- Email: [email protected]
BROMOCRIPTINE IN ACROMEGALY
484
drug apomorphine,
its action depends partly on the presence of catecholamine stores.9 When these are depleted by reserpine or ot-methylparatyrosine, many of the behavioural actions of bromocriptine in animals are lost.1O The effects of bromocriptine on different dopamine systems in the brain are therefore unlikely to be exactly similar to those of levodopa. From this evidence, it is still not certain whether the growth-hormone response to levodopa or dopamine agonists is abnormal in parkinsonism, or whether all brain-dopamine systems are functionally involved in this condition. However, Greenfield and Bosanquet" suggested there was a system degeneration of melanin-neurons rather than dopamine neurons in Parkinson’s disease. The two possibilities may not be mutually exclusive, although the former seems the more probable in view of damage to the dopamine-melanin neurons of the substantia nigra, the noradrenaline-melanin neurons of the locus caeruleus, and other brainstem pigmented systems.
J. D. PARKES
University Department of Neurology, King’s College Hospital and The Institute of Psychiatry, London
A. G. DEBONO C. D. MARSDEN
during this limited period only. This view is repeated papersl-3 and in advertising material. Our patients are chronic schizophrenics whose symptoms are well controlled by injections of fluphenazine decanoate every 4 weeks and no other medication. The dosage causes parkinsonism in each patient and is kept constant (range 25-37.5 mg four-weekly). The severity of physical signs of parkinsonism is assessed using a standardised clinical assessment weekly and a battery of performance tests, including speed of tapping and completion of a grooved peg-board test, twice weekly.. Six patients have been studied so far; one for 6 months, one
be needed
in
for 5 months, three for 4 months, and one for 3 months. The figure shows part of the performance of the first patient. Although the severity of the signs varies from month to month, the general pattern is the same. There is no evidence of a practice effect or of a gradual decline in severity. The signs are most severe in the third week after the injections. The six patients have been studied for a total of 26 months, and the effects seen in the first patient are closely reflected in the other
patients. PARKINSONISM INDUCED BY FLUPHENAZINE DECANOATE
SIR,-Our long-term studies of parkinsonism induced by decanoate suggest that earlier descriptions may be incorrect. All the phenothiazines can induce extrapyramidal syndromes, and this property is shared by the depot preparations of fluphenazine enanthate and decanoate. It is commonly held that any extra pyramidal signs seen are at their worst 3-5 days after the injection and that anti-parkinsonism drugs may
fluphenazine
The observation that the signs of parkinsonism are greatest in the third week after the injections contradicts previous statements about the pattern of signs which follow the administration of fluphenazine, and suggests that where drugs are given to control parkinsonism induced by fluphenazine decanoate for only part of the interval between injections, this is best done around the third week rather than for the first 5-10 days. Where trials of the efficacy of drugs in controlling parkinsonism induced by fluphenazine decanoate are undertaken, assessment of the patients in the third week after the injections is more likely to show differences between treatments, The likely explanation of the changes in the severity of the clinical signs is that they reflect the rate of release of fluphenazine from the depot. We thank Dr M. Aveline, Prof. J. E. Cooper, Dr I. B. Pearson, Dr D. A. Toms, and Dr P. J. A. V. Willems for allowing us to study patients under their care; Sister Nina Burgum and the nurses of the Byron day centre for their help; and E. R. Squibb and Sons Limited who provided funds to support P. L., and their medical adviser, Dr A,
Schiff, for his general assistance. P. LAMB R. H. S. MINDHAM M. A. EZZAT
Professorial Unit,
Mapperley Hospital, Nottingham NG3 6AA
BROMOCRIPTINE IN ACROMEGALY
SIR,-Dr Sachdev and colleagues (Dec. 13, p. 1164) have provided evidence that some patients improve on bromocriptine therapy, but the conclusion that the drug has a primary role in the management of acromegaly is open to question. Bromocriptine was "fully effective" in only 4 of the 21 patients studied. In the others subjective improvement in wellbeing, appearance, and hand or foot size was variable, and was not accompanied by significant effects upon soft-tissue thickWhile carbohydrate tolerance affected. Moreover 10 patients improved, hypertension had had radiotherapy a year or more previously and the full effect of this may not be evident for several,years.5 6 The significance of persisting raised serum growth-hormone, despite clinical remission, is uncertain; but the level of the hormone provides the most direct means of comparing the efficacy ness or
sebum-excretion
rate.
was not
111 out
NOY
n.
JAH
DEC
monthly assessments of parkinsonism in weekly injections (arrows) of fluphenazine decanoate.
First three
a
patient
on
four-
A rise indicates a decrease in severity. The study of this patient was over Christmas and New Year. Injections were given on Dec. 20 and Jan. 17, but the December treatment was not assessed.
interrupted
A=Peg board 10.
B=Impulse
counter
C=Clinical
assessment
Corrodi, H., Farnebo, L-O., Fuxe, K., Hamberger, B. Eur. J. Pharmac. 1975, 30, 172. 11. Greenfield J. G., Bosanquet, F. D. J. Neurol. Neurosurg. Psychiat. 1953, 16, 213.
1. Drug Thera. Bull. 1970, 8, 69. 2. Ayd, F. J., Jr. Compreh. Psychiat. 1974, 15, 277. 3. Ayd, F. J., Jr.Am. J.Psychiat. 1975, 132, 491. 4. Mindham, R. H. S. Br. J. clin. Pharmac. (in the press). 5. Lawrence, J. H., Tobias, C. A., Linfoot, J. A., Born, J. L., Lyman,J. T. Chong, C. Y., Manougian, E., Wei, W. C. J. clin.Endocr. 1970, 31, 180. 6. Wright, A. D., Hartog, M., Palter, H., Tevaarwerk, G., Doyle, F. H, Arnot, R., Joplin, G. F., Fraser, T. R.Proc.R. Soc.Med. 1970, 63, 221
485 of treatments for acromegaly.7 The failure to achieve sustained reductions of growth hormone to normal levels compares unfavourably with the results of trans-sphenoidal ’microsurgery 7 -13 achieved by radical pituitary extirpation7or, more usually, by selective removal of microadenomas. Selective operation is most likely to be feasible in early cases. To temporise with bromocriptine may be to deny the patient his best chance for selective surgery. The escape of hormone levels in 2 patients, and the overswing that followed cessation of therapy in 2 others, suggest that clinical improvement during bromocriptine treatment may mask progression of the tumour: if so, surgery could be required at a stage when complete restoration of pituitary function is no
longer possible. Currently acromegaly
is best managed by early transsphenoidal microsurgery. Removal of only the adenoma, rather than radical pituitary ablation, is encouraged by the possibility of medical therapy for any patients showing only partial initial responses or eventual recurrences. Bromocriptine should not be used routinely as the primary treatment for acromegaly. Institute of Neurological Sciences, Southern General Hospital, Glasgow G51 4TF
GRAHAM TEASDALE
DOPAMINE-INDUCED INHIBITION OF PROLACTIN AND GROWTH HORMONE SECRETION IN ACROMEGALY
StR,-Some dopaminergic drugs (levodopa, apomorphine and bromocriptine) inhibit prolactin secretion’4-16 and, in some acromegalic patients, secretion of growth hormone (G.H.)!’-19 The mechanism is not known and we do not know whether these substances act on the hypothalamus or the hypophysis. 7. Williams, R. A., Jacobs, H. S., Kurtz, A. B., Millar, J. G. B., Oakley, N. W., Spathis, G. S., Sulway, M. J., Nabbarro, J. D. N., Q. J. Med. 1975, 173, 79. 8. Hardy, J. in The Diagnosis and Treatment of Pituitary Tumours (edited by P. O. Kohler); p. 179. Amsterdam, 1973. 9. Rohde, W., Knappe, G., Mennig, H., Unger, R. R. Hormone Res. 1973, 4, 129. 10. Samaan, N. A., Leavens, M. E., Jeese, R. H. J. clin. Endocr. 1974, 38, 957. 11.Atkinson, R. L., Becker, D. P., Martins, A. N., Schaff, M., Dimond, R. C., Wartofsky, L., Earll, J. M. Am. med. Ass. 1975, 233, 1279. 12.Fahlbusch, R., Werder, K. V. Paper presented at the fifth congress of the European Association of Neurosurgical Societies in Oxford, 1975. 13. Ludecke, D., Kautzky, R., Saeger, W., Schrader, D. ibid. 14. Martin, J. B., Lal, S., Tolis, G., Friesen, H. G. J. clin. Endocr. Metab. 1974,
39, 180.
Daughaday, W. H. New Engl. J. Med. 1971, 285, 1160. 16. Del Pozo, E., Brun Del Re, R., Varga, L., Friesen, H. J. clin. Endocr. Metab. 1972, 35, 768. 17. Chiodini, P. G., Liuzzi, A., Botalla, L., Cremascoli, G., Silvestrini, F. ibid. 1974, 38, 200. 18. Liuzzi, A., Chiodini, P. G., Botalla, L., Cremascoli, G., Müller, E. E., Silvestrini, F. ibid. 1974, 38, 910. 19. Camanni, F., Massara, F., Belforte, L., Molinatti, G. M. ibid. 1975, 40, 363. 15. Malarkey, W. B., Jacobs, L. S.,
PLASMA G.H. AND PROLACTIN LEVELS
Examination of prolactin and plasma G.H. after parenteral administration of dopamine provides a way of investigating this phenomenon in man, since this amine does not cross the bloodbrain barrier and its effects, if any, must be felt by the hypo-
physis.
The table shows plasma prolactin and G.H. values in 4 browith high prolactin levels during intravenous administration of 280 tg/min dopamine moqriptine-resoonsive acromegalics
for 120 min. The
radioimmunological method made use of highly specific antibodies and was sensitive to 0.2 ng/ml and 0.3ng/ml for G.H. and prolactin, respectively. A marked fall was observed in all cases for both hormones, with minimum values at the end of perfusion followed by a rapid rebound. Mean (± S.E.M.) values for G.H. fell from 35.619.1 to 3.511.1 ng/ml, and for prolactin from 54.7120.4 to 18.4±7.3 ng/ml. No significant changes were noted in a control test with saline solution. These data provide the first evidence of dopamine-induced prolactin and G.H. inhibition in acromegaly. They also confirm our suggestion’9 that such inhibition is mainly exerted via the
hypophysis. Cattedra di Endocrinologia, Istituto Unificato di Medicina Interna, Universita di Torino, Corso Polonia 14, 10126
F. MASSARA F. CAMANNI L. BELFORTE G. M. MOLINATTI
Turin, Italy
SECRETORY COMPONENT AND SUDDEN INFANT DEATH
SiR,—The report by Ogra et al.’ led
us to
examine the sub-
mandibular glands removed at necropsy of ten infants who had died after a clinical course suggesting sudden-infant-death syndrome (S.l.D.S.). One submandibular gland from each infant was coarsely chopped, suspended in 3 ml phosphate-buffered saline, and
ground. The tissue was centrifuged and the supernatant was lyophilised and reconstituted in 0.3ml of distilled water. The reconstituted fluid was tested by Ouchterlony double diffusion in agar against anti-IgA (Wellcome Reagents batch K8800) and anti-secretory-component (Behringwerke batch 2571A and Nordic Diagnostics batch 6711). The submandibular fluid had IgA and secretory component in all ten cases. The fluid gave a line of complete identity with serum and saliva when the antiserum was anti-IgA and a line of complete identity with saliva when anti-secretory-component was the antiserum. There are a number of possible explanations for the apparent discrepancy in our findings. The cases may not have been comparable. However, matching of patients with S.I.D.S. is very difficult because so little is known about underlying 1.
Ogra, P. L., Ogra,
(ng/ml) DURING AND AFTER 280 Eig/ri7lri DOPAMINE
FOR
S. S.,
120 min
Coppola, P.
IN
4
R. Lancet, 1975, ii, 387.
BROMOCRIPTINE-RESPONSIVE ACROMEGALICS
drug apomorphine,
its action depends partly on the presence of catecholamine stores.9 When these are depleted by reserpine or ot-methylparatyrosine, many of the behavioural actions of bromocriptine in animals are lost.1O The effects of bromocriptine on different dopamine systems in the brain are therefore unlikely to be exactly similar to those of levodopa. From this evidence, it is still not certain whether the growth-hormone response to levodopa or dopamine agonists is abnormal in parkinsonism, or whether all brain-dopamine systems are functionally involved in this condition. However, Greenfield and Bosanquet" suggested there was a system degeneration of melanin-neurons rather than dopamine neurons in Parkinson’s disease. The two possibilities may not be mutually exclusive, although the former seems the more probable in view of damage to the dopamine-melanin neurons of the substantia nigra, the noradrenaline-melanin neurons of the locus caeruleus, and other brainstem pigmented systems.
J. D. PARKES
University Department of Neurology, King’s College Hospital and The Institute of Psychiatry, London
A. G. DEBONO C. D. MARSDEN
during this limited period only. This view is repeated papersl-3 and in advertising material. Our patients are chronic schizophrenics whose symptoms are well controlled by injections of fluphenazine decanoate every 4 weeks and no other medication. The dosage causes parkinsonism in each patient and is kept constant (range 25-37.5 mg four-weekly). The severity of physical signs of parkinsonism is assessed using a standardised clinical assessment weekly and a battery of performance tests, including speed of tapping and completion of a grooved peg-board test, twice weekly.. Six patients have been studied so far; one for 6 months, one
be needed
in
for 5 months, three for 4 months, and one for 3 months. The figure shows part of the performance of the first patient. Although the severity of the signs varies from month to month, the general pattern is the same. There is no evidence of a practice effect or of a gradual decline in severity. The signs are most severe in the third week after the injections. The six patients have been studied for a total of 26 months, and the effects seen in the first patient are closely reflected in the other
patients. PARKINSONISM INDUCED BY FLUPHENAZINE DECANOATE
SIR,-Our long-term studies of parkinsonism induced by decanoate suggest that earlier descriptions may be incorrect. All the phenothiazines can induce extrapyramidal syndromes, and this property is shared by the depot preparations of fluphenazine enanthate and decanoate. It is commonly held that any extra pyramidal signs seen are at their worst 3-5 days after the injection and that anti-parkinsonism drugs may
fluphenazine
The observation that the signs of parkinsonism are greatest in the third week after the injections contradicts previous statements about the pattern of signs which follow the administration of fluphenazine, and suggests that where drugs are given to control parkinsonism induced by fluphenazine decanoate for only part of the interval between injections, this is best done around the third week rather than for the first 5-10 days. Where trials of the efficacy of drugs in controlling parkinsonism induced by fluphenazine decanoate are undertaken, assessment of the patients in the third week after the injections is more likely to show differences between treatments, The likely explanation of the changes in the severity of the clinical signs is that they reflect the rate of release of fluphenazine from the depot. We thank Dr M. Aveline, Prof. J. E. Cooper, Dr I. B. Pearson, Dr D. A. Toms, and Dr P. J. A. V. Willems for allowing us to study patients under their care; Sister Nina Burgum and the nurses of the Byron day centre for their help; and E. R. Squibb and Sons Limited who provided funds to support P. L., and their medical adviser, Dr A,
Schiff, for his general assistance. P. LAMB R. H. S. MINDHAM M. A. EZZAT
Professorial Unit,
Mapperley Hospital, Nottingham NG3 6AA
BROMOCRIPTINE IN ACROMEGALY
SIR,-Dr Sachdev and colleagues (Dec. 13, p. 1164) have provided evidence that some patients improve on bromocriptine therapy, but the conclusion that the drug has a primary role in the management of acromegaly is open to question. Bromocriptine was "fully effective" in only 4 of the 21 patients studied. In the others subjective improvement in wellbeing, appearance, and hand or foot size was variable, and was not accompanied by significant effects upon soft-tissue thickWhile carbohydrate tolerance affected. Moreover 10 patients improved, hypertension had had radiotherapy a year or more previously and the full effect of this may not be evident for several,years.5 6 The significance of persisting raised serum growth-hormone, despite clinical remission, is uncertain; but the level of the hormone provides the most direct means of comparing the efficacy ness or
sebum-excretion
rate.
was not
111 out
NOY
n.
JAH
DEC
monthly assessments of parkinsonism in weekly injections (arrows) of fluphenazine decanoate.
First three
a
patient
on
four-
A rise indicates a decrease in severity. The study of this patient was over Christmas and New Year. Injections were given on Dec. 20 and Jan. 17, but the December treatment was not assessed.
interrupted
A=Peg board 10.
B=Impulse
counter
C=Clinical
assessment
Corrodi, H., Farnebo, L-O., Fuxe, K., Hamberger, B. Eur. J. Pharmac. 1975, 30, 172. 11. Greenfield J. G., Bosanquet, F. D. J. Neurol. Neurosurg. Psychiat. 1953, 16, 213.
1. Drug Thera. Bull. 1970, 8, 69. 2. Ayd, F. J., Jr. Compreh. Psychiat. 1974, 15, 277. 3. Ayd, F. J., Jr.Am. J.Psychiat. 1975, 132, 491. 4. Mindham, R. H. S. Br. J. clin. Pharmac. (in the press). 5. Lawrence, J. H., Tobias, C. A., Linfoot, J. A., Born, J. L., Lyman,J. T. Chong, C. Y., Manougian, E., Wei, W. C. J. clin.Endocr. 1970, 31, 180. 6. Wright, A. D., Hartog, M., Palter, H., Tevaarwerk, G., Doyle, F. H, Arnot, R., Joplin, G. F., Fraser, T. R.Proc.R. Soc.Med. 1970, 63, 221
485 of treatments for acromegaly.7 The failure to achieve sustained reductions of growth hormone to normal levels compares unfavourably with the results of trans-sphenoidal ’microsurgery 7 -13 achieved by radical pituitary extirpation7or, more usually, by selective removal of microadenomas. Selective operation is most likely to be feasible in early cases. To temporise with bromocriptine may be to deny the patient his best chance for selective surgery. The escape of hormone levels in 2 patients, and the overswing that followed cessation of therapy in 2 others, suggest that clinical improvement during bromocriptine treatment may mask progression of the tumour: if so, surgery could be required at a stage when complete restoration of pituitary function is no
longer possible. Currently acromegaly
is best managed by early transsphenoidal microsurgery. Removal of only the adenoma, rather than radical pituitary ablation, is encouraged by the possibility of medical therapy for any patients showing only partial initial responses or eventual recurrences. Bromocriptine should not be used routinely as the primary treatment for acromegaly. Institute of Neurological Sciences, Southern General Hospital, Glasgow G51 4TF
GRAHAM TEASDALE
DOPAMINE-INDUCED INHIBITION OF PROLACTIN AND GROWTH HORMONE SECRETION IN ACROMEGALY
StR,-Some dopaminergic drugs (levodopa, apomorphine and bromocriptine) inhibit prolactin secretion’4-16 and, in some acromegalic patients, secretion of growth hormone (G.H.)!’-19 The mechanism is not known and we do not know whether these substances act on the hypothalamus or the hypophysis. 7. Williams, R. A., Jacobs, H. S., Kurtz, A. B., Millar, J. G. B., Oakley, N. W., Spathis, G. S., Sulway, M. J., Nabbarro, J. D. N., Q. J. Med. 1975, 173, 79. 8. Hardy, J. in The Diagnosis and Treatment of Pituitary Tumours (edited by P. O. Kohler); p. 179. Amsterdam, 1973. 9. Rohde, W., Knappe, G., Mennig, H., Unger, R. R. Hormone Res. 1973, 4, 129. 10. Samaan, N. A., Leavens, M. E., Jeese, R. H. J. clin. Endocr. 1974, 38, 957. 11.Atkinson, R. L., Becker, D. P., Martins, A. N., Schaff, M., Dimond, R. C., Wartofsky, L., Earll, J. M. Am. med. Ass. 1975, 233, 1279. 12.Fahlbusch, R., Werder, K. V. Paper presented at the fifth congress of the European Association of Neurosurgical Societies in Oxford, 1975. 13. Ludecke, D., Kautzky, R., Saeger, W., Schrader, D. ibid. 14. Martin, J. B., Lal, S., Tolis, G., Friesen, H. G. J. clin. Endocr. Metab. 1974,
39, 180.
Daughaday, W. H. New Engl. J. Med. 1971, 285, 1160. 16. Del Pozo, E., Brun Del Re, R., Varga, L., Friesen, H. J. clin. Endocr. Metab. 1972, 35, 768. 17. Chiodini, P. G., Liuzzi, A., Botalla, L., Cremascoli, G., Silvestrini, F. ibid. 1974, 38, 200. 18. Liuzzi, A., Chiodini, P. G., Botalla, L., Cremascoli, G., Müller, E. E., Silvestrini, F. ibid. 1974, 38, 910. 19. Camanni, F., Massara, F., Belforte, L., Molinatti, G. M. ibid. 1975, 40, 363. 15. Malarkey, W. B., Jacobs, L. S.,
PLASMA G.H. AND PROLACTIN LEVELS
Examination of prolactin and plasma G.H. after parenteral administration of dopamine provides a way of investigating this phenomenon in man, since this amine does not cross the bloodbrain barrier and its effects, if any, must be felt by the hypo-
physis.
The table shows plasma prolactin and G.H. values in 4 browith high prolactin levels during intravenous administration of 280 tg/min dopamine moqriptine-resoonsive acromegalics
for 120 min. The
radioimmunological method made use of highly specific antibodies and was sensitive to 0.2 ng/ml and 0.3ng/ml for G.H. and prolactin, respectively. A marked fall was observed in all cases for both hormones, with minimum values at the end of perfusion followed by a rapid rebound. Mean (± S.E.M.) values for G.H. fell from 35.619.1 to 3.511.1 ng/ml, and for prolactin from 54.7120.4 to 18.4±7.3 ng/ml. No significant changes were noted in a control test with saline solution. These data provide the first evidence of dopamine-induced prolactin and G.H. inhibition in acromegaly. They also confirm our suggestion’9 that such inhibition is mainly exerted via the
hypophysis. Cattedra di Endocrinologia, Istituto Unificato di Medicina Interna, Universita di Torino, Corso Polonia 14, 10126
F. MASSARA F. CAMANNI L. BELFORTE G. M. MOLINATTI
Turin, Italy
SECRETORY COMPONENT AND SUDDEN INFANT DEATH
SiR,—The report by Ogra et al.’ led
us to
examine the sub-
mandibular glands removed at necropsy of ten infants who had died after a clinical course suggesting sudden-infant-death syndrome (S.l.D.S.). One submandibular gland from each infant was coarsely chopped, suspended in 3 ml phosphate-buffered saline, and
ground. The tissue was centrifuged and the supernatant was lyophilised and reconstituted in 0.3ml of distilled water. The reconstituted fluid was tested by Ouchterlony double diffusion in agar against anti-IgA (Wellcome Reagents batch K8800) and anti-secretory-component (Behringwerke batch 2571A and Nordic Diagnostics batch 6711). The submandibular fluid had IgA and secretory component in all ten cases. The fluid gave a line of complete identity with serum and saliva when the antiserum was anti-IgA and a line of complete identity with saliva when anti-secretory-component was the antiserum. There are a number of possible explanations for the apparent discrepancy in our findings. The cases may not have been comparable. However, matching of patients with S.I.D.S. is very difficult because so little is known about underlying 1.
Ogra, P. L., Ogra,
(ng/ml) DURING AND AFTER 280 Eig/ri7lri DOPAMINE
FOR
S. S.,
120 min
Coppola, P.
IN
4
R. Lancet, 1975, ii, 387.
BROMOCRIPTINE-RESPONSIVE ACROMEGALICS