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Growth Hormone Deficiency in Adulthood and the Effects of Growth Hormone Replacement: A Review

Address all correspondence and requests for reprints to: GRS Secretariat, Medical Department M, Aarhus Kommunehospital, DK-8000, Aarhus C, Denmark.

	Abstract

Top Abstract I. Introduction II. Body Composition III. Bone Mineral Density... IV. Muscle Strength V. Exercise Performance VI. Cardiovascular System VII. Metabolism VIII. Skin IX. Immune Function X. Psychological Well-Being and... XI. Reported Adverse Effects... XII. Concluding Remarks References

 
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	I. Introduction

Top Abstract I. Introduction II. Body Composition III. Bone Mineral Density... IV. Muscle Strength V. Exercise Performance VI. Cardiovascular System VII. Metabolism VIII. Skin IX. Immune Function X. Psychological Well-Being and... XI. Reported Adverse Effects... XII. Concluding Remarks References

 

GH DEFICIENCY in the human adult most commonly results from pituitary or peripituitary tumors and their treatment (1). The majority of these tumors are benign, and in a large series, pituitary adenoma was the commonest cause of adult hypopituitarism (2). The incidence of adult-onset (AO) GH deficiency is not known, but indirect estimates based on the incidence of pituitary tumors suggest an incidence of 10 people/million annually. In contrast, childhood-onset (CO) GH deficiency is most commonly idiopathic and is not necessarily associated with other pituitary hormone deficiencies.

The limited supplies of pituitary-derived GH restricted research into the use of GH in adults and limited knowledge of the role of GH after the cessation of linear growth. An early study, in which a 35-yr-old hypopituitary adult reported increased vigor, ambition, and well-being after GH replacement, suggested that GH may have biological actions in adulthood (3). More recent evidence suggests that adults with hypopituitarism have reduced life expectancy (2, 4), possibly related to GH deficiency (5). The availability of recombinant GH has led to intensive investigation of the effects of GH in health and disease, and over the past decade, numerous studies have focused on the effects of GH replacement in the adult with GH deficiency.

The first placebo-controlled trials of GH replacement in the GH-deficient adult were reported in 1989 (6, 7). These and subsequent investigations have led to the recognition of a specific clinical syndrome in adults with long standing GH deficiency. This syndrome is associated with characteristic symptoms, signs, and investigative findings. The main features are listed in Table 1. Many studies have assessed the effects of GH replacement on these symptoms and signs. The majority of these data has resulted from both formal randomized placebo-controlled trials and smaller open studies. Consistently, these studies have demonstrated that adults with GH deficiency are both physically and psychologically less healthy than their age-matched peers, and that GH replacement results in substantial and sustained benefits. This review details the important features resulting from GH deficiency and summarizes the information, available up to the beginning of 1997, relating to the effects of GH replacement.

	II. Body Composition

Top Abstract I. Introduction II. Body Composition III. Bone Mineral Density... IV. Muscle Strength V. Exercise Performance VI. Cardiovascular System VII. Metabolism VIII. Skin IX. Immune Function X. Psychological Well-Being and... XI. Reported Adverse Effects... XII. Concluding Remarks References

A wide range of techniques has been used to assess body composition and have been reviewed by de Boer et al. (11). They all rely on assumptions derived from healthy subjects, e.g. constant hydration state of lean body, constant intracellular potassium concentration, or a constant fat-free extracellular compartment. These assumptions may not be valid in AO GH deficiency. Nevertheless, despite the methodological differences, the findings from these studies are strikingly similar. In addition, recent studies using computerized tomography (CT) (12) and magnetic resonance imaging (MRI) (13) have confirmed the previous findings.

A. Body composition in adults with GH deficiency compared with that in healthy controls

1. Lean Body Mass (LBM). Reduced LBM is an important feature of AO GH deficiency. Initial studies demonstrated a mean reduction in LBM of 7–8%, corresponding to approximately 4 kg lean tissue (6). Subsequent studies have confirmed these results (12, 14, 15, 16).

2. Fat mass. Salomon et al. (6) were the first to demonstrate that fat mass was higher by a mean of 7% in GH-deficient patients compared with predicted values based on age, sex, and height. Using a wide range of measurement techniques, this figure has been confirmed by other investigators (15, 17, 18, 19, 20, 21, 22).

The fat mass distribution has been assessed in a number of studies by waist/hip ratio, skin fold thickness (6, 17, 21), CT scan (12), and MRI (13) with consistent results. The excess fat accumulates in a central (abdominal) distribution, mostly in the visceral component. In epidemiological studies, this abdominal distribution has been associated with an increased risk of mortality and morbidity from cardiovascular disease.

3. Fluid volume. Studies employing a radioisotope dilution technique and bioimpedance measurements indicate that total body water is reduced in AO GH deficiency (20, 21). This is mainly due to a reduction in extracellular water (ECW) (15, 23, 24). Recent studies suggest that reduced plasma volume (PV) (24) and total blood volume (25) contribute to the reduced ECW.

B. Effect of GH replacement

The studies investigating the effect of GH on body composition are summarized in Table 2. The range of the GH dose used in these trials was 0.1–0.5 IU/kg·week (5–25 µg/kg·day).

2. Fat mass. GH replacement therapy has resulted in a mean reduction in fat mass of approximately 4–6 kg in GH-deficient adults (6, 7, 12, 13, 14, 15, 16, 17, 21, 26, 27, 28, 29, 30, 31, 32). A recent study suggests that this reduction occurs similarly in both CO and AO GH deficiency (33). Anthropometric measurements indicate that the most important change occurs in the abdominal region (6). In addition, studies using CT (12) and MRI (13) have shown that the reduction in abdominal fat mass is mainly due to a reduction in visceral fat mass.

3. Fluid volume. In studies using radionuclide dilution methods and bioimpedance analysis, GH therapy resulted in an increase in total body water (12, 33, 34, 35), particularly in ECW within 3–5 days (22, 24, 26, 36). A short term study failed to demonstrate an increase in PV after 2 weeks of GH treatment (36), but a longer study has shown that an increase in PV occurs after at least 3 weeks of GH replacement therapy (24). In a recent study, GH therapy resulted in an 400-mL increase in total blood volume after 3 months of treatment (35).

The well known antinatriuretic effect of GH appears to involve a direct action of GH and/or insulin-like growth factor I (IGF-I) on renal tubular sodium reabsorption, but there is also evidence for an activation of the renin-angiotensin system (24, 36).

	III. Bone Mineral Density (BMD) and Bone Metabolism

Top Abstract I. Introduction II. Body Composition III. Bone Mineral Density... IV. Muscle Strength V. Exercise Performance VI. Cardiovascular System VII. Metabolism VIII. Skin IX. Immune Function X. Psychological Well-Being and... XI. Reported Adverse Effects... XII. Concluding Remarks References

 
A. Epidemiological data

A radiological study of 36 adults with long standing GH deficiency demonstrated that 17% had reduced vertebral height, consistent with vertebral fracture, and a further 19% had features of osteopenia (37). In a retrospective study (38), the fracture rate in 89 adult patients with GH deficiency was significantly higher (24.1% vs. 11.8%) than that in a control population (n = 390). These data suggest that adults with GH deficiency are at increased risk of osteoporotic fractures.

B. BMD and bone metabolism in adults with GH deficiency compared with those in healthy controls

The studies investigating BMD in AO GH deficiency are summarized in Table 3. Using different techniques these studies have universally demonstrated reduced bone mass at different skeletal sites in patients with CO (21, 39, 40, 41, 42), AO (43, 44, 45), and mixed onset (19, 46, 47, 48) GH deficiency compared with that in healthy control subjects.

Bone histology of patients with mainly CO GH deficiency showed high trabecular bone volume, increased bone erosion, increased osteoid thickness, and increased mineralization lag time, indicating a delayed bone mineralization (53).

C. Effects of GH replacement on BMD and bone metabolism in adults with GH deficiency

The studies investigating the effects of GH on BMD at different skeletal sites are summarized in Table 4. The dose of GH used in these trials was 0.25 IU/kg·week (12.5 µg/kg·day), except in the study by Amato et al. (21), in which a dose of 0.1 IU/kg·week (5 µg/kg·day) was used. Baum et al. (32) administered a starting dose of 0.2 IU/kg·week (10 µg/kg·day) and adjusted the dose to maintain normal IGF-I levels.

The studies investigating the effect of GH on bone metabolism are summarized in Table 5. Serum bone formation (osteocalcin, bone alkaline phophatase, bone Gla protein, and carboxyl-terminal propeptide of type I procollagen) and urinary resorption markers (deoxypyridinoline, pyridinoline, and cross-linked telopetide of type I collagen) increased in both short and long term studies, indicating an activation of bone remodeling (15, 32, 48, 50, 52, 54, 55, 57, 58, 62). Interestingly, in patients with AO GH deficiency, bone formation appears to be increased at 6 months, with no further change throughout treatment (32, 33). In contrast, patients with CO GH deficiency showed a steep increase up to 12 months of GH therapy, followed by a sharp decrease to baseline value after 18 months GH therapy (33). 1,25-Hydroxyvitamin D increased in one study (15) and was unchanged after 12 months in another (58). PTH did not change (15, 56) or decreased (12, 47, 48, 58), whereas 25-hydroxyvitamin D remained unchanged (58). In three studies (12, 56, 58), serum phosphate and calcium levels were reported to increase after 6–12 months of treatment.

In summary, AO GH deficiency is associated with reduced bone mass, as assessed by BMD measurements. The available data provide evidence that GH is an osteo-anabolic hormone when given to GH-deficient adults. The findings in most of the trials suggest that GH has a biphasic effect; after an initial predominance of bone resorption, stimulation of bone formation leads to a net gain in bone mass after 12–24 months of treatment. Whether these changes in bone metabolism will result in less osteopenia and a reduced fracture rate in adults with GH deficiency requires long term study.

	IV. Muscle Strength

Top Abstract I. Introduction II. Body Composition III. Bone Mineral Density... IV. Muscle Strength V. Exercise Performance VI. Cardiovascular System VII. Metabolism VIII. Skin IX. Immune Function X. Psychological Well-Being and... XI. Reported Adverse Effects... XII. Concluding Remarks References

 
The alterations in body composition that occur in GH deficiency with reduced LBM result in a mild to moderate reduction in muscle strength. Isometric quadriceps force has been shown to be reduced in GH-deficient adults compared with that in matched normal controls (64), and this finding has been supported by a more recent study (65). The reduction in cross-sectional muscle area may account for this finding, but even allowing for this, weakness is evident. Lack of conditioning and endurance training may be responsible for the shortfall.

Several studies have addressed the effects of GH replacement on muscle strength (7, 14, 41, 65, 66). In these studies, limb-girdle force was increased after 6 months of GH treatment (66), but neither isometric quadriceps force (7, 14, 65, 66) nor quadriceps torque (67) increased significantly in any of the studies. This occurred despite clear increases in thigh muscle cross-sectional area. Only after more prolonged GH treatment (at least 12 months) was a significant increase in quadriceps force demonstrated (65, 68), with a further increase and normalization seen after 3 yr (28).

	V. Exercise Performance

Top Abstract I. Introduction II. Body Composition III. Bone Mineral Density... IV. Muscle Strength V. Exercise Performance VI. Cardiovascular System VII. Metabolism VIII. Skin IX. Immune Function X. Psychological Well-Being and... XI. Reported Adverse Effects... XII. Concluding Remarks References

 
Cuneo et al. (64, 66, 69) were the first to study exercise performance and capacity in adults with GH deficiency. The patients had increased shoulder fatigability and reduced quadriceps force, even allowing for the reduction in muscle mass (64). Maximal exercise performance in GH-deficient adults has been assessed in several studies using cycle ergometry (7, 14, 27, 69). Before treatment, values for maximum oxygen uptake were significantly reduced, being, on the average, 72–82% of those predicted for age, sex, and height (14, 69).

After GH treatment (0.25–0.50 IU/kg·week; 12.5–25 µg/kg·day) for up to 6 months, maximum oxygen uptake increased significantly (7, 14, 64), virtually reaching predicted values (69). Similar findings were reported by Nass et al. (70) from a double blind, placebo-controlled study of 20 adults with GH deficiency. In this study, 6 months of GH replacement resulted in significant improvements in exercise capacity and maximum oxygen uptake. When isolated muscle groups were tested, GH therapy increased hip flexor (66) and knee extensor (68) strength. Exercise performance is determined both by muscle mass and cardiac performance (71). Cuneo et al. corrected exercise capacity for changes in LBM and found no alteration from baseline (69), suggesting that the increased exercise performance is mainly caused by the GH-associated increased muscle mass. An increase in erythrocyte mass/oxygen transport capacity due to a stimulatory effect of IGF-I on erythropoiesis may also contribute to an increased exercise capacity (25, 72, 73, 74). The effects of GH replacement on the cardiovascular system are dealt with below.

	VI. Cardiovascular System

Top Abstract I. Introduction II. Body Composition III. Bone Mineral Density... IV. Muscle Strength V. Exercise Performance VI. Cardiovascular System VII. Metabolism VIII. Skin IX. Immune Function X. Psychological Well-Being and... XI. Reported Adverse Effects... XII. Concluding Remarks References

 
Epidemiological data suggest that adults with hypopituitarism have reduced life expectancy compared with that of healthy controls, with a greater than 2-fold increase in mortality from cardiovascular disease (2, 4). These findings were confirmed and extended by Erfurth et al. (75), who found a standardized mortality ratio (SMR) of 1.74 for cardiovascular disease among 344 patients with hypopituitarism in the south of Sweden compared with that in the healthy population in the same catchment area. The increased risk of death was mostly attributable to cerebrovascular disease (SMR = 3.39), especially among female patients (SMR = 4.91). Similar mortality rates have been demonstrated from a study in the UK; however, the cardiovascular mortality was less evident than in earlier studies (4). GH deficiency has been proposed as the variable accounting for this increased mortality (5). These data support the hypothesis that long standing GH deficiency in adulthood predisposes to the development of premature atherosclerosis.

Rosen et al. (76) compared known cardiovascular risk factors in 104 adults with GH deficiency with healthy controls from a population study. The patients had a higher body mass index, higher plasma triglycerides (TG), and lower high density lipoprotein cholesterol (HDL-C). In addition, there was a higher incidence of hypertension in the GH-deficient subjects compared with controls. The mechanisms responsible for the increased cardiovascular mortality remain largely unknown, but carotid artery ultrasonography has demonstrated increased intima-medial thickening and intimal plaque formation (77) and reduced arterial compliance (78) in hypopituitary adults. Johannson et al. (79) compared levels of plasminogen activator inhibitor-1, fibrinogen, blood lipids, and blood pressure in 20 adults with GH deficiency with those in healthy subjects. The patients had increased TG, plasminogen activator inhibitor-1 activity, and fibrinogen compared with controls. These changes may contribute to increased artherogenic propensity and cardiovascular disease.

The role of GH in the regulation of cardiac function and structure has not yet been fully defined. A comprehensive case report demonstrated cardiac chamber dilatation, reduced ventricular wall thickness, and decreased myocardial fibrillar content in a patient with a 20-yr history of GH deficiency (80). GH therapy for 3 months was associated with a decrease in ventricular diameter and increases in wall thickness, ejection fraction, and myofibrillar content. A similar clinical response to GH replacement has been reported in a patient with advanced heart failure (81).

Cuneo et al. (82) reported a small, but significant, increase in resting left ventricular end-diastolic volume and stroke volume after GH treatment, which were attributed to an increase in plasma volume (preload) secondary to the antinatriuretic effect of GH. There was also an increase in left ventricular mass, which occurred in the absence of any change in mean arterial pressure (afterload). The mean increase in left ventricular mass of 5% was comparable with the 5–10% increase in thigh muscle and lean body mass in the same patients, suggesting an anabolic action of GH on not only skeletal but also cardiac muscle. In contrast, a subsequent placebo-controlled study of 20 adults with GH deficiency failed to demonstrate any alteration in cardiac structure after 6 months GH replacement (70).

Two studies comparing echocardiographic findings have demonstrated reduced left ventricular mass and impaired systolic function in adults with GH deficiency compared with healthy controls (21, 83). Treatment with GH for 6 months normalized these indexes, and 6 months after cessation of therapy, cardiac function had returned to baseline. Six months of GH replacement have been shown to increase left ventricular mass (18%), stroke volume (28%), and cardiac output (43%) and reduce peripheral vascular resistance (84) in GH-deficient adults. A sustained effect on cardiac performance has been reported in two open studies up to 3 yr after commencement of GH therapy (85, 86).

Cuocolo et al. (87) studied cardiac function in 14 adults with GH deficiency and 12 matched controls using radionuclide scanning. The GH-deficient patients were studied before and after GH replacement. Compared with controls, the patients had decreased left ventricular ejection fraction, decreased stroke volume index, and decreased cardiac index. GH therapy for 6 months increased these variables, reversing these deficits in cardiac function. In contrast, a controlled study of cardiac function, assessed by echocardiography of 13 adults with GH deficiency compared with controls, revealed no cardiovascular dysfunction in the patients (88).

The long term effects of GH replacement on cardiac function are unknown; however, patients with acromegaly have an increased prevalence of left ventricular hypertrophy, hypertension, cardiac failure, and cardiovascular death compared with the healthy population (89, 90, 91, 92, 93). GH replacement should be aimed at restoring somatic deficiency, including cardiac size and function, and supraphysiological replacement should be avoided.

In summary, patients with long standing GH deficiency have reduced life expectancy largely related to increased mortality from cardiovascular disease. GH deficiency results in smaller left ventricular size and impaired ventricular function. These changes can be reversed by GH replacement and sustained benefit is seen up to 3 yr after commencement of GH therapy.

	VII. Metabolism

Top Abstract I. Introduction II. Body Composition III. Bone Mineral Density... IV. Muscle Strength V. Exercise Performance VI. Cardiovascular System VII. Metabolism VIII. Skin IX. Immune Function X. Psychological Well-Being and... XI. Reported Adverse Effects... XII. Concluding Remarks References

 
A. Energy expenditure

Whole body energy expenditure is largely determined by lean body metabolic activity (94). Resting energy expenditure (REE) has been shown to be increased in acromegaly (95, 96). Recent studies (97, 98) have shown that REE in adults with GH deficiency is lower than predicted values corrected for age, height, and weight. Another study of seven adults with GH deficiency had similar findings, but the difference in REE compared with controls failed to reach statistical significance (16). Expressing REE per LBM in these studies produced conflicting results, with an increase in REE observed in the first, a decreased REE in the second, and a value similar to that in healthy subjects in the third (16, 97, 98) study. Methodological differences in the measurement of LBM may be responsible for these discrepancies.

GH replacement in GH deficiency results in rapid and large increases in REE (6, 16). Restoration of LBM accounts for much of the increase observed in REE, but when changes in REE are expressed per LBM, these rises are still significant, indicating that direct increases in cellular metabolism are responsible for some of the increased REE (6). GH treatment of the GH-deficient adult results in an increase in circulating T₃ levels in both patients receiving T₄ replacement and those with normal thyroid function (6, 12, 99, 100), indicating that GH is a physiological regulator of thyroid function in general and of peripheral conversion of T₄ in particular. This alteration may contribute to the calorigenic effect of GH. In addition, GH replacement has been shown to increase fat oxidation (101, 102, 103) and protein synthesis (15, 104, 105). These processes are energy dependent and result in an increase in energy expenditure.

B. Protein metabolism

Although there have been many studies of the effects of GH on body composition in the GH-deficient adult, there have been comparatively few studies of the direct effects of GH replacement on protein metabolism in these patients. These studies are reviewed below.

Binnerts et al. (15) performed a 6-month open study of the effects of GH replacement (0.5 IU/kg·day; 25 µg/kg·day) in eight adults with GH deficiency using [¹⁵N]glycine as a tracer. Protein synthesis was increased at 1 month, with no alteration in protein degradation. This effect was unsustained and was no longer evident after 3, 6, or 9 months of GH therapy. Importantly, throughout the study when rates of protein metabolism were expressed in terms of LBM, no significant differences were detectable throughout the entire study duration.

In a study of 16 adults with GH deficiency compared with 20 matched controls, Beshyah et al. (104) used L-[1-¹³C]leucine to study protein metabolism. The patients had decreased leucine flux, oxidation, and protein synthesis. Seven of these patients underwent an identical study after 6 months of GH therapy (0.18–0.35 IU/kg·week; 9–17.5 µg/kg·day), which demonstrated a nonsignificant increase in protein flux, oxidation, and synthesis.

A randomized, double blind, placebo-controlled trial of the effect of GH replacement (0.25 IU/kg·week; 12.5 µg/kg·day) on protein metabolism involving 18 GH-deficient adults was performed using L-[1-¹³C]leucine (105). In this study, protein synthesis was significantly increased after 2 months (24%), with no alteration in protein degradation.

The major alterations in body composition occur within 1 month of commencement of GH therapy (6, 7), and it is likely that any significant alteration in protein metabolism would occur over this period. This may account for the results of the studies of protein metabolism, which have demonstrated an increase in protein synthesis up to 2 months (105) after commencement of GH, but little alteration above baseline after 6 months of therapy (15).

In summary, studies of protein metabolism in adults with GH deficiency have demonstrated reduced protein flux and synthesis. GH replacement increases protein synthesis for the first few months, with a return to baseline rates after 6 months, most likely as a result of achieving a new baseline rate of metabolism.

C. Carbohydrate metabolism

Adults with GH deficiency have altered body composition and tend to be obese, with an increase in central adiposity (7, 14). A study of 24 adults with GH deficiency demonstrated fasting insulin levels above the normal reference range and a significant positive correlation between fasting plasma insulin and both fat mass and waist girth (6). Adults with GH deficiency are thus likely to be insulin resistant. This has been confirmed in a hyperinsulinemic euglycemic clamp study of 9 adults with CO GH deficiency (106). Similarly, using a hyperinsulinemic euglycemic clamp (40 mU/m²·min), Johansson et al. (109) demonstrated a decreased glucose infusion requirement in 15 adults with GH deficiency compared with that in matched controls, indicating reduced insulin sensitivity. Similar plasma insulin levels were seen between the 2 groups (in the normal range).

In a double blind, placebo-controlled, cross-over study, Fowelin et al. (107) assessed the effects of 6 months of GH replacement (0.25 IU/kg·week; 12.5 µg/kg·day) on glucose metabolism in nine adults with GH deficiency. Using D-[3-³H]glucose tracer and a hyperinsulinemic euglycemic clamp, they investigated basal glucose and insulin-stimulated glucose metabolism after 6 weeks and 6 months of GH treatment. After 6 weeks of GH therapy, fasting glucose levels and plasma insulin concentrations were elevated, but both had returned to baseline at 26 weeks. The amount of glucose required for euglycemia during the insulin clamp was significantly lower after 6 weeks of therapy, but there was no difference above baseline at 26 weeks. These changes were interpreted as a short term reduction of insulin-stimulated glucose utilization, mediated by GH, with reversal of these changes with time, perhaps as a result of altered body composition.

Using an iv glucose tolerance test, O’Neal et al. (108) performed an uncontrolled study of the effects of GH replacement (0.25 IU/kg·week; 12.5 µg/kg·day) on glucose metabolism in 10 GH-deficient adults. Employing Bergman’s minimal model, these studies demonstrated increased fasting glucose, insulin, and C peptide as well as an increase in both the first and second phases of insulin secretion after 1 week of GH therapy. Insulin-mediated glucose disposal and glucose decay were decreased, but the fractional clearance rate of insulin was unchanged. After 3 months of GH treatment, the fasting plasma insulin and C peptide concentrations remained elevated, but all other variables had returned to baseline values.

Salomon et al. (97) assessed fasting glucose metabolism in 24 GH-deficient adults using D-[3-³H]glucose and indirect calorimetry. In these studies, glucose turnover was within the normal range for healthy adults (expressed per LBM). During the course of the study, glucose turnover correlated positively with fat oxidation, and a reduction occurred in glucose oxidation. These changes are consistent with those observed in normal adults during a prolonged fast and suggest that adults with GH deficiency have reduced stores of glycogen.

Hew et al. (110) assessed glucose metabolism in 14 adults with GH deficiency and 12 matched controls using a hyperinsulinemic euglycemic clamp, with measurement of glycogen synthetic rate by muscle biopsy. Both groups had similar basal rates of glucose utilization, but a reduction (64%) in insulin-stimulated glucose utilization occurred in the GH-deficient adults compared with that in the control subjects. In addition, the insulin sensitivity index of glucose disposal and glycogen synthesis were reduced in the patients. The insulin-stimulated fractional velocity was decreased by 50% compared with that in controls. These data confirm that patients with GH deficiency have insulin resistance, with inhibition of the glycogen synthase pathway.

In summary, GH-deficient adults have hyperinsulinemia, indicating insulin resistance. These features are associated with the central obesity and increased intraabdominal adiposity that are characteristic of GH deficiency. Most of the hyperinsulinemic euglycemic clamp studies have confirmed this insulin resistance. In addition, there is evidence that adults with GH deficiency have reduced hepatic glycogen stores. GH replacement has been demonstrated to further increase insulin resistance over a period of 1–6 weeks of therapy, but although hyperinsulinemia persists, carbohydrate metabolism returns to baseline after 3 months of GH treatment.

D. Lipid and lipoprotein metabolism

1. Plasma lipid and lipoprotein profile in adult GH deficiency. The findings from studies comparing plasma lipids and lipoproteins in GH-deficient adults with those in age-matched healthy controls are summarized in Table 6. Elevated concentrations of total cholesterol (TC), low density lipoprotein cholesterol (LDL-C), and apolipoprotein B (ApoB) have been observed in a substantial proportion of patients compared with those in age- and sex-matched controls or with the predicted range (33, 111, 112). HDL-C levels tend to be low (33, 76, 112) and TG levels high compared with those in healthy controls (76, 79, 112). Thus, GH deficiency appears to be associated with a lipid profile known to be related to premature atherosclerosis and cardiovascular disease.

i. Double blind, placebo-controlled trials The results of seven studies are reported (Table 7) (6, 14, 33, 112, 113, 114, 115, 116). The duration of GH therapy in these studies was at least 2 months, and in most cases it was 6 months. The dose of GH in these trials was 0.25 IU/kg·week (12.5 µg/kg·day), with the exception of the first study (6), in which the patients were treated with 0.5 IU/kg·week (25 µg/kg·day).

ii. Open trials lasting more than 12 months There are four open trials lasting more than a year (26, 33, 117, 118, 119). The results of these studies have shown that the favorable effects of GH replacement on the plasma lipid and lipoprotein profile are sustained up to 4 yr after commencement of GH. It appears that the observed decrease in TC concentration is followed by an increase in HDL-C, a finding that occurs similarly in the GH deficiency of both AO and CO (24, 26, 33).

iii. Lipoprotein(a) [Lp(a)] The only exception to the trend of normalization of cardiovascular risk factors after GH treatment is Lp(a), a proposed independent risk factor for the development of atherosclerosis and myocardial infarction (120, 121). Lp(a) levels rose in five of six studies (26, 113, 116, 118, 122) and did not change in only one study (114). The importance of this observation is not yet clear.

3. Proposed mechanism of action of GH on lipid and lipoprotein metabolism. GH directly stimulates the liberation of free fatty acids within the first weeks of treatment (102, 123). Free fatty acids can be oxidized in the peripheral tissues or taken up by the liver and reesterified into triglycerides (124).

In hypophysectomized rats, GH appears to stimulate very low density lipoprotein (VLDL) secretion in parallel with a stimulation of the editing of ApoB₄₈, leading to a increased clearance of VLDL because of the shorter half-life of VLDL-ApoB₄₈ compared with that of VLDL-ApoB₁₀₀ (125). Consequently, a decreasing fraction of VLDL is converted into LDL, resulting in a decreased synthetic rate of LDL.

LDL-C clearance is regulated by the availability of hepatic LDL receptors. Studies in rats and humans (126) have shown that the administration of GH leads to up-regulation of hepatic LDL receptor and therefore to increased clearance of LDL-C (124). A stable isotope study in eight hyperlipidemic GH-deficient patients demonstrated an increased rate of VLDL-ApoB secretion and a decreased VLDL MCR compared with those of age-, sex-, and body mass index-matched controls (127).

These studies confirm that GH is involved in the regulation of hepatic lipoprotein metabolism and may therefore influence the lipid and lipoprotein profile seen in patients with AO GH deficiency. It is too soon to understand fully the complex action of GH on lipid metabolism; however, the major effects of GH replacement include a reduction in LDL-C and an increase in the circulating concentration of Lp(a). Long term observation will be required to determine whether GH replacement results in a regression of premature atherosclerosis and a reduction in cardiovascular morbidity and mortality of adults with GH deficiency.

	VIII. Skin

Top Abstract I. Introduction II. Body Composition III. Bone Mineral Density... IV. Muscle Strength V. Exercise Performance VI. Cardiovascular System VII. Metabolism VIII. Skin IX. Immune Function X. Psychological Well-Being and... XI. Reported Adverse Effects... XII. Concluding Remarks References

 
Skin thickness and total skin collagen are reduced in hypopituitary adults despite conventional replacement therapy, and the converse is true in acromegaly (128). An increase in skin thickness was demonstrated after GH treatment in normal elderly males selected on the basis of low IGF-I levels (129). Hypopituitary adults are usually described as having dry and thin skin, whereas excessive sweating is a typical feature of acromegaly, and eccrine sweat glands have been shown to possess GH receptors (130). The sweat secretion rate measured in response to pilocarpine iontophoresis was significantly lower in GH-deficient adults than in age- and sex-matched control subjects, and during GH treatment, it increased sufficiently to be perceived by the patients (131). More recently, GH-deficient adults have been shown to have an impaired ability to dissipate heat by sweating after heat stress or exercise (132), and this may be an important contributory factor to their reduced exercise capacity.

	IX. Immune Function

Top Abstract I. Introduction II. Body Composition III. Bone Mineral Density... IV. Muscle Strength V. Exercise Performance VI. Cardiovascular System VII. Metabolism VIII. Skin IX. Immune Function X. Psychological Well-Being and... XI. Reported Adverse Effects... XII. Concluding Remarks References

 
Human peripheral blood T cells, B cells, natural killer (NK) cells, and monocytes express IGF-I receptors. Animal studies suggest a role for IGF-I, and therefore GH, in the modulation of both cell-mediated and humoral immunity. Administration of either GH of IGF-I can reverse the characteristic immunodeficiency of Snell dwarf mice (133, 134).

Human adults with GH deficiency do not usually have compromised immunocompetence. Evidence suggests that GH therapy does not have significant effects on either T or B cell function (135, 136, 137). Hypophysectomized mice display decreased NK cell activity (138), and an improvement in NK cell function has been observed with GH replacement (139). Whether similar effects occur in humans is not known.

	X. Psychological Well-Being and Quality of Life (QoL)

Top Abstract I. Introduction II. Body Composition III. Bone Mineral Density... IV. Muscle Strength V. Exercise Performance VI. Cardiovascular System VII. Metabolism VIII. Skin IX. Immune Function X. Psychological Well-Being and... XI. Reported Adverse Effects... XII. Concluding Remarks References

 
The psychological well-being and QoL of GH-deficient patients and the effects of GH replacement have received considerable attention in recent years. In most studies, self-perceived well-being and QoL have been assessed using validated questionnaires, and comparisons have been made with controls of matched age, sex, and socio-economic status.

Decreased psychological well-being has been reported in hypopituitary adults despite replacement of all hormone deficiencies with the exception of GH (140). Using the Nottingham Health Profile (NHP), Rosen et al. (141) compared psychological well-being in 86 adults with GH deficiency with that in 86 age-matched controls. In this study the GH-deficient patients reported less energy, greater emotional lability, more difficulties with sexual relationships, and a greater sense of social isolation than the control subjects. Stabler et al. (140) evaluated psychosocial adjustment in adults with GH deficiency and in age-, sex-, socio-economic statys-, and height-matched controls. Those with multiple pituitary hormone deficiencies showed less openness and less assertiveness compared with controls.

In a double blind, placebo-controlled study, McGauley et al. (142) were the first to demonstrate that GH replacement (0.5 IU/kg·week; 12.5 µg/kg·day) was associated with an improvement in mood and energy levels in GH-deficient adults. In this study three instruments that assess general health and well-being, the NHP, the Psychological and General Well-Being Schedule (PGWB), and the General Health Questionnaire, all showed significant improvements in subjective well-being and QoL after 6 months of GH replacement. This study was performed without knowledge or expectation of the psychological effects of GH therapy, issues that may be relevant in the interpretation of subsequent studies.

Whitehead et al. (14) examined the effects of GH replacement (0.25 IU/kg·week; 12.5 µg/kg·day) on well-being of 14 adults with GH deficiency in a 6-month, double blind, placebo-controlled, cross-over trial using the NHP and the PGWB. No significant changes in psychological well-being were observed, but many patients failed to demonstrate a significant increase in IGF-I, indicating that noncompliance with GH may have accounted for these findings. Using 2 QoL-rating scales [Comprehensive Psychological Rating Scale (CPRS) and Symptom Checklist-90], Bengtsson et al. (12) examined the effects of 6-month GH replacement (0.25 IU/kg·week; 12.5 µg/kg·day) in 26 adults with GH deficiency in a double-blind, placebo-controlled, cross-over study. GH treatment was associated with a significant improvement in the CPRS, but not in the Symptom Checklist-90. Using the CPRS and General Health Questionnaire-90, Beshyah et al. (29) examined the effects of GH replacement (0.18–0.35 IU/kg·week; 9–17.5 µg/kg·day) on 40 adults in a randomized controlled trial. The initial 6 months were randomized, but thereafter, patients continuing on GH replacement were followed for 18 months. Those initially randomized to placebo reported greater morbidity at baseline, and placebo was associated with a significant improvement in CPRS compared with GH after 6 months of therapy. Compared to the baseline score, patients receiving GH reported an improved CPRS score after 6 and 12, but not 18, months of therapy.

Burman et al. (143) examined psychological capacity and sense of well-being using the Hopkins Symptoms Check List (HSCL), the NHP, and the PGWB in 36 adults with GH deficiency and 36 matched controls. Those with GH deficiency reported a lower QoL, as assessed by the HSCL and NHP. The severity of their distress correlated positively with the duration of GH deficiency. Twenty-one of the patients entered a cross-over, double blind, placebo-controlled study of the effects of GH replacement (0.25 IU/kg·week; 12.5 µg/kg·day) on these measures. The HSCL score improved during the placebo phase, but fell further during active treatment. Active treatment was associated with improvement in the energy and emotional subsections of the NHP. In addition, spouses of the patients reported improved mood and behavior in the subjects during the GH treatment phase.

An uncontrolled study with a small sample size suggested that GH replacement may result in improved memory in adults with GH deficiency (144). The direct mechanism behind alterations in perceived QoL remain unknown. Recently, GH treatment of GH-deficient adults has been shown to alter levels of vasoactive intestinal polypeptide and the dopamine metabolite, homovanillic acid, as well as elevate ß-endorphin levels in cerebrospinal fluid, but whether these changes are responsible for improvements in mood and well-being is not yet known (145). GH, IGF-I, and the IGF-binding proteins may have direct effects on the nervous system. In addition, abnormal sleep patterns have been described in GH-deficient adults, with a restoration to normal patterns after GH replacement (146, 147).

The interpretation of more recent studies of the psychological effects of GH replacement must be made with caution, as maintaining a true double blind protocol is difficult. Patients and physicians may associate common side-effects, such as fluid retention and arthralgia, with active treatment, resulting in biased reporting. In addition, GH-deficient adults who wish to enter a trial of GH therapy may be the patients with the most severe psychological distress, and any interpretation of studies of the psychological effects of GH replacement must allow for this observation (148).

In summary, adults with GH deficiency report reduced psychological well-being and QoL compared with matched healthy controls. Trials of the effects of GH replacement have demonstrated improvements in psychological well-being and QoL.

	XI. Reported Adverse Effects of GH Replacement

Top Abstract I. Introduction II. Body Composition III. Bone Mineral Density... IV. Muscle Strength V. Exercise Performance VI. Cardiovascular System VII. Metabolism VIII. Skin IX. Immune Function X. Psychological Well-Being and... XI. Reported Adverse Effects... XII. Concluding Remarks References

 
As recombinant GH has exact sequence homology with natural human GH, side-effects result from excess replacement alone. The GH replacement dose used in early trials (12, 6, 7, 14, 15, 67) was based on those used for the treatment of GH-deficient children (0.5 IU/kg·week; 25 µg/kg·day). In these trials, clinically relevant adverse effects resulted in a dose reduction in up to 40% of patients. In addition, circulating IGF-I levels were excessively high in a similar number of patients, suggesting that this replacement dose was supraphysiological. Consequently, more recent studies (16, 21, 27, 39, 54) have employed smaller doses of GH.

Evidence suggests that those patients most at risk from adverse effects of GH replacement are older and more obese, with a greater GH response on provocative testing, and the largest IGF-I rise after GH treatment (149). The most common side-effects after GH treatment in GH-deficient adults are those arising from sodium and water retention. Weight gain, dependent edema, a sensation of tightness in the hands, or symptoms of carpal tunnel compression frequently occur within days or weeks. A study of GH replacement in 233 hypopituitary adults, with GH doses ranging from 0.08–0.3 IU/kg·week (4–15 µg/kg·day) resulted in fluid retention (37.4%), arthralgia (19.1%), and muscle pains (15.7%) in the first 6 months of treatment (150). These symptoms resolve rapidly with dose reduction or occasionally disappear over several weeks without any action. Blood pressure has not changed significantly after up to 3 yr of GH treatment (85). Arthralgias involving small or large joints occur in some patients during GH treatment, but there is usually no evidence of effusion or inflammation, and x-rays have shown no abnormality (6). These changes also settle with dose reduction and are possibly due to swelling of articular cartilage, although the precise mechanism remains unknown. Myopathy and arthralgia commonly occur in acromegaly, and it is likely that these symptoms arise from GH excess (151, 152, 153, 154).

Little information is available regarding the effect of GH treatment on tumor development and recurrence in adults with GH deficiency. Data from long term studies in children with both solid tumors and hematological malignancies suggest that there is no increased risk of recurrence associated with GH therapy (155, 156, 157, 158).

GH therapy is recognized to result in hyperinsulinemia (159), which may increase the risk of cardiovascular complications (160), as can elevated serum Lp(a) (121). GH-induced hypertension (6) and atrial fibrillation (12) have been reported, but are rare occurrences. There have been isolated reports of cerebral side-effects in the form of encephalocele (6) and headache with tinnitus (12). Benign intracranial hypertension (BIH) has also been reported in association with GH therapy (161). The majority of affected patients are children, and the BIH has improved with cessation of therapy. Papilloedema was present in the majority of cases. IGF-I has also been reported to cause BIH and papilloedema (161). Cessation of IGF-I therapy has resulted in regression in all reported cases (161). Gynecomastia has been reported as a rare occurrence in elderly men (162).

	XII. Concluding Remarks

Top Abstract I. Introduction II. Body Composition III. Bone Mineral Density... IV. Muscle Strength V. Exercise Performance VI. Cardiovascular System VII. Metabolism VIII. Skin IX. Immune Function X. Psychological Well-Being and... XI. Reported Adverse Effects... XII. Concluding Remarks References

 
The importance of GH throughout adult life is now unequivocally accepted. GH deficiency is recognized to result in alterations in body composition, physical performance, psychological well-being, and substrate metabolism. Many of these alterations can be improved or corrected with GH replacement. It is likely that GH replacement will in the near future become as routine as steroid, thyroid hormone, and sex hormone replacement in management of the hypopituitary adult. The major restriction to the widespread use of GH is cost. It is expected that once the pharmaceutical industry has recovered its developmental expenditure, the cost of GH will decrease.

The prospect of GH replacement becoming routine, however, does raise a number of issues. The most fundamental of these relates to the selection criteria of patients who may benefit from GH therapy. Most of the studies to date have focused on those with absent or profoundly reduced GH secretion. The effect of GH replacement on those with partial GH deficiency has not been addressed. The selection of patients is further complicated by the marked age-associated decline in GH secretion (163, 164). Many elderly patients would meet diagnostic criteria for GH deficiency, and whether such patients would benefit from GH therapy is unknown. In addition, GH secretion is higher in females than in aged-matched males (165), and increasing BMI is associated with a decline in GH secretion (165). Current practice focuses on those patients in whom GH deficiency is present without doubt, and in whom GH replacement has been shown to be of benefit.

The optimal dose of GH replacement for the GH-deficient adult has been the subject of discussion. Early studies employed GH doses that produced IGF-I concentrations in excess of the age-matched normal range and unacceptably high rates of adverse effects (6, 7, 12, 14, 15, 67). As a result, lower doses have been used in more recent studies, which have been better tolerated (16, 21, 27, 39, 54). The choice of replacement therapy has been further complicated by a recent study that demonstrated a marked individual variability in biochemical and body composition responses to GH replacement (165). In this study, men had a greater body composition response to GH therapy than women, and younger patients with low levels of GH-binding protein had the greatest responses.

In the majority of studies, the effect of GH replacement has been rigorously assessed over 6- or 12-month periods. The longer term effects have not been fully addressed, and it remains to be seen whether GH treatment will reduce the incidence of cardiovascular and bone disease over a period of years. There is a need for prospective clinical studies to further guide the duration of GH replacement.

The prospect of life-long GH replacement for many GH-deficient adults means that resources and facilities for long term monitoring must be present. Such monitoring will provide further information regarding the long term issues of GH treatment, such as tumor development, but also determine whether GH replacement is associated with an increase in life expectancy for the GH-deficient adult.

	Acknowledgments

 
This review details the available evidence relating to the consequences of GH deficiency and the effects of GH replacement in the GH-deficient adult. Particular emphasis is made on controlled studies that have been fully reported after peer review. To provide the most current evidence, references are included from abstracts presented at the 1996 meeting of the GRS (London, UK). These are highlighted by an asterisk.

Received July 25, 1997.

Accepted October 15, 1997.

	References

Top Abstract I. Introduction II. Body Composition III. Bone Mineral Density... IV. Muscle Strength V. Exercise Performance VI. Cardiovascular System VII. Metabolism VIII. Skin IX. Immune Function X. Psychological Well-Being and... XI. Reported Adverse Effects... XII. Concluding Remarks References

 

1. Sönksen PH. 1990 Replacement therapy in hypothalamo-pituitary insufficiency after childhood: management in the adult. Horm Res. 33(Suppl 4):45–51.
2. Rosen T, Bengtsson B-Å.1990 Premature mortality due to cardiovascular disease in hypopituitarism. Lancet. 336:285–288.
3. Raben MS. 1962 Clinical use of human growth hormone. N Engl J Med. 266:82–86.
4. Bates AS, Van’t Hoff W, Jones PJ, Clayton RN. 1996 The effect of hyopituitarism on life expectancy. J Clin Endocrinol Metab. 81:1169–1172.[Abstract]
5. Shahi M, Beshyah SA, Hackett D, Sharp PS, Johnston DG, Foale RA. 1992 Myocardial dysfunction in treated adult hypopituitarism: a possible explanation for increased cardiovascular mortality. Br Heart J 67:92–96.
6. Salomon F, Cuneo RD, Hesp R, Sönksen PH. 1989 The effects of treatment with recombinant human growth hormone on body composition and metabolism in adults with growth hormone deficiency. N Engl J Med. 321:1797–1803.[Abstract]
7. Jorgensen JOL, Pedersen SA, Thuesen L, et al. 1989 Beneficial effects of growth hormone treatment in GH-deficient adults. Lancet. 1:1221–1225.[Medline]
8. Davidson MB. 1987 Effect of growth hormone on carbohydrate and lipid metabolism. Endocr Rev. 8:115–131.[Abstract/Free Full Text]
9. Press M. 1988 Growth hormone and metabolism. Diabetes Metab Rev. 4:391–414.[Medline]
10. Ikkos D, Luft R, Gemzell CA. 1959 The effect of human growth hormone in man. Acta Endocrinol (Copenh). 32:341–361.[Medline]
11. De Boer H, Blok GJ, van der Veen VA. 1995 Clinical aspects of growth hormone deficiency in adults. Endocr Rev. 16:63–86.[Abstract/Free Full Text]
12. Bengtsson BA, Eden S, Lonn L, et al. 1993 Treatment of adults with growth hormone deficiency with recombinant human GH. J Clin Endocrinol Metab. 76:309–317.[Abstract]
13. Snel YE, Doerga ME, Brummer RM, Zelissen PM, Koppeschaar HP. 1995 Magnetic resonance imaging-assessed adipose tissue and serum lipid and insulin concentrations in growth hormone-deficient adults. Effect of growth hormone replacement. Arterioscler Thromb Vasc Biol. 15:1543–1548.[Abstract/Free Full Text]
14. Whitehead HM, Boreham C, McIlrath EM, et al. 1992 Growth hormone treatment of adults with growth hormone deficiency: results of a 13-month placebo controlled cross-over study. Clin Endocrinol (Oxf). 36:45–52.[Medline]
15. Binnerts A, Swart GR, Wilson JHP, et al. 1992 The effect of growth hormone administration in growth hormone deficient daults on bone, protein, carbohydrate and lipid homeostasis, as well as body composition. Clin Endocrinol (Oxf). 37:79–87.[Medline]
16. Chong PKK, Jung RT, Scrimgeour CM, Rennie MJ, Paterson CR. 1994 Energy expenditure and body composition in growth hormone deficient adults on exogenous growth hormone. Clin Endocrinol (Oxf). 40:103–110.[Medline]
17. Snel YE, Doerga ME, Brummer RJ, Zelissen PM, Zonderland ML, Koppeschaar HP. 1995 Resting metabolic rate, body composition and related hormonal parameters in growth hormone-deficient adults before and after growth hormone replacement therapy. Eur J Endocrinol. 133:445–450.[Abstract/Free Full Text]
18. Hoffman DM, O’Sullivan AJ, Freund J, Ho KK. 1995 Adults with growth hormone deficiency have abnormal body composition but normal energy metabolism. J Clin Endocrinol Metab. 80:72–77.[Abstract]
19. Beshyah SA, Freemantle C, Thomas E, et al. 1995 Abnormal body composition and reduced bone mass in growth hormone deficient hypopituitary adults. Clin Endocrinol (Oxf). 42:179–189.[Medline]
20. Rosen T, Bosaeus I, Tolli J, Lindstedt G, Bengtsson BA. 1993 Increased body fat mass and decreased extracellular fluid volume in adults with growth hormone deficiency. Clin Endocrinol (Oxf). 38:63–71.[Medline]
21. Amato G, Carella C, Fazio S, et al. 1993 Body composition, bone metabolism, and heart structure and function in growth hormone-deficient adults before and after GH replacement therapy at low doses. J Clin Endocrinol Metab. 77:1671–1676.[Abstract]
22. De Boer H, Blok GJ, Voerman HJ, De Vries PM, van der Veen EA. 1992 Body composition in adult growth deficient men assessed by anthropometry and bioimpedance analysis. Clin Endocrinol Metab. 75:833–837.
23. De Boer H, Blok GJ, Voerman B, de Vries P, Popp-Snijders C, van der Veen E. 1995 The optimal growth hormone replacement dose in adults, derived from bioimpedance analysis. J Clin Endocrinol Metab. 80:2069–2076.[Abstract]
24. Moller J, Frandsen E, Fisker S, Jorgensen JOL, Christiansen JS. 1996 Decreased plasma and extracellular volume in growth hormone-deficient adults and the acute and prolonged effects of GH administration: a controlled experimental study. Clin Endocrinol (Oxf). 44:533–539.[CrossRef][Medline]
25. Christ ER, Cummings MH, Pearson TC, Sönksen PH, Russell-Jones DL. 1997 Effects of growth hormone deficiency on plasma volume and red cell mass. Endocrinol Metab. 4(Suppl)A:60.
26. Johansson G, Rosen T, Lindstedt G, Bosaeus I, Bengtsson BA. 1996 Effect of 2 years of growth hormone treatment on body composition and cardiovascular risk factors in adults with growth hormone deficiency. Endocrinol Metab. 4(Suppl A):3–12.
27. Orme SM, Sebastian JP, Oldroyd B, et al. 1992 Comparison of measures of body composition in a trial of low dose growth hormone replacement therapy. Clin Endocrinol (Oxf). 37:453–59.[Medline]
28. Jorgensen JOL, Thuesen L, Muller J, et al. 1994 Three years of growth hormone treatment in growth hormone-deficient adults: near normalization of body composition and physical performance. Eur J Endocrinol. 130:224–28.[Abstract/Free Full Text]
29. Beshyah SA, Freemantle C, Shahi M, et al. 1995 Replacement therapy with biosynthestic human growth hormone in growth hormone-deficient hypopituitary adults. Clin Endocrinol (Oxf). 42:73–81.[Medline]
30. Lonn L, Johansson G, Sjostrom L, Kvist H, Oden A, Bengtsson BA. 1996 Body composition and tissue distributions in growth hormone deficient adults before and after growth hormone treatment. Obes Res. 4:45–54.[Medline]
31. Hansen TB, Vahl N, Jorgensen JO, Christiansen JS, Hagen C. 1995 Whole body and regional soft tissue changes in growth hormone deficient adults after one year of growth hormone treatment: a double-blind, randomized, placebo-controlled study. Clin Endocrinol. 43:689–696.[Medline]
32. Baum HB, Biller BM, Finkelstein JS, et al. 1996 Effects of physiologic growth hormone therapy on bone density and body composition in patients with adult-onset of growth hormone deficiency. A randomized, placebo-controlled trial. Ann Intern Med. 125:883–890.[Abstract/Free Full Text]
33. Attanasio AF, Lamberts SWJ, Matranga AMC, et al. 1997 Adult growth hormone-deficient patients demonstrate heterogenity between childhood onset and adult onset before and during human GH treatment. J Clin Endocrinol Metab. 82:82–88.[Abstract/Free Full Text]
34. Herlitz H, Jonsson O, Bengtsson BA. 1994 Effect of recombinant human growth hormone on cellular sodium metabolism. Clin Sci. 86:233–237.[Medline]
35. Christ E, Cummings MH, Westwood NB, et al. The importance of growth hormone in the regulation of erythropoiesis, red cell mass, and plasma volume in adults with growth hormone deficiency. J Clin Endocrinol Metab. In press.
36. Hoffman DM, Crampton L, Sernia C, Nguyen TV, Ho KKY. 1996 Short term growth hormone (GH) treatment of GH-deficient adults increases body sodium and extracellular water, but not blood pressure. J Clin Endocrinol Metab. 81:1123–1128.[Abstract]
37. Wüster CHR, Slenczka E, Ziegler R. 1991 Increased prevalence of osteoporosis and arteriosclerosis in patients with conventionally substituted pituitary insufficiency: is there a need for additional growth hormone substitution? Klin Wochenschr. 69:769–773.[CrossRef][Medline]
38. Rosen T, Wilhelmsen L, Landin-Wilhelmsen K, et al. 1996 Increased fracture rate in adults with growth hormone deficiency. Endocrinol Metab. 3(Suppl A):121.
39. O’Halloran DJ, Tsatsoulis A, Whitehouse RW, Holmes SJ, Adams JE, Shalet SM. 1993 Increased bone density after recombinant human growth hormone therapy in adults with isolated GH deficiency. J Clin Endocrinol Metab. 76:1344–1348.[Abstract]
40. Kaufman JM, Taelman P, Vermeulen A, Vandeweghe M. 1992 Bone mineral status in growth hormone-deficient males with isolated and multiple pituitary insuficiencies of childhood onset. J Clin Endocrinol Metab. 74:118–123.[Abstract]
41. Hyer SL, Rodin DA, Tobias JH, Leiper A, Nussey SS. 1992 Growth hormone deficiency during puberty reduces adult bone mineral density. Arch Dis Child. 67:1472–1474.[Abstract/Free Full Text]
42. De Boer H, Blok GJ, Van Lingen A, Teule GJJ, Lips P, Van Der Veen EA. 1994 Consequences of of childhood-onset growth hormone deficiency for adult bone mass. J Bone Miner Res. 9:1319–1326.[Medline]
43. Johannsson AG, Burman P, Westermark K, Ljunghall S. 1992 The bone mineral density in acquired growth hormone deficiency correlates with circulating insulin-like growth factor. J Intern Med. 232:447–452.[Medline]
44. Bing-You RG, Denis MC, Rosen CJ. 1993 Low bone mineral density in adults with previous hypothalamic-pituitary tumors; correlation with GH responses to GHRH, IGF-I and IGFBP-3. Calcif Tissue Int. 52:183–187.[CrossRef][Medline]
45. Holmes SJ, Economou G, Whitehouse RW, Adams JE, Shalet SM. 1994 Reduced bone mineral density in patients with adult onset growth hormone deficiency. J Clin Endocrinol Metab. 78:669–674.[Abstract]
46. Rosen T, Hansson T, Granhed H, Szucs J, Bengtsson BA. 1995 Reduced bone mineral content in adult patients with growth hormone deficiency. Eur J Endocrinol. 132:727–729.[Abstract/Free Full Text]
47. Thoren M, Soop M, Degerblad M, Saaf M. 1993 Preliminary study of the effects of growth hormone substitution therapy on bone mineral density and serum osteocalcin levels in adult growth hormone deficiency. Acta Endocrinol (Copenh). 128(Suppl 2):41–43.
48. Degerblad M, Bengtsson BA, Bramnert M, et al. 1995 Reduced bone mineral density in adults with growth hormone deficiency: increased bone turnover during 12 months of GH substitution. Eur J Endocrinol. 133:180–188.[Abstract/Free Full Text]
49. Nielsen HK, Jorgensen JOL, Brixen K, Christiansen JS. 1991 Serum osteocalcin and bone isoenzyme alkaline phosphatase in growth hormone-deficient patients: dose-response studies with biosynthetic human GH. Calcif Tissue Int. 46:82–87.
50. Johannsen JS, Pedersen SA, Jorgensen JOL, et al. 1990 Effects of growth hormone on bone Gla protein in GH-deficient adults. J Clin Endocrinol Metab. 70:916–919.[Abstract/Free Full Text]
51. Schlemmer A, Johannsen JS, Pedersen SA, Jorgensen JOL, Hassager C, Christiansen C. 1991 The effect of growth hormone therapy on urinary pyridinoline cross-links in GH-deficient adults. Clin Endocrinol (Oxf). 35:471–476.[Medline]
52. Sartorio A, Conti A, Monzani M, Morabito F, Faglia G. 1993 Growth hormone treatment in adults with GH deficiency: effects on new biochemical markers of bone and collagen turnover. J Endocrinol Invest. 16:893–898.[Medline]
53. Bravenoer N, Lips P, Holzmann P, Blok GJ. 1994 The effect of growth hormone on bone mass and bone turnover of growth hormone deficient men [Abstract B253]. J Bone Miner Res. 9(Suppl 1):9.
54. Vandeweghe M, Taelman P, Kaufman JM. 1993 Short and long-term effects of growth hormone treatment on bone turnover and bone mineral content in adult growth hormone-deficient males. Clin Endocrinol (Oxf). 39:409–415.[Medline]
55. Kann P, Piepkorn B, Schehler B, et al. 1995 Replacement therapy with recombinant human growth hormone in GH-deficient adults. Effects on bone metabolism and bone mineral density in a 2-year prospective study. Endocrinol Metab. 2(Suppl B):103–110.
56. Beshyah SA, Thomas E, Kyd P, Sharp P, Fairney A, Johnston DG. 1994 The effect of growth hormone replacement therapy in hypopituitary adults on calcium and bone metabolism. Clin Endocrinol (Oxf). 40:383–391.[Medline]
57. Beshyah SA, Kyd P, Thomas E, Fairney A, Johnston DG. 1995 The effects of prolonged growth hormone replacement on bone metabolism and bone mineral density in hypopituitary adults. Clin Endocrinol (Oxf). 42:249–254.[Medline]
58. Hansen TB, Brixen K, Vahl N, et al. 1996 Effects of 12 months of growth hormone (GH) treatment on calciotropic hormones, calcium homeostasis, and bone metabolism in adults with acquired GH deficiency: a double blind, randomized, placebo-controlled study. J Clin Endocrinol Metab. 81:3352–3359.[Abstract]
59. Holmes SJ, Whitehouse RW, Swindell R, Economou G, Adams JE, Shalet SM. 1995 Effect of growth hormone replacement on bone mass in adults with adult-onset growth hormone deficiency. Clin Endocrinol (Oxf). 42:627–633.[Medline]
60. Ter Maaten JC, De Boer H, Roos JC, Lips P, Van der Veen EA. 1997 Long-term effects of growth hormone treatment on bone density [Abstract O-003]. Endocrinol Metab. 4(Suppl A):8.
61. Rosen T, Johannsson G, Bengtsson BA. 1997 Three years of GH treatment in GH-deficient adults increases bone mineral content and density: gender differences [AbstractP-002]. Endocrinol Metab. 4(Suppl A):36.
62. Johannsson G, Rosen T, Bosaeus I, Sjostrom L, Bengtsson BA. 1996 Two years of growth hormone (GH) treatment increases bone mineral content and density in hypopituitary patients with adult-onset GH deficiency. J Clin Endocrinol Metab. 81:2865–2873.[Abstract/Free Full Text]
63. Bravenboer N, Holzmann P, De Boer H, Lips P. 1997 The effect of growth hormone treatment on bone remodeling in GH-deficient men. Endocrinol Metab. 4(Suppl A):8.
64. Cuneo RC, Salomon F, Wiles CM, et al. 1990 Skeletal muscle performance in adults with growth hormone deficiency. Horm Res. 33(Suppl 4):55–60.
65. Rutherford OM, Beshyah SA, Johnston DG. 1994 Quadriceps strength before and after growth hormone replacement in hypopituitary adults: relationship to changes in lean body mass and IGF-I. Endocrinol Metab. 1:41–47.
66. Cuneo RC, Salomon F, Wiles CM, et al. 1991 Growth hormone treatment in growth hormone-deficient adults. I. effects on muscle mass and strength. J Appl Physiol. 70:688–694.[Abstract/Free Full Text]
67. Degerblad M, Almkvist O, Grunditz R, et al. 1990 Physical and psychological capabilities during substitution therapy with recombinant growth hormone in adults with growth hormone deficiency. Acta Endocrinol (Copenh). 123:185–913.[Abstract/Free Full Text]
68. Jorgensen JOL, Pedersen SA, Thuesen L, et al. 1991 Long-term growth hormone treatment in growth hormone deficient adults. Acta Endocrinol (Copenh). 125:449–453.[Medline]
69. Cuneo RC, Salomon F, Wiles CM, et al. 1991 Growth hormone treatment in growth hormone-deficient adults. II. Effects on exercise performance. J Appl Physiol. 70:695–700.[Abstract/Free Full Text]
70. Nass R, Huber RM, Klauss V, Muller OA, Schopohl J, Strasburger CJ. 1995 Effect of growth hormone (hGH) replacement therapy on physical work capacity and cardiac and pulmonary function in patients with hGH deficiency acquired in adulthood. J Clin Endocrinol Metab. 80:552–557.[Abstract]
71. Wasserman K, Whipp BJ. 1975 Exercise physiology in health and disease. Am Rev Respir Dis. 112:219–249.[Medline]
72. Jepson JH, McGary EE. 1972 Hemopoiesis in pituitary dwarfs treated with human growth hormone and testosterone. Blood 39:238–248.
73. Claustres M, Chatelain P, Sultan C. 1987 Insulin-like growth factor-I stimulates human erythroid colony formation. in vitro. J Clin Endocrinol Metab. 65:78–82.[Abstract/Free Full Text]
74. Merchav S, Tatarsky I, Hochberg Z. 1988 Enhancement of erythropoises in vitro by human growth hormone is mediated by insulin-like growth factor-I. Br J Haematol. 70:267–271.[Medline]
75. Erfurth EM, Buelow B, Mikozy Z, Nordstroem CH, Hagmar L. 1996 Increased cardiovascular mortality in patients with hypopituitarism. Endocrinol Metab. 3(Suppl A):121.
76. Rosen T, Eden S, Larson G, Wilhelmsen L, Bengtsson B-Å. 1993 Cardiovascular risk factors in adult patients with growth hormone deficiency. Acta Endocrinol (Copenh). 129:195–200.[Medline]
77. Markussis V, Beshyah SA, Fisher C, Sharp P, Nicolaides AN, Johnston DG. 1992 Detection of premature atherosclerosis by high-resolution ultrasonography in symptom-free hypopituitary adults. Lancet. 340:1188–1192.[CrossRef][Medline]
78. Lehmann ED, Hopkins KD, Weissberger AJ, Gosling RG, Sönksen PH. 1993 Aortic distensibility in growth hormone deficient adults. Lancet. 341:309.[CrossRef][Medline]
79. Johansson JO, Landin K, Tengborn L, Rosen T, Bengtsson B-Å. 1994 High fibrinogen and plasminogen activator inhibitor activity in growth hormone-deficient adults. Arterioscler Thromb. 14:434–437.[Abstract/Free Full Text]
80. Frustaci A, Perrone GA, Gentiloni N, et al. 1992 Reversible dilated cardiomyopathy due to growth hormone deficiency. Am J Clin Path. 97:503–511.[Medline]
81. Cuneo RC, Wilmshurst P, Lowy C, et al. 1989 Cardiac failure responding to growth hormone. Lancet. 1:838–39.[CrossRef][Medline]
82. Cuneo RC, Salomon F, Wilmshurst P, et al. 1991 Cardiovascular effects of growth hormone treatment in growth hormone-deficient adults: stimulation of the renin-aldosterone system. Clin Sci. 81:587–592.[Medline]
83. Merola B, Cittadini A, Colao A, et al. 1993 Cardiac structural and functional abnormalities in adult patients with growth hormone deficiency. J Clin Endocrinol Metab. 77:1658–1661.[Abstract]
84. Caidahl K, Edén S, Bengtsson B-Å. 1994 Cardiovascular, and renal effects of growth hormone. Clin Endocrinol (Oxf). 40:393–400.[Medline]
85. Thuesen L, Jorgensen JOL, Muller JR, et al. 1994 Short and long-term cardiovascular effect of growth hormone therapy in growth hormone deficient adults. Clin Endocrinol (Oxf). 41:615–620.[Medline]
86. Johannsson G, Bengtsson BA, Andersson B, Isgaard J, Caidahl K. 1996 Long term cardiovascular effects of growth hormone treatment in GH-deficient adults. Preliminary data in a small group of patients. Clin Endocrinol (Oxf). 45:305–314.[CrossRef][Medline]
87. Cuocolo A, Nicolai E, Colao A, et al. 1996 Improved left ventricular function after growth hormone replacement in patients with hypopituitarism: assessment with radionuclide angiography. Eur J Nucl Med. 23:390–394.[CrossRef][Medline]
88. Dunne FP, Elliot P, Gammoge MD, et al. 1995 Cardiovascular function and glucocorticoid replacement in patients with hypopituitarism. Clin Endocrinol (Oxf). 43:623–629.[Medline]
89. Smallridge RC, Rajfer S, Davia J, Schaaf M. 1979 Acromegaly and the heart. Am J Med. 66:22–27.[CrossRef][Medline]
90. Hradec J, Marek J, Petrasek J. 1988 The nature of cardiac hypertrophy in acromegaly: an echocardiographic study. Cor Vasa30 :186–199.
91. Morvan D, Komajda M, Grimaldi A, Turpin G, Grosgogeat Y. 1991 Cardiac hypertrophy and function in asymptomatic acromegaly. Eur Heart J. 12:666–672.
92. Wright AD, Hill DM, Lowy C, Fraser TR. 1970 Mortality in acromegaly. Q J Med. 39:1–16.[Abstract/Free Full Text]
93. Bengtsson B-Å, Eden S, Ernest I, Oden A, Sjögren B. 1988 Epidemiology and long-term survival in acromegaly. Acta Med Scand. 223:327–335.[Medline]
94. Cunningham JJ. 1980 A reanalysis of the factors influencing basal metabolic rate in normal adults. Am J Clin Nutr. 33:2372–2374.[Abstract/Free Full Text]
95. Ikkos D, Ljunggren H, Luft R. 1956 Basal metabolic rate in relation to body size and cell mass in acromegaly. Acta Endocrinol (Copenh). 21:237–244.[Abstract/Free Full Text]
96. O Sullivan AJ, Kelly JJ, Hoffman DM, Freund J, Ho KKY. 1994 Body composition and energy expenditure in acromegaly. J Clin Endocrinol Metab. 78:381–386.[Abstract]
97. Salomon F, Cuneo RC, Umpleby AM, et al. 1994 Interactions of body fat and muscle mass with substrate concentrations and fasting insulin levels in adults with growth hormone deficiency. Clin Sci. 87:201–206.[Medline]
98. Snel YEM, Doerga ME, Zonderland ML, et al. Resting metabolic rate in growth hormone deficient adults. Proc of the 4th Int Meet on Growth Hormone Deficiency in Adults. 1993; 48.
99. Jorgensen JOL, Moller J, Laursen T, et al. 1994 Growth hormone administration stimulates energy expenditure and extrathyroidal conversion of thyroxine to triiodothyronine in a dose-dependent manner and suppresses circadian thyrotrophin levels: studies in GH-deficient adults. Clin Endocrinol (Oxf). 41:609–614.[Medline]
100. Jorgensen JOL, Pedersen SA, Laurberg P, et al. 1989 Effects of growth hormone therapy on thyroid function of growth hormone-deficient adults with and without concomitant thyroxine-substituted central hypothyroidism. J Clin Endocrinol Metab. 69:1127–1132.[Abstract/Free Full Text]
101. Harant I, Beauville M, Cramps F, et al. 1994 Response of fat cells to growth hormone (GH): effect of long term treatment with recombinant human GH in GH-deficient adults. J Clin Endocrinol Metab. 78:1392–1395.[Abstract]
102. Hussain MA, Schmitz O, Mengel A, et al. 1994 Comparison of the effects of growth hormone and insulin-like growth factor I on substrate oxidation and on insulin sensitivity in growth hormone-deficient humans. J Clin Invest. 94:1126–1133.
103. Jorgensen JOL, Moller J, Alberti KGGM, et al. 1993 Marked effects of sustained low growth hormone (GH) levels on day-to-day fuel metabolism: studies in GH-deficient patients and healthy untreated subjects. J Clin Endocrinol Metab. 77:1589–1596.[Abstract]
104. Beshyah SA, Sharp PS, Gelding SV, et al. 1993 Whole-body leucine turnover in adults on conventional treatment for hypopituitarism. Acta Endocrinol (Copenh). 129:158–164.[Abstract/Free Full Text]
105. Russell-Jones DL, Weissberger AJ, Bowes SB, et al. 1993 The effects of growth hormone on protein metabolism in adult growth hormone deficient patients. Clin Endocrinol (Oxf). 38:427–431.[Medline]
106. Karnieli E, Laron Z, Richer N, et al. 1993 Insulin resistance in GH-deficient adult patients treated with growth hormone: evidence for a postbinding defect in vivo. In: Laron Z, Butenandt O, eds. Growth hormone replacement therapy in adults: pros and cons. London, Tel Aviv: Freund; 41–49.
107. Fowelin J, Attvall S, Lager I, Bengtsson BA. 1993 Effects of treatment with recombinant human growth hormone on insulin sensitivity and glucose metabolism in adults with growth hormone deficiency. Metab Clin Exp. 42:1443–1447.
108. O’Neal DN, Kalfas A, Dunning PL, et al. 1994 The effect of 3 months of recombinant human growth hormone (GH) therapy on insulin and glucose-mediated glucose disposal and insulin secretion in GH-deficient adults: a minimal model analysis. J Clin Endocrinol Metab. 79:975–983.[Abstract]
109. Johansson JO, Fowelin J, Landin K, Lager I, Bengtsson BA. 1995 Growth hormone-deficient adults are insulin resistant. Metab. Clin Exp. 44:1126–1129.
110. Hew FL, Koschmann M, Christopher M, et al. 1996 Insulin resistance in growth hormone-deficient adults: defects in glucose utilization and glycogen synthase activity. J Clin Endocrinol Metab. 81:555–564.[Abstract]
111. De Boer H, Blok GJ, Voerman HJ, Phillips M, Schouten JA. 1994 Serum lipid levels in growth hormone-deficient men. Metab Clin Exp. 43:199–203.
112. Cuneo RC, Salomon F, Watts GF, Hesp R, Sonksen PH. 1993 Growth hormone treatment improves serum lipids and lipoproteins in adults with growth hormone deficiency. Metab Clin Exp. 42:1519–1523.
113. Eden S, Wiklund O, Oscarsson J, Rosen T, Bengtsson BA. 1993 Growth hormone treatment of growth hormone-deficient adults results in a marked increase in Lp(a) and HDL cholesterol concentrations. Arterioscler Thromb. 13:296–301.[Abstract/Free Full Text]
114. Russell-Jones DL, Watts GF, Weissberger A, et al. 1994 The effect of growth hormone replacement on serum lipids, lipoproteins, apolipoproteins and cholesterol precursors in adult growth hormone deficient patients. Clin Endocrinol (Oxf). 41:345–350.[Medline]
115. Beshyah SA, Henderson A, Niththyananthan R, et al. 1995 The effects of short and long-term growth hormone replacement therapy in hypopituitary adults on lipid metabolism and carbohydrate tolerance. J Clin Endocrinol Metab. 80:356–363.[Abstract]
116. Weaver JU, Monson JP, Noonan K, et al. 1995 The effect of low dose recombinant human growth hormone replacement on regional fat distribution, insulin sensitivity and cardiovascular risk factors in hypopituitary adults. J Clin Endocrinol Metab. 80:153–159.[Abstract]
117. Johansson G, Oscarsson J, Rosen T, et al. 1995 Effects of 1 year of growth hormone therapy on serum lipoprotein levels in growth hormone-deficients adults. Influence of gender and Apo(a) and Apo(E) phenotypes. Arterioscler Thromb Vasc Biol. 15:2142–2150.[Abstract/Free Full Text]
118. Al-Shoumer KAS, Anyaoku V, Gray R, Hughes C, Richmond W, Johnston DG. 1996 Anthropometric and metabolic effects of four years treatment with biosynthetic growth hormone in hypopituitary adults. Endocrinol Metab. 4(Suppl A):53.
119. Garry P, Collins P, Devlin JG. 1996 An open 36 month study of lipid changes with growth hormone in adults: lipid changes following replacement of growth hormone in adult acquired growth hormone deficiency. Eur J Endocrinol. 134:61–66.[Abstract/Free Full Text]
120. Armstrong VM, Cremer P, Eberle E, et al. 1986 The association between serum Lp(a) concentrations and angiographically assessed coronary atherosclerosis. Atherosclerosis 62:249–257.
121. Bostom AG, Cupples LA, Jenner JL, et al. 1996 Elevated plasma lipoprotein(a) and coronary heart disease in men aged 55 years and younger. A prospective study. J Am Med Assoc. 276:544–548.[Abstract/Free Full Text]
122. Laron Z, Wang XL, Silbergeld A, Wilcken DEL. Growth hormone increases and insulin-like growth factor-I decreases circulating lipoprotein(a). Eur J Endocrinol. In press.
123. Laursen T, Jorgensen JO, Jakobson G, Hansen BL, Christiansen JS. 1995 Continuous infusions vs. daily injections of growth hormone for 4 weeks in GH-deficient patients. J Clin Endocrinol Metab. 80:2410–2418.[Abstract]
124. Angelin B, Rudling M. 1994 Growth hormone and hepatic lipoprotein metabolism. Curr Opin Lipidol. 5:160–165.[Medline]
125. Elam MB, Wilcox HG, Solomon SS, Heimberg M. 1992 In vivo growth hormone treatment stimulates secretion of very low density lipoprotein by the isolated perfused rat liver. Endocrinology 131:2717–2722.
126. Rudling M, Norstedt G, Olivecrona H, Reihner E, Gustafsson JA, Angelin B. 1992 Importance of growth hormone for the induction of hepatic low density lipoprotein receptors. Proc Natl Acad Sci USA. 89:6983–6987.[Abstract/Free Full Text]
127. Cummings MH, Christ E, Umpleby AM, et al. Abnormalities of very low density lipoprotein apolipoprotein B-100 metabolism contribute to the dyslipidaemia of adult growth hormone deficiency. J Clin Endocrinol Metab. In press.
128. Black MM, Shuster S, Bottoms E. 1972 Skin collagen and thickness in acromegaly and hypopituitarism. Clin Endocrinol (Oxf). 1:259–263.[Medline]
129. Rudman D, Feller AG, Nagraj HS, et al. 1990 Effects of human growth hormone in men over 60 years old. N Engl J Med. 323:1–6.[Abstract/Free Full Text]
130. Lobie PE, Brispohl W, Lincoln DT, et al. 1990 Localization of the growth hormone receptor/binding protein in skin. J Endocrinol. 126:467–472.[Abstract/Free Full Text]
131. Pedersen SA, Welling K, Michaelsen KF, et al. 1989 Reduced sweating in adults with growth hormone deficiency. Lancet. 2:681–682.
132. Juul A, Behrenscheer A, Tims T, et al. 1993 Impaired thermoregulation in adults with growth hormone deficiency during heat exposure and exercise. Clin Endocrinol. 38:237–244.[Medline]
133. Holder A, Spencer EM, Preece MA. 1981 Effect of bovine growth hormone and a partially pure preparation of somatomedin on various growth parameters. J Endocrinol. 89:275–282.[Abstract/Free Full Text]
134. Van Buul-Offers S, Ujeda I, Van den Brande JL. 1986 Biosynthestic somatomedin C increases the length and weight of Snell dwarf mice. Pediatric Res. 20:825–877.[Medline]
135. Ammann AJ, Sherman BM. 1987 Effect of growth hormone therapy on immune function. J Pediatr. 110:663–664.
136. Rongen-Westerlaken C, Rijkers GT, Scholtens EJ, et al. 1991 Immunologic studies in Turner syndrome before and during treatment with growth hormone. J Pediatr. 119:268–272.[CrossRef][Medline]
137. Wit JM, Kooijman R, Rijkers GT, Zegers BJM. 1993 Immunological findings in growth hormone treated patients. Horm Res. 39:107–110.
138. Saxena GB, Saxena RK, Adler WH. 1982 Regulation of natural killer activity in vivo. III. Effect of hypophysectomy and growth hormone treatment on he natural killer activity of the mouse spleen population. Int Arch Allergy Immunol. 67:169–174.
139. Bozzola M, Valtorta A, Moretta A, Cisternino M, Biscaldi I, Schimpff R. 1990 In vitro and in vivo effect of growth hormone on cytotoxic activity. J Pediatr. 117:596–602.[CrossRef][Medline]
140. Stabler B, Turner JR, Girdler SS, Light KC, Underwood LE. 1992 Reactivity to stress and psychological adjustment in adults with pituitary insufficiency. Clin Endocrinol (Oxf). 6:467–473.
141. Rosen T, Wiren L, Wilhelmsen L, Wiklund I, Bengtsson BA. 1994 Decreased psychological well-being in adult patients with growth hormone deficiency. Clin Endocrinol (Oxf). 40:111–116.[Medline]
142. McGauley GA. 1989 Quality of life assessment before and after growth hormone treatment in adults with growth hormone deficiency. Acta Pediatr Scand. 356(Suppl):70–74.
143. Burman P, Broman JE, Hetta J, et al. 1995 Quality of life in adults with growth hormone (GH) deficiency: response to treatment with recombinant human GH in a placebo-controlled 21-month trial. J Clin Endocrinol Metab. 80:3585–3590.[Abstract]
144. Almqvist O, Thoren M, Sääf, Eriksson O. 1986 Effects of growth hormone substitution on mental performance in adults with growth hormone deficiency: a pilot study. Psychoneuroendocrinology. 11:347–352.[CrossRef][Medline]
145. Johansson JO, Larson G, Andersson M, et al. 1995 Treatment of growth hormone-deficient adults with recombinant human growth hormone increases the concentration of growth hormone in the cerebrospinal fluid and affects neurotransmitters. Neuroendocrinology. 61:57–66.[Medline]
146. Åström C, Lindholm J. 1990 Growth hormone deficient young adults have decreased deep sleep. Neuroendocrinology. 51:82–84.[Medline]
147. Åström C, Pedersen SA, Lindholm J. 1990 The influence of growth hormone on sleep in adults with growth hormone deficiency. Clin Endocrinol. 33:496–500.
148. Holmes SJ, Shalet SM. 1995 Characteristics of adults who wish to enter a trial of growth hormone replacement. Clin Endocrinol (Oxf). 42:613–618.[Medline]
149. Holmes SJ, Shalet SM. 1995 Which adults develop side-effects of growth hormone replacement? Clin Endocrinol (Oxf). 43:143–149.[Medline]
150. Mårdh G, Lundin K, Borg G, Jonsson B, Lindeberg A. 1994 Growth hormone replacement therapy in adult hypopituitary patients with growth hormone deficiency: combined data from 12 European placebo-controlled trials. Endocrinol Metab. 1(Suppl A):43–49.
151. Molitch ME. 1992 Clinical manifestations of acromegaly. Clin Endocrinol Metab. 21:597–614.
152. Pickett JBE, Layzer RB, Levin SR, Schneider V, Campbell MJ, Sumner AJ. 1975 Neuromuscular complications of acromegaly. Neurology 25:638–645.
153. Nagulesparen M, Trickey R, Davies MJ, Jenkins JS. 1976 Muscle changes in acromegaly. Br Med J. 2:914–915.
154. Liebermann SA, Björkengren AG, Hoffman AR. 1992 Rheumatologic and skeletal changes in acromegaly. Clin Endocrinol Metab. 21:615–631.
155. Taback SP, Dean HJ. 1996 Mortality in Canadian children with growth hormone (GH) deficiency receiving GH therapy 1967–1992. The Canadian Growth Hormone Advisory Commitee. J Clin Endocrinol Metab. 81:1693–1696.[Abstract]
156. Moshang Jr T, Rundle AC, Graves DA, Nickas J, Johanson A, Meadows A. 1996 Brain tumor recurrence in children treated with growth hormone: the National Cooperative Growth Study experience. J Pediatr. 128:S4–S7.
157. Buchanan CR, Preece MA, Milner RD. 1991 Mortality, neoplasia, and Creutzfeld-Jakob disease in patients treated with human pituitary growth hormone in the United Kingdom. Br Med J. 302:824–828.
158. Blethen SL, Allen DB, Graves D, August G, Moshang T, Rosenfeld R. 1996 Safety of recombinant deoxyribonucleic acid-derived growth hormone: The National Cooperative Growth Study Experience. J Clin Endocrinol Metab. 81:1704–1710.[Abstract]
159. Møller J, Jørgensen JOL, Lauersen T, et al. 1993 Growth hormone dose regimens in adult GH deficiency: effects on biochemical growth markers and metabolic parameters. Clin Endocrinol (Oxf). 39:403–408.[Medline]
160. Reaven GM. 1988 Role of insulin resistance in human disease. Diabetes. 37:1595–1607.[Abstract]
161. Malozowski S, Tanner LA, Wysowski D, Fleming GA. 1993 Growth hormone, insulin-like growth factor-I, and benign intracranial hypertension. N Engl J Med. 329:665–666.[Free Full Text]
162. Cohn L, Feller AG, Draper MW, Rudman IW, Rudman D. Carpal tunnel syndrome and gynaecomastia during growth hormone treatment of elderly men with low circulating IGF-I concentrations. Clin Endocrinol (Oxf). 39:417–425.
163. Rudman D, Kutner MH, Rogers CM, et al. 1981 Impaired growth hormone secretion in the adult population: relation to age and adiposity. J Clin Invest. 67:1361–1369.
164. Zadik Z, Chalew SA, McCarter RJ, et al. 1985 The influence of age on the 24-hour integrated concentration of growth hormone in normal individuals. J Clin Endocrinol Metab. 60:513–516.[Abstract/Free Full Text]
165. Johannsson G, Bjarnason R, Bramnert M, et al. 1996 The individual responsiveness to growth hormone (GH) treatment in GH-deficient adults is dependent on the level of GH-binding protein, body mass index, age, and gender. J Clin Endocrinol Metab. 81:1575–1581.[Abstract]

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				L. J. Woodhouse, A. Mukherjee, S. M. Shalet, and S. Ezzat The Influence of Growth Hormone Status on Physical Impairments, Functional Limitations, and Health-Related Quality of Life in Adults Endocr. Rev., May 1, 2006; 27(3): 287 - 317. [Abstract] [Full Text] [PDF]

				M. E. Molitch, D. R. Clemmons, S. Malozowski, G. R. Merriam, S. M. Shalet, M. L. Vance, and for The Endocrine Society's Clinical Guidelines Su Evaluation and Treatment of Adult Growth Hormone Deficiency: An Endocrine Society Clinical Practice Guideline J. Clin. Endocrinol. Metab., May 1, 2006; 91(5): 1621 - 1634. [Abstract] [Full Text] [PDF]

				M. Salerno, V. Esposito, V. Farina, G. Radetti, A. Umbaldo, D. Capalbo, L. Spinelli, S. Muzzica, G. Lombardi, and A. Colao Improvement of Cardiac Performance and Cardiovascular Risk Factors in Children with GH Deficiency after Two Years of GH Replacement Therapy: An Observational, Open, Prospective, Case-Control Study J. Clin. Endocrinol. Metab., April 1, 2006; 91(4): 1288 - 1295. [Abstract] [Full Text] [PDF]

				V K B Prabhakar and S M Shalet Aetiology, diagnosis, and management of hypopituitarism in adult life. Postgrad. Med. J., April 1, 2006; 82(966): 259 - 266. [Abstract] [Full Text] [PDF]

				E. R Christ, M. H Cummings, M. Stolinski, N. Jackson, P. J Lumb, A. S Wierzbicki, P. H Sonksen, D. L Russell-Jones, and A M. Umpleby Low-density lipoprotein apolipoprotein B100 turnover in hypopituitary patients with GH deficiency: a stable isotope study. Eur. J. Endocrinol., March 1, 2006; 154(3): 459 - 466. [Abstract] [Full Text] [PDF]

				S. K. Paulsen, S. B. Pedersen, J. O. L. Jorgensen, S. Fisker, J. S. Christiansen, A. Flyvbjerg, and B. Richelsen Growth Hormone (GH) Substitution in GH-Deficient Patients Inhibits 11{beta}-Hydroxysteroid Dehydrogenase Type 1 Messenger Ribonucleic Acid Expression in Adipose Tissue J. Clin. Endocrinol. Metab., March 1, 2006; 91(3): 1093 - 1098. [Abstract] [Full Text] [PDF]

				R. D. Murray, J. E. Adams, and S. M. Shalet A Densitometric and Morphometric Analysis of the Skeleton in Adults with Varying Degrees of Growth Hormone Deficiency J. Clin. Endocrinol. Metab., February 1, 2006; 91(2): 432 - 438. [Abstract] [Full Text] [PDF]

				A. Mukherjee, J. E Adams, L. Smethurst, and S. M Shalet Interdependence of lean body mass and total body water, but not quality of life measures, during low dose GH replacement in GH-deficient adults Eur. J. Endocrinol., November 1, 2005; 153(5): 661 - 668. [Abstract] [Full Text] [PDF]

				J. Bollerslev, J. Hallen, K. J Fougner, A. P. Jorgensen, C. Kristo, H. Fagertun, O. Gudmundsen, P. Burman, and T. Schreiner Low-dose GH improves exercise capacity in adults with GH deficiency: effects of a 22-month placebo-controlled, crossover trial Eur. J. Endocrinol., September 1, 2005; 153(3): 379 - 387. [Abstract] [Full Text] [PDF]

				A. Colao, C. Di Somma, A. Cuocolo, L. Spinelli, W. Acampa, S. Spiezia, F. Rota, M. C. Savanelli, and G. Lombardi Does a Gender-Related Effect of Growth Hormone (GH) Replacement Exist on Cardiovascular Risk Factors, Cardiac Morphology, and Performance and Atherosclerosis? Results of a Two-Year Open, Prospective Study in Young Adult Men and Women with Severe GH Deficiency J. Clin. Endocrinol. Metab., September 1, 2005; 90(9): 5146 - 5155. [Abstract] [Full Text] [PDF]

				J. Verhelst, P. Kendall-Taylor, E. M. Erfurth, D. A. Price, M. Geffner, M. Koltowska-Haggstrom, P. J. Jonsson, P. Wilton, and R. Abs Baseline Characteristics and Response to 2 Years of Growth Hormone (GH) Replacement of Hypopituitary Patients with GH Deficiency due to Adult-Onset Craniopharyngioma in Comparison with Patients with Nonfunctioning Pituitary Adenoma: Data from KIMS (Pfizer International Metabolic Database) J. Clin. Endocrinol. Metab., August 1, 2005; 90(8): 4636 - 4643. [Abstract] [Full Text] [PDF]

				A. Vigano, S. Mora, P. Manzoni, L. Schneider, S. Beretta, M. Molinaro, B. di Natale, and P. Brambilla Effects of Recombinant Growth Hormone on Visceral Fat Accumulation: Pilot Study in Human Immunodeficiency Virus-Infected Adolescents J. Clin. Endocrinol. Metab., July 1, 2005; 90(7): 4075 - 4080. [Abstract] [Full Text] [PDF]

				J. Nuver, A. J. Smit, B. H.R. Wolffenbuttel, W. J. Sluiter, H. J. Hoekstra, D. T. Sleijfer, and J. A. Gietema The Metabolic Syndrome and Disturbances in Hormone Levels in Long-Term Survivors of Disseminated Testicular Cancer J. Clin. Oncol., June 1, 2005; 23(16): 3718 - 3725. [Abstract] [Full Text] [PDF]

				S. V Haijma, P S. van Dam, W. R de Vries, I. Maitimu-Smeele, C. Dieguez, F. F Casanueva, and H. P F Koppeschaar The GHRH/GHRP-6 test for the diagnosis of GH deficiency in elderly or severely obese men Eur. J. Endocrinol., April 1, 2005; 152(4): 575 - 580. [Abstract] [Full Text] [PDF]

				H. Kim, E. Barton, N. Muja, S. Yakar, P. Pennisi, and D. LeRoith Intact Insulin and Insulin-Like Growth Factor-I Receptor Signaling Is Required for Growth Hormone Effects on Skeletal Muscle Growth and Function in Vivo Endocrinology, April 1, 2005; 146(4): 1772 - 1779. [Abstract] [Full Text] [PDF]

				M. Gola, S. Bonadonna, M. Doga, and A. Giustina Growth Hormone and Cardiovascular Risk Factors J. Clin. Endocrinol. Metab., March 1, 2005; 90(3): 1864 - 1870. [Abstract] [Full Text] [PDF]

				M. Alba, A. V. Schally, and R. Salvatori Partial Reversibility of Growth Hormone (GH) Deficiency in the GH-Releasing Hormone (GHRH) Knockout Mouse by Postnatal Treatment with a GHRH Analog Endocrinology, March 1, 2005; 146(3): 1506 - 1513. [Abstract] [Full Text] [PDF]

				S.-i. Kawachi, N. Takeda, A. Sasaki, Y. Kokubo, K. Takami, H. Sarui, M. Hayashi, N. Yamakita, and K. Yasuda Circulating Insulin-Like Growth Factor-1 and Insulin-Like Growth Factor Binding Protein-3 Are Associated With Early Carotid Atherosclerosis Arterioscler Thromb Vasc Biol, March 1, 2005; 25(3): 617 - 621. [Abstract] [Full Text] [PDF]

				B. Olsson, M. Bohlooly-Y, S. M. Fitzgerald, F. Frick, A. Ljungberg, B. Ahren, J. Tornell, G. Bergstrom, and J. Oscarsson Bovine Growth Hormone Transgenic Mice Are Resistant to Diet-Induced Obesity but Develop Hyperphagia, Dyslipidemia, and Diabetes on a High-Fat Diet Endocrinology, February 1, 2005; 146(2): 920 - 930. [Abstract] [Full Text] [PDF]

				F. Reis, M. V. Campos, M. Bastos, L. Almeida, M. Lourenco, C. A. Ferrer-Antunes, A. Palmeiro, J. D. Santos-Dias, J. F. Mesquita, M. Carvalheiro, et al. Platelet Hyperactivation in Maintained Growth Hormone-Deficient Childhood Patients after Therapy Withdrawal as a Putative Earlier Marker of Increased Cardiovascular Risk J. Clin. Endocrinol. Metab., January 1, 2005; 90(1): 98 - 105. [Abstract] [Full Text] [PDF]

				H K Gleeson and S M Shalet The impact of cancer therapy on the endocrine system in survivors of childhood brain tumours Endocr. Relat. Cancer, December 1, 2004; 11(4): 589 - 602. [Abstract] [Full Text] [PDF]

				R. Coutant, F. B. de Casson, S. Rouleau, O. Douay, E. Mathieu, F. Gatelais, N. Bouhours-Nouet, C. Voinot, M. Audran, and J. M. Limal Divergent Effect of Endogenous and Exogenous Sex Steroids on the Insulin-Like Growth Factor I Response to Growth Hormone in Short Normal Adolescents J. Clin. Endocrinol. Metab., December 1, 2004; 89(12): 6185 - 6192. [Abstract] [Full Text] [PDF]

				I. N. M. Day, X.-h. Chen, T. R. Gaunt, T. H. T. King, A. Voropanov, S. Ye, S. Rodriguez, H. E. Syddall, A. A. Sayer, E. M. Dennison, et al. Late Life Metabolic Syndrome, Early Growth, and Common Polymorphism in the Growth Hormone and Placental Lactogen Gene Cluster J. Clin. Endocrinol. Metab., November 1, 2004; 89(11): 5569 - 5576. [Abstract] [Full Text] [PDF]

				K. Link, C. Moell, S. Garwicz, E. Cavallin-Stahl, J. Bjork, U. Thilen, B. Ahren, and E. M. Erfurth Growth Hormone Deficiency Predicts Cardiovascular Risk in Young Adults Treated for Acute Lymphoblastic Leukemia in Childhood J. Clin. Endocrinol. Metab., October 1, 2004; 89(10): 5003 - 5012. [Abstract] [Full Text] [PDF]

				K.-C. Leung, G. Johannsson, G. M. Leong, and K. K. Y. Ho Estrogen Regulation of Growth Hormone Action Endocr. Rev., October 1, 2004; 25(5): 693 - 721. [Abstract] [Full Text] [PDF]

				P. V. Carroll, W. M. Drake, K. T. Maher, K. Metcalfe, N. J. Shaw, D. B. Dunger, T. D. Cheetham, C. Camacho-Hubner, M. O. Savage, and J. P. Monson Comparison of Continuation or Cessation of Growth Hormone (GH) Therapy on Body Composition and Metabolic Status in Adolescents with Severe GH Deficiency at Completion of Linear Growth J. Clin. Endocrinol. Metab., August 1, 2004; 89(8): 3890 - 3895. [Abstract] [Full Text] [PDF]

				J. Svensson, B.-A. Bengtsson, T. Rosen, A. Oden, and G. Johannsson Malignant Disease and Cardiovascular Morbidity in Hypopituitary Adults with or without Growth Hormone Replacement Therapy J. Clin. Endocrinol. Metab., July 1, 2004; 89(7): 3306 - 3312. [Abstract] [Full Text] [PDF]

				S. M. Harman and M. R. Blackman Hormones and Supplements: Do They Work?: Use of Growth Hormone for Prevention or Treatment of Effects of Aging J. Gerontol. A Biol. Sci. Med. Sci., July 1, 2004; 59(7): B652 - B658. [Abstract] [Full Text] [PDF]

				P. Maison, S. Griffin, M. Nicoue-Beglah, N. Haddad, B. Balkau, and P. Chanson 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., May 1, 2004; 89(5): 2192 - 2199. [Abstract] [Full Text] [PDF]

				R. D. Murray, J. E. Adams, and S. M. Shalet Adults with Partial Growth Hormone Deficiency Have an Adverse Body Composition J. Clin. Endocrinol. Metab., April 1, 2004; 89(4): 1586 - 1591. [Abstract] [Full Text] [PDF]

				E. R. Christ, M. H. Cummings, N. Jackson, M. Stolinski, P. J. Lumb, A. S. Wierzbicki, P. H. Sonksen, D. L. Russell-Jones, and A. M. Umpleby Effects of Growth Hormone (GH) Replacement Therapy on Low-Density Lipoprotein Apolipoprotein B100 Kinetics in Adult Patients with GH Deficiency: A Stable Isotope Study J. Clin. Endocrinol. Metab., April 1, 2004; 89(4): 1801 - 1807. [Abstract] [Full Text] [PDF]

				R. D. Murray, B. Columb, J. E. Adams, and S. M. Shalet Low Bone Mass Is an Infrequent Feature of the Adult Growth Hormone Deficiency Syndrome in Middle-Age Adults and the Elderly J. Clin. Endocrinol. Metab., March 1, 2004; 89(3): 1124 - 1130. [Abstract] [Full Text] [PDF]

				S. G. Albert and A. D. Mooradian Low-Dose Recombinant Human Growth Hormone as Adjuvant Therapy to Lifestyle Modifications in the Management of Obesity J. Clin. Endocrinol. Metab., February 1, 2004; 89(2): 695 - 701. [Abstract] [Full Text] [PDF]

				M. S. Sandhu, J. M. Gibson, A. H. Heald, D. B. Dunger, and N. J. Wareham Association between Insulin-Like Growth Factor-I: Insulin-Like Growth Factor-Binding Protein-1 Ratio and Metabolic and Anthropometric Factors in Men and Women Cancer Epidemiol. Biomarkers Prev., January 1, 2004; 13(1): 166 - 170. [Abstract] [Full Text] [PDF]

				S. R. Edmondson, S. P. Thumiger, G. A. Werther, and C. J. Wraight Epidermal Homeostasis: The Role of the Growth Hormone and Insulin-Like Growth Factor Systems Endocr. Rev., December 1, 2003; 24(6): 737 - 764. [Abstract] [Full Text] [PDF]

				S. G. Thomas, J. G. Esposito, and S. Ezzat Exercise Training Benefits Growth Hormone (GH)-Deficient Adults in the Absence or Presence of GH Treatment J. Clin. Endocrinol. Metab., December 1, 2003; 88(12): 5734 - 5738. [Abstract] [Full Text] [PDF]

				M. Lange, U. Feldt-Rasmussen, O. L. Svendsen, K. W. Kastrup, A. Juul, and J. Muller High Risk of Adrenal Insufficiency in Adults Previously Treated for Idiopathic Childhood Onset Growth Hormone Deficiency J. Clin. Endocrinol. Metab., December 1, 2003; 88(12): 5784 - 5789. [Abstract] [Full Text] [PDF]

				J. Shi, R. V. Sekhar, A. Balasubramanyam, K. Ellis, P. J. Reeds, F. Jahoor, and M. D. Sharma Short- and Long-Term Effects of Growth Hormone (GH) Replacement on Protein Metabolism in GH-Deficient Adults J. Clin. Endocrinol. Metab., December 1, 2003; 88(12): 5827 - 5833. [Abstract] [Full Text] [PDF]

				A. Mukherjee, J. P. Monson, P. J. Jonsson, P. J. Trainer, and S. M. Shalet Seeking the Optimal Target Range for Insulin-Like Growth Factor I during the Treatment of Adult Growth Hormone Disorders J. Clin. Endocrinol. Metab., December 1, 2003; 88(12): 5865 - 5870. [Abstract] [Full Text] [PDF]

				D. E. Meyers and R. C. Cuneo Controversies Regarding the Effects of Growth Hormone on the Heart Mayo Clin. Proc., December 1, 2003; 78(12): 1521 - 1526. [Abstract] [PDF]

				P. Maison and P. Chanson Cardiac Effects of Growth Hormone in Adults With Growth Hormone Deficiency: A Meta-Analysis Circulation, November 25, 2003; 108(21): 2648 - 2652. [Abstract] [Full Text] [PDF]

				M. Tauber, B. Jouret, A. Cartault, N. Lounis, M. Gayrard, C. Marcouyeux, C. Pienkowski, I. Oliver, P. Moulin, P. Otal, et al. Adolescents with Partial Growth Hormone (GH) Deficiency Develop Alterations of Body Composition after GH Discontinuation and Require Follow-Up J. Clin. Endocrinol. Metab., November 1, 2003; 88(11): 5101 - 5106. [Abstract] [Full Text] [PDF]

				B. E. Engstrom, P. Burman, C. Holdstock, and F. A. Karlsson Effects of Growth Hormone (GH) on Ghrelin, Leptin, and Adiponectin in GH-Deficient Patients J. Clin. Endocrinol. Metab., November 1, 2003; 88(11): 5193 - 5198. [Abstract] [Full Text] [PDF]

				M. L. Healy, J. Gibney, D. L. Russell-Jones, C. Pentecost, P. Croos, P. H. Sonksen, and A. M. Umpleby High Dose Growth Hormone Exerts an Anabolic Effect at Rest and during Exercise in Endurance-Trained Athletes J. Clin. Endocrinol. Metab., November 1, 2003; 88(11): 5221 - 5226. [Abstract] [Full Text] [PDF]

				L. Katznelson, W. P. Fairfield, N. Zeizafoun, B. E. Sands, M. A. Peppercorn, D. I. Rosenthal, and A. Klibanski Effects of Growth Hormone Secretion on Body Composition in Patients with Crohn's Disease J. Clin. Endocrinol. Metab., November 1, 2003; 88(11): 5468 - 5472. [Abstract] [Full Text] [PDF]

				W. F. Blum, E. P. Shavrikova, D. J. Edwards, M. Rosilio, M. L. Hartman, F. Marin, D. Valle, A. J. van der Lely, A. F. Attanasio, C. J. Strasburger, et al. Decreased Quality of Life in Adult Patients with Growth Hormone Deficiency Compared with General Populations Using the New, Validated, Self-Weighted Questionnaire, Questions on Life Satisfaction Hypopituitarism Module J. Clin. Endocrinol. Metab., September 1, 2003; 88(9): 4158 - 4167. [Abstract] [Full Text] [PDF]

				J. H Koeslag, P. T Saunders, and E. Terblanche A reappraisal of the blood glucose homeostat which comprehensively explains the type 2 diabetes mellitus-syndrome X complex J. Physiol., June 1, 2003; 549(2): 333 - 346. [Abstract] [Full Text] [PDF]

				J. Svensson, K. Stibrant Sunnerhagen, and G. Johannsson Five Years of Growth Hormone Replacement Therapy in Adults: Age- and Gender-Related Changes in Isometric and Isokinetic Muscle Strength J. Clin. Endocrinol. Metab., May 1, 2003; 88(5): 2061 - 2069. [Abstract] [Full Text] [PDF]

				W. M. Drake, P. V. Carroll, K. T. Maher, K. A. Metcalfe, C. Camacho-Hubner, N. J. Shaw, D. B. Dunger, T. D. Cheetham, M. O. Savage, and J. P. Monson The Effect of Cessation of Growth Hormone (GH) Therapy on Bone Mineral Accretion in GH-Deficient Adolescents at the Completion of Linear Growth J. Clin. Endocrinol. Metab., April 1, 2003; 88(4): 1658 - 1663. [Abstract] [Full Text] [PDF]

				K. C. Oeffinger, A. C. Mertens, C. A. Sklar, Y. Yasui, T. Fears, M. Stovall, T. A. Vik, P. D. Inskip, and L. L. Robison Obesity in Adult Survivors of Childhood Acute Lymphoblastic Leukemia: A Report from the Childhood Cancer Survivor Study J. Clin. Oncol., April 1, 2003; 21(7): 1359 - 1365. [Abstract] [Full Text] [PDF]

				A. Colao, C. Di Somma, S. Spiezia, M. Filippella, R. Pivonello, and G. Lombardi Effect of Growth Hormone (GH) and/or Testosterone Replacement on the Prostate in GH-Deficient Adult Patients J. Clin. Endocrinol. Metab., January 1, 2003; 88(1): 88 - 94. [Abstract] [Full Text] [PDF]

				M. R. Blackman, J. D. Sorkin, T. Munzer, M. F. Bellantoni, J. Busby-Whitehead, T. E. Stevens, J. Jayme, K. G. O'Connor, C. Christmas, J. D. Tobin, et al. Growth Hormone and Sex Steroid Administration in Healthy Aged Women and Men: A Randomized Controlled Trial JAMA, November 13, 2002; 288(18): 2282 - 2292. [Abstract] [Full Text] [PDF]

				E. M. Erfurth, B. Bulow, G. Svahn-Tapper, B. Norrving, K. Odh, Z. Mikoczy, J. Bjork, and L. Hagmar Risk Factors for Cerebrovascular Deaths in Patients Operated and Irradiated for Pituitary Tumors J. Clin. Endocrinol. Metab., November 1, 2002; 87(11): 4892 - 4899. [Abstract] [Full Text] [PDF]

				W. L. Isley Growth Hormone Therapy for Adults: Not Ready for Prime Time? Ann Intern Med, August 6, 2002; 137(3): 190 - 196. [Abstract] [Full Text] [PDF]

				D. M. Cook Shouldn't Adults with Growth Hormone Deficiency Be Offered Growth Hormone Replacement Therapy? Ann Intern Med, August 6, 2002; 137(3): 197 - 201. [Abstract] [Full Text] [PDF]

				C. Hoybye, A. Hilding, H. Jacobsson, and M. Thoren Metabolic Profile and Body Composition in Adults with Prader-Willi Syndrome and Severe Obesity J. Clin. Endocrinol. Metab., August 1, 2002; 87(8): 3590 - 3597. [Abstract] [Full Text] [PDF]

				S. Ezzat, S. Fear, R.-C. Gaillard, C. Gayle, H. Landy, S. Marcovitz, T. Mattioni, S. Nussey, A. Rees, and E. Svanberg Gender-Specific Responses of Lean Body Composition and Non-Gender-Specific Cardiac Function Improvement after GH Replacement in GH-Deficient Adults J. Clin. Endocrinol. Metab., June 1, 2002; 87(6): 2725 - 2733. [Abstract] [Full Text] [PDF]

				A. Kehely, P. C. Bates, P. Frewer, M. Birkett, W. F. Blum, P. Mamessier, S. Ezzat, K. K. Y. Ho, G. Lombardi, A. Luger, et al. Short-Term Safety and Efficacy of Human GH Replacement Therapy in 595 Adults with GH Deficiency: A Comparison of Two Dosage Algorithms J. Clin. Endocrinol. Metab., May 1, 2002; 87(5): 1974 - 1979. [Abstract] [Full Text] [PDF]

				J. A. S. Barreto-Filho, M. R. S. Alcantara, R. Salvatori, M. A. Barreto, A. C. S. Sousa, V. Bastos, A. H. Souza, R. M. C. Pereira, P. E. Clayton, M. S. Gill, et al. Familial Isolated Growth Hormone Deficiency Is Associated with Increased Systolic Blood Pressure, Central Obesity, and Dyslipidemia J. Clin. Endocrinol. Metab., May 1, 2002; 87(5): 2018 - 2023. [Abstract] [Full Text] [PDF]

				A. F. Attanasio, P. C. Bates, K. K. Y. Ho, S. M. Webb, R. J. Ross, C. J. Strasburger, R. Bouillon, B. Crowe, K. Selander, D. Valle, et al. Human Growth Hormone Replacement in Adult Hypopituitary Patients: Long-Term Effects on Body Composition and Lipid Status--3-Year Results from the HypoCCS Database J. Clin. Endocrinol. Metab., April 1, 2002; 87(4): 1600 - 1606. [Abstract] [Full Text] [PDF]

				A. Colao, C. di Somma, R. Pivonello, A. Cuocolo, L. Spinelli, D. Bonaduce, M. Salvatore, and G. Lombardi The Cardiovascular Risk of Adult GH Deficiency (GHD) Improved after GH Replacement and Worsened in Untreated GHD: A 12-Month Prospective Study J. Clin. Endocrinol. Metab., March 1, 2002; 87(3): 1088 - 1093. [Abstract] [Full Text] [PDF]

				M. E. Molitch Diagnosis of GH Deficiency in Adults--How Good Do the Criteria Need to Be? J. Clin. Endocrinol. Metab., February 1, 2002; 87(2): 473 - 476. [Full Text] [PDF]

				P. Marzullo, C. Buckway, K. L. Pratt, A. Colao, J. Guevara-Aguirre, and R. G. Rosenfeld Leptin Concentrations in GH Deficiency: The Effect of GH Insensitivity J. Clin. Endocrinol. Metab., February 1, 2002; 87(2): 540 - 545. [Abstract] [Full Text] [PDF]

				H. S. Randeva, R. D. Murray, K. C. Lewandowski, C. J. O'Callaghan, R. Horn, P. O'Hare, G. Brabant, E. W. Hillhouse, and S. M. Shalet Differential Effects of GH Replacement on the Components of the Leptin System in GH-Deficient Individuals J. Clin. Endocrinol. Metab., February 1, 2002; 87(2): 798 - 804. [Abstract] [Full Text] [PDF]

				R. D. Murray, K. H. Darzy, H. K. Gleeson, and S. M. Shalet GH-Deficient Survivors of Childhood Cancer: GH Replacement during Adult Life J. Clin. Endocrinol. Metab., January 1, 2002; 87(1): 129 - 135. [Abstract] [Full Text] [PDF]

				C. Christmas, K. G. O'Connor, S. M. Harman, J. D. Tobin, T. Munzer, M. F. Bellantoni, C. St. Clair, K. M. Pabst, J. D. Sorkin, and M. R. Blackman Growth Hormone and Sex Steroid Effects on Bone Metabolism and Bone Mineral Density in Healthy Aged Women and Men J. Gerontol. A Biol. Sci. Med. Sci., January 1, 2002; 57(1): M12 - 18. [Abstract] [Full Text] [PDF]

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