Acromegaly L. Lazarus* From the Garvan Institute of Medical Research, St. Vincent's Hospital. Sydney
Whilst the clinical diagnosis of acromegaly is simple, the assessment of severity and the choice of therapy pose serious problems for the clinician. For many years it was accepted that acromegaly was a primary pituitary disease due to a growth hormone (GH) secreting pituitary adenoma. Studies of hypothalamic-pituitary control. however, have produced data to suggest that acromegaly is a neurocndocrine disorder of pituitary control with persistent excessive hypothalamic stimulation of- the GH secreting cells and progression from hyperplasia t o adcnoma formation.*.2 This concept is based upon observations of paradoxical responses to hypothalamic-pituitary stimulation. the identification of pituitary stimulating activity in the serum of acroinegalic patients, the association of acromegaly with apudomas and the high incidence of recurrence following surgery. In the acromegalic patient paradoxical G H responses have been noted with hypothalamic hormones, apomorphine, L-dopa, sleep and hyperglycaemia. Failure to respond to one or other of the hypothalamic-pituitary stimuli has been taken as evidence of "autonomy" of the adenoma in the past but recent studies have revealed that with adequate stimuli a GH response may be obtained in all acromegalic patients. thus revealing that the G H secrction, whilst being excessive. remains responsive to hypothalamic ~ o n t r o l If . ~acromegaly were due to excessive brain-pituitary drive then one would expect to find a stimulator of pituitary GH release in the serum of acromegalic subjects. This has, in fact, becn reported by a number of workers who have incubated normal pituitary __
*Director. Correspondence. Dr. L. Lazarus, Garvan Institute of Medical Research, St Vincent s Hospital. Darlinghurst. NSW 2010
cells with acromcgalic serum and noted the release of G H , a response not seen with normal serum.4 In their studies of the GI3 stimulator in the serum of acromegalics Hagen rt al.' reported that the highest level was found following surgical hypophysectomy suggesting that there was persistent stimulation of the pituitary remnant and providing a n cxplanation for the high incidence of recurrences following therap!.. The association of acromegaly with carcinoid and multiple endocrine adenomas is not fortuitous and may now be explained by the Fact that GH secreting cells belong to the APUD neurocndocrine group of cells and the pituitary adenoma in acromegaly is one of the apudomas5 The pituitary adenoinas in acromegaly are composed of G H sccret.ing cells6 but no significant correlation has been noted betw-een the histology of the adenoma or the size of the adenoma and clinical activity.' The adenomas frequently invade the dura of the pituitary fossa. thus making removal of all hormone secreting tissue almost impossible in some patients.' It is the continued neuroendocrine stimulation of these remnants which is thought to be the cause of the continued growth hormone secretion and recurrence in many patients. More recent studies have also revealed that in a significant proportion of acroinegalic subjects the adenoma is a mixed growth hormone and prolactin secreting adenoma6 The development of radioimmunoassays for serum G H gave promise of precise. specific assays by which acromcgalic patients could be assessed. Clinical assessment has failed to realise these hopes. Levels of serum GH in the normal range have been recorded in patients with clinically active acromegaly in many series. In the series reported by Miins and Bethune' five out of 62 patients ( V J had a mean 24-hour serum G H
level of less than 20 pUiml which would be considered to be normal in most laboratories. N o group has reported a good correlation between the absolute level of serum G H and the clinical status of the patient. In a careful study of 26 patients studied before and twelve months after therapy, Kanis er al.“’ reported that neither the initial serum G H levels nor the change in GH levels could be related to symptoms. signs or other biochemical abnormalities. It was their conclusion that serum G H determinations are not a good index of severity, activity or of responses to therapy. Although there is no unequivocal evidence to indicate that an acromegalic patient’s disease state will ameliorate if the serum GH levels are returned to the ”normal” range, many clinicians now seek to suppress serum GH levels to the “normal“ range and will submit patients to repeated therapeutic manoeuvres until this is achieved. The use of serum GW radioimmunoassays a s precise, absolute therapeutic targets requires further consideration. as apart from the lack of correlation with clinical status there is evidence that the assays have neither the specificity nor the precision assumed by the clinicians. The observed difficulties with the interpretation of serum G H radioimmunoassays in acromegaly pose the problem ofwhy this should be so. There are three contributing factors. One is the fact that the circulating serum G H in acromegaly is physically different from normal pituitary GH, the second is the large interlaboratory error in reporting G H assays and the third is the evidence that the growth promoting activity of acromegalic serum is not due to the serum GH.” I t is now apparent from the studies of the circulating form of growth hormone in acromegaly that it is heterogeneous consisting of many polymeric forms of growth hormone and is physically different from the monomeric pituitary growth hormone used as the ligand in the assays. As a result the G H radioimmunoassay becomes analytically invalid and great caution should be exercised in the interpretation of the assay data, particularly when serial determinations are used to assess responses to therapy. Considerable interlaboratory variation has been observed for GH radioimmunoassays. In a recent survey conducted by the Human Pituitary
Advisory Committee an acromegalic serum sample was sent to 23 laboratories who reported GH levels ranging from 14 pU/ml to 52 pU;ml with a mean of 30 pU;ml. Similar interlaboratory variation has been reported for surveys in other countries. The measurement of growth hormone in serum by bioassay has been known for many years to reveal lcvcls many times greater than those found by the use of radioimmunoassay. In a comparative study of bioassay versus radioimmunoassay in acromegalic serum. Lazarus rr a/.” reported biological activity ofup to 100 times greater than radioimmunological activity in the whole serum and biological activity of up to 1,000 times that of immunological activity in some isolated serum fractions. Whether the biological activity found in the acromegalic serum is due to biologically active fragments of pituitary growth hormone or due to peripherally stimulated trophic substances is not yet known but there is a considerable body of evidence to support the former concept. The somatomedins are a group of insulin-like growth hormone dependent trophic substances produced under the stimulation of pituitary growth hormone. It was hoped that the mcasurement of somatomedin in serum would provide a better index of activity in patients with acromegaly and the reports which have appeared have supported these expectations. Unfortunately, up until very recently, the performance of somatomedin assays was by time-consuming and tedious bioassay which precluded the widespread use of this assay in clinical medicine. More recently. somatomedins have been prepared in purified form from human serum and a new series of assays using either radio-receptor techniques or radioimmunoassays are now becoming available. A recent paper reports a good correlation between somatomedin activity measured by radioimmunoassay and clinical activity in acromegalic subjects.’2 In the past therapy of the acromegalic was reserved for the treatment of pituitary local pressure effects or systemic complications but it is now generally accepted that clinically active acromegaly warrants therapy to reduce the excessive serum growth promoting activity. Although the concept of a “burnt out case” is
dear to the heart of students, there is little evidence t o support this likelihood except in the case of those rare patients who experience pituitary apoplexy. Serial studies of serum GH levels in untreated patients with acromegaly have been recorded by Hunter rt d 3 who followed 23 patients periodically over a period of four years. They reported that the general picture was one of unchanging growth hormone levels with many patients showing essentially unvarying levels over periods of many months or years and with no patient showing spontaneous diminution of levels. All tissucs in thc acromegalic are affected by the excessive growth activity of the serum and as well as the obvious acral changes, crippling osteoarthritis, entrapment syndromes and diabetes inellitus all acromegalic patients have evidence of visceromegaly, particularly cardioinegaly. There is now evidence indicating that acromegalic patients have a poor prognosis if left untreated with their discase proceeding inexorably to the development of complications and early death.“ Selection of the mode of therapy by the clinician is, however, very difficult as neither surgery, radiotherapy nor drug therapy is clearly effective in achieving the aims of rcducing growth activity and retaining normal pituitary function. The recent development of transsphenoidal microsurgery has considerably improved the surgical approach with decreased morbidity and more effective removal of the adenoma. The incidence of recurrences is high but this is not surprising in view of the data indicating that involvement of the dura by the adenoma is common8 and the evidence of continued neuroendocrine stimulation of the pituitary remnant^.^ Radiotherapy may be undertaken with either an external beam, a heavy particle beam or interstitial irradiation. Conventional external beam irradiation recently has received favourable reports although for some years there had been doubt regarding the effectiveness of the dosc of up to 5OOOR which is given with this technique. Several groups, including Lawrence tit al.”, have reported good responses with this type of therapy in 70”;.1 of acromegalics although all workers have stressed that a prolonged time interval of up to
three )ears may bc necessary for a bcncficial effect to become apparent followning the therapy. Using modern techniques and dosage schedules the incidence of side effects is extremely low. Of considerable importance is a consideration of the manner in which the irradiation works as this may provide an important series of clues to the planning of future forms of therapy. Although normal pituitary cells are remarkably radio-resistant it has been suggested that the more active cells of an adenoma are radiosensitive. Histological examination of the pituitary gland after irradiation for acromegaly however has revealed no signs of a direct effect of the irradiation on the pituitary cells.L5 As the irradiation usually includes the hypothalamus Lawrence and her cow o r k e r ~ ’have ~ suggested that the radiotherapy is effective by virtue of its effect on the neuroendocrine contfol of the pituitary rather than a direct effect upon the pituitary cells themselves. This concept is supported by recent evidence revealing a high incidence of hypopituitarism, particularly involving growth hormone secretion, in children whose brain has been irradiated for leukaemia.I6 In their experimental studies Mosier and Jansons” have also reported that irradiation of the area of the brain in the region of the hypothalamus in young rats results in a serious stunting of growth in adult life and a significant diminution in the size of the pituitary gland. Previous reports of responses to irradiation in acromegaly had suggested also that other pituitary modalities had been retained intact whilst the growth hormone only had been decreased. A recent report by Aloia and Archambeau18, however, has revealed a high incidence of hypopituitarism appearing up to three years following irradiation. Whether this hypopituitarism is due to irradiation necrosis of pituitary cells or due to hypothalamic irradiation is not clear but in view of the lack of histological evidence of radiation necrosis the latter suggestion seems more likely. Drug therapy of various types has been utilised for many years in attempts to treat patients with acromegaly.” Oestrogens have been used for a considerable period of time and have been thought to exert their effect by peripheral blockade of the activity of growth
hormone or somatoinedins. The doses required, however, are large and the side effects are usually unacceptable to the patients. A number of agents acting via brain biogenic amines have been reported to suppress the secretion of growth hormone in the acromcgalic. These have included medrox!--profcsterone acetatc. chlorpromazine, L-dopa and the dopamine agonist bromocriptine. The only one of these agents which has stood up to clinical trial is broniocriptiiie.'O The evidence currently available would indicate that some but not all acromegalic subjects respond to bromocriptine but that the doses required may be large (up to 120 mg per day) coinpared with the sinall doses (5-10 mg per day) which are effective in treating patients with prolactinomas. In those patients who do respond there is clinical improvement with a resolution of headache. a decrease or sweating and a diminution of' lethargy- which so often troubles these patients. Whether the bromocriptine is effective in reducing the levels of growthpromoting activity in serum and the size of the pituitary adenoma yet remains to be clarified. In those patients who do respond to bromocriptine the cessation of therapy results in a prompt rebound of clinical activity, presumably due to the persistent neurocndocrine drive. and raises serious problems with regard to the long term therapy of patients with this type of agent. Whilst the clinical manageinent of the acromegalic patient has improved considerably in recent years the clinician is faced in each case with a difficult problem as there is no reliable index of activity and a lack of knowledge regarding the aetiology. Therapy will continue to
be unsatisfactory until such time as there is a clear understanding of the underlying disease process and a reliable means of assessing severity and response to therapy.
References I . D ~ u G l l n l ~ W. v . 11.. (:RYER. 1'. E.and JACIIRS. 1.. S. (1973): Thc ralc of the hypothalamus in the pathogenesis of pituivary tumwrs. in IXripnosis rind 7ruarainir ot't'iririitir~ fiiiwim. p. 26. ed. h> P.0 Kohler and G.T. Ross. hmerican Elwvicr. S e w Yurk. 2. I.A?ARLS. 1.. (1077): I'ituitar) adenoinas and dyspituitari.*ni. .41N. ;V.% J . Surx. 47. 590. 3. 11ASI.W. K..AlDA. .M.. TAXO. T..OIlU,\. M.. SISlIlZ.Al1~. I;..Ml'RAK.\YI. 0.. SIIIMA. M. and Ycaiii%ntiA. K.(1976): Differences in autonomil) ofgrowlh hormone secretion in palienls with acromcgiily. Ibhokv J. crp. Urrl. 120. l5Y. 4. li~t;i.\.T. C . l.~wai:sc;:. A M. and KIHS studicr ol'plasina gruwth hormonr: releasing a of acromegal). Ilrirt~i.Mrruh. Rm. 10. 310. 5. WBl.BOI:Rs. K.8. (1977). Current rtalusol'll~capudnmas. Anii. Sury. 185, 1. b. H(IRV,\TII. F!. and KO\ACX. K. (1976): Illtrastmctural classiticalion of piluilar) adsnomas. (biiud. J. X ~ i r r d Sci. . 3. Y. 7. Hoi. S. I;.. Wii.xn. C:. B. and TVKREI.~.. J. 8.(IYi7): I'ranssphmoidal microphyophysectomy in acromegaly. J. !Veiirosiirp. 47, X40. X. WRl(iH.i?iOls. 1.' (1978): Cuiixrvatiw reinoval ofsmall pituitary tumours: IS II jusrificd by rhe pdlhologicalfindings. J. ,Vruro/. A'?zrros~rrg.P.v~'chiuf. 41.?83. 9. Yim. R. B. and I ~ ~ T I K SJ.E .E. (1974): Aurumcgal> with normal fasting p r o w h hormonc concentrations but abnormal growth hormone regulation. Aiin. iiilerii. .Met/. 81. 781. It). KAMS.J. .A. ~ ~ l l . l . l > ~ i l1' ~.AJ..~ lIlARIUS. . P..1Il)RX. I). H.. IILN1F.K. W. M.. R r n ~ 4 ~ 1A. r .1 .and STROW. J. r\. (1974): Clinical and lahorntor) study o i acromcgaly: assesrmcnt bciore arid one ?car alicr trcalmenl. Quurt. J. M i d 43, 409. 11. LAZAR~JS. L.. S'ILART.M.C. and ~'ERC;t:sou.K. A. (19781: Growth hormonc asvays in acromegaly. Proc. 6111,lsh & Ori.a,,iu Cong. ~f'Iii(locriiio/. 2.492. 12. I~I:RLASI:T.I.O. R. W.. LKI)FXWIXII). 1.I!.. VAS W r r . J. J . and D'ERI-OLE. A. J. (lY77): Estimation of somatomedin C Icwls in normals and patients with pitiiitary diseuse bq radioimmunoassaq. J. r/iii. Irivrsr. 60,h48. 1.; t!LSrER. w.Y., ~ l i . l . l ~ C ~ ~ l A I'. MJ.., HARRIS.P.. KAVlS. J. ,%.. bl&I IRK. F. M..M~Liii LAW. J. and S I H ~ ~I.CA.. (1974): Scrial assays of planma :rowth hormonc in trcatrd and untreated acromepdly. J. Enclocr. 63, 21. 14. WK1I;lll. A. D.. 1111.1. I). X I . . I.invau.C. and ~;KASI:R.T. K.I 1970):Mortality in acronicpaly. Q w r r . J. Aferl. 39. 1. IS. I.AWRI;S~I..A. M..I'I\IFKY.S. Y. imdCioi.rmh.i., 1. D. (1971): Conventional . 369. radiation thcrapy in acromegaly. Arch. Ltrcrn. M P ~128, 16. S I I A I . ~S.~ .M.. 1 3 1 . ~ 1 t i ~ ~ .C. i . i .Ci., . ' l w i ~ i : 1. ~ .A ,, Jostr. P. II. M. and Pr-*RSln. D. (1977): h d o c r i n c function fdlowinp the treatment 01' acute ~eukacniiain childhood. 1. l'cdiuf. 90, 920. 17. Ml611'R. H. 1). and J~sx)sS.R.A. (19701: Ellcct ol'x-irradialion of~clccled area5 or the head of the newhorn rat on growth. R u h r . Re.$.43, Y?. 18. Ai.tri.%.1. t . and ARCIIAMRINL J. 0.(1'978): Hypopiiuilarism following
(1978): M d i c a l treatment ofacrcmcgaly.
IY. KOBR~RI.IXG. J. and SCI I
with broinocrintinc. Arir.
rn1.d.
J . 1. 875.
Whilst the clinical diagnosis of acromegaly is simple, the assessment of severity and the choice of therapy pose serious problems for the clinician. For many years it was accepted that acromegaly was a primary pituitary disease due to a growth hormone (GH) secreting pituitary adenoma. Studies of hypothalamic-pituitary control. however, have produced data to suggest that acromegaly is a neurocndocrine disorder of pituitary control with persistent excessive hypothalamic stimulation of- the GH secreting cells and progression from hyperplasia t o adcnoma formation.*.2 This concept is based upon observations of paradoxical responses to hypothalamic-pituitary stimulation. the identification of pituitary stimulating activity in the serum of acroinegalic patients, the association of acromegaly with apudomas and the high incidence of recurrence following surgery. In the acromegalic patient paradoxical G H responses have been noted with hypothalamic hormones, apomorphine, L-dopa, sleep and hyperglycaemia. Failure to respond to one or other of the hypothalamic-pituitary stimuli has been taken as evidence of "autonomy" of the adenoma in the past but recent studies have revealed that with adequate stimuli a GH response may be obtained in all acromegalic patients. thus revealing that the G H secrction, whilst being excessive. remains responsive to hypothalamic ~ o n t r o l If . ~acromegaly were due to excessive brain-pituitary drive then one would expect to find a stimulator of pituitary GH release in the serum of acromegalic subjects. This has, in fact, becn reported by a number of workers who have incubated normal pituitary __
*Director. Correspondence. Dr. L. Lazarus, Garvan Institute of Medical Research, St Vincent s Hospital. Darlinghurst. NSW 2010
cells with acromcgalic serum and noted the release of G H , a response not seen with normal serum.4 In their studies of the GI3 stimulator in the serum of acromegalics Hagen rt al.' reported that the highest level was found following surgical hypophysectomy suggesting that there was persistent stimulation of the pituitary remnant and providing a n cxplanation for the high incidence of recurrences following therap!.. The association of acromegaly with carcinoid and multiple endocrine adenomas is not fortuitous and may now be explained by the Fact that GH secreting cells belong to the APUD neurocndocrine group of cells and the pituitary adenoma in acromegaly is one of the apudomas5 The pituitary adenoinas in acromegaly are composed of G H sccret.ing cells6 but no significant correlation has been noted betw-een the histology of the adenoma or the size of the adenoma and clinical activity.' The adenomas frequently invade the dura of the pituitary fossa. thus making removal of all hormone secreting tissue almost impossible in some patients.' It is the continued neuroendocrine stimulation of these remnants which is thought to be the cause of the continued growth hormone secretion and recurrence in many patients. More recent studies have also revealed that in a significant proportion of acroinegalic subjects the adenoma is a mixed growth hormone and prolactin secreting adenoma6 The development of radioimmunoassays for serum G H gave promise of precise. specific assays by which acromcgalic patients could be assessed. Clinical assessment has failed to realise these hopes. Levels of serum GH in the normal range have been recorded in patients with clinically active acromegaly in many series. In the series reported by Miins and Bethune' five out of 62 patients ( V J had a mean 24-hour serum G H
level of less than 20 pUiml which would be considered to be normal in most laboratories. N o group has reported a good correlation between the absolute level of serum G H and the clinical status of the patient. In a careful study of 26 patients studied before and twelve months after therapy, Kanis er al.“’ reported that neither the initial serum G H levels nor the change in GH levels could be related to symptoms. signs or other biochemical abnormalities. It was their conclusion that serum G H determinations are not a good index of severity, activity or of responses to therapy. Although there is no unequivocal evidence to indicate that an acromegalic patient’s disease state will ameliorate if the serum GH levels are returned to the ”normal” range, many clinicians now seek to suppress serum GH levels to the “normal“ range and will submit patients to repeated therapeutic manoeuvres until this is achieved. The use of serum GW radioimmunoassays a s precise, absolute therapeutic targets requires further consideration. as apart from the lack of correlation with clinical status there is evidence that the assays have neither the specificity nor the precision assumed by the clinicians. The observed difficulties with the interpretation of serum G H radioimmunoassays in acromegaly pose the problem ofwhy this should be so. There are three contributing factors. One is the fact that the circulating serum G H in acromegaly is physically different from normal pituitary GH, the second is the large interlaboratory error in reporting G H assays and the third is the evidence that the growth promoting activity of acromegalic serum is not due to the serum GH.” I t is now apparent from the studies of the circulating form of growth hormone in acromegaly that it is heterogeneous consisting of many polymeric forms of growth hormone and is physically different from the monomeric pituitary growth hormone used as the ligand in the assays. As a result the G H radioimmunoassay becomes analytically invalid and great caution should be exercised in the interpretation of the assay data, particularly when serial determinations are used to assess responses to therapy. Considerable interlaboratory variation has been observed for GH radioimmunoassays. In a recent survey conducted by the Human Pituitary
Advisory Committee an acromegalic serum sample was sent to 23 laboratories who reported GH levels ranging from 14 pU/ml to 52 pU;ml with a mean of 30 pU;ml. Similar interlaboratory variation has been reported for surveys in other countries. The measurement of growth hormone in serum by bioassay has been known for many years to reveal lcvcls many times greater than those found by the use of radioimmunoassay. In a comparative study of bioassay versus radioimmunoassay in acromegalic serum. Lazarus rr a/.” reported biological activity ofup to 100 times greater than radioimmunological activity in the whole serum and biological activity of up to 1,000 times that of immunological activity in some isolated serum fractions. Whether the biological activity found in the acromegalic serum is due to biologically active fragments of pituitary growth hormone or due to peripherally stimulated trophic substances is not yet known but there is a considerable body of evidence to support the former concept. The somatomedins are a group of insulin-like growth hormone dependent trophic substances produced under the stimulation of pituitary growth hormone. It was hoped that the mcasurement of somatomedin in serum would provide a better index of activity in patients with acromegaly and the reports which have appeared have supported these expectations. Unfortunately, up until very recently, the performance of somatomedin assays was by time-consuming and tedious bioassay which precluded the widespread use of this assay in clinical medicine. More recently. somatomedins have been prepared in purified form from human serum and a new series of assays using either radio-receptor techniques or radioimmunoassays are now becoming available. A recent paper reports a good correlation between somatomedin activity measured by radioimmunoassay and clinical activity in acromegalic subjects.’2 In the past therapy of the acromegalic was reserved for the treatment of pituitary local pressure effects or systemic complications but it is now generally accepted that clinically active acromegaly warrants therapy to reduce the excessive serum growth promoting activity. Although the concept of a “burnt out case” is
dear to the heart of students, there is little evidence t o support this likelihood except in the case of those rare patients who experience pituitary apoplexy. Serial studies of serum GH levels in untreated patients with acromegaly have been recorded by Hunter rt d 3 who followed 23 patients periodically over a period of four years. They reported that the general picture was one of unchanging growth hormone levels with many patients showing essentially unvarying levels over periods of many months or years and with no patient showing spontaneous diminution of levels. All tissucs in thc acromegalic are affected by the excessive growth activity of the serum and as well as the obvious acral changes, crippling osteoarthritis, entrapment syndromes and diabetes inellitus all acromegalic patients have evidence of visceromegaly, particularly cardioinegaly. There is now evidence indicating that acromegalic patients have a poor prognosis if left untreated with their discase proceeding inexorably to the development of complications and early death.“ Selection of the mode of therapy by the clinician is, however, very difficult as neither surgery, radiotherapy nor drug therapy is clearly effective in achieving the aims of rcducing growth activity and retaining normal pituitary function. The recent development of transsphenoidal microsurgery has considerably improved the surgical approach with decreased morbidity and more effective removal of the adenoma. The incidence of recurrences is high but this is not surprising in view of the data indicating that involvement of the dura by the adenoma is common8 and the evidence of continued neuroendocrine stimulation of the pituitary remnant^.^ Radiotherapy may be undertaken with either an external beam, a heavy particle beam or interstitial irradiation. Conventional external beam irradiation recently has received favourable reports although for some years there had been doubt regarding the effectiveness of the dosc of up to 5OOOR which is given with this technique. Several groups, including Lawrence tit al.”, have reported good responses with this type of therapy in 70”;.1 of acromegalics although all workers have stressed that a prolonged time interval of up to
three )ears may bc necessary for a bcncficial effect to become apparent followning the therapy. Using modern techniques and dosage schedules the incidence of side effects is extremely low. Of considerable importance is a consideration of the manner in which the irradiation works as this may provide an important series of clues to the planning of future forms of therapy. Although normal pituitary cells are remarkably radio-resistant it has been suggested that the more active cells of an adenoma are radiosensitive. Histological examination of the pituitary gland after irradiation for acromegaly however has revealed no signs of a direct effect of the irradiation on the pituitary cells.L5 As the irradiation usually includes the hypothalamus Lawrence and her cow o r k e r ~ ’have ~ suggested that the radiotherapy is effective by virtue of its effect on the neuroendocrine contfol of the pituitary rather than a direct effect upon the pituitary cells themselves. This concept is supported by recent evidence revealing a high incidence of hypopituitarism, particularly involving growth hormone secretion, in children whose brain has been irradiated for leukaemia.I6 In their experimental studies Mosier and Jansons” have also reported that irradiation of the area of the brain in the region of the hypothalamus in young rats results in a serious stunting of growth in adult life and a significant diminution in the size of the pituitary gland. Previous reports of responses to irradiation in acromegaly had suggested also that other pituitary modalities had been retained intact whilst the growth hormone only had been decreased. A recent report by Aloia and Archambeau18, however, has revealed a high incidence of hypopituitarism appearing up to three years following irradiation. Whether this hypopituitarism is due to irradiation necrosis of pituitary cells or due to hypothalamic irradiation is not clear but in view of the lack of histological evidence of radiation necrosis the latter suggestion seems more likely. Drug therapy of various types has been utilised for many years in attempts to treat patients with acromegaly.” Oestrogens have been used for a considerable period of time and have been thought to exert their effect by peripheral blockade of the activity of growth
hormone or somatoinedins. The doses required, however, are large and the side effects are usually unacceptable to the patients. A number of agents acting via brain biogenic amines have been reported to suppress the secretion of growth hormone in the acromcgalic. These have included medrox!--profcsterone acetatc. chlorpromazine, L-dopa and the dopamine agonist bromocriptine. The only one of these agents which has stood up to clinical trial is broniocriptiiie.'O The evidence currently available would indicate that some but not all acromegalic subjects respond to bromocriptine but that the doses required may be large (up to 120 mg per day) coinpared with the sinall doses (5-10 mg per day) which are effective in treating patients with prolactinomas. In those patients who do respond there is clinical improvement with a resolution of headache. a decrease or sweating and a diminution of' lethargy- which so often troubles these patients. Whether the bromocriptine is effective in reducing the levels of growthpromoting activity in serum and the size of the pituitary adenoma yet remains to be clarified. In those patients who do respond to bromocriptine the cessation of therapy results in a prompt rebound of clinical activity, presumably due to the persistent neurocndocrine drive. and raises serious problems with regard to the long term therapy of patients with this type of agent. Whilst the clinical manageinent of the acromegalic patient has improved considerably in recent years the clinician is faced in each case with a difficult problem as there is no reliable index of activity and a lack of knowledge regarding the aetiology. Therapy will continue to
be unsatisfactory until such time as there is a clear understanding of the underlying disease process and a reliable means of assessing severity and response to therapy.
References I . D ~ u G l l n l ~ W. v . 11.. (:RYER. 1'. E.and JACIIRS. 1.. S. (1973): Thc ralc of the hypothalamus in the pathogenesis of pituivary tumwrs. in IXripnosis rind 7ruarainir ot't'iririitir~ fiiiwim. p. 26. ed. h> P.0 Kohler and G.T. Ross. hmerican Elwvicr. S e w Yurk. 2. I.A?ARLS. 1.. (1077): I'ituitar) adenoinas and dyspituitari.*ni. .41N. ;V.% J . Surx. 47. 590. 3. 11ASI.W. K..AlDA. .M.. TAXO. T..OIlU,\. M.. SISlIlZ.Al1~. I;..Ml'RAK.\YI. 0.. SIIIMA. M. and Ycaiii%ntiA. K.(1976): Differences in autonomil) ofgrowlh hormone secretion in palienls with acromcgiily. Ibhokv J. crp. Urrl. 120. l5Y. 4. li~t;i.\.T. C . l.~wai:sc;:. A M. and KIHS studicr ol'plasina gruwth hormonr: releasing a of acromegal). Ilrirt~i.Mrruh. Rm. 10. 310. 5. WBl.BOI:Rs. K.8. (1977). Current rtalusol'll~capudnmas. Anii. Sury. 185, 1. b. H(IRV,\TII. F!. and KO\ACX. K. (1976): Illtrastmctural classiticalion of piluilar) adsnomas. (biiud. J. X ~ i r r d Sci. . 3. Y. 7. Hoi. S. I;.. Wii.xn. C:. B. and TVKREI.~.. J. 8.(IYi7): I'ranssphmoidal microphyophysectomy in acromegaly. J. !Veiirosiirp. 47, X40. X. WRl(iH.i?iOls. 1.' (1978): Cuiixrvatiw reinoval ofsmall pituitary tumours: IS II jusrificd by rhe pdlhologicalfindings. J. ,Vruro/. A'?zrros~rrg.P.v~'chiuf. 41.?83. 9. Yim. R. B. and I ~ ~ T I K SJ.E .E. (1974): Aurumcgal> with normal fasting p r o w h hormonc concentrations but abnormal growth hormone regulation. Aiin. iiilerii. .Met/. 81. 781. It). KAMS.J. .A. ~ ~ l l . l . l > ~ i l1' ~.AJ..~ lIlARIUS. . P..1Il)RX. I). H.. IILN1F.K. W. M.. R r n ~ 4 ~ 1A. r .1 .and STROW. J. r\. (1974): Clinical and lahorntor) study o i acromcgaly: assesrmcnt bciore arid one ?car alicr trcalmenl. Quurt. J. M i d 43, 409. 11. LAZAR~JS. L.. S'ILART.M.C. and ~'ERC;t:sou.K. A. (19781: Growth hormonc asvays in acromegaly. Proc. 6111,lsh & Ori.a,,iu Cong. ~f'Iii(locriiio/. 2.492. 12. I~I:RLASI:T.I.O. R. W.. LKI)FXWIXII). 1.I!.. VAS W r r . J. J . and D'ERI-OLE. A. J. (lY77): Estimation of somatomedin C Icwls in normals and patients with pitiiitary diseuse bq radioimmunoassaq. J. r/iii. Irivrsr. 60,h48. 1.; t!LSrER. w.Y., ~ l i . l . l ~ C ~ ~ l A I'. MJ.., HARRIS.P.. KAVlS. J. ,%.. bl&I IRK. F. M..M~Liii LAW. J. and S I H ~ ~I.CA.. (1974): Scrial assays of planma :rowth hormonc in trcatrd and untreated acromepdly. J. Enclocr. 63, 21. 14. WK1I;lll. A. D.. 1111.1. I). X I . . I.invau.C. and ~;KASI:R.T. K.I 1970):Mortality in acronicpaly. Q w r r . J. Aferl. 39. 1. IS. I.AWRI;S~I..A. M..I'I\IFKY.S. Y. imdCioi.rmh.i., 1. D. (1971): Conventional . 369. radiation thcrapy in acromegaly. Arch. Ltrcrn. M P ~128, 16. S I I A I . ~S.~ .M.. 1 3 1 . ~ 1 t i ~ ~ .C. i . i .Ci., . ' l w i ~ i : 1. ~ .A ,, Jostr. P. II. M. and Pr-*RSln. D. (1977): h d o c r i n c function fdlowinp the treatment 01' acute ~eukacniiain childhood. 1. l'cdiuf. 90, 920. 17. Ml611'R. H. 1). and J~sx)sS.R.A. (19701: Ellcct ol'x-irradialion of~clccled area5 or the head of the newhorn rat on growth. R u h r . Re.$.43, Y?. 18. Ai.tri.%.1. t . and ARCIIAMRINL J. 0.(1'978): Hypopiiuilarism following
(1978): M d i c a l treatment ofacrcmcgaly.
IY. KOBR~RI.IXG. J. and SCI I
with broinocrintinc. Arir.
rn1.d.
J . 1. 875.
