Growth hormone deficiency in adults

INTRODUCTION — Growth hormone (GH) deficiency in adults is important for two reasons: the evidence that GH deficiency can have adverse effects and the availability of GH preparations for treatment [1,2]. The clinical manifestations, diagnosis, and treatment of GH deficiency in adults are discussed here. GH deficiency in children is discussed elsewhere. (See "Diagnosis of growth hormone deficiency in children" and "Treatment of growth hormone deficiency in children".)

ETIOLOGY — The causes of GH deficiency are the same as the causes of deficiencies of other pituitary hormones (table 1) (see "Causes of hypopituitarism"). A study of 172 adults with hypopituitarism found the following distribution of etiologies [3]:

●A pituitary tumor or the consequences of treatment of the tumor, including surgery and/or radiation therapy – 76 percent

●An extrapituitary tumor (eg, craniopharyngioma) – 13 percent

●Cause unknown – 8 percent

●Sarcoidosis – 1 percent

●Sheehan syndrome – 0.5 percent (see "Causes of hypopituitarism")

As a general rule, the secretion of GH and gonadotropins is more likely to be affected by organic pituitary disease than that of corticotropin (ACTH) and thyroid-stimulating hormone (TSH). The likelihood of GH deficiency in such patients has been estimated to range from approximately 45 percent in patients with no other pituitary hormone deficits to virtually 100 percent in patients with multiple deficits [4].

When GH deficiency occurs in childhood due to any of the organic causes above, the deficiency will almost always persist into adulthood. In contrast, idiopathic GH deficiency in childhood may not persist. This topic is discussed in detail elsewhere. (See "Growth hormone treatment during the transition period", section on 'Isolated growth hormone deficiency' and "Treatment of growth hormone deficiency in children", section on 'Duration of therapy'.)

Although an entity referred to as "idiopathic adult growth hormone deficiency" has been postulated, it has not been well documented. A low GH response to a stimulus in the absence of a documented cause could result from obesity, which typically blunts the response to any stimulus [5].

CLINICAL MANIFESTATIONS — The most prominent feature of GH deficiency in children is short stature (see "Diagnosis of growth hormone deficiency in children"). Individuals who develop GH deficiency in adulthood experience a decrease in lean body mass, bone mineral density (BMD), and quality of life; an increase in fat mass; and increased rate of fractures, cardiovascular disease, and mortality [2]. Individuals with childhood-onset GH deficiency that persists into adulthood have more severe clinical manifestations than those who develop it as adults [6].

The contribution of GH deficiency itself to the clinical manifestations is uncertain because of the possible contribution of concomitant conditions, including the other pituitary hormonal deficiencies; treatment or overtreatment with replacement hormones, such as glucocorticoids; and the consequences of surgery on the pituitary or hypothalamus.

Body composition — Studies using different techniques indicate that lean body mass is decreased in adults who are deficient in GH and not replaced compared with those who have normal GH secretion [7-10]. As an example, computed tomographic (CT) measurements of the cross-sectional area of arm and thigh muscle show that muscle mass is decreased in patients with GH deficiency when compared with normal subjects [10]. Improvement in body composition is probably the best-documented effect of GH treatment in adults with hypopituitarism. (See 'Potential beneficial effects of treatment' below.)

Bone mineral density and fractures — BMD of the lumbar spine is somewhat lower in patients with adult-onset GH deficiency and not replaced, compared with normal subjects. The degree of osteopenia appears to correlate directly with the degree of GH deficiency; however, the number and severity of other hormonal deficiencies are also more pronounced in patients with more severe GH deficiency [11]. As a result, it is not possible to determine from available data if growth hormone deficiency itself or associated conditions are more important in the development of low BMD.

Limited data suggest an increased incidence of fractures in patients with GH deficiency. In one report, the prevalence of a history of fracture in 107 patients, males and females, with hypopituitarism, including GH deficiency, was more than three times that in a control group of 323 [12]. In a second study, in 422 patients with a pituitary disorder, those who had a subnormal GH response to stimulation had nearly five times more fractures than those who had a normal GH response [13].

Quality of life — Patients who develop GH deficiency in adulthood often perceive themselves as less healthy and less energetic than normal subjects of the same age [14-16]. They have lower scores on quality of life questionnaires when compared with healthy controls, which improved in response to GH therapy. (See 'Potential beneficial effects of treatment' below.)

Cardiovascular risk factors — Some, but not all, data suggest that adults with GH deficiency have dyslipidemia [17-19], increased inflammatory markers [20], and an increase in biochemical markers of endothelial dysfunction [21,22].

●In a trial of 665 adults with GH deficiency, increased total and low-density lipoprotein (LDL) cholesterol, or low high-density lipoprotein (HDL) cholesterol was seen in 22 to 45 percent of patients prior to treatment [19].

●In a report of 53 females with hypopituitarism, biochemical markers of inflammation (interleukin [IL]-6 and C-reactive protein) were significantly higher when compared with healthy controls [20].

●In a third study, several biochemical markers of endothelial dysfunction were higher in patients with GH deficiency than in matched controls, as was endothelium-dependent vasodilatation [21]. Carotid intima-media thickness by ultrasonography, however, was not different.

●Individuals with GH deficiency are more likely than healthy controls to have high coronary calcium scores (a marker of subclinical atherosclerosis) [23].

Mortality — Patients who develop hypopituitarism in adult life have reduced life expectancy (no single cause) as compared with age- and sex-matched normal subjects, in spite of replacement of adrenal, thyroid, and gonadal hormones [3,24,25]. In one retrospective study, patients with hypopituitarism had a mortality rate twice that of age- and sex-matched normal subjects, a difference due to an increased number of cardiovascular events [24]. A later report by the same authors and another series found an increase in overall mortality in patients with hypopituitarism but did not confirm that the increased mortality was due to cardiovascular disease [3,25].

DIAGNOSIS — The diagnosis of GH deficiency in an adult should be based on the combination of documented pituitary or hypothalamic disease, panhypopituitarism, and a subnormal serum insulin-like growth factor-1 (IGF-1) concentration (lower than the sex- and age-specific lower limit of normal). If the IGF-1 value is equivocal, a subnormal serum GH response to a potent stimulus will confirm the diagnosis.

Who should be evaluated? — Because the manifestations of GH deficiency are subtle and nonspecific, evaluation for this disorder should be undertaken only in individuals with a high likelihood of GH deficiency including:

●Adults with known hypothalamic or pituitary disease (see "Causes of hypopituitarism"). The diagnosis of GH deficiency in adults is likely if the patient has documented panhypopituitarism, that is, documented deficiencies of thyroid-stimulating hormone (TSH), corticotropin (ACTH), and gonadotropins. In a retrospective analysis of 817 adults who were evaluated for consideration of GH therapy, multiple deficiencies of other pituitary hormones correlated highly with a subnormal GH response to a stimulation test [26]. As noted below, a low serum IGF-1 concentration confirms the diagnosis of GH deficiency in these patients; provocative testing is not required [27].

●Adults with a history of GH deficiency in childhood. Some will be found to have normal GH secretion as adults, although this is not likely in those with GH deficiency due to an organic cause, such as a craniopharyngioma. (See "Growth hormone treatment during the transition period", section on 'Testing for continuing growth hormone deficiency'.)

Who should not be evaluated? — Normal aging is not a reason to evaluate for GH deficiency. Human GH is widely used as an anti-aging therapy, based upon the observation that serum GH and IGF-1 decrease with age. However, these declines have not been associated with important clinical consequences.

We also recommend against the use of GH therapy to otherwise healthy, older individuals. While administration of GH results in a decrease in fat mass and increase in lean body mass, these potential benefits are outweighed by its adverse effects, including soft tissue edema, arthralgias, carpal tunnel syndrome, and glucose intolerance [28]. In the United States, the off-label use of recombinant human GH (rhGH) as an anti-aging intervention is illegal. (See 'Older adults' below.)

Serum IGF-1 — A serum insulin-like growth factor-1 (IGF-1) concentration lower than the sex- and age-specific lower limit of normal in a patient who has organic pituitary disease confirms the diagnosis of GH deficiency [29].

Provocative tests — If IGF-1 is equivocal, a subnormal GH response to a provocative test will confirm the diagnosis. For many years, the two standard tests have been insulin-induced hypoglycemia or the combination of arginine and GH-releasing hormone (GHRH). More recently, macimorelin, a synthetic agonist of the ghrelin receptor that is active orally, has been developed and has received regulatory approval. A subnormal increase in the serum GH concentration in a patient who has organic pituitary disease confirms the diagnosis of GH deficiency in those whose serum IGF-1 was equivocal (figure 1) [29]. Because obesity impairs GH release, the GH cutoff to diagnose deficiency should be lower for patients with obesity than for those of normal weight. The effects of obesity on some specific tests are given below.

Other stimuli, such as arginine alone, clonidine, L-DOPA, and the combination of arginine and L-DOPA are much weaker and therefore more likely to give false-positive results. All tests of GH secretion are more likely to give false-positive results in obesity. All are performed in the morning after an overnight fast.

Choice of test — In countries where GHRH is available, we recommend the arginine-GHRH test. In countries where GHRH is not available (including the United States), we recommend a macimorelin stimulation test. Although it is newly available, its excellent sensitivity and specificity, convenience of oral administration, and low incidence of side effects make it an attractive alternative. If neither GHRH nor macimorelin is available, we recommend a glucagon stimulation test.

Macimorelin stimulation test — Macimorelin is a synthetic agonist of the ghrelin receptor that, when administered orally, stimulates GH in a dose-dependent manner [30]. The dose of 0.5 mg/kg body weight is administered in the morning fasting, and blood for GH is sampled before and after 30, 45, 60 and 90 minutes. In a study of 166 patients with graded likelihood of growth hormone deficiency, the accuracy and reproducibility of macimorelin was compared with the insulin-tolerance test [31]. At a GH cutoff of 5.1 ng/mL, the macimorelin test had a sensitivity of 92 percent, specificity 96 percent and reproducibility of 97 percent. Using the same 5.1 ng/mL cutoff for both tests, the negative agreement was 94 percent and positive agreement 82 percent. Although the package insert recommends a cutoff of 2.8 ng/mL and that value gives similar specificity, it gives lower sensitivity. We therefore recommend a cutoff of 5.1 ng/mL.

Some patients experienced transient dysgeusia after ingesting macimorelin. In an earlier study, QT prolongation occurred, so discontinuation of drugs that cause QT prolongation is recommended before performing this test.

Glucagon stimulation test — This test has been used for many years and lately has been recommended by some for use in countries where GHRH is not available [32]. It is performed by administering 1 mg of glucagon intramuscularly (or 1.5 mg for patients who weigh >90 kg) and measuring GH every 30 minutes for four hours. The cutoff is considered to be <3 ng/mL (<3 mcg/L) for those of normal weight, but in patients with obesity, a cutoff of 1 ng/mL gives the best sensitivity and specificity [33]. Side effects, including nausea, vomiting, diaphoresis, and headaches, occur in 10 to 30 percent.

Arginine-GHRH — We recommend this test in countries where GH-releasing hormone (GHRH) is available (GHRH is not available in the United States) (see 'Choice of test' above). A bolus dose of GHRH, 1 mcg/kg body weight, is given intravenously at time 0, followed immediately by an intravenous infusion of arginine hydrochloride, 0.5 g/kg body weight (to a maximum of 30 g) over 30 minutes. Serum GH is measured at -30, 0, 30, 60, 90, and 120 minutes (figure 1) [34]. The cutoff value in one study was <4.1 ng/mL (<4.1 mcg/L) [29] and in another study <3.7 ng/mL (<3.7 mcg/L) [35]. Yet another study demonstrated that the cutoff value varies by waist circumference, body mass index (BMI), and age [36]. Transient facial flushing often occurs immediately after administration of GHRH, but otherwise, there are no side effects of this test.

Insulin-induced hypoglycemia — We no longer suggest using this test, as it requires constant supervision by a clinician, and it is very unpleasant for the patient. However, when it is performed, 0.1 unit of insulin per kg of body weight is administered intravenously and serum (or blood) glucose and GH are measured before and 15, 30, 60, 90, and 120 minutes after the injection [37]. A subnormal increase in serum GH (<5.1 ng/mL [<5.1 mcg/L]) confirms the diagnosis of GH deficiency. If severe hypoglycemia occurs, it may be dangerous in patients with coronary or cerebrovascular disease. (See "Insulin-induced hypoglycemia test protocol".)

GH THERAPY

Potential beneficial effects of treatment — There is substantial evidence that GH treatment in adults who acquired GH deficiency in adulthood results in an increase in muscle mass, a decrease in body fat, and an improvement in some parameters of cardiac function. The evidence for improvement in bone mineral density (BMD) is less convincing and the evidence for improvements in the sense of well-being, muscle strength, serum lipids, and other cardiovascular risk markers is conflicting. The data on the effect of GH treatment on mortality are limited.

●Body composition – In GH-deficient adults, there is good evidence that exogenous GH administration increases muscle mass and decreases fat mass, as illustrated by the following (see 'Body composition' above):

•In a meta-analysis of 54 trials in over 3400 patients, a reduction in body weight and body fat, and an increase in lean body mass was observed. There were no significant changes in body mass index or bone mineral density [38].  

•In a study of 10 patients with GH deficiency using a placebo-controlled, double-blind, crossover design (placebo and GH each were given for six months), subcutaneous adipose tissue mass, as measured by computed tomography (CT), decreased by 13 percent, visceral adipose tissue mass decreased by 30 percent, and muscle mass increased by 5 percent during the period of GH administration [39].

•Similar results were noted in a randomized, placebo-controlled trial in which body fat, measured by dual-energy x-ray absorptiometry (DXA), decreased from 32 to 28 percent during the administration of GH [40,41]. Eighteen months after discontinuing GH treatment, mean body fat had returned to its baseline value [41].

•In a randomized, placebo-controlled study in 43 females with GH deficiency, GH replacement decreased total body fat, measured by DXA, and visceral fat, but not subcutaneous fat, measured by CT [42].

●Exercise capacity and muscle strength – Because replacement of GH increases lean body mass, one might expect it to improve muscle function as well, but data are conflicting. One meta-analysis of 11 randomized, placebo-controlled studies demonstrated that GH improved parameters of exercise capacity, such as maximal power and maximal oxygen uptake [43]. However, another meta-analysis of eight randomized, placebo-controlled studies reported that GH replacement did not improve muscle strength [44].

●Bone mineral density – Many reports have demonstrated an increase in BMD when GH is administered to patients with GH deficiency, but most did not have a placebo group and virtually all used GH doses that resulted in supraphysiologic serum GH concentrations (see 'Bone mineral density and fractures' above). The results from placebo-controlled trials show an increase in BMD in males but not females [40,45].

•In a placebo-controlled trial, GH treatment of males with GH deficiency increased BMD by 5 percent in the spine and 2 percent in the femoral neck [40].

•In another two-year, placebo-controlled trial of physiologic GH repletion in 67 males and females with acquired GH deficiency, GH therapy improved spine BMD in males but not in females [45]. A randomized, non-placebo-controlled study also showed no effect of GH on BMD in females, even though the serum insulin-like growth factor-1 (IGF-1) concentration achieved was supraphysiologic [46], suggesting a sex-specific effect of GH. The reason for this difference is unknown.

•There are no data on the effect of GH treatment on fractures.

●Quality of life – Data on the effects of GH treatment are variable [14,40,47]. In a systematic review of 16 trials, 11 reported a beneficial effect of GH on quality of life; a meta-analysis was not possible [38]. (See 'Quality of life' above.)

Other effects of treatment

●Cardiovascular risk factors – The effects of GH replacement on several markers of cardiovascular risk, including lipids, markers of inflammation, endothelial function, and vascular disease, have been studied. Studies on the effects of GH replacement on serum lipids and lipoproteins have given conflicting results. (See 'Cardiovascular risk factors' above.)

•Low-density lipoprotein (LDL) cholesterol and apolipoprotein B – Some studies have reported no change in LDL cholesterol in response to GH replacement [42,48,49], while others have reported a decrease [47,50-53]. In one trial, serum total and LDL cholesterol concentrations fell during the first three months of therapy, but this effect was not maintained at 6 to 18 months [54]. In a study in which apolipoprotein B was also measured, it decreased, as did LDL cholesterol [53].

•High-density lipoprotein (HDL) cholesterol and apolipoprotein(a) – In one study, serum HDL cholesterol fell in the placebo-treated females but not in the GH-treated females [42], but in three other studies, GH treatment had no effect compared with placebo [47,53,54].

•Apolipoprotein(a) – There are also conflicting data on the effect of GH therapy on serum lipoprotein(a) concentrations (a lipoprotein associated with an increased risk of coronary heart disease). In two studies, the concentrations increased [54,55], while a third found no change [56]. (See "Lipoprotein(a)".)

•The effect of GH replacement on markers of inflammation include a consistently beneficial effect on C-reactive protein [42,53,54], conflicting results for interleukin (IL)-6 [53,54], and no effect on fibrinogen in one study [42]. GH replacement decreased homocysteine levels in a study in males [57] but not in another study in females [42].

•A decrease in carotid arterial intima-media thickness after one year of GH in one study [58] and after five years of treatment in another [59].

●Cardiac function – In a meta-analysis of 16 studies (nine placebo-controlled, randomized trials, and seven open studies) involving 468 adults with GH deficiency, GH treatment was associated with significant increases in left ventricular mass, wall thickness, end-diastolic diameter, and stroke volume [60].

●Cancer – The risk of cancer does not appear to be increased with GH therapy. In a prospective observational database of 15,809 patients with GH deficiency (KIMS) who were treated with growth hormone for a mean of 5.3 years, the occurrence of all cancers and individual cancers GH-treated patients was similar to that in the general population [61].

●Mortality – One prospective, surveillance study of 2430 patients with GH deficiency followed for an average of 2.3 years reported similar mortality rates in those who were treated or not treated with GH (33 of 1988 [1.7 percent] versus 11 of 442 [2.5 percent], respectively) [62].

Who should be treated? — There are differences in opinion about when to administer GH to adults with GH deficiency [63].

We suggest GH treatment to most adults who have childhood onset of GH deficiency due to organic disease (eg, craniopharyngioma) since it is often more severe than adult onset. For those already taking GH, it should be continued, and for those who are not, it should be re-initiated. (See "Growth hormone treatment during the transition period".)

For most patients with adult-onset GH deficiency, we suggest not prescribing GH therapy, but patient values and preferences play an important role in the decision. We first discuss with each patient the potential benefits and risks of GH therapy. We emphasize that they are unlikely to experience a marked increase in energy from taking GH, which is the reason many patients ask about it. Although we typically suggest that they not take GH therapy, we do treat if that is the patient's strong preference.

Our approach differs from the 2016 Hormonal Replacement in Hypopituitarism in Adults clinical practice guidelines of the Endocrine Society, which favor treating most adults with GH deficiency [27]. Our reluctance to recommend it for most patients who have GH deficiency is that we consider the modest improvement in body composition and modest increase in BMD (in males) insufficient to justify the very high cost (in the United States) and the burden of daily injections. As noted below, a once-weekly injection has been approved for use. Its efficacy appears to similar to that of daily injections, but its role in the management of adult GH deficiency is not yet established. (See 'Weekly' below.)

The criteria for therapy are different in children in whom GH is required for normal growth. (See "Treatment of growth hormone deficiency in children".)

Treatment protocol

Daily — Several preparations of daily recombinant human GH (rhGH) have been approved in many countries for treating adults with GH deficiency [2,4]. No differences in efficacy among the preparations are known.

rhGH is administered by subcutaneous injection once a day, usually in the evening. The initial goal is to start with a lower than maintenance dose and to gradually increase the dose (to minimize side effects). The eventual goal is to find the GH dose that maintains the serum IGF-1 concentration within the middle of the age-adjusted normal range [4]. This regimen is similar to that outlined by the Endocrine Society Clinical Guidelines [27].

In most patients over age 60 years, the serum IGF-1 concentration can be maintained within the reference range when the dose is approximately 5 mcg/kg body weight; a few need only one-half this dose [64]. Females who are taking estrogen orally will usually need higher doses than males or females taking estrogen transdermally [65].

We suggest the following protocol to minimize side effects:

●The starting dose should be 2 to 5 mcg/kg body weight once daily toward the lower end of the range for males, females taking estrogen transdermally, and those over age 60 years, and the upper end for females taking estrogen orally. This weight-based recommendation is for the starting dose only. The goal should be to start with low doses and increase gradually until the serum IGF-1 concentration is normal.

●If the serum IGF-1 concentration has not increased to within the normal range after two months, the daily dose should be increased stepwise in 1 to 2 mcg/kg increments at two-month intervals until it is normal. A dose of greater than 10 to 12 mcg/kg is not likely to be needed.

●If side effects occur or the serum IGF-1 concentration increases to above normal at any dose, the dose should be decreased.

Weekly — Somapacitan is a long-acting formulation of GH linked to albumin that has been approved for once-weekly treatment of adults with GH deficiency [66]. In a trial of 301 adults with GH deficiency (not previously treated or off therapy for at least six months), patients were assigned to receive subcutaneous injections of weekly somapacitan, weekly placebo, or daily GH (somatropin) [67]. After 34 weeks of therapy, somapacitan reduced truncal fat percentage (the primary endpoint) more than placebo (-1.2 versus + 0.6 percent, respectively), but slightly less than daily GH (-1.2 versus -2.5 percent, respectively). The weekly and daily GH regimens showed similar reductions of visceral fat, and similar increases in total lean body mass and appendicular skeletal muscle mass. Although once-weekly GH therapy is more convenient than daily GH, its effect on truncal fat may be slightly less beneficial.

Duration of therapy — There is currently no agreed upon duration of therapy for GH-deficient adults, although we usually recommend continuing treatment indefinitely. Some patients, however, tire of the daily injections, and others cannot maintain authorization from their health insurance. A systematic review of 23 studies of long-term GH therapy suggests that it may have some sustained benefits for body composition, lipid profile, carotid intima media thickness, and BMD but not for muscle strength [68]. The data on quality of life and glucose/insulin changes were inconclusive. Of note, these data are difficult to interpret without a comparison group of similar GH-deficient patients who did not receive therapy.

Stopping therapy may have adverse effects on body composition, lipids, and inflammatory markers but beneficial effects on insulin sensitivity. One study of 60 adult patients with hypopituitarism who had been taking GH for at least three years and were randomized to continue GH or placebo for four months showed that those who took placebo demonstrated an increase in waist circumference (but not waist-to-hip ratio) and visceral and subcutaneous fat compared with those who continued GH [69]. The placebo-treated patients also exhibited an increase in C-reactive protein and increases in both LDL and HDL cholesterol but improved insulin sensitivity and decreased glycated hemoglobin (A1C). Quality of life, as assessed by three instruments, showed no difference between the two treatment groups.

Monitoring — Measurement of serum IGF-1 is probably the best single test of the adequacy of GH treatment [70]. GH treatment should increase the serum IGF-1 concentration to within, but not higher than, the age-specific range of normal to avoid over-replacement.

We suggest measuring a serum IGF-1 two months after starting therapy. As noted above, if the serum concentration is below the normal age-specific range, the daily GH dose should be increased stepwise in 1 to 2 mcg increments at two-month intervals until it is within the normal range.

Once serum IGF-1 is in the normal range, we suggest repeating it every 6 to 12 months. If IGF-1 is ever above normal, the GH dose should be decreased by 1 to 2 mcg/kg increments and serum IGF-1 should be repeated every two months until it returns to the normal range.

Side effects — The most common side effects of GH treatment in adults with hypopituitarism are peripheral edema, arthralgias, carpal tunnel syndrome, paresthesias [71], and worsening of glucose tolerance [72]. Side effects appear to be more common in patients who are older, heavier, and are over treated, as judged by a high serum IGF-1 concentration during therapy [71]. An open-label study over three years suggested that the adverse effects might persist [73].

Macular edema or proliferative retinopathy in the absence of diabetes mellitus has been described in a few patients [74]. However, this complication is rare; fundoscopic examination of 61 GH-deficient adults receiving long-term GH therapy revealed no retinal abnormalities [75].

Active malignancy is considered to be a contraindication to GH treatment because of the theoretical possibility that the treatment could stimulate tumor growth, but available evidence to date does not support this concern [76].

Benign intracranial hypertension (pseudotumor cerebri) has been reported, mostly in children [77,78].

Exogenous GH therapy does not appear to be associated with hypothalamic-pituitary tumor growth or recurrence. This was illustrated in a study of 100 patients whose hypopituitarism was secondary to a hypothalamic-pituitary tumor and/or its treatment. When they were subsequently treated with GH, recurrence was rare during three years of observation [79]. Although most of these patients had been treated by radiation to the tumor, the lack of evidence that GH treatment stimulates any kind of tumor growth suggests that the presence of residual adenoma should not be a major factor in the decision to treat with GH.

Special populations

Older adults — Normal aging is not a reason to evaluate for GH deficiency, and we recommend that GH not be used as an anti-aging therapy. GH secretion and serum GH concentrations fall with age, both basally and in response to provocative stimuli, and there is a parallel decrease in serum concentrations of IGF-1 [80-82]. The fall in GH secretion is due to a decrease in hypothalamic GH-releasing hormone (GHRH) secretion, as well as a decrease in pituitary responsiveness to GHRH (decreased GH pulse amplitude) [81,83,84]. The precise roles of the three peptide factors (GHRH, somatostatin, and ghrelin), whose interactions modulate GH secretion, have yet to be elucidated, but GH deficiency does not appear to be due to reductions in ghrelin, since levels of this enterokine secretagogue actually increase in older adults. Low physical fitness and higher adiposity also contribute to the decrease in GH secretion in older subjects [85]. (See "Physiology of growth hormone" and "Physiology of insulin-like growth factor 1".)

Because most GH is secreted during slow-wave sleep, the relationship of GH to age-associated sleep disturbances is also relevant. There is an age-associated decrease in GH secretion that is due to a decrease in GH pulse amplitude. Pharmacologically induced increases in stage III and IV slow-wave sleep enhances GH pulsatile episodes in young adults [86], but whether this is the case in older adults remains unknown.

The observations that some of the decrease in lean body mass and in bone density in older subjects can be reversed by administration of GH lends support to the concept that their lower GH secretion and IGF-1 production have clinical consequences [87]. In a randomized trial of rhGH replacement with or without sex steroid replacement in 131 older males and females (ages 65 to 88 years), GH administration increased lean mass and decreased fat mass but led to significant side effects, including edema, carpal tunnel syndrome, and arthralgias [88]. In a meta-analysis of 18 randomized trials of GH therapy in 220 older males and females, GH was associated with 2.1 kg mean increase in lean body mass and 2.1 kg decrease in fat mass but greater likelihood of developing soft tissue edema, arthralgias, carpal tunnel syndrome, and gynecomastia [28].

Athletes — The use of GH therapy by athletes is reviewed separately. (See "Use of androgens and other hormones by athletes", section on 'Growth hormone'.)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Growth hormone deficiency and other growth disorders".)

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SUMMARY AND RECOMMENDATIONS

●Etiology – The causes of growth hormone (GH) deficiency are the same as the causes of deficiencies of other pituitary hormones (table 1). (See 'Etiology' above.)

●Clinical manifestations – Adults who have GH deficiency exhibit increased fat mass, decreased lean body mass, decreased bone mineral density (BMD), less energy, and greater mortality. The evidence for worse cardiovascular risk factors is conflicting. (See 'Clinical manifestations' above.)

●Diagnosis – A serum insulin-like growth factor-1 (IGF-1) concentration lower than the age-specific lower limit of normal in a patient who has organic pituitary disease confirms the diagnosis of GH deficiency [29]. If IGF-1 is equivocal, a subnormal GH response to a provocative test will confirm the diagnosis. In countries where GHRH is available, we recommend the arginine-GHRH test. In countries where GHRH is not available (including the United States), we recommend a macimorelin stimulation test. (See 'Diagnosis' above.)

•Candidates for evaluation – Evaluation should be performed in adults who had been diagnosed as having GH deficiency in childhood because many of them have been found to have normal GH secretion in adulthood. (See 'Diagnosis' above.)

Normal aging is not a reason to evaluate for GH deficiency. The risks of human GH as an anti-aging intervention outweigh its benefits. In the United States, this off-label use of GH is illegal. (See 'Who should not be evaluated?' above.)

●Benefits of GH therapy – Substantial evidence suggests that GH treatment in adults who acquired GH deficiency in adulthood results in an increase in muscle mass and a decrease in body fat, improvement in exercise capacity though not in muscle strength, improvement in BMD in males but not females, and improvement in some parameters of cardiac function. The evidence concerning improvements in the sense of well-being and serum lipids and other markers of cardiovascular risk is conflicting. (See 'GH therapy' above.)

●Who should be treated? – For adult patients with childhood onset of GH deficiency due to organic diseases and severe clinical manifestations and unequivocal biochemical evidence of GH deficiency, we suggest GH replacement (Grade 2C). (See 'Who should be treated?' above.)

For those with adult onset of GH deficiency, we do not routinely treat with GH. However, patient values and preferences may affect this decision. (See 'Who should be treated?' above.)

•Dosing – To minimize side effects, we start with low doses of daily GH (2 to 5 mcg/kg body weight once daily) (see 'Treatment protocol' above). Although a weekly GH formulation is now available, its role in the treatment of adult GH deficiency is not yet well established.

If the serum IGF-1 concentration has not increased to within the normal range after two months of therapy, the daily dose should be increased stepwise in 1 to 2 mcg/kg increments at two-month intervals until it is normal. If side effects occur or the serum IGF-1 concentration increases to above normal at any dose, the dose should be decreased. (See 'Treatment protocol' above.)