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Adult Growth Hormone Deficiency

Robert Bennett MD, FRCP

Growth hormone is essential for normal linear growth and the attainment of an adult mature height. It also plays an important role in the cartilage growth and the attainment of normal bone mass. There is only one rheumatic disorder, namely acromegaly, in which abnormalities of growth hormone production play a major etiological role. However, there is increasing appreciation that suboptimal growth hormone secretion, leading to a state of adult growth hormone deficiency, may occur in the setting of chronic inflammatory disease, chronic corticosteroid use and fibromyalgia. Thus the evaluation and effective management of both growth hormone over secretion and under secretion is relevant to practicing rheumatologists.
Under secretion of Growth Hormone

Under secretion of growth hormone gives rise to pituitary dwarfism in children and the syndrome of adult growth hormone deficiency in adults. This latter problem is of relevance to rheumatologists as there are several scenarios in which they may encounter adult growth hormone deficiency. The experience of rheumatologists in this respect is very different from that of an endocrinologist in which the cause of deficient growth hormone secretion is usually due to a disordered pituitary or its adjacent structures. Thus, the common causes of adult growth hormone deficiency in an endocrinological practice are a pituitary tumor, surgical resection of the tumor or pituitary radiation (about 75% of cases), an adjacent tumor (e.g. craniopharyngioma -- about 15% of cases), infiltrative disorders (e.g. sarcoidosis, hemochromatosis -- about 1% of cases), Sheehan's syndrome (about 0 5% of cases). In a rheumatology practice the cause of adult growth hormone deficiency is seldom due to pituitary disease itself, but results from a dysregulation of the hypothalamic hormones controlling the pituitary secretion of growth hormone or a peripheral insensitivity to growth hormone.

The syndrome of adult growth hormone deficiency (AGDH)

There has been increasing realization over the last 10 years that the secretion of growth hormone is not only important in promoting normal linear growth and hence an adult stature, but is also important in the attainment of an optimal hormone milieu in adults. Deficiency of growth hormone in adults is now well accepted to cause a distinctive syndrome known as adult growth hormone deficiency (AGHD) . In large part, this burgeoning awareness of adult growth hormone deficiency (AGHD) has been due to the increasing availability of growth hormone supplementation, from the use of DNA recombination technology, and its beneficial effects in GH deficient in adults.

As might be predicted from the actions of growth hormone the most obvious clinical features of AGHD are changes in body composition resulting in a decreased muscle mass and increased total body fat . The fat accumulation is preferentially intra-abdominal, a distribution that has been associated with dyslipidemia, insulin intolerance, hypertension and some malignancies (breast and colon).

A major factor contributing to reduced life expectancy in AGHD is the additive effect of several consequences deleterious to cardiac function . These include a reduced to left ventricular ejection fraction, stroke volume and cardiac index (a result of reduced left ventricular wall thickness) and the atherogenic lipid profile. Thus it is not surprising that patients with AGHD, from whatever cause, have a twofold increase in cardiovascular and are. three fold increase in cerebrovascular related mortality .

The cause of fatigue in adult growth hormone deficiency probably results from an accumulation of several factors: to wit, a reduced cardiac index, a reduction in maximal oxygen uptake, reduced muscle strength, reduced red cell blood volume, reduced plasma volume and an array of psychosocial difficulties. These latter include a significantly reduced overall quality of life, low self-esteem, poor socio-economic achievement, dysthymia and reduced vitality .

Diagnosis of AGHD

Because GH has a very short half life and is secreted in a pulsatile manner, mainly at night and after vigorous exercise, the measurement of a single growth hormone level is a useless exercise. The most stringent test for growth hormone deficiency is to measure growth hormone levels every 10 to 20 minutes in order to obtain an integrated 24-hour GH profile. As this is impractical outside the research setting, the recommended screening test for AGHD is the measurement of an IGF 1 level. The levels of IGF-1 (which has a half life of about 22 hours) are stable throughout the day with minimal diurnal variation and thus measurement of an IGF 1 level does not require the subject to be in fasting state. A low IGF-I level, age-adjusted, is a very specific indicator of AGHD. However its sensitivity is poor, especially in the setting of pituitary disease. In this situation there are often coexistent endocrine deficiencies as part of a syndrome of pan-hypopituitarism which provide initial diagnostic clues. The sensitivity of IGF 1 level for diagnosing AGHD in the setting that most rheumatologists are likely to encounter (i.e. hypothalamic dysregulation or peripheral insensitivity to GH) has not been rigorously studied. Unfortunately, non-pituitary AGHD is not recognized by most insurance companies in the United States as they require "confirmation" of growth hormone deficiency with a GH stimulation test. These tests were initially developed in the pediatric population and basically assess the pituitary’s ability to secrete growth hormone under conditions of maximal stimulation. Currently the most widely used GH stimulation test involves the oral administration of arginine (and amino acid that inhibits hypothalamic somatostatin tone) concurrently with intravenous growth hormone releasing hormone (GHRH) at a dose of 1 ng/kg. Growth hormone levels are measured every 30 minutes over the next two hours. A single GH level of ≥5 ng/ml is considered indicative of normal pituitary function. As the problem in rheumatological causes of AGHD is not at the level of the pituitary, most patients with conditions such as rheumatoid arthritis, chronic corticosteroids usage and fibromyalgia will be shown to have a normal pituitary secretion of growth hormone in response to this test and are thus ineligible for supplemental growth hormone therapy through most insurers.

Fibromyalgia and Growth Hormone Deficiency

A possible link between AGHD in fibromyalgia was reported in 1992, based on the theory that fibromyalgia patients may have impaired GH production due to the alpha-delta sleep anomaly - stages 3 and 4 of non-REM sleep are a prime time for GH secretion . Several subsequent studies have supported a disordered GH/IGF 1 axis in fibromyalgia and some other studies have not . Most of the negative studies have been underpowered. When IGF-1 levels were measured in a cohort of 500 fibromyalgia patients was there was a very significant reduction compared to healthy controls (p=0.0000001) . A subsequent nine-month placebo-controlled therapeutic trial in fibromyalgia patients, with low IGF 1 levels, reported a significant clinical benefit . Paiva has reported an impaired GH response to the stress of exercise to volitional exhaustion, the GH response was normalized after the subjects had taken pyridostigmine (an acetyl cholinesterase inhibitor that reduces hypothalamic somatostatin tone by stimulation of cholinergic pathways). McCall-Hosenfeld has reported a similar impairment of GH secretion to the stress of hypoglycemia. The latter article found a correlation of increasing BMI with an impaired GH response to hypoglycemia, whether this is the cause of the impairment or a result of GH deficient patients having increased fat stores is not known. The current hypothesis is that a subset of fibromyalgia patients (about 30%) develop AGHD due to a stress induced increase in corticotropin releasing factor (CRF) which in turn stimulates hypothalamic somatostatin tone.

References

(1) Cook DM, Ludlam WH, Cook MB. The adult growth hormone deficiency syndrome. Adv Intern Med 2000; 45:297-315.

(2) Rosen T, Wilhelmsen L, Bengtsson BA. Altered lipid pattern explains increased cardiovascular mortality in hypopituitary patients with growth hormone deficiency. Clin Endocrinol (Oxf) 1998; 48(4):525-526.

(3) Shahi M, Beshyah SA, Hackett D, Sharp P, Johnston DG, Foale R. Cardiac function and structure in growth hormone deficiency. Br Heart J 1991; 66:58-63.

(4) Bennett RM, Clark SR, Campbell SM, Burckhardt CS. Low levels of somatomedin C in patients with the fibromyalgia syndrome. A possible link between sleep and muscle pain. Arthritis Rheum 1992; 35(10):1113-1116.

(5) Davis KD, Hutchison WD, Lozano AM, Tasker RR, Dostrovsky JO. Human anterior cingulate cortex neurons modulated by attention-demanding tasks. J Neurophysiol 2000; 83(6):3575-3577.

(6) Ferraccioli G, Guerra P, Rizzi V, Baraldo M, Salaffi F, Furlanut M et al. Somatomedin C (insulin-like growth factor 1) levels decrease during acute changes of stress related hormones. Relevance for fibromyalgia. J Rheumatol 1994; 21:1332-1334.

(7) Riedel W, Layka H, Neeck G. Secretory pattern of GH, TSH, thyroid hormones, ACTH, cortisol, FSH, and LH in patients with fibromyalgia syndrome following systemic injection of the relevant hypothalamic-releasing hormones. Z Rheumatol 1998; 57 Suppl 2:81-87.

(8) Landis CA, Lentz MJ, Rothermel J, Riffle SC, Chapman D, Buchwald D et al. Decreased nocturnal levels of prolactin and growth hormone in women with fibromyalgia. J Clin Endocrinol Metab 2001; 86(4):1672-1678.

(9) Leal-Cerro A, Povedano J, Astorga R, Gonzalez M, Silva H, Garcia-Pesquera F et al. The growth hormone (GH)-releasing hormone-GH-insulin-like growth factor-1 axis in patients with fibromyalgia syndrome. J Clin Endocrinol Metab 1999; 84(9):3378-3381.

(10) Griep EN, Boersma JW, de Kloet ER. Altered reactivity of the hypothalamic-pituitary-adrenal axis in the primary fibromyalgia syndrome. J Rheumatol 1993; 20:469-474.

(11) Griep EN, Boersma JW, de Kloet ER. Pituitary release of growth hormone and prolactin in the primary fibromyalgia syndrome. J Rheumatol 1994; 21(11):2125-2130.

(12) Buchwald D, Umali J, Stene M. Insulin-like growth factor-I (somatomedin C) levels in chronic fatigue syndrome and fibromyalgia. J Rheumatol 1996; 23:739-742.

(13) Dessein PH, Shipton EA, Joffe BI, Hadebe DP, Stanwix AE, Van der Merwe BA. Hyposecretion of adrenal androgens and the relation of serum adrenal steroids, serotonin and insulin-like growth factor-1 to clinical features in women with fibromyalgia. Pain 1999; 83(2):313-319.

(14) Jacobsen S, Main K, Danneskiold-Samsoe B, Skakkebaek NE. A controlled study on serum insulin-like growth factor-I and urinary excretion of growth hormone in fibromyalgia. J Rheumatol 1995; 22:1138-1140.

(15) McCall-Hosenfeld JS, Goldenberg DL, Hurwitz S, Adler GK. Growth Hormone and Insulin-like Growth Factor-1 Concentrations in Women with Fibromyalgia. J Rheumatol 2003; 30(4):809-814.

(16) Bennett RM, Cook DM, Clark SR, Burckhardt CS, Campbell SM. Hypothalamic-pituitary-insulin-like growth factor-I axis dysfunction in patients with fibromyalgia. J Rheumatol 1997; 24(7):1384-1389.

(17) Bennett RM, Clark SR, Walczyk J. A randomized, double-blind, placebo-controlled study of growth hormone in the treatment of fibromyalgia. Am J Med 1998; 104(3):227-231.

(18) Paiva ES, Deodhar A, Jones KD, Bennett R. Impaired growth hormone secretion in fibromyalgia patients: evidence for augmented hypothalamic somatostatin tone. Arthritis Rheum 2002; 46(5):1344-1350.

(19) Bennett RM. Adult growth hormone deficiency in patients with fibromyalgia. Curr Rheumatol Rep 2002; 4(4):306-312.

(20) Neeck G, Riedel W. Hormonal pertubations in fibromyalgia syndrome. Ann N Y Acad Sci 1999; 876:325-38; discussion 339.:325-338.

(21) Katakami H, Arimura A, Frohman LA. Involvement of hypothalamic somatostatin in the suppression of growth hormone secretion by central corticotropin-releasing factor in conscious male rats. Neuroendocrinology 1985; 41:390-393.

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