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THE LANCET

Who Needs Growth Hormone?

THE days when we thought we knew how to usehuman growth hormone (hGH) are over: the prospectof growth-hormone-releasing hormone (GHRH) andgenetically engineered biosynthetic hGH in unlimitedquantities raises a new set of questions. In the past, inthe United Kingdom, pituitary hGH has been given toall children who are clinically, auxologically, andbiochemically GH deficient. Over twenty years theUK experience is probably as great as any.’ Newerinformation about GH secretion and its control makesit imperative that we build on this experience ratherthan rest on it.The idea that children are either GH deficient or not

is incorrect. There are a very few children who havedeletion of the GH gene and are truly totally GHdeficient. These children, who have acquired noimmunological tolerance for the GH molecule, mounta brisk antibody response to exogenously administeredGHz and are in a class all of their own. The remainderof children fall into what is becoming an increasinglywide spectrum, and the demonstration that hGH canenhance the growth rate of children who are able toproduce "normal" levels of GH to provocativestimuli3,4 places us in a new position of uncertaintywith regard to the definition of biochemical normality.This position needs to be resolved before we can definethe indications for the therapeutic use of hGH inchildhood.We cannot investigate the GH secretion of entirely

normal children, since this would contravene theethical criteria for the conduct of medical research, butquite a lot is known about the secretory patterns of

growth hormone in adult volunteers of normal statureand in short children, tall children, and children whomay be of normal stature but who are not growing at anormal rate. Reasonable extrapolations can be made towhat happens in normally growing children but thiscan never be the same as the direct experimentalapproach.A second difficulty is that the physiological stimuli to

GH secretion, the most important of which is deepsleep (stage IV), not only operate differently from thepharmacological stimuli used for diagnostic purposes(principally insulin-induced hypoglycaemia) but also

1 Milner RDG, Russell-Fraser T, Brook CGD, et al Experience with human growthhormone in Great Britain the report of the MRC Working Party Clin Endocrinol1979; 11: 15-38.

2 Illig R, Prader A, Ferrandez A, Zachmann M. Hereditary prenatal growth hormonedeficiency with increased tendency to growth hormone antibody formation. SympDt Ges Endokrinol 1970; 16: 246-47.

3 Gertner JM, Genel M, Gianfredi SP, et al. Prospective clinical trial of human growthhormone in short children without growth hormone deficiency J Pediatr 1984, 104:172-76

4 Van Vliet G, Styne DM, Kaplan SL, Grumbach MM Growth hormone treatment forshort stature. N Engl J Med 1983, 309: 1016-22

give rather different results. At present there is a

disproportionate emphasis on tests of the latter typewhen children are being assessed for treatment withhGH.There is a parallel here with recent advances in

knowledge of the control of gonadotropin secretion.The pulsatile secretion of gonadotropins, which can beevoked by the pulsatile administration of gonadotropin-releasing hormone, is crucial to normal puberty andreproductive function. If the frequency or amplitude ofthe pulse is varied outside certain limits, normalfunction ceases. In other words, the pattern ofhormonal secretion is as important in reproductiveterms as the absolute amount of hormone secreted. Thesame is very likely true of GH. Dysfunction of GHsecretion may be very important in the slow growth ofsome children and may be overcome by hGHtreatment.’This leaves us in a very insecure position with regard

to the use of hGH or GHRH in clinical practice. Smallchildren and tall children differ in the total amount ofGH they secrete.6 At present, we describe children whosecrete very little GH as being "GH deficient". Welabel children who secrete somewhat more GH to

provocative stimuli, and whose growth is a little nearerto normality, as having partial GH deficiency;’ but,since we do not understand normal GH secretion, suchdistinctions become increasingly arbitrary. The ideathat there is a GH concentration detected byradioimmunoassay (with all the problems that

involves) which is normal, and another which is not, isridiculous.hGH has not yet been given to small children who are

growing at a normal rate. This experiment has to beundertaken but will not be easy because growth is notsimply a matter of food and hormones. The

psychological dimension is of the greatest importanceand if hGH was beneficial in short children without GH

deficiency some might attribute the effect to physicianattention rather than hGH. It is greatly to the credit ofthe Health Services hGH Committee that the first UKtrials of hGH treatment in children who are not

biochemically GH deficient include a period of placebotreatment. A subnormal growth rate, however, is stillrequired for inclusion in this trial, and this of itself begsthe question that most needs to be answered in thepresent climate.We should not extrapolate the effects of hGH

administered to children who have either a quantitativeor a qualitative abnormality of secretion of GH to whatwill happen when GH is given to a normal short child.This experiment is not without risk. Suppose growth-inhibiting hGH antibodies appear? The child mightthen make antibodies to his own GH and his

predicament would be infinitely worse. Although few5. Spiliotis BE, August GP, Hung W, Sums W, Mendelson W, Bercu BB Growth

hormone neurosecretory dysfunction A treatable cause of short stature. JAMA1984; 251: 2223-30.

6 Albertsson-Wikland K Growth hormone secretory patterns in tall and small children

Human Growth Hormone Symposium, Baltimore, 19837 Milner RDG. Burns EC Investigation of suspected growth hormone deficiency Arch

Dis Child 1982, 57: 944-47

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children nowadays acquire growth-inhibitingantibodies when given pituitary hGH, anxiety muststill remain. It is, after all, the incidence of clinicallyunimportant antibodies that has held up the marketingof synthetic (methionyl) hGH.B For the same reason,biosynthetic GH is going to be extremely expensive:the process by which the adjuvant Escherichia coli

proteins have been eliminated from the product, so thatit is probably no longer immunogenic, has been

immensely costly and this cost will have to be recoveredfrom consumers. Thus, despite the prospect of GH inunlimited amounts, we might be hard-pressed to

justify treatment of children who are apparentlynormal. Financial analysis will almost certainly lead tothe answer No, but such an answer is hardly likely tosatisfy the tax-paying parents of a child who is failing atschool through the unhappiness caused by shortstature.

Where then do we go from here? In the first place, weshould turn away from pharmacological tests of GHsecretion towards assessment of the pattern of GHsecretion in terms of quality and quantity. GHsecretion during sleep is probably more informativethan GH, responses to unphysiological stimuli such ashypoglycaemia, but there can be no clear distinctionbetween what is normal and what is not until we havean empirical basis for the distinction.The comfortable situation which we enjoyed when

we thought we were using a safe preparation for clearclinical indications with a reasonably assured outcomehas been shattered. We do not know who needs GH andwe do not know what will happen when we give it tonormal short children. We have about two years to findthe answers to these questions before hGH is availablein large quantities and consumer pressure begins torise. A final point: because the activity of GHRH seemsto be contained in only 29 aminoacid radicals, we mayneed to contemplate wholesale reorientation. Such asmall molecule can be synthesised by the ordinaryprinciples of organic chemistry and the cost oftreatment with GHRH, if it proved effective, could bevastly less than that with biosynthetic hGH. The priceto pay might be in the mode of administration: becausehGH is effective through the generation of the

somatomedins, it has been given infrequently-eventhough more frequent administration of hormone maybe more effective. GHRH will probably have to begiven by pulsatile administration, perhaps at night, if itis to be clinically effective.

Medical Student Selection in the UK

FOR some time there has been dissatisfaction over the

way medical students are believed to be selected, andmuch inconclusive discussion continues. The publicinterest should of course be the paramountconsideration, for it requires good doctors; but no one

8 Kaplan S Clinical experience with bio-synthetic growth hormone Human GrowthHormone Symposium, Baltimore, 1983

really knows how to measure the quality of the eventualproduct. The related agonising that goes on overmedical education has been even less conclusive

despite a flourishing industry in which teachers havebecome educationists. The liberal encouragementgiven to medical schools by the General MedicalCouncil, in 1967, to experiment with the syllabus andto do each its own thing, has made the integration oftheir individual curricula difficult, discouraging thedesirable migration of students between schools andmaking the schools themselves consequently moreparochial. Despite the conviction with which certaininstitutions proclaim their own practices, few othersare converted. The McMaster experiment has not beenwidely taken up, any more than have the innovations ofthe newer medical schools in the UK; and the

imperfections of continuous assessment and thedifficulties of integrated and topic teaching havebecome apparent. Again, no one knows really what todo-but does this really matter, now that students areapparently so much brighter and harder working thanthey used to be, and provided that their teachers can bepersuaded to spend as much time as possible with themand simply do their best to help and stimulate them tothink and learn for themselves? The iconoclast mightwell ask, Is there any evidence that a better or worsegeneral practitioner or consultant is now emergingthan when students of comparable quality to today’swere trusted (or left) so much more to educatethemselves? Some believe that, irrespective of themedical school of origin, much the same sort of youngdoctor emerges on the wards at the start of the

preregistration year. If this is so, perhaps medicalschools should concentrate more on the general qualityof the students they select for admission.

Criticism of the selection of medical students has

understandably been directed less towards the publicinterest (which is in any case remote at this stage andalways intangible) than to the immediate question offairness to all those well-qualified applicants who areperfectly fit to be trained to become good doctors butmust first compete fiercely for a place. No one who hasnot faced this task can appreciate how formidable it iswhen one is confronted by bright and eager seventeen-year-olds, nearly all of whom see a medical career as themost attractive (and remunerative) way of satisfyingboth their considerable intellectual aspirations andtheir desire to do good among their fellow citizens.Provided that they are sufficiently intelligent andpsychologically robust to survive the rigours of themedical course, including the postgraduate phase, andprovided that their behaviour is not such that they arelikely to be in trouble later with the General MedicalCouncil, almost all will be capable of being trained tobe good doctors in one of the numerous branches ofmedicine. (For those whose enthusiasm for pastoraland clinical responsibility may later evaporate, thereare now more opportunities than ever before to escapeinto administrative or other careers not involvingpatient care.)