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Christie Hospital NHS Trust Withington, Manchester M20 4BX, United Kingdom
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Introduction |
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 Top Introduction References |
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The philosophical attitude of endocrinologists toward adult GH replacement varies. A minority may believe in the principle that a hormone deficiency automatically warrants hormone replacement and, therefore, GH replacement is justified for all adults with severe GHD. On the other hand, there are obvious examples where this is not the case (e.g. calcitonin is not replaced following total thyroidectomy).
Other endocrinologists, however, believe that in a health care system divorced from financial considerations the current evidence is strong enough to recommend GH replacement for all patients with severe GHD. The supporting evidence for this view is based primarily on the known adverse cardiovascular risk factors, such as increased waist to hip ratio (1, 2), lipid abnormalities (3, 4), increased fibrinogen and plasminogen activator inhibitor levels (5), and insulin resistance (6) associated with severe GHD.
Furthermore, an increased incidence of cardiac dysfunction (7), exercise-induced electrocardiogram changes (8), atherosclerosis (9), and vascular mortality (10, 11) has been reported in adult patients with hypopituitarism compared with controls. In addition, there is a significant reduction in bone mass and quality of life measures associated with severe GHD. Therapeutic studies have lent some support to the "treatment for all" position in that, in general, GH replacement improves the profile of cardiovascular risk factors, and 2 yr GH replacement significantly increases bone mineral density in those in whom it is reduced (12). Nonetheless, a reduction in cardiovascular mortality and fracture rate in response to GH replacement therapy remains to be established.
With the exclusion of the complete nihilist, the remaining endocrinologists’ stance toward adult GH replacement, and the one which I currently adopt, is to accept that, in the real world, rationing of health care resources does exist, and this means that there is a need for endocrinologists to devise priorities and guidelines before these are totally left to non-endocrinologists. To a large extent, endocrinologists have already initiated this rationing process by stating that only those patients with severe GHD should receive GH replacement. GH insufficiency (mild GHD) undoubtedly exists in adult life (13), but no information is available regarding the adverse impact of mild degrees of GHD on any of the biological end points known to be affected by GH status. Nonetheless, the biochemical definition of severe GHD, i.e. a peak GH response <3 ng/mL (9 mU/L) to an insulin tolerance test is completely arbitrary in the sense that this threshold definition has not been shown to bear any relationship to any of the adverse biological events associated with GHD; the definition of severe GHD stemming from the work of Hoffman et al. (14), in which they observed a 100% demarcation between hypopituitary patients and age-matched controls using a threshold of 3 ng/mL for a peak GH response to an insulin tolerance test.
Thus, unlike the pediatric situation, in which there is an established relationship between the degree of impairment in GH status and reduction in height velocity, no equivalent biological end point has been defined for severe GHD in adult life. This is not entirely a disadvantage; using the auxological and biochemical data, the pediatricians attempt to treat all grades of GHD from severe to mild. The latter approach, as might be predicted, poses major problems in distinguishing GH insufficiency from normal short stature. In contrast, in the adult patient, the biochemical diagnosis of GHD, if restricted to severe GHD, is rarely a problem, except in the elderly or in the obese patient with pituitary disease but no additional pituitary hormone deficits.
For those who believe that the impact of GH replacement on adverse cardiovascular risk factors is sufficient to warrant GH replacement for all severe GHD patients, there is the implication that treatment should be life-long. In other words, this is not a therapeutic trial but a life-long commitment in the same manner as hydrocortisone or T4 replacement therapy for ACTH and TSH deficiency, respectively, is prescribed for the same patient. There are, however, at least two major differences between GH replacement and the replacement of other pituitary hormone deficits—the cost and the manner of administration. The average cost of GH replacement in the United Kingdom for an adult with GHD is between 4500–6000 United States dollars, and it is administered by a daily sc injection each evening.
In light of these observations, we need to review more critically the potential benefits of GH replacement. If we accept the hypothesis that GHD may be responsible for a substantial component of the increased cardiovascular mortality in hypopituitary patients, it will be a number of years before confirmatory evidence becomes available that GH replacement reduces the cardiovascular mortality. Furthermore, an excess vascular mortality has not been observed in all epidemiological studies. A preliminary report from Birmingham, United Kingdom, on mortality in a cohort of 349 patients (200 men) with pituitary disease diagnosed between 1968 and 1992 has been presented (15). Thus far, the number of deaths has been less than a quarter of the total cohort (53 men and 29 women died during the study period at a median age of 64 yr). The observed to expected ratio for overall mortality was 1.3 (95% confidence intervals 0.99–1.6; P < 0.05), but there was no excess vascular mortality in either sex (15).
In addition, the conclusions regarding the adverse nature of the cardiovascular risk factors are drawn from group studies and, in most instances, rarely applied to the individual patient. A number of individual patients with severe GHD will have normal fibrinogen and plasminogen activator inhibitor levels, a normal lipid profile, and show no evidence of cardiac dysfunction or insulin resistance, although the only estimates routinely carried out in a clinical setting are waist to hip ratio and a lipid profile; other cardiovascular risk factors are assumed to be perturbed based on group studies, which show a range of individual results from normal to abnormal. Even if we take into account the therapeutic studies, the effect of GH replacement on the lipid profile is not all advantageous (16), and long-term changes in carbohydrate metabolism will probably reflect a compromise between altered body composition, changes in insulin sensitivity, and ß-cell function. Furthermore, if cardiovascular risk is to be made the primary basis for the proposal to treat all severe GHD patients, what are we to do about heavy smokers? Hypopituitary patients either smoke to the same extent as age- and sex-matched controls (9) or even less than the general population (17). Nonetheless, will the potential cardiovascular benefit of GH replacement by seriously attenuated by cigarette smoking? Is it economically and morally justified for a health care system to spend a significant sum of money over a lifetime (purely for cardiovascular benefit) on an individual, who through a deliberate and voluntary decision has chosen to increase his or her risk of cardiovascular death? Thus, in my opinion, the cardiovascular changes alone are not persuasive enough at the present time to recommend GH replacement for all adults with severe GHD.
The remaining potential benefits of GH therapy are reduction in fracture risk and improvement in quality of life. Two years of GH replacement undoubtedly leads to a significant increase in bone mineral density (12), and this is predictive of a reduction in future fracture rate. Nonetheless, in the latter study (12), 30% of patients were skeletal nonresponders to GH replacement, and other studies have shown that, as a group, GHD adults, aged 50 yr or more, are no more osteopenic than age-matched controls (18, 19). Thus, the skeletal indication is an important one, but careful patient selection for a therapeutic trial remains necessary.
I believe that at the present time quality of life concerns are a major indication for a trial of GH replacement. This in turn implies that the decision-making involved in the selection of whom to treat will be heavily influenced by the attitude of the patients as well as that of the doctors. There is already evidence to support this belief. In the early fixed dose trials of GH replacement those patients most prepared to undergo a trial of GH replacement were those who perceived their quality of life to be reduced (20). Extrapolating from such studies to clinical practice reveals the same patient attitudes to an individual therapeutic trial of GH replacement. Furthermore, at the end of a double-blind, placebo-controlled study (1-yr study, six months placebo-controlled), those patients expressing a desire to continue GH replacement long term tended to have a greater severity of GHD, experienced more distress in terms of energy at entry into the study, and experienced an improvement in energy after 6 months of GH replacement (21).
Albeit with the understanding that it is on the back of overall metabolic/cardiovascular effects, which are beneficial for the majority of adult patients with severe GHD, the proposal that reduced quality of life should be a major indication for offering GH replacement is not new! Pediatricians have been offering GH replacement to GH-deficient children for very many years to improve quality of life, but reporting outcome in terms of growth measurements. Statural gain, however, is not beneficial per se unless it leads to an improvement in quality of life (i.e. reduced misery, improved educational attainment, employment prospects, and so forth), yet auxological benefit is the end point by which the success of GH replacement is judged.
Unfortunately, early quality of life measures were disappointing; initially, we used nonspecific questionnaires, such as the Nottingham Health Profile (22), but we then progressed to the disease-specific validated questionnaires derived from interviews with the adult GH-deficient population (23). The questionnaires provide an objective measure of change in quality of life in response to GH replacement, but in the selection of patients for a trial of GH therapy we rely heavily on the clinical interview. If the patient states clearly that his or her quality of life is fine, then we do not offer a trial of GH replacement; Such patients continue to be seen by ourselves and reported by others. If we and the patient conclude that quality of life is significantly reduced we offer a therapeutic trial of GH replacement. This involves an initial period of 2–3 months to titrate the appropriate GH dose using insulin-like growth factor I SDS measurements and lack of side effects, followed by a 6-month therapeutic trial with the selected dose. Since we adopted the policy of initiating GH replacement with a low dose, independent of size or weight, side effects have been reduced dramatically (24, 25).
Other authors (26) have suggested that physiological GH replacement may not result in an improvement in quality of life, and they have proposed that the benefits observed in earlier studies were related to the use of supraphysiological GH doses associated with abnormally elevated insulin-like growth factor I levels (26). With our strategy of selecting patients based on a patient perceived impairment in quality of life, generic and disease-specific questionnaire data have shown a greater degree of impairment of quality of life at baseline and a greater response to GH replacement than previously published studies in unselected GH-deficient adults (24). Within our cohort of 65 patients it has been demonstrated that the degree of improvement in quality of life is dependent on the level of impairment of quality of life before commencement of GH replacement (24). The real reason for the negative findings of Baum et al. (26) is the unselected study cohort rather than the dose of GH.
The above policy applies to the adult onset GHD patient or the childhood onset GHD patient who stopped GH replacement at the end of linear growth a number of years earlier. For the GHD teenager who is approaching completion of linear growth, it remains unsettled as to whether or not he or she should continue on GH replacement seamlessly through adult life or if he or she could stop GH for a few years without being placed at an irreversible disadvantage (i.e. acquisition of peak bone mass). At the same time, it is also unclear when such an individual should be switched from the typical pediatric to the adult GH replacement dose schedule. There are also no disease-specific quality of life measures devised for this age group. It is my view that we need multicenter studies to determine the optimal strategy for replacing GH in this particular situation.
The first documented studies (27, 28) of GH replacement in adults with GHD were reported in 1989, and we have learned an enormous amount over the last 9 yr, but we are not yet in a position to justify an offer of GH replacement to all adults with severe GHD on a routine basis.
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References |
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TopIntroductionReferences |
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V, Beshyah SA, Fisher C, Sharp P,
Nicolaides AN, Johnston DG. 1992 Detection of premature
atherosclerosis by high-resoluation ultrasonography in symptom-free
hypopituitary adults. Lancet. 340:1188–1192.[CrossRef][Medline]
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