Clinical Endocrinology (1992) 37, 387-397
Review
The growth hormone deficiency syndrome in adults R. C. Cuneo, F. Saiomon, 0. A. McGauiey and P. H. Sdnksen Department of Endocrinology and Chemical Pathology, St Thomas’ Hospital, London, UK (Received 27 February 1992; returned for revision 27 April 1992; finally revised 30 June 1992; accepted 23 July 1992)
The effects of growth hormone (GH) deficiency in childhood are well recognized. These include shortness of stature with normal proportions, slow linear growth rate, delayed bone age with reduced bone density, excess adiposity with a predominantly truncal distribution, reduced lean tissue mass, and fasting hypoglycaemia (Collip et al., 1973; Hopwood et al., 1975; Tanner et al., 1977; Milner et al., 1979; Parra et al., 1979, Shore et al., 1980). These effects reflect the known metabolic actions of GH (Davidson, 1987; Press, 1988); GH promotes anabolism and lipolysis, and has complex actions on carbohydrate metabolism which can be summarized as insulinotrophic and insulin antagonistic. The effects of G H deficiency in adults have been appreciated only recently. There may be several reasons for this. Firstly, adults who developed panhypopituitarism from mass effects of a pituitary tumour or the treatment of the tumour survived, often returning to reasonably functional lives with conventional pituitary hormone replacement therapy. Secondly, G H treatment of such patients was not possible due to limited supplies of human pituitary-derived GH. The introduction of recombinant DNA technology has resulted in the production of authentic sequence human G H (rhGH) in potentially unlimited supplies, allowing treatment of conditions other than short stature. The aims of this review are to summarize the recent studies of GH treatment in adults with G H deficiency, thereby defining the syndrome of G H deficiency in adults, and to highlight areas for future investigation. The definition of the OH deficiency syndrome in adults
The GH deficiency syndrome in adults has been derived from a number of independent studies using biochemical selection criteria (see below). A summary of the clinical and biochemical features suggestive of the syndrome are provided in Table 1. Correspondence: Professor P. H. Sonksen, Department of Endocrinology and Chemical Pathology, UMDS, St Thomas’ Hospital, Lambeth Palace Road, London, SEI 7EH, UK.
Selection criteria for
GH deficiency
Three groups have published data on adults with G H deficiency, each with slightly different and arbitrary criteria for selection of patients. At St Thomas’ Hospital, London, patients had severe GH deficiency, defined as peak G H response to an adequate insulin-induced hypoglycaemic stimulus of less than 3 mU/l (Salomon et al., 1989). Limited overnight GH sampling in the placebo-treated group confirmed severe G H deficiency, where no patient recorded a peak G H greater than 2.0 mu/], 85% of samples being below the assay detection limit. The Aarhus group in Denmark studied young adults who had been treated for G H deficiency during childhood, and who were retested in adult life with GH responses to clonidine of less than 5 pg/l (approximately 10 mu/]; Jsrgensen et al., 1989b). The Belfast group selected patients with peak G H response to insulin hypoglycaemia of less than 7 mU/I, who were also shown to have severely limited GH production during modified 24-hour sampling (Whitehead ef ul. 1990, 1991, 1992). Circulating pretreatment insulin-like growth factor-I (IGF-I) concentrations could not be used as a reliable index for the selection of patients with G H deficiency as defined above. Even within the St Thomas’ patients who had severe GH deficiency, several individuals had plasma IGF-I concentrations within the low-normal range. This observation is in keeping with the paediatric literature (Furlanetto, 1990). Many of these patients had multiple pituitary hormone deficiences, treated conventionally. Attempts have been made to deliver other pituitary hormone replacement in a physiological manner (Jsrgensen el al., 1989b; Salomon et al., 1989), based on clinical and biochemical assessments. At present, no differences have been shown between patients with isolated G H deficiency and those with panhypopituitarism with respect to responses to rhGH treatment (Jsrgensen et al., 1989b). The numbers of patients studied are, however, small. Hence, features attributed to G H deficiency are not thought to be caused by deviations from ‘physiological’ conventional pituitary hormone replacement, in that such features (i.e. abnormalities of body composition, metabolism, or exercise physiology) resolve with rhGH treatment and (preliminary data suggest) they accumulate with rhGH withdrawal.
GH treatment dore Doses similar to those used in childhood GH deficiency, based on body weight or surface area, have been used in the 387
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R. C. Cuneo e ta /.
Table 1 Features suggestive of GH
deficiency in adults: patients with isolated GH deficiency or multiple pituitary hormone deficiency receiving conventional replacement therapy
Symptoms (a) known pituitary pathology (b) impaired psychological well-being: poor general health impaired emotional reaction depressed mood impaired self control anxiety reduced vitality and energy increased social isolation (c) increasing abdominal adiposity (d) reduced strength and exercise capacity (e) cold intolerance Signs
(a) mixed truncalfgeneralizedadiposity (b) increased waist:hip ratio (c) thin, dry skin; cool peripheries; poor venous access (d) minor reductions in skeletal muscle strength (e) moderate reductions in exercise performance (f) psychological state characterized by low, labile mood
Tests
(a) (b) (c) (d)
stimulated GH < 3-5 mU/1 (?) low or low-normal serum IGF-I (? low IGF-BP3) hypercholesterolaemia(? also hypertriglyceridaemia)high LDL cholesterol low glomerular filtration rate and renal plasma flow (e) reduced lean body mass/increased fat mass increased waist:hip ratio (?> 0.85) (f) ? reduced basal metabolic rate/body weight (9) ? reduced bone density
treatment of adults with GH deficiency. The St Thomas’ and Belfast groups used 0.07 U/kg body weight as a nightly subcutaneous dose. Side-effects (arthralgias, fluid retention, or carpal tunnel symptoms) forced a reduction in dose to 0.035 U/kg in three of the 12 actively treated patients. The Aarhus group used a dose of 2 U/m2(approximately 0.05 U/ kg per day). One subject withdrew from the trial with symptoms of fluid retention. Plasma IGF-I concentrations increased into the high-normal age-related reference range in the St Thomas’ study, and to values equal to age-matched controls in the Aarhus study. Subsequent experience in treating larger numbers of patients at St Thomas’ has shown considerable inter-individual variation in sensitivity to differing GH doses (unpublished observations); the explanation for this is unknown but may lie in differing degrees of GH deficiency (Rudman et al., 1971). In summary, the doses of rhGH used in these studies can be considered as essentially physiological or marginally supraphysiological in some individuals. The absorption profile of subcutaneously administered rhGH in GH deficient adults is, however, far from physiological, resulting in a broad peak lasting more than 12 hours (Salomon et al., 1989; Jergensen J., 1991).
Treatment protocols differed between these trials (parallel for 6 months at St Thomas’, cross-over for 4 months at Aarhus and 6 months at Belfast, with 4 and 1 month washout periods, respectively). Results from the groups were remarkably consistent. Body composition
Some of the most dramatic effects of GH deficiency and rhGH treatment involved alterations in body composition. In children with GH deficiency, marked increases in lean body mass and reductions in fat mass are seen following GH treatment, especially in the first month (Collip et al., 1973; Tanner et al., 1977). Fat mass
In adults with GH deficiency, body fat is excessive and is distributed more in a central (abdominal) than peripheral pattern. As a percentage of body weight, mean fat mass (derived from the two-compartment model composition using whole body “K counting) was 37.9% in the S t Thomas’ patients (males 33*3%, females 47.6%), exceeding that
Clinical Endocrinology (1992) 37
predicted from age, sex, height, and weight (Boddy et al., 1972)by a mean of 7%. No patient had the fat distribution of glucocorticoid excess (e.g. supraclavicular fat pads, buffalo hump). Larger population studies with suitable control groups are required precisely to quantitate the excess adiposity in GH deficiency in adults, since reference data on fat mass of the relevant populations are limited. Following rhGH treatment, highly significant reductions in fat mass (mean of 5.7 kg or 18%) were noted. The greatest reductions occurred in the truncal region, as shown by both skinfold thicknesses and waist: hip ratios (Salomon et al. 1989).
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389
Total body weight
Body weight does not appear to be influenced by G H deficiency by itself, since in none of the published studies does body weight change with long-term treatment. The presence of multiple pituitary hormone deficiency appears to favour increased weight (Libber et al., 1990; Jerrgensen et al., 1989b;Salomon, unpublished data). It should be emphasized that body mass index (BMI; kg/m2) is an insensitive estimate of adiposity in adults with GH, since all patients in the St Thomas’ study with a normal BMI ( c 26) had excessive fat mass (unpublished observations).
Lean body mass
Adults with GH deficiency showed a significant deficit in mean lean body mass measured by whole body @K counting of 7-8% (range - 24 to 9%), corresponding to approximately 4 kg of lean tissue (Salomon et al, 1989). Predicted values were based on age, sex, height, and weight. Following rhGH treatment, lean body mass normalized over 6 months, increasing significantly by a mean of 4 kg or 10-12% (Salomon et al, 1989). As in children, much of the increase occurred in the first month.
+
Skeletal muscle mass
Whether all components of the lean body mass are reduced in GH deficient adults is uncertain. Skeletal muscle normally comprises approximately 50% of lean body mass. No detailed reference data are available for adult skeletal muscle mass, but using comparison with age-matched controls, Jerrgensen et al. (1989b) found the ratio of muscle to fat from the mid-thigh as assessed by computerized tomography (CT) to be significantly reduced in adults with G H deficiency. Similarly, CT area of mid-thigh muscle/body weight was significantly lower in adults with G H deficiency than in controls matched for age, sex, and activity (Cuneo et al., 1990). Neither method satisfactorily assesses absolute muscle mass in isolation from the excessive fat mass. Following rhGH treatment, significant increases have been noted in thigh muscle mass or cross-sectional area assessed by CT (mean 558%; Jsrgensen et al., 1989a; Whitehead et al., 1990; Cuneo el al., 1991a), along with 24hour urinary creatinine excretion (18-21 %; Salomon et al., 1989), an indirect measure of skeletal muscle. The greater increase in creatinine excretion than thigh muscle crosssectional area may reflect disproportionate increases in other skeletal muscles, but interpretation is limited by the renal effect of rhGH (see below).
Miscellaneous somatic effects
The effect of G H deficiency on bone mass in adults is unknown. In one small uncontrolled, open study, lumbar bone mineral density increased after 40 weeks of rhGH treatment (Van der Veen & Netelembos, 1990), but confirmation is required. In adults, rhGH treatment resulted in significant increases in both serum calcium and phosphorus (mean increases of 0.12 and 0.23 mmol/l; Salomon et al., 1989), suggesting a vitamin D-related effect. Further data regarding the effects of G H deficiency and rhGH treatment on bone density and fracture rate are awaited. Paediatric (Novak et al., 1972; Shore et al., 1980) and experimental (Jerrgensen, P., et al., 1991) data suggest that bone density and mechanical strength may be improved. Adults with treated hypopituitarism and G H deficiency have reduced skin thickness and total skin collagen (Black et al., 1972). The crow’s foot sign of facial wrinkling characteristic of hypopituitarism may be related to GH deficiency. It is our clinical impression that skin thickness increases after rhGH treatment, as suggested by Rudman et al. (1990) following rhGH treatment in elderly males selected on the basis of low serum IGF-I concentration. This impression is supported by the increases in serum Type I11 procollagen concentrations in GH-deficient children following rhGH treatment (Jensen e f al., 1991).
Physical performance characteriatlcs Skeletal muscle function
Details of skeletal muscle function have been assessed most carefully in the quadriceps group. Before treatment, adults with G H deficiency had significantly reduced isometric quadriceps force compared to carefully matched, normal
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individuals (Cuneo et al., 1990). Most of this deficit could be explained by reduced muscle cross-sectional area. When force was expressed per muscle cross-sectional area, an additional small deficit was still evident, particularly in males; possible explanations include differences in training, muscle fibre or myofibrillar density, or neuromuscular excitation. Normal muscle histology (see below) and CT density of quadriceps muscle (Cuneo et al., 1991a) suggest that muscle fibre density was not at fault. Isometric force in muscle groups other than the quadriceps have shown essentially no difference from a normal population (Cuneo et al., 1990). Further studies with carefully selected control subjects are required to confirm this finding. Following rhGH treatment, all three studies have noted no statistically significant increase in quadriceps force despite clear increases in thigh muscle cross-sectional area during 4-6 months controlled observations. Longer-term, uncontrolled follow-up on the Danish patients has shown a progressive increase in quadriceps isometric force toward normal over 12 months (Jerrgensen et al., 1990~).The most likely explanation for the failure to observe increased force generation following initial rhGH treatment is the insufficient statistical power of the studies. This conclusion is supported by the findings of Rutherford et al. (1991) who performed an uncontrolled study of G H deficient children during one year after the cessation of rhGH treatment when final height was attained. They found significant reductions in quadriceps cross-sectional area and force (with a trend toward reduced muscle-fibre areas on biopsy) over the year. Proximal, limb-girdle muscle force has been shown to increase significantly in adults with GH deficiency after rhGH treatment (Cuneo et al., 1991a). Exercise performance
Maximal exercise performance has been assessed by cycle ergometry with or without respiratory gas analysis. Before treatment, maximal oxygen uptake ( Yo2max) was significantly reduced compared to predicted (mean of 72-82% of that predicted from age, sex and height; Cuneo et al. 1991b; Whitehead et al., 1992). Power output is also likely to be reduced (Jsrgensen et al., 1989b; Whitehead et al., 1990, 1992; Cuneo et al., 1991b).Maximal heart rate averaged 90% of predicted, and respiratory exchange ratio (RER) exceeded 1.0 (Cuneo el al., 1991b), suggesting maximal or near maximal subjective effort had been obtained. Following rhGH treatment, maximal and sub-maximal exercise performance improved markedly and significantly (Jsrgensen et al., 1989b; Whitehead etal., 1990,1992; Cuneo et al., 1991b). Vozmax increased to a mean of 97% of predicted (based on age, sex and height; Cuneo et al., 1991b),
Clinical Endocrinology (1992) 37
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Flg. 1 a, Maximal oxygen uptake; b, power output; and c, percentage
of predicted maximal oxygen uptake in adults with growth hormone
recombinant human growth hormone deficiency treated with (rhGH dose 0.07 U/kg per day) or 0, placebo in the double blind trial at St Thomas' Hospital, London. Statistical difference between the treatment groups was assessed by analysis of covariance, based on the mean values of the post-treatment data (P=0.016,0.047,and 0.018, respectively). Data presented with permission of The American Physiological Society.
and maximal power output increased proportionally (Fig. 1). Maximal heart rate was either unchanged (Cuneo et nl., 1991b) or increased (Jsrgensen et al., 1989b)following rhGH treatment. The reason for thediscrepancy is unclear, but may be related to increased subjective effort in the latter. Submaximal exercise performance, measured as anaerobic threshold, also increased significantly (Cuneo et al., 1991b), suggesting that activities performed during daily life would be accomplished with less metabolic stress. These changes were paralleled by subjective reports from patients that activities could be performed more easily following rhGH treatment. Explanations for the increase in maximal exercise performance certainly lie with increased lean body mass and
Clinical Endocrinology (1992) 37
skeletal muscle mass (Cuneo et a/., 1991b), with a possible contribution from maximal cardiac output, as suggested by echocardiographic data (see below), and the significant increases in maximal oxygen pulse (an index of stroke volume; Cuneo et al., 1990b) and resting renal plasma flow (Jergensen et al., 1989b). Alterations in fuel utilization during exercise following rhGH treatment have not been assessed.
Growth hormone deficiency syndrome
391
rhGH treatment, and frank hypertension was an uncommon event, responding to a dose reduction (Salomon el al., 1989). Detailed assessments of total body water and sodium will be required to confirm the transience of this phenomenon. Echocardiography
Histology of vastus lateralis taken by needle biopsy from adults with G H deficiency has shown normal fibre type proportions and areas (Whitehead et al., 1989). No features of Cushingoid myopathy were evident. Differences in fibre type function have not been assessed in detail, but significant correlations between type I relative fibre area and maximal aerobic performance and between type 11 relative fibre area and maximal force generation (Cuneo et al., 1990) suggest that individual muscle fibre-type function is qualitatively normal. Following treatment, vastus lateralis histology remained unchanged (Whitehead et al., 1989). In particular, no features of an acromegalic myopathy were seen. These observations confirm the impression that alterations in force generation and exercise performance lie predominantly with altered muscle mass.
In adults with G H deficiency, rhGH treatment has been shown to result in small but significant increases in resting left ventricular (LV) end-diastolic and stroke volumes, most likely resulting from the increase in plasma volume (Cuneo et al., 1991~).LV wall mass also showed a small but significant increase in the St Thomas’ study, despite no change in mean arterial pressure, suggesting the anabolic action of G H on not only skeletal but myocardial muscle. Considering the LV dimensions and wall thicknesses were within normal limits before and after treatment, and the significant association between increased diastolic volume and Vozmax, the echocardiographic changes appear beneficial. No changes in echocardiographically determined LV wall mass were observed in the Aarhus study, possibly reflecting the lower dose and shorter duration of rhGH used (Jergensen et al., 1989b). A single case report of dramatic improvements in cardiac output following rhGH treatment in a man with cardiomyopathy of complex origins (Cuneo et al., 1989) highlights the potential for potent effects of rhGH on the cardiovascular system.
Cardlovaclcularlrenal effects
Renal effects
Skeletal muscle histology
Antinatriuretic action
The antinatriuretic action of G H is well known (Henneman et al., 1960; Rudman et al., 1971) but seldom is it of clinical concern in paediatric practice. Difficulties with cold intolerance (despite optimal thyroid hormone and glucocorticoid replacement) and venous access, both of which resolved rapidly following rhGH treatment, may have reflected reduced plasma volume in our G H deficient patients. Extracellular fluid volume has been reported to be reduced in GH-deficiency (Ikkos et al., 1959; Parra et al., 1979). Diminished sweating has been documented in patients with GH deficiency (Pedersen et al., 1989), possibly adversely influencing thermoregulation. Clinical evidence of sodium and water retention following rhGH treatment in adults with G H deficiency was commonly observed in the current studies (see G H dose; see above). Weight gain, dependent oedema, and carpal tunnel symptoms occurred promptly (often within days to weeks), resolving either with a reduction in rhGH dose (after days to weeks) or spontaneously (after several months). Mean arterial blood pressure did not change significantly following
Renal effects of rhGH treatment in adults with G H deficiency were clearly shown by the Aarhus study. Glomerular filtration rate and renal blood flow increased significantly after rhGH treatment, reaching control values (Jerrgensen et al., 1989b). Filtration fraction and albumin excretion were unaffected by treatment. Whether these changes reflect an increase in cardiac output or specific intra-renal effects of GH remains to be established. The mechanism underlying the antinatriuretic and other renal actions of G H remains unclear. The time course of renal effects, paralleling that of increasing circulating IGF-I (Hirschberg et al., 1989), suggests that they are mediated via IGF-I. Indeed, IGF-I infusion in normal adults resulted in a 30% increase in creatinine clearance (as a measure of glomerular filtration rate) without change in creatinine excretion (Guler et al., 1989). In addition to this direct renal effect, significant activation of the renin-angiotensin-aldosterone system following rhGH treatment has been implicated in sodium retention in normal adults (Ho et al., 1990) and in adults with G H deficiency (Cuneo et al., 1991~). Reducton in atrial natriuretic peptide levels folIowing rhGH
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Clinical Endocrinology (1992) 37
R.C . Cuneo et at.
treatment in normal adults should also favour sodium retention (Msller et al., 1991). The mechanisms underlying these latter effects are unknown. Metabollc effects
An extensive review of the multitude of metabolic effects of GH is beyond the scope of this article. The area is reviewd by Davidson (1987) and Press (1988). Energy expenditure
The anabolic action of GH was associated with a marked increase in energy expenditure. Basal metabolic rate (BMR) increased 22% after one month rhGH treatment, and was still 16% higher than at baseline after 6 months (Salomon et al., 1989). When related to LBM, as the main physiological determinant, BMR increased significantly at one month and returned toward baseline by 6 months. The action of GH to increase peripheral conversion of thyroxine to tri-iodothyronine (Jsrgensen et al., 1989a) also appeared to contribute to the early increase in BMR (Cuneo, 1990). While caloric intake was not monitored, the increase in BMR could be accounted for by the changes in body composition (lipolysis and anabolism). The changes in energy expenditure and plasma urea concentrations suggest that a new anabolic steady state had been reached by 6 months, but longer follow-up is required to be certain. Carbohydrate metabolism
Fasting hypoglycaemia in adults with GH deficiency appears to be less common than in children. In lean adults with GH deficiency, fasting plasma glucose and insulin concentrations are normal (Merimee et al., 1971), while in obese GH deficient adults fasting hyperinsulinaemia suggests a degree of insulin resistance (Salmon, unpublished observations). Hypoglycaemic responsiveness to intravenous insulin is normal in patients with GH deficiency, but the recovery is delayed (Landon et al., 1966). Thus, a spectrum of ‘insulin sensitivity’ exists in adult GH deficiency, requiring further characterization. Following rhGH treatment, fasting plasma glucose rose significantlyafter one month, but returned toward pretreatment levels by 6 months (Salomon et al., 1989). Fasting plasma insulin and C-peptide levels increased quite dramatically, especially after one month, again returning toward pretreatment levels by 6 months. The explanation for these observations lies with the insulin antagonistic (Davidson, 1987; Press, 1988) and the insulinotrophic (Swenne & Hill, 1989)actions of GH. Formal assessment of insulin resistance
will be required to determine the relative contribution of these two mechanismsto the increased fasting plasma insulin levels. The cause of the increase in insulin:C-peptide ratio following long-term GH treatment (Salomon et al., 1989) remains speculative.No acute insulin-agonisticeffects of GH were clinically detected. Protein metabolism
Nitrogen retention has been clearly documented following GH treatment in deficiency (Henneman et al., 1960), in the long term resulting in the previously mentioned changes in body composition. Protein turnover studies should shed further light on the mechanism and timing of this process. Lipid metabolism
The lipolytic effects of GH are well known, characterized by an early increase in serum FFA levels (Davidson, 1987; Press, 1988). GH deficiency has been shown to result in increased triglyceride and cholesterol (predominantly LDL cholesterol) of a mild degree in 20-50% of cases in earlier reports mostly involving children (Merimee et al., 1972, 1973; Winter et al., 1979; Blackett et ul., 1982; Asayama et al., 1984; LaFranchi et al., 1985; Gacs & Romics, 1987). In adults with GH deficiency, mild increases in LDL and total cholesterol levels have been reported in 40-50% of patients compared to age, weight and sex-matchedcontrols (Libber et al., 1990; Cuneo et al., 1992). These same studies reported a low prevalence of hypertriglyceridaemia, but differed in reporting increased and reduced HDL-cholesterol concentrations, respectively. GH treatment in children with GH deficiency has shown equivocal changes in cholesterol concentrations (Winter et al., 1979; Merimee & Pulkkinen, 1980; Blackett et al., 1982; Heubi et al., 1983; Asayama et al., 1984; Winter & Green, 1984; LaFranchi et al., 1985). Long-term rhGH treatment in adults with GH deficiency has shown a significant reduction in total cholesterol (mean decrease 1 mmol/l), LDL-cholesterol, and apolipoprotein B, without change in HDLcholesterol levels (Cuneo et al., 1992). Whitehead et al. (1992) showed no change in total cholesterol after rhCH treatment; factors possibly contributing to a negative result were the limited washout period and possible poor compliance in a number of subjects. Clearly, more studies are required to clarify the effects of GH on cholesterol metabolism. The mechanisms underlying these effects are unknown. It is noted that IGF-I treatment reduced total cholestero1:HDL cholesterol ratio in normal adults (Froesch et al., 1990).
Clinical Endocrinology (1992) 37
The long-term follow-up of adults with hypopituitarism is characterized by increased total and cardiovascular mortality rates (Rosen & Bengtsson, 1990). This study should be interpreted with some caution since G H status was directly assessed in a minority of subjects (although it may be safe to assume most were GH deficient) and sex steroid replacement may also confound the interpretation that G H deficiencywas the factor responsible for increased cardiovascular mortality. Whether long-term G H treatment in adults with G H deficiency reduces cardiovascular mortality remains to be assessed. Psychologlcal effects
Many of our GH deficient patients complained of lethargy. It was not until detailed assessment of their quality of life that the magnitude of the physical and psychological difficulties experienced by these patients became apparent. Detailed assessment of psychological well-being, using validated questionnaires with comparisons with normal individuals matched for age, gender, social class, and geographical location, has shown that adults with G H deficiency perceive themselves as having much greater physical and psychological health problems (McGauley et al., 1990). Over one-third of the patients scored in the range consistent with psychiatric disturbance requiring therapy. Particular areas of concern to the patients were poor energy, emotional lability, low mood and social isolation. It has not been possible to control adequately for prior treatment of pituitary disease and ongoing medication dependence in this study. In the absence of extensive psychosocial support, similar conclusions have been reached in studies of adults with childhood onset G H deficiency, despite G H treatment to assist growth (Dean et al., 1985; Galatzer et al., 1987). Following rhGH treatment, psychological well-being improved, many patients reporting increased energy within one week. Quantitation by questionnaire confirmed the clinical impression with statistically significant improvements in perceived psychological distress and physical health after 6 months treatment (McGauley et at., 1990). Areas of particular improvement were in perceptions of energy and mood. Conflicting results, where subjective or no improvement in well-being was noted (Degerblad et d., 1987; Whitehead et al., 1992), suggest this important area requires further study. The mechanisms underlying these changes are obscure. Correlation with changes in lean body mass (McGauley et al., 1990) could account for ipprovement in physical wellbeing in the long term, but would be unlikely to explain the acute changes. These latter effects may be related to improved cerebral blood flow, glucose utilization, or even
Growth hormone deficiency syndrome
393
direct effects of G H on the hypothalamus, or IGF-I within the central nervous system. Abnormal sleep in young adults with G H deficiency which improves with rhGH treatment ( h t r o m & Jochumsen, 1989; Astrom et al., 1990) offers an additional explanation. Other effects
Arthralgias involving metacarpophalangial joints, wrists, elbows and knees have been reported in some patients soon after the commencement of rhGH treatment. No evidence of effusion or inflammation has been evident, and radiographic assessment has shown no abnormality. These changes settle with dose reduction, and probably represent swelling of articular cartilage. No long-term sequelae have been reported. Several patients reported mild discomfort in muscles (particularly quadriceps and shoulder girdle) during the first few months of rhGH treatment, described as ‘growing pains’; their significance remains to be defined. How to deflne the syndrome of OH deflclency In adults
The clinical features, summarized in Table 1, can be confidently attributed to G H deficiency, since all are reversed with rhGH treatment, and evidence is accumulating that they recur with G H withdrawal. Since the current biochemical diagnosis of G H deficiency in adults based on stimulated serum G H levels is clearly arbitrary, further assessment of the correlation between clinical features and physiological or pharmacologically stimulated G H concentrations and serum IGF-I concentrations is required. The utility of IBF-BP3 levels in the diagnosis of G H deficiency in adults deserves attention in view of its apparent sensitivity in children (Blum & Ranke, 1990). Considerable difficulty with the definition of GH deficiency in the elderly is envisaged. Mean 24-hour GH concentrations, G H pulsatility and serum IGF-I concentrations decline considerably in disease free humans with advancing age (Florini et al., 1985; Ho et al., 1987; Rudman et al., 1981). Overlapping G H and IGF-I levels could be predicted between patients with pituitary pathology and ‘normal’ elderly individuals, making the distinction difficult after the age of approximately 60 years. Further studies are required to define normal G H production and its regulation in normal elderly subjects with respect to obesity, nutrition and activity. This area of overlap with normal ageing may become clinically important with the demonstration of beneficial effects of rhGH treatment in men over 60 years selected on the basis of low IGF-I levels (Rudman et al., 1990). Significant improvements were reported in lean body mass, fat mass, skin thickness and bone density.
394 R. C . Cuneo et a / .
Clinical Endocrinology (1992) 37
Future directions GH pharmacology
Initial sensitivity to small doses of rhGH, with the subsequent ability to tolerate larger doses (unpublished observations) is unexplained, but may relate to GH-induced upregulation of GH receptors (Baxter et al., 1984; Grichting & Goodman, 1986). This hypothesis is supported by the reports of G H treatment increasing GH-binding protein (GH-BP), the extramembrane component of the GH receptor (Hochberg et af., 1991; Postel-Vinay et al., 1991). Type 1 IGF receptors have been noted to be increased in GH deficiency (LeRoith et al., 1991), further enhancing the early response to GH. In agreement with the experience in children, many of the anabolic and metabolic effects (viz body compositional changes, carbohydrate metabolism, and antinatriuretic effects) of rhGH treatment in adults diminished or plateaued with time despite continued treatment. The reason for this observation is unclear, but cannot be explained by a decreased IGF-I response to rhGH, since IGF-I levels were constant during 6 months treatment (Salomon et al., 1989). Alterations in IGF-binding protein (IGF-BP) or IGF receptor status may be responsible. The physiological role of IGFBPs remains undefined, but considerable evidence suggests that IGF-BPI and IGF-BP3 can inhibit the effects of IGF-I in certain in-vitro situations (see Cianfarani & Holly, 1989; Sara & Hall, 1990 for reviews).We observed an initial decline in IGF-BPI concentration one month after rhGH treatment, with recovery toward pretreatment concentrations by 6 months (Fig. 2), changes consistent with the inhibitory regulation of IGF-BPI production by insulin (Snyder & Clemmons, 1990). IGF-BP3 has been reported to increase following rhGH treatment in GH deficient children (Jsrgensen et al., 1990a). No data are available on the Type 1 IGF receptor status in adults following GH deficiency. The pharmacology of rhGH treatment has been recently reviewed (Jsrgensen J., 1991). Current recommendations include (a) evening injections (area under the G H absorption curve is higher after an evening as opposed to a morning injection; Jsrgensen et al., 1990b);(b) subcutaneous injection into the abdomen (higher area under the curve compared to injection into the thigh; Beshyah ef al., 1991); and (c) separation of glucocorticoid and GH replacement therapies into morning and evening respectively (to obtain maximal anabolic effects from GH). Our experience would lead us to initiate treatment with a low dose of rhGH (0.0125-0.025 U/kg per day), and increase as tolerated (over 2-4 weeks) to between 0.035 and 0.07 U/kg per day, with IGF-I monitoring to ensure adequacy of dose. Optimum adjustment of GH dosages may await detailed
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Time (months) Flg. 2 a, Serum insulin-likegrowth factor binding protein-I (IBP-1) concentrations obtained after an overnight fast (0900 h) in adults with growth hormone deficiency treated with M, recombinant human growth hormone (rhGH dose 0.07 U/kg per day) or 0, placebo in the double blind trial at St Thomas’ Hospital, London. Holly, St BartholoAssays were kindly performed by Dr J.M.P. mew’s Hospital, London, accordingto published methods (Holly el al., 1988). Statisticalanalysis as in Fig. 1 (P=0.028). Normal values for o900 h are 3&50 &I. b, Insulin (P
Review
The growth hormone deficiency syndrome in adults R. C. Cuneo, F. Saiomon, 0. A. McGauiey and P. H. Sdnksen Department of Endocrinology and Chemical Pathology, St Thomas’ Hospital, London, UK (Received 27 February 1992; returned for revision 27 April 1992; finally revised 30 June 1992; accepted 23 July 1992)
The effects of growth hormone (GH) deficiency in childhood are well recognized. These include shortness of stature with normal proportions, slow linear growth rate, delayed bone age with reduced bone density, excess adiposity with a predominantly truncal distribution, reduced lean tissue mass, and fasting hypoglycaemia (Collip et al., 1973; Hopwood et al., 1975; Tanner et al., 1977; Milner et al., 1979; Parra et al., 1979, Shore et al., 1980). These effects reflect the known metabolic actions of GH (Davidson, 1987; Press, 1988); GH promotes anabolism and lipolysis, and has complex actions on carbohydrate metabolism which can be summarized as insulinotrophic and insulin antagonistic. The effects of G H deficiency in adults have been appreciated only recently. There may be several reasons for this. Firstly, adults who developed panhypopituitarism from mass effects of a pituitary tumour or the treatment of the tumour survived, often returning to reasonably functional lives with conventional pituitary hormone replacement therapy. Secondly, G H treatment of such patients was not possible due to limited supplies of human pituitary-derived GH. The introduction of recombinant DNA technology has resulted in the production of authentic sequence human G H (rhGH) in potentially unlimited supplies, allowing treatment of conditions other than short stature. The aims of this review are to summarize the recent studies of GH treatment in adults with G H deficiency, thereby defining the syndrome of G H deficiency in adults, and to highlight areas for future investigation. The definition of the OH deficiency syndrome in adults
The GH deficiency syndrome in adults has been derived from a number of independent studies using biochemical selection criteria (see below). A summary of the clinical and biochemical features suggestive of the syndrome are provided in Table 1. Correspondence: Professor P. H. Sonksen, Department of Endocrinology and Chemical Pathology, UMDS, St Thomas’ Hospital, Lambeth Palace Road, London, SEI 7EH, UK.
Selection criteria for
GH deficiency
Three groups have published data on adults with G H deficiency, each with slightly different and arbitrary criteria for selection of patients. At St Thomas’ Hospital, London, patients had severe GH deficiency, defined as peak G H response to an adequate insulin-induced hypoglycaemic stimulus of less than 3 mU/l (Salomon et al., 1989). Limited overnight GH sampling in the placebo-treated group confirmed severe G H deficiency, where no patient recorded a peak G H greater than 2.0 mu/], 85% of samples being below the assay detection limit. The Aarhus group in Denmark studied young adults who had been treated for G H deficiency during childhood, and who were retested in adult life with GH responses to clonidine of less than 5 pg/l (approximately 10 mu/]; Jsrgensen et al., 1989b). The Belfast group selected patients with peak G H response to insulin hypoglycaemia of less than 7 mU/I, who were also shown to have severely limited GH production during modified 24-hour sampling (Whitehead ef ul. 1990, 1991, 1992). Circulating pretreatment insulin-like growth factor-I (IGF-I) concentrations could not be used as a reliable index for the selection of patients with G H deficiency as defined above. Even within the St Thomas’ patients who had severe GH deficiency, several individuals had plasma IGF-I concentrations within the low-normal range. This observation is in keeping with the paediatric literature (Furlanetto, 1990). Many of these patients had multiple pituitary hormone deficiences, treated conventionally. Attempts have been made to deliver other pituitary hormone replacement in a physiological manner (Jsrgensen el al., 1989b; Salomon et al., 1989), based on clinical and biochemical assessments. At present, no differences have been shown between patients with isolated G H deficiency and those with panhypopituitarism with respect to responses to rhGH treatment (Jsrgensen et al., 1989b). The numbers of patients studied are, however, small. Hence, features attributed to G H deficiency are not thought to be caused by deviations from ‘physiological’ conventional pituitary hormone replacement, in that such features (i.e. abnormalities of body composition, metabolism, or exercise physiology) resolve with rhGH treatment and (preliminary data suggest) they accumulate with rhGH withdrawal.
GH treatment dore Doses similar to those used in childhood GH deficiency, based on body weight or surface area, have been used in the 387
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Table 1 Features suggestive of GH
deficiency in adults: patients with isolated GH deficiency or multiple pituitary hormone deficiency receiving conventional replacement therapy
Symptoms (a) known pituitary pathology (b) impaired psychological well-being: poor general health impaired emotional reaction depressed mood impaired self control anxiety reduced vitality and energy increased social isolation (c) increasing abdominal adiposity (d) reduced strength and exercise capacity (e) cold intolerance Signs
(a) mixed truncalfgeneralizedadiposity (b) increased waist:hip ratio (c) thin, dry skin; cool peripheries; poor venous access (d) minor reductions in skeletal muscle strength (e) moderate reductions in exercise performance (f) psychological state characterized by low, labile mood
Tests
(a) (b) (c) (d)
stimulated GH < 3-5 mU/1 (?) low or low-normal serum IGF-I (? low IGF-BP3) hypercholesterolaemia(? also hypertriglyceridaemia)high LDL cholesterol low glomerular filtration rate and renal plasma flow (e) reduced lean body mass/increased fat mass increased waist:hip ratio (?> 0.85) (f) ? reduced basal metabolic rate/body weight (9) ? reduced bone density
treatment of adults with GH deficiency. The St Thomas’ and Belfast groups used 0.07 U/kg body weight as a nightly subcutaneous dose. Side-effects (arthralgias, fluid retention, or carpal tunnel symptoms) forced a reduction in dose to 0.035 U/kg in three of the 12 actively treated patients. The Aarhus group used a dose of 2 U/m2(approximately 0.05 U/ kg per day). One subject withdrew from the trial with symptoms of fluid retention. Plasma IGF-I concentrations increased into the high-normal age-related reference range in the St Thomas’ study, and to values equal to age-matched controls in the Aarhus study. Subsequent experience in treating larger numbers of patients at St Thomas’ has shown considerable inter-individual variation in sensitivity to differing GH doses (unpublished observations); the explanation for this is unknown but may lie in differing degrees of GH deficiency (Rudman et al., 1971). In summary, the doses of rhGH used in these studies can be considered as essentially physiological or marginally supraphysiological in some individuals. The absorption profile of subcutaneously administered rhGH in GH deficient adults is, however, far from physiological, resulting in a broad peak lasting more than 12 hours (Salomon et al., 1989; Jergensen J., 1991).
Treatment protocols differed between these trials (parallel for 6 months at St Thomas’, cross-over for 4 months at Aarhus and 6 months at Belfast, with 4 and 1 month washout periods, respectively). Results from the groups were remarkably consistent. Body composition
Some of the most dramatic effects of GH deficiency and rhGH treatment involved alterations in body composition. In children with GH deficiency, marked increases in lean body mass and reductions in fat mass are seen following GH treatment, especially in the first month (Collip et al., 1973; Tanner et al., 1977). Fat mass
In adults with GH deficiency, body fat is excessive and is distributed more in a central (abdominal) than peripheral pattern. As a percentage of body weight, mean fat mass (derived from the two-compartment model composition using whole body “K counting) was 37.9% in the S t Thomas’ patients (males 33*3%, females 47.6%), exceeding that
Clinical Endocrinology (1992) 37
predicted from age, sex, height, and weight (Boddy et al., 1972)by a mean of 7%. No patient had the fat distribution of glucocorticoid excess (e.g. supraclavicular fat pads, buffalo hump). Larger population studies with suitable control groups are required precisely to quantitate the excess adiposity in GH deficiency in adults, since reference data on fat mass of the relevant populations are limited. Following rhGH treatment, highly significant reductions in fat mass (mean of 5.7 kg or 18%) were noted. The greatest reductions occurred in the truncal region, as shown by both skinfold thicknesses and waist: hip ratios (Salomon et al. 1989).
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Total body weight
Body weight does not appear to be influenced by G H deficiency by itself, since in none of the published studies does body weight change with long-term treatment. The presence of multiple pituitary hormone deficiency appears to favour increased weight (Libber et al., 1990; Jerrgensen et al., 1989b;Salomon, unpublished data). It should be emphasized that body mass index (BMI; kg/m2) is an insensitive estimate of adiposity in adults with GH, since all patients in the St Thomas’ study with a normal BMI ( c 26) had excessive fat mass (unpublished observations).
Lean body mass
Adults with GH deficiency showed a significant deficit in mean lean body mass measured by whole body @K counting of 7-8% (range - 24 to 9%), corresponding to approximately 4 kg of lean tissue (Salomon et al, 1989). Predicted values were based on age, sex, height, and weight. Following rhGH treatment, lean body mass normalized over 6 months, increasing significantly by a mean of 4 kg or 10-12% (Salomon et al, 1989). As in children, much of the increase occurred in the first month.
+
Skeletal muscle mass
Whether all components of the lean body mass are reduced in GH deficient adults is uncertain. Skeletal muscle normally comprises approximately 50% of lean body mass. No detailed reference data are available for adult skeletal muscle mass, but using comparison with age-matched controls, Jerrgensen et al. (1989b) found the ratio of muscle to fat from the mid-thigh as assessed by computerized tomography (CT) to be significantly reduced in adults with G H deficiency. Similarly, CT area of mid-thigh muscle/body weight was significantly lower in adults with G H deficiency than in controls matched for age, sex, and activity (Cuneo et al., 1990). Neither method satisfactorily assesses absolute muscle mass in isolation from the excessive fat mass. Following rhGH treatment, significant increases have been noted in thigh muscle mass or cross-sectional area assessed by CT (mean 558%; Jsrgensen et al., 1989a; Whitehead et al., 1990; Cuneo el al., 1991a), along with 24hour urinary creatinine excretion (18-21 %; Salomon et al., 1989), an indirect measure of skeletal muscle. The greater increase in creatinine excretion than thigh muscle crosssectional area may reflect disproportionate increases in other skeletal muscles, but interpretation is limited by the renal effect of rhGH (see below).
Miscellaneous somatic effects
The effect of G H deficiency on bone mass in adults is unknown. In one small uncontrolled, open study, lumbar bone mineral density increased after 40 weeks of rhGH treatment (Van der Veen & Netelembos, 1990), but confirmation is required. In adults, rhGH treatment resulted in significant increases in both serum calcium and phosphorus (mean increases of 0.12 and 0.23 mmol/l; Salomon et al., 1989), suggesting a vitamin D-related effect. Further data regarding the effects of G H deficiency and rhGH treatment on bone density and fracture rate are awaited. Paediatric (Novak et al., 1972; Shore et al., 1980) and experimental (Jerrgensen, P., et al., 1991) data suggest that bone density and mechanical strength may be improved. Adults with treated hypopituitarism and G H deficiency have reduced skin thickness and total skin collagen (Black et al., 1972). The crow’s foot sign of facial wrinkling characteristic of hypopituitarism may be related to GH deficiency. It is our clinical impression that skin thickness increases after rhGH treatment, as suggested by Rudman et al. (1990) following rhGH treatment in elderly males selected on the basis of low serum IGF-I concentration. This impression is supported by the increases in serum Type I11 procollagen concentrations in GH-deficient children following rhGH treatment (Jensen e f al., 1991).
Physical performance characteriatlcs Skeletal muscle function
Details of skeletal muscle function have been assessed most carefully in the quadriceps group. Before treatment, adults with G H deficiency had significantly reduced isometric quadriceps force compared to carefully matched, normal
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individuals (Cuneo et al., 1990). Most of this deficit could be explained by reduced muscle cross-sectional area. When force was expressed per muscle cross-sectional area, an additional small deficit was still evident, particularly in males; possible explanations include differences in training, muscle fibre or myofibrillar density, or neuromuscular excitation. Normal muscle histology (see below) and CT density of quadriceps muscle (Cuneo et al., 1991a) suggest that muscle fibre density was not at fault. Isometric force in muscle groups other than the quadriceps have shown essentially no difference from a normal population (Cuneo et al., 1990). Further studies with carefully selected control subjects are required to confirm this finding. Following rhGH treatment, all three studies have noted no statistically significant increase in quadriceps force despite clear increases in thigh muscle cross-sectional area during 4-6 months controlled observations. Longer-term, uncontrolled follow-up on the Danish patients has shown a progressive increase in quadriceps isometric force toward normal over 12 months (Jerrgensen et al., 1990~).The most likely explanation for the failure to observe increased force generation following initial rhGH treatment is the insufficient statistical power of the studies. This conclusion is supported by the findings of Rutherford et al. (1991) who performed an uncontrolled study of G H deficient children during one year after the cessation of rhGH treatment when final height was attained. They found significant reductions in quadriceps cross-sectional area and force (with a trend toward reduced muscle-fibre areas on biopsy) over the year. Proximal, limb-girdle muscle force has been shown to increase significantly in adults with GH deficiency after rhGH treatment (Cuneo et al., 1991a). Exercise performance
Maximal exercise performance has been assessed by cycle ergometry with or without respiratory gas analysis. Before treatment, maximal oxygen uptake ( Yo2max) was significantly reduced compared to predicted (mean of 72-82% of that predicted from age, sex and height; Cuneo et al. 1991b; Whitehead et al., 1992). Power output is also likely to be reduced (Jsrgensen et al., 1989b; Whitehead et al., 1990, 1992; Cuneo et al., 1991b).Maximal heart rate averaged 90% of predicted, and respiratory exchange ratio (RER) exceeded 1.0 (Cuneo el al., 1991b), suggesting maximal or near maximal subjective effort had been obtained. Following rhGH treatment, maximal and sub-maximal exercise performance improved markedly and significantly (Jsrgensen et al., 1989b; Whitehead etal., 1990,1992; Cuneo et al., 1991b). Vozmax increased to a mean of 97% of predicted (based on age, sex and height; Cuneo et al., 1991b),
Clinical Endocrinology (1992) 37
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of predicted maximal oxygen uptake in adults with growth hormone
recombinant human growth hormone deficiency treated with (rhGH dose 0.07 U/kg per day) or 0, placebo in the double blind trial at St Thomas' Hospital, London. Statistical difference between the treatment groups was assessed by analysis of covariance, based on the mean values of the post-treatment data (P=0.016,0.047,and 0.018, respectively). Data presented with permission of The American Physiological Society.
and maximal power output increased proportionally (Fig. 1). Maximal heart rate was either unchanged (Cuneo et nl., 1991b) or increased (Jsrgensen et al., 1989b)following rhGH treatment. The reason for thediscrepancy is unclear, but may be related to increased subjective effort in the latter. Submaximal exercise performance, measured as anaerobic threshold, also increased significantly (Cuneo et al., 1991b), suggesting that activities performed during daily life would be accomplished with less metabolic stress. These changes were paralleled by subjective reports from patients that activities could be performed more easily following rhGH treatment. Explanations for the increase in maximal exercise performance certainly lie with increased lean body mass and
Clinical Endocrinology (1992) 37
skeletal muscle mass (Cuneo et a/., 1991b), with a possible contribution from maximal cardiac output, as suggested by echocardiographic data (see below), and the significant increases in maximal oxygen pulse (an index of stroke volume; Cuneo et al., 1990b) and resting renal plasma flow (Jergensen et al., 1989b). Alterations in fuel utilization during exercise following rhGH treatment have not been assessed.
Growth hormone deficiency syndrome
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rhGH treatment, and frank hypertension was an uncommon event, responding to a dose reduction (Salomon el al., 1989). Detailed assessments of total body water and sodium will be required to confirm the transience of this phenomenon. Echocardiography
Histology of vastus lateralis taken by needle biopsy from adults with G H deficiency has shown normal fibre type proportions and areas (Whitehead et al., 1989). No features of Cushingoid myopathy were evident. Differences in fibre type function have not been assessed in detail, but significant correlations between type I relative fibre area and maximal aerobic performance and between type 11 relative fibre area and maximal force generation (Cuneo et al., 1990) suggest that individual muscle fibre-type function is qualitatively normal. Following treatment, vastus lateralis histology remained unchanged (Whitehead et al., 1989). In particular, no features of an acromegalic myopathy were seen. These observations confirm the impression that alterations in force generation and exercise performance lie predominantly with altered muscle mass.
In adults with G H deficiency, rhGH treatment has been shown to result in small but significant increases in resting left ventricular (LV) end-diastolic and stroke volumes, most likely resulting from the increase in plasma volume (Cuneo et al., 1991~).LV wall mass also showed a small but significant increase in the St Thomas’ study, despite no change in mean arterial pressure, suggesting the anabolic action of G H on not only skeletal but myocardial muscle. Considering the LV dimensions and wall thicknesses were within normal limits before and after treatment, and the significant association between increased diastolic volume and Vozmax, the echocardiographic changes appear beneficial. No changes in echocardiographically determined LV wall mass were observed in the Aarhus study, possibly reflecting the lower dose and shorter duration of rhGH used (Jergensen et al., 1989b). A single case report of dramatic improvements in cardiac output following rhGH treatment in a man with cardiomyopathy of complex origins (Cuneo et al., 1989) highlights the potential for potent effects of rhGH on the cardiovascular system.
Cardlovaclcularlrenal effects
Renal effects
Skeletal muscle histology
Antinatriuretic action
The antinatriuretic action of G H is well known (Henneman et al., 1960; Rudman et al., 1971) but seldom is it of clinical concern in paediatric practice. Difficulties with cold intolerance (despite optimal thyroid hormone and glucocorticoid replacement) and venous access, both of which resolved rapidly following rhGH treatment, may have reflected reduced plasma volume in our G H deficient patients. Extracellular fluid volume has been reported to be reduced in GH-deficiency (Ikkos et al., 1959; Parra et al., 1979). Diminished sweating has been documented in patients with GH deficiency (Pedersen et al., 1989), possibly adversely influencing thermoregulation. Clinical evidence of sodium and water retention following rhGH treatment in adults with G H deficiency was commonly observed in the current studies (see G H dose; see above). Weight gain, dependent oedema, and carpal tunnel symptoms occurred promptly (often within days to weeks), resolving either with a reduction in rhGH dose (after days to weeks) or spontaneously (after several months). Mean arterial blood pressure did not change significantly following
Renal effects of rhGH treatment in adults with G H deficiency were clearly shown by the Aarhus study. Glomerular filtration rate and renal blood flow increased significantly after rhGH treatment, reaching control values (Jerrgensen et al., 1989b). Filtration fraction and albumin excretion were unaffected by treatment. Whether these changes reflect an increase in cardiac output or specific intra-renal effects of GH remains to be established. The mechanism underlying the antinatriuretic and other renal actions of G H remains unclear. The time course of renal effects, paralleling that of increasing circulating IGF-I (Hirschberg et al., 1989), suggests that they are mediated via IGF-I. Indeed, IGF-I infusion in normal adults resulted in a 30% increase in creatinine clearance (as a measure of glomerular filtration rate) without change in creatinine excretion (Guler et al., 1989). In addition to this direct renal effect, significant activation of the renin-angiotensin-aldosterone system following rhGH treatment has been implicated in sodium retention in normal adults (Ho et al., 1990) and in adults with G H deficiency (Cuneo et al., 1991~). Reducton in atrial natriuretic peptide levels folIowing rhGH
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R.C . Cuneo et at.
treatment in normal adults should also favour sodium retention (Msller et al., 1991). The mechanisms underlying these latter effects are unknown. Metabollc effects
An extensive review of the multitude of metabolic effects of GH is beyond the scope of this article. The area is reviewd by Davidson (1987) and Press (1988). Energy expenditure
The anabolic action of GH was associated with a marked increase in energy expenditure. Basal metabolic rate (BMR) increased 22% after one month rhGH treatment, and was still 16% higher than at baseline after 6 months (Salomon et al., 1989). When related to LBM, as the main physiological determinant, BMR increased significantly at one month and returned toward baseline by 6 months. The action of GH to increase peripheral conversion of thyroxine to tri-iodothyronine (Jsrgensen et al., 1989a) also appeared to contribute to the early increase in BMR (Cuneo, 1990). While caloric intake was not monitored, the increase in BMR could be accounted for by the changes in body composition (lipolysis and anabolism). The changes in energy expenditure and plasma urea concentrations suggest that a new anabolic steady state had been reached by 6 months, but longer follow-up is required to be certain. Carbohydrate metabolism
Fasting hypoglycaemia in adults with GH deficiency appears to be less common than in children. In lean adults with GH deficiency, fasting plasma glucose and insulin concentrations are normal (Merimee et al., 1971), while in obese GH deficient adults fasting hyperinsulinaemia suggests a degree of insulin resistance (Salmon, unpublished observations). Hypoglycaemic responsiveness to intravenous insulin is normal in patients with GH deficiency, but the recovery is delayed (Landon et al., 1966). Thus, a spectrum of ‘insulin sensitivity’ exists in adult GH deficiency, requiring further characterization. Following rhGH treatment, fasting plasma glucose rose significantlyafter one month, but returned toward pretreatment levels by 6 months (Salomon et al., 1989). Fasting plasma insulin and C-peptide levels increased quite dramatically, especially after one month, again returning toward pretreatment levels by 6 months. The explanation for these observations lies with the insulin antagonistic (Davidson, 1987; Press, 1988) and the insulinotrophic (Swenne & Hill, 1989)actions of GH. Formal assessment of insulin resistance
will be required to determine the relative contribution of these two mechanismsto the increased fasting plasma insulin levels. The cause of the increase in insulin:C-peptide ratio following long-term GH treatment (Salomon et al., 1989) remains speculative.No acute insulin-agonisticeffects of GH were clinically detected. Protein metabolism
Nitrogen retention has been clearly documented following GH treatment in deficiency (Henneman et al., 1960), in the long term resulting in the previously mentioned changes in body composition. Protein turnover studies should shed further light on the mechanism and timing of this process. Lipid metabolism
The lipolytic effects of GH are well known, characterized by an early increase in serum FFA levels (Davidson, 1987; Press, 1988). GH deficiency has been shown to result in increased triglyceride and cholesterol (predominantly LDL cholesterol) of a mild degree in 20-50% of cases in earlier reports mostly involving children (Merimee et al., 1972, 1973; Winter et al., 1979; Blackett et ul., 1982; Asayama et al., 1984; LaFranchi et al., 1985; Gacs & Romics, 1987). In adults with GH deficiency, mild increases in LDL and total cholesterol levels have been reported in 40-50% of patients compared to age, weight and sex-matchedcontrols (Libber et al., 1990; Cuneo et al., 1992). These same studies reported a low prevalence of hypertriglyceridaemia, but differed in reporting increased and reduced HDL-cholesterol concentrations, respectively. GH treatment in children with GH deficiency has shown equivocal changes in cholesterol concentrations (Winter et al., 1979; Merimee & Pulkkinen, 1980; Blackett et al., 1982; Heubi et al., 1983; Asayama et al., 1984; Winter & Green, 1984; LaFranchi et al., 1985). Long-term rhGH treatment in adults with GH deficiency has shown a significant reduction in total cholesterol (mean decrease 1 mmol/l), LDL-cholesterol, and apolipoprotein B, without change in HDLcholesterol levels (Cuneo et al., 1992). Whitehead et al. (1992) showed no change in total cholesterol after rhCH treatment; factors possibly contributing to a negative result were the limited washout period and possible poor compliance in a number of subjects. Clearly, more studies are required to clarify the effects of GH on cholesterol metabolism. The mechanisms underlying these effects are unknown. It is noted that IGF-I treatment reduced total cholestero1:HDL cholesterol ratio in normal adults (Froesch et al., 1990).
Clinical Endocrinology (1992) 37
The long-term follow-up of adults with hypopituitarism is characterized by increased total and cardiovascular mortality rates (Rosen & Bengtsson, 1990). This study should be interpreted with some caution since G H status was directly assessed in a minority of subjects (although it may be safe to assume most were GH deficient) and sex steroid replacement may also confound the interpretation that G H deficiencywas the factor responsible for increased cardiovascular mortality. Whether long-term G H treatment in adults with G H deficiency reduces cardiovascular mortality remains to be assessed. Psychologlcal effects
Many of our GH deficient patients complained of lethargy. It was not until detailed assessment of their quality of life that the magnitude of the physical and psychological difficulties experienced by these patients became apparent. Detailed assessment of psychological well-being, using validated questionnaires with comparisons with normal individuals matched for age, gender, social class, and geographical location, has shown that adults with G H deficiency perceive themselves as having much greater physical and psychological health problems (McGauley et al., 1990). Over one-third of the patients scored in the range consistent with psychiatric disturbance requiring therapy. Particular areas of concern to the patients were poor energy, emotional lability, low mood and social isolation. It has not been possible to control adequately for prior treatment of pituitary disease and ongoing medication dependence in this study. In the absence of extensive psychosocial support, similar conclusions have been reached in studies of adults with childhood onset G H deficiency, despite G H treatment to assist growth (Dean et al., 1985; Galatzer et al., 1987). Following rhGH treatment, psychological well-being improved, many patients reporting increased energy within one week. Quantitation by questionnaire confirmed the clinical impression with statistically significant improvements in perceived psychological distress and physical health after 6 months treatment (McGauley et at., 1990). Areas of particular improvement were in perceptions of energy and mood. Conflicting results, where subjective or no improvement in well-being was noted (Degerblad et d., 1987; Whitehead et al., 1992), suggest this important area requires further study. The mechanisms underlying these changes are obscure. Correlation with changes in lean body mass (McGauley et al., 1990) could account for ipprovement in physical wellbeing in the long term, but would be unlikely to explain the acute changes. These latter effects may be related to improved cerebral blood flow, glucose utilization, or even
Growth hormone deficiency syndrome
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direct effects of G H on the hypothalamus, or IGF-I within the central nervous system. Abnormal sleep in young adults with G H deficiency which improves with rhGH treatment ( h t r o m & Jochumsen, 1989; Astrom et al., 1990) offers an additional explanation. Other effects
Arthralgias involving metacarpophalangial joints, wrists, elbows and knees have been reported in some patients soon after the commencement of rhGH treatment. No evidence of effusion or inflammation has been evident, and radiographic assessment has shown no abnormality. These changes settle with dose reduction, and probably represent swelling of articular cartilage. No long-term sequelae have been reported. Several patients reported mild discomfort in muscles (particularly quadriceps and shoulder girdle) during the first few months of rhGH treatment, described as ‘growing pains’; their significance remains to be defined. How to deflne the syndrome of OH deflclency In adults
The clinical features, summarized in Table 1, can be confidently attributed to G H deficiency, since all are reversed with rhGH treatment, and evidence is accumulating that they recur with G H withdrawal. Since the current biochemical diagnosis of G H deficiency in adults based on stimulated serum G H levels is clearly arbitrary, further assessment of the correlation between clinical features and physiological or pharmacologically stimulated G H concentrations and serum IGF-I concentrations is required. The utility of IBF-BP3 levels in the diagnosis of G H deficiency in adults deserves attention in view of its apparent sensitivity in children (Blum & Ranke, 1990). Considerable difficulty with the definition of GH deficiency in the elderly is envisaged. Mean 24-hour GH concentrations, G H pulsatility and serum IGF-I concentrations decline considerably in disease free humans with advancing age (Florini et al., 1985; Ho et al., 1987; Rudman et al., 1981). Overlapping G H and IGF-I levels could be predicted between patients with pituitary pathology and ‘normal’ elderly individuals, making the distinction difficult after the age of approximately 60 years. Further studies are required to define normal G H production and its regulation in normal elderly subjects with respect to obesity, nutrition and activity. This area of overlap with normal ageing may become clinically important with the demonstration of beneficial effects of rhGH treatment in men over 60 years selected on the basis of low IGF-I levels (Rudman et al., 1990). Significant improvements were reported in lean body mass, fat mass, skin thickness and bone density.
394 R. C . Cuneo et a / .
Clinical Endocrinology (1992) 37
Future directions GH pharmacology
Initial sensitivity to small doses of rhGH, with the subsequent ability to tolerate larger doses (unpublished observations) is unexplained, but may relate to GH-induced upregulation of GH receptors (Baxter et al., 1984; Grichting & Goodman, 1986). This hypothesis is supported by the reports of G H treatment increasing GH-binding protein (GH-BP), the extramembrane component of the GH receptor (Hochberg et af., 1991; Postel-Vinay et al., 1991). Type 1 IGF receptors have been noted to be increased in GH deficiency (LeRoith et al., 1991), further enhancing the early response to GH. In agreement with the experience in children, many of the anabolic and metabolic effects (viz body compositional changes, carbohydrate metabolism, and antinatriuretic effects) of rhGH treatment in adults diminished or plateaued with time despite continued treatment. The reason for this observation is unclear, but cannot be explained by a decreased IGF-I response to rhGH, since IGF-I levels were constant during 6 months treatment (Salomon et al., 1989). Alterations in IGF-binding protein (IGF-BP) or IGF receptor status may be responsible. The physiological role of IGFBPs remains undefined, but considerable evidence suggests that IGF-BPI and IGF-BP3 can inhibit the effects of IGF-I in certain in-vitro situations (see Cianfarani & Holly, 1989; Sara & Hall, 1990 for reviews).We observed an initial decline in IGF-BPI concentration one month after rhGH treatment, with recovery toward pretreatment concentrations by 6 months (Fig. 2), changes consistent with the inhibitory regulation of IGF-BPI production by insulin (Snyder & Clemmons, 1990). IGF-BP3 has been reported to increase following rhGH treatment in GH deficient children (Jsrgensen et al., 1990a). No data are available on the Type 1 IGF receptor status in adults following GH deficiency. The pharmacology of rhGH treatment has been recently reviewed (Jsrgensen J., 1991). Current recommendations include (a) evening injections (area under the G H absorption curve is higher after an evening as opposed to a morning injection; Jsrgensen et al., 1990b);(b) subcutaneous injection into the abdomen (higher area under the curve compared to injection into the thigh; Beshyah ef al., 1991); and (c) separation of glucocorticoid and GH replacement therapies into morning and evening respectively (to obtain maximal anabolic effects from GH). Our experience would lead us to initiate treatment with a low dose of rhGH (0.0125-0.025 U/kg per day), and increase as tolerated (over 2-4 weeks) to between 0.035 and 0.07 U/kg per day, with IGF-I monitoring to ensure adequacy of dose. Optimum adjustment of GH dosages may await detailed
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Time (months) Flg. 2 a, Serum insulin-likegrowth factor binding protein-I (IBP-1) concentrations obtained after an overnight fast (0900 h) in adults with growth hormone deficiency treated with M, recombinant human growth hormone (rhGH dose 0.07 U/kg per day) or 0, placebo in the double blind trial at St Thomas’ Hospital, London. Holly, St BartholoAssays were kindly performed by Dr J.M.P. mew’s Hospital, London, accordingto published methods (Holly el al., 1988). Statisticalanalysis as in Fig. 1 (P=0.028). Normal values for o900 h are 3&50 &I. b, Insulin (P
