AIDS RESEARCH AND HUMAN RETROVIRUSESVolume 19, Number 9, 2003, pp. 739–741© Mary Ann Liebert, Inc.

Short Communication

Gynecomastia in HIV-Infected Patients ReceivingAntiretroviral Therapy

TERESA GARCÍA-BENAYAS, FRANCISCO BLANCO, LUZ MARTÍN-CARBONERO, EULALIA VALENCIA, ANA BARRIOS, JUAN GONZÁLEZ-LAHOZ, and VINCENT SORIANO

ABSTRACT

Thirty-four HIV-positive men with gynecomastia were seen in an HIV outclinic during a 20-month period (in-cidence of 2.4 cases/100 patients receiving HAART per year). It developed mainly in subjects having good im-munologic and virologic status, after an average of 3 years of HAART. No hormone abnormalities were found,or association with specific drugs. Although initially unilateral, more than half of cases progressed to bilat-eral gynecomastia. Spontaneous resolution occurred in most subjects with 12 months without modifying therapy.

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ENDOCRINE AND METABOLIC ABNORMALITIES often complicatethe management of antiretroviral therapy in HIV-infected

individuals.1 With the widespread use of highly active anti-retroviral therapy (HAART), rare side effects of HIV medica-tions have become more apparent. Among them, breast en-largement has been reported with increasing frequency in men.At first assessment, breast malignancy should be excluded,2 al-though malignant breast disease in HIV-positive men is ex-tremely rare.3 More often, infection, lipomastia, and glandulartissue enlargement (true gynecomastia) are found. Breast in-fections are easy to rule out on the basis of clinical findings(pain, fever, etc.). Ultrasonography allows distinction betweenlipomastia (fat deposition) and benign proliferation of the glan-dular tissue of the male breast (gynecomastia).4 Lipomastia mayappear as part of the HAART-associated lipodystrophy syn-drome.5 In contrast, true gynecomastia develops in patientswith5 or without body shape changes.6,7 Although some drugsmay cause proliferation of the glandular tissue by inducing anincrease in the estrogen-to-androgen ratio,4 no clear etiology orhormone abnormalities are found in more than half of cases ofgynecomastia.4

Before the use of triple antiretroviral drug combinations, gy-necomastia was rarely reported in subjects with HIV infection.8

With the advent of HAART, the number of cases has increasedsignificantly.9 Protease inhibitors (PIs) have been involved fre-

quently,10–14 but reports linking gynecomastia to either nucle-oside analogs (NAs)14–16 or nonnucleosides (efavirenz) haveequally appeared in the literature.6,7,17 So far there are no con-clusive data supporting a role for any specific drug in the development of gynecomastia. Mitochondrial toxicity18 and immune restoration7 have been proposed as pathogenic mech-anisms. Interestingly, most cases develop after prolonged ex-posure to antiretroviral therapy.19

The management of gynecomastia in the setting of HIV in-fection is not well defined. It appears to be a benign condition,although concern exists about its possible association withbreast cancer.20,21 Discontinuation of some antiretroviral drugshas been followed occasionally by the reversion of gyneco-mastia13,15; however, spontaneous resolution may occur as wellwithout modifying treatment.7 When gynecomastia persists forlonger than 1 year, glandular tissue may be replaced by fibroustissue. This has minimal chances of significant regression withany medical intervention (i.e., topical treatment with dihy-drotestosterone),22 and then only surgery may be useful. Infor-mation about the natural history of HAART-related gyneco-mastia and its management is scarce.

We conducted a descriptive study of all cases of gyneco-mastia diagnosed in a large HIV outpatient clinic in Madridduring a 20-month period (from January 2001 to August 2002).Assessment of prior history of exposure to drugs potentially

Service of Infectious Diseases, Hospital Carlos III, Instituto de Salud Carlos III, 28035 Madrid, Spain.

linked to gynecomastia, exploratory findings, clinical evolution,breast ultrasonography, and antiretroviral therapy was per-formed. Laboratory studies included liver, renal, and thyroidfunction tests, as well as measurement of prolactin, total andfree testosterone, and luteinizing hormone. Serum lactate aswell as HIV immunologic and virologic parameters were alsoanalyzed. The diagnosis of gynecomastia was based on physi-cal examination and confirmed by ultrasonography. Antiretro-viral treatment was not modified after the diagnosis of gy-necomastia.

A total of 34 HIV-positive men (mean age, 41 6 7 years old)from a group of 1400 patients on regular follow-up at our clinic(900 of them receiving antiretroviral therapy) complained ofpainful breast enlargement during the study period. Ultra-sonography confirmed gynecomastia in 33 patients and lipo-mastia in 1 patient. All of them were receiving HAART (inci-dence of 2.4 cases per 100 patients receiving HAART per year).High alcohol intake was recorded in 9% of subjects and 41%

suffered from chronic hepatitis C. One patient was receiving ana-metil dopa agonist, which could induce gynecomastia.Among the remaining 32 individuals, gynecomastia was idio-pathic. Their mean CD41 cell count was 681 6 381 cells/mland plasma HIV RNA was below 50 copies/ml in 77%. All buttwo patients (93%) presented initially with unilateral gyneco-mastia; however, 53% of them developed bilateral gynecomas-tia thereafter. Spontaneous resolution occurred within 17months (mean, 8.8 6 2 months) in 20 of 21 patients monitoredfor more than 1 year. Tamoxifen was prescribed for one patientwhose gynecomastia was unchanged and painful after 9 monthsof follow-up; however, no improvement was seen in the fol-lowing 8 months of treatment. Biochemical and hormonal testswere within normal values in all patients. Body shape changescharacteristic of the lipodystrophy syndrome were recorded in70.5% of patients, and grouped as follows: mixed syndrome in54.5%, pure lipoatrophy in 37.3%, and pure lipohypertrophy in8.2% of patients.

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TABLE 1. MAIN FEATURES OF 35 HIV-INFECTED MALES WITH GYNECOMASTIA REPORTED IN THE LITERATURE

CD41 Time onAge cell count Viral load HAART

No. (years) Location (cells/ml) (copies/ml) Treatment (months) Ref.

1 41 Bilateral 130 40,000 d4T/3TC/RTV 13 132 42 Bilateral 168 ,200 d4T/3TC/RTV 9 133 49 Unilateral 640 ,500 d4T/3TC/IDV 2 124 65 Bilateral 210 ,500 AZT/3TC/IDV 6 125 25 Bilateral 171 17,609 d4T/3TC — 156 29 Bilateral 600 ,500 AZT/3TC/NFV 11 117 35 Bilateral 92 10,000 AZT/3TC/IDV 8 108 38 Unilateral 331 110 d4T/ddl/NFV 24 149 39 Bilateral NA NA d4T/3TC/NFV 38 14

10 39 Bilateral 775 ,80 AZT/3TC/IDV 10 1411 39 Unilateral 283 ,400 d4T/ddl/NFV 16 1412 39 Bilateral 493 ,400 d4T/ddl/NFV 9 1413 37 Unilateral 806 ,50 d4T/3TC/EFV 6 614 33 Unilateral 286 ,50 d4T/3TC/EFV 48 615 40 Unilateral 396 ,50 d4T/3TC/EFV 19 616 42 Unilateral 411 ,200 d4T/ddl/RTV/SQV 29 2217 38 Bilateral 887 ,200 d4T/ddl/RTV 14 2218 42 Bilateral 631 ,200 d4T/ddl/3TC/ABC/RTV/IDV/NFV/EFV 24 2219 43 Bilateral 440 ,200 d4T/RTV/SQV/NVP 32 2220 39–57 Bilateral 72–446 ,50–46,000 d4T/3TC/IDV 3–7 921 39–57 Bilateral 72–446 ,50–46,000 d4T/3TC/NFV 3–7 922 39–57 Bilateral 72–446 ,50–46,000 d4T/ddl/RTV/SQV 3–7 923 39–57 Bilateral 72–446 ,50–46,000 d4T/3TC — 924 42 Unilateral 195 ,50 HAART NA 225 74 Unilateral 390 ,50 HAART NA 226 39 Unilateral 110 1,100 HAART NA 227 51 Unilateral NA NA d4T/3TC/EFV 31 228 43 Unilateral NA NA d4T/ddl/EFV 37 229 52 Unilateral NA NA d4T/3TC/EFV 48 230 49 Unilateral NA NA RTV/APV/EFV 36 231 39–55 Bilateral 431–578 ,50 d4T/3TC NA 1632 39–55 Bilateral 431–578 ,50 d4T/ddl NA 1633 39–55 Bilateral 431–578 ,50 d4T/ddl/EFV NA 1634 39–55 Bilateral 431–578 ,50 d4T/3TC/EFV NA 1635 39–55 Bilateral 431–578 ,50 d4T/3TC/NVP NA 16

Abbreviations: NA, not available; AZT, zidovudine; d4T, stavudine; ddl, didanosine; ABC, abacavir; EFV, efavirenz; NVP,nevirapine; IDV, indinavir; NFV, nelfinavir; RTV, ritonavir; APV, amprenavir.

Antiretroviral drugs prescribed at the time gynecomastia wasdiagnosed were stavudine (70%), efavirenz (55%), lamivudine(51%), didanosine (47%), zidovudine (18%), lopinavir (12%),nelfinavir (9%), nevirapine (9%), abacavir (6%), ritonavir (6%),saquinavir (3%), and amprenavir (3%). Overall, there was nooverrepresentation of any drug in this population compared withthe rest. The mean time on HAART for subjects who devel-oped gynecomastia was 39 6 13 months.

To our knowledge, this is the largest series of gynecomastiareported in HIV-infected patients. Table 1 records the main fea-tures of another 35 cases from the literature. The incidence ofgynecomastia in our setting was 2.4 cases per 100 patients re-ceiving HAART per year, which is in accordance with previ-ous estimations.18 HIV-related gynecomastia develops mainlyin patients with good immunologic and virologic status, with-out evidence of hormone abnormalities, and after prolonged pe-riods of therapy (more than 3 years of HAART on average).Moreover, there is no clear association with features of thelipodystrophy syndrome. Accordingly, gynecomastia shouldnot be considered as part of it. Interestingly, spontaneous res-olution occurred in most cases of gynecomastia in our serieswithout changing the medication, and no involvement of anyspecific antiretroviral agent was found. Therefore, a switch ordiscontinuation of antiretroviral drugs does not seem to be jus-tified. Pain is mild and well tolerated in most cases, and anal-gesics are rarely needed. In patients with long-standing gy-necomastia (more than 12 months), treatment should beconsidered in an attempt to prevent fibrosis. Drugs that modifythe estrogen-to-testosterone ratio may be appropriate, such asnonaromatizable androgens (danazol), antiestrogens (tamoxifenand clomiphene), and aromatase inhibitors (testolactone, anas-trozole, and letrozole). When medical treatment fails, breastglandular tissue may be surgically removed.

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Address reprint requests to:Vincent Soriano

Calle Nueva Zelanda 54, 4° B28035 Madrid, Spain

E-mail: vsoriano@dragonet.es

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