Download 80 KB - International Medical Press

Antiviral Therapy 9:511-517
Gynaecomastia in HIV-infected men on highly
active antiretroviral therapy: association with
efavirenz and didanosine treatment
José A Mira1, Fernando Lozano2, Jesús Santos3, Emilia Ramayo4, Alberto Terrón5, Rosario Palacios3, Eva M
León2, Manuel Márquez3, Juan Macías1,2, Ana Fernández-Palacín6, Jesús Gómez-Mateos2 and Juan A
Pineda1,2* for the Grupo Andaluz para el Estudio de las Enfermedades Infecciosas (GAEI)
1
Servicio de Medicina Interna, 2Unidad de Enfermedades Infecciosas, 4Servicio de Bioquímica, 6Departamento de Estadística, Hospital
Universitario de Valme, Sevilla, Spain
3
Unidad de Enfermedades Infecciosas, Hospital Universitario Virgen de la Victoria, Málaga, Spain
5
Unidad de Enfermedades Infecciosas, Hospital Universitario de Jerez, Cádiz, Spain
*Corresponding author: Tel: +34 955 015 887; Fax: +34 955 015 747; E-mail: [email protected]
Background: Gynaecomastia has been described in HIVinfected men undergoing highly active antiretroviral
therapy (HAART). However, there are insufficient data on
the relationship between gynaecomastia and any specific
antiretroviral drug and hormone abnormality.
Objective: To assess the frequency of gynaecomastia in
HIV-infected men receiving HAART and its association
with antiretroviral drugs and hormone abnormalities.
Methods: We carried out a prospective study of 1304
HIV-infected men undergoing HAART. In addition, we
included a case (with gynaecomastia)-control (without
gynaecomastia) analysis in the second part of this study.
Cases and controls were matched according to age, HIV
infection CDC clinical category, HCV infection, the date of
study and the physician responsible for the patient.
Patients bearing known causes of gynaecomastia were
excluded. We analysed epidemiological, clinical, haematological and immunological characteristics and the use
and duration of the antiretroviral therapy. In 13 cases
and 13 controls a sexual hormone profile was carried out.
Results: A total of 30 (2.3%) HIV-infected men presented
with gynaecomastia of unexplained cause. In 22 (73%) of
these individuals, gynaecomastia completely resolved
after a median time of 9 months (range: 5–22 months).
The percentage of individuals who were receiving
efavirenz and didanosine at the time of the study was
higher among patients with gynaecomastia [57% vs 17%
(P=0.004) and 50% vs 13% (P=0.003), respectively].
Plasma total testosterone, free testosterone index and
bioavailable testosterone levels were lower in patients
with gynaecomastia, whereas plasma free testosterone
levels were not significantly different in either population.
Conclusions: Gynaecomastia is not uncommon in HIVinfected men undergoing HAART and it is usually
transient. Efavirenz and didanosine treatment are associated with the emergence of gynaecomastia. An
underlying hypoandrogenism seems to contribute to the
emergence of this disorder in these patients.
Introduction
Human immunodeficiency virus (HIV)-infected
patients who are treated with highly active antiretroviral therapy (HAART) can develop breast
enlargement due to benign and malignant mammary
diseases. Malignant diseases include adenocarcinoma,
lymphoma, Kaposi’s sarcoma and metastasis [1].
Benign disorders comprise infections and changes in
the breast stroma, including pseudoangiomatous
stromal hyperplasia, lipomastia and true gynaecomastia [1]. Lipomastia consists of adipose tissue
deposits in the setting of a lipodystrophy syndrome,
whereas true gynaecomastia is an enlargement of the
male breast due to proliferating glandular tissue [1].
©2004 International Medical Press 1359-6535/02/$17.00
It is common knowledge that an increase in
oestrogen levels or a decrease in testosterone levels can
cause gynaecomastia. These hormone changes may be
due to testicular neoplasia, renal or hepatic diseases,
drugs, or primary or secondary hypogonadism [2].
Since the introduction of HAART, a number of cases of
gynaecomastia have been reported in HIV-infected men
taking several antiretroviral drugs such as stavudine,
didanosine, efavirenz, nevirapine and protease
inhibitors (PIs) [3–15]. However, these results came
from studies performed in small populations and are far
from consistent. Likewise, it has been suggested that
hypoandrogenism could be the cause of gynaecomastia
511
JA Mira et al.
in HIV-infected men [1]. In line with this hypothesis, it
has been reported that gynaecomastia in HIV-infected
men can subside after treatment with percutaneous
dihydrotestosterone [14]. However, the frequency and
the relationship between gynaecomastia and any
specific antiretroviral drug or hormone abnormality
need to be clarified – we undertook this study for these
reasons. The goals were to assess the frequency of
gynaecomastia in HIV-infected men receiving HAART
and determine its association with antiretroviral drugs
and hormone abnormalities.
Materials and methods
single therapy treatment and who showed clinical or
immunological evidence of HIV disease progression
were offered the possibility of dual therapy with nucleoside reverse transcriptase inhibitors (NRTIs) (that is,
zidovudine plus didanosine or zalcitabine). Lamivudine and stavudine were included later as part of this
drug regimen. PIs were not extensively available in
these hospitals until 1997. Thereafter, all patients who
received care in our clinics were offered HAART (a
combination of two NRTIs plus a PI). As of 1999, nonnucleoside reverse transcriptase inhibitors (NNRTIs)
were included in HAART. Likewise, from 2000,
abacavir was included in highly active therapies with
three NRTIs.
Populations and follow-up
From April 1989 to May 2003 inclusive, 2752 HIVinfected patients, more than 18 years old and on
antiretroviral therapy were prospectively followed at
three university hospitals in southern Spain. All the
individuals underwent scheduled clinical, haematological and immunological examinations at baseline and
every 3 months after starting therapy. We assessed the
frequency of gynaecomastia in the 1304 HIV-infected
men belonging to this cohort who were seen at our
clinics from January 2000 to May 2003 and who
fulfilled the following criteria: (i) they were on HAART
and (ii) known causes of gynaecomastia were ruled
out. These causes were, specifically, patients with liver
cirrhosis, chronic renal failure, alcoholism, breast
carcinoma and testicular tumour; patients who were
receiving drugs known to cause gynaecomastia such as
anabolic steroids, digoxin, phenytoin, ketoconazole,
spironolactone, methadone, cytotoxic drugs, isoniazid
and methotrexate were also excluded.
In the second part of this study, designed as case
control, we entered the males with gynaecomastia from
this cohort who met the criteria stated in (i) and (ii)
above. We also included a matched control for each
case. Controls were selected from the same cohort who
were also on HAART and did not have known causes
of gynaecomastia. Cases and controls were matched
according to age, HIV infection CDC clinical category,
hepatitis C virus (HCV) infection, date of study (±3
months around the date of gynaecomastia diagnosis in
the cases) and the physician responsible for the patient.
All patients provided their written informed consent to
participate in the study. The study was approved by the
Ethics Committee of the three participating hospitals.
Therapeutic strategies
Patients received antiretroviral drugs depending on
drug availability at the time and always according to
international recommendations. Until 1993, zidovudine was the only commercial antiretroviral drug
available. As of that date, the patients who began
512
Diagnosis of gynaecomastia
All patients included in this survey underwent breast
examinations at each visit during the study period. When
breast enlargement was felt, an ultrasound examination
and/or a mammography were performed. A diagnosis of
true gynaecomastia was performed when the following
criteria were fulfilled: (i) the patient showed a unilateral
or bilateral breast enlargement, (ii) physical examination
identified true glandular tissue around the areola, and
(iii) ultrasonography and/or mammography showed
enlargement of mammary tissue and no tumours, lipomastia or other causes of pseudogynaecomastia.
Laboratory procedures
Plasma HIV RNA load was measured using PCR
(Amplicor, Hoffman-La Roche, Basel, Switzerland) or
NASBA (Nuclisens, Organon Teknika, Boxtel, The
Netherlands), depending on the availability at each
hospital. The limits of detection varied between 20 and
80 copies/ml, according to the time when the analysis
was carried out and the procedure used. CD4+ cell
counts were measured by a standard flow cytometry
procedure. In the cases and controls included by one of
the participant hospitals, a plasma hormone profile
was carried out on the same day of study. Samples were
obtained between 8 am and 10 am to minimize circadian variation in testosterone concentrations. Cortisol,
prolactin, total testosterone, luteinizing hormone (LH),
follicle-stimulating hormone (FSH), beta-human chorionic gonadotropin (β-HCG) and dehydroepiandrosterone sulphate (DHEAS) were measured by means of
an electrochemiluminescence immunoassay (Modular
E-170, Roche Diagnostics, Mannheim, Germany). To
determine sex hormone-binding globulin (SHBG)
levels, commercial kits consisting of fluoroimmunometric assays were used (Auto-Delfia, Perkin Elmer,
Turku, Finland). Free testosterone was measured by
means of a radioimmunoassay (RIA) method
(Diagnostics Products, Los Angeles, Calif., USA). Free
testosterone index and bioavailable testosterone were
©2004 International Medical Press
Gynaecomastia in HIV-infected men on HAART
calculated using the method described by Vermeulen
[16]. Both parameters are calculated from total testosterone, SHBG and albumin concentration. The
formula for calculating both parameters can be found
on the International Society for the Study of the Aging
Male (ISSAM) website at www.issam.ch/freetesto.htm.
Triglyceride concentrations were measured in all
patients using an enzymatic method (Modular D1,
Roche Diagnostics, Mannheim, Germany).
Statistical study
The relationship between gynaecomastia and the
following potential risk factors were assessed: risk
group for HIV transmission [intravenous (iv) drug users
versus non-iv drug users], CD4+ cell counts at beginning HAART, CD4+ cell counts and undetectable viral
load at the time of the study, plasma triglyceride levels,
lipodystrophy, body mass index (BMI), time under
HAART, use of each therapeutic group (NRTI, NNRTI
and PI) and specific antiretroviral drugs at any time
before the inclusion in the study and when gynaecomastia appeared, duration of therapy and different
hormone values. Continuous variables are expressed as
median (range) and categorical variables are expressed
as the number of cases (percentage). Continuous variables were compared using the Wilcoxon test. The
frequencies were compared using the Mc Nemar test.
Data were analysed using the SPPS statistical software
package release 11.0 (SPSS Inc., Chicago, Ill., USA).
Study power calculations were made using nQuery
Advisor 4.0 (Statistical Solutions, Saugus, Mass., USA).
Results
Characteristics of the entire study cohort
The median age of the 1304 individuals studied was 34
(range 19–77) years old. Of these patients, 1056 (81%)
acquired HIV infection through iv drug use and 912
(70%) were HCV positive. HIV infection was categorized as C according to the CDC classification in 469
(36%) patients. On beginning HAART, the median
CD4+ cell count was 205 (1–1520) cells/mm3 and the
median log plasma HIV RNA was 4.3 (1–6.9)
copies/mm3.
Frequency of gynaecomastia and characteristics of
the cases and controls
A total of 63 HIV-infected men showed gynaecomastia
during the study period. However, 33 (52%) individuals were excluded from this study as known causes of
gynaecomastia were identified. Of these, 22 patients
suffered from liver failure and 11 individuals showed
liver failure and were receiving spironolactone. Thus,
30 (2.3%) out of 1304 individuals studied presented
with gynaecomastia of unexplained cause. Of the 30
Antiviral Therapy 9:4
patients with gynaecomastia, 16 (53%) had unilateral
breast enlargement and 25 (83%) complained of
mammary pain. In 22 (73%) individuals, gynaecomastia completely disappeared after a median time of
9 months (range 5–22 months). Among patients with
resolution of their gynaecomastia, 20 (91%) had no
antiretroviral treatment changes due to the presence of
gynaecomastia. Equally, individuals without complete
resolution of their gynaecomastia had no antiviral
therapy changes after the emergence of breast enlargement. One patient presented with a relapse of
unilateral gynaecomastia in the contralateral breast 10
months after the spontaneous resolution of the first
episode. One case and one control had a BMI greater
than 30 kg/m2. Other relevant characteristics of both
populations are shown in Table 1.
Relationship between gynaecomastia and
antiretroviral therapy
Patients with gynaecomastia had been on potent antiretroviral therapy for a median time of 49 months
(range 17–64 months). The development of gynaecomastia was associated with efavirenz therapy at any
time before the inclusion in the study, whereas nevirapine use was associated with a lower frequency of
such a disorder (Table 2). The percentage of individuals
who were receiving efavirenz and didanosine treatment
at the time of the study was higher among cases than
among controls [57% vs 17% (P=0.004) and 50% vs
13% (P=0.003), respectively]. In this same analysis, the
use of zidovudine, lamivudine and nevirapine was more
frequent among controls (Table 3). The time that
patients had been on zidovudine treatment was shorter
among those showing gynaecomastia. The duration of
the therapy with the remaining antiretroviral drugs or
specific drug family was not associated with the emergence of gynaecomastia (Table 4).
Relationship between gynaecomastia and
biochemical determinations
Hormone determinations were performed in 13 cases
and their corresponding controls. Plasma total testosterone, free testosterone index and bioavailable
testosterone levels were lower in patients with gynaecomastia, whereas plasma free testosterone levels were not
significantly different in either population (Table 5).
However, the power of this study to detect significant
differences in free testosterone levels was only 17%.
There were no differences in the levels of the remaining
plasma hormones that were analysed between cases
and controls (Table 5). Patients with gynaecomastia
showed a median (range) level of plasma triglycerides
263 mg/dl (range 83–1114), whereas individuals
without gynaecomastia had a median level of
177 mg/dl (range 65–432) (P=0.048).
513
JA Mira et al.
Table 1. Characteristics of the populations
Characteristic
Patients with
gynaecomastia (n=30)
Patients without
gynaecomastia (n=30)
P value
Age (years)*
IDU (%)
HIV infection CDC clinical category C (%)
Patients with HCV infection (%)
Time on HAART (months)*
CD4+ cell count (cells/mm3) at the beginning of HAART*
CD4+ cell counts (cells/mm3) at the time of the study*
Patients with undetectable plasma viral load at the time of the study (%)
Patients with lipodystrophy (%)
BMI (kg/m2)*
40 (28–63)
53
46
57
49 (17–64)
146 (15–775)
459 (115–1140)
57
60
23.9 (15.8–30.1)
40 (26–63)
60
43
57
52 (24–67)
178 (12–636)
359 (34–1574)
60
43
23.5 (18.7–33)
1
0.5
1
1
0.3
0.5
0.8
1
0.2
0.8
*Median (range). IDU, intravenous drug users; HIV, human immunodeficiency virus; HCV, hepatitis C virus; HAART, highly active antiretroviral therapy; BMI, body
mass index.
Table 2. Relationship between gynaecomastia and the antiretroviral drugs taken at any time before the inclusion in the study
Drug
Patients with gynaecomastia (n=30)
Patients without gynaecomastia (n=30)
P value
NRTI
Stavudine
Zidovudine
Lamivudine
Didanosine
Abacavir
NNRTI
Efavirenz
Nevirapine
PI
Indinavir
Saquinavir
Nelfinavir
30 (100)
25 (83)
29 (97)
29 (97)
23 (77)
9 (30)
24 (80)
21 (70)
6 (20)
27 (90)
18 (60)
14 (47)
18 (60)
30 (100)
21 (70)
26 (87)
29 (97)
17 (57)
7 (23)
19 (63)
7 (23)
16 (53)
26 (87)
18 (60)
12 (40)
13 (43)
1
0.4
0.2
1
0.2
0.7
0.06
0.01
0.01
1
1
0.8
0.2
Values are expressed as number of cases (percentage). NRTI, nucleoside reverse transcriptase inhibitors; NNRTI, non-nucleoside reverse transcriptase inhibitors;
PI, protease inhibitors.
Table 3. Relationship between gynaecomastia and the antiretroviral drugs that patients were taking at the time of the study
Drug
Patients with gynaecomastia (n=30)
Patients without gynaecomastia (n=30)
P value
NRTI
Stavudine
Zidovudine
Lamivudine
Didanosine
Abacavir
NNRTI
Efavirenz
Nevirapine
PI
Indinavir
Saquinavir
Nelfinavir
30 (100)
17 (57)
5 (16)
13 (43)
15 (50)
8 (27)
20 (66)
17 (57)
3 (10)
10 (33)
3 (10)
1 (3)
6 (20)
30 (100)
15 (50)
13 (43)
21 (70)
4 (13)
7 (23)
16 (53)
5 (17)
11 (37)
11 (36)
5 (17)
1 (3)
5 (17)
1
0.8
0.02
0.04
0.003
1
0.1
0.004
0.02
1
0.6
1
1
Values are expressed as number of cases (percentage). NRTI, nucleoside reverse transcriptase inhibitors; NNRTI, non-nucleoside reverse transcriptase inhibitors;
PI, protease inhibitors.
514
©2004 International Medical Press
Gynaecomastia in HIV-infected men on HAART
Table 4. Relationship between gynaecomastia and the duration (weeks) of therapy with each antiretroviral drug
Drug
Patients with gynaecomastia (n=30)
Patients without gynaecomastia (n=30)
P value
NRTI
Stavudine
Zidovudine
Lamivudine
Didanosine
Abacavir
NNRTI
Efavirenz
Nevirapine
PI
Indinavir
Saquinavir
Nelfinavir
522 (104–1025)
197 (5–304)
86 (4–299)
146 (21–304)
96 (5–211)
50 (28–73)
72 (10–143)
60 (8–143)
38 (17–72)
120 (5–430)
49 (5–232)
49 (13–240)
91 (27–190)
484 (212–937)
174 (3–284)
194 (47–384)
176 (3–273)
85 (2–222)
78 (54–119)
99 (38–218)
67 (38–104)
97 (43–218)
132 (16–298)
97 (16–216)
65 (4–155)
99 (52–202)
0.6
0.3
0.009
0.6
0.7
0.2
0.07
0.5
0.07
0.6
0.07
0.75
0.6
Values are expressed as median (range). NRTI, nucleoside reverse transcriptase inhibitors; NNRTI, non-nucleoside reverse transcriptase inhibitors; PI, protease inhibitors.
Table 5. Relationship between gynaecomastia and plasma hormone levels
Hormone
Patients with gynaecomastia (n=13)
Patients without gynaecomastia (n=13)
P value
Cortisol (µg/dl)
DHEAS (µg/dl)
Total testosterone (ng/ml)
Free testosterone (pg/ml)
SHBG (nmol/l)
Free testosterone index (ng/ml)
Bioavailable testosterone (ng/ml)
Prolactin (ng/ml)
LH (UI/l)
FSH (mUI/l)
β-HCG (mUI/ml)
18 (12–36)
0.9 (0.2–6.7)
4 (0.4–11.4)
58 (23–126)
100 (42–207)
0.04 (0.005–0.10)
0.81 (0.12–2.08)
12.2 (5.5–38.7)
7.9 (0.9–18.3)
6.4 (1.6–50.5)
0.12 (0.1–2.7)
24 (11–31)
2.1 (0.2–4.2)
6.6 (2.5–10.8)
77 (34–144)
63 (33–144)
0.07 (0.03–0.16)
1.69 (0.73–3.31)
14 (5.8–30.6)
6.9 (3.4–24.5)
6.3 (2.6–13)
0.14 (0.1–0.6)
0.2
0.5
0.04
0.5
0.2
0.02
0.001
0.7
0.8
0.2
0.7
Values are expressed as median (range). DHEAS, dehydroepiandrosterone sulphate; SHBG, sex hormone-binding globulin; LH, luteinizing hormone; FSH, folliclestimulating hormone; β-HCG, beta-human chorionic gonadotrophin.
Discussion
The results reported here show that the frequency of
gynaecomastia is not negligible in HIV-infected men on
HAART. This breast enlargement is usually transient
without modifying therapy. Likewise, gynaecomastia
in HIV-infected men is associated with efavirenz and
didanosine treatment. On the other hand, an underlying hypoandrogenism seems to exist in male
individuals suffering from this disorder.
This study has some limitations due to the fact that
the sample size is relatively small and that hormone
analyses were not performed in the entire population.
Consequently, the study has limited statistical power to
detect some differences that otherwise could have been
observed. However, this series is one of the largest in
which this issue has been evaluated [3,7–10,14,15]. It
is also the first controlled study where the relationship
between gynaecomastia and antiretroviral drug intake
has been statistically analysed in depth, including
Antiviral Therapy 9:4
simultaneous hormone studies in a population. The
exclusion of patients with other causes of gynaecomastia is an additional strength of this survey.
Marijuana use, a practice that has been said to be
related to the emergence of gynaecomastia [17], was
not considered as an exclusion criterion in this study.
The reason for this decision was that more than 70%
of the patients included in this cohort reported
smoking marijuana or derivatives. Moreover, the relationship between cannabis use and gynaecomastia has
not been found in all studies [18,19].
The finding of an association between gynaecomastia and high plasma triglyceride levels might
suggest that lipomastia was misdiagnosed as gynaecomastia. However, the diagnosis of this disorder was
made according to strict clinical and ultrasonographic
criteria. Examiners identified the typical consistency of
mammary gland tissue in breast palpation, and it was
also necessary for an enlargement of mammary tissue
to be seen at ultrasound examination to make this
515
JA Mira et al.
diagnosis. Moreover, gynaecomastia subsided in 73%
of cases and was painful in 25 patients – neither spontaneous resolution nor pain is characteristic of
lipomastia [20]. In our opinion, the association
between gynaecomastia and hypertriglyceridaemia
rather suggests that both disorders are parallel, but
independent to each other.
There have been a number of reports in which
gynaecomastia in HIV-infected men was found to be
associated with antiretroviral drugs [3–15]. In a
previous study, the percentage of patients treated with
stavudine, didanosine and nelfinavir was greater
among the individuals with gynaecomastia than among
those without gynaecomastia [10]. Our study confirms
the association between gynaecomastia and didanosine
therapy. Most cases and controls in this study had been
treated with stavudine in the past, since this drug has
been extensively used in our area. This fact could mask
the effect of this drug on gynaecomastia. More cases
than controls had received nelfinavir, but the difference
did not reach statistical significance. In addition,
protective roles of zidovudine, lamivudine and nevirapine were observed in our study. This finding may be
due to the fact that efavirenz and nevirapine were
usually alternative and mutually excluding therapies,
rather than to a true protective effect of the latter drug.
A similar relationship may exist between lamivudine
and zidovudine with regard to didanosine.
It has been reported that prolonged HAART, particularly with PI [13,15], is a risk factor for the development
of gynaecomastia. However, we did not observe such a
finding. Moreover, the associations between efavirenz
and didanosine treatment with gynaecomastia shown in
our study were not dependent on the length of time on
these drugs. These facts suggest that gynaecomastia
emergence depends more on the use of specific drugs
than on the duration of therapy.
It has been suggested that hypoandrogenism may be
the cause of gynaecomastia in HIV-infected men [1].
Androgen deficiency is a common endocrine abnormality among patients harbouring HIV infection
[21–24]. Thus, although it is less common in HIVinfected men in a stable clinical condition in the HAART
era [23], this hormonal disturbance continues to occur
with considerable frequency in men with AIDSassociated wasting syndrome, involving nearly 20% of
this population [24]. Total testosterone plasma levels
were lower in patients with gynaecomastia in our study.
Nevertheless, total testosterone level is not a reliable
marker of androgen deficiency in HIV-infected patients,
since many of these individuals harbour altered plasma
SHBG levels [25]. Changes of this binding protein lead
to modifications in plasma levels of total testosterone
[25,26]. Therefore, the most useful laboratory markers
of androgen deficiency are plasma concentrations of free
516
and bioavailable testosterone [25–27]. Bioavailable
testosterone measures the proportion of testosterone not
bound to SHBG (free testosterone plus albumin-bound
testosterone). This parameter can accurately reflect the
level of testosterone deficiency [26,27]. In our study,
plasma free testosterone levels were lower in patients
with gynaecomastia, but this difference did not reach
statistical significance, probably due to a lack of statistical power. In addition, when free testosterone index
and bioavailable testosterone were calculated by the
method proposed by Vermeulen et al. [16], both parameters were associated with the development of
gynaecomastia. These results support the premise that a
hypogonadism is involved in the emergence of breast
enlargement in these patients.
The association between hypogonadism and gynaecomastia could suggest a possible link between HAART
and hypoandrogenism. In studies where the impact of
antiretroviral drugs on free and total testosterone levels
has been appraised, the results have been conflicting
[23,24]; no relationship has been reported between
hypoandrogenism and HAART including efavirenz or
didanosine therapy [23,24]. In addition to androgen
deficiency, gynaecomastia can be due to other causes
that would explain the association with antiretroviral
drug intake. Thus, mitochondrial toxicity has been
proposed to be related to the emergence of gynaecomastia [10]. The association with hypertrygliceridaemia
found in this and in other studies would support such a
hypothesis [7,10]. On the other hand, it has been stated
that gynaecomastia may be a consequence of enhanced
interleukin-2 production due to immune restoration [9].
However, most immune reconstitution manifestations
appear early in the few weeks or months after beginning
HAART, whereas gynaecomastia arose in our patients
after a median of 49 months on HAART. This finding
argues against the latter hypothesis.
In summary, gynaecomastia is not uncommon in
HIV-infected men under HAART, especially in those
taking efavirenz and didanosine. When gynaecomastia
develops in patients on HAART, other causes, particularly malignancy, need to be excluded. Even if another
cause is not proved, stopping the regimen is not
warranted. This is a mild and usually transient condition that subsides spontaneously in a few months in
many patients. Additional studies are needed in order
to further clarify the relationship between androgen
deficiency and the antiretroviral therapy.
References
1.
Pantanowitz L & Connolly JL. Pathology of the breast
associated with HIV/AIDS. Breast Journal 2002;
8:234–243.
2.
Ismail AA & Barth JH. Endocrinology of gynaecomastia.
Annals of Clinical Biochemistry 2001; 38:596–607.
©2004 International Medical Press
Gynaecomastia in HIV-infected men on HAART
3.
Peyriere H, Mauboussin JM, Rouanet I, Merle C, Sotto A,
Arnaud A, Hillaire-Buys D & Balmes P. Report of gynecomastia in five male patients during antiretroviral therapy
for HIV infection. AIDS 1999; 13:2167–2169.
4.
Melbourne KM, Brown SL & Silverblatt FJ. Gynecomastia
with stavudine treatment in an HIV-positive patient.
Annals of Pharmacotherapy 1998; 32:1108.
5.
Schurmann D, Bergmann F, Ehrenstein T & Padberg J.
Gynecomastia in a male patient during protease inhibitor
treatment for acute HIV disease. AIDS 1998;
12:2232–2233.
6.
Caeiro JP, Visnegarwala F & Rodríguez MC.
Gynecomastia associated with indinavir therapy. Clinical
Infectious Diseases 1998; 27:1539–1540.
7.
Manfredi R, Calza L & Chiodo F. Gynecomastia associated with highly active antiretroviral therapy. Annals of
Pharmacotherapy 2001; 35:438–439.
8.
Arranz Caso JA, de Miguel Prieto J, Casas E & Sanz J.
Gynecomastia without lipodystrophy syndrome in HIVinfected men treated with efavirenz. AIDS 2001;
15:1447–1448.
9.
Qazi NA, Morlese JF, King DM, Ahmad RS, Gazzard BC
& Nelson MR. Gynecomastia without lipodystrophy in
HIV-1-seropositive patients on efavirenz: an alternative
hypothesis. AIDS 2002; 16:506–507.
10. Paech J, Lorenzen T, von Krosigk A, Graefe K, Stoehr A &
Plettenberg A. Gynaecomastia in HIV-infected men: association with effects of antiretroviral therapy. AIDS 2002;
16:1193–1194.
11. Toma E & Therrien R. Gynecomastia during indinavir
antiretroviral therapy in HIV infection. AIDS 1998;
12:681–682.
12. Herry I, Bernard L, de Truchis P & Perronne C.
Hypertrophy of the breast in a patient with indinavir.
Clinical Infectious Diseases 1997; 25:937–938.
13. Evans DL, Pantanowitz L, Dezube BJ & Aboulafia DM.
Breast enlargement in 13 men who were seropositive for
human immunodeficiency virus. Clinical Infectious
Diseases 2002; 35:1113–1119.
14. Benveniste O, Simon A & Herson S. Successful percutaneous dihydrotestosterone treatment of gynecomastia
occurring during highly active antiretroviral therapy: four
cases and a review of the literature. Clinical Infectious
Diseases 2001; 33:891–893.
15. García-Benayas T, Blanco F, Martín-Carbonero L, Valencia
E, Barrios A, González-Lahoz J & Soriano V.
Gynecomastia in HIV-infected patients receiving antiretroviral therapy. AIDS Research & Human Retroviruses
2003; 19:739–741.
16. Vermeulen A, Verdonack L & Kaufman JM. A critical
evaluation of simple methods for the estimation of free
testosterone in serum. Journal of Clinical Endocrinology &
Metabolism 1999; 84:3666–3672.
17. Harmon J & Aliapoulios MA. Gynecomastia in marihuana
users. New England Journal of Medicine 1972; 287:936.
18. Thompson DF & Carter JR. Drug-induced gynecomastia.
Pharmacotherapy 1993; 13:37–45.
19. Cates W Jr & Pope JN. Gynecomastia and cannabis
smoking. A nonassociation among US Army soldiers.
American Journal of Surgery 1977; 134:613–615.
20. Mauss S. HIV-associated lipodystrophy syndrome. AIDS
2000; 14(Suppl. 3):197–207.
21. Grispoon S & Bilezikian JP. HIV disease and the endocrine
system. New England Journal of Medicine 1992;
327:1360–1365.
22. Dobs AS, Dempsey MA, Ladenson PW & Polk BF.
Endocrine disorders in men infected with human
immunodeficiency virus. American Journal of Medicine
1988; 84:611–616.
23. Collazos J, Martínez G, Mayo J & Ibarra S. Sexual
hormones in HIV-infected patients: the influence of antiretroviral therapy. AIDS 2002; 16:934–937.
24. Rietschel P, Corcoran C, Stanley T, Basgoz N, Klibanski A
& Grinspoon SK. Prevalence of hypogonadism among men
with weight loss related to human immunodeficiency virus
infection who were receiving highly active antiretroviral
therapy. Clinical Infectious Diseases 2000; 31:1240–1244.
25. Mylonakis E, Koutkia P & Grinspoon S. Diagnosis and
treatment of androgen deficiency in human
immunodeficiency virus-infected men and women. Clinical
Infectious Diseases 2001; 33:857–864.
26. Vermeulen A & Kaufman JM. Diagnosis of hypoandrogenism in the aging male. Aging Male 2002; 5:170–176.
27. Morley JE & Perry III HM. Androgen treatment of male
hypogonadism in older males. Journal of Steroid
Biochemistry & Molecular Biology 2003; 85:367–373.
Received 12 December 2003, accepted 22 March 2004
Antiviral Therapy 9:4
517