Education Resource from the Society for Endocrinology
Professor Stephen Shalet
Christie Hospital, Manchester, UK
Summer School 15-18 July 2003
University of Manchester, Hulme Hall, Manchester, UK
GHD in adult life is associated with increased fat mass, particularly distributed in the truncal region, reduced lean mass, osteopenia, an adverse lipid profile, glucose intolerance, insulin resistance, impaired fibrinolysis, altered cardiac structure and function, reduced exercise capacity, and reduced quality of life. Despite the impressive list of clinical features, there is no single symptom or sign that is pathognomonic of GHD in adult life; this is particularly true of patients with multiple pituitary hormone deficits in whom thyroxine, glucocorticoids, and sex steroids may be under- or over- replaced. There is increasing evidence, however, that the profile of adverse sequelae associated with GHD in adult life differs in adults with childhood-onset compared with adult-onset disease.
There is no single biological endpoint in an adult suspected of being GHD that offers the same diagnostic usefulness as the growth rate of a child. There is, however, the natural history of evolution of hypopituitarism in patients with a mass lesion of the hypothalamic-pituitary region or in those who have undergone surgery and/or radiotherapy to this region. GH is usually the first of the anterior pituitary hormones to be affected by these various pathological insults, which means that in a patient with multiple pituitary hormone deficits the probability of GHD being present is extremely high. Unlike the situation in the pediatric age group in whom pituitary adenomas are rare, this observation is of enormous importance in adults in whom non-functioning pituitary adenomas and/or their treatment are the most common causes of GHD.
Whom to consider for treatment ? Severe GHD
Definition of GH status
Difficult issues over diagnosis of GHD that remain or lie ahead
1. ‘Severe’ GHD - isolated
2. Elderly - isolated
3. ‘Transitional’ GHD - isolated
4. Partial GHD - isolated
Whom to offer GH Replacement?
1. All severe GHD patients, on basis that it represents available hormone
replacement for ‘measurable’ hormone deficiency?
2. Specific indication within GHD population?
- Reduced QOL
- Skeletal health
- Reduce the increased cardiovascular/cerebrovascular mortality observed
in hypopituitary population not receiving GH replacement.
3. None? - insufficient evidence?
- cost-benefit ratio unfavourable?
Evidence
Significant benefit in QOL from GH replacement for approximately 35% of total
cohort of severe GHD patients.
- Patient response, generic and “disease-specific” questionnaires
- Benefit maintained for up to 9 years in single center study
- Selection process means that only about 5% discontinue GH at end of trial
on grounds of lack of effect.
Characteristics
1. Greatest gain in QOL in those with worst QOL at baseline
2. Severe ? in QOL more frequently seen in AO GHD vs CO GHD
3. No correlation between QOL at baseline or QOL response to GH, and baseline
biochemistry, i.e. IGF-I status.
Missing information/explanation
1. Mechanism underlying improvement in QOL?
2. QOL improves but rarely normalises on GH replacement; Why?
3. Randomised placebo-controlled study has never been carried out in subset
of patients with severe impairment of QOL.
Evidence
1. ? incidence of fractures in adults with hypopituitarism
2. Significant proportion of GHD patients have a pathologically reduced BMD
3. GH replacement ? BMD in those patients with reduced BMD if given for over
one year; GH replacement increases markers of bone turnover.
Characteristics
1. Pathologically reduced BMD is not a feature of GHD patients over age of 45
years.
2. Reduced BMD primarily a problem in those patients under the age of 30 years.
3. Markers of bone turnover reduced in GHD.
Missing Information/Explanation
1. Reduction in fracture rate for GHD patients on GH replacement?
2. Acquisition of peak bone mass?
- window of opportunity?
- dose of GH?
3. Confounding variables?
Evidence
1. Approximately 2-fold increase in vascular mortality in hypopituitary patients
on standard endocrine replacement but not GH.
2. Adverse CVS risk factors in untreated GHD patients: lipid profile, waist-hip
ratio, endothelial dysfunction, cardiac dysfunction, fibrinogen, IMT, etc.
3. Improvement in CVS risk factors on GH; lipid profile, waist-hip ratio, endothelial
function, IMT, and fibrinogen.
Characteristics
1. CVS risk factors not adverse in all GHD patients.
2. No relationship between CVS risk factors and baseline biochemistry
Missing Information/Explanation
1. Confounding variables affect risk of vascular disease in hypopituitary patients,
i.e. sub-optimal replacement of additional pituitary hormone deficits, pituitary
radiotherapy?
2. ‘Normalise’ mortality rate in hypopituitary patients on GH replacement?
3. Is there clustering of adverse CVS risk factors?
4. No randomised placebo-controlled study carried out in selected subset of
patients with most adverse CVS risk factors.
Influenced by therapeutic indication policy;
1. QOL – start low dose GH independent of weight or surface area (lower
dose in elderly GHD).
Titrate dose over 3 months and then carry out 6 month trial of GH (9 month total).
2. Adverse Vascular Prognosis – lifelong treatment.
3. Skeletal Health – GH treatment until peak bone mass acquired or lifelong?
Problems
1. If use GH replacement as HRT for all GHD patients ? cessation of ‘thinking’
2. Fail to treat on basis of lack of evidence
– neglect of patients’ needs.
3. ‘Transitional’ GHD.
4. Optimisation of GH replacement; need for alternative markers other than IGF-I.
The opinions expressed in this paper are those of the speaker and do not necessarily reflect the views of the Society
Revised:
04-Sep-2003