Introduction

A growth- promoting activity of anterior pituitary extracts was discovered a century ago, and growth hormone (GH) was isolated in 1944 and tested in human subjects ten years after. The protein anabolic and lipid catabolic effects of GH were documented in both children and adults, and it was hypothesized that GH re placement therapy in adults with hypopituitarism could be beneficial. Growth hormone for clinical use originally derived from human cadaveric pituitaries and the limited supply was restricted to treat hypopituitary children with severe growth retardation. The introduction of biosynthetic human GH enabled other indications such as GH replacement in adult patients with GH deficiency (GHDA).

The first placebo- controlled trial included young adult patients with childhood- onset GHDA in whom prior GH treatment dis continued several years before. A significant increase in muscle mass and reduction in fat mass were recorded together with improved aerobic exercise capacity. The study also revealed a marked increase in the circulating and urinary levels of bone remodelling biomarkers, increased extrathyroidal conversion of T4 to T3, and increased sweating. The second placebo- controlled trial comprised adult patients with adult- onset GHD due to a pituitary tumour and its treatment. Lean body mass increased significantly after 6 months GH replacement together with a significant reduction in fat mass. This was associated with an increase in energy expenditure and exercise capacity. These pivotal findings were confirmed by numerous groups and led to the approval of GHDA as an indication for GH replacement.

Pathophysiology

 It is important to emphasize that GHDA as a disease entity only exists within a clinical context of overt pituitary pathology. The reasons for this are several. First, GH secretion in the general population declines gradually as a function of age and adiposity, and the symptoms and signs of GHDA are unspecific. Second, even though diagnostic biochemical criteria exist, they are not sufficiently specific to exclude the diagnosis in elderly individuals with simple obesity. Third, a clinical benefit of GH replacement has only been documented in patients with a clinical history of pituitary disease.

One appropriate clinical context is a history of childhood- onset GHDA, which accounts for approximately 30% of GHDA. The cardinal symptom of GH deficiency (GHD) in childhood is longitudinal growth retardation and the underlying cause in this group is frequently idiopathic.

The second clinical context is adult- onset GHDA caused by a pituitary mass lesion or its treatment, of which pituitary adenomas constitute 70% (Box 1).

Box1. Aetiology of GHDA

GH is typically the first pituitary hormone to become deficient in response tumour pressure, pituitary surgery, cranial irradiation, or any other trauma. Traumatic brain injury (TBI), which is a very frequent occurrence, may cause hypopituitarism, but the prevalence of permanent GHD after TBI is only 1%. The annual incidence and the prevalence of adult- onset GHDA are approximately 15/ million and 300/ million, respectively.

Clinical Features

The syndrome of GHDA is used as a term to describe the clinical features and the effects of GH replacement. The syndrome overlaps with the metabolic syndrome as regards visceral obesity, hyperlipidaemia, and atherosclerosis (Box 2). Moreover, premature cardiovascular morbidity and mortality are prevalent in GH- untreated hypopituitary adults. Untreated GHDA is accompanied by reduced total body water and extracellular fluid volume, which is reversed by GH replacement. Impaired thermoregulation in response to the ambient outside temperature and during strenuous exercise are also present and partly attributed to reduced sweating capacity.

Box2. The clinical features of GHDA

Insulin resistance, which is a hallmark of the metabolic syn drome, is not part of the GHDA syndrome, rather the opposite. GH antagonizes the effects of insulin on glucose metabolism in both the liver and skeletal muscle, which is causally linked to the lipolytic effects of GH. Indeed, increased insulin sensitivity and reactive hypoglycaemia is characteristic of children with GHD, whereas the opposite is true for active acromegaly. The insulin- antagonistic effect of GH is rapidly reversible and in normal physiology, it operates in the fasting state, where insulin activity is low.

Diagnosis of Adult GHD

 In the absence of specific clinical indicators to discriminate GHDA from the normal population, the diagnosis is based on the results of biochemical testing within an appropriate clinical context. For childhood- onset GHD, retesting in adulthood is necessary in patients with isolated idiopathic GHD, since spontaneous normalization of GH status is recorded in almost 70%. Retesting is not required for those with an identified genetic cause and those with more than three pituitary hormone deficits.

Since GH is secreted in a pulsatile fashion, a single random GH measurement is only informative if a high value is incidentally encountered. Therefore, a stimulation test is necessary to perform. The insulin tolerance test (ITT) is the ‘gold standard’ but is contra indicated in patients with ischaemic heart disease or seizures [10]. Alternative tests include the glucagon stimulation test, GH re leasing hormone (GHRH) with arginine, and GHRH with growth hormone- releasing peptide 6. The diagnostic threshold for the ITT and the GST is less than 3 μg/ L. The response to GHRH + arginine is reduced in obesity, wherefore threshold levels stratified by body mass index (BMI) are recommended (Box 3).

Box3. Diagnosis of GHDA

The anabolic effects of GH are mainly mediated by insulin- like growth factor I (IGF- I), which is present in the circulation and not subject to diurnal fluctuations. In the absence of severe concomitant illness, a low serum IGF- I level is a strong predictor of GHD, but a normal serum IGF- I level does not rule out the diagnosis. Thus, in patients at high à priori risk of GHD, a subnormal serum IGF- I value may substitute for a GH stimulation test.

Effects of GH Replacement

 Several meta- analyses of placebo- controlled trials of GH replacement in GHDA have been published on outcomes such as cardio vascular risk factors, muscle strength and exercise capacity, bone mineral density, body composition, and cardiac function (Figure 1).

Fig1. Results of meta- analysis of GH effects on cardiovascular risk factors from Maison et al. (28). Abbreviations: Lean B mass, Lean body mass; TG, triglycerides; Chol, cholesterol; DBP, diastolic blood pressure; SBP, systolic blood pressure; ns, non- significant. Reproduced with permission from Maison P, Griffin S, Nicoue- Beglah M, Haddad N, Balkau B, Chanson P. Impact of growth hormone (GH) treatment on cardiovascular risk factors in GH- deficient adults: a Metaanalysis of Blinded, Randomized, Placebo- Controlled Trials. J Clin Endocrinol Metab. 2004;89(5):2192– 9. Copyright © 2004, Oxford University Press.

The studies confirm and substantiate beneficial effects of GH replacement on body composition, bone mineral density, cardiac function, and exercise capacity, as well as side effects attributable to fluid retention and insulin resistance.

GHDA patients are highly sensitive to GH in terms of serum IGF- I generation and side effects, and male patients are more responsive to GH as compared to females.

It remains an open question whether GH replacement therapy improves patient- reported outcomes such as quality of life (QoL) or cognitive function in the adult patient, since neither original studies nor meta- analyses provide unambiguous answers. Most QoL studies have utilized generic or disease- specific questionnaires, which mainly record and depend on the respondents’ remembrance and it is possible that improvements in remembered QoL wane with time. It is interesting that the most compelling beneficial effects of adult GH replacement on QoL was recorded in a placebo- controlled crossover study, in which the spouse of the patient was asked to score the patient. The National Institute for Health and Care Excellence (NICE) in the United Kingdom requires impaired pretreatment QoL in order to initiate adult GH replacement.

Transition from childhood to Adulthood

Normal puberty marks the transition from childhood to adult hood and is dominated by the pubertal growth spurt and the development of secondary sexual characteristics and reproductive capacity. Muscle and bone mass increase markedly during the transition and depend in part on a marked physiological increase in GH secretion and action resulting in grossly elevated IGF- I levels (Figure 2).

Fig2. Serum IGF- I levels (2.5%, 50%, and 97.5% percentiles) as a function of age. The insert shows the corresponding daily GH dosage targeted to achieve a serum IGF- I level within the upper normal range. The IGF- I figure is modified with permission from Bidlingmaier M, Friedrich N, Emeny RT, Spranger J, Wolthers OD, Roswall J, et al. Reference intervals for insulin- like growth factor- 1 (igf- i) from birth to senescence: results from a multicenter study using a new automated chemiluminescence IGF- I immunoassay conforming to recent international recommendations. J Clin Endocrinol Metab. 2014;99(5):1712– 21. Copyright © 2014, Oxford University Press.

A placebo- controlled study comparing continuation vs. discontinuation of GH in transition patients revealed that GH discontinuation result in decreased IGF- I levels and increased body fat, which re versed by resumption of GH therapy. Therefore, childhood- onset GH replacement should continue during the transition period and into adulthood, but it is important to retest GH status in the absence of either a genetic cause or additional pituitary deficiencies.

The Senescence

The decline in endogenous GH and IGF- I production with age [46] runs in parallel with senescent changes in body composition and physical performance (Figure 2). Interestingly, in midlife adults, abdominal adiposity is the strongest and negative determinant of endogenous GH secretion. These associations have led to speculations about a causal link between reduced GH pro duction and the physical frailties of ageing, which has been coined ‘somatopause’. This concept is dubious and a meta- analysis of GH treatment studies in elderly subjects without overt pituitary disease record only limited positive effects and a high prevalence of GH- related side effects.

Despite the age- associated decline GH secretion, GHDA patients aged 60– 80 years have reduced GH and IGF- I levels compared to age- matched controls and seem to respond to respond to GH replacement in the same manner as younger patients.

GH Dosing and Side effects

The goal of GH replacement in GHDA is to correct the abnormalities associated with adult GHD with a minimum of side effects. The daily starting dose of GH in young men and women are 0.2 and 0.3 mg, respectively, and in older patients 0.1 mg (Figure 2).

Serum IGF- I is a useful biomarker of GH replacement and the aim is to achieve a level within the upper half of the age- related normal range. GH is administered as subcutaneous self- injections in the evening. Quantification of body composition and bone mineral density by dual X- ray absorptiometry (DXA) should be considered on an individual basis, and body composition can also be assessed using anthropometric measures such waist to hip ratio or skinfold thickness, and bioelectrical impedance. Regular measurements of cardiovascular risk factors such as plasma lipids are also recommended, since they may be abnormal at baseline and modified favourably by GH replacement. Growth hormone replacement is considered life- long, but a trial of withdrawal can be considered if a patient perceives no benefit. In the United Kingdom, NICE advises that GH replacement should be discontinued in patients who fail to demonstrate improvement in QoL the first 9 months of therapy. This recommendation, however, is pragmatic rather than based on evidence from placebo- controlled trails.

Oral oestrogen treatment suppresses hepatic IGF- I production and the GH dose requirement may change accordingly. GH replacement may modify the dose of levothyroxine or unmask incipient central hypothyroidism by increasing the peripheral conversion of T4 to T3. Finally, GH reduces the enzymatic conversion of cortisone to cortisol, wherefore GH replacement occasionally necessitates a dose increase of glucocorticoid replacement in a patient with concomitant adrenocortical insufficiency.

Reversible fluid retention is a frequent but reversible and dose- dependent side effect of GH replacement in GHDA. The mechanism involves sodium retention. Of note, this increase in hydration accounts for a part of the GH- induced changes in body composition. The direct insulin- antagonistic effects of GH do not compromise glucose tolerance during physiological conditions, since endogenous GH levels are suppressed by food intake. Daily subcutaneous GH injections in the evening, however, is unable to fully imitate the endogenous GH pattern, wherefore GH re placement therapy may result in moderate elevations in fasting levels pf glucose and insulin despite favourable changes in body composition.

Absolute contraindications for adult GH replacement therapy include active malignancy and proliferative retinopathy.

Although early pregnancy is not a contraindication, GH replacement is discontinued after the first trimester, where placental GH production sets in.

GH Replacement and Mortality

Increased mortality in hypopituitary patients due to cardiovascular disease is well established and has been attributed to unsubstituted GHDA. However, numerous underlying mechanisms may be equally— or more— likely, e.g. the underlying disease, treatment complications, and suboptimal substitution of additional pituitary deficiencies. It is also noteworthy, that mortality and cancer incidence are increased in acromegaly, and epidemiological human studies suggest a U- shaped association between serum IGF- I levels and all- cause mortality in the general population. Controlled studies of GH replacement therapy with mortality as an endpoint do not exist, but observational studies in GHDA suggest that mortality is reduced in GH replaced patients as compared to GH- untreated patients.

conclusion

Metabolic effects of GH were documented in hypopituitary adult patients more than half a century ago, and GH replacement in GHDA has been routinely used for 15 years. The change in body composition with reduced fat mass and increased lean body mass is the most robust effect, together with improved aerobic exercise capacity and cardiac function. Bone turnover is acutely stimulated and there is evidence to suggest increased bone mineral density (BMD) after prolonged GH replacement therapy. Whether this reduces the risk of osteoporotic fractures is uncertain, but observational studies suggest a reduced fracture risk. The impact on QoL is less certain, since the results from placebo- controlled trials are ambiguous, and the results from open and observational studies are likely biased. Cancer risk is not increased with GH treatment, and mortality, if anything, is reduced. Side effects in terms of fluid retention and impaired insulin sensitivity are recognized, but are dose- dependent, rapidly reversible, and probably of limited concern. Nevertheless, caution is mandated to avoid overtreatment, not least of the elder patient.

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مواضيع ذات صلة

Hypopituitary crisis

Thyroid Replacement in TSH Deficiency

Glucagon’s Structure

Insulin and Its Glucose Transporter

Insulin Receptor

Insulin Structure

Biological Actions of T3

Adrenal Replacement in ACTH Deficiency

Rathke cleft cysts

Biological Actions of Oxytocin

GHD with Accompanying Features

Biological Actions of Arginine Vasopressin (AVP)