DIAGNOSIS AND MANAGEMENT OF GROWTH HORMONE DEFICIENCY IN ADULTS

NEUROENDOCRINOLOGY

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DIAGNOSIS AND MANAGEMENT OF GROWTH HORMONE DEFICIENCY IN ADULTS Stavros Stavrou, MD, and David L. Kleinberg, MD

Most adults with growth hormone deficiency (GHD) have pituitary or hypothalamic disorders. The most common cause is a pituitary tumor,”O but there are many other potential causes as follows: Pituitary adenoma Functional adenoma Nonfunctional adenoma Postsurgery or postradiation for pituitary or peripituitary tumor Post-whole-brain radiation Trauma Craniopharyngioma Rathke’s cleft cyst Vasculitis Hypophysitis Sheehan syndrome Empty sella syndrome Meningioma Glioma Dysgerminoma Pinealoma Epidermoid cyst Post-tuberculosis Histiocytosis Hypothalamic origin Idiopathic From the Department of Medicine, New York University School of Medicine, New York, New York

ENDOCRINOLOGY AND METABOLISM CLINICS OF NORTH AMERICA VOLUME 30 NUMBER 3 SEPTEMBER 2001

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In children, idiopathic GHD is the most common form, accounting for as many as 90% of cases.8 In a growing number of children, GHD occurs as a result of a genetic abnormality, but a discussion of these disorders is beyond the scope of this review, which is limited to the presentation of GHD in adults. CLINICAL PRESENTATION

Although the symptoms of GHD in adults are often nonspecific, the signs are specific and may lead to problems that result in a shortened life span. Symptoms, signs, and other features of GHD in adults are as follows: Symptoms Impaired psychologic well-being Decreased vitality and energy Decreased physical mobility Depressed mood Emotional lability Impaired self-control Anxiety Disturbances in sexual function Increased social isolation Signs Changes in body composition Decreased lean body mass Increased fat mass Increased abdominal adiposity Decreased body water Decreased bone density Decreased strength Decreased exercise capacity Higher body mass index Increased waist-to-hip circumference ratio Abnormal lipid profile Elevated total cholesterol Elevated low-density lipoprotein (LDL) cholesterol Elevated apolipoprotein B (ApoB) Elevated triglyceride Lower high-density lipoprotein (HDL) cholesterol levels Other features Increased cardiovascular risk Increased plasminogen activator inhibitor (PAI-1) activity Increased fibrinogen Lower degree of physical exercise during spare time Decreased exercise performance Some patients are entirely asymptomatic, whereas others have fatigue, decreased energy, depressed mood, anxiety, disturbances.in sexual

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function, and other problems that impair quality of life. Unfortunately, many of these symptoms are so nonspecific that they can be ascribed to many other conditions. In patients with pituitary disease, a response to therapy after GHD may be the only means of assessing whether the symptoms are indeed a result of the deficiency. The following sections discuss problems associated with adult GHD presented by organ systems. Cardiovascular System Cardiovascular Risk Factors

Adult patients with GHD have a shortened life span, in large measure because of an increase in cardiovascular mortality. In addition to a higher prevalence of treated hypertension, obesity, diabetes mellitus (in females), and a lower degree of physical exercise during spare time, patients with GHD also exhibit a higher body mass index, waist-to-hip ratio, and a tendency to increase the atherothrombotic propensity with 25* 74, 112 higher PAI-1 activity and increased fibrin~gen.~, Abnormal lipid profiles are also a regular feature of GHD. These abnormalities include elevated total cholesterol, increased LDL cholesterol, high ApoB, and high triglycerides in some reports. Some studies of GHD report a low HDL? whereas others do not.*,36, 42, 74, 112, 131 An elevated HDL to LDL ratio has been observed (Table 1);however, some studies have found lipid profiles to be normal. One group of investigators suggested that the abnormal lipid profile of patients with GHD may be partially explained by a significantly higher hepatic secretion rate of very-low-density lipoprotein (VLDL) apoB and a reduced catabolism of VLDL apoB when compared with the values in control Another explanation is that growth hormone may indirectly modulate cholesterol metabolism through regulation of hepatic cholesterol 7 alphahydroxylase activity, the rate-limiting enzyme of bile acid synthesis.58 Table 1. LIPID ABNORMALITIES IN PATIENTS WITH GROWTH HORMONE DEFICIENCY Study Rosen et al, 1993Il2 Cuneo et al, 1993% Johansson et al, 199474 de Boer et al, 199442 Attanasio et al, 19978 Evans et al, 199947 Johansson et al, 199968 Bulow et al, 199925 =

Number of Patients 104 24 20 64 99 A 0 74 co 17 40 33

Total Cholesterol LDL tf

T

* t t t

tf

T

HDL

1 7 . 1 T

* f

f

T

t

T tf

1

* f

Triglyceride

f

t . 1 J

*

ApoB

t t T

LDL = low-density lipoprotein; HDL = high-density lipoprotein; ApoB = apolipoprotein B; A 0 adult onset; CO = childhood onset; tf = no changes; T = increased; 1 = decreased.

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Elevated serum insulin and impaired glucose metabolism also increase the risk of cardiovascular disease. Patients with GHD have sig59, 117 and glycosylated hemogl06in,4~ nificantly higher fasting insulin47* and are insulin The latter defect has been demonstrated by studies using a hyperinsulinemic euglycemic clamp.59 Vascular Impairment

Endothelial dysfunction has been noted in growth hormone-deficient adults before the onset of overt atherosclerotic disease, as demonstrated by brachial artery Doppler Conflicting results have been published regarding carotid intima-media thickness and arteries with plaques. In two studies using high-resolution ultrasonography, patients who had GHD were found to have greater carotid intima-media thickness than controls.88,105 They also had more plaques in the carotid arteries.88Intima-media thickness was negatively correlated with serum insulin-like growth factor 1 (IGF-l).Io5In another study, carotid artery intima-media thickness and plaque numbers did not differ in patients and The Heart in Growth Hormone Deficiency

Several studies have shown a significant cardiac impairment, including a reduction in left ventricular mass index, a reduced lower left ventricular systolic function? 90 a reduction in interventricular septa1 size by 22%, and a reduction in left ventricular posterior wall thickness by 33y0.~’ When equilibrium radionuclide angiography was performed at rest and during physical exercise, patients with childhood and adulthood onset of GHD had an impaired left ventricular systolic performance at &st and during physical exercise and reduced exercise tolerance, as shown by the significantly lower values of peak workload, peak ratepressure product, and exercise duration.85 Other studies have shown no significant cardiac impairment.”, 132 Left ventricular dimensions, mass, and systolic function were normal in patients with adult-onset GHD132but were reduced in childhoodonset GHD.90

Musculoskeletal System

Muscles

Adult patients with GHD have a reduced cross-sectional area of thigh muscle and reduced quadriceps force.38,115 Muscle strength is lower in the knee extensor, knee flexor, and h a n d g r i ~ .Maximal ~~ exercise performance is reduced.34.73

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Bone Density and Fracture Risk

Patients with childhood-onset and adult-onset GHD have decreased bone mass.6, 19. 40, 43. 63. 66. 83, 98, 113 In contrast, patients with GHD who are older than 50 years are no more osteopenic than age-matched controls.7o, lZ9Patients with GHD also have increased fracture rates.'@ One recent study reported a 2.66-fold increase in fracture risk in patients with hypopituitarism and GHD. Although the researchers suggested a clear relationship to the deficiency in growth hormone rather than to other features of hypopituitarism, they did not provide proof for that asserti~n.'~~ Body Composition

Adults with GHD have an increase in body fat. A 7% to 8% increase in subcutaneous and visceral adipose tissue corresponding to 2.4 to 6.6 kg has been reported. Coincident with the increase in body fat is a 7% to 8% decrease in lean body mass, corresponding to approximately 4 117, 138 These changes in body composition result in an kg8,20, 41, 76, 136 The deficits in body composition are increased waist-to-hip often more pronounced in adults with childhood-onset deficiency than with onset during adulthood.95Complicating the measurement of lean body mass versus fat mass is the fact that adults with GHD have decreased total body water as measured by radioisotope dilution techniques.'j, 111 Patients with GHD have less body water than persons who are growth hormone sufficient or who are given exogenous human growth hormone. Extracellular water,'9a, 41 plasma vo1ume:l and total blood volume33have all been reported to be decreased. QUALITY OF LIFE AND PSYCHOLOGIC WELL-BEING

Several different instruments have been used in assessing quality of life. The Nottingham Health Profile was used in the initial studies. Patients who have GHD report that quality of life is reduced in terms of less energy, a greater sense of social isolation, greater emotional lability, sexual difficulties, and a tendency toward earlier retirement when compared with control subjects.39, 89, 114 In a large multicenter study assessing the quality of life in 1034 patients with GHD using a diseasespecific questionnaire (QoL-AGHDA),the quality of life was reduced in a comparison with normal populations described in published ~ t u d i e s . ~ MORTALITY One of the major reasons why pituitary endocrinologists often favor replacing human growth hormone in patients with GHD is that, in

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addition to the effects on the body listed previously, patients with hypopituitarism have increased mortality.' Mortality owing to cardiovascular causes is most prevalent."O An increase in cerebrovascular mortality has been reported, but the issue of the potential role of radiotherapy as a cause of cerebrovascular disease must be considered.26Not in question is the fact that women with hypopituitarism and presumed or proven GHD have an increase in cardiovascular disease, an increase in the consumption of cardioactive drugs, and an increase in cardiovascular risk fact0rs.2~In addition to a lower degree of physical exercise when compared with controls, these patients have an increase in other cardiovascular risk factors. The mortality rate from cancer was not different from the rate for normal subjects in one study and was decreased by 50% in another study.', 26 TESTING FOR GROWTH HORMONE DEFICIENCY

Growth hormone secretion is pulsatile and is frequently not measurable during much of the day in normal individuals6I; therefore, the diagnosis of GHD must be established by demonstrating that human growth hormone is subnormal, even after stimulation by growth hormone secretagogues. The insulin tolerance test is considered the gold standard; however, insulin-induced hypoglycemia is contraindicated in patients with seizures or coronary artery disease and perhaps in patients older than 60 years.127,130 The utility of the insulin tolerance test may also be limited because it is usually performed in special endocrine units with a physician and a nurse in attendance. Alternative tests have included stimulation of human growth hormone with levodopa, arginine, growth hormone-releasing hormone (GHRH), glucagon, clonidine, and combinations of these agents. Recent studies have indicated that several of these tests may not be reliable enough to differentiate between patients with true GHD and other conditions. These include levodopa, clonidine, arginine, GHRH, and glucagon stimulations, and the authors' studies no longer recommend that these tests be used. Recent studies have shown that there is relatively clear delineation between patients who have GHD and patients who do not when the combination of arginine and GHRH is used. Ghigo and ~ o - w o r k e r s ~ ~ reported that all 54 patients with GHD had peak growth hormone responses to arginine and GHRH less than 9.5 ng/mL (range, 0.1-9.5 ng/mL), whereas 326 normal controls had peak growth hormone greater than 16.1 ng/mL (range, 16.1-119 ng/mL). Two other studies have reported similar results.133Biller and colleagues evaluated 39 adults with pituitary disease and two or more pituitary hormone deficiencies and 34 matched controls using the combined GHRH plus arginine tests. A cut-off value of 4.1 ng/mL had 95% sensitivity and 91% specificity. In the same study, a cut-off value of 5.1 ng/mL during insulin tolerance testing had 96% sensitivity and 92% specificity (Biller, 2001 Pituitary

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Congress, abstract accepted). It is not clear why the peak growth hormone response to the combined GHRH plus arginine stimulation was much lower in this report when compared with the Ghigo report. Gasperi and co-workersS1proposed using the combination of two secretagogues (GHRH and hexarelin). The peak growth hormone response to GHRH plus hexarelin in normal controls was 49 to 124 ng/ mL versus 0.1 to 11.1ng/mL in patients with GHD. Popovic and c o - ~ o r k e r sproposed '~~ another test using the combination of two secretagogues (GHRH and growth hormone releasing peptide-6 [GHRP-61).They studied 125 adults with a history of pituitary or hypothalamic lesions in whom growth hormone deficiency had been proven by insulin tolerance testing (peak growth hormone <3 ng/mL). All normal controls had human growth hormone responses of greater than 15 ng/mL. Furthermore, all normal controls except two had human growth hormone responses of greater than 20 ng/mL in response to the combination of the two secretagogues. All patients with GHD had human growth hormone responses less than 20 ng/mL and all of these patients except 15 had responses less than 10 ng/mL.Io7 Using the combination of GHRH and arginine, GHRP-6, or hexarelin caused a much greater rise in human growth hormone when compared with insulin tolerance testing. Although it seems clear that GHRH combined with one of the three other stimuli can be used to differentiate GHD and non-GHD patients, the significance of the apparent robust response to these secretagogues is not clear physiologically. It is rare to observe human growth hormone of 139 ng/mL during episodic or sleeprelated growth hormone peaks. The stimulation test and the assay used are important parameters in defining GHD. US Food and Drug Administration (FDA) criteria do not define the specific stimulation test. The FDA has defined that the peak serum growth hormone concentration should be less than 5 ng/ mL if measured by radioimmunoassay (RIA) or less than 2.5 ng/mL if measured by immunoradiometric assay (IRMA). Other authorities have recommended that the diagnosis be based on a stimulated serum growth hormone value of less than 3 ng/mL using insulin tolerance testing2 Investigators using insulin tolerance testing and polyclonal RIA with an 80/505 standard suggest cut-off values of less than 4.5 ng/ mL,lZ7whereas others using IRMA and a 66/217 standard suggest a cutoff of 2.5 ng/mL.130 Adult patients with hypothalamic-pituitary disease and one or more additional pituitary hormone deficits require only one stimulation test of growth hormone secretion for the diagnosis of deficiency. On the contrary, to establish the diagnosis of isolated growth hormone deficiency in adults, it is recommended that two stimulation tests of growth hormone secretion be abnormal.% Insulin-like Growth Factor 1 in Adults

The IGF-1 concentration is not completely reliable as a single diagnostic test for growth hormone deficiency in adults unless it is below

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normal and accompanies other pituitary hormone deficiencies.=,62,78,8O, lZo Hilding and co-workers@showed that all patients with childhood-onset GHD had IGF-1 values below -2 standard deviations (SD). On the contrary, in patients with adult-onset GHD, 34% of the IGF-1 levels were within normal range, increasing to 40% in the subgroup above 60 years of age. In the absence of other conditions known to lower serum IGF-1 levels, a low serum IGF-1 strongly points to GHD in patients younger than 40 years.5 Conditions that may present with low IGF-1 are liver disease, malnutrition, poorly controlled diabetes mellitus, and hypothyroidism. In the presence of two or more pituitary hormone deficiencies, a low serum IGF-1 level is highly indicative of growth hormone deficiency5It has been proposed that patients with three or four additional pituitary hormones deficiencies or a serum IGF-1 level less than 84 mg/ L (or below the age-appropriate standard deviation score [SDS] limit) do not require growth hormone stimulation testing for the diagnosis of adult GHD.57 In the presence of pituitary disease, a serum IGF-1 level less than 84 mg/L reliably predicted severe GHD with a high positive predictive value (95%) and high specificity (89%), but low sensitivity (69Y0):~

Retesting Patients with Childhood-Onset Growth Hormone Deficiency

In some studies, 40% to 67% of young adults with childhood-onset GHD did not meet the adult criteria for GHD when they were retested in adulthood.80,96, 125, 135 On the contrary, when strict criteria were used to define GHD in childhood (<5 ng/mL on each of two stimulation tests), on repeat testing in adulthood, 93% of patients were found to be growth hormone deficient. The cause of GHD in childhood is an important determinant of GHD in adults. As many as 67% of children initially diagnosed with idiopathic GHD had normal growth hormone responses when they were retested for GHD after growth hormone treatment was stopped.86,lZ5 In contrast, patients with GHD owing to organic diseases, such as tumors or defined genetic abnormalities, continue to have true GHD.', 31 The diagnosis of GHD should be reconfirmed before growth hormone treatment is continued into adulthood unless the patient has panhypopituitarism or a defined genetic or developmental abnormality that causes complete deficiency of growth hormone.'18 Recently, mutations in the growth hormone gene97,123 or the GHRH receptor gene12,l3 have been identified as the cause of isolated growth hormone deficiency. Mutations in the PropP4 or PitP" '02-'04, lo8,124 gene were identified as the cause of growth hormone deficiency combined with other anterior pituitary hormone deficiencies.

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TREATMENT

Growth hormone treatment reverses or improves many of the signs and symptoms associated with GHD. The most striking changes are noted in body composition. Body Composition Several studies have shown similar results.8,*l, 14, 56, 70, 94, 117, 136, 138 In one study, adipose tissue mass decreased by 4.7 kg and subcutaneous adipose tissue decreased by 13%, whereas visceral adipose tissue was reduced by 30% and muscle volume increased by 2.5 kg (5%).16As a result of these changes, the waist-to-hip ratio decreased.&,l5 Cardiovascular Left ventricular mass and cardiac output have been shown to be increased and diastolic abnormalities reversed in several studies.27,132 Boger and colleaguesz suggested that the improvement was caused by a decrease in peripheral resistance. In another study, no significant changes were noted concerning the measured left ventricular posterior wall, left atrium, or interventricular septum thickness or the left ventricular end-diastolic dimension (LVEDD), and left ventricular end-systolic dimension (LVESD).94This difference might have been explained by the dose of human growth hormone administered. Growth hormone treatment also normalized the intima-media thickness of the common carotid artery and significantly improved endothelial Lipid Most double-blind, placebo-controlled studies and open-label studies have shown an improvement in the lipid profile, although the improvement is not always uniform. A decrease in the total cholesterol and LDL cholesterol seem to be most c0mm0n.17~20~117 HDL has been reported to increase in some studies? l7 and to remain unchanged in others.2o,36 An increase in the HDL-to-LDL ratio was also reported.8 Triglyceride and apoA remained unchanged in most of the studies.*,17, 'l7* 136 Lipoprotein (a) elevation, which is associated with increased atherosclerosis,7.23 increased during growth hormone treatment in one study"" but remained unchanged in two other^.'^^,^^^ Carbohydrate In one study, there was no change in the fasting plasma glucose, glycosylated hemoglobin A1,135and carbohydrate tolerance138during

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growth hormone therapy, but fasting insulin and C-peptide and the mean area under the curve (AUC) for glucose and for insulin during the oral glucose tolerance test were significantly in~reased.'~ Studies showing an increase in the glycosylated hemoglobin have also been published.65 Patients who have GHD are insulin resistant, and, theoretically, this resistance may worsen during growth hormone treatment. In fact, high replacement doses of growth hormone have been shown to increase insulin resistance in the initial 1 to 6 weeks of therapy, but these changes are reversed with time (3-6 months), perhaps secondary to a reduction in visceral fat.50,99 To the authors' knowledge, this side effect has not been demonstrated with currently recommended lower doses of growth hormone. Muscle-Exercise Performance

Growth hormone replacement leads to an increase in total crosssectional area of thigh muscle and quadriceps muscle measured by CT.37,76 In short-term trials, only the strength of hip flexors and limb girdle muscles increased.37The quadriceps force and torque were increased in longer-duration studies (1-3 years).75,77 In another report, 2 years of growth hormone treatment significantly increased and normalized isometric knee extensor and flexor strengths but did not change handgrip strength. Again, the improvement was first observed after 1 year of treatrnent.'j9 Treatment with growth hormone significantly increased maximum oxygen cons~mption~~, 79, 94, 138 and exercise capacity.79, 138 The increased exercise performance was mainly caused by the growth hormoneassociated increased muscle mass.34 Thyroid and Glucocorticoid

Total and free triiodothyronine (T3) concentrations are significantly increased16,65 after growth hormone treatment. Patients receiving glucocorticoid-replacement therapy may need higher doses because growth hormone replacement may increase cortisol deg1-adati0n.l~~ Bones

Short- and long-term studies show an increase in bone remodeling as evidenced by increased markers of bone formation and bone resorption.6,11, 16, 18, 32, 41,43, 48, 55, 71,'09, 134 Growth hormone has a biphasic effect on the bones in adults with GHD. In short trials (up to 12 months), cortical and vertebral bone mass mildly decreased or remained unchanged over a 12-month treatment period.43, 82, lo9 Longer-duration studies have shown an increase in bone mineral 563

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density in the femur, vertebral, and forearm bone.98,126,134 Even after 4 years of growth hormone treatment, bone density continues to improve.82 Different response by gender has been reported. Total body bone mineral content, femoral neck bone mineral density, and bone mineral content and spinal bone mineral content were significantly increased in males but not in females after 45 months of therapy, although men received lower doses of growth hormone than did women.” Quality of Life

Assessing the effect of growth hormone therapy on quality of life has been complicated by the variety and nonspecificity of tests used for this analysis. Most of the initial studies used the Nottingham Health Profile questionnaire, which was designed to evaluate perception of pain, energy, sleep, emotional reactions, physical mobility, and social isolation. In a double-blind, placebo-controlled trial using the latter questionnaire, patients with GHD showed improvement in mood and energy levels, pain, and emotional reaction when compared with matched controls.35,89 Similar results were shown in a longer retrospective study for 50 months.139The quality of life improvement was maintained 10 years after the initiation of therapy.53In contrast, three randomized, double-blind, placebo-controlled studies of growth hormone replacement showed no significant changes in quality of lifelo and psychologic well-being.49, 138 In recent years, more specific tests have been used, such as the quality of life assessment of GHD in adults (QOL-AGHDA).~ Questions regarding energy, physical/mental drive, concentration/memory, personal/close relationships, social life, and emotions/cognition were asked so that a single score could be obtained. Using this more specific questionnaire, significant improvement was noted in males and females with adult-onset GHD but not in patients with childhood-onset GHD. The number of patients in the childhood-onset group was small. Patients receiving the highest doses of growth hormone demonstrated the greatest improvement in quality of life.15 Side Effects

The most common side effects of human growth hormone are edema, arthralgias, and myalgias, which have been reported to occur in approximately one third of patients.8,35 In addition, tightness in the hands or compression symptoms of carpal tunnel are common. These side effects are dose dependent and usually resolve within days or a few weeks after dose reduction. In the early, randomized growth hormone-replacement studies, higher doses of growth hormone were used. As a result of the high dose, the incidence of side effects was high.67 Patients at a higher risk for adverse effects on growth hormone

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replacement are older, obese, and have higher growth hormone responses on provocative testing and higher IGF-1 after growth hormone treatment.@Side effects are more common among patients with adultonset deficiency than among patients with childhood-onset GHD.30 Currently, the starting doses for adults with GHD are approximately 75% lower than the doses used in 1989. The starting dose can be given according to weight (e.g., 3 pg/kg/day) or generalized as 0.3 mg/day. The doses are then titrated to achieve and maintain serum concentrations of IGF-1 within normal limits and to avoid side effects.45, 93 Of some concern are recent reports associating high-normal IGF-1 with prostate cancer riskz8,55, lo6, and breast cancer risk in premenopausal women.z4~55~128 In these studies, the IGF-1 levels were in the upper quintile or quartile for age and sex. For this reason, some endocrinologists have tried raising the IGF-1 level into the midnormal range. In view of these findings, it is difficult to understand why patients with acromegaly do not have an increased incidence of cancer. In fact, the only cancer that has been found to be increased in acromegaly is colon cancer.lol Benign intracranial hypertension (BIH)has been reported in association with growth hormone mainly in children. This complication has improved with cessation of therapy. Data regarding tumor recurrence exist only from long-term studies in children. No increased risk of recurrence is associated with growth hormone therapy.21,92, 121, lZ2 Contraindications

Absolute contraindications for growth hormone treatment are active malignancy, carpal tunnel syndrome, benign intracranial hypertension, and proliferative or preproliferative diabetic retinopathy. SUMMARY

In adults, GHD is a clinical syndrome that occurs in patients with pituitary or hypothalamic disease. It may be asymptomatic or present with relatively nonspecific constitutional symptoms. Most patients have abnormal body composition, consisting of increased fat mass and decreased lean mass. Life expectancy is significantly decreased in hypopituitary patients with GHD, with cardiovascular disease a common cause of death. Treatment with growth hormone reverses abnormalities in body composition and may reduce cardiovascular risk factors; however, the long-term treatment outcomes regarding mortality, the incidence of cardiovascular disease, bone fractures, tumor development, and recurrence are not known. Longer prospective clinical studies are needed. The major manufacturers of growth hormone have initiated postmarketing surveillance databases to monitor the safety of growth hormone treatment.

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References 1. The Canadian Growth Hormone Advisory Committee: The specificity of growth hormone stimulation tests in childhood and adolescence. Clin Invest Med 13(s~ppl):B28-B28,1990 2. Consensus guidelines for the diagnosis and treatment of adults with growth hormone deficiency: Summary statement of the Growth Hormone Research Society Workshop on Adult Growth Hormone Deficiency. J Clin Endocrinol Metab 83:379-381, 1998 3. Abs R, Bengtsson BA, Hemberg-Stahl E, et al: GH replacement in 1034 growth hormone deficient hypopituitary adults: Demographic and clinical characteristics, dosing and safety. Clin Endocrinol (Oxf) 50:703-713,1999 4. Aimaretti G, Comeli G, Razzore P, et a1 Comparison between insulin-induced hypoglycemia and growth hormone (GH)-releasing hormone + arginine as provocative tests for the diagnosis of GH deficiency in adults. J Clin Endocrinol Metab 83:16151618, 1998 5. Aimaretti G, Comeli G, Razzore P, et al: Usefulness of IGF-I assay for the diagnosis of GH deficiency in adults. J Endocrinol Invest 21:506-511, 1998 6. Amato G, Carella C, Fazio S, et al: Body composition, bone metabolism, and heart structure and function in growth hormone (GH)deficient adults before and after GH replacement therapy at low doses. J Clin Endocrinol Metab 771671-1676, 1993 7. Armstrong VW, Cremer P, Eberle F, et a1 The association between serum Lp(a) concentrations and angiographically assessed coronary atherosclerosis: Dependence on serum LDL levels. Atherosclerosis 62:249-257, 1986 8. Attanasio AF, Lamberts SWJ, Matranga AMC, et al: Adult growth hormone (GH)deficient patients demonstrate heterogeneity between childhood onset and adult onset before and during human GH treatment. J Clin Endocrinol Metab 828248, 1997 9. Bates AS, Van't Hoff W, Jones PJ, et al: The effect of hypopituitarism on life expectancy. J Clin Endocrinol Metab 81:1169-1172, 1996 10. Baum HB, Katznelson L, Sherman JC, et al: Effects of physiological growth hormone (GH) therapy on cognition and quality of life in patients with adult-onset GH deficiency. J Clin Endocrinol Metab 83:3184-3189, 1998 11. Baum HBA, Biller BMK, Finkelstein JS, et al: Effects of physiologic growth hormone therapy on bone mineral density and body composition in patients with adult-onset growth hormone deficiency. Ann Intem Med 125:883490, 1996 12. Baumann G: Mutations in the growth hormone releasing hormone receptor: A new form of dwarfism in humans. Growth Horm IGF Res 9(suppl B):24-29; discussion, 29-30:24-29,1999 13. Baumann G, Maheshwari H: The dwarfs of Sindh Severe growth hormone (GH) deficiency caused by a mutation in the GH-releasing hormone receptor gene. Acta Paediatr Suppl423:3>38,1997 14. Bengtsson B, Eden S, Lonn L, et al: Treatment of adults with growth hormone (GH) deficiency with recombinant human GH. J Clin Endocrinol Metab 76:309-317,1993 15. Bengtsson BA, Abs R, Bennmarker H, et a1 The effects of treatment and the individual responsiveness to growth hormone (GH) replacement therapy in 665 GH-deficient adults: K N S Study Group and the KIMS International Board. J Clin Endocrinol Metab W3929-3935,1999 16. Bengtsson BA, Eden S, LOM I, et al: Treatment of adults with growth hormone (GH) deficiency with recombinant human GH. J Clin Endocrinol Metab 76309-317,1993 17. Beshyah SA, Henderson A, Niththyananthan R, et a1 The effects of short and long term growth hormone replacement therapy in hypopituitary adults on lipid metabolism and carbohydrate tolerance. J Clin Endocrinol Metab 80356-363, 1995 18. Beshyah SA, Thomas E, Kyd P, et al: The effect of growth hormone replacement therapy in hypopituitary adults on calcium and bone metabolism. Clin Endocrinol 40:383-391, 1994 19. Bing-You RG, Denis MC, Rosen CJ: Low bone mineral density in adults with previous hypothalamic-pituitary tumors: Correlations with serum growth hormone responses to GH-releasing hormone, insulin-like growth factor I, and IGF binding protein 3. Calcif Tissue Int 52:183-187, 1993 19a. Binnerts A, Deurenberg , ' l Swart GR, et al: Body composition in growth hormonedeficient adults. Am J Clin Nutr 55:918-923, 1992

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