medicine endocrinology - bmj

Postgrad Med J (1991) 67, 23 - 32 ) The Fellowship of Postgraduate Medicine, 1991

Reviews in Medicine

Endocrinology

M.A. Baxter and M.C. Sheppard

Department ofMedicine, University ofBirmingham, Queen Elizabeth Hospital, Edgbaston, BirminghamB15 2TH, UK

Introduction

In our review of current endocrine literature wehave tried to identify areas which are likely tocontinue to be of interest through the 1990s. This isnot simply because of the likelihood of scientificprogress but also because in each instance it isprobable that our approach to the investigationand management of the relevant clinical problemwill alter. Thus the management of Graves' oph-thalmopathy, osteoporosis and growth hormonedeficiency in adults, and the investigation ofthyroid hormone resistance syndromes and hyper-calcaemia of malignancy, are continuing problemsfor all clinical endocrinologists, and in all of theseclear progress has occurred recently. We hope andbelieve that the information will be of interest andrelevance to those other than specialist endo-crinologists.

The management of Graves' ophthalmopathy

Ophthalmopathy is an autoimmune disorder whichmay be an integral part of Graves' disease or aclosely related but distinct entity. It can be a mostdistressing and disabling clinical problem, itscourse is difficult to predict, and treatment is oftenonly partly successful. The temporal relation withGraves' disease is close, since ophthalmopathy firstappears in approximately 75% of patients in theyear before or the year after the development oftheir hyperthyroidism. One of the longstandingdebates in the thyroid literature is whether anti-thyroid therapy, in particular radioiodine, causesor exacerbates ophthalmopathy. The standardview is that radioiodine therapy should be avoidedin patients with eye disease. If this is true there areconsiderable implications for the current manage-ment of Graves' disease since increasingly radio-iodine is being used as the treatment of choice,particularly in North America where a recentsurvey of members of the American Thyroid

Association showed that 69% favoured radio-iodine as first treatment in patients with Graves'disease.' A recent letter in the Lancet entitled'Radioiodine and aggravation of Graves' ophthal-mopathy'2 reinforced this view. The authors statethat in Denmark (where the study originated) thereis an increasing tendency to use radioiodine forGraves' disease and their impression was that thismay worsen any associated ophthalmopathy. Theydescribe a small study of 50 patients given radio-iodine and followed for 24 months. In 5 patientswith pre-existing ophthalmopathy the eye condi-tion worsened and in one patient without eyedisease ophthalmopathy developed. These patientswere not in any way compared with a control groupreceiving anti-thyroid drugs and in view of theknown close temporal relationship of ophthal-mopathy and hyperthyroidism it is difficult to beconvinced that this was a direct effect of therapy.As the authors point out, however, there have

been few attempts to evaluate the effects ofdifferenttreatment modalities on the development andprogression of eye disease. A small prospectivestudy some years ago showed a slower progressionwith surgery or radioiodine than propylthiouracil.3The most extensive and informative study in theliterature has now been published.4 Among 288hyperthyroid patients with no ophthalmopathywho were followed up for I to 11 years, eye diseasedeveloped in 6.7, 7.1 and 4.9% after antithyroiddrug, surgery and radioiodine therapy respectively.In addition, in a prospective study (discussedbelow) of glucocorticoid therapy5 none of 10 hyper-thyroid patients with no ophthalmopathy acquiredit in the first 18 months after radioiodine therapy.In the study of Sridama and DeGroot4 the inci-dence and degree of progression of ophthal-mopathy in patients who already had exophthal-mos before treatment were similar in the medically,surgically, and radioiodine treated groups (19.2%,19.8% and 22.7%, respectively). The incidence ofimprovement of ophthalmopathy was also similar(14.1%, 12.6% and 12.3% in the medically, sur-gically and radioiodine treated patients). Althoughthis is a retrospective study, the numbers are large

Correspondence: Professor M.C. Sheppard, Ph.D.,F.R.C.P.

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24 M.A. BAXTER & M.C. SHEPPARD

(506 patients analysed) and it seems quite clear thatthere was no influence of the type of therapy forhyperthyroidism on the clinical course of Graves'ophthalmopathy. Previous conflicting reports ofthe deleterious effects of radioiodine are probablydue to to the small number of patients studied orbecause the effects of only one form of treatmentwere observed. Although this is not likely to be apopular or consensus view it would seem that thereis little evidence that any antithyroid therapy,including radioiodine, causes or exacerbates oph-thalmopathy. The eye disease and hyperthyroidismusually appear at about the same time and in mostpatients the ophthalmopathy changes little afterthat, no matter how the patient is treated. Cur-rently too much emphasis is placed on anecdotalevidence.6 Hyperthyroidism should be treated as ifophthalmopathy were not present.The treatment ofGraves' ophthalmopathy is not

satisfactory particularly for those patients withmoderate eye disease. Treatment of severe eyedisease is still best managed with high dose steroidsor surgical decompression, areas in which littleprogress has been made in the last few years otherthan the suggestion that intravenous methylpred-nisolone followed by oral prednisolone may be thepreferred approach.7 The results of orbital irradia-tion have been quite variable, and so it is not nowwidely used.Two recent articles in the New EnglandJournal of

Medicine have provided information of interestprovoking further discussion. In the study ofBartalena et al.5 26 patients were randomly assoc-iated to treatment with radioiodine alone and 26 totreatment with radioiodine and concomitant oralprednisone. In no patient without ophthalmopathybefore treatment did ocular symptoms appear. Inpatients with eye disease treated with radioiodinealone, eye disease worsened in 56% and wasunchanged in 44%; in the second group ophthal-mopathy improved in 52% and was unchanged in48%. The authors concluded that systemic cor-ticosteroid therapy prevented the exacerbations ofGraves' ophthalmopathy that occur after radioio-dine therapy. In view of the large retrospectivestudy discussed above showing no such deleteriouseffect specific to radioiodine, and the known sideeffects of glucocorticoids, the conclusion in anaccompanying editorial8 was that the routine use ofglucocorticoids to prevent progression is unwar-ranted. A control group of patients treated withantithyroid drugs with or without steroids wouldhave provided important information. The secondpaper, from Prummel et al.9 looked once again atthe question of the use of cyclosporin which mayinterfere with the cellular and humoral autoim-mune processes thought to have a role in Graves'ophthalmopathy; results of clinical trials, however,are conflicting. In their single blind, randomized

clinical trial in 36 patients they found that singledrug therapy with prednisone was more effectivethan cyclosporin and the combination could beeffective in patients who do not respond to eitherdrug alone. These findings are not conclusive,however, since although prednisone was moreeffective it caused more side effects. A final point ofinterest - cigarette smoking has been associatedwith Graves' ophthalmopathy and patients shouldbe advised to stop smoking.10

Thyroxine replacement therapy and osteoporosis

Thyroid hormone excess has long been recognizedas one of several risk factors for osteoporosis.Thyroid hormones accelerate the rate of boneremodelling, and the increased turnover of bonethat develops in thyrotoxicosis is characterized byan increase in the ratio of resorptive to formativebone surfaces, the net result being loss of bone. Ithas long been believed, however, that there is littlerisk associated with long-term exogenous thyrox-ine treatment. Thyroxine for replacement therapyin conventional doses (100-200 pg/day) or supp-ressive therapy for goitre as well as for less clearindications - a recent follow up study of theFramingham cohort in the USA showed that 15%of those taking thyroid hormone did so for condi-tions such as obesity or fatigue" - has consequentlybeen administered frequently in 'supraphysiolog-ical' doses without regular monitoring of tests ofthyroid function. Since the introduction of assaysfor TSH with improved sensitivity (which are ableto distinguish between normal and reduced levels)it has become clear that many patients receivingthyroxine treatment have TSH values which areeither below the lower limit of the normal range orare suppressed below detectable levels. Theseresults are argued by some clinicians to representover-treatment.Controversy exists as to whether such patients,

who usually do not have any symptoms or signs ofhyperthyroidism, have adverse tissue effects relatedto their thyroxine excess. Currently there is aspecific argument as to whether exogenous thyroidhormone therapy in excess can predispose to thedevelopment of osteoporosis, in the same way asendogenous hyperthyroidism. Many previous stu-dies were confounded by failure to distinguishbetween pre- and postmenopausal women and bythe lack of comparable control populations. Rosset al.'2 examined bone density in 28 pre-meno-pausal women taking routinely prescribed doses ofthyroxine for 5 or more years (mean dose 171 tLg/day); TSH was found to be suppressed in 23.Women who had taken thyroxine for 10 or moreyears had a 9% reduction in bone density com-pared with normal age-matched controls without

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ENDOCRINOLOGY 25

any evidence ofthyroid disease, leading the authorsto conclude that mild subclinical or biochemical'hyperthyroidism resulting from thyroxine therapyhas an adverse effect on bone and that ... patientsshould be given the smallest dose of thyroxine toachieve a clinical response'. Paul et al.'3 reported a12.8% lower bone density at the femoral neck and a10.1% lower bone density at the femoral tro-chanter in 31 premenopausal women treated withthyroxine for a minimum of 5 years, compared withmatched controls. These authors again concludedthat 'it is advisable to employ a dosage ofthyroxinethat is carefully monitored to avoid the long-termuse of dosages that are excessive'. These findingsand conclusions prompted editorial comment inthe Journal of the American Medical Association'4and extensive discussions at the 1989 meeting oftheAmerican Thyroid Association, most discussantsbeing in favour of reduction of thyroxine dosageand repeated biochemical assessment of thyroidhormones and TSH.Two recent studies came to slightly different

conclusions. In the first, forearm bone mineralcontent (BMC) was measured in 60 women treatedwith triiodothyronine (T3) or thyroxine (T4) foreuthyroid goitre, in 13 untreated goitre patients,and in 2 controls matched for age and menopausalstate for each goitre patient.'5 BMC was notdifferent between untreated goitre patients andcontrols. In 36 premenopausal patients, treated for1 to 23 years (mean 5.8) a slight decrease in BMC ofabout 5% compared to controls was observed. In24 postmenopausal patients treated for 2 to 19years (mean 10.0) a 20% deficit was found. Wheth-er the difference between the 2 treatment groupswas due to menopausal state or duration of treat-ment is not clear. The authors concluded thatthyroid hormone therapy under these circum-stances had a clear adverse effect on bone mineralstatus in postmenopausal patients. In the secondstudy both serial and cross-sectional studies wereperformed in subjects with thyroid disease.'6 Inpatients with primary hypothyroidism a meandecrease of5.4% for vertebral bone mineral density(BMD), 7.3% for trochanter and 7% for femoralneck was observed after one year of treatment withthyroxine (mean dose 135 jig/day). In contrast, inthe cross-sectional study, vertebral BMD was notsignificantly different from age-matched normalvalues in patients receiving either replacement(mean dose 104 1tg/day) or suppressive (mean dose154 jig/day) doses of thyroxine for at least 2 years.It is suggested that bone mass reduction could betransient and reversible due to new bone formationat the end of the resorptive sequence.As the authors point out, the apparent reduction

in BMD that may accompany exogenous thyroidhormone administration has not been shown to beassociated with an increased fracture risk. The lack

of prospective studies of fracture rates in thyroidhormone treated subjects raises the question of theclinical significance of such a decrease in bonedensity. The risk may not be the same for malepatients. Toh and Brown report a 3 year follow-upstudy of 35 male patients, including 24 patientswith hypothyroidism receiving thyroid hormonereplacement to the euthyroid state, and 11 patientswith treated Graves' disease who were euthyroid.'7There was no significant difference in bone mineralcontent of the distal radius between the 2 groupsand values were no different from those in 23age-matched normal males.

If these concerns of an osteoporosis risk arecorrect then fundamental changes need to occur inour prescribing habits for patients with hypothy-roidism, as well as in biochemical monitoring, withconsiderable implications for cost, time and patientcompliance and inconvenience. It is crucial to note,however, that while it is of great importance toavoid any increased risk of osteoporosis and frac-ture associated with over-zealous thyroxine treat-ment, the findings pose a number of questionswhich are as yet unanswered. Are pre- and post-menopausal women equally at risk? Does apreceding episode of thyrotoxicosis, and henceprevious accelerated bone loss, exert an effect ofany significance and are there clear-cut differencesin risk between those given 'suppressive' doses ofthyroxine and those given 'physiological' doses? Isthe problem only related to thyroxine therapy orare other patients with suppressed TSH secretion(e.g. due to goitre, glucocorticoids, non-thyroidalillness) equally at risk? What is the clinicalsignificance of small but statistically significantdecreases in bone density? How realistic are theserecommendations on reducing thyroxine doses?The overall prevalence of thyroid hormone use inan unselected population of older adults in theFramingham cohort (94% aged 60 years or older,the remainder aged 58 or 59 years, average age68.6) was 6.9% (10.0% in women and 2.3% inmen)." Thirty seven percent of those definitelyhypothyroid had a clearly elevated serum TSHlevel (> 10 mU/l) despite thyroid therapy. In ourown study of patients over 60 years of age in asingle general practice approximately 50% of sub-jects taking thyroxine had abnormal TSH values.'8Our view remains the same as that outlined earlierthis year.'9 We believe that, given the current stateof knowledge, it is wise to avoid prescribing higherthan conventional doses of thyroxine for hypothy-roidism unless suppression of TSH secretion isimportant, as in patients with a history of thyroidcarcinoma; steps should be taken to ensure longterm compliance with thyroxine and to avoidundertreatment, and that means occasionalbiochemicah monitoring with adjustment ofthyroxine dose when necessary. It almost goes

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without saying that further long term studies arerequired and are in progress.

Generalized thyroid hormone resistance (GTHR)

Cloning and sequencing of the genes encoding thethyroid hormone receptors have led to a rapidadvance in our understanding of the pathogenesisof this apparently rare syndrome, and an apprecia-tion that it may in fact be a more commoncondition than originally thought:

Thyroid homeostasis is maintained largely by anegative feedback effect of T4 and T3 on TSHsynthesis and secretion from the anterior pituitary;primary thyroid failure leading to a reduction incirculating levels of thyroid hormones is associatedwith an increase in circulating TSH, while increasesin T4 and T3 are associated with suppression ofTSH secretion. The recent development of TSHassays with improved sensitivity which are able todifferentiate normal from reduced values, has led tothe recognition of increasing numbers of patientswith discrepancies between clinical thyroid statusand tests of thyroid function, as well as betweencirculating concentrations of thyroid hormonesand TSH. Patients with thyroid hormone levelsabove the normal range in association with unex-pectedly normal or high TSH levels are said toexhibit 'inappropriate TSH secretion' and patientswith resistance to thyroid hormones fall within thiscategory. Inappropriate secretion of TSH frompituitary glands which do not have a TSH-secretingtumour has been described in association with aeuthyroid, hyperthyroid and rarely hypothyroidclinical state. Generalized thyroid hormone resis-tance (GTHR) is the most commonly recognizedform of the defect and because the anteriorpituitary is affected in addition to the 'peripheral'tissues of the body, the defect is usually compen-sated in the untreated patient so that a euthyroidstate is maintained by high circulating free thyroidhormone levels. In contrast, in the rarer situation ofselective pituitary resistance to thyroid hormones,the clinical picture differs in that hyperthyroidismis evident.

Analysis of the familial pattern of the diseasesuggests that it usually follows an autosomaldominant pattern of inheritance, although reces-sive inheritance has been reported. The diseaseaffects males and females with equal frequency.Most patients are clinically euthyroid but in chil-dren the condition may be associated with deafnessor stunted growth and thus thyroid hormonetherapy may be indicated. The biochemical hall-mark of the condition is the presence of detectablelevels of TSH, as well as a normal or exaggeratedresponse to thyrotrophin releasing hormone(TRH), despite elevated thyroid hormones. A

recent report showing that the TSH response toTRH is proportional to the basal TSH level, andthat TRH responsiveness is maintained while tak-ing T3, confirms thyrotroph resistance to thyroidhormone.20There have been considerable advances in our

understanding of the mechanisms by which thyroidhormones act to regulate gene expression in recentyears, the most important breakthroughs arisingfrom cloning and sequencing of T3 receptorcDNAs (see reviews refs 21, 22). These advances ledto the recognition that at least two major classes ofT3 receptor proteins exist, termed a and P which areencoded by separate genes on different chromo-somes. The precise physiological roles of the tworeceptors have yet to be elucidated. Activation ofgene transcription by thyroid hormones is depen-dent on the dimerisation of receptor molecules andinteraction with specific regulatory DNA sequen-ces in target genes. Attention has focussed on therole of thyroid hormone receptor abnormalities inthe aetiology ofGTHR. Reduced binding affinity ofcell nuclei for T3 was described some years ago butmore recently possible linkage ofthe receptor genesto the syndrome of GTHR has been investigated.The first report revealed the presence of tightlinkage of the gene conferring the GTHR pheno-type to the T3 receptor P gene locus on chrom-osome 3.23 It thus appeared likely that the synd-rome resulted from a mutation of the T3 receptor Pgene. This hypothesis was supported by a subse-quent study using polymerase chain reactionamplification ofgenomic DNA, describing a singlebase substitution in exon 8 resulting in a changefrom proline to histidine, a mutation predicted toalter the secondary structure of the T3 bindingregion.24 Expression of the mutant receptor in vitrorevealed that it bound T3 with an approximately10-fold lower affinity than normal receptor, butwas capable of binding normally to thyroid hor-mone response elements in DNA.25 In similarstudies of another affected patient a single basesubstitution in exon 7 was found resulting in aglycine to arginine substitution in the hormonebinding region of one of two P receptor alleles.26Several similar base substitutions have been des-cribed by this group in different families exhibitinga dominant pattern of inheritance, although it isclear that different mutations are present indifferent kindreds.27 A small number of familieswith a recessive pattern of inheritance of thyroidhormone resistance has also been reported. Thepresence of a homozygous mutant T3 receptor Pgene allele has been described in one individualfrom such a family, sequence analysis againindicating the presence of an abnormality in thehormone binding region of the 13 gene.25 In addi-tion, Southern blot analysis has revealed a majordeletion involving several exons of the P receptor

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ENDOCRINOLOGY 27

gene including those encoding hormone bindingand DNA binding domains in affected subjects in afurther family exhibiting a recessive pattern ofinheritance.27

These specific T3 gene mutations provide someinsight into the functional characteristics ofnormaland mutated thyroid hormone receptor proteins. Inthe majority of families showing a dominant pat-tern of inheritance, only one abnormal T3 receptorallele is present, while presumably both alleles aretranscribed and translated. It has been suggestedthat expression of the abnormal allele results inreduced levels of the normal receptor gene product,the activity of which may be reduced further bycompetition for binding between the normal andabnormal gene product for thyroid hormone res-ponse elements.26 The situation in affected individ-uals may be similar to that seen in transfectionstudies of human and rat cells in which the a2 geneproduct (which does not bind T3 but which isstructurally homologous to the functional T3 bind-ing ax1 gene product) has been shown to inhibit thecellular response to T3 mediated by either P or oalreceptor proteins.26 This 'dominant negative inhibi-tion' phenomenon may be present in GTHR andmay result from the formation of dimeric mole-cular structures comprising an abnormal and nor-mal P receptor molecule, the 'heterodimer' inhibit-ing normal receptor activation of transcription.24This inhibition is probably overcome (as in most ofthe patients described) by increased T3 saturationof normal receptors consequent on high circulatingendogenous hormone concentrations or from ad-ministration of exogenous thyroid hormone. Therecent description of a family with a recessivepattern of inheritance of GTHR with affectedmembers possessing a major deletion of the T3receptor P gene extends this hypothesis. Sinceheterozygous members of the family wereunaffected, it is clear that the presence of a singlenormal allele in the absence of a mutated allele issufficient for normal T3 receptor function. Thepresence of the abnormal gene product in thedominantly inherited syndrome, however,interferes with the function of the normal receptorprotein.Thus the introduction of sensitive TSH assays

with the recognition of syndromes of 'inappro-priate TSH secretion', combined with the advancesofmolecular biology, resulting in the definition ofavariety ofmutations in the thyroid hormone recep-tor genes, has led to an increasing frequency of thediagnosis of the syndrome of GTHR. What is notclear as yet is whether such individuals requiretreatment with thyroid hormone, particularly inchildhood, what the dose should be, and whetherthe prevalence is sufficiently high for screeningprogrammes to be considered.

The role of growth hormone in adults

The physiological role of growth hormone (GH) inchildren is well established but its function in adultsis less clear. There is as yet no defined clinicalsyndrome of adult GH deficiency. GH has bothanabolic and lipolytic activity and these metaboliceffects appear to be mediated by insulin-like growthfactor 1 (IGFl) which is produced by the liver inresponse to GH stimulation. It has been proposedthat in adults the metabolic activities ofGH may beimportant for maintaining lean body mass. In 1988a small study was published on the effects ofexogenous GH on the body composition of eighthealthy, fit adults aged between 22- 33 years.29 Thetrial was of a placebo-controlled, double-blind,cross-over design. The duration of treatment was 6weeks and human growth hormone (hGH) dosage8 mg (2 U/mg) per week. The authors report thatGH caused a significant increase in lean body mass(3-7%) and a fall in body fat (1%). IGFI levelswere increased after GH treatment from0.67 ± 0.09 U/ml to 1.51 ± 0.23 U/ml but this finalfigure was still within the normal range for the agegroup studied (upper limit 2.2 U/ml). The authorsconcluded that supraphysiological levels ofexogenous growth hormone can alter body com-position.Salomon et al.30 studied the effects of growth

hormone treatment in adults with biochemicalgrowth hormone deficiency. Subjects, who had allpreviously undergone pituitary surgery, were sel-ected on the criterion of sustained GH deficiencyfor 12 months or more, with peak GH levels of lessthan 3 mU/I on a formal insulin tolerance test.IGF1 levels were also depressed in these patients(0.41 ± 0.5 U/I). There were 12 subjects in bothtreatment and placebo groups and their averageage was 39 years, all were obese according to theirideal body weights 131 ± 7%. The treatment groupreceived 0.07 U/kg (0.19 mg/kg) of hGH daily, amuch higher dose than in the previously discussedstudy. After 1 month of therapy, lean body massincreased by 10.8% and body fat levels had fallenby 2.2%. The study continued for 6 months andalthough the major increase in lean body mass wasseen within the first month, a small effect wasapparent throughout the study [52.0 ± 3.5 kg (0);56.1 ± 4.1 kg (1 month); 58.2 ± 4.8 kg (6)]. Asimilar time course was observed for the effect ofGH on total body fat [30.5 ± 3.3 kg (0),28.3 ± 2.7 kg (1 month) and 25.5 ± 3.6 kg (6months)]. These coordinated changes in bodycomposition meant that after 6 months of hGHtherapy, lean body mass increased to 104 ± 3.4%of the predicted ideal value. Compliance in the trialwas high (96 ± 2% in treatment group) with onlyone patient withdrawing because of non-specificside effects. Three patients required a reduction in

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GH dose because of oedema or hypertension. Fivepatients reported mild arthralgia which settledwithin the first 3 months of the trial. Althoughthere was some increase in insulin resistance duringtreatment (blood sugar 4.6 ± 0.2 mmol/l to5.3 ± 0.2 mmol/l) no patient developed overtdiabetes mellitus. There also seemed to be apotentially beneficial lowering ofserum cholesterolin the treatment group from 5.8 ± 0.3 to5.1 ± 0.3 mmol/l. These authors suggest that therole ofGH in adults may be to maintain lean bodymass. Jorgensen et al.3 performed a similar studyon 22 growth hormone-deficient adults and madeidentical conclusions.Rudman et al.32 extended this idea by looking at

the effects ofGH therapy in men over the age of 60years. It is argued that as people age there is aphysiological fall in lean body mass and increase inadipose tissue. It is also known that GH and IGFllevels fall with age, 5% of men between the ages of20 and 40 have IGFl levels below 350 U/l but thisfigure rises to 30%, even in healthy men, over 60years of age. It is proposed that the fall in serumGH/IGF1 concentrations and the age relatedchanges in body composition may be mechanis-tically linked. The study initially recruited 95 menby age, of these only 33 had IGFI levels less than350 U/l. The final study population was 21 anddivided into a treatment (n = 12) and controlgroup. The test subjects received hGH, 0.03 mg/kgthree times weekly, which is approximately half thedose used by Salomon et al.30 After 1 month ofGHtherapy IGFI values became markedly elevated(230 ± 66 mU/1 to 830 ± 339 mU/l). Lean bodymass increased by 8.8% and adipose mass fell by14.4%. Cholesterol levels were unaffected byGH inthis study. The authors argue that the data supportthe hypothesis that GH helps maintain lean bodymass and further suggest that the changes in bodycomposition associated with aging are a reflectionof declining GH and IGFI levels.These claims have been highlighted by the lay

press who proclaimed that GH therapy in theelderly may promote prolonged youthfulness andvigour and could therefore become a standardtreatment for the future. An editorial in the NewEngland Journal of Medicine highlights33 the pos-sible ethical, logistic and financial problems whichcould be generated if GH therapy was advocatedon a large scale in the elderly population. However,even before such arguments are entertained, somequestions concerning these studies need to beaddressed. The reported studies when takentogether, provide a strong argument that sup-raphysiological doses of hGH may increase leanbody mass in healthy, young, slim subjects,29 GHdeficient obese subject,30'3' and elderly male sub-jects.32 The study of Soloman30 and Jorgenson3'also suggests that in adults, prolonged GH

deficiency may cause alterations in body composi-tion. However, claims that the increases in adiposetissue mass which occur with aging are a functionof diminished GH/IGF levels are less easily estab-lished. Firstly, Rudman et al.3' state that 30% ofmen over 60 have IGFI levels outside the normalrange. The 'normal range' used may not be validfor this age group as the distribution of values isclearly severely skewed to the left of the mean.This suggests that an age-related normal range forIGFI needs to be employed. Secondly, bydefinition 70% of the 60 + year old populationhave 'normal' IGF1. There are no data presentedto show if the high and low IGF1 populations aresignificantly different in respect of body weight,body composition, overall health, level of normalactivity or exercise habits. If these sub-populationsare similar then the observed difference in IGFIbecomes less significant. Ifthe populations differ, itbecomes important to determine if altered IGFIlevels are in fact the cause or effect of suchdifferences. Thirdly, measurements ofIGF1 can betechnically difficult and the possibility ofchanges inthe concentration of binding and transport pro-teins needs to be excluded in the apparentlyIGF 1-deficient population. It is probable that aphysiological role for GH in adults has been foundand that a clinical syndrome of GH deficiency isabout to be defined. However, the widespread useof hGH in the general or aged population seemsunlikely at the present time.

Growth hormone and Turner's syndrome

The use of hGH in Turner's syndrome appears tobe slightly less contentious. Rosenfeld (1989)34reviewed the available trial data including theGenetech Collaborative Study. It is pointed outthat hGH doses in all trials have been randomlyselected and that no data are available which wouldallow the optimum hGH dosage regime to bedetermined. Despite this shortcoming it is con-cluded that hGH therapy does produce asignificant increase in growth rate in patients withTurner's syndrome. Although the studies have yetto achieve completion it is predicted that hGHtherapy will also lead to an increase in final adultheight. The augmentation of hGH with anabolicsteroids or low dose oestrogens is also discussed.Oxandrolone appears to cause a significant increasein growth velocity. One study reports a 3.2 cm/yearincrease in growth velocity with the group treatedwith hGH and oxandrolone when compared to thehGH alone treated group.35 Similarly the data fromthe Genetech study suggests that while hGH treat-ment alone leads to 82% of patients exceeding the50th centile for untreated patients with Turner'ssyndrome, the addition of oxandrolone led to 41%

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exceeding the 90th centile, while 33% were in factabove the 10th centile growth curve for normalgirls.34 Worries concerning premature epiphysealfusion appear to be unsubstantiated and it ispredicted that the final adult height in the com-bined treatment group will be similar to hGHalone.The use of low dose oestrogens is less clear.

Vanderschuem36 has argued that the use of hGHdoes allow the early introduction of low-doseoestrogen therapy therefore assisting the inductionof normal maturation. These studies suggest thatall girls with Turner's syndrome should be treatedwith hGH ± anabolic steroids to allow them tomaximize their adult height. Additionally low doseoestrogens should be introduced at an early stageto minimize the period of oestrogen deficiency andallow maximum maturation.

Growth hormone and ovulation induction

Attempts to increase the efficiency of artificially-induced ovulation has led to the discovery thathGH treatment can increase the sensitivity of theovarian follicles to human chorionic gonado-trophin (HCG). Therapeutically hGH treatmentallows significant reductions in both the dose andduration of HCG therapy. Homburg et al.37reported the use of hGH in 7 patients who were'resistant' to HCG therapy. The use of hGH20 IU/day dramatically reduced the dosage ofHCG required to induce ovulation. A larger trialby the same authors38 studied 16 women whorequired induction of ovulation. The test group(n = 8) received HCG and hGH while the controlgroup received HCG and placebo. The test groupshowed a 30% reduction in HCG requirement.After 1 cycle of therapy, 2 patients in the test groupbecame pregnant, with one pregnancy occurring inthe placebo group. A single case report39 has alsosuggested that hGH therapy may augment the useof pulsatile gonadotrophic releasing hormone(GnRH) treatment. This paper describes the induc-tion of a twin pregnancy after two cycles ofpulsatile GnRH and hGH therapy (10 ,ug/90 min-utes and 0.1 U/kg/day from day 1 to 12) in a patientwith hypothalamic amenorrhoea. These authorssuggest that hGH may have a physiological role inovulation and could have a significant effect on thetreatment of some forms of infertility.

Parathyroid hormone related peptide (PTHrP) andthe hypercalcaemia of malignancy

The occurrence of hypercalcaemia in certain malig-nancies has been recognized since the 1920s. It wasinitially argued that this reflected metastatic spread

of the disease to bone. The observation thathypercalcaemia can occur in the absence of skeletalmetastasis and that the number ofbone metastasesdoes not correlate with the degree of systemichypercalcaemia suggested that the physical pres-ence oftumour alone does not stimulate osteolysis.This led to the suggestion that two separatemechanisms may be involved in the generation ofhypercalcaemia. The first reiterated the idea thathypercalcaemia could be produced by the localosteolytic action ofbone metastasis, additionally itwas speculated that certain tumours produced asystemic humoral agent which, like parathyroidhormone (PTH), could elevate serum calcium. Theidentification ofa number of local paracrine agentswhich stimulate osteoclast activity and mediatehypercalcaemia (interleukin 1, tumour necrosisfactor a; B, cytokines and prostaglandins) streng-thened the argument for local metastasis butsuggested that the hypercalcaemia ofmalignancy isbasically humorally driven either at a paracrine orendocrine level.The continued search for a systemic humoral

agent responsible for malignancy related hypercal-caemia has now identified a candidate peptide,parathyroid hormone related peptide (PTHrP).4This peptide is a product ofa gene on the short armof chromosome 12, unlike PTH and calcitoninwhich are coded for on the short arm of chromo-some 11. However, these chromosomal segmentsare products ofduplication and it is possible that allthese peptides are teliologically closely related.Active PTHrP is composed of 141 aminoacids.Although the N-terminal 13 amino acids ofPTHrPare identical to those of PTH, the peptides sharelittle homology over their remaining sequence. TheN-terminal sequence contains the active site ofboth PTH and PTHrP and the homology in thisarea probably explains the similarity in physio-logical function of the two peptides. It is alsoargued that the dissimilarity of the remainingsequence explains why there is little or no cross-reactivity between the two peptides in conventionalradioimmunoassays. PTHrP appears to be ex-pressed in both malignant and normal tissue,particularly those of epithelial origin.A recent report,4' using in vitro hybridization,

has shown that mRNA for PTHrP was present inall 7 tumours taken from patients with hypercal-caemia of malignancy. These tumours werehistologically malignant and none were of para-thyroid tissue origin. Malignant tumours from 14normocalcaemic patients were also studied. PTHrPmRNA was found in all 3 squamous cell car-cinomas of the lung, one hepatocellular carcinomaand one of four adenocarcinomas of the lung.None of the 4 colonic adenocarcinomas werepositive for PTHrP mRNA. It is suggested thattumours which are commonly associated with

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clinical hypercalcaemia frequently appear to ex-press mRNA for PTHrP. The authors point outthat the expression ofmRNA does not necessarilyindicate that translation into active peptide occurs.However, the demonstration that biological activePTHrP was extracted from one of the bronchialcarcinomas and that high peripheral blood concen-trations of PTHrP were found in 2 of the studypatients (one with a malignant phaeochromo-cytoma and the other with an islet cell tumour)argues strongly for the involvement of PTHrP.Similarly, the hypothesis that a humoral agent iscontrolling the hypercalcaemia in these patients issupported by the observation that 3 patients wererendered normocalcaemic following removal of theprimary tumour.The exact relationship between PTHrP and

hypercalcaemia is complex and may depend onfactors such as the rate of mRNA translation,peptide secretion and the relative activities of othercalcium homeostatic mechanisms. Considerableresearch remains to be done in this area. Therecognition that PTHrP is also expressed in normaltissue presents the exciting problem of determiningthe physiological function for this novel peptide.

Bisphosphonates and the treatment ofhypercalcaemia of malignancy

Hypercalcaemia of malignancy is a significantclinical problem. It affects 10% of all cancerpatients, is the commonest cause ofhypercalcaemiain hospital practice and contributes significantly tothe morbidity of malignant disease. While basicmedical research continues to give an insight intothe underlying mechanisms of the disorder, appliedresearch has provided data suggesting a rationaltreatment regime for patients in the clinical situa-tion. A recent study42 reports the effects of intra-venous bisphosphonates on the serum calcium ofpatients with hypercalcaemia of malignancy.Forty-eight patients who had a corrected serumcalcium in excess of 2.8 mmol/l and were symp-tomatic from their hypercalcaemia were recruitedto one of the 3 study arms. All patients initiallyreceived 6 litres ofnormal saline intravenously over48 hours. Sodium repletion caused a significant fallin mean serum calcium from 3.45 mmol/l to3.25 mmol/I (P<0.001; n = 48). The subsequenttreatment limbs of the study consisted of either (i)pamidronate (30 mg in 0.9% saline over 4 h i.v.),(ii) clodronate (600 mg in 500 ml 0.9% saline over6 h i.v.), or (iii) etidronate (7.5 mg/kg body weightin 500 ml 0.9% saline over 2 h i.v. on 3 consecutivedays). All three bisphosphonate therapies pro-duced a significant fall in serum calcium concentra-tions. However, pamidronate induced a morerapid fall, a lower nadir value (2.45 mmol/l) and a

more protracted suppression of serum calcium (upto 29 days) than the other agents. It is argued thatpamidronate is the superior agent and this mightreflect the unique in vitro action of the drug onosteoclast synthesis and recruitment.43 There hasbeen some criticism of the study in relation to therelative doses of bisphosphonates chosen. How-ever, these drugs in general and perhaps pamid-ronate in particular, now seem to be established asfirst line agents for the treatment ofhypercalcaemiain malignancy.

Bisphosphonates and postmenopausal osteoporosis

Bisphosphonates may have also found a role in thetreatment of postmenopausal osteoporosis." Thiscostly and disabling condition is currently treatedby a number of agents including oral oestrogens,parenteral calcitonin, sodium fluoride, thiazidediuretics and calcium supplemented diets. Thenumber and variety of therapies reflects the factthat none is entirely satisfactory. Expense, routesof administration, safety and lack of provenefficacy limit their widespread use. Bisphospho-nates inhibit osteoclast activity thus reducing bonereabsorption45 and appear theoretically to belogical therapeutic agents for osteoporosis. A largenumber of small, short term uncontrolled studieshave produced conflicting results on the efficacy ofbisphosphonates in osteoporosis.44 Recently, how-ever, the results of a large, 2 year prospective,multicentred, placebo controlled, double-blind,randomized trial assessing the efficacy of intermit-tent oral etidronate on postmenopausalosteoporosis has been published.' The study rec-ruited 429 women by media announcement. Theywere below the age of75 years and had body weightbetween 40 and 80 kg. All patients were white orAsian with postmenopausal osteoporosis definedradiologically as vertebral osteopenia with 1 to 4vertebral compression fractures. Women who hadreceived therapy within the preceding 12 monthswere excluded and none of the subjects hadpreviously taken sodium fluoride, bisphosphonatesor calcitonin. All patients were counselled toincrease dietary calcium intake to 700 mg daily, inaddition they also received calcium supplements(500 mg) to be taken on days when no other drugtherapies were given. The subjects were ran-domized to treatment groups. Initially patientsreceived either placebo or phosphate tablets(250 mg phosphate) twice daily for 3 days. This wasfollowed by 14 days of treatment with eitherplacebo or etidronate (400 mg). All patients thenreceived calcium supplementation (500 mg) for thenext 74 days. Treatment cycles were repeated every91 days for 2 years. This protocol generated 4 studygroups namely: placebo-placebo, placebo-eti-

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ENDOCRINOLOGY 31

dronate, phosphate-placebo and phosphate--etidronate. Three hundred and sixty-three patientscompleted the study (86%), of the 60 patients whowithdrew only 7 (1.6%) claimed adverse side effectsof therapy.The study recorded the effects of treatment on

bone mass and fracture rate. In both groupsreceiving etidronate (placebo-etidronate; phos-phate-etidronate), there was a significant increasein vertebral bone density after 12, 18 and 24 monthsof therapy. Increase in bone density in other siteswas less pronounced and it is suggested thattrabecular bone may be preferentially affected byetidronate treatment. Review of fracture rates wasperformed by comparing the cumulative fracturesin the groups treated with and without etidronate.This showed a striking reduction of 50% in thefracture rates of the etidronate treated group(29.5/1000 patient years compared to 62.9/1000patient years). This cumulative figure, howeverdepends heavily on the markedly lower fracturerate in the etidronate-phosphate group (14.8/1000patient years) which is significantly different fromthe etidronate-placebo group (44.2/1000 patientyears). In fact the fracture rate in the etidro-nate-placebo group is very similar to the non-

etidronate treated groups (68.0 and 57.7/1000patient years). This point is not discussed in thereport. The authors also state that phosphatetherapy confers no additional benefit to etidronatetreatment. This statement is only correct if the dataon bone density and fracture rates are consideredtogether. The authors do, however, stress that theredoes appear to be a substantiated inverse relation-ship between bone density and fracture rates whichprobably makes the combined analysis valid.A similar but smaller trial ofthe effects ofcyclical

oral etidronate therapy in postmenopausal osteo-porosis was also reported in the New EnglandJournal of Medicine.47 Sixty-six patients weretreated with 400 mg of etidronate orally each dailyfor 2 weeks in 15 week cycles over 3 years. Theresults of this study were indentical to that ofNelson et al.' showing that etidronate therapyproduced significant increase in the mineral con-tent of trabecular bone and a dramatic fall invertebral fracture rates (6 vs 54 fractures per 100patient years). The results from these studies areencouraging and it appears that oral etidronatemay have an important and significant role in thefuture treatment of postmenopausal osteopor-osis 444647

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