A *very* interesting article I can't reasonably withold from the list! shhhh.

[Guest guest]

<snip> permission not sought for posting here.

QJM

© Copyright Oxford University Press 1995.

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Volume 88(6)             June 1995             pp 391-399

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Growth hormone deficiency in adults and its response to growth hormone

replacement

[Review]

From the Department of Neurosurgery, Derriford Hospital, Plymouth (E.K.

Labram); and Department of Medicine, Plymouth Postgraduate Medical School,

Plymouth, UK (T.J. Wilkin).

------------------------------------------------------------------------

Address correspondence to Mr E.K. Labram, Department of Neurosurgery,

Derriford Hospital, Derriford Road, Plymouth PL6 8DH

Introduction

The influence of the pituitary gland on lipid and carbohydrate metabolism

became apparent at the beginning of this century when its involvement in

growth promotion was first described. In 1921, an abstract, alluding to the

primary growth promoting effect of an extract of the pituitary gland, was

published. [1]

Radioisotope techniques were introduced in the late 1950s, and these enabled

studies on the role of growth hormone (GH) in carbohydrate metabolism to be

undertaken. [2] Subsequent experiments and the availability of purified

human growth hormone (hGH), led to the description of the secretory pattern

and speculations concerning the complex interactions with insulin in

carbohydrate, lipid and protein metabolism. [3]

The advancement of recombinant DNA technology led to successful attempts in

the late 1970s to determine the sequence of hGH. The biochemical and

preclinical research were completed in two years, and in the early 1980s

clinical trials with rhGH (recombinant hGH) were started. [5,6] The

production of a purified rhGH was completed in 1984.

In 1985, pituitary-derived GH was withdrawn from clinical use because some

GH-deficient patients had contracted Creutzfeldt-Jakob disease, an uncommon

viral cause of dementia and death. [4] The use of rhGH in its place is now

well-established, and the provision of essentially limitless supplies of

rhGH for clinical use has resulted in an explosion of studies exploring

additional uses.

The characteristics of GH deficiency in adults were investigated in the late

1980s, following the introduction of rhGH. It is now recognized that GH

deficiency may exert important adverse metabolic effects in adults, and that

these effects can be reversed or attenuated by treatment with rhGH. [7-11]

Growth hormone deficiency in adults

Definition, selection and inclusion criteria

The diagnostic criteria used to define GH deficiency in adulthood differ,

adding to the difficulty of defining which patients might benefit from GH

replacement therapy. Characteristically, GH deficiency syndrome in adults,

as defined in a number of independent studies, consists of changes in body

composition. These include an increase in body fat and waist:hip ratio, and

decreases in lean body mass, extracellular water and bone density. [7-10,12]

In addition, both subjective and objective measures of physical and

psychological well-being are impaired. [7-9,13-15]

Salomon et al. [10] defined severe GH deficiency as peak GH response of less

than 3 mU/l. In his placebo-treated group, limited overnight GH sampling

confirmed severe GH deficiency, where no patient recorded a peak GH greater

than 2 mU/l, and 85 percent of the samples were below the assay detection

limit. In Denmark, nsen et al. [8] studied young adults with GH

responses less than 10 mU/l who had been treated for GH deficiency during

childhood and retested in adult life. Whitehead et al. selected patients

with a peak GH response of less than 7 mU/l who were also shown to have

severely limited GH production during modified 24-h sampling. [9,14,16]

In the above studies, IGF-I concentrations could not be used as a reliable

index for the selection of GH-deficient patients, because even in the study

of Salomon et al., where patients had severe GH deficiency, many had plasma

IGF-I concentrations within the low-normal range. [10]

There has been uncertainty and concern about the biochemical cut-off point

used to define GH secretion in adults, making it difficult to compare

studies, given that the same sample may not yield the same GH value when

tested in different laboratories. There are several methods for GH assay

which may account for the differences in the biochemical tests. The

conditions, standards, reagents and antibodies used, differences in

technical precision, errors, etc may account for some of the variance. [22]

There are other factors that can affect the assessment of GH secretion.

Elderly or obese patients may show blunted GH responses to stimulation tests

which may result in false diagnosis. Stimulation test responses should

ideally be compared to those from age-, weight- and sex-matched healthy

control groups to improve their interpretation. [18]

As a first step, a suggested approach will be to measure IGF-I and

IGF-binding protein-3 (IGF-BP-3). When these are found to be low, further

assessment by GH stimulation tests could then be carried out. [19-21]

GH can readily be measured in urine, but urinary GH can only give a crude

description of pulsatile secretion and there is up to 30 percent day-to-day

variation within individuals.

Most studies to date have selected healthy controls in their clinical trials

of GH replacement therapy, but it has been pointed out that certain aspects

of the GH deficiency syndrome in adults are common to patients with other

conditions. The inclusion of patients with other chronic diseases or obesity

as controls may help to establish the beneficial effects specific to GH more

clearly. Our understanding and knowledge of the range of physiological and

symptomatic responses of GH replacement would be enhanced if clear

differences between patients with GH deficiency and these controls were

established.

Aetiology and incidence

The incidence of adult GH deficiency is unknown, but estimates based on the

number of patients with pituitary tumours suggest that GH deficiency

acquired in adulthood may affect 1/100 000 adults annually. [12] GH

deficiency may arise through genetic defect, from disease, surgery or

adjuvant therapy, with irradiation or drug toxicity affecting the

hypothalamus or pituitary. Anecdotal evidence indicates that adults

outnumber childhood-onset cases of GH deficiency by as many as 20:1.

[12,23,24] It is important to distinguish adults who acquired GH deficiency

in childhood or congenitally from those who acquired it in adulthood.

Susceptibility to hormone loss following pituitary damage in disease follows

a characteristic sequence in which GH levels are the first to decrease,

followed by LH and FSH, and finally TSH and ACTH. [12]

Further studies are needed in order to provide up-to-date epidemiological

data on the incidence and prevalence of GH deficiency in patients operated

on for pituitary neoplasms of various sizes and types, and the effect of

adjuvant therapy, and to evaluate how GH deficiency correlates with

decreased secretion of other pituitary hormones.

Body composition in GH deficiency

Body composition is influenced by genotype, age, nutrition, hormonal status

and physical activity. [25] Changes in body composition are important

determinants in the diagnosis of GH deficiency in adults and evaluation of

the response to GH replacement.

The effects of GH on carbohydrate, protein and lipid metabolism are well

established. [26,27] In adults with GH deficiency, GH therapy prevents

hypoglycaemia during starvation. [26] Both in vivo and in vitro studies have

documented the lipolytic effect of GH. GH decreases lipogenesis, [28] and

promotes a redistribution of fat from abdominal (android) to a more

peripheral (gynoid) distribution. [28] Anabolic [29] and anti-natriuretic

actions [30] of GH have also been described.

In a study of 22 GH-deficient adults previously treated with GH, nsen

et al. [8] assessed fat and muscle volumes of the thigh using CT scanning.

In the placebo group, the distributions of fat and muscle were measured as

37 percent and 63 percent, respectively, compared to 15 percent and 85

percent normally found in healthy adults. The reported increase in the

muscle volume, as determined by CT within the 4 months of the study, could

not however be easily distinguished from change in tissue fluid, increased

blood volume and/or connective tissue content. Similarly, Salomon et al.

[10] found GH-deficient adults to be overweight (skin fold thickness) and to

have decreased lean body mass (total body potassium method). Similar results

have been published by Whitehead et al. [31] Although these studies were

different in design, methods and patient populations, a significant change

in body composition, with decreasing fat and increasing muscle mass, was

reported after GH replacement. [32-35] The heterogeneity of the populations

and the short period in which the studies were conducted make it difficult,

however, to draw any definite conclusions regarding the impact of these

reversible changes vis a vis the period of GH deprivation.

There is no gold standard among the methods used to determine body

composition. All the methods available make specific assumptions and errors.

In GH-deficient adults, there is an associated change in fluid balance

between the extra/intracellular spaces, making assumptions based on

two-compartment models invalid. [36]

Fluid homeostasis

GH deficiency has been shown to be associated with reduced total body water.

[29] In a study of 106 adults with GH deficiency, values calculated using

the four-compartment model were compared to predicted values from 476

randomly selected healthy adults. The GH-deficient adults had significantly

reduced extracellular water of approximately 15 percent. [37] This decrease

in extracellular water was attributed to reduced activity in the Na-K ion

pump.

Studies suggest that the anti-natriuretic action of GH is due to an effect

on the renal tubules, which by increasing sodium pump activity [73] can be

partly counteracted by an alleged sodium transport inhibitor. [74]

Consequently, the observed decrease in extra-cellular fluid volume in

GH-deficient adults might be attributed to a decrease in the activity of the

Na-K ion pump.

The effect of GH in retaining Na and therefore increasing body fluid volume

is said to be mediated through its direct action on the kidneys [38] and

indirectly via the renin-angiotensin system through increased renin

activity. [39] In the 1950s, GH was shown to have anti-natriuretic action

[30] and this was later suggested to be independent of aldosterone. [38]

Further studies, however, showed that supraphysiological doses of GH in

normal adults increases the concentrations of both plasma renin and

aldosterone activity. Total body water is restored to normal in GH-deficient

adults treated with GH. Bengtsson et al. [40] showed an increase of 15

percent in total body water of ten patients with adult-onset pituitary

insufficiency who had received GH treatment for 6 months. In a study of 22

adults with childhood-onset GH deficiency, nsen et al. [8] demonstrated

a significant increase in glomerular filtration rate and renal plasma flow

after 4 months GH treatment.

Fat mass and lipid homeostasis

In adults with GH deficiency, body fat is excessive and distributed in a

more central than peripheral pattern. Rosen et al. [37] found GH-deficient

patients to be heavier than their predicted weight. These patients also had

significantly more body fat than predicted for their weight. [10,17,37] The

upper-body fat distribution was demonstrated on CT scan of ten patients who

acquired GH deficiency as adults. [40] Although the excess was modest and

the study population small, the results were highly significant. Larger

studies with suitable control groups are needed to measure the excess fat in

GH-deficient adults, since reference data on fat mass of the relevant

populations are limited.

GH has a lipolytic effect in man. [41] Recent evidence suggests that

nocturnal GH peaks may activate the mobilization of fat stores [42] and also

stimulate the differentiation of pre-adipocytes into adipocytes, thereby

increasing the number of cells in adipose tissue.

In addition to the increased fat mass in GH-deficient adults, there is

evidence of abnormal lipoprotein metabolism. [37,40] There is a significant

increase in mean serum triglyceride concentration, and a significant

decrease in the mean HDL-cholesterol concentration compared with those of an

age-matched control population. [34]

The effects of GH on different lipoprotein fractions and apolipoprotein

levels in man are yet to be clarified in further studies. However, both GH

excess [43] and GH deficiency [24] result in an increased risk of death from

cardiovascular disease. The lowering of total plasma cholesterol, in

addition to the decrease in fat mass may have a long-term beneficial effect

on cardiovascular morbidity and mortality.

Twenty-four patients with adult-onset GH deficiency were reported to have a

significantly lower plasma cholesterol concentration than controls. [10] In

contrast, Whitehead et al. [14] found no significant difference in

GH-deficient patients. None of the studies to date have found any

significant change in the serum triglyceride levels of adults with GH

deficiency who have received GH replacement therapy. [10,14,44]

Lean body and protein mass

Using the whole body 40K counter, Salomon et al. [10] demonstrated a

significant deficit in mean lean body mass of adults with GH deficiency. It

is, however, uncertain whether all components of the lean body mass are

reduced in GH-deficient adults. Approximately 50 percent of lean body mass

is made up of skeletal muscle. Direct comparative measurements of thigh

muscle by CT scan in GH-deficient adults has shown a significantly smaller

total muscle area than in matched controls, [8,45,46] although no standard

reference data are available for adult skeletal mass.

Following treatment with rhGH, significant increases (mean 5-10 percent)

were noted in thigh muscle mass and cross-sectional area assessed by CT

[8,14,47] along with 24-h urinary creatinine excretion, mean 18-21 percent,

[10] an indirect measure of skeletal muscle. [34,46] The difference between

the increase in creatinine excretion and thigh muscle cross-sectional area

may reflect increases in other skeletal muscles.

Despite the decrease in thigh muscle cross-sectional area, Cuneo et al.,

[46] comparing 21 GH-deficient adults with age- and sex-matched controls,

demonstrated that the mean skeletal muscle fibre areas and proportions of

type I and II fibres were the same in both groups, and that the GH-deficient

patients had no obvious features of myopathy. No detectable changes in fibre

areas and proportions were noted after 6 months treatment with rhGH.

Since the number of myofibres is considered to remain constant in adults, a

reduction in the cross-sectional area of muscle is more likely than

hypoplasia to occur in adults with GH deficiency. A study showing GH-induced

proliferation of skeletal muscle satellite cells, [71] which can develop

into myofibres, indicates that the number of myofibres may also be reduced

in GH-deficient adults.

Physical performance

GH-deficient adults perform less well than expected in exercise capacity

tests. This is probably due, in part, to a reduction in cardiac function,

and the significant reduction in muscle mass, although there is also

evidence for a reduction in muscle strength. Several studies have shown that

the maximal isometric force generated by the quadriceps muscle is reduced in

GH-deficient adults when compared with age- and sex-matched controls.

[14,33,45] Following treatment with rhGH, maximal and submaximal exercise

performance improve significantly. [8,9,13]

GH-deficient patients are said to complain of lethargy, and this is thought

to be due to muscle fatigue. [72] The muscle fatigue in adults with GH

deficiency may be due to alteration in muscle glucose utilization or

storage, since IGF-I is known to stimulate transport of glucose into

skeletal muscle and to stimulate glycogen synthetase.

The increase in exercise performance in GH-deficient adults on treatment is

largely due to increased lean body mass [13] with a possible contribution

from increased cardiac output and maximal oxygen delivery. [45] Exercise

performance is also influenced by the effects of GH on carbohydrate and

lipid metabolism. GH increases hepatic and muscle glycogen stores and,

although it is lipolytic, [10] the contribution of free fatty acids as a

source of fuel to the increase in exercise performance is limited. [13]

Further studies are, however, needed to clarify the relative contributions

attributable to increased cardiac output, erythrocyte mass and substrate

supply.

Bone density

The effect of GH on bone metabolism is not restricted to the prepubertal

period. Bone formation and resorption occur continuously in adults. Several

studies have shown an increase in the plasma levels of osteocalcin, a marker

of bone formation, after GH replacement in adults. [34,40,48-51,55]

GH has been shown to act via IGF-I to stimulate renal

25-hydroxy-1a-hydroxylase activity, and to increase intestinal absorption of

calcium and phosphate. GH also enhances renal absorption of phosphate.

[52,53,55] Bone mineral is reduced in adults with GH deficiency, [54,72] and

increases following replacement with GH. [32,53] In a small (six patients),

non-randomized study, bone mineral density at distal and proximal sites in

the forearm increased after one year of GH therapy. No such increase was

reported in an untreated GH-deficient control group. [32] GH-induced

increase of bone in GH-deficient adults is most rapid in trabecular bone,

and is therefore detected earlier in the spinal vertebrae than in the

appendicular cortical bones. [32]

The increases in bone mineral content seen in GH-deficient adults treated

with GH are paralleled by increases in the plasma levels of markers for bone

turnover. Both osteocalcin and alkaline phosphatase are increased,

indicating an increase in bone formation. [14,40,48] Other biochemical

markers of bone metabolism (serum calcium, phosphate,

1,25-dihydroxycholecalciferol and parathyroid hormone) in patients with GH

deficiency nevertheless lie within the normal range. However, caution must

be exercised in the interpretation of isolated measurements of biochemical

markers of bone turnover when the production rates, plasma levels and

clearance rates of such circulating substances is unknown.

The effect of GH on bone density appears to reach a plateau after one year,

with no further increase with continued treatment. [54] Further studies need

to confirm whether this is due to a 'catch-up' in bone resorption.

The reduced bone mineral density in adults with GH deficiency [32,54]

predisposes them to an increased risk of osteoporotic fractures. The

available data does not, however, take into account the hypogonadism

suffered by many GH-deficient patients, and further work is required to

clarify which deficiency is predominantly responsible to clarify which

deficiency is predominantly responsible. Long-term clinical trials must

determine if alterations in bone mineral density as a result of GH

replacement therapy translate into reduction in the fracture rate and its

consequences.

Energy expenditure

Basal metabolic rate is said to increase by 22 percent after a few weeks of

commencing GH replacement therapy in GH-deficient adults, and is still 16

percent higher than at baseline after 6 months treatment. [10] The marked

increase in energy expenditure is largely accounted for by the anabolic

action of GH. The increased peripheral conversion of thyroxine to

tri-iodothyronine by GH also appears to contribute to the early increase in

basal metabolic rate. [45]

Recent studies by Chong et al. [56] showed an increase in resting metabolic

rate by 15.9 percent after treatment with rhGH for 2 weeks and this remained

elevated at 12.1 percent after 3 months. However, the ratio of the resting

metabolic rate to lean body mass remained unaltered. The conclusions were

that overweight GH-deficient adults did not have a reduced energy

expenditure to account for their obesity, and that most of the energy was

expended in physical activity and thermogenesis comparable to that observed

in healthy adults. This was, however, a small, non-randomized and not

placebo-controlled study. The conclusions regarding the maintenance of

obesity by defects in appetite control and calorie intake need further

clarification and confirmation in a larger controlled study over a much

longer period.

Psychological well-being

GH-deficient adults experience more psychological difficulties than similar

age- and sex-matched controls. [61,62] Typical complaints include tiredness,

low energy levels, lack of initiative, lack of concentration, memory

difficulties and irritability.

Using two self-rating quality-of-life questionnaires--The Nottingham Health

Profile and the Psychological General Well-Being Index--McGualey et al. [62]

found significantly lower quality-of-life scores in 24 GH-deficient adults

compared with matched controls. This study, however, included a mixed

population, nine of whom had Cushing's disease. Similar findings have been

confirmed in other studies using psychological self-rating questionnaires.

[14,61-63]

In a recent study of 86 patients with GH deficiency, Rosen et al. [57]

measured psychological well-being, and compared the data to controls matched

for age, gender, marital status and socioeconomic class. The GH-deficient

adult patients were found to have decreased well-being in terms of energy,

social isolation and emotional reaction, and a disturbed sex-life compared

to the controls. There was also a tendency to earlier retirement. This study

used the Nottingham Health Profile questionnaire, which is not designed to

measure well-being in GH deficiency, and therefore could not quantify the

ability of the patients and normal control groups to meet their human needs.

Following rhGH treatment, psychological well-being is claimed to improve,

many patients reporting increased energy within one week. [62] Other

results, however, have not shown any subjective improvements in well-being.

[7,14,63]

The benefits of GH replacement therapy have so far been confined to

self-report measures which might reflect only an improvement in the

patient's sense of well-being without a corresponding change in function.

Since the report by Almqvist et al. [58] on five GH-deficient patients whose

mental performance was assessed by five different cognitive tests, no

performance tests have been carried out on GH-deficient adults to determine

their ability and motivation before and after treatment with rhGH. Although

this study was unsophisticated and on a small scale, Almqvist et al. were

able to demonstrate significant improvement in the cognitive psychometric

performance of the GH-deficient patients during treatment. Performance tests

indicate where improvement in well-being, which might be achieved by means

other than GH, has been a source of motivation without primary improvement

in ability.

The mechanisms underlying the beneficial effects of GH on quality of life

are unclear. Correlation with changes in lean body mass [15] could account

for improvement in physical well-being in the long term, but would not

explain the acute changes. The decrease in the extracellular fluid volume

reported in GH-deficient patients might explain some of the tiredness noted.

[37] The rapid improvement in well-being with GH replacement may in part be

due to restoration of the low extracellular fluid volume. Improved cerebral

blood flow, glucose utilization, or even direct effects of GH on the

hypothalamus, or IGF-I within the central nervous system, may account for

some of the effects of GH. It has also been recently observed that human

plasma has a proteolytic activity, which may release active opioid peptides

from the hypothalamus by GH, which themselves exert stimulatory effects on

the central nervous system. [59]

The type of patients and controls used in the assessment of psychological

well-being of GH-deficient patients on GH replacement therapy must be taken

into account. Many older patients with adult-onset GH deficiency due to

treatment for pituitary tumours have undergone major surgery, or have

received much higher doses of irradiation than would be considered

acceptable today, and effects of these past traumas may add to the effects

of GH deficiency in lowering psychological well-being. Similarly, obese

patients may have lower quality of life than GH-deficient adults. Most

studies have used the Nottingham Health Profile to examine quality of life

in GH-deficient patients. Again, the Nottingham Health Profile was not

designed specifically to measure quality of life; it is a general instrument

for measuring distress and limitations due to illness across a range of

normal daily activities.

Dr Hunt and her group in Manchester are developing a new questionnaire

designed specifically for use in assessing quality-of-life of patients with

GH deficiency. Their new questionnaire is based upon interviews of 36 adult

patients with GH deficiency in their own homes. The interviews were

unstructured, but directed, so that all points were covered even if patients

did not raise them spontaneously. [60] Work completed to date shows that

adults with GH deficiency can be divided into two groups: those with

childhood-onset GH deficiency, who often live alone or with parents, are

dependent on others, have low expectations for their future and may have

difficulty finding employment; and those with adult-onset GH deficiency, who

are often married and have families and jobs. Validation of this model and

its method of use will hopefully produce an instrument that is sensitive to

detect changes produced by GH replacement therapy. It should provide a

specific and standardized instrument for comparisons to be made between

studies, and facilitate data-gathering on this aspect of GH deficiency in

adults.

Preliminary data from Dr Hunt's group [60] identified the following problems

as being the major areas of concern by the majority of GH-deficient

patients: (i) energy-related problems, including becoming tired easily; (ii)

physical and mental drive problems; (iii) concentration and memory problems;

(iv) dislike of over-stimulation and noise; (v) short temper and

irritability; (vi) lack of strength and stamina; (vii) problems relating to

weight distribution and associated poor self-image.

Large-scale studies will be needed to make a detailed analysis of these

problems, given the multiple and varied psycho-physical problems from which

GH-deficient patients suffer, before any valid and universal conclusions can

be drawn from this preliminary data. The consequences of the problems

identified seem to differ according to age of onset. Patients who had

acquired GH deficiency as adults had worked for several years, were married

with children and integrated socially before becoming GH-deficient. Their

perception of the repercussions must inevitably differ from those who had GH

deficiency in childhood.

Pharmacoeconomics of GH replacement

Health economics

It is clinically logical to replace hormone deficiencies, but GH is

expensive and must be justified. Results from an increasing number of

clinical trials have demonstrated the beneficial effects of GH replacement

therapy in adults with GH deficiency, [7-10,13-16,32-35,40,47,50,57,62-64]

albeit most of it in the short term. Ongoing clinical trials are not far

from setting and defining the diagnostic criteria of GH-deficient adults,

and confirming the long-term benefits of GH replacement therapy. There is,

however, the question of economic evaluation, to identify, measure and

reveal the costs and benefits of GH replacement therapy. In the short term,

the economic analysis of direct and indirect costs, including any savings,

will not be easy to measure. Methods that could be used to measure treatment

outcome include cost-utility analysis, which is a multidimensional outcome

based on the quality-adjusted life year (QALY), and/or cost-benefit

analysis, expressing outcome as an absolute monetary value used to balance

the cost of treatment. [67,68]

Calculations based on cost-utility analysis make it possible to compare

treatment primarily aimed at improving survival to that aimed at improving

quality of life. [69] The problem in constructing and interpreting cost/QALY

ratios is that the methods and theory do not provide true assessments of the

health-care treatment, particularly the overall allocation of resources.

[69] Neither does cost-benefit analysis estimate willingness to pay or

increased production (earnings) from improvements in health which are

neither easy to measure nor applicable to all groups of patients.

The change in the cost of GH deficiency to society and following replacement

therapy will be difficult to establish and will be greatly influenced by the

point at which treatment is started during the patient's life or age at

onset of his disease. Increased economic potential of GH replacement rather

than actual economic gains should therefore be the aim of treatment based on

significant increases in quality of life and cognitive performance. Such

improvements following GH replacement will hopefully maximize economic

potential for both patient and society.

Quality-of-life measures in health economics are the standard means of

comparing and assessing the results of health care, [67,70] and assist in

making decisions about the allocation of resources. The measures and

instruments used should therefore be valid, reliable, practical, sensitive

and effective. [67]

Considering the excess mortality reported among GH-deficient adults from

cardiovascular disease, [24] potential increase in loss of working days and

psychosocial morbidity, the evaluation of the cost-effectiveness of GH

treatment needs to be included in all future studies.

Pharmacology

Doses similar to those used in childhood GH deficiency, based on body weight

or surface area, were initially used in the treatment of adults with GH

deficiency. Side-effects forced a reduction in dosage from 0.07 U/kg to

0.035 U/kg. [10,12,33,64,65] The doses of rhGH used in these studies can be

considered as essentially physiological or marginally supraphysiological in

some individuals. The absorption profile of subcutaneously administered rhGH

in GH-deficient adults is, however, far from physiological, resulting in a

broad peak lasting more than 12 h. [10,33] The optimum dose of rhGH

replacement has been estimated at 0.125 IU/kg/week for the first 4 weeks,

and 0.25 IU/kg/week thereafter, [71] but patients may vary in their

sensitivity to GH. Starting at the lower dose is thought to minimize the

incidence of side effects, most commonly peripheral oedema and arthralgia.

Long-term administration of GH to GH-deficient adults may cause side-effects

such as oedema, hypertension, carpal tunnel syndrome and arthralgia.

[8,10,14,40] In one study, the fluid-retaining effect of exogenous GH was

associated with a decrease in plasma atrial natriuretic peptide levels and

significant increases in levels of angiotensin II and aldosterone. [66]

Adverse drug effects are mostly related to the dose of GH, as reflected by

the supraphysiological increases in circulating IGF-I levels occurring with

higher doses.

It is not known whether GH in the long term increases risks of vascular

disease, and its influence on tumour initiation, promotion and progression

remains a subject of active interest.

Overview

GH deficiency in adults is associated with a change in body composition

towards increased body fat and decreased lean body and bone mass. In

addition, GH-deficient patients show impaired physical performance and a

reduced sense of well-being. Preliminary results from a number of clinical

trials have shown beneficial effects of GH replacement therapy in these

patients.

The small populations and heterogenous groups used in the study of rhGH

replacement therapy of GH-deficient adults make it difficult to compare

results, or to draw authoritative conclusions on improvements in their

physical and psychological functional capacity and quality of life.

Large-scale longitudinal studies in adults with GH deficiency are therefore

required.

Acknowledgements

Mr E.K. Labram is generously supported by the Cavitron Fund (Plymouth, UK).

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