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Koutkia P, Canavan B, Breu J, Torriani M, Kissko J, Grinspoon S. Growth Hormone–Releasing Hormone in HIV-Infected Men With Lipodystrophy: A Randomized Controlled Trial. JAMA. 2004;292(2):210–218. doi:10.1001/jama.292.2.210
Author Affiliations: Massachusetts General Hospital Program in Nutritional Metabolism and Neuroendocrine Unit (Drs Koutkia and Grinspoon, Ms Canavan) and Department of Radiology (Dr Torriani and Mr Kissko), Harvard Medical School, Boston, Mass; General Clinical Research Center, Massachusetts Institute of Technology, Cambridge (Mr Breu).
Context Reduced growth hormone (GH) concentrations are observed in men with
human immunodeficiency virus (HIV) lipodystrophy.
Objective To investigate the effects of growth hormone–releasing hormone
(GHRH), a GH secretagogue, in treatment of HIV lipodystrophy.
Design, Setting, and Participants Randomized, double-blind, placebo-controlled trial conducted at a research
center in the United States between October 2002 and June 2003 and enrolling
31 HIV-infected men aged 18 to 60 years with evidence of lipodystrophy.
Interventions Participants were assigned to receive GHRH (1 mg subcutaneously twice
daily) or placebo for 12 weeks.
Main Outcome Measures The primary outcome was change in concentrations of insulin-like growth
factor 1 (IGF-1) to detect overall change in GH levels in response to GHRH.
Secondary end points included body composition by dual-energy x-ray absorptiometry
and computed tomography, lipodystrophy ratings, and levels of glucose, insulin,
Results Mean (SD) IGF-1 concentrations increased significantly in the GHRH group
vs the placebo group (104  ng/mL vs 6  ng/mL, P = .004). Lean body mass significantly increased in the GHRH group
vs the placebo group (0.9 [1.3] kg vs −0.3 [1.7] kg, P = .04), trunk fat significantly decreased (−0.4 [0.7] kg vs
0.2 [0.6] kg, P = .03), and the ratio of trunk to
lower extremity fat improved significantly (−0.22 [0.32] vs 0.14 [0.29], P = .005). Abdominal visceral fat was reduced (–19.2
[36.6] cm2 vs 2.3 [24.3] cm2, P =
.07) and the ratio of abdominal visceral fat to abdominal subcutaneous fat
improved significantly more in the GHRH group (–0.19 [0.28] vs 0.07
[0.27], P = .02). Both physician and patient rating
of lipodystrophy in the arms, legs, and abdomen also improved significantly.
Levels of glucose, insulin, and lipids did not change significantly.
Conclusions GHRH was well tolerated and effectively increased levels of IGF-1 in
HIV-infected men with lipodystrophy. Total and regional body composition improved
in response to GHRH, with increased lean mass and reduced truncal and visceral
fat. Use of GHRH may potentially be a beneficial treatment strategy for this
The human immunodeficiency virus (HIV) lipodystrophy syndrome is highly
prevalent among patients receiving antiretroviral therapy.1 Although
heterogeneous in its presentation, the syndrome is often characterized by
excessive truncal and visceral adiposity, subcutaneous and extremity fat loss,2 and metabolic abnormalities including hypertriglyceridemia,
reduced high-density lipoprotein cholesterol levels, and insulin resistance,
which may increase risk of coronary artery disease.3,4 Cross-sectional
studies do not uniformly show an association between lipodystrophy and antiretroviral
therapy,5 but longitudinal cohort studies suggest
that protease inhibitors (PIs) and nucleoside reverse transcriptase inhibitors
(NRTIs) may be associated with loss of peripheral fat.6 Prospective
studies of body composition in antiretroviral-naive individuals suggest loss
of extremity fat and gain in truncal fat with institution of highly active
antiretroviral therapy.7 In a randomized study
of antiretroviral-naive individuals initiating antiretroviral therapy, use
of a stavudine-containing regimen was associated with a greater loss of limb
fat than was use of other NRTIs, and use of nelfinavir was associated with
greater loss of extremity fat than an efavirenz-based regimen.8 It
is unknown whether newer, low-dose, "boosted" PIs are less significantly associated
with the development of lipodystrophy. Accumulation of truncal fat is a significant
cardiovascular risk factor in non–HIV-infected patients,9,10 and
preliminary data suggest that the severity of the metabolic abnormalities
increases in association with excess visceral adiposity in patients with HIV.11 Men with HIV lipodystrophy have reduced levels of
growth hormone (GH) secretion in association with excess visceral fat,12,13 and this may further contribute to
increased cardiovascular risk in this population.
To date, no effective therapy has been established to treat the lipodystrophy
syndrome. Use of GH is a potentially appealing strategy to treat the lipodystrophy
syndrome because of its known lipolytic actions to reduce visceral fat in
GH-deficient patients14 and because of the
recent data suggesting low GH concentrations in individuals with HIV lipodystrophy.12 However, use of high-dose GH may be associated with
insulin resistance and fluid retention, myalgias, and other adverse effects.15-19 Although
restoration of normal GH levels may be possible and safe with low-dose GH
administration, another approach is to treat with a natural GH secretagogue,
such as growth hormone–releasing hormone (GHRH), to restore a more physiologic
pattern of GH than that achieved with pharmacologic GH therapy. With GHRH,
feedback inhibition of insulin-like growth factor 1 (IGF-1) (a hepatic factor
the secretion of which is stimulated by GH and which is responsible for many
of its actions) may help to prevent excessive GH secretion and adverse effects.20,21 In contrast, exogenous GH administration
is not significantly affected by feedback inhibition from IGF-1, titration
is more difficult, and adverse effects may occur relating to GH excess. We
used concentration of IGF-1 as the primary end point of the study to assess
the changes in the GH axis in response to GHRH. Because GH is pulsatile, use
of IGF-1, an integrated measure of GH secretion, is better suited to assess
increases in GH secretion. Prior studies indicate that levels of IGF-1 are
lower by approximately 100 ng/mL in HIV-infected patients with lipodystrophy,13 and the GHRH regimen used in this study increased
IGF-1 to this degree.
From 2002 to 2003 (individuals were screened from September 10, 2002,
through January 31, 2003), 31 HIV-infected men with HIV-related lipodystrophy
were recruited through community advertisements and contact with physicians
in the multidisciplinary HIV practice at the Massachusetts General Hospital
in Boston. The lipodystrophy was not congenital and was acquired in all participants
in the context of treatment of HIV disease. Participants were asked to report
when they first noted fat redistribution, and the mean (SD) duration of self-reported
lipodystrophy was 32 (22) months.
Inclusion criteria included: men aged 18 to 60 years previously diagnosed
with HIV infection; stable antiviral regimen for at least 6 weeks prior to
enrollment; waist-to-hip ratio of 0.90 or greater; and evidence of at least
1 of the following recent changes: (1) increased abdominal girth, (2) relative
loss of fat in the extremities, and (3) relative loss of fat in the face.
A similar algorithm was previously used to identify patients with HIV having
fat redistribution and decreased levels of GH.12 Participants
were excluded if they had diabetes mellitus (defined as fasting blood glucose
>126 mg/dL [7.0 mmol/L]); body mass index less than 20; hemoglobin concentration
less than 9 g/dL; or if they had used GH, GHRH, oral or parenteral glucocorticoids,
megesterol acetate, or antidiabetic agents within the 3 months prior to study
The protocol was approved by the institutional review board of the Massachusetts
General Hospital and written informed consent was obtained from each participant
prior to testing (ie, at the beginning of the study, before any tests were
performed), in accordance with the Subcommittee on Human Studies at the Massachusetts
The primary outcome was change in levels of IGF-1 to detect overall
changes in levels of GH in response to GHRH. Secondary end points included
body composition determined by dual-energy x-ray absorptiometry (DXA) and
computed tomography (CT); lipodystrophy ratings; levels of glucose, insulin,
lipids, and glycosylated hemoglobin (HbA1c); energy expenditure;
caloric intake; blood pressure; CD4 cell count; viral load; and GH pulse dynamics.
After a 12-hour overnight fast, participants reported to the General
Clinical Research Center (GCRC) at the Massachusetts General Hospital for
a screening visit for measurement of glucose levels and complete blood cell
count. Data regarding past and current use of antiretroviral medications were
provided by the participant during the medical history intake and recorded.
Participants had a physical examination that included measurement of the neck,
mid arm, trunk, and waist-to-hip ratio. Eligible participants returned to
the GCRC for an inpatient baseline visit, outpatient safety visit at 1 and
6 weeks, and an inpatient end-of-study visit at 12 weeks.
During the baseline and end-of-study visits the following data were
collected after a 12-hour overnight fast: (1) height and weight; (2) levels
of IGF-1, glucose, HbA1c, insulin, cholesterol, low-density lipoprotein
cholesterol, high-density lipoprotein cholesterol, and triglycerides; (3)
75-g oral glucose tolerance test to determine levels of glucose and insulin;
(4) CD4 cell count and viral load; (5) resting energy expenditure and 4-day
food record; (6) whole-body DXA scan; (7) single-slice abdominal CT scan at
L4 and mid thigh; (8) physician and participant rating of lipodystrophy; and
(9) overnight GH sampling, from 7 PM to 7:40 AM every
After baseline testing was completed, participants were randomly assigned
to receive daily subcutaneous injections of Geref (GHRH 1-29; Serono, Rockland,
Mass) (1 mg every 12 hours) or identical placebo. An investigational new drug
application was filed for the use of GHRH in this study, but an exemption
was granted by the US Food and Drug Administration. The GHRH dose was determined
from a prior study in elderly persons22 in
which a similar dose of GHRH (1 mg subcutaneously twice daily) was safely
used in elderly men to restore physiologic GH levels over 14 days.22 Randomization codes were available to the study statistician
and the Massachusetts General Hospital pharmacy, but not to study investigators.
Placebo was manufactured by the Massachusetts General Hospital pharmacy and
was identical to active drug in color, consistency, and packaging. Participants
received instruction on self-administration of the study medication by the
nursing staff of the GCRC and study drug administration was witnessed at the
baseline and 1-week visits to ensure proper technique. Compliance history
and vial count were performed at each visit. Compliance was measured by return
of used vials and review of medication use at each subsequent visit by the
investigator and nursing staff. Missing or broken vials were assumed to be
unused. Of those men completing the study (n = 29), 2 were unable to continue
with study drug injections; for those 2 men and for 2 men (1 in each group)
who were lost to follow-up, compliance was not calculated.
Whole-body and regional fat was determined by DXA. The technique has
a precision error, in our laboratory, of 1.7% for fat and 2.4% for fat-free
mass. Lower extremity fat, trunk fat, and trunk-to-extremity ratios were assessed
using DXA as in prior studies.23 Single-slice
cross-sectional abdominal CT scanning was also performed to assess the relative
distribution of abdominal subcutaneous adipose tissue (SAT), abdominal visceral
adipose tissue (VAT), and mid-thigh SAT as previously described.24
Levels of IGF-1 were measured by 2-site radioimmunometric assay (RIA)
(Diagnostic Systems Laboratories Inc, Webster, Tex) (intra-assay coefficient
of variation [CV], 4.93%). Levels of GH were measured by RIA (Corning Inc,
Nichols Institute, San Juan Capistrano, Calif) (intra-assay CV, 3.33%; sensitivity,
0.01 ng/mL). Insulin levels were determined by RIA (Diagnostic Products Corp,
Los Angeles, Calif) (intra-assay CV, 5.2%). Glucose, HbA1c, and
lipid concentrations were measured by standard techniques.25 Concentrations
of direct low-density lipoprotein cholesterol were determined by immunoseparation
spectrophotometry (Specialty Laboratories, Santa Monica, Calif) (intra-assay
CV, 3.0%). The CD4 cell count was performed using standard flow cytometry
technology (B-D TruCount; Becton Dickinson, San Jose, Calif), and the HIV
viral load was determined by ultrasensitive assay (Roche Amplicor HIV-1 Monitor
Assay Version 1.0; Roche, Indianapolis, Ind), with a lower limit of detection
of 50 copies/mL.
Circulating GH levels in humans fluctuate widely due to pulsatile GH
secretion by the pituitary gland. As a result, random measurement of serum
GH will not establish accurate GH secretory patterns. We therefore used standard
pulsatility techniques and sampling rates to determine the pattern of GH pulse
secretion as has been previously established to assess GH pulsatility in response
to GHRH administration.26,27 To
assess growth hormone pulsatility we used Cluster28,29 and
specified individual test-cluster sizes for the nadir and peak width of 2
(2 × 2).30
Physicians and participants independently rated lipodystrophy in the
face, abdomen, arms, and legs at the baseline and final visit using a 4-point
rating scale (none, mild, moderate, or severe), and the changes in rating
scores were compared between the groups. The patient rating scale was adapted
from Lichtenstein et al.31,32 In
contrast to prior studies using this scale, we limited our analysis to the
face, arms, legs, and abdomen to allow assessment of the relative distribution
of fat in the trunk and extremities in response to GHRH. Lipodystrophy ratings
were performed by a single investigator (P.K.).
At the final visit, participants also completed a self-administered
questionnaire regarding change in overall appearance over 3 months. Participants
were asked if they believed their overall appearance to be much worse, somewhat
worse, not different, somewhat better, or much better compared with 3 months
previous. All questionnaires were completed at the final visit prior to unblinding
of the study. Participants were not prompted or aided by the investigators
in their answers.
The primary end point of the study was change in levels of IGF-1 between
the groups. The study enrolled 31 men with a planned 10% dropout rate and
was powered to detect a treatment difference of 105 ng/mL in IGF-1 level at
a 2-sided P<.05 significance level, based on prior
data showing the standard deviation of IGF-1 level in this population to be
87.0 ng/mL.12 The study was not powered in
advance to detect changes in other metabolic variables but achieved statistical
significance in many secondary end points (see "Results" section). Post hoc
power analyses showed that the study was well powered to detect clinically
relevant changes into the abnormal range in levels of glucose (91% power at P<.05) and HbA1c (99% power at P<.05) but may have been underpowered to detect significant changes
in some variables. The t test was used to compare
baseline data. Treatment effect was determined by comparison of change from
baseline between treatment groups using the t test.
For viral load and CD4 cell count, baseline values and the changes between
treatment groups were compared with the Wilcoxon test. Race and overall antiretroviral
use were compared using χ2 likelihood ratios. The Fisher exact
test was used for comparison of individual antiretroviral medications. All
available data are included in the analyses in an intention-to-treat design.
Similar results were obtained excluding the follow-up data from the 2 participants
in the placebo group who completed the trial on an intention-to-treat basis
(Grinspoon et al, unpublished data, February 2004). Also, we performed another
analysis with the last observation carried forward for the 2 men who discontinued
placebo injections and the results were again similar. Their treatment status
was made available for safety reasons (because of adverse effects) (see "Results"
section). In terms of missing data, we were unable to obtain follow-up data
(and thus unable to calculate change from baseline) for 2 men, 1 in the treatment
group and 1 in the placebo group. These men were unwilling or unable to make
the follow-up visits (see "Results" section), and no interim data were available
for them. We performed an analysis with the last observation carried forward
for these 2 men and the results were nearly identical. P values remained significant for all the variables that are significant
in the current analysis (Grinspoon et al, unpublished data, February 2004).
Thus, these missing data do not skew the results, even with a conservative
approach to impute missing data.
Outlier analysis was performed using the Dixon criterion.33 The
randomization code was determined by the GCRC biostatistician using a permuted-block
algorithm. All statistical analyses were performed using SAS JMP Statistical
Database Software version 4 (SAS Institute Inc, Cary, NC). Statistical significance
was defined as a 2-tailed α value of P≤.05.
Results are mean (SD) unless otherwise indicated.
Growth hormone–releasing hormone is generally well tolerated and
adverse effects have been shown to occur in a minority of patients. Adverse
effects known to occur rarely in response to GHRH administration include brief
injection-site reactions, headache, flushing, dizziness, and urticaria.34 Approximately 60% of patients may develop anti-GHRH
antibodies with no effect on response.35 With
excess dosing, adverse effects similar to those observed with high-dose GH
may occur, including arthralgias and fluid retention.36,37 In
children, rare hypothyroidism can occur.35 An
independent data and safety monitoring board, consisting of an AIDS expert,
statistician, and community advocate, met every 3 months during the study
to review adverse events.
The 12-week treatment phase of the study took place from October 9,
2002, through June 15, 2003. Two of the 31 participants were unable to complete
the protocol (Figure 1). One participant,
assigned to the placebo group, withdrew from the study immediately after the
baseline visit because of poor vision and an inability to learn the injection
techniques. A second participant, assigned to the treatment group, was incarcerated
after the baseline visit and unavailable to continue with the study. Two additional
participants in the placebo group discontinued the study medication after
the baseline visit because of adverse events (chest pain and rash) but agreed
to remain in the study (without receiving further doses of study drug) and
return for all subsequent study evaluations.
Clinical and demographic characteristics for the HIV-infected participants
are shown in Table 1. Baseline
characteristics, including age, weight, racial demographics, and risk factors
for HIV infection, did not differ between the treatment groups (P>.05 for all baseline comparisons) (Table 1). The percentages of men using PI-, NRTI-, and NNRTI-containing
regimens did not differ between the groups (Table 1). At baseline, use of individual drugs among the study participants
was: abacavir (16%), abacavir in combination with lamivudine and zidovudine
(Trizivir; GlaxoSmithKline, Research Triangle Park, NC) (10%), amprenavir
(3%), didanosine (19%), efavirenz (39%), indinavir (3%), lamivudine (32%),
lopinavir in combination with ritonavir (Kaletra; Abbott Laboratories, Abbott
Park, Ill) (16%), nelfinavir (10%), nevirapine (23%), ritonavir (10%), saquinavir
(3%), stavudine (39%), tenofovir (23%), zidovudine (6%), and zidovudine in
combination with lamivudine (Combivir; GlaxoSmithKline) (16%). The rate of
stavudine use was not statistically different (20% vs 56% for GHRH vs placebo, P = .07). Also, controlling for stavudine use did not affect
the results for trunk and extremity fat (Grinspoon et al, unpublished data,
May 2004). There were no significant differences for any of the baseline antiretroviral
drugs except for nevirapine (40% vs 6% for GHRH vs placebo, P = .04). However, nevirapine may not have an effect on body composition.38,39 Moderate to severe fat accumulation
in the abdomen was observed in 94% of the men, moderate to severe fat loss
in the legs or arms in 87%, and moderate to severe fat loss in the face in
84%, as determined by physician rating of lipodystrophy at baseline.
Changes in response to GHRH treatment for metabolic and body composition
variables are shown in Table 2.
Variables did not differ at baseline between treatment groups (P>.05 for all baseline comparisons). Mean (SD) concentrations of IGF-1
increased significantly in the GHRH group compared with the placebo group
in response to GHRH (104  ng/mL vs 6  ng/mL for GHRH vs placebo, P = .004). Lean body mass increased significantly (0.9
[1.3] kg vs −0.3 [1.7] kg, P = .04), whereas
total fat mass did not change significantly between the groups (0.0 [1.3]
kg vs –0.1 [1.4] kg, P = .80). By DXA, lower
extremity fat increased in the GHRH group vs the placebo group (0.2 [0.4]
kg vs –0.1 [0.3] kg, P = .05), whereas trunk
fat decreased significantly (−0.4 [0.7] kg vs 0.2 [0.6] kg, P = .03), with a significant change in the ratio of trunk fat to lower
extremity fat (−0.22 [0.32] vs 0.14 [0.29], P =
.005) (Table 2).
By CT, abdominal VAT decreased on average 9% in the GHRH group and increased
1% in the placebo group (−19.2 [36.6] cm2 vs 2.3 [24.3] cm2 for GHRH vs placebo, P = .07) (Table 2). In contrast, abdominal SAT increased 4% in the GHRH-treated
group and decreased 2% in the placebo group, although these changes were not
significant. The net overall effect of GHRH on the ratio of abdominal VAT
to abdominal SAT was significant and amounted to a 12% decrease in the GHRH
group vs a 7% gain in the placebo group (P = .02)
(Table 2). Subcutaneous fat at
the mid thigh decreased less in the GHRH group vs the placebo group (−0.1
[5.0] cm2 vs –3.8 [4.7] cm2, P = .05).
Levels of fasting glucose, HbA1c, fasting insulin, total
cholesterol, and triglycerides, as well as glucose area under the curve, insulin
area under the curve, and lipid profile, did not change significantly between
treatment groups (Table 2). One
person in the GHRH group developed an asymptomatic fasting glucose level greater
than 126 mg/dL (7.0 mmol/L) at the end-of-study visit (P = .22). Neither CD4 cell count nor viral load changed significantly
between treatment groups (Table 2).
Physician and patient rating of lipodystrophy improved significantly
in the arms, legs, and abdomen in the GHRH group vs the placebo group (Table 3). Participants were also asked
to answer an exit question at the final visit as to how their overall appearance
compared with that 3 months previous. The percentages of men answering were
as follows: much worse (0% vs 0% for GHRH vs placebo), somewhat worse (0%
vs 20%), no difference (21% vs 53%), somewhat better (50% vs 27%), much better
(29% vs 0%) (overall P = .005 by likelihood ratio).
Initial lipodystrophy ratings did not correlate with change in overall appearance
as assessed by exit questionnaire.
Pulse dynamics were determined from every 20-minute frequent sampling.
The number of secretion peaks did not change between the 2 groups, but the
peak height decreased whereas the valley mean level and nadir increased significantly
in the GHRH group vs the placebo group (Table 4).
Compliance with study drug was assessed as described above and was 94%
for the GHRH group and 95% for the placebo group (P =
.86). One person in each group discontinued antiretroviral medications. Two
men in the GHRH group changed therapy: 1 switched from an NRTI/NNRTI regimen
to an NRTI/PI regimen and the second added another NRTI. Use of PIs, NRTIs,
and NNRTIs were not different between the groups at the end-of-study visits
(end-of-study PI use: 29% vs 40% for GHRH vs placebo, P = .52; NRTI use: 79% vs 87%, P = .56; NNRTI
use: 64% vs 53%, P = .55). Use of individual drugs
did not change significantly between groups over the course of the study (Grinspoon
et al, unpublished data, February 2004).
Blood pressure did not increase in the GHRH group (Table 2), and no participant experienced edema, arthralgias, or
any other symptoms of GH excess. No participant in the GHRH group dropped
out of the study due to adverse effects. Three months after completion of
the study, 1 participant in the GHRH group with a history of anal warts was
diagnosed with anal carcinoma. The participant's IGF-1 level did not exceed
the normal range during the study. This event was believed by the data and
safety monitoring board not to be related to GHRH.
The study was powered for the primary end point only. Although many
secondary end points changed significantly in response to GHRH, the study
may have been underpowered to detect changes in certain variables, eg, abdominal
VAT, which approached statistical significance. Post hoc power analysis showed
that the study was well powered to detect significant changes in the primary
safety parameters, eg, levels of glucose and HbA1c (see "Statistical
In this study, we investigated the novel use of GHRH to restore physiologic
GH levels in HIV-infected men with lipodystrophy. Restoration of physiologic
GH levels has been investigated in non–HIV-infected patients with abdominal
obesity,40 but prior studies have only used
administration of pharmacological GH and not previously investigated GHRH
in the HIV population. Body composition improved without adverse effects on
glucose levels or GH excess, suggesting the potential usefulness of this strategy
in the HIV population.
In the HIV population, markedly reduced mean GH secretion and pulse
area are observed in association with increased visceral adiposity.13 Reduced GH secretion is observed in other populations
with abdominal obesity41 and may further contribute
to increased abdominal adiposity, in a vicious cycle of adiposity and reduced
GH. Among non–HIV-infected individuals, restoration of more normal GH
concentrations results in improved fat distribution and improved metabolic
parameters.40 Our data suggest that interruption
of the GH-adiposity cycle by restoration of more normal GH concentrations
can result in an improved pattern of fat distribution. The study was approved
for men by the institutional review board and the General Clinical Research
Center Scientific Advisory Committee because of the known effects of sex on
the GH axis.42-45 Seventy-one
percent of the population was white, and further studies in women and minorities
will be important.
A number of prior studies have investigated GH administration in HIV-infected
patients and shown positive effects on abdominal fat, but all such studies
have used administration of pharmacological GH. For example, Wanke et al15 investigated a GH dose of 6 mg/d in an open-label
study and demonstrated a reduction in abdominal adiposity, but glucose level
increased significantly in 1 patient and complaints of myalgias and stiffness
were common. Engelson et al18 demonstrated
an approximate 50% reduction in abdominal VAT after 24 weeks in response to
growth hormone at 6 mg/d in an open-label study, but 3 participants developed
diabetes. Lo et al19 used a lower dose of 3
mg/d in an open-label study of 8 patients, and observed beneficial effects
on trunk fat, but IGF-1 levels increased to 3 times the upper end of the normal
range, and glucose intolerance worsened initially in all patients. Although
glucose levels tended to return to normal, 1 patient developed overt diabetes
mellitus and arthralgias necessitating dose reduction, and 2-hour glucose
levels as well as glucose area under the curve remained increased at the end
of the study compared with baseline.19 Kotler
et al46 reported on the results of a large,
double-blind, randomized, dose-finding study of GH in individuals with HIV
and with lipodystrophy and marked visceral obesity, demonstrating significant
reductions in visceral fat in the 4-mg daily group, but not in the group receiving
4 mg on alternate days. Significant reductions in trunk fat determined by
DXA, ratio of trunk fat to limb fat, and levels of serum total and non–high-density
lipoprotein cholesterol were observed at both dosages. Insulin resistance
tended to worsen initially but then improve toward baseline with continued
Endogenous GHRH is a natural secretagogue for GH.47 Prior
studies have used GHRH to restore normal GH levels and increase levels of
IGF-1.22 Once-daily dosing with nightly GHRH
is less effective than multiple daily doses of GHRH,48 and
we chose twice-daily dosing.
The use of GHRH to restore physiologic GH levels is less often associated
with adverse effects than is GH itself and may reduce abdominal adiposity
without inducing insulin resistance, fluid retention, or myalgias,35 because IGF-1 feedback inhibition remains intact.
Corpas et al22 investigated the use of GHRH
(Geref; 1 mg subcutaneously twice per day) in elderly men to restore levels
of IGF-1 and physiologic GH without an increase in glucose levels. No adverse
effects were reported. A longer-term study using GHRH in children also demonstrated
excellent tolerability and efficacy.35
Our data demonstrate that physiological increases in GH levels after
administration of GHRH result in fat redistribution that includes an improved
ratio of abdominal VAT to SAT. Similar changes in fat distribution with sparing
of subcutaneous fat have been shown in response to low-dose GH in non–HIV-infected
GH-deficient patients.14,49 Although
further studies will be necessary to determine the long-term effects of GHRH
on body composition, our data suggest that GHRH at the dose and duration used
in this study is not lipolytic for subcutaneous fat.
In this study, we did not observe adverse effects on levels of glucose
and HbA1c. It is unlikely that we would have detected clinically
significant changes, even with a much larger population based on a post hoc
power analysis. Individuals with diabetes mellitus were excluded from this
study, and larger increases in glucose levels may be observed in those with
higher baseline levels. No significant changes in levels of cholesterol or
triglycerides were observed between treatment groups, but the study may have
been underpowered to detect such changes based on the variability in responses.
GHRH was well tolerated. Blood pressure did not differ between groups, and
no evidence of edema or GH excess was observed in participants receiving GHRH.
Further studies of longer duration will be needed to confirm the absence of
clinically significant effects of GHRH on glucose levels in HIV-infected patients,
and those with significant elevations in blood glucose levels should be excluded
from such studies. In addition, individuals with underlying malignancy are
not appropriate for treatment with GHRH. Further long-term studies are needed
to determine if changes in fat distribution from administration of GHRH are
associated with improvement in insulin resistance and to determine the durability
and optimal dosing duration for GHRH.
Immunological parameters remained stable. Growth hormone has been shown
to increase CD4 cell counts and thymic mass in patients with HIV.50 In addition, GH secretagogues have been shown to
have immunomodulatory effects in both animal51 and
human52 studies. Further studies are needed
to determine the long-term effects of GHRH on immune function in HIV-infected
Our data suggest a mixed effect on pulse dynamics, with increased nadir
and valley but decreased peak height in response to GHRH vs placebo. One potential
explanation of our data is a direct stimulatory effect of GHRH to increase
the basal GH secretion and nadir, with feedback inhibition of increased IGF-1
on peak height.
No established therapy yet exists to treat patients with HIV and lipodystrophy.
The novel strategy investigated in this study, treatment with GHRH, addresses
a physiologic abnormality, eg, reduced GH levels, to achieve physiological
increases in GH levels and significant changes in fat redistribution. GHRH
is not currently approved for chronic treatment of HIV lipodystrophy and not
commercially available, approved, or recommended for any indication in adults.
The cost of such a treatment is unknown. However, an estimate based on the
previously published price in children53 would
be approximately $1775 per month at 2 mg/d. Twice-daily subcutaneous injections
may not be feasible, but other GH secretagogues dosed orally or by less-frequent
injections may be developed and useful to study in the HIV population. Treatment
of reduced GH levels might alternatively use low-dose physiologic GH to reduce
visceral fat and improve ratios of central fat to peripheral fat. Metformin54,55 and rosiglitazone56-58 may
improve insulin sensitivity, and rosiglitazone may increase subcutaneous fat.56,58 It is unknown how long a patient
would need to continue to receive treatment with GHRH.
The present study provides initial evidence of the principle that restoration
of physiologic GH levels may be beneficial in HIV-infected men with reduced
GH levels and suggests the need for further studies using GHRH, other secretagogues,
or physiologic GH to improve fat distribution in HIV-infected patients.
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