Dr John Monson
St Bartholomews Hospital

Adult Growth hormone (GH) replacement is a relatively recent advent on the adult endocrinology scene, although the first adult patient with hypopituitarism was treated with GH over thirty years ago by a physician who recognised that the individual, despite apparently adequate replacement, was rather less well than they might be. The patient actually improved with a very short series of GH injections.

Because of lack of availability of GH and the need for GH for those children who were GH-deficient, it was obvious that they would take priority. It is only more recently, with the advent of synthetic GH, that people have asked whether or not there is a need for GH replacement in adults. It might seem a rather bizarre question to ask, growth hormone is for growth, but of course we now recognise that GH has very little to do with linear growth, but much to do with the maintenance of health.

When we talk about GH deficiency in adults, we are in the most part talking about hypopituitarism. There are, of course, children who are GH-deficient without structural pituitary disease and a proportion of these may continue to have GH deficiency in adult life, but the vast majority of patients who may need this treatment also have other replacement needs.

Proven signs of GH deficiency include increased fat mass, which tends to have a central accumulation. There is a reduction in muscle mass. GH-deficient people tend to have a decrease in bone density and we now know that they probably have an increased rate of fracture in middle age and beyond. They tend to have a reduction in cardiac function. They probably have an increased tendency to build up atheroma, that is hardening of the arteries and the accumulation of cholesterol plaques within arteries, which may lead to blood vessel occlusion, particularly in the circulation to the heart and brain. Importantly, they also have an increased risk of developing mild diabetes - the sort that does not require insulin, but nonetheless puts people at increased risk of developing major blood vessel disease. Another feature is impaired thermo-regulation, which does not matter in most areas of the UK, but may to a sportsman doing endurance sports or if you live in a particularly hot climate.

The symptoms that the patient may complain of are also very non-specific; they may feel below par, have reduced exercise capacity, and have decreased muscle strength. In the context of a busy GP's surgery or a hospital clinic, these symptoms may not be given the importance they deserve.

For purchasing authorities, one of the main factors in judging the value of GH is its effect on premature death. Very good data from Sweden show that those who are hypopituitary and GH-deficient have some increased risk of death from cardiovascular disease. Why should a patient with hypopituitarism and GH deficiency be at risk of vascular death? Well, there is a higher prevalence of high blood pressure in many of the studies that have been performed. Most studies have shown subtle increments in LDL cholesterol, that's the bad cholesterol, and decreases in the HDL cholesterol which tends to have a protective effect. As I have mentioned, there is increased total fat mass and increased central fat, and that body habitus is in itself possibly a cardiovascular risk factor. There is a decrease in sensitivity to insulin and there are chemical abnormalities which make it likely that the blood will be more coagulable. Added to this, cardiac output is reduced in some patients, which may also explain decreased exercise tolerance.

The long-term effects of GH treatment on these various risk factors include reduction of the fat accumulated around your middle. There is also a reduction in the adverse blood cholesterol levels, which is not major but, in terms of overall risk is probably very important, particularly for hypopituitary women, who lose much of the protective effect of being female against vascular disease. There are some beneficial changes in blood clotting. As far as we can tell, there is no dramatic improvement in insulin resistance, but that may require longer-term treatment. At St. Bartholomew's, we have also shown, as have others, that over many years of treatment, the majority of patients have an increase in the density of bone, to an extent that would be predicted to reduce the risk of fracture. This is not observed until the patients have been treated for at least twelve to eighteen months.

What about measuring quality of life? Well, quality of life means different things to different people and, in health economic terms, it is an extremely soft thing to measure, but disease-specific questionnaires have been developed. The quality-of-life measures that we look at include energy, physical and mental drive, concentration, the ability to form happy and close relationships, social life and various emotional factors, as well as how people respond to their everyday life. If you look at the results after GH therapy, you can see that quality of life, using the AGHDA score, progressively improves in both males and females, compared to the non-deficient population.

The GH dose required by adults is extremely low compared to children. It is lower in men than in women, and the time taken to reach maintenance is short, four weeks in men and about twelve weeks in women. The reason for this gender difference is that, in health, women produce more GH than men.

Another question is whether GH treatment makes your Pituitary tumour regrow. That is something we worry about, but data so far suggest that GH is not dangerous in that regard, although we need longer term data. Hypertension is not exacerbated. Glucose intolerance does not seem to get worse. So there is much to be enthusiastic about, but we have to be careful and monitor patients closely.