Introduction: Growth hormone deficiency (GHD) is common in patients cured of acromegaly by surgery or radiation therapy, affecting up to 70% of this population. GHD is linked to a variety of negative consequences in these patients, including increased total and visceral adiposity, increased serum C-reactive protein levels, impaired cardiac function, and decreased quality of life compared with patients cured of acromegaly who do not have GHD. This study was designed to establish the long-term safety and efficacy of GH replacement in patients with GHD following treatment of acromegaly compared with that in patients with GHD following treatment of nonfunctioning pituitary adenomas (NFPA).
Primary outcome measures included quality of life (QoL); body mass index (BMI); waist circumference; blood pressure; body composition data; serum lipids, glucose, and hemoglobin A1c levels; serious adverse events (eg, all-cause mortality, new primary cancer, brain tumors, cardiovascular and cerebrovascular-related mortality; new-onset diabetes mellitus); and additional safety endpoints.
Methods: The authors used analysis of the KIMS database (Pfizer International Metabolic Database) to assess the effectiveness and safety of GHD. Effectiveness outcomes were based on data from adults with cured acromegaly and GHD (n=115) and patients with GHD following treatment of NFPA (n=142) who were matched for age, gender, and body mass index (BMI). QoL was measured by the Assessment of Growth Hormone Deficiency in Adults scale (QoL-AGHDA). Treatment, whether for patients with acromegaly or NFPA, consisted of pituitary surgery and/or radiation therapy. These patients were followed for up to 5 years of GH replacement therapy. Safety outcomes were assessed in the entire population of patients with cured acromegaly and GHD (n=164) and the entire population of adult patients with GHD due to NFPA (n=2,469), all of whom received GH replacement.
Results: At year 5 of GH replacement therapy, the median dose of GH was 0.3 mg/d in both the cured acromegaly group and the treated NFPA group. The groups had comparable improvements in quality of life (with lower AGHDA scores indicating higher QoL) as well as improvements in total cholesterol and low-density lipoprotein (LDL) cholesterol levels (Table), despite having no significant change in BMI or body adiposity. Minor changes in fasting glucose and hemoglobin A1c levels were found in both groups.
The post-acromegaly group had a significantly increased rate of cardiovascular mortality compared with the post-NFPA group (standard mortality ratio, 3.03; P=0.0092) and compared with the general population (data not shown). The study groups had similar incidences of all cancers, benign or malignant brain tumors, and diabetes mellitus.
Compared with the general population, all-cause mortality was similar to general population comparator groups in the cured acromegaly group but was lower in the treated NFPA group (ratio between observed/expected cases, 1.32 and 0.58 in the respective groups). In both study groups, patients with a previous history of radiotherapy had an increased risk for malignant brain tumors compared with the general population.
Conclusion: GH replacement has similar and beneficial effects on quality of life and on cholesterol levels in patients with GHD resulting from treatment of acromegaly or from treatment of NFPA. With the exception of an increased rate of cardiovascular mortality in the post-acromegaly group compared with the NFPA group, the safety profile of GH replacement was similar between the 2 patient populations.
Tritos NA, Johannsson G, Korbonits M, et al. Effects of long-term growth hormone replacement in adults with growth hormone deficiency following cure of acromegaly: a KIMS analysis. J Clin Endocrinol Metab. 2014;99(6):2018-2029.
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 and other papers reviewed in this EndoScan, GHD is associated with morbidities that can be addressed by GH replacement. While GH is often measured for possible deficiency following pituitary surgery for adenomas that are non-functional or that secrete hormones other than GH, this is less often the case after surgery for acromegaly.
Several cross-sectional studies and randomized controlled clinical trials have shown the impact of post-acromegaly GHD on cardiovascular outcomes, body composition, and QOL, and the benefit to replacement, but these trials have been relatively small.1-5 The KIMS database offers a large population (>16,000 subjects) for investigating the impact of GHR in patients with GHD after treatment of acromegaly vs treatment of NFPA. This study was careful to include only subjects with adult-onset pituitary disease and rigorously defined GHD; some of the subjects had previously received GHR, though not for the 6 months prior to the defined observation period.
In contrast to some of the referenced trials, a growth hormone-sufficient post-acromegaly control cohort was not available via KIMS; the age-, sex-, and BMI-matched NFPA cohort was thus selected, as well as general population comparator cohorts for safety analyses. Regarding safety data, given the known impact of acromegaly on cardiac morbidity and mortality, the difference in cardiovascular mortality is perhaps not surprising (and while the cardiovascular mortality rate was higher in post-acromegaly GHD group vs the post-NFPA GHD group, there was no difference in the incidence of cardiovascular disease between groups). Studies of GHR in adults with post-acromegaly GHD do suggest improvement in cardiovascular parameters,2,3 and further study of this population before and after GHR is warranted.
We focus here on QoL efficacy data; impairments in QoL are an important aspect of GHD. The measurement of QoL used in this study is the QoL-Assessment of Growth Hormone Deficiency in Adults (QoL-AGHDA), which was developed expressly for use in a GHD population. Similar levels of impairment in QOL were found in a post-acromegaly GHD population using the Short-Form Health Survey (SF-36) (with degrees of impairment similar to patients with recent MI) and the Symptom Questionnaire in addition to the AGHDA;1 in that study, QoL was significantly worse by all measurements than comparator patients who were GH sufficient after treatment of acromegaly, with AGHDA score inversely related to peak GH concentration.1
Quality of life improved with GH replacement in both groups with GHD, regardless of GHD etiology. These improvements were statistically and clinically significant, similar between groups, and sustained across the 5-year time period. From baseline median QoL-AGHDA scores of 13 and 12 (post-acromegaly GHD and NFPA GHD), the 1-year, 3-year, and 5-year scores were 5 and 3, 6 and 4, and 5 and 4, respectively; at each time-point within each group, the change from baseline was statistically significant (P<0.001). (Lower scores on the QoL-AGHDA represent higher QoL.)
In contrast, a small 6-month study of GHR by Valassi and colleagues found that women with GHD from acromegaly (n=17) showed more QoL improvements than women with GHD from other hypothalamic/pituitary causes (n=38), as measured by AGHDA score, 4 SF-36 subscales, and the somatic Symptom Questionnaire symptoms subscale.6 The authors posit that this may be related to greater pre-GHR QoL impairment in the women with a history of acromegaly.
In another large, prospective, observational study, Mo and colleagues followed QoL measurements in GHD adults receiving GHR across 10 years. They found that QoL improvements, measured by the Questions on Life Satisfaction-Hypopituitarism scale (QLS-H) were sustained over this 10-year time period.7 Their study used the HypoCCS database (a postmarketing surveillance database by Eli Lilly and Company); the cohort had not previously received GH, and of all subjects with adult-onset GHD (n=1,436), 54.2% had GHD due to pituitary adenoma.
The study by Tritos and colleagues provides retrospective analysis of a large cohort over 5 years. Taken with smaller randomized controlled studies, as well as a recent large prospective observational study, it offers additional confirmation that quality of life impairment seen in GHD can be addressed with GHR, and that this effect is sustained.
1. Wexler T, Gunnell L, Omer Z, et al. Growth hormone deficiency is associated with decreased quality of life in patients with prior acromegaly. J Clin Endocrinol Metab. 2009 Jul;94(7):2471-2477.
2. Wexler TL, Durst R, McCarty D, Picard MH, et al. Growth hormone status predicts left ventricular mass in patients after cure of acromegaly. Growth Horm IGF Res. 2010;20(5):333-337.
3. Giavoli C, Profka E, Verrua E, et al. GH replacement improves quality of life and metabolic parameters in cured acromegalic patients with growth hormone deficiency. J Clin Endocrinol Metab. 2012;97(11):3983-3988.
4. Lin E, Wexler TL, Nachtigall L, et al. Effects of growth hormone deficiency on body composition and biomarkers of cardiovascular risk after definitive therapy for acromegaly. Clin Endocrinol (Oxf). 2012;77(3):430-438.
5. Miller KK, Wexler T, Fazeli P, et al. Growth hormone deficiency after treatment of acromegaly: a randomized, placebo-controlled study of growth hormone replacement. J Clin Endocrinol Metab. 2010;95(2):567-577.
6. Valassi E, Brick DJ, Johnson JC, Biller BM, Klibanski A, Miller KK. Effect of growth hormone replacement therapy on the quality of life in women with growth hormone deficiency who have a history of acromegaly versus other disorders. Endocr Pract. 2012;18(2):209-218.
7. Mo D, Blum WF, Rosilio M, Webb SM, Qi R, Strasburger CJ. Ten-year change in quality of life in adults on growth hormone replacement for growth hormone deficiency: an analysis of the hypopituitary control and complications study. J Clin Endocrinol Metab. 2014;99(12):4581-4588.