Introduction: Up to 40% of people with chronic heart failure (CHF) have coexisting growth hormone deficiency (GHD). In a previous study by Cittadini et al, 6-month treatment with GH replacement improved physical and cardiac performance in CHF patients with low peak serum GH on GH releasing hormone (GHRH)-arginine stimulation testing. This study was designed to examine the effects of long-term GH therapy in patients with CHF on functional capacity and CHF progression.
Methods: This study is an extension of a randomized, controlled, single-blind trial in which 63 of 158 consecutive patients with CHF were found to have low peak serum GH after screening for GHD using GHRH-arginine stimulation testing. Fifty-six of the patients with CHF and GHD were randomized to a 6-month course of either GH therapy [0.012 mg/kg sc GH qod] plus standard CHF therapy (n=28) or standard CHF therapy alone (control group; n=28). Based on observed positive effects of GH treatment on exercise capacity and cardiac function at 6 months, the trial was extended to 4 years. The primary efficacy outcome was peak oxygen consumption (VO2), which is an independent predictor of CHF progression, according to the study authors.
Results: A total of 17 patients in the GH therapy group and 14 patients in the control group completed the 4-year trial. At baseline, the two groups had a similar peak VO2 (12.9–13.1 ml/kg/min). At 4 years, the GH replacement group showed a significantly higher mean peak VO2 compared with that in the control group (21 vs 11.8 ml/kg/min; P=0.001). The mean change in VO2 was 7.1 ml/kg/min in the GH group compared with –1.8 ml/kg/min in the control group from baseline to year 4 (P<0.001).
Mean left ventricular ejection fraction (LVEF) increased by 10% in the GH group and decreased by 2% in the control group at 4 years (P<0.001). The mean change in LV end-systolic volume index was significantly greater in the GH group than in the control group (–22 and 8 ml/m2; P=0.005).
No major adverse events were reported in the GH group. Other than 2 patients reporting arthralgia, no other side effects deemed related to GH treatment were reported.
Conclusion: Long-term use of GH replacement therapy in patients with comorbid CHF and GHD markedly improves exercise and cardiac performance. The authors noted the need for large scale, multicenter, placebo-controlled, double-blind trials to determine whether long-term GH replacement therapy can delay the progression of CHF in patients with comorbid GHD.
Cittadini A, Marra AM, Arcopinto M, et al. Growth hormone replacement delays the progression of chronic heart failure combined with growth hormone deficiency: an extension of a randomized controlled single-blind study. JACC Heart Fail. 2013;1(4):325-330.
Commentary by Tamara L Wexler MD, PhD
Tamara L. Wexler, MD, PhD, is an endocrinologist specializing in neuroendocrinology and reproductive endocrinology. She is the Director of the NYU Langone Medical Center Pituitary Center in New York, NY, as well as an Attending in Medicine at Massachusetts General Hospital, Boston, MA.
As discussed in the overview, growth hormone deficiency is associated with increased cardiovascular morbidity.1 Growth hormone replacement in individuals with GHD improves cardiovascular function and risk markers, increasing HDL (particularly in women), decreasing hsCRP and (in studies, which find increased intima-media thickness in GHD) decreasing intima-media thickness. A number of recent studies have suggested that treatment with GH benefits patients with chronic heart failure (CHF), particularly if the CHF is due to LV systolic dysfunction.2,3 Up to 40% (or more) of people with CHF have co-existing low GH or IGF-1 levels by serum measurements;4,5 however, assessing the etiology of the measured low serum levels, and whether replacement is warranted, is more complicated.
In this paper, Cittadini and colleagues report that treatment with GH improved CHF parameters over a 4-year period in patients with low peak serum GH. Their study is an extension of a controlled single-blind and single-center study of 56 subjects, taken from 158 consecutive patients with CHF (NYHA class II-IV) seen at a single site and screened by GHRH-arginine stimulation testing; GHD was diagnosed by peak GH < 9 μg/L. Included subjects had LVEF ≤ 40%, LV end-diastolic dimension ≥ 60 mm, and were on CHF treatment (including beta-blockade) at stable doses for at least 1 month. This cohort was deemed to have GHD by a single dynamic test, but without known pituitary or other cause for GHD, may not meet The Endocrine Society Guideline for GHD diagnosis.
Subcutaneous GH (dose 0.012 mg/kg) every other day was provided to 28 of the 56 subjects; no placebo dose was given. Both groups were receiving standard therapy for CHF. The authors previously reported positive results of 6 months of GH treatment in the cohort found to have low peak GH as described above. The extension study was conducted both to ensure that the positive benefits persisted, and to investigate whether insulin resistance or diabetes developed with longer-term exogenous GH. Seventeen subjects in the GH-treated group (14 men, 3 women) and 14 subjects in the control group (12 men, 2 women) participated in follow-up to 4 years.
After 4 years, changes were seen in LVEF and peak VO2. The treated group showed a 10% increase in LVEF compared to a 2% decrease in the control group. The GH-treated group also showed a significantly higher mean peak VO2 compared to the control group (21 vs 11.8 ml/kg/min; P=0.001). The mean change in VO2 was 7.1 ml/kg/min in the GH group compared with –1.8 ml/kg/min in the control group from baseline to year 4. Average VO2 in healthy men is 35–40 mL/kg·min, and lower in women (~27–31 mL/kg·min); VO2 is affected by a number of parameters, including age and sex. The changes noted were felt to be clinically as well as statistically significant.
Given the change in measured parameters, the GH-treated group had a lower NYHA classification at the end of the extension period.
Also of interest, CHF exacerbation-related hospitalizations were lower in the treated group (11 vs 20 subjects); cardiac mortality rates were also lower, with 6 subjects in the GH-treated group and 10 in the control group dying of cardiac causes during the follow-up period. While these were not designated outcome measures, the difference is intriguing.
There are some limitations inherent in the study design. This was a single-center and single-blinded study; no placebo was given to the control group. There was also a high dropout rate during the extension period of the study, with only 31 of the initial 56 subjects reaching four years of follow-up. Age, sex, and BMI also effect GH measurements; there was no significant difference in age, BMI, or sex, but there was a trend towards higher BMI in the treated group, and the entire group was largely male. There was no separation between those classified as GHD (peak GH < 9 μg/L) and those classified as GH sufficient (peak GH ≥ 9 μg/L) at enrollment; however, in the full group initially diagnosed as GHD (n=63, 56 of whom consented to the study), it was noted that all but 5 had peak GH < 5μg/L.5
In addition to recognizing limitations from study size and design, it is important to recognize that the included cohort is distinct from other GHD groups discussed in this EndoScan: as mentioned above, there was no known structural or traumatic cause of GH deficiency, and with only one dynamic GH test used to assess for GHD, the studied cohort did not qualify as GHD per The Endocrine Society guidelines. It has been hypothesized that GH and IGF-1 are down-regulated in CHF, and there is not agreement on whether low GH levels in CHF are pathologic and warrant replacement.
Improvements in CHF parameters (as well as the noticed clinical endpoints) over 4 years of GH treatment in the small cohort followed suggests that further study may be warranted.
1. Rosén T, Bengtsson BA. Premature mortality due to cardiovascular disease in hypopituitarism. Lancet. 1990;336(8710):285-288.
2. Castellano G, Affuso F, Conza PD, Fazio S. The GH/IGF-1 Axis and Heart Failure. Curr Cardiol Rev. 2009;5(3):203-215.
3. Tritos NA, Danias PG. Growth hormone therapy in congestive heart failure due to left ventricular systolic dysfunction: a meta-analysis. Endocr Pract. 2008;14(1):40-49.
4. Saccà L. Heart failure as a multiple hormonal deficiency syndrome. Circ Heart Fail. 2009;2(2):151-156.
5. Cittadini A, Saldamarco L, Marra AM, et al. Growth hormone deficiency in patients with chronic heart failure and beneficial effects of its correction. J Clin Endocrinol Metab. 2009;94(9):3329-3336.