Bailliere's clinical endocrinology and metabolism最新文献

Acquired growth hormone resistance (AGHR) may be defined as the combination of a raised serum growth hormone (GH) concentration, low serum insulin-like growth factor-1 (IGF-1) concentration and a reduced anabolic response to exogenous GH. A wide range of conditions exhibit the syndrome to a variable degree, including sepsis, trauma, burns, AIDS, cancer, and renal or liver failure. The primary defect seems to be a reduction in IGF-1 concentration which then leads to increased GH concentration by a loss of negative feedback. It is not clear whether IGF-1 concentration falls because of decreased production or increased clearance from the circulation, or both. Treatment to reverse the biochemical defect by restoring IGF-1 levels, either by the administration of GH or IGF-1, has resulted in improvements in a wide range of metabolic parameters and, more recently, to definite clinical benefit in well-defined groups, such as patients with AIDS. These results cannot be extrapolated to other groups with AGHR as a recent unpublished report suggested increased mortality in critically ill patients treated with GH. Research needs to focus on the molecular basis of AGHR if we are to develop therapies for catabolism.

The aim of this review is to answer two questions. The first question is: is there any alternative provocative test equal to, or even better than, the insulin-tolerance test (ITT), the so-callel gold standard, for the diagnosis of growth hormone deficiency (GHD) in adults and the elderly? The answer is ‘yes’. In fact, when combined with arginine or pyridostigmine, growth hormone-releasing hormone (GHRH) becomes one of the most potent and reproducible, tests for distinguishing patients with severe GHD from normal subjects. Owing to its tolerability and its suitability for use in the elderly, the GHRH+arginine test is the best alternative choice and is at least as sensitive as the ITT provided that appropriate cut-off limits are given. The second question is: is there any therapeutic approach alternative to recombinant human growth hormone (rhGH) for adult and elderly patients with GHD and/or for the somatopause? At present, the answer is ‘no’. Growth hormone (GH)-releasing substances need the functional integrity of somatotroph cells to induce the release of growth hormone. Probably only patients with childhood-onset, isolated GHD (frequently hypothalamic-dependent) could benefit from treatment with GHRH or growth hormone secretagogues (GHS). Whenever restoration of the activity of the GH/insulin-like growth factor-1 (IGF-1) axis in the elderly would be of use, GHRH and/or GH secretagogues would be good candidates. In fact, the existence of a considerable pool of releasable growth hormone has been demonstrated in the elderly.

Adults with childhood-onset growth hormone deficiency (GHD) and younger adults with adult-onset GHD have a reduced bone mineral content (BMC). Recent trials with prolonged GH replacement therapy have demonstrated increased BMC in such patients.

GH treatment in animals increases the amount of bone and the total strength while the density (BMC per unit volume) and the quality of the bone is not increased. A sensitive non-invasive parameter for the detection of effects of GH on bone in clinical studies is therefore to use the BMC from dual-energy X-ray absorption (DEXA) analysis.

Bone density is strongly related to fracture risk in women. A number of other risk factors for fractures can be identified in adult GHD patients which, collectively, might explain the increased fracture frequency observed in these patients.

The increase in BMC in response to long-term GH replacement therapy is promising. Whether more prolonged treatment will result in a normalization of the bone mass and reduced fracture frequency remains to be established.

The majority of studies (but not all) have demonstrated that adults with hypopituitarism of both childhood and adult onset have a diminished quality of life (QOL) in comparison with the normal population. Reductions in physical and mental energy, dissatisfaction with body image and poor memory have been reported most consistently. A specific role for growth hormone (GH) deficiency, as opposed to multiple pituitary hormone deficiency, has been observed for the memory deficit, which extends to both short-and long-term momory. Comparisons with normal siblings have confirmed the reduced QOL, although differences have been small. There is less consensus for a reduction in QOL when hypopituitary subjects are compared with patients with other chronic diseases, with studies supporting (in comparison with diabetics) and refuting (in comparison with patients following mastoid surgery) the reduction in QOL. GH replacement in adult has improved QOL, particularly in the domains of energy level and self-esteem, and memory has improved. The social impact of these changes may be considerable, with patients requiring fewer days' sick leave. A major placebo effect is present, however, and neutral results as well as positive have been reported in placebo-controlled trials. Where a positive effect has been observed, it has been more likely to occur in patients with a low QOL at the outset. It is otherwise impossible to predict at the outset those who will benefit from GH replacement. GH treatment has effects on body composition, exercise capacity, muscle strength, total body water and intermediary metabolism which would be expected to improve QOL. Replacement therapy also has side-effects, and it is the variable balance of the positive and negative effects, coupled with the difficulties of measuring QOL, which have led to the disparate results in the literature. There is probably also a true inter-individual variation, although the mechanisms of this are currently unknown.

Growth and reproductive development are closely co-ordinated during puberty but there is also evidence that growth hormone (GH) may have a physiological role in adult ovarian function. Both GH and the insulin-like growth factors (IGFs) have been shown to augment granulosa cell proliferation and steroidogenesis in the human Graafian follicle, suggesting that GH may act as a ‘co-gonadotrophin’ at ovarian level. Furthermore, the intra-ovarian ‘IGF system’ (i.e. IGFs and IGF-binding proteins) may be implicated in folicular atresia and in disorders of follicular function associated with polycystic ovary syndrome (PCOS). The clinical importance of GH to ovarian function in the adult is illustrated by the finding that adjuvant GH treatment reduces the dose of exogenous gonadotrophin which is required to induce folliculogenesis in women with hypogonadotrophic hypogonadism. There is, however, no evidence that GH supplementation is of significant clinical benefit in the management of patients with other ovulatory disorders—including PCOS—or in superovulation protocols for in vitro fertilzation.

There is now little doubt that growth hormone (GH) and insulin-like growth factor-1 (IGF-1) play a role in cardiac development and in cardiovascular physiology in adult life. Congenital lack of GH is associated with defective cardiac growth, ventricular wall thinning, and impaired systolic function. These abnormalities limit exercise capacity and contribute to the poor quality of life in patients with GH deficiency. In addition, studies with in vitro muscle preparations have shown that IGF-1 affects myocardial contractility by a direct mechanism. These findings suggested that GH would benefit patients affected by heart failure. Indeed, GH and/or IGF-1 have proven beneficial in various models of experimental heart failure. Tested in patients with classes II–IV heart failure, they improved cardiac performance and clinical status. These effects were associated with improved myocardial energetics and de-activation of the neurohormonal system. Because of the uncontrolled nature of the studies and the small number of cases examined, conclusions as to the effectiveness of GH and IGF-1 must await the results from larger trials.

Organic growth hormone (GH) deficiency in adults results in many adverse changes similar to the changes which occur in humans with increasing age. The secretion of GH from the anterior pituitary declines with increasing age. This observation, together with the changes in body composition associated with organic GH deficiency in adults, has led to the suggestion that the elderly without hypothalamic-pituitary disease are GH deficient and may benefit from GH therapy.

The impact of organic disease of the hypothalamic-pituitary axis in the elderly may result in a reduction in GH secretion of up to 90%. This reduction in GH secretion is sufficient to cause a fall in the serum insulin-like growth factor-1 (IGF-1) concentration, abnormal body composition and abnormal bone turnover, although bone mineral density is unaffected. These changes are distinct from those associated with the hyposomatotropism of the elderly, but are less severe than those seen in younger adults with organic GH deficiency.

In this chapter we discuss the effects of organic GH deficiency in elderly subjects and the potential effects of GH replacement therapy. We also examine the potential for GH therapy to correct some of the detrimental effects of the ageing process.

Administration of growth hormone (GH) induces changes in body composition, namely, increases in both bone and lean mass and a decrease in fatty tissue. However, the contrary issue, i.e. the way in which body composition affects the secretion of GH, is highly controversial. Disease states such as obesity and chronic hypercortisolism are associated with increased adiposity and/or the central distribution of fat. Ageing, characterized by excess adiposity, is also associated with impaired secretion of GH. In these states, both spontaneous and stimulated secretion of GH is severely impeded. At the other extreme, malnutrition and fasting are both associated with increased secretion of GH when confronted with most, if not all, stimuli.

As the common factor in all of these situations is the increased or decreased adiposity, or the changes in energy homeostasis, it has been postulated that adipose tissue exerts a relevant role in the control of GH secretion in man. The link between adipose tissue and GH seems to be exerted through at least two signals produced by adipocytes: free fatty acids (FFA) and the recently cloned protein, leptin. An increase in FFA blocks secretion of GH, while a decrease in FFA enhances secretion. Leptin, a hormone whose main role is to regulate the intake of food and energy expenditure, seems to regulate GH secretion by acting at the hypothalamic level.

In summary, body composition affects GH secretion by way of the degree of adiposity, and free fatty acids and leptin would appear to be the messages through which adipocytes participate in the regulation of GH secretion. This framework clarifies the metabolic control of GH, a hormone with profound metabolic activities.

It is now recognized that growth hormone (GH) deficiency in adults represents a distinct clinical syndrome that encompasses reduced psychological well-being as well as specific metabolic abnormalities. The latter features, which include hypertension, central obesity, insulin resistance, dyslipidaemia and coagulopathy, closely resemble those of metabolic insulin resistance syndrome. The increased cardiovascular morbidity and mortality demonstrated in these GH-deficient (GHD) adults reinforce the close association between the two syndromes.

Replacement of GH in GHD adults has resulted in a marked reduction of central obesity and significant reduction in total cholesterol but little change in other risk factors, in particular insulin resistance and dyslipidaemia. The persistent insulin resistance and dyslipidaemia, together with the elevation of plasma insulin levels and lipoprotein (a) with GH replacement in these subjects are of concern. Long-term follow-up data are required to assess the impact of GH replacement on the cardiovascular morbidity and mortality of GHD adults. Further exploration of the appropriateness of the GH dosage regimens currently being employed is also indicated.