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The Journal of Clinical Endocrinology and Metabolism logoLink to The Journal of Clinical Endocrinology and Metabolism
. 2009 Apr 14;94(7):2471–2477. doi: 10.1210/jc.2008-2671

Growth Hormone Deficiency Is Associated with Decreased Quality of Life in Patients with Prior Acromegaly

Tamara Wexler 1,a, Lindsay Gunnell 1,a, Zehra Omer 1, Karen Kuhlthau 1, Catherine Beauregard 1, Gwenda Graham 1, Andrea L Utz 1, Beverly Biller 1, Lisa Nachtigall 1, Jay Loeffler 1, Brooke Swearingen 1, Anne Klibanski 1, Karen K Miller 1
PMCID: PMC2708960  PMID: 19366847

Abstract

Context: Both GH deficiency (GHD) and GH excess are associated with a decreased quality of life. However, it is unknown whether patients with GHD after treatment for acromegaly have a poorer quality of life than those with normal GH levels after cure of acromegaly.

Objective: The aim of the study was to determine whether patients with GHD and prior acromegaly have a poorer quality of life than those with GH sufficiency after cure of acromegaly.

Design and Setting: We conducted a cross-sectional study in a General Clinical Research Center.

Study Participants: Forty-five patients with prior acromegaly participated: 26 with GHD and 19 with GH sufficiency.

Intervention: There were no interventions.

Main Outcome Measures: We evaluated quality of life, as measured by 1) the Quality of Life Adult Growth Hormone Deficiency Assessment (QoL-AGHDA); 2) the Short-Form Health Survey (SF-36); and 3) the Symptom Questionnaire.

Results: Mean scores on all subscales of all questionnaires, except for the anger/hostility and anxiety subscales of the Symptom Questionnaire, showed significantly impaired quality of life in the GH-deficient group compared with the GH-sufficient group. Peak GH levels after GHRH-arginine stimulation levels were inversely associated with QoL-AGHDA scale scores (R = −0.53; P = 0.0005) and the Symptom Questionnaire Depression subscale scores (R = −0.35; P = 0.031) and positively associated with most SF-36 subscale scores.

Conclusions: Our data are the first to demonstrate a reduced quality of life in patients who develop GHD after cure of acromegaly compared to those who are GH sufficient. Further studies are warranted to determine whether GH replacement would improve quality of life for patients with GHD after cure from acromegaly.

Reduced quality of life is present in patients who develop growth hormone deficiency after cure of acromegaly compared to those who are GH-sufficient.

GH deficiency (GHD) is associated with a decreased quality of life in patients with hypopituitarism due to organic hypothalamic/pituitary disease from causes other than acromegaly (1,2,3,4,5,6,7,8). Quality of life is also diminished in patients with GH excess (acromegaly) (6,7,9,10,11,12). The goal of treatment for acromegaly is normalization of endogenous GH levels and/or IGF-I levels and reversal of the associated metabolic complications. Although quality of life has been shown to improve after cure of acromegaly (11,13,14), studies generally show that it does not return to normal (15,16,17,18). GHD is a common consequence of the treatment of pituitary tumors, including those secreting GH, particularly as a result of radiation therapy (19,20,21,22). Little is known about whether patients with GHD after treatment for acromegaly experience a poorer quality of life than those who have normal GH levels after cure.

Therefore, we studied 45 patients who had been cured from acromegaly to determine whether GHD conferred a poorer quality of life than GH sufficiency in this population.

Subjects and Methods

Subjects

A total of 45 subjects with documented biochemical remission of acromegaly were recruited from the Massachusetts General Hospital Neuroendocrine Clinical Center, by referring endocrinologists, and through advertising. All subjects had been treated by surgery or radiation therapy at least 6 months before study entry and demonstrated biochemical cure, defined as GH suppression to less than 1 ng/ml during an oral glucose tolerance test and/or normal serum IGF-I for age. Subjects were excluded from participation if they were receiving somatostatin analogs, dopamine agonists, or GH receptor antagonists. Additional exclusion criteria included unstable cardiovascular disease, uncontrolled hypertension or diabetes mellitus, cancer, and pregnancy, or breastfeeding within 1 yr before study enrollment. One subject had received GH therapy previously and for less than 1 yr, discontinuing it more than 3 yr before study enrollment. Subjects with hypopituitarism were required to have been receiving stable hormone replacement therapy doses for at least 3 months before enrollment. Subjects with adrenal insufficiency were all receiving 4–5 mg of prednisone or 15–30 mg of hydrocortisone daily. The range of doses of testosterone replacement in hypogonadal men was 5 to 7.5 g of a transdermal gel, except for one male subject who was receiving im testosterone esters at a dose of 200 mg every 2 wk. All but two (one of whom was receiving transdermal estradiol and the other oral conjugated equine estrogens) of the women receiving gonadal steroids were receiving oral contraceptives. Diagnosis of GHD was defined as a peak GH level of less than 5 ng/ml on GHRH-arginine stimulation testing, or an IGF-I level more than 2 sd values below the age-specific normal range in the presence of at least three anterior pituitary deficiencies (n = 5) (23). Subjects were categorized as GH-sufficient based on peak GH levels above 9 ng/ml on a GHRH-arginine stimulation test (24,25). Two additional subjects tested did not qualify as GH-deficient or GH-sufficient (peak GH levels ≥5 ng/ml or ≤9 ng/ml) and were included for analyses in which data were used as continuous variables. One was a 45-yr-old female, and the other was a 31-yr-old male. GHRH-arginine testing was performed using the standard protocol for diagnosis of GHD in adults with hypopituitarism (GHRH 1 μg/kg plus arginine 0.5 g/kg to a maximum of 30 g were administered iv, and GH levels were measured at baseline and every 30 min for 2 h) (26).

The study was approved by the Partners Healthcare, Inc. Institutional Review Board, and written informed consent was obtained from all subjects.

Protocol

All data were collected during two outpatient visits at the Massachusetts General Hospital General Clinical Research Center. The initial screening visit included a GHRH-arginine stimulation test. The subsequent baseline visit (for qualifying subjects) included a fasting IGF-I level and administration of the following questionnaires to assess quality of life.

Quality of life assessment of growth hormone deficiency in adults (QoL-AGHDA)

The QoL-AGHDA is a disease-generated questionnaire developed to measure quality of life in adults with GHD (27,28) based on 36 in-depth interviews with GH-deficient patients. It consists of 25 statements with “yes/no” responses. The statements assess energy, physical and mental drive, concentration/memory, personal relationships, social life, emotions, and cognition, and are based on the assumption that quality of life is determined by the degree to which human needs are met. Higher scores indicate a poorer quality of life.

Symptom questionnaire

The Symptom Questionnaire is a 92-item questionnaire assessing four scales: 1) anxiety, 2) depression, 3) somatic symptoms, and 4) anger/hostility (29). It has been validated and widely used in clinical studies since it was developed in 1976 (30,31,32,33,34). Higher scores indicate greater symptom severity. Domain scores between 1 and 2 sd values above the mean for healthy controls indicate moderate distress, and scores greater than 2 sd values above the mean suggest severe distress or psychopathology (29).

Short-form health survey (SF-36)

The SF-36 is a well-validated self-administered questionnaire consisting of 36 items that address physical and psychological well-being during the preceding 4 wk (35,36). Questions and statements are answered with either “yes/no” responses or scaled responses ranging from three options (“yes, limited a lot”; “yes, limited a little”; “no, not limited at all”) to six options (“all of the time”; “most of the time”; “a good bit of the time”; “some of the time”; “a little of the time”; “none of the time”). The following quality of life modalities are assessed: 1) physical functioning, 2) role limitations due to physical functioning, 3) general health perception, 4) pain, 5) vitality, 6) emotional well-being, 7) role limitations due to emotional health, and 8) social functioning. Scores are represented on a 0–100 scale. Higher scores indicate a better quality of life.

Assays

Serum IGF-I levels were measured using the Immulite 2000 automated immunoanalyzer (Diagnostic Products Corp., Inc., Los Angeles, CA), with a solid-phase, enzyme-labeled, chemiluminescent immunometric assay, with an interassay coefficient of variation (cv) of 3.7% (at an IGF-I level of 75 ng/ml) to 4.2% (at an IGF-I level of 169 ng/ml). Serum GH levels were measured by a chemiluminescent immunometric assay (Nichols Institute Diagnostics, San Juan Capistrano, CA) with an intraassay cv of less than or equal to 5.4% and a sensitivity of 0.02 ng/ml until July 12, 2005. Subsequently, serum GH levels were measured using an immunoradiometric assay kit (Diagnostic Systems Laboratories, Inc., Webster, TX), with a minimum detection limit of 0.01 ng/ml, an intraassay cv of 3.1–5.4%, and an interassay cv of 5.9–11.5%. We performed univariate correlational and agreement analyses between the two GH assays, with n = 12 and a range of 0.97 to 27.9 ng/ml. The R2 was 0.98, the slope was 1.083 with an intercept of −0.4457, and the average bias was 8.4%.

Statistical analysis

JMP Statistical Discoveries (version 5.0.1.2; SAS Institute, Inc., Cary, NC) was used for statistical analyses. Normality was assessed using the Shapiro-Wilk test, and means were compared with ANOVA for normally distributed variables. All variables not normally distributed were compared using the Wilcoxon test. The Fisher’s exact test was used to assess differences between categorical variables. Univariate and multivariate regression models were constructed to determine predictors of quality of life. The square root was taken of all variables that were not normally distributed before they were entered into regression models. Statistical significance was defined as a two-tailed P value <0.05. All results are expressed as mean ± sd.

Results

Clinical characteristics are shown in Table 1. Quality of life data are shown in Table 2 and Figs. 1 through 4. Subjects with GHD had a significantly poorer quality of life, as measured by all scales and subscales except the Anxiety and Anger/Hostility subscales of the Symptom Questionnaire, and these differences remained significant after controlling for potentially confounding factors that differed between the groups (as shown in Table 1).

Table 1.

Clinical characteristics

Demographics (mean ± sd) GH deficient (n = 26) GH sufficient (n = 19) P value
Age (yr) 47.0 ± 11.9 45.5 ± 12.1 NS
Sex (males/females) 10/16 6/13 NS
IGF-I (ng/ml) 90.3 ± 44.7 141.3 ± 62.9 0.0019
IGF-I sd score −2.0 ± 0.6 −1.4 ± 0.9 0.0018
BMI (kg/m2) 31.9 ± 6.7 27.1 ± 4.2 0.0236
History of TSS, n (%) 24 (92) 19 (100) NS
Time since TSS (months) 134.3 ± 77.1 64.6 ± 58.3 0.0013
History of XRT, n (%) 22 (85) 4 (21) <0.0001
Time since XRT (months) 163.8 ± 107.0 72.0 ± 38.0 NS
History of GH-lowering medication 5 (45) 5 (26) NS
Time since diagnosis of acromegaly 163.7 ± 104.9 70.0 ± 60.0 NS
Age at diagnosis of acromegaly (yr) 33.4 ± 11.4 39.7 ± 13.1 NS
Time since cure (months) 92.1 ± 81.0 58.0 ± 53.3 NS
No. of pituitary hormone deficiencies
 0 0 16 (84) <0.0001
 1 1 (4) 2 (11) NS
 2 4 (15) 0 NS
 3 9 (35) 0 0.0035
 4 8 (31) 1 (5) 0.037
 5 4 (15) 0 NS
Central ACTH insufficiency 12 (46) 1 (5) 0.0027
Central TSH deficiency 20 (77) 2 (11) <0.0001
Free T4 (ng/dl) 1.1 ± 0.2 1.2 ± 0.2 NS
T3 (ng/dl) 127 ± 38 124 ± 32 NS
Male hypogonadism, n (%) 8 (80) 1 (17) 0.0245
 Testosterone replacement 7 (87.5) 0 NS
Menopause, n (%) 3 (19) 5 (38) NS
 Estrogen replacement 1 (33) 0 NS
Female 2° hypogonadism, n (%) 13 (81) 2 (15) 0.0006
 Estrogen replacement 9 (69) 2 (100) NS
Current tobacco use, n (%) 3 (12) 4 (21) NS
Antidepressant use 8 (31) 2 (11) NS
Antihypertensive use 6 (23) 9 (47) NS
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XRT, Radiation therapy; TSS, transsphenoidal surgery; 2°, secondary; NS, not significant. 

Table 2.

Quality of life

GH deficient (n = 26) % scoring below 25% of normal GH sufficient (n = 19) % scoring below 25% of normal P value P valuea
Tests in which higher scores reflect poorer QOL
 QoL-AGHDA 8.6 ± 5.5 2.7 ± 3.4 0.0002 0.0001
 Symptom questionnaire
  Anxiety 6.4 ± 5.4 3.3 ± 2.4 NS NS
  Depression 5.0 ± 4.8 1.6 ± 2.0 0.007 0.005
  Anger/hostility 3.0 ± 4.3 2.7 ± 2.8 NS NS
  Somatic 7.8 ± 4.8 5.0 ± 3.7 0.049 NS
Tests in which higher scores reflect better QOL
 SF-36
  Physical functioning 72.0 ± 22.1 32 94.4 ± 7.5 5 0.0006 0.003
  Role limitations due to physical health 68.0 ± 38.5 8 100.0 ± 0.0 5 0.001 0.004
  Bodily pain 64.9 ± 30.0 44 84.6 ± 13.1 5 0.028 NS
  General health 55.2 ± 22.9 56 78.3 ± 16.6 11 0.0007 0.034
  Vitality 38.4 ± 22.8 52 66.8 ± 16.3 32 <0.0001 0.002
  Social functioning 74.5 ± 20.6 44 95.8 ± 8.6 5 0.0003 <0.0001
  Role limitations due to emotional health 72.0 ± 36.9 16 100.0 ± 0.0 5 0.004 0.003
  Mental health 66.7 ± 19.8 40 78.2 ± 12.1 11 0.032 0.012
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Values are reported as mean ± sem. NS, Not significant; QOL, quality of life. 

a

P value after controlling for BMI, history of radiotherapy, time since surgery, and ACTH deficiency. 

Figure 1.

Figure 1

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Mean (±sem) AGHDA scores were higher in the GH-deficient than GH-sufficient subjects with prior acromegaly. Black bar, GH-deficient; gray bar, GH-sufficient. *, P = 0.0002. Higher scores on the AGHDA indicate poorer quality of life.

Figure 2.

Figure 2

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Mean (±sem) Symptom Questionnaire scores were higher for all subscales, except for anxiety and anger/hostility, in the GH-deficient than GH-sufficient subjects with prior acromegaly. Black bars, GH-deficient; gray bars, GH-sufficient. *, P < 0.05. Higher scores on the Symptom Questionnaire indicate poorer quality of life.

Figure 3.

Figure 3

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Mean (±sem) SF-36 scores were lower for all subscales in the GH-deficient than GH-sufficient subjects with prior acromegaly. Black bars, GH-deficient; gray bars, GH-sufficient; whiskers, normal ranges. *, P < 0.03. Lower scores on the SF-36 questionnaire indicate poorer quality of life.

Figure 4.

Figure 4

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Peak GH levels after GHRH-arginine stimulation levels were inversely associated with QoL-AGHDA scale scores. Higher scores on the AGHDA indicate poorer quality of life.

The percentage of GH-deficient subjects scoring more than 2 sd values above the mean on the Depression subscale was higher than that of the GH-sufficient group (25% GH-deficient vs. 0% GH-sufficient; P = 0.022), and there was a trend toward a higher percentage of GH-deficient subjects scoring more than 2 sd values above the mean on the anxiety subscale (17% GH-deficient vs. 0% GH-sufficient; P = 0.086). There was no significant difference between percentages of GH-deficient and GH-sufficient subjects who scored more than 2 sd values above the mean on the Anger/Hostility (8% GH-deficient vs. 0% GH-sufficient; P = 0.32) or Somatic symptom (29% GH-deficient vs. 11% GH-sufficient; P = 0.13) subscales.

There were no significant differences in mean quality of life scores between males and females for any scales or subscales within the GH-deficient group. There was an inverse association of the Anger/Hostility symptom subscale with age (R = −0.53; P = 0.0004), such that, in general, older subjects reported higher levels of anger and hostility. No other subscales correlated with age. Previous radiotherapy was a negative predictor of the vitality subscale of the SF-36 questionnaire (P = 0.02) but of no other questionnaire or questionnaire subscale. It was no longer a significant predictor of the SF-36 vitality subscale after controlling for the presence or absence of GHD (P = 0.69).

Peak GH levels after GHRH-arginine stimulation levels were inversely associated with QoL-AGHDA scale scores (R = −0.53; P = 0.0005) (Fig. 4). All subscale scores of the SF-36 were associated with GHRH-arginine stimulation peak GH levels except for Bodily Pain and for Role Limitations due to Emotional Health (Physical Functioning, R = 0.43, P = 0.006; Role Limitations due to Physical Health, R = 0.37, P = 0.023; Bodily Pain, R = 0.26, P=0.11; General Health: R = 0.42, P = 0.008; Vitality, R = 0.46, P = 0.003; Social Functioning, R = 0.36, P = 0.023; Role Limitations due to Emotional Health, R = 0.31, P = 0.05; Mental Health, R = 0.32, P = 0.041). Depression Symptom Questionnaire subscale scores were inversely associated with peak GH after GHRH-arginine stimulation (R = −0.35; P = 0.031); other Symptom Questionnaire subscale scores were not associated with peak GH levels.

IGF-I sd scores were significantly associated with General Health (R = 0.46; P = 0.002), and Vitality SF-36 subscale scores (R = 0.40; P = 0.009), but not with any other SF-36 subscale scores, QoL-AGHDA, or Symptom Questionnaire subscale scores.

Discussion

To our knowledge, these are the first data to demonstrate a reduced quality of life in patients who develop GHD after cure of acromegaly compared with those who are GH-sufficient. We report diminished quality of life in such patients using a quality-of-life questionnaire developed specifically to detect symptoms associated with GHD and also using questionnaires that have been validated in patients with a wide range of illnesses. Our data suggest that avoiding GHD in patients after cure of acromegaly may be important and raise the question of whether GH replacement would benefit such patients despite increased prior exposure to GH.

A study using the KIMS database showed that patients with GHD after treatment for acromegaly had a similar (in males) or poorer (in females) quality of life than patients with GHD from other pituitary causes, as measured by the AGHDA (37). Our results are consistent with the notion that patients with GHD after cure of acromegaly may experience impaired quality of life, although we did not detect a gender-specific difference in magnitude. Our comparison with GH-sufficient patients who also had prior acromegaly demonstrates that impaired quality of life in patients with GHD and prior acromegaly is not due primarily to the residual effects of the acromegaly itself. This is an important point because acromegaly itself is associated with an impaired quality of life, and although cure has been shown to be accompanied by improvements in quality of life, most studies do not demonstrate recovery to normal (10,11,13,14,15,16,18,38). In another study, a U-shaped relationship between glucose-suppressed GH levels and quality of life scores was observed in a study cohort that included patients with active and cured acromegaly, such that patients with nadir values between 0.3 and 1.0 ng/ml had better quality of life scores than those with lower or higher values (18). Although the presence of GHD was not formally assessed in the study, the results support the concept that low GH levels may confer an impaired quality of life, consistent with our data.

An important question is whether the magnitude of difference in quality of life subscales between GH-deficient and GH-sufficient patients with prior acromegaly is clinically important. Comparisons with data from other GH-deficient populations and from other groups of patients with known impaired quality of life suggest that the differences observed in our study are clinically relevant in addition to being statistically significant. Data comparing quality of life measures between patients with GHD due to hypothalamic/pituitary lesions other than acromegaly and healthy controls reveal a similar magnitude of difference as in our study (4,29,38,39). SF-36 subscale scores for our population of GH-deficient subjects are similar to those of subjects with type II diabetes (n = 541) and recent acute myocardial infarction (n = 107) and are significantly worse than in subjects with hypertension (n = 2089) and other minor medical conditions (35,36). Moreover, studies of the effects of antidepressant therapy on quality of life measures have demonstrated changes that are of similar magnitude to those we have observed between GH-deficient and GH-sufficient patients with prior acromegaly (32,33,39). For example, an 8-wk study of the effects of fluoxetine on somatic symptoms in 384 subjects with major depressive disorder demonstrated a mean improvement in the Symptom Questionnaire Somatic symptom subscale from 9.6 ± 5.6 to 6.1 ± 5.3 (32), similar to the difference between groups in our study. Therefore, we conclude that the diminution in quality of life in GH-deficient patients with prior acromegaly detected by this study is likely to be clinically relevant.

Limitations of our study include the fact that a cross-sectional study cannot determine causality and that there were a number of possible confounders, including the potential effects of body mass index (BMI), radiation therapy, and hormone deficiency and replacement regimens. We addressed this latter issue by controlling for parameters that differed between the groups, but further studies are warranted. We found that, in general, the impairment in quality of life in the GH-deficient subjects could not be attributed to differences in BMI, radiation therapy, or hormone deficiencies. This is in contrast to published studies on quality of life in subjects after treatment for acromegaly, in which radiation therapy has been shown to be a significant independent predictor of diminished quality of life (9,15,18,40). However, most of these studies included patients with active, controlled, and cured disease, without differentiating GH status. Therefore, it is possible that at least some of the adverse effects reported may have in fact been attributable to GHD, not radiation therapy as surmised. Further studies are needed to clarify causality. In addition, the GHRH-arginine and IGF-I cutoffs used have not been validated specifically in patients who have a history of acromegaly. GH levels are also laboratory dependent, and GHD is BMI dependent (41,42,43). Fundamentally, GH status is a continuum, and cutoffs by their nature are not absolute but instead are arbitrary. To address these issues, we included analyses using peak GH as a continuous variable and also controlled our analyses for BMI. In addition, the relatively small sample size of the GH-sufficient and GH-insufficient groups and subgroups does not allow us to completely rule out confounders such as time since diagnosis of acromegaly, time since cure of acromegaly, or time since radiation therapy, the means of which appeared different but did not differ statistically and may also have limited our ability to detect other differences between the groups. For example, we cannot rule out a difference between the GH-deficient and GH-sufficient groups in anxiety symptom severity; the mean score in the GH-deficient group was nearly double that in the GH-sufficient group, but they did not differ statistically. Another potential confounder that we cannot entirely exclude as a cause of our findings is the influence of other pituitary hormone deficiencies and replacement therapy regimens for them. Finally, we were careful to limit the number of variables we entered into the models, i.e. the number of variables for which we controlled simultaneously. However, a higher ratio of study subjects to variables entered into the multivariate models would have been preferable, and a larger total “n” would have allowed us to control for a greater number of variables. It should also be noted that we cannot conclude from our data that GHD is the only cause of diminished quality of life in this group of patients, only that it may be an important contributing factor.

We have demonstrated that GHD in patients with prior acromegaly is associated with a diminished quality of life and that the magnitude of mean changes are likely clinically relevant. Before the development of pharmacological therapy for acromegaly over the last decade, enabling reduction of GH and/or IGF-I levels into the normal range in most patients with acromegaly, the focus of research and treatment for this disease was on diminishing exposure to supraphysiological GH and IGF-I levels. There are few data regarding the optimal level of posttreatment GH or IGF-I levels in patients with controlled or cured acromegaly. Radiation and pegvisomant therapy can result in GHD, and both surgery and somatostatin analog therapy can have similar effects. GHD due to organic hypothalamic or pituitary disease other than acromegaly has been shown to be associated with a diminished quality of life, and randomized, placebo-controlled studies (44,45,46,47), as well as numerous open-label trials and retrospective studies have demonstrated improvements in these measures with GH replacement therapy (1,2,7,37,48,49,50,51,52,53). The diagnosis of GHD is not often pursued in patients with acromegaly, and, when discovered, replacement is often not considered because of concerns about cumulative GH exposure. One retrospective study suggested that quality of life in patients with GHD after cure of acromegaly did not benefit from GH therapy; this was in contrast to patients with GHD due to other organic etiologies (37). Our data suggest that randomized, placebo-controlled studies are needed to investigate the effects of GH replacement therapy on quality of life in this particular population.

Acknowledgments

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

Footnotes

This work was supported by National Institutes of Health Grants MO1 RB01066 and UL1 RR025758, an investigator initiated grant from Pfizer Inc. and by Leo and Laurie Guthart.

Disclosure Summary: A.K. received funding for this investigator-initiated study from Pfizer Inc. B.B. consults for Pfizer Inc. No other authors have any conflicts to declare.

First Published Online April 14, 2009

Abbreviations: BMI, Body mass index; cv, coefficient of variation; GHD, GH deficiency.

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