0021-972X/99/$03.00/0 Vol. 84, No.

6
The Journal of Clinical Endocrinology & Metabolism Printed in U.S.A.
Copyright © 1999 by The Endocrine Society

Endocrine and Metabolic Evaluation of Human

Immunodeficiency Virus-Infected Patients with Evidence
of Protease Inhibitor-Associated Lipodystrophy
JACK A. YANOVSKI*, KIRK D. MILLER*, TOMOSHIGE KINO,
THEODORE C. FRIEDMAN, GEORGE P. CHROUSOS, CONSTANTINE TSIGOS†, AND
JUDITH FALLOON
Developmental Endocrinology Branch (J.A.Y., T.C.F., G.P.C., T.K., C.T.), National Institute of Child
Health and Human Development; the Department of Critical Care, Warren Grant Magnuson Clinical
Center (K.D.M.); and the Laboratory of Immunoregulation (J.F.), National Institute of Allergy and
Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892; and the Division of
Endocrinology, Department of Medicine, Cedars-Sinai Medical Center Burns and Allen Research
Institute, University of California School of Medicine (T.C.F.), Los Angeles, California 90048

ABSTRACT hydroxycorticosteroid excretion was significantly greater in PIAL

Multidrug antiretroviral regimens that include human immuno-
deficiency virus-1 (HIV-1) protease inhibitors are associated with
distinct lipodystrophy, hypertriglyceridemia, hyperinsulinemia, and
deposition of visceral abdominal adipose tissue. To determine
whether these findings are related to abnormalities of adrenal func-
tion, we compared the hypothalamic-pituitary-adrenal axes of HIV-
positive patients who had evidence of protease inhibitor-associated
lipodystrophy (PIAL), control volunteers (CON), and patients with
Cushing’s syndrome (CS). To elucidate the metabolic consequences of
the observed lipodystrophy, we measured basal serum lipids and
compared glucose and insulin concentrations during an oral glucose
tolerance test.
Spontaneous plasma cortisol showed normal diurnal variation in
PIAL. Cortisol levels were similar in CON and PIAL, and levels in
these groups were less than those in CS at all times of the night or
day (P , 0.005). Ovine CRH-stimulated morning plasma cortisol
levels were similar in PIAL and CON. ACTH was significantly greater
in PIAL than CON (P , 0.05) at 0, 15, and 30 min after CRH stim-
ulation. Urinary free cortisol in PIAL (mean 6 SD, 76 6 51 nmol/day)
was significant lower than those in CON (165 6 64 nmol/day; P ,
0.001) and CS (1715 6 1203 nmol/day; P , 0.001). However, 17-
(43 6 23 mmol/day) than in CON (17 6 8 mmol/day; P , 0.001),
although lower than that in CS (74 6 47 mmol/day; P , 0.01). Scat-
chard analysis revealed normal glucocorticoid receptor number and
affinity in PIAL. Serum triglycerides were significantly greater in
PIAL (6.57 6 5.63 mmol/L) than in CS (1.78 6 0.83 mmol/L; P , 0.001)
or CON (1.36 6 0.84 mmol/L; P , 0.001). Although triglyceride levels
were significantly correlated with body mass index for CON and CS,
these were not correlated for PIAL. During an oral glucose tolerance
test, similar glucose and insulin values were found in PIAL and CS
that were greater (P , 0.05) than CON values at 30, 60, 90, and 120
min.
We conclude that the lipodystrophy associated with use of HIV-1
protease inhibitors is a syndrome of increased intraabdominal adi-
posity with concomitant dyslipidemia and insulin resistance, but
without total body weight gain and is distinct from any known form
of hypercortisolism. Although urinary cortisol disposition seems to be
altered in HIV-infected patients who are being treated with multidrug
regimens that include protease inhibitors, the decreased free cortisol
and increased 17-hydroxycorticosteroid excretion appear to be un-
likely explanations for the observed lipodystrophy. The cause remains
to be elucidated. (J Clin Endocrinol Metab 84: 1925–1931, 1999)

T HE ADDITION of reversible inhibitors of the human

immunodeficiency virus-1 (HIV-1) aspartic acid pro-
tease to antiretroviral regimens has been a major advance in
the treatment of HIV-1 infection (1). Since their introduction,
HIV-positive patients are experiencing fewer opportunistic
complications from their disease and are living longer, more
productive lives (2– 4). At present, four protease inhibitors,
saquinavir, ritonavir, nelfinavir, and indinavir, are available
for general use in the United States.
As survival with HIV-1 has improved, attention has been
Received July 17, 1998. Revision received January 12, 1999. Accepted
February 24, 1999.
Address all correspondence and requests for reprints to: Jack A.
Yanovski, M.D., Ph.D., National Institutes of Health, 10 Center Drive,
MSC 1862, Building 10, Room 10N262, 9000 Rockville Pike, Bethesda,
Maryland 20892-1862. E-mail: jy15i@nih.gov.
* Commissioned officers, USPHS.
† Current address: Division of Basic Research, Hellenic National Di-
abetes Center, 3 Ploutarchou Street, 106 75 Athens, Greece.
directed toward the adverse consequences of HIV treatment
regimens. Numerous side-effects have been reported with
protease inhibitor use, including abnormalities in glucose
homeostasis, hyperlipidemia, and changes in body compo-
sition including redistribution of body adipose tissue (5–19).
In HIV-1-infected patients treated with indinavir with such
symptoms, we have previously reported increased triglyc-
eride concentrations and disproportionate amounts of intra-
abdominal adipose tissue, without increased amounts of sc
abdominal adipose tissue (18).
A number of reports in other conditions have found
greater hypothalamic-pituitary-adrenal (HPA) axis activity
in those with greater amounts of intraabdominal adipose
tissue (20 –25). We hypothesized that the greater intraab-
dominal adipose tissue of HIV-infected patients treated with
protease inhibitors might be related to abnormalities of ad-
renal function. We therefore studied the HPA axis of HIV-
1-infected men and women with protease inhibitor-associ-
ated lipodystrophy (PIAL), using patients with Cushing’s

1925
1926 YANOVSKI ET AL. JCE & M • 1999
Vol 84 • No 6

syndrome (CS) and control volunteers as comparison

groups. To elucidate the metabolic consequences of the ob-
served lipodystrophy, we also studied plasma lipid concen-
trations and assessed glucose tolerance in study participants.

Subjects and Methods

Subjects
We studied 12 HIV-1-infected patients who were identified as having
protease inhibitor-associated lipodystrophy (PIAL), 28 patients with CS,
and 43 healthy control volunteers (CON) believed to have normal HPA
axis activity.
The diagnosis of PIAL was based on the presence of characteristic
changes in body fat distribution that have been associated with PIAL
(Fig. 1). These changes include increased visceral abdominal fat, loss of
facial fat, development of dorsocervical and supraclavicular fat pads,
and breast enlargement in women (11–19). Patients with signs or symp-
toms of visceral abdominal fat accumulation were evaluated by com-
puted tomography scan (18) for evidence of visceral abdominal adipose
accumulation (Fig. 1).
The mean CD41 lymphocyte count of patients with PIAL (Table 1)
was 911 6 357 (mean 6 sd). All but two had HIV-1 viral loads below
500 copies/mL, the lower limit of detection of a branched HIV-1 DNA
assay (Chiron Corp., Emeryville, CA). No patient had an active oppor-
tunistic or other infection at the time of evaluation. Nine of the 12
patients with PIAL were participating in ongoing trials of intermittent
interleukin-2 therapy in the treatment of HIV-1 infection (Table 1). No
subject had received treatment with interleukin-2 more recently than 4
weeks before evaluation. All subjects with PIAL were prescribed anti-
retroviral regimens that included a protease inhibitor at the time of
evaluation (Table 1). Subjects with PIAL had been treated with protease
inhibitors for an average of 17.4 6 7.5 (mean 6 sd) months. The single
patient (no. 5) not prescribed indinavir at the time of study had dis-
continued it 8 months previously and had been treated since then with
Ritonavir and saquinavir. Three other patients who were taking indi-
navir at the time of evaluation had taken saquinavir, and two had taken
Ritonavir in the past.
All patients with CS had clinical and biochemical evidence of hy-
percortisolism, including urinary free cortisol (UFC) excretion greater
than 248 nmol/day (normal, 27–248 nmol/day), and had the etiology of
CS confirmed at surgery. Of the 28 patients with CS, 21 had CD, 6 had
the syndrome of ectopic ACTH secretion, and 1 had primary pigmented
nodulocortical adrenal disease (26). Healthy control volunteers had nor-
mal physical examinations, were taking no medications on a regular
basis, had 24-h UFC measurements within the normal range, and had
no evidence of cardiac, pulmonary, hepatic, renal, or endocrine illnesses.
All subjects were studied after discontinuing any medication known to
affect the HPA axis. Informed consent was obtained from all subjects,
and the study protocols were approved by the NICHHD institutional
review board. Diurnal cortisol results from 12 CON and 12 CS and oral
glucose tolerance test results from 16 CS described in this paper have
previously been published (27, 28).

Protocol
Subjects were admitted to the Warren Grant Magnuson Clinical Cen-
ter for study. In all subjects, the 24-h excretion of UFC, 17-hydroxycor- FIG. 1. Patient 1, with multiple features of PIAL, including loss of
ticosteroids (17-OHCS), and creatinine was measured for 1 day. An oral facial fat, dorsocervical tissue accumulation, and abdominal disten-
glucose tolerance test was performed in 11 PIAL, 18 CS, and 11 CON. tion (top panel). An abdominal computed tomography scan shows
Each subject ingested 75 mg dextrose by mouth, and serum glucose and abundant visceral abdominal adipose tissue causing abdominal dis-
insulin concentrations were measured at 0, 30, 90, and 120 min. Serum tention (bottom panel).
for the measurement of cortisol was collected from an indwelling iv
catheter in 10 PIAL, 13 CS, and 12 CON at the following times: 0600, 0700,
0800, 1000, 1200, 1400, 1600, 1800, 2000, 2200, 2300, 2400, 0100, 0300, 0500,
0600, and 0700 h. Samples for cortisol from an additional 15 CS and 14 and ACTH 1 min before CRH stimulation and then 15, 30, and 60 min
CON were obtained only from 0600 – 0800 h and from 2300 – 0100 h. after CRH.
Fasting samples were obtained for triglycerides, total cholesterol, and
HDL cholesterol from all subjects. In 11 PIAL, 28 CS, and 35 CON, a CRH Hormonal analyses
stimulation test was performed. Ovine CRH (Bachem California, Inc.,
Torrance, CA) was administered as an iv bolus injection at a dose of 1 UFC, 17-OHCS, and creatinine excretion were measured as previ-
mg/kg between 0800 – 0810 h. Plasma samples were assayed for cortisol ously described (29). Plasma ACTH, cortisol, and cortisol-binding glob-
 ENDOCRINE ABNORMALITIES AND USE OF PROTEASE INHIBITORS 1927

TABLE 1. Characteristics of patients with PIAL

CD41 Antiretroviral Interval since Duration

Patient Viral load
Gender Lipodystrophy manifestations lymphocytes regimen when treatment with IL-2 of PI use
no. (copies/mL)
(%) evaluated (months) (months)
1 M Dorsocervical fat pad, 748 (34) ,500 Indinavir, lamivudine, Never treated 13
abdominal distention, nevirapine
facial wasting
2 M Abdominal distention, facial 1167 (41) ,500 Indinavir, lamivudine, 2 19
wasting didanosine
3 M Abdominal distention, facial 968 (53) ,500 Indinavir, lamivudine, 3 30
wasting stavudine
4 M Abdominal distention 1210 (49) ,500 Indinavir, stavudine, 9 6
zalcitabine
5 M Dorsocervical fat pad 34 (2) 115,900 Lamivudine, ritonavir, Never treated 25
saquinavir,
zidovudine
6 M Abdominal distention 784 (66) ,500 Indinavir, lamivudine, 22 17
zidovudine
7 M Dorsocervical fat pad, 961 (41) ,500 Indinavir, lamivudine, Never treated 4
abdominal distention stavudine
8 M Abdominal distention, facial 1251 (49) ,500 Indinavir, lamivudine, 4 18
wasting stavudine
9 M Abdominal distention, facial 1292 (35) ,500 Indinavir, lamivudine, 19 19
wasting stavudine
10 F Truncal obesity, breast 805 (42) 2,119 Indinavir, stavudine, 3 18
enlargement didanosine
11 M Abdominal distention, facial 1133 (31) ,500 Indinavir, lamivudine, 1.25 25
wasting zidovudine
12 F Truncal obesity, breast 578 (35) ,500 Indinavir, lamivudine, 1 15
enlargement zidovudine
Percentages are given in parentheses.

ulin were measured as previously described (30) by Covance Labora-
tories, Inc. (Vienna, VA).
Glucose, triglyceride, total cholesterol, and high density lipoprotein
cholesterol assays were performed at the NIH’s Warren Grant Magnu-
son Clinical Center Clinical Pathology Laboratory using standard col-
orimetric methods on a Hitachi 736 –30 analyzer (Boehringer Mannheim,
Indianapolis, IN). High density lipoprotein cholesterol was measured
after precipitation with phosphotungstic acid. Insulin was measured by
RIA at Covance Laboratories, Inc.
Glucocorticoid receptor binding affinity and number
Glucocorticoid receptor binding affinity and number were deter-
mined by standard methods (31). Briefly peripheral blood mononuclear
cells were isolated using Ficoll-Isopaque and were seeded at 2 3 106
cells/well in 500 mL incubation medium (RPMI 1640 supplemented with
50 mg/mL streptomycin and 50 U/mL penicillin) in 24-well tissue cul-
ture plates. 3H-Labeled dexamethasone, in six different concentrations
ranging from 1.5–50 nmol/L, was then added. Nonspecific binding was
determined in the presence of a 200-fold excess of cold dexamethasone.
Binding capacity and Kd values were determined by Scatchard analysis.
Statistical analyses
Data were analyzed on a Macintosh PowerPC using SuperAnova 1.11
and StatView 4.5 software (Abacus Concepts, Inc., Berkeley, CA).
ANOVA, with repeated measures where appropriate, was used to com-
pare the hormone concentrations during the ovine CRH and glucose
tolerance tests, followed by preplanned, paired and unpaired Fisher’s
least significant difference tests, corrected for multiple comparisons.
Due to heteroscadasticity of variance, hormone measurements were
subjected to logarithmic transformation before analysis. For the ovine
CRH test, the 21 patients with CD were compared to CON and PIAL,
although results were not significantly altered when all patients with CS
were included in the analysis (data not shown).
Results
The characteristics of subjects with PIAL are compared to
those of CON and CS in Table 2. Body mass index was
significantly lower in PIAL (26.1 6 3.9 kg/m2) and CON
(25.8 6 4.7 kg/m2) than in CS (33.4 6 8.0 kg/m2; P , 0.005
vs. CON or PIAL).
Diurnal cortisol sampling demonstrated normal cortisol
levels throughout the day and night in both PIAL and CON
and abnormally high values in CS (Fig. 2). There were no
significant differences between PIAL and CON at any time
point. After CRH stimulation (Fig. 3), cortisol responses of
PIAL and CON were similar. ACTH was significantly greater
in PIAL than CON at baseline, 15 min, and 30 min (P , 0.05).
Both PIAL and CON had significantly lower plasma ACTH
and cortisol levels than CS at all times examined (P , 0.01).
The urinary excretion (Table 2) of free cortisol in PIAL
(mean 6 sd, 76 6 51 nmol/day) was within the normal range,
but significantly lower than those in CON (165 6 64 nmol/
day; P , 0.001) and CS (1715 6 1203 nmol/day; P , 0.001).
However, excretion of 17-OHCS was significantly greater in
PIAL (43 6 23 mmol/day) than in CON (17 6 8 mmol/day;
P , 0.0001), but was still significantly lower than that in CS
(74 6 47 mmol/day; P , 0.01). When urinary excretion of
17-OHCS was expressed per g creatinine, and free cortisol
1928 YANOVSKI ET AL. JCE & M • 1999
Vol 84 • No 6

TABLE 2. Study subjects

Protease inhibitor-associated Healthy control volunteers Cushing’s syndrome

lipodystrophy (n 5 12) (n 5 53) (n 5 28)
Age (yr) 45.1 6 7.3 38.7 6 10.3 38.4 6 10.3
Body mass index (kg/m2) 25.9 6 4.1 25.8 6 4.7 33.4 6 8.0a
Gender (% of total) 2 female (17) 12 female (23) 22 female (78)a
Race 11 Caucasian, 1 African 40 Caucasian, 1 Hispanic, 23 Caucasian, 3 Hispanic,
American 12 African American 2 African American
Fasting plasma insulin (pmol/L) 119.6 6 78.9 77.6 6 35.5 201.5 6 80.7
24-h urinary free cortisol (normal, 50 – 76 6 51b 165 6 64 1715 6 1203a
250 nmol/day)
24-h urinary free cortisol, corrected for 47.7 6 29.8b 110.2 6 43.8 1057.9 6 771.3a
body surface area (nmol/day z m2)
Urinary 17-hydroxycorticosteroid 43 6 23b 17 6 8 74 6 47a
(normal, 5.5–22.0 mmol/day)
Urine 17-hydroxycorticosteroid 2.8 6 1.9b 1.1 6 0.5 5.4 6 3.4a
corrected for creatinine (mmol/mmol)
Serum cholesterol (mmol/L) 6.42 6 1.79c 4.69 6 1.15 5.80 6 1.13a
Serum HDL (mmol/L) 0.59 6 0.15b 1.16 6 0.32 1.54 6 0.80
Serum triglycerides (mmol/L) 7.01 6 5.62b 1.36 6 0.84 1.78 6 0.83
Percentages are given in parentheses.
a
P , 0.005, Cushing’s syndrome vs. healthy control volunteers.
b
P , 0.001, PIAL vs. healthy control volunteers and vs. Cushing’s syndrome.
c
P , 0.001, patients with protease inhibitor-associated lipodystrophy vs. control volunteers.

FIG. 2. Diurnal plasma cortisol concentrations (mean 6 SEM) in pa-

tients with PIAL, CON, and CS. **, P , 0.005, CS vs. PIAL and vs.
CON at all time points.

was expressed per m2 surface area (Table 2), the comparisons

were unchanged; UFC excretion was significantly lower in
PIAL than in CON (P , 0.001) or CS (P , 0.001), whereas
17-OHCS excretion was greater in PIAL than in CON (P ,
0.01), but lower than that in CS (P , 0.005).
The morning plasma cortisol-binding globulin level in
PIAL was 716.2 6 155.7 nmol/L, comparable to results in
CON (652.3 6 132.2) and well within the published normal
range for cortisol-binding globulin (27, 32). The glucocorti-
coid receptor number and affinity of patients with PIAL were
within the range reported as normal (33). As determined by
Scatchard analysis, patients with PIAL had 2702 6 865 glu-
cocorticoid receptors/mononuclear cell, and the Kd was
4.4 6 1.7 nmol.
During an oral glucose tolerance test, glucose and insulin
values were significantly higher (P , 0.05) in PIAL and CS
than in CON at 30, 60, 90, and 120 min and were similar in
PIAL and CS (Fig. 4). Total serum cholesterol was similar in
PIAL and CS and was significantly greater in both than in
CON. Serum triglycerides were significantly greater in PIAL
FIG. 3. Plasma ACTH and cortisol concentrations (mean 6 SEM) dur-
ing an ovine CRH stimulation test in patients with PIAL, CON, and
CS. *, P , 0.05, PIAL vs. CON; **, P , 0.01, CS vs. PIAL and vs. CON
at all time points.
(6.57 6 5.63 mmol/L) than in CS (1.78 6 0.83 mmol/L; P ,
0.02) or CON (1.36 6 0.84 mmol/L; P , 0.01). Although
triglyceride levels were significantly correlated with body
mass index for CON and CS, these were not correlated in
patients with PIAL (Fig. 5).
Discussion
In this study, we systematically examined the HPA axis of
patients with PIAL to determine whether abnormalities in
this axis might account for the observed changes in body
composition. Individuals with PIAL showed no laboratory
findings consistent with systemic hypercortisolism. Patients
 ENDOCRINE ABNORMALITIES AND USE OF PROTEASE INHIBITORS
FIG. 4. Serum glucose and insulin concentrations (mean 6 SEM) in
patients with PIAL, CON, and CS. *, P , 0.05, CON vs. CS; Œ, P ,
0.05, CON vs. PIAL and vs. CS.
with PIAL had normal diurnal cortisol secretion, normal
cortisol secretory dynamics after the administration of ovine
CRH, normal cortisol-binding globulin levels, and normal
glucocorticoid receptor number and affinity. Thus, although
this study is limited by the absence of HIV-positive subjects
not treated with protease inhibitors, the lack of abnormali-
ties, compared with normal controls, in circulating cortisol
levels or in glucocorticoid receptor number or affinity rules
out hyperactivity of the HPA axis as a primary cause of PIAL.
These results are consistent with other reports of normal UFC
measurements and normal dexamethasone suppression in
patients with PIAL (19).
We also observed that basal and CRH-stimulated plasma
ACTH and 24-h urinary 17-OHCS excretion were signifi-
cantly greater, whereas UFC excretion was significantly
lower, in PIAL than in CON. These results were quite distinct
from those observed in CS, where plasma ACTH, cortisol,
urinary 17-OHCS, and UFC were all increased to a signifi-
cantly greater extent. Others have reported UFC levels
within the normal range for patients with PIAL (19), but did
not compare them to levels in body mass index-matched
controls. We do not believe that interleukin-2 therapy af-
fected these results, because most subjects had not received
interleukin-2 within several months of evaluation.
The increased plasma ACTH in concert with greater 17-
OHCS and lower UFC lead us to conclude that the metab-
olism of cortisol is altered by the medication regimens em-
ployed in HIV-positive patients with PIAL, but in a manner
that allows for normal plasma cortisol concentrations. Many
medications interfering with cortisol metabolism induce he-
patic cytochrome P-450 enzymes that enhance the metabo-
lism of cortisol to 6b-hydroxycortisol and 6b-hydroxycorti-
sone, but such medications would not produce the observed
findings, because these steroids do not form Porter-Silber
chromogens measured as 17-OHCS (34). Others, such as
spironolactone or hydroxyzine, may increase apparent 17-
1929
FIG. 5. Relation between serum triglycerides and body mass index in
patients with PIAL, CON, and CS.
OHCS values because they may also produce a yellow color
(35). Spectrophotometric analysis at three wavelengths was
performed in the present study to avoid including such in-
terfering substances; no such substances were identified in
any of the samples.
The most parsimonious hypothesis for these findings is
that the metabolism of cortisol is altered in PIAL by one or
more of the anti-HIV medications taken by these individuals,
such that one or more of the steroids measured as 17-OHCS,
but not as free cortisol, is increased. The Porter Silber chro-
mogens include 11-deoxycortisol, cortisol, cortisone, 11-de-
oxytetrahydrocortisol, tetrahydrocortisol, tetrahydrocorti-
sone, and their glucuronidated forms. The UFC assay
employed in this study is specific, measuring only cortisol.
Greater activity of the renal 11-ketosteroid reductase en-
zyme, which catalyzes the conversion of cortisol to cortisone,
or partial inhibition of the adrenal 11-hydroxylase enzyme,
which catalyzes the conversion of 11-deoxycortisol to corti-
sol, are explanations consistent with the available data.
Because we did not study a group of HIV-infected indi-
viduals who had not been treated with protease inhibitors,
we cannot specifically ascribe these alterations in cortisol
metabolism to the use of protease inhibitors. However, as
laboratory alterations and symptoms coincided with the on-
set of protease inhibitor treatment, we believe that it is most
likely that the increased plasma ACTH and urinary 17-OHCS
and decreased UFC are side-effects of protease inhibitors.
Aspartic acid proteases may be important in the processing
of many different biological molecules, possibly including
enzymes important in cortisol metabolism. Thus, protease
inhibitors may have a number of biological effects not easily
predicted ex vivo. We are currently attempting to determine
which urinary steroids are increased by the administration of
protease inhibitors. Nevertheless, because plasma cortisol is
unaltered, we cannot ascribe the signs of PIAL to these al-
terations in steroid metabolism. One remaining possibility is
that protease inhibitors specifically alter the sensitivity to
glucocorticoids of particular adipose tissue depots, including
visceral abdominal adipose tissue, without action at other fat
depots, thus leading to increased visceral abdominal adipose
tissue deposition and the metabolic derangements observed
1930 YANOVSKI ET AL.
without leading to a generalized Cushingoid habitus or ab-
normalities in circadian cortisol secretion.
Because the catalytic HIV-1 aspartic acid protease has ap-
proximately 60% homology with the low density lipoprotein
receptor-related protein and the cytoplasmic retinoic acid-
binding protein type 1 or 2, one group has proposed that
incomplete inhibition of the actions of these proteins could
change serum lipid concentrations and increase rates of ap-
optosis in peripheral adipocytes. This, in turn, might stim-
ulate visceral abdominal adipose tissue accumulation, be-
cause fewer peripheral adipocytes would be available to
process circulating fatty acids (36). It also remains possible
that PIAL is due at least in part to a reactive change that
occurs in response to the marked changes in viral load that
occur after initiation of protease inhibitor treatment or is an
ongoing process that may predate the onset of protease in-
hibitor therapy, but be exacerbated by it. Future studies are
needed in this area to determine both the cause of PIAL and
the best approach for treating this complication of protease
inhibitor therapy.
We also confirm previously reported findings of elevated
triglycerides and insulin resistance in patients treated with
HIV protease inhibitors (6 –10). Carr et al. described signif-
icantly greater fasting insulin and triglyceride levels in HIV-
positive patients treated with protease inhibitors compared
either to healthy men or to HIV-positive men not treated with
protease inhibitors, and greater fasting insulin in those with
PIAL compared to HIV-positive patients without PIAL (17).
Two of their protease inhibitor-treated patients developed
new-onset type II diabetes. In the present study, cholesterol
and insulin levels were elevated to a similar extent in PIAL
and CS, whereas triglyceride values were significantly
greater in PIAL than in either CS or CON. The uncoupling
of the relationship between body mass and triglyceride levels
in PIAL is evidence that the antiretroviral regimens of pa-
tients with PIAL induce a unique syndrome that is distinct
from either simple body fat gain or even gain of intraab-
dominal adipose tissue, as is seen in CS, although as we have
reported previously (18), triglyceride concentrations in PIAL
remain correlated with the degree of trunkal obesity and
intraabdominal adipose tissue.
Carr et al. reported that 64% of HIV-positive patients
treated with a protease inhibitor developed PIAL, with an
estimated median time to lipodystrophy of 10 months after
starting protease inhibitor treatment (17). As determined by
dual energy x-ray absorptiometry, patients with PIAL have
less fat than HIV-positive men not treated with protease
inhibitors in body regions other than the central abdomen
(17), where we have previously found greater intraabdomi-
nal adipose tissue in such patients (18). One feature of PIAL
that is decidedly different from CS is wasting of facial fat.
This has been a striking feature in our patients taking pro-
tease inhibitors and has been described previously (12, 15,
17). Although PIAL shares some characteristics of known
lipodystrophies, such as Barraquer-Simmons lipodystrophy
(37), it appears to be distinct from all previously described
syndromes (38).
We conclude that the lipodystrophy found with protease
inhibitor treatment is a syndrome of increased intraabdomi-
nal adiposity with associated dyslipidemia and insulin re-
JCE & M • 1999
Vol 84 • No 6
sistance, but without total body weight gain, and is distinct
from any known form of hypercortisolism. Although cortisol
metabolism is altered by anti-HIV treatment such that
plasma ACTH levels are increased and a significantly greater
amount of cortisol is excreted as 17-hydroxycorticosteroids,
abnormalities in the HPA axis do not affect either plasma
cortisol or glucocorticoid receptor number and affinity. The
observed alterations in glucocorticoid clearance appear un-
likely to explain the observed lipodystrophy. The underlying
mechanism by which protease inhibitors induce the lipo-
dystrophy observed in HIV-1-infected patients remains to be
elucidated.
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