The somatotroph cells of the anterior pituitary gland produce growth hormone (GH), which is stimulated by GH-releasing hormone (GHRH) and inhibited by somatostatin, both of which are produced by the hypothalamus.
GH deficiency in adults usually manifests as reduced physical performance and impaired psychological well-being. It results in alterations in the physiology of different systems of the body, manifesting as altered lipid metabolism, increased subcutaneous and visceral fat, decreased muscle mass, decreased bone density, low exercise performance, and reduced quality of life.[1]
Adult GH deficiency can be a transition from childhood-onset GH deficiency or it can be acquired during adulthood. The majority of cases are caused by pituitary tumors or by their treatment with surgery, radiation therapy, or both. Traumatic brain injury is another important cause.[2, 3, 4]
The goals of GH therapy in adults are to improve conditioning, strength, body composition, and quality of life, as well as reduce the burden of associated medical conditions such as cardiovascular disease and decreased bone mineral density.
Patients should be educated about the technique of subcutaneous injection of GH.
For patient education resources, see Thyroid and Metabolism Center as well as Growth Hormone Deficiency, Growth Hormone Deficiency Medications, and Growth Hormone Deficiency FAQs.
The main cause of growth hormone (GH) deficiency is a pituitary tumor or the consequences of treatment of the tumor, including surgery and/or radiation therapy. Traumatic brain injury is increasingly recognized as an important cause of GH deficiency, both during the acute stage of the injury and during the rehabilitation stage.[2, 3, 4]
Causes of GH deficiency can be divided into three categories: congenital, acquired, and idiopathic.[5]
Congenital conditions are caused by genetic abnormalities or structural brain defects. Genetic abnormalities include transcription factor defects (PIT-1, PROP-1, LHX3/4, HESX-1, PITX-2), GH-releasing hormone (GHRH) receptor gene defects, GH gene defects, and GH-receptor or post-receptor defects. Structural defects include agenesis of the corpus callosum, septo-optic dysplasia, empty sella syndrome, encephalocele, hydrocephalus, and arachnoid cyst. GH deficiency can occur in association with midline facial defects such as single central incisor, cleft lip, and cleft palate.
Acquired conditions of GH deficiency include tumors of the pituitary gland or the hypothalamus and metastatic disease; surgery or radiation therapy of the pituitary or hypothalamus; infiltrative diseases such as sarcoidosis, tuberculosis, histiocytosis X, hemochromatosis, and lymphocytic hypophysitis; infarction of the pituitary or hypothalamus (which can be spontaneous or result from Sheehan syndrome); and head trauma.
In some cases, no clear etiology can be determined.
An estimated 6,000 adults are diagnosed with growth hormone (GH) deficiency every year in the United States.[2] Adult GH deficiency has been estimated to affect 1 in 100,000 people annually, whereas its incidence is approximately 2 cases per 100,000 population when childhood-onset GH deficiency patients are considered. About 15%-20% of the cases represent the transition of childhood GH deficiency into adulthood.[6]
The age of presentation of acquired GH deficiency in adults often coincides with the discovery of pituitary tumors, usually between the fourth and fifth decades of life.
Patients with growth hormone (GH) deficiency usually have a history of pituitary tumors that may have been treated with surgery or radiation, or they may have had a history of head trauma. Some patients also have manifestations of deficiency of other pituitary hormones, such as gonadal, adrenal, and thyroid hormones. About 15%-20% of cases involve transitioning of childhood GH deficiency into adulthood.[6]
The symptoms of GH deficiency in adults are often nonspecific. Reported symptoms include low physical and mental energy, decreased muscle strength and exercise tolerance, increased weight or difficulty losing weight, poor memory, emotional instability, and impaired sleep.[7, 8] Some patients are asymptomatic.
Most patients with GH deficiency have a normal physical examination. Some patients may have reduced skeletal muscle and lean body mass but increased fat mass, mainly in the abdominal region.[9]
Evaluation for growth hormone (GH) deficiency is recommended in patients with hypothalamic-pituitary disease, surgery or irradiation in these areas, head trauma, or the presence of other pituitary hormone deficiencies.[7] For patients with childhood-onset GH deficiency, retesting for GH deficiency is indicated after achievement of adult height to determine the need to continue therapy. In these patients, discontinuing GH therapy for at least 1 month is recommended before retesting. Patients with congenital or irreversible hypothalamic-pituitary structural abnormalities do not require retesting for GH deficiency.[7]
Magnetic resonance imaging (MRI) of the hypothalamic-pituitary region may be used to define the anatomy of this region for the presence of tumors or structural abnormalities.
Dual-energy x-ray absorptiometry (DXA) may be used to assess bone mineral density.
Random serum growth hormone (GH) levels are of little value because of the pulsatile nature of GH secretion.
GH deficiency is diagnosed by a low level of serum insulin-like growth factor-1 (IGF-1), but a normal IGF-1 level does not exclude the possibility of GH deficiency and requires the use of stimulation tests.[7] The presence of deficiency of three or more pituitary axes makes GH deficiency more likely; in this setting, provocative testing is optional.[7]
Either the insulin tolerance test (ITT) or the combination of GH-releasing hormone (GHRH) and arginine (GHRH-arginine test) can be used as stimulation tests for the diagnosis of GH deficiency.[5, 7, 10]
If GHRH is not available and performance of an ITT is either contraindicated or not practical in a given patient, the glucagon stimulation test can be used.[5, 7, 10] Because GHRH is not widely available (the only US commercial formulation was discontinued in 2008) and because of safety concerns over the use of ITT, the glucagon stimulation test is being increasingly used.[5, 7]
In December 2017, the FDA approved macimorelin, an oral ghrelin agonist, for the diagnosis of adults with GH deficiency (AGHD).[11] Approval was based on comparative test results between macimorelin and ITT results in adult patients with different pretest probability of GH deficiency and healthy control subjects. Agreement between ITT and macimorelin was 89% for a positive diagnosis and 100% for a negative diagnosis in patients with a high likelihood of AGHD. The maximally stimulated serum GH level below 2.8 ng/mL (ie, at the 30-, 45-, 60- and 90-minute time points) following macimorelin administration confirms the presence of adult GH deficiency.[12] A GH cut-off of 5.1 ng/mL for the ITT and macimorelin test appears to have a 92% sensitivity and 96% specificity for both tests.[13]
Patients should have adequate replacement of other deficient pituitary hormones before being tested for GH secretion. All stimulation tests are done after an overnight fast and involve measuring serum GH levels.
In the ITT, insulin is administered intravenously at a dose of 0.1 unit/kg (time 0) to produce a lowering in plasma glucose level to less than 40 mg/dL (2.2 mmol/L). Glucose levels are monitored by capillary samples every 15 minutes and until symptoms of hypoglycemia develop. A repeated dose of insulin can be administered if hypoglycemia does not develop by 30-60 minutes. Serum glucose and serum GH levels are measured at 0, 15, 30, 60, 90, and 120 minutes after administering insulin. GH deficiency is diagnosed if peak GH level is less than 5.1 mcg/L.[5] Patients usually develop symptoms of hypoglycemia, including sweating, palpitations, and, rarely, convulsions and loss of consciousness. Therefore, the test should be undertaken by an experienced staff under the direct supervision of a physician. It should be avoided in patients with cardiovascular disease, cerebrovascular disease, or seizure disorders.
In the glucagon stimulation test, glucagon is administered intramuscularly at a dose of 1 mg (1.5 mg for patients who weigh >90 kg); GH levels are measured just before the injection and every 30 minutes for 4 hours. The American Association of Clinical Endocrinologists initially recommended to use a peak GH level of less than 3.1 mcg/ L to diagnose GH deficiency[14] ; this was later proposed to be revised to a cut-point of less than 1 mcg/L,[15] whereas the Endocrine Society recommends a cut-point of between 2.5 and 3 mcg/L.[7]
In the GHRH-arginine test, GHRH is administered intravenously at a dose of 1 mcg/kg body weight (time 0), followed by an intravenous infusion of 0.5 g/kg body weight (maximum 30 g) of arginine over 30 minutes. Serum GH is measured at -30, 0, 30, 60, 90, and 120 minutes.
Because body mass index (BMI) can influence the GH response, the following criteria are used to establish the diagnosis of GH deficiency when using the GHRH-arginine test[7] :
In patients with GH deficiency of hypothalamic origin (eg, irradiation), GHRH can stimulate the pituitary and therefore yields falsely normal results.[7] In such cases, using alternative stimulation tests is recommended.
Growth hormone (GH) replacement therapy is provided in the form of human recombinant GH. This is available in subcutaneous injection form. The starting dose of GH depends on the age and clinical condition of the patient. A dose regimen that is based on age along with dose titration has been associated with less adverse effects compared with a weight-based regimen.[16] The following regimen is suggested[7] :
For patients with adherence issues, a less frequent dose regimen such as alternate days or 3 times per week using the same total weekly dosage can be used.[7]
Follow-up is usually planned at intervals of 1-2 months when the dose of GH can be adjusted by increments of 0.1-0.2 mg/day based on the clinical response, serum insulin-like growth factor-1 (IGF-1) levels, and side effects. Longer time intervals and smaller dose increments are suggested for older patients.
Serum IGF-1 levels are the main determinant for adjusting the dose of GH. No studies are available to guide this decision. A commonly used target is the upper half of the normal range appropriate for age and sex, unless significant side effects develop.[5]
Once maintenance doses of GH are achieved, follow-up is provided at intervals of 6 months. Monitoring includes clinical evaluation, assessment of side effects, and measurement of serum IGF-1, fasting glucose, and lipid profile. Quality of life (QOL) is also assessed using standardized questionnaires. If the initial bone mineral density findings, measured by dual-energy x-ray absorptiometry (DXA) scanning, are abnormal, repeat testing at intervals of 2-3 years is recommended.[5]
No studies are available regarding the optimal length of GH replacement therapy. Patients with childhood GH deficiency who attained adult height and had persistent deficiency on retesting should continue to receive GH therapy.[5]
GH therapy can also be continued indefinitely if benefits such as significant improvement in QOL and objective improvements in biochemistry and body composition are observed. If no objective or subjective benefits are seen after 1 year of treatment, discontinuation of GH therapy should be considered.[7]
Published data do not confirm an association between GH therapy and recurrence or regrowth of pituitary tumors or craniopharyngiomas.[17, 18, 19] However, because of the possible association between increased IGF-1 levels and the risk of malignancy, there has been a theoretical concern that GH therapy could lead to regrowth of malignancies.[20] Therefore, GH therapy is not recommended for use in patients with a previous history of malignancy or in the presence of active malignancy.[5, 7]
A separate, more recent population-based study of 6874 adult French patients treated with recombinant GH in childhood for isolated GH deficiency, short stature associated with low birth weight or length, or idiopathic short stature found an increased risk of bone tumors but not an overall cancer risk in these individuals.[21]
GH therapy may increase the activity of the cytochrome P-450 system and alter the clearance of some medications known to be metabolized by this system, such as corticosteroids, anticonvulsants, sex steroids, and cyclosporine. Therefore, monitoring is advised when such medications are used in patients receiving GH therapy.
The most common side effects of GH therapy are related to fluid retention and include paresthesias, joint stiffness, peripheral edema, arthralgia, myalgia, carpal tunnel syndrome, and increased blood pressure. Most of these adverse effects improve with dose reduction. Older age, higher body mass index (BMI), and female sex confer higher risk of these complications.[22]
GH therapy is associated with a mild increase in both fasting serum glucose and fasting plasma insulin levels.[23] Patients with diabetes mellitus who receive GH therapy may require adjustment in their glucose-lowering medications.
Because GH therapy can decrease levels of serum free T4 and cortisol, regular monitoring of thyroid and adrenal function is recommended. Patients on concurrent thyroid or adrenal hormone replacement may need dose adjustments after starting GH therapy. Patients who have normal thyroid and adrenal function require monitoring of serum free T4 and assessment of the hypothalamic-pituitary-adrenal axis because GH therapy can unmask central hypothyroidism and hypoadrenalism.[24, 25]
Patients who are on testosterone-replacement therapy may require their GH doses to be lowered, because testosterone can potentiate GH action and exacerbate GH-induced adverse effects.[26]
Women who are taking oral estrogen replacement therapy usually need higher doses of GH, but those on transdermal estrogen preparations may not.[27]
Consult with an endocrinologist. Consult with a neurosurgeon for evaluation of pituitary tumors.
Growth hormone (GH) deficiency has been associated with cardiovascular disease, osteopenia/osteoporosis, alteration in body composition, decreased life expectancy, psychological disturbances, and insulin resistance.
Early epidemiologic data showed that patients with hypopituitarism who were on hormone replacement therapy, not including GH, had increased cardiac events, suggesting an association of GH deficiency with cardiovascular disease.[14, 28, 29, 30, 31] Patients with GH deficiency have increased rates of the presence of markers of cardiovascular disease, such as greater intima-media thickness of the carotid arteries, reduced left ventricular mass, decreased ejection fraction, high levels of serum low-density lipoprotein (LDL) cholesterol (LDL-C) and triglycerides, low levels of high-density lipoprotein (HDL) cholesterol (HDL-C), and high coronary calcium scores.[14, 29, 30, 32] GH therapy improves certain markers of cardiovascular disease, such as serum lipids (reduction of LDL-C levels and increase in HDL-C levels), systolic function, intima-media thickness of the carotid arteries, endothelial function, left ventricular mass, and cardiac output.[29, 33, 34, 35] However, evidence is limited regarding the effect of GH replacement therapy on cardiovascular morbidity and mortality.[28, 29, 36]
A study that evaluated the prevalence of metabolic syndrome and associated cardiovascular complications in adult-onset GH deficiency during GH replacement therapy found an essentially unchanged prevalence of metabolic syndrome in these patients during 1 year of GH therapy.[37] However, there was a significant reduction in abnormal waist circumference (P< 0.001), a significant increase in impaired glucose metabolism (P < 0.001), and a decrease in HDL-C (P = 0.011). Moreover, over a 7-year period of GH therapy, those with metabolic syndrome had a 66% higher risk of developing a new coronary disease compared to those without metabolic syndrome (P = 0.0016).[37]
Patients with GH deficiency have reduced bone mineral density and increased rates of fractures.[38, 39] A gender difference in the response to GH treatment has been hypothesized, as bone mineral density has been show to improve with this therapy more in men than in women.[40, 41, 42] The effect of GH therapy on fracture rate was less pronounced, with stabilization of the incidence of clinical fracture after GH treatment.[40]
Patients with GH deficiency tend to have a relative increase in fat mass with a preferential increase in visceral fat and a relative decrease in muscle mass.[43, 44] GH therapy decreases total body fat and increases muscle mass.[43, 45] Some, but not all, studies have shown increased muscle strength along with improved exercise capacity and physical performance after GH therapy.[45, 46, 47]
In an observational retrospective monocentric study of 47 patients with GH deficiency who were treated with GH during childhood, investigators evaluated changes in pediatric growth parameters relative to an increase of insulin-like growth factor-1 (IGF-I) z-score as well as other indexes of GH response, such as body composition and lipid profile, after 1 year of treatment in adulthood.[48] The investigators noted the following[48] :
Patients with hypopituitarism have decreased life expectancy compared with age- and gender-matched healthy people despite replacement with adrenal, thyroid, and gonadal hormones, primarily owing to cardiovascular and cerebrovascular disease.[7, 49, 50, 51] Therefore, it has been speculated that GH deficiency in patients with hypopituitarism is associated with premature mortality.[7] However, other factors potentially contribute to the increased mortality in these patients, including the following[7] :
There are no published studies on the effect of GH therapy on mortality. Observational data suggest a lower mortality in those who receive GH therapy compared to those who remain untreated, but these findings may be a result of selection bias.[36]
Compared with matched healthy persons, patients with GH deficiency have lower quality-of-life scores, with reduced energy, social isolation, and disturbed sexual life.[52]
Impaired glucose metabolism characterized by insulin resistance and fasting hyperinsulinemia has been reported in patients with GH deficiency.[10]
The Endocrine Society clinical practice guideline on the evaluation and treatment of adult growth hormone (GH) deficiency includes the following recommendations[7] :
The goals of pharmacotherapy are to reduce morbidity and prevent complications.
Clinical Context: Human recombinant growth hormone is produced by recombinant deoxyribonucleic acid (DNA) technology. It stimulates the growth of linear bone, skeletal muscle, and organs and stimulates erythropoietin, increasing red blood cell mass. Actions are either direct or from the hepatic production of IGF-I. It is currently widely available in subcutaneous injection form.
Published data do not confirm an association between GH therapy and recurrence or regrowth of pituitary tumors or craniopharyngiomas. However, because of the possible association between increased IGF-1 levels and the risk of malignancy, there has been a theoretical concern that GH therapy could lead to regrowth of malignancies. Therefore, professional guidelines recommend not using GH therapy in patients with previous history of malignancy or in the presence of active malignancy.
GH therapy may increase the activity of cytochrome P-450 system and alter the clearance of some medications known to be metabolized by this system such as corticosteroids, anticonvulsants, sex steroids, cyclosporine. Therefore, monitoring is advised when such medications are used in patients receiving GH therapy.
The most common side effects of GH therapy are related to fluid retention and include paresthesia, joint stiffness, peripheral edema, arthralgia, myalgia, carpal tunnel syndrome and increased blood pressure. Most of these adverse effects improve with dose reduction. Older age, higher BMI and female gender confer higher risk of these complications.
GH therapy is associated with a mild increase in both fasting serum glucose and fasting plasma insulin levels. Patients with diabetes mellitus who receive GH therapy may require adjustment in their glucose-lowering medications.
- Because GH therapy can decrease levels of serum free T4 and cortisol, regular monitoring of thyroid and adrenal function is recommended. Patients on concurrent thyroid or adrenal hormone replacement may need dose adjustments after starting GH therapy. Patients who have normal thyroid and adrenal function require monitoring of serum free T4 and assessment of the hypothalamic-pituitary-adrenal axis since GH therapy can unmask central hypothyroidism and hypoadrenalism.
Patients who are on testosterone-replacement therapy may require their GH doses to be decreased as testosterone can potentiate GH action and exacerbate GH-induced adverse effects.
Women who are taking oral estrogen replacement usually need higher doses of GH, but those on transdermal estrogen preparations may not.
Clinical Context: Macimorelin is an oral ghrelin agonist. Ghrelin is a neuropeptide released mainly from cells in the stomach and pancreas in response to hunger and is a growth hormone-releasing peptide. It stimulates GH release by activating GH secretagogue receptors present in the pituitary and hypothalamus. Macimorelin is indicated for diagnosis of adult growth hormone deficiency.