Growth Hormone Deficiency In Adults And Children: Etiology, Clinical Manifestations, Diagnosis, And Treatment
Introduction
Growth hormone, also known as somatotropic hormone (GH), is a hormone produced by somatotropic cells in the anterior pituitary gland. Its deficiency is clinically important in both children and adults. It is a rare endocrine disorder that often occurs together with deficiencies of other pituitary hormones. Growth hormone deficiency causes significant changes in body composition, bone mineral density (BMD), quality of life, and other health indicators (1). This article reviews the etiology, clinical manifestations, diagnosis, and treatment of growth hormone deficiency.
Etiology
The most common causes of growth hormone deficiency are generally the same as those responsible for other pituitary hormone deficiencies and can be classified into causes related to hypothalamic and pituitary diseases (Table 1) (2). In the United Kingdom, among 172 cases of hypopituitarism, the most common identified cause was pituitary tumors or treatment-induced hypopituitarism (76%). Other causes were much less frequent: 13% were due to tumors of surrounding tissues (e.g., craniopharyngiomas), 8% were of unknown origin, 1% were associated with sarcoidosis, and 0.5% with Sheehan's syndrome (3). Table 1. Main causes of hypopituitarism| Hypothalamic diseases |
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| Pituitary diseases |
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Studies have shown that in cases of organic pituitary disease, the secretion of growth hormone and gonadotropins is more frequently impaired than the secretion of adrenocorticotropic hormone (ACTH) and thyroid-stimulating hormone (TSH). In cases of pituitary damage, the probability of growth hormone deficiency in the absence of other hormone deficiencies is approximately 45%, whereas if deficiencies of other pituitary hormones are also present, the probability can reach 100% (4).
Growth hormone deficiency caused by organic disorders usually manifests during childhood and often persists into adulthood, whereas idiopathic growth hormone deficiency may develop either during childhood or adulthood. Some sources indicate that up to 20% of adults who were treated for growth hormone deficiency in childhood continue to exhibit GH deficiency (1). Idiopathic GH deficiency in adults is not well documented but is often associated with inadequate evaluation or incomplete history-taking, such as forgotten childhood head trauma (5).
Clinical Manifestations of Growth Hormone Deficiency
The most obvious manifestation of growth hormone deficiency in children is short stature. In adults with acquired GH deficiency, there is a decrease in lean body mass and BMD, deterioration in quality of life, increased fat mass, a higher incidence of bone fractures, increased cardiovascular disease risk, and greater mortality (6). GH deficiency that develops during childhood and persists into adulthood is associated with more severe clinical manifestations than GH deficiency that develops later in life. The relationship between growth hormone deficiency and the severity of clinical manifestations is not straightforward because of concomitant diseases, including deficiencies of other pituitary hormones, treatment or overtreatment with replacement hormone therapies such as glucocorticoids, and the consequences of pituitary or hypothalamic surgery (7).
Further detailed are the clinical manifestations of growth hormone deficiency:
- Changes in body composition. Various studies evaluating the impact of GH deficiency on body composition have demonstrated a reduction in lean body mass compared with individuals with normal GH levels (8–11). In one study, computed tomography was used to assess muscle mass in the hands and thighs. Compared with the control group (individuals with normal GH concentrations), lower muscle mass was observed in patients with growth hormone deficiency. One of the best indicators of treatment effectiveness in GH deficiency caused by hypopituitarism is improvement in body composition (11);
- Changes in bone mineral density and bone fractures. Patients who developed growth hormone deficiency (GHD) in adulthood had lower lumbar spine BMD than the control group. The severity of osteopenia correlates with the severity of GHD; however, it is important to remember that more severe GHD is usually accompanied by deficiencies of other pituitary hormones. Therefore, it is often difficult to determine which factors contribute most significantly to reduced BMD (12). Bone fractures are also more common among individuals with GH deficiency, although available data are limited. In one study, a control group of 323 individuals was compared with patients with hypopituitarism, including those with GH deficiency, and it was found that fracture risk among 107 participants was three times higher (13). In another study involving 422 individuals with pituitary pathology, nearly a fivefold increase in fractures was observed among patients with impaired GH response to stimulation compared with those who had a normal GH response;
- Decrease in quality of life. When GHD develops only in adulthood, there is an increased risk of depression and social isolation, making it more difficult to obtain well-paid employment (1). These individuals frequently perceive themselves as less healthy and less active than healthy people of the same age (14–16). Assessments based on quality-of-life questionnaires demonstrate lower scores among adults with GHD compared with healthy controls, although adequate treatment has been shown to improve quality of life (17);
- Cardiovascular risk factors. Numerous studies have demonstrated that individuals with GHD exhibit dyslipidemia, elevated inflammatory markers, and signs of endothelial dysfunction (18–22). An evaluation of lipid profiles in 665 individuals revealed elevated total cholesterol and low-density lipoprotein cholesterol levels or reduced high-density lipoprotein cholesterol levels in 22% to 45% of patients before treatment initiation. In another study, inflammatory markers, including interleukin-6 and C-reactive protein, were significantly higher in women with hypopituitarism than in the control group (21). Higher markers of endothelial dysfunction and impaired endothelium-dependent vasodilation were also observed, although carotid artery intima-media thickness did not differ between groups (22). It is believed that individuals with GHD have a greater amount of calcium in the coronary vessels, a subclinical marker of atherosclerosis (23);
- Mortality. When hypopituitarism develops during adulthood, life expectancy is reduced compared with healthy individuals matched for sex and age, regardless of replacement therapy with adrenal, thyroid, or sex hormones (3, 24–25). One retrospective study reported a twofold increase in mortality among patients with hypopituitarism after adjustment for age and sex, with the difference attributed to cardiovascular events (24). In subsequent studies conducted by the same authors, higher overall mortality was again observed, although the difference could not be explained solely by cardiovascular disease (3, 25).
Diagnosis
Evaluation for suspected growth hormone deficiency is recommended:- in patients diagnosed with hypothalamic or pituitary pathology. In cases of panhypopituitarism, where deficiencies of TSH, ACTH, or gonadotropins are present, growth hormone deficiency is often also present;
- in patients with a history of growth hormone deficiency during childhood. In some patients, GH levels may normalize; however, in the presence of organic pathology (e.g., pituitary adenomas), there is a high probability of persistent growth hormone deficiency (26–27).
- IGF-1: In cases of growth hormone deficiency, serum IGF-1 levels are reduced relative to age- and sex-specific reference ranges (28);
- Provocative tests: These are performed when IGF-1 values are inconclusive. Growth hormone secretion may be stimulated by insulin-induced hypoglycemia, growth hormone-releasing hormone (GHRH) combined with arginine (this combination is recommended when GHRH is available), levodopa combined with arginine, or other stimuli. An insufficient serum growth hormone response to stimulation in patients with organic pituitary pathology and inconclusive IGF-1 values confirms the diagnosis of growth hormone deficiency. The use of arginine, clonidine, levodopa, levodopa combined with arginine, or glucagon alone carries a higher risk of false-positive results because of inadequate GH stimulation. Obesity affects growth hormone secretion; therefore, lower GH cut-off values are recommended when evaluating growth hormone deficiency in obese patients compared with normal-weight individuals (28–29).
Treatment
Growth hormone deficiency is recommended to be treated in most patients who developed GH deficiency due to organic causes during childhood, and continuation of treatment initiated in childhood is also recommended. If GH deficiency develops in adulthood, treatment with GH is often not recommended; however, the decision regarding treatment indications should be made individually by the treating physician (31). Treatment consists of recombinant human growth hormone (somatropin, rhGH), administered subcutaneously once daily in the evening. The dose is selected individually according to body weight (or body surface area) and adjusted based on IGF-1 levels (2). The 2016 guidelines of the European Society of Endocrinology recommend an initial somatropin dose of 0.2–0.4 mg/day for patients up to 60 years of age and 0.1–0.2 mg/day for those older than 60 years (27). Other sources recommend an initial somatropin dose of 2–5 µg/kg per day (2). Women taking oral estrogens require higher GH doses than men or women using transdermal estrogen preparations (27, 32). The goal of treatment is to administer a GH dose that results in an average age- and sex-adjusted IGF-1 level (4). If the target IGF-1 level is not achieved within 2 months of treatment, the GH dose should be gradually increased by 1–2 µg/kg every 2 months. Doses exceeding 10–12 µg/kg are not recommended. If adverse effects occur or IGF-1 levels become excessive, the somatropin dose should be reduced (2, 27). The duration of treatment in adult patients is not strictly defined. A systematic review of 23 studies evaluating long-term GH therapy demonstrated beneficial effects on body composition, lipid profile, intima-media thickness, and bone mineral density, but not on muscle strength. Positive effects on quality of life, as well as changes in glucose and insulin metabolism, were not confirmed (33). In addition, continuation of somatropin therapy during pregnancy is not recommended (27). Based on various sources, the following positive effects have been observed in adult patients receiving GH treatment:- increase in muscle mass and reduction in fat mass (34);
- increase in muscle strength and physical endurance (35);
- increase in bone mineral density (36–37);
- improvement in quality of life (17);
- reduction in cardiovascular disease risk factors, including dyslipidemia, inflammatory markers, and endothelial dysfunction (38–44);
- improvement in cardiac function due to increased left ventricular mass, wall thickness, end-diastolic diameter, and stroke volume (45).
- once every 2 months until the optimal GH dose has been determined (dose adjustment described above);
- once every 6–12 months after achieving the target IGF-1 level.
