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The Journal of Clinical Endocrinology and Metabolism logoLink to The Journal of Clinical Endocrinology and Metabolism
. 2009 Dec 16;95(2):693–698. doi: 10.1210/jc.2009-1919

Adipokine Profile and Urinary Albumin Excretion in Isolated Growth Hormone Deficiency

Carla R P Oliveira 1, Roberto Salvatori 1, Rafael A Meneguz-Moreno 1, Manuel H Aguiar-Oliveira 1, Rossana M C Pereira 1, Eugênia H A Valença 1, Vanessa P Araujo 1, Natália T Farias 1, Débora C R Silveira 1, Jose G H Vieira 1, Jose A S Barreto-Filho 1
PMCID: PMC2840862  PMID: 20016047

Abstract

Background: GH deficiency (GHD) is often associated with cardiovascular risk factors, including abdominal fat accumulation, hypercholesterolemia, and increased C-reactive protein. Despite the presence of these risk factors, adults with congenital lifetime isolated GHD (IGHD) due to an inactivating mutation in the GHRH receptor gene do not have premature atherosclerosis.

Objective: The aim was to study the serum levels of adiponectin and leptin (antiatherogenic and atherogenic adipokine, respectively), and the urinary albumin excretion (UAE) in these IGHD individuals.

Design and Patients: We conducted a cross-sectional study of 20 IGHD individuals (seven males; age, 50.8 ± 14.6 yr) and 22 control subjects (eight males; age, 49.9 ± 11.5 yr).

Main Outcome Measures: Anthropometric factors, body composition, blood pressure, serum adiponectin, leptin, and UAE were measured.

Results: Adiponectin was higher [12.8 (7.1) vs. 9.7 (5) ng/ml; P = 0.041] in IGHD subjects, whereas no difference was observed in leptin [7.3 (6.3) vs. 9.3 (18.7 ng/ml] and UAE [8.6 (13.8) vs. 8.5 (11.1) μg/min].

Conclusions: Subjects with lifetime untreated IGHD have an adipokine profile with high adiponectin and normal leptin levels that may delay vascular damage and lesions of the renal endothelium.

Adiponectin is high in isolated GH deficiency.

GH deficiency (GHD) in adults has been associated with an increase in cardiovascular mortality (1), thought to be due to atherosclerotic changes (2) linked to abdominal adiposity, dyslipidemia [high levels of total and low-density lipoprotein (LDL) cholesterol, and low levels of high-density lipoprotein (HDL)] and C-reactive protein (CRP) (3). However, this association is based on studies obtained in heterogeneous cohorts of patients with acquired GHD of different etiologies and severities, who have often undergone pituitary surgery or radiation, and with multiple associated pituitary deficits, all factors that may affect vascular mortality.

In Itabaianinha County, in northeastern Brazil, we have identified a large kindred with approximately 100 affected individuals, with isolated GHD (IGHD), due to a homozygous null mutation in the splice donor site of intron 1 (IVS1 + 1G→A) of the GHRH receptor gene (GHRH-R) (4). These IGHD individuals have very low serum GH and IGF-I and present throughout life an adverse cardiovascular risk profile, including a reduction in fat-free mass (FFM) and an increase in percentage fat mass (%FM) and waist-hip ratio, total and LDL cholesterol, CRP, and systolic blood pressure. Conversely, they have no insulin resistance and no evidence of premature atherosclerosis, as shown by normal carotid intima-media thickness and stress echocardiogram (5,6,7,8).

To understand the mechanism of the lack of premature atherosclerosis despite such risk factors, we have studied other factors linked to vascular damage and atherosclerosis, such as leptin, adiponectin, and a marker of endothelial disease, urinary albumin excretion (UAE). Adiponectin, the most abundant protein of adipose origin, decreases with obesity and is positively associated with whole-body insulin sensitivity (9,10) and inversely associated with the risk of type 2 diabetes (11). Leptin, another specific adipose protein, usually elevated in obesity, plays an atherogenic, prothrombotic, and angiogenic role by stimulating vascular inflammation, oxidative stress, and smooth muscle hypertrophy contributing to hypertension, atherosclerosis, and other cardiovascular diseases (12,13,14,15). UAE, even when below the threshold diagnostic of microalbuminuria, is considered an independent risk factor and predictor of both renal and cardiovascular disease and a subclinical marker of endothelial cell dysfunction, a condition that is believed to promote atherogenesis (16).

Data on these three parameters are controversial in GHD: leptin has been reported to be elevated (17,18) or normal (19,20), and adiponectin low (10,21) or normal (18,22), whereas UAE has been reported to be normal (23,24). We tested the hypothesis of a favorable pattern of these three parameters in congenital, lifetime IGHD.

Subjects and Methods

Subjects

In a cross-sectional study, IGHD and control subjects were recruited by advertising placed in the local Dwarfs Association building and by word of mouth among the inhabitants of Itabaianinha. Exclusion criteria were: age less than 25 yr; use of statins, tobacco, estrogens, antipsychotics, anticonvulsants, analgesics, or antiinflammatories; use of GH in childhood or during the last 3 yr; viral syndrome during the last 30 d; coronary insufficiency; Chagas disease, and other chronic or systemic diseases. Twenty-two IGHD subjects and 24 controls volunteered. Two IGHD individuals were excluded, one due to the use of tobacco, and another due to the use of anticonvulsant. In the control group, two individuals were excluded, one due to the use of tobacco and anticonvulsant, and another due to chronic anemia. A total of 20 IGHD individuals (seven males; age, 50.8 ± 14.6 yr) and 22 control subjects (eight males; age, 49.9 ± 11.5 yr) were enrolled. Six individuals of the IGHD group were GH naive, and 14 had been treated with a long-acting GH for 6 months (as adults) and had stopped this treatment for more than 3 yr before this protocol. Because we found no difference in the studied variables between the GH naive and those individuals who had received GH for this short period of time, all of them were included in the IGHD group.

Study protocol

Anthropometric, body composition, and blood pressure measurements

Height, body weight, waist and hip circumferences were measured. Body mass index (BMI) was calculated using the formula: weight (kilograms)/height (meters)2. Body surface area (BSA) (in square meters) was calculated using the formula: w0.425 × h0.725 × 71.84 × 10−4, where w is the weight in kilograms, and h is the height in centimeters. sd scores (SDS) for height (SDS/h), weight (data not shown), and BMI (SDS/BMI) were calculated by using the SDS Individual Calculator for British 1990 Growth Reference Data (http://www.phsim.man.ac.uk/SDSCalculator/SDSCalculator. aspx). Fat mass (FM) (kilograms), %FM, FFM (kg), and %FFM were measured using near-infrared interactance, as previously reported (7). Blood pressure was registered as the mean value of three measurements after 10 min in a seated position.

Laboratory assessment

Total cholesterol, triglycerides, and glucose were measured by the enzymatic Trinder colorimetric test. HDL cholesterol was separated using the phosphotungstic acid/magnesium chloride method, and the LDL cholesterol concentration was calculated indirectly (Friedewald formula). IGF-I was measured by an immunoradiometric assay, with double extraction and an assay sensitivity of 0.8 ng/ml (5600; Diagnostic Systems Laboratories, Inc., Webster, TX). The intraassay and interassay variabilities were 2.25 and 2.6%, respectively. Insulin resistance was estimated using the homeostasis model assessment of insulin resistance (HOMAIR) with the formula: fasting serum insulin (microunits per milliliter) × fasting plasma glucose (millimoles per liter)/22.5.

Adiponectin was measured by ELISA (Linco Research, St. Charles, MO) with sensitivity of 0.78 ng/ml and intra- and interassay variation of 7.4 and 8.4%. Leptin was measured by IRMA assay (Laboratory Fleury, São Paulo, Brazil) with sensitivity of 0.5 ng/ml, and both intra- and interassay variation of 10%. Adiponectin, leptin, and insulin were expressed in absolute and corrected values for BSA (adiponectin/BSA, leptin/BSA, and insulin/BSA), and unit of FM in kilograms (adiponectin/FM kg, leptin/FM kg, and insulin/FM kg). UAE (micrograms per minute) was measured in timed overnight collections by immunonephelometry (Immage; Beckman Coulter, Fullerton, CA) with an intra- and interassay coefficient of variability of 4% (sensitivity limit of the assay, 0.02 mg/liter). Microalbuminuria was defined with a UAE between 20 and 200 μg/min.

The Federal University of Sergipe Institutional Review Board approved these studies, and all subjects gave written informed consent.

Statistics

Variables with normal and not normal distribution were compared in the two groups by t test and Mann-Whitney test, respectively. Data are reported as mean (sd) and median (interquartile range) when appropriate. We used a stepwise multiple regression model to determine independent predictors of both log of leptin and log of adiponectin. We have shown that in children, FM, GHD status, and sex explained 73% of the variability of leptin (25). In this paper, we used age, sex, GHD (GHD = 1, control = 2), FM, %FM, FFM, and log of IGF-I as independent variables. A P value of 0.10 was used to enter and leave the model. Colinearity was ruled out within covariates in the model, and all the assumptions of this model were checked. Statistical analysis was performed by the software SPSS/PC 15.0 (SPSS Inc., Chicago II). Probability values less than or equal to 0.05 were considered statistically significant.

Results

Anthropometric, body composition, and blood pressure data are shown in Table 1. As expected, height, weight, BSA, and FFM (kilograms) were reduced without difference in BMI (both in absolute values and SDS/BMI) and FM, whereas %FM was increased in IGHD subjects. Both SBP and DBP were higher in the IGHD group.

Table 1.

Anthropometric, body composition, and blood pressure data in IGHD and control groups

IGHD Control P
Height (m) 1.2 (0.1) 1.6 (0.1) <0.0001
SDS height −7.0 (1.2) −1.23 (0.98) <0.0001
Weight (kg) 37.1 (6.2) 63.6 (10.5) <0.0001
BSA (m2) 1.11 (0.1) 1.63 (0.29) <0.0001
BMI (kg/m2) 25.1 (4.6) 24.7 (2.8) 0.752
SDS BMI 1.24 (1.37) 1.18 (0.76) 0.88
W/H 0.95 (0.1) 0.91 (0. 1) 0.085
FFM (kg) 23.2 (4.4) 47.8 (11. 8 ) <0.0001
FM (kg) 14.0 (3.3) 16.2 (7.0) 0.212
%FM 37.7 (6.7) 25.4 (10.2) <0.0001
SBP (mm Hg) 134.0 (28.5) 116.2 (17.0) 0.021
DBP (mm Hg) 83.0 (14.3) 74.0 (11.4) 0.031
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Values are expressed as mean (sd) for all variables, except for body surface which is expressed as median (interquartile range). SBP, Systolic blood pressure; DBP, diastolic blood pressure; W/H, waist/hip ratio. 

Laboratory data are shown in Table 2. IGF-I levels were extremely low in IGHD individuals, who had higher CRP and LDL cholesterol and lower insulin and HOMAIR, as we had previously reported (7,8). Adiponectin, in absolute and corrected values for BSA and unity of FM (kilograms), was higher in the IGHD group (Fig. 1). There were no differences in leptin (in absolute or corrected values) and UAE. Only two individuals had microalbuminuria in each group.

Table 2.

Levels of adiponectin, leptin, lipids, glucose, insulin, HOMAIR, CRP, and UAE in IGHD and control groups

IGHD Control P
IGF-I (ng/ml) 11.9 (15.7) 161.9 (63.4) <0.0001
CRP (mg/dl) 0.84 (0.6) 0.31 (0.27) <0.0001
Cholesterol (mg/dl) 221.3 (49.7) 193.45 (47.0) 0.069
LDL (mg/dl) 140.1 (44.0) 114.32 (38.9) 0.05
HDL (mg/dl) 44.7 (9.98) 47.8 (11.4) 0.345
Triglycerides (mg/dl) 140.5 (189.25) 112.5 (107.5) 0.571
Glucose (mg/dl) 102 (25) 101.5 (9.75) 0.801
Insulin (mU/liter) 3.5 (2.75) 6.5 (5.25) 0.004
Insulin/BSA 3.13 (2.37) 3.99 (3.63) 0.237
Insulin/FM kg 0.24 (0.24) 0.45 (0.3) 0.001
HOMAIR 0.88 (0.96) 1.74 (1.52) 0.008
Leptin (ng/ml) 7.35 (6.3) 9.3 (18.68) 0.93
Leptin/BSA 6.97 (6.67) 6.37 (11.14) 0.279
Leptin/FM kg 0.63 (0.44) 0.7 (0.6) 0.703
Adiponectin (ng/ml) 12.83 (7.15) 9.73 (5) 0.041
Adiponectin/BSA 12.37 (2.37) 5.86 (3.64) <0.0001
Adiponectin/FM kg 0.85 (0.44) 0.6 (0.44) 0.027
UAE (μg/min) 8.6 (13.8) 8.5 (11.1) 0.236
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Values are expressed as median (interquartile range) for all variables except for CRP, cholesterol, LDL, HDL, and leptin/FM kg, which are expressed as mean (sd). 

Figure 1.

Figure 1

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Serum adiponectin levels (nanograms per milliliter) in GHD and control groups.

Stepwise multiple regression identified FM and GHD as responsible for 50.6% of the variability of log leptin and FFM, and age for 30.6% of the variability of log adiponectin (Table 3). Because high adiponectin levels may be the cause or the consequence of increased insulin sensitivity, we extended the stepwise multiple regression analysis to include HOMAIR as another independent variable and log adiponectin as a dependent variable. In this model, 45.5% of variability of log of adiponectin was explained by age (β standardized coefficient = 0.456; t = 3.868; P = 0.0004), %FM (β standardized coefficient = 0.384; t = 3.311; P = 0.002), and HOMAIR (β standardized coefficient = −0.419; t = −3.569; P < 0.0001, R2 adjusted = 0.455).

Table 3.

Stepwise multiple linear regression analyses to assess the determinants of log of leptin and adiponectin concentrations

Dependent variable Variables in equation Unstandardized coefficient R2 adjusted P
Log leptin FM 0.072 0.467 <0.0001
GHD 0.248 0.506 0.048
Log adiponectin FFM −0.006 0.191 0.002
Age 0.006 0.306 0.009
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The values of R2 adjusted (in bold) corresponds to the R2 adjusted when both variables had been entered. 

Discussion

We have found high serum adiponectin and normal leptin levels, associated with normal UAE, in adult IGHD individuals. These results delineate an adipokine profile that differs from what is found in most forms of obesity (high leptin and low adiponectin levels). Interestingly, our findings are in agreement with recent data showing that GH receptor-deficient mice had elevated adiponectin levels (25), and that acromegalic patients have low serum adiponectin (26). Adiponectin and leptin are important in glucose homeostasis. Adiponectin reverses insulin resistance associated with both lipoatrophy and obesity (27), and the administration of leptin in patients with severe leptin deficiency and lipodystrophy improves insulin sensitivity (28). Leptin resistance is associated with insulin resistance and type II diabetes (13). Therefore, both high adiponectin and normal leptin can improve insulin sensitivity, thereby delaying the progression of atherosclerosis in IGHD individuals. Increased insulin sensitivity is a hallmark feature of longevity (as shown in centenarians) (29), and it is one of the possible explanations of the lack of premature cardiovascular mortality in IGHD subjects from Itabaianinha. Accordingly, the increase in adiponectin could be linked to the increased insulin sensitivity, a feature that differentiates our congenital IGHD subjects from adults with acquired GHD, who are often insulin resistant (3,30).

In a recent study, relative rather than absolute GHD, together with the excess of urinary cortisol and low adiponectinemia, were significant contributors to increased levels of markers of cardiovascular risk in obese adolescent girls (31). It has been exhaustively shown that insulin resistance is a key factor for the establishment of lipid abnormalities, visceral fat accumulation, and atherosclerosis observed in obese, hypertensive, and diabetic individuals (7). Adults with hypopituitarism have abdominal obesity, insulin resistance, dyslipidemia, increase in CRP, and atherosclerosis (1,2,3). The strength of this association with GHD is not certain, due to the fact that only very few of the hypopituitary patients have true and naive IGHD, and most lack other important pituitary hormones whose replacement may be suboptimal. In contrast, the lower fasting insulin level and HOMAIR in our IGHD group indicates increased insulin sensitivity compared with the control group.

We now show that FM and GHD are the principal predictors of leptin, and that FFM (negatively) and age are the most important predictors of adiponectin levels. Our IGHD individuals do not have increased absolute FM, but they do have increased %FM, and this is mirrored by reduced FFM, which may explain the fact that FFM is a negative predictor of serum leptin. Furthermore, we show that HOMAIR, age, and %FM explain a large part of the variability of adiponectin. Although a causal relationship cannot be proven from multiple regression analyses, it is important to underline that aging and increase of %FM usually tend to reduce insulin sensitivity and decrease adiponectin levels. This strongly suggests a favorable influence of GHD on adiponectin, which may counteract the deleterious effects of increased %FM and aging.

Adiponectin directly regulates GH secretion from somatotrophs in vitro by binding to adiponectin receptors, and, similar to GHRH, adiponectin induces GH secretion, depending mainly on Ca2+ influx via voltage-gated channels. Adiponectin treatment increases GHRH receptor expression in anterior pituitary cell cultures, which suggests a potential indirect regulatory role of adiponectin on GH secretion (32). Therefore, the high adiponectin levels in our model of GHRH resistance could be a compensatory mechanism to the lack of GHRH action. Independently from the mechanism by which adiponectin is increased, we speculate that this phenomenon contributes to delaying the appearance of atherosclerosis in IGHD individuals that present very low GH and IGF-I levels throughout life, differently from most models of acquired GHD with less severe IGF-I reduction. Alternatively, atherosclerosis could be delayed due to other mechanisms, such as low levels of adhesion molecules and platelet-derived factors, not studied in this paper.

We have previously reported high levels of leptin in children and adolescents with IGHD (5). The reasons for the decline of leptin to normal values in adult IGHD individuals, despite the persistent increase in %FM and total and LDL cholesterol, are still unknown. The normal leptin values in adults can also confer some protection against vascular inflammation (33,34), counteracting the high CRP levels found in these individuals.

In addition to the favorable adipokine profile, IGHD individuals have similar UAE and rate of microalbuminuria as control subjects, despite having increased systolic and diastolic blood pressure. The interaction between the GH-IGF-I axis and renal function is not well defined. GH may influence renal function either directly or via IGF-I, which has been shown to reduce renal vascular resistance both in rodents (35) and in humans (36). UAE is considered a subclinical marker of endothelial cell dysfunction, preceding atherosclerosis (16). Because GH increases inducible nitric oxide synthase expression in mesangial cells of mice (37), it is possible that the very low GH and IGF-I levels may reduce inducible nitric oxide synthase in such cells, thereby slowing the progressive extracellular matrix accumulation that leads to the increase of UAE (38,39).

It has to be noted that some of the IGHD individuals had been treated with a long-acting GH preparation for 6 months as part of a clinical research protocol (40) completed more than 3 yr before this evaluation. Roemmler et al. (41) recently showed a reduction in leptin levels by GH replacement, comparing a GH-treated group with a group that had stopped GH replacement 2 yr before. We are therefore confident that the effects of GH on the parameters we have studied would have disappeared after a 3-yr period.

In conclusion, the findings of high adiponectin, normal leptin and UAE, despite unfavorable body composition and increased blood pressure, together with very low serum IGF-I levels and high insulin sensitivity, are likely protecting factors that counteract the cluster of adverse cardiovascular risk factors found in the IGHD individuals from Itabaianinha, avoiding the premature appearance of atherosclerosis.

Acknowledgments

We thank Dr. Enaldo V. Melo for statistical assistance, Mrs. Ivanilde Santana de Sousa for secretarial assistance, and Fapese (“Fundação de Apoio a Pesquisa e Extensão de Sergipe”) for administrative assistance.

Footnotes

This work was supported in part by National Institutes of Health Grant 1R01 DK065718 (to R.S.). M.H.A.-O. was supported by Grant BEX 4309/08-1 from Capes (“Coordenação de Aperfeiçoamento de Pessoal de Nível Superior”), from the Brazilian Government.

Disclosure Summary: The authors have nothing to disclose.

First Published Online December 16, 2009

Abbreviations: BMI, Body mass index; BSA, body surface area; CRP, C-reactive protein; FFM, fat-free mass; FM, fat mass; GHD, GH deficiency, or GH-deficient; HDL, high-density lipoprotein; HOMAIR, homeostasis model assessment of insulin resistance; IGHD, isolated GHD; LDL, low-density lipoprotein; SDS, sd score; UAE, urinary albumin excretion.

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