Pharmacological treatment of growth hormone deficiency (GHD) in adults began in clinical practice more than 20 years ago.
Since then, a great volume of experience has been accumulated on its effects on the symptoms and biochemical alterations that characterize this hormonal deficiency.
The effects on body composition, muscle mass and strength, exercise capacity, glucose and lipid profile, bone metabolism, and quality of life have been fully demonstrated. The advance in knowledge has also taken place in the biological and molecular aspects of the action of this hormone in patients who have completed longitudinal growth.
In recent years, several epidemiological studies have reported interesting information about the long-term effects of GH replacement therapy in regard to the possible induction of neoplasms and the potential development of diabetes.
In addition, GH hormone receptor polymorphism could potentially influence GH therapy. Long-acting GH is under development to create a more convenient GH dosing profile while retaining the excellent safety, efficacy, and tolerability of daily GH.
In this article, we compile the most recent data on GH replacement therapy in adults, as well as the molecular aspects that may condition a different sensitivity to this treatment.
Growth Hormone Deficiency Syndrome
The syndrome of growth hormone deficiency (GHD) in adulthood has been fully defined and is characterized by alterations in body composition, decreased capacity for exercise and quality of life (QoL), as well as a series of unfavorable changes in cardiovascular function, and lipid and carbohydrate metabolism.
Its diagnosis is based on the combination of pituitary disease, hypopituitarism, and a decrease in the concentration of insulin-like growth factor I (IGF-I) or in diminished GH responses to different stimuli.
A concentration of IGF-I below normal for age and sex in a patient with involvement of three or more pituitary axes is diagnostic of GHD. Expert consensus defines severe GHD as a GH response peak after insulin hypoglycemia below 3 μg/L.
This is an arbitrary limit that depends on the assay method, the laboratory, and the type of stimulation. Other stimuli used have been the GH-releasing hormone (GHRH) plus arginine, GHRH plus GH-releasing peptide (GHRP-6), glucagon, or the long oral glucose test.
Replacement therapy with recombinant human GH has been available since the 1980s. The experience accumulated since then is extensive, and nowadays there is no doubt that this therapy improves or reverses most of the signs and symptoms of this hormonal deficiency. However, chronic GH administration is not without potential risks.
We herein review the most recent data and summarize our current knowledge about the benefits and risks of GH replacement therapy in adults deficient in this hormone. All articles related to replacement therapy for growth hormone deficiency were searched in MEDLINE from 1985 to 2017.
The search was performed by using the terms “replacement therapy” and “adult” as subheadings of the term “growth hormone deficiency” in the Medical Subject Headings (MeSH) thesaurus. All clinical trials and systematic reviews related to growth hormone deficiency were also searched at the Cochrane Database of Systematic Reviews and The Cochrane Central Register of Controlled Trials.
The selection criteria included all prospective and retrospective studies, all case series, all case reports, and reviews concerning the effects of growth hormone replacement therapy on adult patients with GHD. Duplicated articles were excluded.
This search was supplemented by a review of reference lists of potentially eligible studies and a manual search of key journals in the field of endocrinology.
Benefits of Treatment with Growth Hormone
GH replacement therapy is associated with beneficial effects on body composition, bone structure, health-related QoL, and several cardiovascular risk factors.
1. Body Composition
Initial studies showed that treatment with GH induced a decrease in fat mass and an increase in lean mass. Elbornsson et al. in a cohort of 156 patients with GHD, reported an improvement in lean mass maintained for 15 years, and a marked initial decrease in fat mass, followed by a slowly progressive increase over time, in possible relation to the aging process.
A recent systematic review concluded that the long-term effects on body mass index appear to be inconclusive, with some studies reporting an increase and others reporting no change. On the other hand, most long-term studies report no effect of GH replacement therapy on the waist-hip ratio or waist circumference.
A slight but significant increase in waist circumference has been reported in one study. It has been postulated that the observed increase in body mass index and waist circumference in some studies is in line with changes due to the normal aging process.
In other words, it is possible that in long-term studies the aging process attenuates some of the beneficial effects of GH treatment on body composition.
Interestingly, data from the study by Filipsson Nystrom et al. showed that discontinuation of GH therapy for four months, after more than three years of treatment, was followed by an increase in abdominal subcutaneous and visceral fat and a decrease in thigh muscle mass.
A recent meta-analysis of 22 trials, including 591 GH- and 562 placebo-treated patients, found that mean lean body mass increased by 2.61 kg in GH-treated subjects versus 0.04 in the placebo group, and that fat mass was reduced by 2.19 kg versus 0.31 (GH vs. placebo).
Changes in lean body mass and fat mass were dose-related, with high dose (HD) being more effective than low dose.
Lean body mass, including both skeletal muscle mass and tissue hydration, is increased with GH replacement therapy. GH therapy causes an increase in the tubular reabsorption of sodium in the distal nephron.
This is accompanied by an increase in plasma renin activity and decreased brain natriuretic peptide levels. In addition, although treatment with GH is accompanied by an increase in lean body mass, most studies do not allow differentiating between extracellular water and intracellular mass.
Therefore, the lean body mass data may not be accurate, as GH replacement is associated with an increase in the intracellular water component. However, GH replacement therapy increases muscle strength and exercise capacity in patients with GH deficiency.
In the study by Gotherstrom, GH treatment for 10 years in patients with GHD increased muscle strength during the first half of the study and later protected from the decline in muscular strength that occurs with aging. These data, although indirectly, clearly suggest a real increase in muscle mass.
2. Bone Structure
Replacement therapy with GH in adult patients with GHD increases bone mineral density (BMD) and helps to optimize peak bone acquisition in patients who have persistent GH deficiency during the transition from adolescence to adulthood.
The effect on BMD is greater at vertebral than femoral level and after 18–24 months of treatment, and most studies show an increase of 4–10% of BMD. In patients with childhood-onset GHD, it has been shown that the continuation or reinstitution of treatment for two years, in patients who completed growth, induced a significant increase in BMD compared to untreated patients.
Therefore, the continuation of GH treatment during the period of transition from childhood to adulthood is recommended to obtain complete bone maturation. A prospective study in 18 patients with GHD showed that seven years of GH treatment induced an increase in lumbar spine BMD, which stabilizes during long-term therapy.
However, a significant positive effect on bone microarchitecture could not be demonstrated in these patients. Furthermore, two recent meta-analyses have suggested that the beneficial effect of GH therapy on BMD in adults with GHD is mainly affected by gender, age, dose, and treatment duration.
In a cohort of 230 adult GHD patients, followed up to 15 years, Appelman-Dijkstra et al. demonstrated a sustained increase in BMD at the lumbar spine, particularly in men, and stabilization of BMD values at the femoral neck. This study suggested that the clinical fracture incidence was not increased during long-term GH replacement.
Estrogenic hormonal status exerts also an influence on the GH replacement therapy effects on bone metabolism. In a prospective, single-center study, including 87 consecutive patients (52 men and 35 women) with adulthood onset GHD, GH replacement induced a sustained increase in total, lumbar and femoral neck BMD and bone mineral content.
There was a tendency for women on estrogen treatment to have a greater increase in bone mass and density compared with women without estrogen replacement. This study suggests that adequate estrogen replacement is needed in order to have an optimal response in bone mineral density in GHD women.
3. Quality of Life
GH treatment improves health-related QoL in the majority of patients. Most of the improvement in QoL occurs during the first year of treatment, although this beneficial effect persists in the medium and long term. Sustained improvement in QoL scores has been shown to be more marked in women and in patients with low QoL at baseline.
A special group consists of patients with a previous history of acromegaly who subsequently presents GHD. This particular group of patients exhibits a significant deterioration of health-related QoL that is improved by GH replacement.
4. Cardiovascular Risk Markers
Treatment with GH in patients with GHD improves several cardiovascular risk factors, such as lipid profile, endothelial function, and cardiovascular inflammatory markers.
Dyslipidemia has been considered the strongest contributor to the excess cardiovascular risk associated with hypopituitarism. Most studies have shown an increase in high-density lipoprotein (HDL) cholesterol and a decrease in total cholesterol and low-density lipoprotein (LDL) cholesterol after administration of GH.
Withdrawal of GH treatment for four months, after more than three years of administration, was accompanied by an increase in total and LDL cholesterol, which indirectly shows one of the great benefits of GH therapy in patients with GHD.
The positive effect of GH therapy on lipid profile has been confirmed in a long-term 15-year prospective study.
Furthermore, a slight decrease in diastolic blood pressure has been demonstrated in a meta-analysis of placebo-controlled studies. Inflammatory markers are elevated in patients with GHD and treatment with GH can improve low-grade inflammation, as documented by a reduction in C-reactive protein, TNF-α, and interleukin-6.
Increased thickness of the carotid intima-media is an important predictor of coronary disease in epidemiological studies. Replacement with GH in patients with GHD has been shown to decrease this parameter. The study by Makimura et al. is of particular interest in this context.
In patients with obesity and decreased GH secretion, randomized and placebo-controlled administration of a GHRH analog induced a decrease in visceral fat mass and in the intima-media thickness of the carotid, in addition to a moderate elevation of IGF-I.
5. Influence of Severity
Patients who are most likely to benefit from GH replacement therapy include those with severe GH deficiency, defined by the response to GH provocative testing and serum IGF-1 levels, including patients with genetic and other congenital causes of GH deficiency.
Retesting during the transition to adulthood in children with idiopathic GH deficiency is necessary but is not mandatory in patients expected to have lifelong severe GH deficiency owing to causes such as genetic mutations, structural lesions, or deficiencies of multiple pituitary hormones.
In addition, continued GH replacement therapy during the transition period after completion of linear growth is recommended to permit the achievement of full skeletal and muscle maturation.
6. Influence of Age
The patient’s age should be taken into account when considering GH replacement therapy. GH secretion normally decreases with age, and older patients have an increased susceptibility to GH-related side effects.
Therefore, GH dose requirements are lower in older patients and higher in some transition and young adult patients, especially if serum IGF-I is very low. On the other hand, there are no well-conducted prospective studies on the effect of age on the benefits and risks of GH replacement.
In a systematic review of eleven studies in patients older than 60, treatment with GH decreased total and low-density lipoprotein cholesterol levels but did not alter high-density lipoprotein or triglyceride levels.
In addition, GH did not affect body mass index, blood pressure, or bone mineral density but decreased waist circumference, increased lean body mass and decreased total fat mass. GH replacement consistently improved QoL.
There are no data on the efficacy and safety of GH treatment in patients older than eighty years. In a prospective, single-center, open-label study, the effects of GH replacement were determined in 24 GHD adults above 65 years of age and in 24 younger GHD patients.
Despite the lower dose in the elderly group, these patients had a more marked reduction in waist/hip ratio and serum low-density lipoprotein-cholesterol level, and these differences remained also after correction for the duration of hypopituitarism.
There was no difference at baseline or in responsiveness in lean mass, bone mineral density, and glucose homeostasis.
7. Other Beneficial Effects
Sleep disturbances have been reported in patients with GHD. Morselli et al. have shown that four months of GH replacement therapy partly reversed sleep disturbances previously observed in untreated patients. Cardiac size and cardiac performance have been reported to improve with GH replacement therapy.
A prospective study in 14 patients with adult-onset GHD showed that one year of GH therapy improves coronary flow reserve and left ventricular diastolic function in the patient population analyzed, thereby encouraging the early start of GH replacement therapy.
Six months of GH treatment significantly improved anaerobic capacity and physical function in a time-dependent manner in adults with GHD.
Retrospective and prospective studies have shown that patients with hypopituitarism treated with usual replacement therapy without GH exhibit increased mortality in comparison with the general population, especially concerning CV disease.
In a group of 1411 hypopituitary adults without GH replacement, Svensson et al. found that overall mortality and the rates of myocardial infarctions, cerebrovascular events, and malignancies were increased compared with the normal population.
In a cohort of 289 patients on GH replacement, overall mortality and the rate of malignancies were similar to the normal population.
The rate of myocardial infarctions was lower than that in the background population, although there was a tendency toward an increased rate of cerebrovascular events in this cohort. Therefore, it has been suggested that GH replacement appeared to provide protection from myocardial infarctions.
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