The term “gynecomastia” is derived from the Greek word gynec (female) and mastos (breast) and was first coined by Galen way back in the second century. Gynecomastia is defined as benign proliferation of the glandular tissue of the male breast. It is common in infancy, puberty, and in middle-aged to older men. Multiple etiologies has been implicated to persistent gynecomastia, common causes are drugs, hypogonadism (primary or secondary), persistent pubertal gynecomastia, cirrhosis or malnutrition, chronic kidney disease, hyperthyroidism or testicular tumors. Even after extensive evaluation the etiology remains unclear in 25 percent of cases. Gynecomastia is seen in individuals with human immunodeficiency virus (HIV) receiving highly active antiretroviral therapy (HAART) [1]. True gynecomastia in must be differentiated from pseudogynecomastia or lipomastia, which occurs as a part of a fat redistribution syndrome (lipodystrophy) seen in HIV individuals on HAART. True gynecomastia in HIV individuals has also been described due to adverse effect of anti-retroviral (ARV) drugs like efavirenz, stavudine and didanosine [2].

A 24 years old male, with known retro viral disease, presented to our infectious disease clinic with complaint of bilateral breast enlargement since 6months. The patient was diagnosed with human immunodeficiency virus 1(HIV 1) ( WHO clinical stage III) in 2017with a baseline CD4+ count of 280/microL and was put on first line ART- tenofovir (TDF) 300 mg daily, lamivudine(3TC) 300 mg daily and efavirenz (EFV)600mg daily since then. The patient was doing well with no complications until now, when he noticed gradual onset breast enlargement which was painless and not associated with any nipple discharge. On local examination, both breasts were symmetrical with no apparent skin changes, elastic and rubbery in consistency with glandular tissue cantered beneath the nipple areola complex. There was no discrete swelling or tenderness present. The gynecomastia was graded 2a on Simon classification and grade II on Rohrich classification. On general examination, the patient had average built and height with well-developed secondary sexual characteristics. There was no loss of axillary or pubic hair , both testes were normally descended and normal in size with no associated testicular mass. Penis was found to be normal with no loss of libido. There was no history of intake of any over the counter medication/herbal medication apart from ART. There was no history or signs suggestive of chronic kidney or liver disease or hypothyroidism. Routine blood investigations (complete blood count, liver function test, kidney function test) along with thyroid investigations were found to be normal. Biochemical work up for gynecomastia revealed normal serum levels of testosterone, luteinizing hormone, estradiol(E2), and human chorionic gonadotropin (hog) ruling out malignancy and central and peripheral endocrine cause. Ultrasonography of breast showed retro areola r fan shaped/ triangular hypo echoing mass confirming true gynecomastia. After ruling out multiple etiological factors, the gynecomastia was finally attributed to being drug induced with efavirenz being the culprit drug. Efavirenz was stopped and the ART regimen was changed. Efavirenz was replaced with the integrate strand transfer inhibitor (INSTI) Dolutegravir. After 6 month follow up in our infectious disease clinic, patient was found to be doing well with some reduction in the size of breasts.

Figure 1: Image of the patient showing enlarged breast (gynecomastia).

Gynecomastia is defined as benign proliferation of glandular tissue of male breast. It can be clinically appreciated by the presence of a firm or rubbery mass extending concentrically away from the nipple(s) [3]. It may be unliteral or bilateral and can present at any age. An imbalance in estrogen to androgen activity is primarily responsible for gynecomastia, although the etiology may be many [4]. Many drug have been associated with gynecomastia, among anti-retroviral drugs, efavirenz (EFV) has been often implicated for it. Although exact mechanism is not known, Matthew et al in an in-vitro study using estrogen receptor-positive breast cancer cell lines (MCF-7, T47D and ZR-75-1) found, efavirenz directly binds and activates the ER- alpha receptor in the breast tissue, promoting glandular proliferation [5]. Apart from efavirenz other anti-retroviral drugs like stavudine and didanosine has also been remotely linked to cause gynaecomastia [6] in past, although these agents are not currently in use due to availability of better drugs. Qazi et al had also put forward a hypothesis for gynaecomastia. Immune restoration in HIV patients (those with low CD4+) after staring ART may be responsible for development of gynaecomastia. Although underlying mechanism is unclear they had postulated that an increase T helper cells cytokine response leading to increase in IL-2 and IL-6 levels may be responsible for breast tissue estrogen availability causing gynecomastia [7]. The incidence of Efavirenz induced gynecomastia has ranged between 2.8-6% in various studies. In a recent study done by Sandra et al in Zimbabwe, the incidence was 22.1/1000 person-years; with 73 out of 1432 (5%) adult men on Efavirenz containing ART regimen had developed gynecomastia [8]. Similarly in other prospective studies, the prevalence was found to be 6% in Malawi (2017) in a study by Victor Singano [9], 2.8% in France (2009) by L.Piroth [10], 2.8% in Spain (2004) by José A Mira [11]. In all the cases of efavirenz induced gynaecomastia more than half were bilateral (roughly 60%) and around 80% had developed it within first two years of starting efavirenz based ART [8]. Other associated symptoms like pain, nipple discharge were also seen, though not commonly. No significant associations were observed between confirmed gynecomastia and age, body mass index, CD4+ counts and WHO disease stage at ART initiation, duration of ART, history of tuberculosis and presence of lipodystrophy [9].  It becomes very important to differentiate true gynecomastia from lipomastia (lipodystrophy syndrome) in the backdrop of HIV infection. Other differentials to be considered are dermis cysts, lipomas, sebaceous cysts, ductal ectasia, lymphoplasmacytic inflammation, hematomas and fat necrosis. A simple USG can differentiate between them. Mammography is to be considered if there is suspicion of malignancy which has a high sensitivity for the same [12]. All retro positive patients must be thoroughly evaluated. A proper detailed clinical examination including that of gonads, past medical history and drug history must be taken. Other important investigations include complete hormonal profile (testosterone, luteinising hormone, estradiol), tumor markers (beta HCG), thyroid function tests, biochemical profiles, serum cholesterol, triglycerides and other tumor markers which can provide some diagnostic clue. Common causes of gynecomastia (Table 1), should be ruled out before attributing the etiology to drugs [13].

Table 1: Pathological causes of gynecomastia.

Although World Health Organization (WHO) its recent update has recommended INSTI (dolutegravir) based combination as the first line therapy in HIV treatment, efavirenz is still being used in many low income countries. Its becomes essential to differentiate between true and pseudo gynecomastia, as further management would depend on it. All male patients on ART (especially on efavirenz based regimen) should be monitored for gynecomastia during therapy. Prompt withdrawal of the offending drug (efavirenz) while substituting it with other ARV drugs remains the most effective treatment.

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