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The Journal of Clinical Endocrinology and Metabolism logoLink to The Journal of Clinical Endocrinology and Metabolism
. 2008 Apr 29;93(7):2507–2514. doi: 10.1210/jc.2008-0169

Growth Hormone Deficiency by Growth Hormone Releasing Hormone-Arginine Testing Criteria Predicts Increased Cardiovascular Risk Markers in Normal Young Overweight and Obese Women

Andrea L Utz 1, Ami Yamamoto 1, Linda Hemphill 1, Karen K Miller 1
PMCID: PMC2453050  PMID: 18445664

Abstract

Context: Little is known about the relationship between GH and cardiovascular risk markers in women without organic hypothalamic/pituitary disease.

Objective: The objective of the study was to determine whether healthy young overweight and obese women, who would be classified as having GH deficiency (GHD) based on standard criteria used in hypopituitarism (peak GH after stimulation with GHRH and arginine < 5 ng/ml), have increased cardiovascular risk markers.

Design: This was a cross-sectional study.

Setting: The study was conducted at the General Clinical Research Center.

Study Participants: Forty-five women of reproductive age, mean age 33.1 ± 1.2 yr and mean body mass index (BMI) 30.9 ± 1.0 kg/m2.

Intervention: There was no intervention.

Main Outcome Measures: Measures included carotid intima-medial thickness, high-sensitivity C-reactive protein (hsCRP), total cholesterol, high-density lipoprotein (HDL), low-density lipoprotein, triglycerides, E-selectin, soluble intercellular adhesion molecule-1, TNF-α receptor I, TNF-α receptor II, fasting insulin levels, and oral glucose tolerance testing.

Results: Twenty-six percent of overweight or obese subjects and none with BMI less than 25 kg/m2 met criteria for GHD. Subjects who met GHD criteria had a mean BMI of 37.0 ± 1.7 kg/m2 (range 28.6–43.6 kg/m2), and their mean waist circumference (110.1 ± 3.5 cm) was higher than in overweight/obese women with GH sufficiency (P = 0.007). Mean carotid intima-media thickness, hsCRP, soluble intercellular adhesion molecule-1, TNF-α receptor I, and TNF-α receptor II levels were higher, and HDL lower, in women meeting GHD criteria than in GH sufficiency. Differences in HDL, hsCRP, and TNF-α receptor II remained after controlling for age plus BMI, waist circumference, or trunk fat. There were no differences in measures of insulin resistance.

Conclusions: There may be a relative GHD syndrome in overweight and obese women without organic pituitary or hypothalamic disease that confers increased cardiovascular risk, independent of weight.

Healthy, young, overweight, and obese women, who would be classified as GH-deficient based on standard criteria used in hypopituitarism, have abnormal cardiovascular risk marker levels, including high-sensitivity C-reactive protein and high-density lipoproteins, even after controlling for age and body mass index, waist circumference, or trunk fat. There may be a relative GH deficiency syndrome in overweight and obese women without organic pituitary or hypothalamic disease that confers increased cardiovascular risk, independent of weight.

Hypopituitarism is associated with increased cardiovascular mortality, women are disproportionally affected, and GH deficiency (GHD) has been posited as a contributory factor (1,2,3,4,5). The increased mortality is reflected in elevated cardiovascular risk markers, including high-sensitivity C-reactive protein (hsCRP) and carotid intima-media thickness (IMT), in both women and men with GHD due to hypopituitarism (5,6,7,8,9,10,11,12,13,14). Moreover, GH replacement results in improvements in these markers (12,15,16,17,18,19). However, little is known about whether the association between decreased GH secretion and increased cardiovascular risk markers observed in patients with GHD and hypopituitarism occurs in overweight and obese men and women without organic hypothalamic or pituitary disease. Although it is known that obesity is associated with reduced GH secretion, the association of cardiovascular risk marker levels with diminished GH secretion has been primarily investigated in obese men and women older than 50 yr. These studies, which have focused on traditional lipid and lipoprotein analyses, have demonstrated inverse associations of IGF-1 and GH secretion with low-density lipoprotein (LDL) cholesterol and triglycerides and positive associations with high-density lipoprotein (HDL) cholesterol (20). However, well-established predictors of cardiovascular events representing other atherogenic pathways, including hsCRP and carotid IMT, have not been studied. Whether there is a relative GHD syndrome in overweight or obese men and women that confers an increased risk of cardiovascular events, independent of increased weight itself, is unknown. Moreover, data in women of reproductive age are particularly lacking, and it is important to identify risk factors for future cardiovascular disease in this population. We therefore studied 45 healthy women of reproductive age with GHRH-arginine stimulation testing, IGF-1 levels, and cardiovascular risk markers, including hsCRP and carotid IMT, to investigate whether peak GH after stimulation with GHRH and arginine, and IGF-1 predict levels of cardiovascular risk markers in healthy young women.

Subjects and Methods

Subjects

We studied 45 healthy female volunteers recruited from the community through advertisements. No subject had a history of a hypothalamic or pituitary disorder. All subjects had regular menses. Exclusion criteria included estrogen or glucocorticoid use, diabetes mellitus, and other chronic illnesses, including inflammatory diseases. Women more than 280 lb were excluded from participation due to the limitations of the radiology equipment.

Methods

All data were collected during two morning outpatient visits on the Massachusetts General Hospital General Clinical Research Center. Testing for each study participant included: 1) a GHRH-arginine stimulation test, 2) a 75-g oral glucose tolerance test (OGTT), performed on a different day than the GHRH-arginine stimulation test, 3) a fasting blood draw for IGF-1 and serum cardiovascular risk markers, and 4) carotid IMT. The GHRH-arginine test was performed using the standard protocol used to diagnose GHD in adults with hypopituitarism [GHRH 1 μg/kg plus arginine 0.5 g/kg (maximum 30 g) iv were administered and GH levels drawn at baseline and every 30 min for 2 h] (21). In more than 70% of cases, testing was performed in the early follicular phase of the menstrual cycle. Carotid IMT was measured by acquiring long-axis B-mode images from the distal 1 cm of the common carotid artery using a variable-frequency, 5- to 12-MHz ultrasound transducer on a Philips HDI 5000 ultrasound system (Philips Medical Systems, Bothell, WA). Images were digitized, and average carotid IMT over the length of the 1 cm segment was calculated using semiautomated edge detection software. Right and left carotids were scanned, and the average IMT of the two is reported. All scans were analyzed by one investigator (L.H.). Total body and trunk fat mass was measured by dual-energy x-ray absorptiometry using a Hologic QDR-4500 densitometer (Hologic Inc., Waltham, MA), with an accuracy error for body fat mass of 1.7% (22). Mid-waist circumference was measured as the midpoint between the iliac crest and the lowest rib. Largest waist circumference was recorded as the largest of the following four measurements: 1.) mid-waist circumference, 2.) circumference measured at the umbilicus 3.) circumference measured at the iliac crest, and 4.) circumference measured at the level of the maximum extension of the buttocks; all were taken in a horizontal plane. The study was approved by the Partners Healthcare Inc. Institutional Review Board, and written informed consent was obtained from all subjects.

Biochemical analyses

Serum samples were collected and stored at −80 C. Serum GH was measured using an immunoradiometric assay kit (Diagnostic Systems Laboratories, Inc., Webster, TX), with a sensitivity of 0.01 ng/ml, an intraassay coefficient of variation (cv) of 3.1–5.4% and an interassay cv of 5.9–11.5%. Serum IGF-1 levels were measured using an Immulite 2000 automated immunoanalyzer (Diagnostic Products Corp., Inc., Los Angeles, CA), by a solid-phase enzyme-labeled chemiluminescent immunometric assay, with an interassay cv of 3.7% (at an IGF-1 level of 75 ng/ml) to 4.2% (at an IGF-1 level of 169 ng/ml). hsCRP was measured using a latex particle-enhanced immunoturbidimetric assay on the Hitachi 917 (Equal Diagnostics, Exton, PA), with an interassay cv of less than 5.08%. Insulin was measured using an RIA kit (Linco, Research, Inc., St. Charles, MO), with a sensitivity of 2 μU/ml, with an intraassay cv of 2.2–4.4% and an interassay cv of 2.9–6.0%. E-selectin was measured by ELISA (R&D Systems, Minneapolis, MN), with an interassay cv of 5.7–8.8% and a sensitivity of 0.1 ng/ml. Soluble intercellular adhesion molecule-1 (sICAM-1) was measured by ELISA (R&D Systems), with a sensitivity of 0.35 ng/ml and an interassay cv of 6.0–10.1%. TNF-α receptor I was measured by ELISA (R&D Systems), with an interassay cv of 3.7–8.8%. TNF-α receptor II was measured by ELISA (R&D Systems), with an interassay cv of 3.6–5.1%. Total, HDL, and LDL cholesterol and triglycerides were measured using previously described methods (23).

Statistical analysis

JMP Statistical Discoveries (version 4.0.2; SAS Institute, Inc., Cary, NC) was used for statistical analyses. All variables were tested for normality using the Shapiro-Wilk test. All variables that were not normally distributed were log transformed before analysis. Means were compared with ANOVA. Univariate regression models were constructed to determine predictors of cardiovascular risk marker levels. Multivariate models using standard least-squares analysis were constructed to control for age, BMI, midwaist circumference, and trunk fat. Statistical significance was defined as a two-tailed P < 0.05. Results are expressed as mean ± sem.

Results

Clinical characteristics of study subjects

Clinical characteristics of study subjects and mean baseline cardiovascular risk marker levels are shown in Table 1. The age range of study participants was 19–45 yr, and the body mass index (BMI) ranged from 19.2 to 43.6 kg/m2. Subjects were classified as meeting the criteria for GHD based on standard criteria used to diagnose adults with hypopituitarism (peak GH after stimulation with GHRH and arginine < 5 ng/ml) (21,24,25). Clinical characteristics of women classified as meeting GHD criteria vs. those who did not are presented in Table 2. Twenty-six percent of overweight or obese subjects met criteria for GHD, but no subjects with BMI less than 25 kg/m2 did. The group of subjects classified as meeting hypopituitary GHD criteria had a mean BMI of 37.0 ± 1.7 kg/m2, with a range of 28.6–43.6 kg/m2, and midwaist circumference of 110 ± 3 cm (mean largest waist circumference 120.0 ± 5.3 cm), significantly higher than in all subjects with GH sufficiency (P = 0.005 for midwaist circumference and P = 0.006 for largest waist circumference) and than overweight and obese women with GH sufficiency (P = 0.007 for midwaist circumference and P = 0.0006 for largest waist circumference). However, there was considerable overlap between the groups in both BMI (stimulated GH < 5 ng/ml BMI range: 28.6–43.6 kg/m2; stimulated GH ≥ 5 ng/ml BMI range: 19.2–42.3 kg/m2) and waist circumference, whether mid-waist circumference (stimulated GH < 5 ng/ml mid-waist circumference range: 95.6–127.5 cm; stimulated GH ≥ 5 ng/ml mid-waist circumference range: 69.5–122.4 cm) or largest waist circumference (stimulated GH < 5 ng/ml largest waist circumference range: 99.9–146.5; stimulated GH ≥ 5 ng/ml largest waist circumference range: 73.6–124.3 cm). The GHD group had a higher mean age than the GH-sufficient group 38.4 ± 2.1 vs. 31.8 ± 1.4, P = 0.03).

Table 1.

Clinical characteristics and cardiovascular risk marker levels

All subjects (n = 45)
Age (yr) 33.1 ± 1.2
Weight (kg) 82.8 ± 2.7
BMI (kg/m2) 30.9 ± 1.0
Mid-waist circumference (cm) 95 ± 2
Total body fat (kg) 33.2 ± 1.9
Trunk fat (kg) 15.4 ± 1.0
IGF-1 (ng/ml) 182.7 ± 10.2
GH stimulation peak (ng/ml) 14.9 ± 1.6
Carotid IMT (mm) 0.57 ± 0.01
Total cholesterol (mg/dl) 167.4 ± 4.7
HDL (mg/dl) 51.1 ± 1.6
LDL (mg/dl) 96.8 ± 4.1
Triglyceride (mg/dl) 97.6 ± 9.2
hsCRP (mg/liter) 3.35 ± 0.5
E-selectin (ng/ml) 31.2 ± 2.0
sICAM-1 (ng/ml) 238 ± 9
TNF-α receptor I (pg/ml) 1152 ± 40
TNF-α receptor II (pg/ml) 2339 ± 82
Fasting glucose (mg/dl) 84.5 ± 1.5
Two-hour OGTT glucose (mg/dl) 119.4 ± 3.8
Glucose AUC (mg/dl/120 min) 15561 ± 376
Fasting insulin (μIU/ml) 12.5 ± 1.5
Insulin AUC (μIU/ml/120 min) 8385 ± 587
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Table 2.

Cardiovascular risk marker levels in GH-deficient and GH-sufficient subjects

GH peak < 5 ng/ml (n = 9) GH peak ≥ 5 ng/ml (n = 36) P value
Age (yr) 38.4 ± 2.1 31.8 ± 1.4 0.03
BMI (kg/m2) 37.0 ± 1.7 29.4 ± 1.0 0.0012
Mid-waist circumference (cm) 110 ± 4 91 ± 2 0.0005
Total body fat (kg) 46.8 ± 3.4 29.7 ± 1.8 0.0001
Trunk fat (kg) 22.5 ± 1.9 13.6 ± 1.0 0.0001
IGF-1 (ng/ml) 124 ± 17 197 ± 11 0.0002
Carotid IMT (mm) 0.62 ± 0.020 0.56 ± 0.014 0.044
Total cholesterol (mg/dl) 168 ± 13 167 ± 5 NS
HDL (mg/dl) 41 ± 3 54 ± 2 0.0012a
LDL (mg/dl) 102 ± 13 96 ± 4 NS
Triglyceride (mg/dl) 122 ± 30 91 ± 9 NS
hsCRP (mg/liter) 5.9 ± 1.1 2.1 ± 0.3 0.0032a
E-selectin (ng/ml) 38.9 ± 6.6 29.3 ± 1.8 NS
sICAM-1 (ng/ml) 284.9 ± 22.9 226.8 ± 3.3 0.0059b
TNF-α receptor I (pg/ml) 1311 ± 81 1112 ± 43 0.043
TNF-α receptor II (pg/ml) 2927 ± 181 2192 ± 75 0.0001a
Fasting glucose (mg/dl) 90 ± 4 83 ± 2 0.086
Two-hour OGTT glucose (mg/dl) 130 ± 9 116 ± 4 NS
Glucose AUC (mg/dl/120 mm) 16402 ± 1063 15325 ± 379 NS
Fasting insulin (μIU/ml) 14.0 ± 3.4 12.1 ± 1.6 NS
Insulin AUC (μIU/ml/120 min) 9440 ± 1044 7971 ± 678 NS
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a

For cardiovascular risk markers, P < 0.05 after controlling for age and Bm1, waist circumference, or trunk fat. 

b

For cardiovascular risk markers, P < 0.05 after controlling for age. 

BMI was strongly and inversely associated with peak GH after stimulation with GHRH and arginine (R = −0.74, P < 0.0001) (Fig. 1A) and IGF-1 levels (R = −0.52, P = 0.0003) (Fig. 1B). Both of these associations remained significant after controlling for age. Age was a predictor of IGF-1 levels but not peak GH after stimulation with GHRH and arginine. IGF-1 levels correlated with peak GH after GHRH-arginine stimulation (R = 0.50, P = 0.0005).

Figure 1.

Figure 1

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Peak GH after stimulation with GHRH and arginine (A) and IGF-1 (B) were inversely associated with BMI.

Cardiovascular risk markers

Mean levels of cardiovascular risk markers were compared between the GHD and GH-sufficient groups (Table 2). Mean carotid IMT, hsCRP, sICAM-1, TNF-α receptor I and TNF-α receptor II levels were all higher, and HDL cholesterol lower, in subjects who would have been classified as GHD based on hypopituitary criteria, compared with GH-sufficient subjects. hsCRP, TNF-α receptor II and HDL levels remained significantly different between the two groups after controlling for age plus a measure of adiposity, whether BMI, mid-waist circumference, or trunk fat (Table 2) (hsCRP: P = 0.006 after controlling for age and BMI, P = 0.007 after controlling for age and waist circumference, and P = 0.01 after controlling for age and trunk fat; TNF-α receptor II: P = 0.005 after controlling for age and BMI, P = 0.009 after controlling for age and waist circumference, and P = 0.009 after controlling for age and trunk fat; HDL cholesterol: P = 0.02 after controlling for age and BMI, P = 0.05 after controlling for age and waist circumference, and P = 0.04 after controlling for age and trunk fat). Sixty-seven percent of GHD and 28% of GH-sufficient (38% of GH-sufficient overweight or obese women) had high-risk hsCRP levels [>3 mg/liter (26)]; no woman with BMI less than 25 kg/m2 had an hsCRP level in the high-risk range. There were no differences between the groups in any measures of insulin resistance.

Peak GH after stimulation with arginine and GHRH was inversely associated with carotid IMT (R = −0.41, P = 0.005) (Fig. 2), hsCRP (R = −0.55, P < 0.0001) (Fig. 3A), TNF-α receptor II (R = −0.44, P < 0.0001) (Fig. 3B), sICAM-1 (R = −0.43, P = 0.004) (Fig. 3C), and E-selectin (R = −0.26, P = 0.088) (trend) (Fig. 3D). IGF-1 levels were significantly and negatively associated with the following cardiovascular risk markers: TNF-α receptor II (R = −0.33, P = 0.029), TNF-α receptor I (R = −0.37, P = 0.013), and E-selectin (R = −0.33, P = 0.03). There was a trend toward an association between IGF-1 and hsCRP (R = −0.28, P = 0.06). IGF-1 levels were not significantly associated with carotid IMT or sICAM-1.

Figure 2.

Figure 2

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Peak GH after stimulation with GHRH and arginine was inversely associated with carotid IMT.

Figure 3.

Figure 3

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hsCRP (A), TNF-α receptor II (B), sICAM-1 (C), and E-selectin (D) were inversely associated with peak GH after stimulation with GHRH and arginine.

Measures of insulin resistance were inversely associated with peak GH levels after stimulation [vs. fasting glucose (R = −0.36, P = 0.017); vs. glucose 2 h after OGTT (R = −0.55, P = 0.0002); vs. area under the curve (AUC) glucose (R = −0.39, P = 0.012) (Fig. 4A); vs. fasting insulin (R = −0.42, P = 0.005); vs. insulin AUC (R = −0.45, P = 0.0045) (Fig. 4B). In contrast, IGF-1 was associated (inversely) with fasting glucose levels only (R = −0.32, P = 0.038) and was not associated with any other measures of insulin resistance, including glucose or insulin AUC (Fig. 4, C and D). All cardiovascular risk markers tested were significantly associated with BMI, with correlation coefficients ranging from 0.13 to 0.28.

Figure 4.

Figure 4

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Glucose AUC during 2-h OGTT (A) and insulin AUC (B) were inversely associated with peak GH after stimulation with GHRH and arginine. Neither AUC glucose (C) nor AUC insulin (D) was associated with IGF-1 levels.

Discussion

We demonstrate that 26% of apparently healthy overweight and obese women of reproductive age meet standard diagnostic criteria used to diagnose GHD in hypopituitarism (21). Importantly, we also demonstrate that meeting such criteria is associated with a deleterious cardiovascular marker risk profile. This includes increases in nontraditional predictors of future cardiovascular events, including carotid IMT and hsCRP, and decreases in the traditional lipoprotein maker, HDL cholesterol. Moreover, we report strong inverse associations of GH peak after stimulation by GHRH and arginine with cardiovascular risk markers in a group of healthy women with a range of weights. Our findings link low peak GH after GHRH-arginine stimulation to elevations in cardiovascular risk markers that are established to be strong predictors of future cardiovascular events, including carotid IMT and hsCRP, in young overweight and obese women. These data raise the question of whether decreased endogenous GH secretion may contribute to an elevated risk of future cardiovascular events in young overweight and obese women. Further studies are warranted to investigate this hypothesis.

GHD is thought to be an important contributory factor to the increased risk of cardiovascular events and mortality in women and men with hypopituitarism (27,28), and GH replacement results in improvements in cardiovascular risk markers in this population (12,15,16,17,18,19). Although studies have demonstrated that being overweight or obese in the absence of hypopituitarism is associated with decreased GH secretion (29,30,31,32,33,34,35), little is known about the association of endogenous GH with cardiovascular risk markers in such women. A few studies have examined the relationship between reduced GH secretion and traditional cardiovascular risk markers, specifically lipids and lipoproteins, in healthy obese women; however, it is not known whether low endogenous GH levels in obesity are associated with elevations in inflammatory cardiovascular risk markers and formation of arterial plaque. In two studies, both in subjects older than those studied in our protocol, GH levels were shown to be inversely related to lipid and lipoprotein levels. In a report by Weltman et al. (35) women older than 60 yr were studied with 24-h GH frequent sampling, and inverse associations between mean GH levels and both lipid and lipoprotein levels were demonstrated. In addition, Carmichael et al. (20) performed GHRH-arginine stimulation testing and measured cardiovascular risk markers in 86 male and female volunteers aged 50–90 yr old. They also demonstrated inverse relationships between peak GH and both LDL cholesterol and triglycerides, whereas a positive association was observed with HDL cholesterol; they also reported a correlation between insulin and peak GH levels.

To our knowledge, our investigation is the first to demonstrate an association between carotid IMT and peak GH after stimulation and to focus on apparently healthy eumenorrheic women of reproductive age. Moreover, relationships with inflammatory and adhesion markers have not been previously reported, except for hsCRP in our previous study in a small group of healthy women, which included postmenopausal women (32), and therefore, associations in premenopausal women could not be isolated. Carotid IMT and hsCRP have been shown to be particularly important predictors of cardiovascular events. Carotid IMT is a structural measure of atherogenesis and an accurate predictor of cardiovascular events (36). In an open-label study, GH administration has been shown to result in a marked decrease in carotid IMT in patients with GHD due to hypopituitarism (6), but the effects of GHD and replacement on carotid IMT in normal overweight or obese women has not been investigated. hsCRP is the most validated inflammatory marker and has been shown to be a stronger predictor of cardiovascular events than LDL cholesterol (37). In the Physician’s Health Study, baseline hsCRP levels in the highest quartile predicted a 3-fold increased risk of myocardial infarction and 2-fold increased risk of stroke, independent of other cardiovascular risk factors (38). Although most studies focus on men, a large cohort of women has been studied in the Women’s Health Initiative Observational Study (39), which demonstrated that elevated hsCRP levels predicted a 2-fold increase in risk of developing coronary heart disease in women.

We show in this study that healthy women of reproductive age with peak GH levels of less than 5 ng/ml after GHRH and arginine stimulation, a standard criterion used to diagnose GH deficiency in women with hypopituitarism (21), is associated with increased carotid IMT and hsCRP levels. Additional markers in the inflammatory pathway, including sICAM-1 (an adhesion marker) and TNF-α receptor II were elevated in patients with peak GH levels less that 5 ng/ml, and HDL was low in this group. hsCRP and TNF-α receptor II levels remained significantly higher, and HDL significantly lower, in women with stimulated GH levels less than 5 ng/ml, even after controlling for age, and BMI or trunk fat. This suggests that there may be a relative GHD syndrome associated with increased cardiovascular risk, in the absence of organic hypothalamic or pituitary disease, in apparently healthy overweight and obese women.

We observed strong relationships between peak GH after stimulation and carotid IMT, measures of insulin resistance and hsCRP. In contrast to the strong inverse associations observed between cardiovascular risk markers and peak GH after stimulation, our data demonstrate weaker associations with IGF-1 levels. We observed no statistical relationship between IGF-1 and carotid IMT or insulin resistance, and although there tended to be an inverse association between hsCRP and IGF-1, it was not statistically significant. Our data are consistent with a published study by Maccario et al. (40), which did not find an association between IGF-1 levels and traditional lipid or lipoproteins markers in 286 patients, male and female combined, aged 18–71 yr, all of whom were obese; additional cardiovascular risk markers were not studied. These data raise the question of whether there may be effects of GH on cardiovascular risk that are independent of those of IGF-1. Although most effects of GH are mediated by IGF-1, direct effects of GH have been demonstrated on a few end points. Most notable are GH’s independent lipolytic and antiinsulin effects (41,42,43,44,45). In contrast to what would be predicted from the known actions of these hormones, we showed inverse associations between measures of insulin resistance and peak GH after stimulation and no relationship between IGF-1 and measures of glucose homeostasis. Therefore, the inverse relationship between GH and measures of insulin resistance observed in our study may be mediated by indirect effects of GH and IGF-1 action, such as body composition. Further studies are warranted.

A limitation of our study is that statistical testing of cross-sectional data cannot determine the extent to which decreased peak GH after GHRH-arginine stimulation and BMI or trunk fat may be independent predictors of elevations in cardiovascular risk markers because these variables are colinear, i.e. tightly correlated with each other. However, when we divided the group into those women who met GHD criteria and those who did not, several important cardiovascular risk marker levels differed between the groups, even after controlling for age and BMI, waist circumference or trunk fat with multivariate modeling. This suggests that meeting hypopituitarism criteria for GHD may be an independent predictor of cardiovascular risk in overweight and obese women.

These results raise the additional, unanswered, question of whether GH replacement will improve cardiovascular risk marker levels in obese women of reproductive age and low endogenous GH levels. A few small interventional studies in obese men and women have yielded results that are consistent with the hypothesis that GH replacement may improve a number of cardiovascular risk markers in obese men and women with low endogenous GH secretion. In two studies, one of postmenopausal women and one of men, GH replacement resulted in decreases in mean total and LDL cholesterol without causing a deterioration in insulin resistance; in addition, hsCRP and IL-6 decreased in postmenopausal women receiving GH (46,47,48). The combination of GH and caloric restriction in 40 obese patients, men and women with a mean age in the mid-30s, led to decreased weight and body fat and increased HDL cholesterol (49) but no change in hsCRP (50). In another study, GH, as an adjunct to caloric restriction and exercise, resulted in reductions in total cholesterol, triglycerides, free fatty acids, fibrinogen, and plasminogen activator inhibitor-1 in type 2 diabetics with poor glycemic control (51). Further studies are needed to investigate the hypothesis that lower endogenous GH secretion may contribute to an adverse cardiovascular risk profile in overweight and obese men and women and to determine whether GH replacement may ameliorate some of these abnormalities.

In summary, to our knowledge, our data are the first to demonstrate inverse associations between peak stimulated GH and cardiovascular risk markers, other than traditional lipids and lipoproteins, in otherwise healthy women of reproductive age. This includes carotid IMT, an anatomical and important predictor of future cardiovascular events (36), which has not previously been shown to be associated with GHD in women without organic pituitary or hypothalamic disease. It also includes hsCRP, an inflammatory cardiovascular risk marker, which is a stronger predictor of cardiovascular events than LDL cholesterol (52). In addition, we raise the question of whether there is a relative GHD syndrome in overweight and obese women without organic pituitary or hypothalamic disease that confers an increased risk of a deleterious cardiovascular risk profile. It is not known whether GH replacement in growth hormone deficient women of reproductive age, but without organic hypothalamic or pituitary disease, would result in improvements in cardiovascular risk markers and a decrease in cardiovascular events and whether the effects on insulin resistance would be positive or deleterious. Therefore, routine screening in a clinical setting for GHD in overweight and obese women is not indicated, and GH is not approved by the Food and Drug Administration for this indication. Rather, our data suggest that further study of these issues is warranted.

Acknowledgments

We thank the nurses and bionutritionists of the Massachusetts General Hospital General Clinical Research Center and the patients who participated in the study.

Footnotes

This work was supported by Grants HL077674 and MO1 RR01066.

The authors have no conflicts of interest to declare.

First Published Online April 29, 2008

Abbreviations: AUC, Area under the curve; BMI, body mass index; cv, coefficient of variation; GHD, GH deficiency; HDL, high-density lipoprotein; hsCRP, high-sensitivity C-reactive protein; IMT, intima-media thickness; LDL, low-density lipoprotein; OGTT, oral glucose tolerance test; sICAM-1, soluble intercellular adhesion molecule-1.

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