 34 HIV-positive men with gynecomastia in what they call "the largest series of gynecomastia reported in HIV-infected patients."

The patients came from a cohort of 1400 HIV-positive men. Of these, 900 were receiving antiretroviral therapy, the authors report, for an incidence of 2.4 cases per 100 patients receiving HAART per year.

In a recent observational longitudinal study, investigators report on five patients diagnosed with gynecomastia associated with efavirenz (Sustiva)-based HAART regimens. In all five cases, gynecomastia regressed after efavirenz withdrawal (mean period of 5 months).

In a letter to the editor of AIDS (June 18, 2004), researchers review the issue of HIV-related gynecomastia and report on its manifestation in the Swiss HIV Cohort study.

In HIV-1-uninfected individuals, gynecomastia is found most frequently during puberty, in elderly and obese individuals as well as in individuals with liver cirrhosis. The pathogenesis appears to be a hormonal imbalance such as a decreased ratio of androgens to estrogens or an increased tissue sensitivity to estrogens.

According to the authors, gynecomastia has also been associated with the use of spironolacton, digitalis compounds, cimetidine, enalapril, and amiodarone as well as heroin, marijuana, amphetamine, and alcohol consumption.

In HIV-1-infected individuals, the estimated prevalence ranges from 2 to 3%. Gynecomastia in HIV-1 infection may be associated with the use of potent antiretroviral therapy. Alternatively, gynecomastia has been interpreted as a distinct form of immune reconstitution illness. In addition, a significant relationship between the emergence of gynecomastia and the presence of the lipodystrophy syndrome has been noted.

In the Swiss HIV Cohort Study, researchers studied the characteristics of 47 individuals who received ART from 1996 to 2002 and were HIV-1 infected for a median time of 105 ± 52 months. They presented with an enlargement of the breast gland, measuring on average 2.5 cm in diameter. The age of the individuals was significantly greater compared with the average age of SHCS participants (median 40 versus 35.9 years; P = 0.001).

Twenty-six individuals (55%) showed bilateral involvement and 27 patients (57%) suffered from breast pain. The median duration of ART was 28.5 months (interquartile range 21.7-43.7). ART consisted either of a protease inhibitor (83%; saquinavir n = 10; ritonavir n = 12; indinavir n = 9; nelfinavir n = 16; amprenavir n = 2; lopinavir n = 3) or a non-nucleoside reverse transcriptase inhibitor (36%; nevirapine n = 1; efavirenz n = 16) in combination with nucleoside analogues.

Of interest is the fact that stavudine [Zerit] and didanosine [Videx] were used more frequently in patients with gynecomastia than in other patients in the SHCS (75 versus 45% and 36.2 versus 10.6%; P < 0.001 for both comparisons).

Cholesterol and triglyceride levels were elevated in 38.3 and 53.2% of patients with gynecomastia, respectively. Fourteen patients (30%) suffered from concomitant lipodystrophy (fat accumulation). Twenty-two of the 47 individuals (46.8%) also showed elevated liver transaminases.

In four out of 14 patients (28.6%) testosterone concentrations were decreased. None of the four patients with low testosterone concentrations had increased luteinizing hormone levels. A low oestradiol level was only found in one out of 10 individuals. Prolactin (n = 13), beta-human chorionic gonadotrophin (n = 13) and thryroid-stimulating hormone (n = 14) values were in the normal range.

Hepatitis C virus co-infection was detected in 42.6% of patients with gynecomastia and in 43.5% of cohort patients without gynecomastia (P > 0.05). Nine out of 47 patients reported regular marijuana use, whereas heroine and cocaine use was known in five out of 47 individuals (10.6%).

In summary, the authors write, “Our case series shows that the onset of gynecomastia in HIV-1-infected patients usually occurs more than 2 years after the initiation of ART.”

“The large proportion of 75% of patients with gynecomastia who had received stavudine supports the hypothesis that this nucleoside analogue may play a causal role, which is in agreement with two other studies. In addition, the percentage of patients receiving didanosine was high.”

“However, the pathophysiology of gynecomastia may be multifactorial. We found decreased testosterone levels in 29% of tested patients, although none of these individuals showed increased luteinizing hormone levels, indicating primary hypogonadism.”

“Similarly, Piroth et al. noted decreased testosterone levels in three out of 10 patients, but Peyrier et al. and Qazi et al. did not find relevant hormonal changes. Therefore, the role of hormonal disbalance for the pathogenesis of gynecomastia remains to be determined.”

“The hypothesis that gynecomastia may be triggered by the reconstitution of the immune system is not supported by our results, because of the late onset of gynecomastia 28 months after the initiation of ART. Additional factors contributing to gynecomastia in our study may have been long-term marijuana and heroin use.”

06/14/04

References

S Strub and others. Gynecomastia and potent antiretroviral therapy. AIDS 18(9): 1347-1349. June 18, 2004.

L Piroth and others. Incidence of gynecomastia in men infected with HIV and treated with highly active antiretroviral therapy. Scandinavian Journal of Infectious Diseases 33: 559-560. 2001.