Growth Hormone in Adults With Growth Hormone Deficiency
Growth Hormone in Adults With Growth Hormone Deficiency
Due to the positive effects demonstrated in randomized clinical trials on cardiovascular surrogate markers and bone metabolism, a positive effect of growth hormone (GH) treatment on clinically relevant end-points seems feasible. In this review, we discuss the long-term efficacy and safety of GH treatment in adult patients with growth hormone deficiency (GHD) with emphasis on morbidity: fatal and nonfatal cardiovascular disease (CVD) and stroke, fractures, fatal and nonfatal malignancies and recurrences, and diabetes mellitus. A positive effect of GH treatment on CVD and fracture risk could be concluded, but study design limitations have to be considered. Stroke and secondary brain tumours remained more prevalent. However, other contributing factors have to be taken into account. Regrowth and recurrences of (peri)pituitary tumours were not increased in patients with GH treatment compared to similar patients without GH treatment. All fatal and nonfatal malignancies were not more prevalent in GH-treated adults compared to the general population. However, follow-up time is still relatively short. The studies on diabetes are difficult to interpret, and more evidence is awaited. In clinical practice, a more individualized assessment seems appropriate, taking into consideration the underlying diagnosis of GHD, other treatment regimens, metabolic profile and the additional beneficial effects of GH set against the possible risks. Large and thoroughly conducted observational studies are needed and seem the only feasible way to inform the ongoing debate on health care costs, drug safety and clinical outcomes.
Since the early sixties, growth hormone (GH) has been administered to children with impaired growth. Initially, GH was recovered from donor pituitaries and was therefore scarce. In 1985, GH treatment was banned because of the discovery of Creutzfeldt–Jakob disease in more than one recipient of human GH. Almost at the same time, however, recombinant human GH was manufactured, and thereby, the shortage came to an end. Broadening of the indications for GH treatment was enabled.
Growth hormone deficiency (GHD) in adults has been recognized as a metabolic syndrome, characterized by an adverse body composition and lipid profile. This negative metabolic profile has been hypothesized to be responsible for the increased cardiovascular mortality encountered in patients with hypopituitarism with all, but GH, substitution therapies. In addition, there is decreased bone mineral density, muscle strength, exercise capacity, cognitive function and quality of life (QoL) in patients with severe GHD. Since the late eighties, more and more studies, mostly short term, have demonstrated positive effects of GH treatment on the above-mentioned outcome measures. Subsequently, it has been demonstrated that the effects of GHD in adults result in increased direct and indirect health care costs, including more inpatient care, use of disability pension and sick leave, compared with the general population. Based on the above-mentioned studies, GH treatment was approved for adults with severe GHD in Europe in 1995 and in the United States (US) in 1996.
As GH treatment has been administered for more than 20 years to numerous adults with severe GHD, more data on long-term efficacy and safety should be arising. Most long-term data come from observational studies, mainly postmarketing surveillance databases (Pfizer International Metabolic Database (KIMS) and Hypopituitary Control and Complications Study (HypoCCS) from Eli Lilly & Company) and some national registries. These long-term studies, as recently described in a systematic review by Appelman-Dijkstra et al., demonstrated a sustained positive effect on QoL. The long-term results for cardiovascular risk factors are variable. Whether long-term GH treatment has implications for the incidence of cardiovascular morbidity and fractures remains to be established. In a recent review, four studies investigating the effect of GH treatment on all-cause mortality are described, and no increased mortality was found in men compared to the general population. Women and patients from high-risk groups (previous craniopharyngioma, Cushing's disease, malignant causes of hypopituitarism or aggressive tumours) still have a slightly increased risk, but probably lower than in untreated GHD seen in earlier studies. Next to efficacy, more data are awaited on safety measures. Active acromegaly, with pathologically high insulin-like growth factor-1 (IGF-1) levels, has been suggested to be associated with an increased risk for colonic neoplasia. Epidemiological studies have reported associations of even high-normal IGF-1 levels with an increased risk of developing prostate and breast cancer, while other studies have not. IGF-1 is a key regulator of cell proliferation and an inhibitor of apoptosis and necrosis, but also acts as insulin antagonist. It has been demonstrated that adults with GHD have an impaired insulin sensitivity, which deteriorates during the first months of treatment with GH. Whether this subsequently leads to sustained impairment during long-term treatment, and to a higher incidence of diabetes mellitus, is unclear. The heterogeneity of adults with GHD, the mostly inevitable observational nature of studies, and the dependence on data from postmarketing studies make research in this field challenging.
In this review, we discuss the literature on the long-term efficacy and safety of GH treatment in adult patients with GHD, with particular emphasis on morbidity: fatal and nonfatal CVD and stroke, fractures, fatal and nonfatal malignancies and recurrences, and diabetes mellitus.
Abstract and Introduction
Abstract
Due to the positive effects demonstrated in randomized clinical trials on cardiovascular surrogate markers and bone metabolism, a positive effect of growth hormone (GH) treatment on clinically relevant end-points seems feasible. In this review, we discuss the long-term efficacy and safety of GH treatment in adult patients with growth hormone deficiency (GHD) with emphasis on morbidity: fatal and nonfatal cardiovascular disease (CVD) and stroke, fractures, fatal and nonfatal malignancies and recurrences, and diabetes mellitus. A positive effect of GH treatment on CVD and fracture risk could be concluded, but study design limitations have to be considered. Stroke and secondary brain tumours remained more prevalent. However, other contributing factors have to be taken into account. Regrowth and recurrences of (peri)pituitary tumours were not increased in patients with GH treatment compared to similar patients without GH treatment. All fatal and nonfatal malignancies were not more prevalent in GH-treated adults compared to the general population. However, follow-up time is still relatively short. The studies on diabetes are difficult to interpret, and more evidence is awaited. In clinical practice, a more individualized assessment seems appropriate, taking into consideration the underlying diagnosis of GHD, other treatment regimens, metabolic profile and the additional beneficial effects of GH set against the possible risks. Large and thoroughly conducted observational studies are needed and seem the only feasible way to inform the ongoing debate on health care costs, drug safety and clinical outcomes.
Introduction
Since the early sixties, growth hormone (GH) has been administered to children with impaired growth. Initially, GH was recovered from donor pituitaries and was therefore scarce. In 1985, GH treatment was banned because of the discovery of Creutzfeldt–Jakob disease in more than one recipient of human GH. Almost at the same time, however, recombinant human GH was manufactured, and thereby, the shortage came to an end. Broadening of the indications for GH treatment was enabled.
Growth hormone deficiency (GHD) in adults has been recognized as a metabolic syndrome, characterized by an adverse body composition and lipid profile. This negative metabolic profile has been hypothesized to be responsible for the increased cardiovascular mortality encountered in patients with hypopituitarism with all, but GH, substitution therapies. In addition, there is decreased bone mineral density, muscle strength, exercise capacity, cognitive function and quality of life (QoL) in patients with severe GHD. Since the late eighties, more and more studies, mostly short term, have demonstrated positive effects of GH treatment on the above-mentioned outcome measures. Subsequently, it has been demonstrated that the effects of GHD in adults result in increased direct and indirect health care costs, including more inpatient care, use of disability pension and sick leave, compared with the general population. Based on the above-mentioned studies, GH treatment was approved for adults with severe GHD in Europe in 1995 and in the United States (US) in 1996.
As GH treatment has been administered for more than 20 years to numerous adults with severe GHD, more data on long-term efficacy and safety should be arising. Most long-term data come from observational studies, mainly postmarketing surveillance databases (Pfizer International Metabolic Database (KIMS) and Hypopituitary Control and Complications Study (HypoCCS) from Eli Lilly & Company) and some national registries. These long-term studies, as recently described in a systematic review by Appelman-Dijkstra et al., demonstrated a sustained positive effect on QoL. The long-term results for cardiovascular risk factors are variable. Whether long-term GH treatment has implications for the incidence of cardiovascular morbidity and fractures remains to be established. In a recent review, four studies investigating the effect of GH treatment on all-cause mortality are described, and no increased mortality was found in men compared to the general population. Women and patients from high-risk groups (previous craniopharyngioma, Cushing's disease, malignant causes of hypopituitarism or aggressive tumours) still have a slightly increased risk, but probably lower than in untreated GHD seen in earlier studies. Next to efficacy, more data are awaited on safety measures. Active acromegaly, with pathologically high insulin-like growth factor-1 (IGF-1) levels, has been suggested to be associated with an increased risk for colonic neoplasia. Epidemiological studies have reported associations of even high-normal IGF-1 levels with an increased risk of developing prostate and breast cancer, while other studies have not. IGF-1 is a key regulator of cell proliferation and an inhibitor of apoptosis and necrosis, but also acts as insulin antagonist. It has been demonstrated that adults with GHD have an impaired insulin sensitivity, which deteriorates during the first months of treatment with GH. Whether this subsequently leads to sustained impairment during long-term treatment, and to a higher incidence of diabetes mellitus, is unclear. The heterogeneity of adults with GHD, the mostly inevitable observational nature of studies, and the dependence on data from postmarketing studies make research in this field challenging.
In this review, we discuss the literature on the long-term efficacy and safety of GH treatment in adult patients with GHD, with particular emphasis on morbidity: fatal and nonfatal CVD and stroke, fractures, fatal and nonfatal malignancies and recurrences, and diabetes mellitus.