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Table of Contents
REVIEW ARTICLE
Year : 2011  |  Volume : 15  |  Issue : 7  |  Page : 197-202

Adult growth hormone deficiency


Department of Endocrinology, Jaslok Hospital and Research Centre, Mumbai, India

Date of Web Publication13-Sep-2011

Correspondence Address:
Vishal Gupta
Department of Endocrinology, Jaslok Hospital and Research Centre, 15, Deshmukh Marg, Mumbai 400 026
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/2230-8210.84865

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   Abstract 

Adult growth hormone deficiency (AGHD) is being recognized increasingly and has been thought to be associated with premature mortality. Pituitary tumors are the commonest cause for AGHD. Growth hormone deficiency (GHD) has been associated with neuropsychiatric-cognitive, cardiovascular, neuromuscular, metabolic, and skeletal abnormalities. Most of these can be reversed with growth hormone therapy. The insulin tolerance test still remains the gold standard dynamic test to diagnose AGHD. Growth hormone is administered subcutaneously once a day, titrated to clinical symptoms, signs and IGF-1 (insulin like growth factor-1). It is generally well tolerated at the low-doses used in adults. Pegylated human growth hormone therapy is on the horizon, with a convenient once a week dosing.

Keywords: Adult growth hormone deficiency, growth hormone, growth hormone deficiency, hypopituitarism, panhypopituitarism


How to cite this article:
Gupta V. Adult growth hormone deficiency. Indian J Endocr Metab 2011;15, Suppl S3:197-202

How to cite this URL:
Gupta V. Adult growth hormone deficiency. Indian J Endocr Metab [serial online] 2011 [cited 2019 Jul 23];15, Suppl S3:197-202. Available from: http://www.ijem.in/text.asp?2011/15/7/197/84865


   Introduction Top


Adult onset growth hormone deficiency (AGHD) may represent two distinct clinical situations:

  1. Children with growth hormone (GH) deficiency transitioning to adulthood or
  2. GH deficiency acquired during adulthood (structural/trauma or idiopathic).


Over the past decade, there has been an increasing recognition of premature mortality associated with hypopituitarism. There is a two- to three-fold increase in standardized mortality in these patients with hypopituitarism. [1] The increased mortality is probably related to macrovascular disease (cardiovascular and cerebrovascular). [2] The fact that these patients with increased mortality were replaced with steroids, thyroxine and a majority were on male hormone replacement, led some experts to believe that GHD may have contributed to the increased mortality.

GH is the first hormone to deplete following any pituitary insult. It was not until 1995 that the concept of growth hormone replacement became popular and recognized.


   Historical Review Top


In 1922 Evans and Long [3] injected the beef pituitary extract to animals (rats) and reported excessive growth. Smith, [4] a few years later, showed the opposite effect of growth cessation following hypophysectomy in rats with re-growth following implantation of pituitary tissue. This suggested the possibility of a substance in the pituitary responsible for growth.

In 1908, it was further thought that this pituitary factor promoting growth might be diabetogenic. [5] It was only after 1950 that the combined effects were explained by one single substance, growth hormone. Houssay's was awarded the Nobel Prize in 1947 for his extensive work on the hypophysis and carbohydrate metabolism. [6] Salmon and Daughaday [7] suggested that GH action was mediated via a factor, named sulfation factor, only later to be identified as somatomedin. This was given a new name: insulin-like growth factor-1 (IGF-1) to indicate its chemical similarity to (pro)insulin. The complete structure with 70 amino acids was reported in 1978.

In 1944, Li and Evans were the first to claim that bovine GH had been isolated. [8],[9] Berson and Yalow engineered a radioimmunoassay for GH that was later used to determine plasma IGF-1. [10],[11]

The first results of treating children with GH were published in 1932. [12] The report by Raben [13] is quoted as the first successful example of the use of GH extracted from human pituitaries. The patient was a young hypopituitary man who responded to GH treatment with an accelerated growth.

As the source of GH (human pituitaries) was limited, in most countries, distribution and use of GH was regulated and supervised by official bodies, for example in the United States by the National Pituitary Agency (NPA). Creutzfeldt-Jakob's disease was a dreaded complication of GH therapy obtained from human pituitary, resulting in death of patients. [14] In 1979, a commercial company (Genentech) decided to produce GH by inserting the gene controlling GH synthesis into bacteria. [15] From around 1985, pharmaceutical companies started manufacturing recombinant GH.


   Physiology of Growth Hormone Top


The 24-h profile of plasma growth hormone levels in normal adults consists of stable low levels interrupted by bursts of secretion. The most reproducible pulse occurs shortly after the onset of sleep associated with the first phase of slow-wave sleep (stages III and IV). [16]

In men, approximately 70% of the GH pulses during sleep coincide with slow-wave sleep. The GH pulse is generally the largest and often the only pulse observed over a 24-h period. In women, in contrast to the men, GH pulses occur predominantly during daytime contributing to the greater part of the 24-h release of GH. The total amount and the temporal distribution of GH release are strongly dependent on age. As age advances from term infants (tonic GH secretion) to mature infants the frequency and amplitude of the GH pulses decrease, and tonic secretion diminishes. As puberty is reached, the pulsatile pattern of GH release occurs with increased amplitudes during sleep in both boys and girls. Maximal overall GH concentrations are reached in early puberty in girls and in late puberty in boys. The amount of GH secreted daily in healthy men older than 65 years of age is generally less than one-third that in men younger than 30 years. [17],[18],[19],[20]


   Etiology of Growth Hormone Deficiency Top


The KIMS database, [21] which is a multinational pharmaco-epidemiological surveillance database for adult hypopituitary patients receiving growth hormone therapy, revealed pituitary adenoma and carniopharyngioma as the most important cause for AGHD accounting for 65% of the patients. The HypoCCS study revealed an elegant distribution of possible etiologies of GHD with differences in presentations in the mid-1990s and mid-2000s. In the mid-1990s, pituitary adenoma (50.2%), idiopathic growth hormone deficiency (13.9%), carniopharyngioma (13.3%), non-pituitary intracranial tumors (8.2%), non-common diagnosis (sarcoidosis, empty sella, hypophysitis, pituitary infection, known and unknown genetic abnormalities, and cranial irradiation) (7.4%), pituitary hemorrhage (5.8%), and unspecified diagnosis (1.3%) were reported as common causes. The same authors demonstrated an increase in idiopathic growth hormone deficiency (19.3%), non-common causes (15.8%), and undefined causes (8.6%) by the mid-2000s with a decrease in other causes such as pituitary adenoma (38%), carniopharyngioma (8.4%), and pituitary hemorrhage (2.8%). [22]

Traumatic brain injury (6-20%) and subarachnoid hemorrhage (12-37%) may result in GHD more frequently than previously suspected. [23]


   Clinical Features of Growth Hormone Deficiency Top


The symptomology can be discussed under neuropsychiatric-cognitive, cardiac, metabolic, muscular, and bone symptoms, such as:

  • Changes in memory, processing speed and attention
  • Lack of well-being
  • Depression
  • Anxiety
  • Social isolation
  • Fatigue
  • Lack of strength
  • Fibromyalgia syndrome
  • Neuromuscular dysfunction
  • Central adiposity
  • Decreased muscle mass
  • Decreased bone density
  • Impaired cardiac function
  • Decreased insulin sensitivity
  • Accelerated atherogenesis with increased carotid intima-media thickness
  • Increased low-density lipoprotein
  • Prothrombotic state
  • Decreased sweating and thermoregulation. [24],[25],[26],[27],[28],[29],[30],[31],[32]


Neuropsychiatric-cognitive abnormalities

Patients with GHD frequently complain of low energy levels, emotional lability, and mental fatigue, resulting in a low perceived quality of life. GH replacement treatment for 6-12 months can lead to significant improvements in body composition, muscle strength, self-esteem scores, energy levels, and emotional reactions. [33]

Another study demonstrated that up to 70% of patients with the fibromyalgia syndrome exhibited a suboptimal growth hormone response to dynamic testing. Treatment with growth hormone resulted in improvement in perceived energy levels, body image, and pain level [24] and cognition. [34]

Cardiovascular morbidity and mortality

Although a matter of much debate, several authors have demonstrated increased cardiovascular mortality. [1],[2],[35] GH deficiency and insufficiency are associated with higher levels of plasminogen activator inhibitor-I levels (prothrombotic), carotid intima-media thickness, and loss of circulating CD34+ cells, suggesting endothelial dysfunction. Some groups have also shown compromised coronary reserved flow. [36] The degree of GHD is directly related to increased total cholesterol, low-density lipoprotein-C (LDL), truncal fat, waist-hip ratio, and risk of hypertension, all responsible for the proposed increased cardiovascular mortality. [32],[37],[38] A meta-analysis on the effects of various cardiovascular parameters were studied in patients treated with GH and it was seen that lean body mass, LDL cholesterol, total cholesterol, and diastolic blood pressure improved significantly with use of GH in GH-deficient adults. [39]

Body composition and metabolic abnormalities

GHD adults have reduced lean body mass and increased abdominal adiposity. In a study of 15 healthy adult women, the authors showed that GH secretion was much reduced in patients with high truncal fat compared to those with low truncal fat. [40] Truncal obesity is associated with metabolic syndrome and insulin resistance. Although the truncal fat improves (reduces) as early as 3 months of GH replacement, the antagonistic actions of GH on insulin, mediated by hepatic effects and increased plasma free fatty acids, cause further decline in insulin sensitivity that improves only after 1 year of GH therapy. [28],[41],[42] GH deficiency is associated with hypertriglyceridemia, hypertension, [33] and low levels of high density lipoprotein (HDL) which has shown to improve following recombinant GH replacement. [43] A meta-analysis of 37 blinded, randomized, placebo-controlled trials found an overall beneficial effect of GH replacement therapy on LDL cholesterol and total cholesterol profiles, however did not show consistent benefits on HDL cholesterol or triglyceride levels. [39]

Muscular abnormalities

GH deficiency has been associated with reduced lean muscle mass and impaired neuromuscular function. [44],[45] There was an improvement of lean mass, neuromuscular function (isometric knee flexor strength) that was sustained over a 10-year period while of GH replacement. In a very interesting study of patients with the fibromyalgia syndrome, up to 70% of patients were shown to have GHD which showed a marked improvement in symptomology following growth hormone replacement. [24]

Bone abnormalities

Although GH may act directly on skeletal cells, most of its effects are mediated by IGF-I, which is present in the systemic circulation and is synthesized by peripheral tissues. AGHD causes low bone turnover osteoporosis with high risk of vertebral and nonvertebral fractures, and the low bone mass. GH replacement reverses this situation rapidly, resulting in increases in markers of bone formation (e.g. osteocalcin and bone-specific alkaline phosphatase) and bone resorption (e.g. urine deoxypyridinoline). This increase in bone metabolism eventually results in an increase in bone mineral density (BMD), but it is only after 18 months of therapy that it becomes evident. [46],[47],[48]

Diagnosis

There are consensus guidelines for the diagnosis and management of GHD in adults. Recombinant GH therapy got approved by the U.S. Food and Drug Administration (FDA) in 1996.

Dynamic testing forms the mainstay of diagnosis. Patients with childhood-onset GHD should be retested for GHD as adults, unless they have known mutations, embryopathic lesions, or irreversible structural lesions/damage, as reversal of diagnosed GHD is known to occur. Adult patients with structural hypothalamic/pituitary disease, surgery or irradiation in these areas, or other pituitary hormone deficiencies should be considered for evaluation for acquired GHD.

Available dynamic testing options are:

  1. The insulin tolerance test (GH peak measurement of 3 μg/l or less is indicative of severe AGHD) [49] for an optimal cutoff of GH of 5.1 μg/l (96% sensitivity and 92% specificity). [49],[50] This remains the gold standard.
  2. The glucagon stimulation test.
  3. Combined growth hormone releasing hormone (GHRH) and the arginine test (95% sensitivity and 91% specificity at a GH cutoff of 4.1 μg/l). [50],[51]
  4. Levodopa.
  5. Arginine plus levodopa.
  6. Clonidine.
  7. Growth-hormone-releasing peptide 2. [52]


A cutoff of 3 μg/l defines severe GHD, whereas a cutoff value of 5 μg/l defines GHD. A balance between high sensitivity and high specificity can be achieved with a cutoff level of GH 5.1 μg/l. [50] Amongst all the dynamic tests, the Insulin tolerance test and combined GHRH and arginine test have the best sensitivity and specificity.

Other ancillary diagnostic tests include:

  1. IGF-1 (Insulin like growth factor-1).
  2. IGF-BP3 (IGF-binding protein 3).


Having normal levels of IGF-I and IGFBP-3 does not exclude a diagnosis of GHD in adults. [49],[50],[53] IGF-I can be of some diagnostic assistance if levels are below the age-adjusted normal range. Although IGF-1 can be very useful in diagnosis of AGHD, appropriate population based cutoffs, expressed as a IGF-1 standard deviation score (IGF-1 SDS), can prove to be more useful as an isolated diagnostic marker in adults. IGF-BP3, although useful, does not provide any further diagnostic accuracy over IGF-1. [54]

Treatment

Once the diagnosis of GHD is established, an ideal replacement regimen should be instituted and titrated to a clinical response and serum IGF-1 level. Several quality of life questionnaires have been used to assess clinical response, e.g. adult growth hormone deficiency assessment (AGHDA) score, Nottingham Health Profile (NHP); Psychological General Well Being Scale (PGWB) and disease-specific questionnaires like {Questions on Life Satisfaction Hypopituitarism (QLS-H)}. [55]

GH therapy can affect the metabolism of other hormones. GH is known to affect 11BHSD-1 (11-betahydroxydehydrogenase-1), hence initiation of GH may lead to partial cortisol deficiency. [56] GH may also interact with the TSH axis. Patients on thyroxine replacement frequently require an increase in their dose [57] probably because of enhanced peripheral conversion of T4 to T3 mediated via GH. It may also have a central inhibitory effect on TSH. Women require a higher GH dose than men to achieve a similar increment in IGF-I. GH sensitivity is blunted in females on oral estrogen. [58] Therefore, a thorough assessment of the pituitary gland in its entirety is required before considering isolated GH therapy.

Dosing regimens have evolved from weight-based dosing to individualized dose-titration strategies. In general, women require higher doses of GH to achieve the same IGF-I response. [48] GH secretion normally decreases with age. GH dose requirements are lower in older patients. For patients aged 30-60 years, a starting dose of 300 μg/day is reasonable and is usually not associated with any side effects. Daily dosing should be increased by 100-200 μg every 1-2 months titrated to the IGF-1, which should generally be kept in the upper half of the reference range, although no published studies offers specific guidance in this regard. Clinical benefits may not become apparent for 6 or more months of treatment. Older (>60 years) patients should be started on lower doses (100-200 μg/day) and increased more slowly. Younger (<30 years) patients may benefit from higher initial doses (400-500 μg/day); for patients transitioning from pediatric treatment, even higher doses may be appropriate. [49] Pegylated long-acting human growth hormone is on the horizon, which has been found to be efficacious, safe, well-tolerated, once-weekly treatment of adult patients with GHD. [59]

Most adverse effects include fluid retention (5-18%), hypertension, paresthesias, joint stiffness, peripheral edema, arthralgia, and myalgias, carpal tunnel syndrome (2%). Adult patients who are older, heavier, or female are more prone to develop these complications. [60] Most of these adverse reactions improve with dose reduction. Insulin resistance and type 2 diabetes [61] can occur or worsen in patients with pre-existing diabetes. Retinopathy, benign intracranial hypertension, and gynecomastia are rare. [62],[63],[64]

Although there might have been some concern with respect to the risk of cancer with the use of GH therapy, an increase in the recurrence rates of either intracranial or extracranial tumors has not been demonstrated in AGHD. [65],[66]


   Conclusions Top


GHD (isolated or as part of multiple hormone deficiencies) is being increasingly recognized as a cause of premature mortality. Over the last decade or two, much of our understanding on various clinical presentations of GHD has improved. The documented benefits of replacement therapy have helped improve the quality of life of many patients lives with AGHD. Replacement is well tolerated. The long-term fears of tumor recurrence or re-growth have not been confirmed by most observational studies, and until proven otherwise, GH therapy should be routinely prescribed and titrated to reap clinical benefits.

 
   References Top

1.Rosen T, Bengtsson BA. Premature mortality due to cardiovascular disease in hypopituitarism. Lancet 1990;336:285-8.  Back to cited text no. 1
    
2.Bülow B, Hagmar L, Mikoczy Z, Nordström CH, Erfurth EM. Increased cerebrovascular mortality in patients with hypopituitarism. Clin Endocrinol (Oxf) 1997;46:75-81.  Back to cited text no. 2
    
3.Evans HM, Long JA. Characteristic effects upon growth, oestrus, and ovulation induced by the intra peritoneal administration of fresh anterior hypophyseal substance. Proc Natl Acad Sci U S A 1922;8:38-9.  Back to cited text no. 3
    
4.Smith PE. The disabilities caused by hypophysectomy and their repair. J Am Med Assoc 1927;88:158-61.  Back to cited text no. 4
    
5.Borchardt. Die Hypophysenglykosurie und ihre Beziehun- gen zum Diabetes bei der Akromegalie. Z Klin Med L 1908;66:332-48.   Back to cited text no. 5
    
6.Houssay BA, Biasotti A. The hypophysis, carbohydrat metabolism and diabetes. Endocrinology 1957;15:511-23.  Back to cited text no. 6
    
7.Salmon WD Jr, Daughaday WH. A hormonally controlled serum factor which stimulates sulfate incorporation by cartilage in vitro. J Lab Clin Med 1957;49:825-36.  Back to cited text no. 7
    
8.Li CH, Evans HM. The isolation of pituitary growth hormone. Science 1944;99:183-4.  Back to cited text no. 8
    
9.Li CH, Yamashiro D. The synthesis of a protein possessing growth-promoting and lactogenic action. J Am Chem Soc 1970;92:7608-9.  Back to cited text no. 9
    
10.Glick SM, Roth J, Yalow RS, Berson SA. Immunoassay of human growth hormone. Nature 1963;199:784-7.  Back to cited text no. 10
    
11.Furlanetto RW, Underwood L, Van Wyk JJ, d'Ercole AJ. Estimation of somatomedin-C levels in normals and patients with pituitary disease by radioimmunoassay. J Clin Invest 1977;60:648-57.  Back to cited text no. 11
    
12.Engelbach W. The growth hormone. Endocrinology 1932;16:1-19.  Back to cited text no. 12
    
13.Raben MS. Treatment of pituitary dwarf with human growth hormone. J Clin Endocrinol Metab 1958;18:901-3.  Back to cited text no. 13
    
14.Koch TK, Berg BO, De Armand SJ, Gravina RF. Creutzfeldt-Jakob disease in a young adult with idiopathic hypopituitarism. Possible relationship to administration of cadaveric human growth hormone. N Engl J Med 1985;313:731-3.  Back to cited text no. 14
    
15.Cronin MJ. Pioneering recombinant growth hormone manufacturing: Pounds produced per mile of height. J Pediatr 1997;131:55-7.  Back to cited text no. 15
    
16.Van Cauter E, Kerkhofs M, Caufriez A, Van Onderbergen A, Thorner MO, Copinschi G. A quantitative estimation of GH secretion in normal man: Reproducibility and relation to sleep and time of day. J Clin Endocrinol Metab 1992;74:1441-50.  Back to cited text no. 16
    
17.Takahashi Y, Kipnis DM, Daughaday WH. Growth hormone secretion during sleep. J Clin Invest 1968;47:2079-90.  Back to cited text no. 17
    
18.Miller JD, Esparza A, Wright NM, Garimella V, Lai J, Lester SE, et al. Spontaneous growth hormone release in term infants: Changes during the first four days of life. J Clin Endocrinol Metab 1993;76:1058-62.  Back to cited text no. 18
    
19.Costin G, Kaufman FR, Brasel JA. Growth hormone secretory dynamics in subjects with normal stature. J Pediatr 1989;115:537-44.  Back to cited text no. 19
    
20.Ho KY, Evans WS, Blizzard RM, Veldhuis JD, Merriam GR, Samojlik E, et al. Effects of sex and age on the 24-hour profile of growth hormone secretion in man: Importance of endogenous estradiol concentrations. J Clin Endocrinol Metab 1987;64:51-8.  Back to cited text no. 20
    
21.Abs R, Bengtsson BA, Hernberg-Stahl E, Monson JP, Tauber JP, Wilton P, et al.; On behalf of the KIMS Study Group. Growth hormone replacement in 1034 GH deficient adults: Demographic and clinical characteristics, dozing and safety. Clin Endocrinol 1999;50:703-13.  Back to cited text no. 21
    
22.Webb SM, Strasburger CJ, Mo D, Hartman ML, Melmed S, Jung H, et al.; HypoCCS International Advisory Board. Changing patterns of adult growth hormone deficiency diagnosis documented in decade long global surveillance disease. J Clin Endocrinol Metab 2009;94:392-9.  Back to cited text no. 22
    
23.Schneider HJ, Kreitschmann-Andermahr I, Ghigo E, Stalla GK, Agha A. Hypothalamopituitary dysfunction following traumatic brain injury and aneurismal subarachnoid hemorrhagic: A systematic review. JAMA 2007;298:1429-38.  Back to cited text no. 23
    
24.Romano T. Adult growth hormone deficiency in fibromyalgia. PB89 Pain Practice Issue: Volume 9 Sup 1, March 2009, p 118  Back to cited text no. 24
    
25.Van Dam PS. Neurocognitive function in adults with growth hormone deficiency. Horm Res 2005;64 Suppl 3:109-14.  Back to cited text no. 25
    
26.Murray RD, Adams JE, Shalet SM. Adults with partial growth hormone deficiency have an adverse body composition. J Clin Endocrinol Metab 2004;89:1586-91.  Back to cited text no. 26
    
27.Murray RD, Adams JE, Shalet SM. A densitometric and morphometric analysis of the skeleton in adults with varying degrees of growth hormone deficiency. J Clin Endocrinol Metab 2006;91:432-8.  Back to cited text no. 27
    
28.Murray RD, Shalet SM. Insulin sensitivity is impaired in adults with varying degrees of GH deficiency. Clin Endocrinol 2005;62:182-8.  Back to cited text no. 28
    
29.Colao A, Cerbone G, Pivonello R, Aimaretti G, Loche S, Di Somma C, et al. The growth hormone (GH) response to the arginine plus GH-releasing hormone test is correlated to the severity of lipid profile abnormalities in adult patients with GH deficiency. J Clin Endocrinol Metab 1999;84:1277-82.  Back to cited text no. 29
    
30.Colao A, Di Somma C, Cuocolo A, Filippella M, Rota F, Acampa W, et al. The severity of growth hormone deficiency correlates with the severity of cardiac impairment in 100 adult patients with hypopituitarism: An observational, case-control study. J Clin Endocrinol Metab 2004;89:5998-6004.  Back to cited text no. 30
    
31.Colao A, Di Somma C, Pivonello R, Loche S, Aimaretti G, Cerbone G, et al. Bone loss is correlated to the severity of growth hormone deficiency in adult patients with hypopituitarism. J Clin Endocrinol Metab 1999;84:1919-24.  Back to cited text no. 31
    
32.Murray RD, Wieringa G, Lawrance JA, Adams JE, Shalet SM. Partial growth hormone deficiency is associated with an adverse cardiovascular risk factor profile and increased carotid intima-medial thickness. Clin Endocrinol (Oxf) 2010;73:508-15.  Back to cited text no. 32
    
33.Wallymahmed ME, Foy P, Shaw D, Hutcheon R, Edwards RH, MacFarlane IA. Quality of life, body composition and muscle strength in adult growth hormone deficiency: The influence of growth hormone replacement therapy for up to 3 years. Clin Endocrinol 1997;47:439-46.  Back to cited text no. 33
    
34.Sathiavageeswaran M, Burman P, Lawrence D, Harris AG, Falleti MG, Maruff P, et al. Effects of GH on cognitive function in elderly patients with adult-onset GH deficiency: A placebo-controlled 12-month study. Eur J Endocrinol 2007;156:439-47.  Back to cited text no. 34
    
35.Bengtsson BA. Untreated growth hormone deficiency explains premature mortality in patients with hypopituitarism. Growth Horm IGF Res 1998;8 Suppl A:77-80.  Back to cited text no. 35
    
36.Oflaz H, Sen F, Elitok A, Cimen AO, Onur I, Kasikcioglu E, et al. Coronary flow reserve is impaired in patients with adult growth hormone (GH) deficiency. Clin Endocrinol (Oxf) 2007;66:524-9.  Back to cited text no. 36
    
37.Verhelst J, Abs R. Cardiovascular risk factors in hypopituitary GH-deficient adults. Eur J Endocrinol 2009;161 Suppl 1:S41-9.  Back to cited text no. 37
    
38.van der Klaauw AA, Pereira AM, Rabelink TJ, Corssmit EP, Zonneveld AJ, Pijl H, et al. Recombinant human GH replacement increases CD34+ cells and improves endothelial function in adults with GH deficiency. Eur J Endocrinol 2008;159:105-11.  Back to cited text no. 38
    
39.Maison P, Griffin S, Nicoue-Beglah M, Haddad N, Balkau B, Chanson P. Impact of growth hormone (GH) treatment on cardiovascular risk factors in GH-deficient adults: A metaanalysis of blinded, randomized, placebo-controlled trials. J Clin Endocrinol Metab 2004;89:2192-9.   Back to cited text no. 39
    
40.Miller KK, Biller BM, Lipman JG, Bradwin G, Rifai N, Klibanski A. Truncal adiposity, relative growth hormone deficiency and cardiovascular risk. J Clin Endocrinol Metab 2005;90:768-74.  Back to cited text no. 40
    
41.Fowelin J, Attrall S, Lager I, Bengtsson BÅ. Effects of treatment with recombinant human growth hormone on insulin sensitivity and glucose metabolism in adults with growth hormone deficiency. Metabolism 1993;42:1443-7.  Back to cited text no. 41
    
42.Weaver JU, Monson JP, Noonan K, John WG, Edwards A, Evans KA, et al. 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 1995;80:153-9.  Back to cited text no. 42
    
43.van der Klaauw AA, Biermasz NR, Feskens EJ, Bos MB, Smit JW, Roelfsema F, et al. The prevalence of the metabolic syndrome is increased in patients with GH deficiency, irrespective of long-term substitution with recombinant human GH. Eur J Endocrinol 2007;156:455-62.  Back to cited text no. 43
    
44.Webb SM, de Andrés-Aguayo I, Rojas-García R, Ortega E, Gallardo E, Mestrón A, et al. Neuromuscular dysfunction in adult growth hormone deficiency. Clin Endocrinol (Oxf) 2003;59:450-8.  Back to cited text no. 44
    
45.Götherström G, Elbornsson M, Stibrant-Sunnerhagen K, Bengtsson BA, Johannsson G, Svensson J. Muscle strength in elderly adults with GH deficiency after 10 years of GH replacement. Eur J Endocrinol 2010;163:207-15.  Back to cited text no. 45
    
46.Giustina A, Mazziotti G, Canalis E. Growth hormone, insulin-like growth factors, and the skeleton. Endocr Rev 2008;29:535-59.  Back to cited text no. 46
    
47.Johannsson G, Rosen T, Bosaeus I, Sjostrom L, Bengtsson BÅ. 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 1996;81:2865-7.  Back to cited text no. 47
    
48.Drake WM, Coyte D, Camacho-Hübner C, Jivanji NM, Kaltsas G, Wood DF, et al. Optimising growth hormone replacement therapy by dose titration in hypopituitary adults. J Clin Endocrinol Metab 1999;83:3913-9.  Back to cited text no. 48
    
49.Molitch ME, Clemmons DR, Malozowski S, Merriam GR, Shalet SM, Vance ML; Endocrine Society's Clinical Guidelines Subcommittee. Evaluation and treatment of adult growth hormone deficiency: An endocrine society clinical practice guideline. J Clin Endocrinol Metab 2006;91:1621-34.  Back to cited text no. 49
    
50.Biller BM, Samuels MH, Zagar A, Cook DM, Arafah BM, Bonert V, et al. Sensitivity and specificity of six tests for the diagnosis of adult GH deficiency. J Clin Endocrinol Metab 2002;87:2067-79.  Back to cited text no. 50
    
51.Chanson P, Cailleux-Bounacer A, Kuhn JM, Weryha G, Chabre O, Borson-Chazot F, et al. Comparative validation of the growth hormone-releasing hormone and arginine test for the diagnosis of adult growth hormone deficiency using a growth hormone assay conforming to recent international recommendations. J Clin Endocrinol Metab 2010;95:3684-92.  Back to cited text no. 51
    
52.Bowers CY, Merriam GR, Veldhuis JD. Validation of growth-hormone-releasing peptide 2 for the diagnosis of adult growth hormone deficiency. Nat Clin Pract Endocrinol Metab 2008;4:68-9.  Back to cited text no. 52
    
53.Hilding A, Hall K, Wivall-Helleryd IL, Saaf M, Melin AL, Thoren M. Serum levels of insulin-like growth factor I in 152 patients with growth hormone deficiency, aged 19-82 years, in relation to those in healthy subjects. J Clin Endocrinol Metab 1999;84:2013-9.  Back to cited text no. 53
    
54.Boquete HR, Sobrado PG, Fideleff HL, Sequera AM, Giaccio AV, Suárez MG, et al. Evaluation of diagnostic accuracy of insulin-like growth factor (IGF)-I and IGF-binding protein-3 in growth hormone-deficient children and adults using ROC plot analysis. J Clin Endocrinol Metab 2003;88:4702-8.  Back to cited text no. 54
    
55.Webb SM. Measurements of quality of life in patients with growth hormone deficiency. J Endocrinol Invest 2008;31 Suppl 9:52-5.  Back to cited text no. 55
    
56.Toogood AA, Taylor NF, Shalet SM, Monson JP. Modulation of cortisol metabolism by low-dose growth hormone replacement in elderly hypopituitary patients. J Clin Endocrinol Metab 2000;85:1727-30.  Back to cited text no. 56
    
57.Agha A, Walker D, Perry L, Drake WM, Chew SL, Jenkins PJ, et al. Unmasking of central hypothyroidism following growth hormone replacement in adult hypopituitary patients. Clin Endocrinol (Oxf) 2007;66:72-7.  Back to cited text no. 57
    
58.Span JP, Pieters GF, Sweep CG, Hermus AR, Smals AG. Gender difference in insulin-like growth factor - I response to Growth Hormone (GH) treatment in GH-deficient adults: Role of sex hormone replacement. J Clin Endocrinol Metab 2000;85:1121-5.  Back to cited text no. 58
    
59.Søndergaard E, Klose M, Hansen M, Hansen BS, Andersen M, Feldt-Rasmussen U, et al. Pegylated long-acting human growth hormone possesses a promising once-weekly treatment profile, and multiple dosing is well tolerated in adult patients with growth hormone deficiency. J Clin Endocrinol Metab 2011;96:681-8.  Back to cited text no. 59
    
60.Holmes SJ, Shalet SM. Which adults develop side-effects of growth hormone replacement? Clin Endocrinol (Oxf) 1995;43:143-9.  Back to cited text no. 60
    
61.Svensson J, Fowelin J, Landin K, Bengtsson BA, Johansson JO. Effects of seven years of GH-replacement therapy on insulin sensitivity in GH-deficient adults. J Clin Endocrinol Metab 2002;87:2121-7.  Back to cited text no. 61
    
62.Malozowski S, Tanner LA, Wysowski D, Fleming GA. Growth hormone, insulin-like growth factor I, and benign intracranial hypertension. N Engl J Med 1993;329:665-6.  Back to cited text no. 62
    
63.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) 1993;39:417-25.  Back to cited text no. 63
    
64.Tuffli GA, Johanson A, Rundle AC, Allen AB. Lack of increased risk for extracranial, nonleukemic neoplasms in recipients of recombinant deoxyribonucleic acid growth hormone. J Clin Endocrinol Metab 1995;80:1416-22.  Back to cited text no. 64
    
65.Hatrick AG, Boghalo P, Bingham JB, Ayres AB, Sonksen PH, Russell-Jones DL. Does GH replacement therapy in adult GH-deficient patients result in recurrence or increase in size of pituitary tumours? Eur J Endocrinol 2002;146:807-11.  Back to cited text no. 65
    
66.Stochholm K, Gravholt CH, Laursen T, Jørgensen JO, Laurberg P, Andersen M, et al. Incidence of GH deficiency - A nationwide study. Eur J Endocrinol 2006;155:61-71.  Back to cited text no. 66
    



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