49 CHROMOSOME CONSTITUTION OF GESTATIONAL TROPHOBLASTIC DISEASE et al.l,2 have suggested that hydatidiform be divided into two categories. "Partial moles" have non-hydropic villi interspersed with hydropic villi, do not show marked trophoblastic hyperplasia or anaplasia, are associated with a fetus, cord, and/or amniotic membrane, and have an abnormal chromosome constitution frequently triploidy; they do not undergo malignant change. In "complete moles" all villi are hydropic, there is marked trophoblastic hyperplasia or anaplasia, there is no fetus, cord, or amniotic membrane, and the chromosome constitution is 46,XX; these moles do tend to
SIR,-Vassilakos
moles
can
undergo malignant transformation. Kajii and Ohama’ have analysed the chromosome heteromorphisms of seven complete moles and the parents. The chroconstitutions were all 46,XX and all 46 chromosomes in origin. The observations could be explained by loss of the maternal haploid complement and fertilisation either by a normal haploid sperm, which then underwent division without cytokinesis resulting in a diploid parthenogenetic zygote or by a diploid sperm formed as a result of failure of the second meiotic division. Either mechanism assumes the loss of the predicted 46,YY class of parthenogenetic zygote before it produced a recognisable pregnancy. Our cytogenetic observations in four cases of trophoblast disease confirm the observations of Kajii and Ohama. mosome were
paternal
The
trophoblast disease in patient A was reported as a hydatidiform
villi are found interspersed with the abnormal ones. This appears to be an exception to the postulated generalisation that in "complete" moles all villi are hydropic. Secondly, while the trophoblast does not have a 46,XX chromosome constitution, it is clearly androgenetic in origin. Thirdly, the distribution of chromosome counts is that classically associated with clinically overt malignancy. In fact our observations are very similar to those reported by Makino et al. on direct preparai tions of a choriocarcinoma. D was While case reported as a possible malignancy with a moderate degree of trophoblast proliferation, there was no evidence of frank malignancy. Thus the cytogenetic observations suggest a degree of severity not matched by the pathological appearance of the tumour. While the discrepancies between Vassilakos’ descriptions of "complete" moles, the appearance of case D, and the cytogenetic results are of considerable interest, they are of secondary importance to the basic observation of Kajii and Ohama,3 confirmed in this report, that the class of moles with malignant propensities are androgenetic in origin. The way is now open for a complete reappraisal of the biology and epidemiology of
ing
case
trophoblast disease. We thank Dr Thomas Kobara for the
and Dr M. Dr T. Tseu for their help in obtaining access to an information from the patients. This work was supported by grant HD 07879 from the National Institutes of Health and grant 6-47 from the National Foundation March of Dimes.
mole, grade I with only slight trophoblastic proliferation while that of
patients B and C was reported grade n with moderate trophoblastic proliferation. Patients A and B are well and their H.C.G. levels returned to normal in 10 and 8 weeks, respectively, without chemotherapy. However, the H.c.G. level in patient C remained high, and 6 weeks after the original diagnosis she had a bleeding episode. A menstrual aspiration specimen soon afterwards showed degenerating decidua which, in some areas of necrosis, contained atypical trophoblastic cells with irregular nuclei and abundant cytoplasm. Chemotherapy started and the H.c.G. level fell to normal in 18 weeks. The trophoblast disease in patient D was reported as possibly malignant. Sections showed a mixture of well-preserved villi of normal appearance and enlarged villi with moderate proliferation of the cytotrophoblast and nuclei showing irregular chromatin distribution and increased mitotic activity. However, there was no evidence of frank malignancy. Patient D had a hysterectomy, her H.c.G. levels returned to normal without chemotherapy in 4 weeks, and she remains well some 6 months later. was
The chromosome constitution of cells cultured from the trophoblast of patients A, B, and C was 46,XX, and Q and C band heteromorphisms clearly demonstrate that the chromosomes were paternal. Patient A had identical heteromorphisms on both chromosomes 3, on both chromosomes 9, and on both chromosomes 13 and these could only have been inherited from the father. Similarly in patient B chromosomes 3, 13, 15, and 22 all appeared identical and paternally derived. The father of patient C was not available: however, the mole had identical chromosomes 1, 21, and 22 which were different from those of the mother and therefore presumed to be paternal. In case D no cell had 46 chromosomes. In the earliest culture we harvested we saw one cell which appeared to be a true 92,XXXX tetraploid while the remaining cells from this and all other cultures were hypotetraploid or aneuploid. There was a wide variety of chromosome-counts with the major mode at 85-86 and a minor cell line in the 55-57 range. Analysis of the chromosomes of the trophoblast and the parents show that all the chromosomes of the trophoblast were paternally derived and the karyotypes we observed had arisen by changes, probably involving tetraploidy and subsequent loss and rearrangement of chromosomes, superimposed on a basic 46,XX pattern. This case is of interest for several reasons. First while the trophoblast is clearly androgenetic in origin, and thus in the "complete" mole category of Vassilakos et al., normal-appear1. 2.
Vassilakos, P., Kajn, T. Lancet, 1976, i, 259. Vassilakos, P., Riotton, G., Kajn, T. Am. J. Obstet. Gynecol. 1977, 127, 3. Kajn, T., Ohama, K. Nature, 1977, 268, 633.
167.
pathology reports
Bautista, Dr G. Li, Dr P. McNamee, and
Department of Anatomy and Reproductive Biology, University of Hawaii School of Medicine, Honolulu, Hawaii 96822, U.S.A.
PATRICIA A. JACOBS TERRY J. HASSOLD AILEEN M. MATSUYAMA IRENE M. NEWLANDS
SMOKING AND DIABETIC RETINOPATHY an editorial last year’ you drew attention to a of Paetkau and her colleagues2 suggesting that the risk of diabetic retinopathy might be enhanced by smoking cigarettes, and you described some mechanisms, such as anoxia, by which smoking might produce adverse effects. Both of these publications cited the need for more data, especially since the association observed might have been affected by confounding variables. Moreover, Paetkau et al. indicated that a significant association between smoking and retinopathy was observed only in diabetes of long duration and only between smoking and proliferative retinopathy. There were 181 patients in that study of whom 65 were long-duration cases (diabetes for twenty years or more). We have examined the relationship between retinopathy and cigarette smoking in a consecutive series of 695 Oklahoma Indians with adult-onset diabetes. Retinal examinations were done on all patients, with pupils dilated, using the standardised procedure of the multinational study of the World Health Organisation. Results are presented in the table. They were strikingly negative both for retinopathy and proliferative
SIR,-In
study
retinopathy. We examined the possibility that one or more confounding variables might have obscured a causal association. The smokers had slightly lower levels of blood-pressure and bloodglucose, but it does not seem likely that these differences would be sufficient to hide an effect of smoking on retinopathy. Duration of diagnosed diabetes, the strongest known. risk factor for retinopathy, was the same in smokers and non-smokers. Data were examined separately for a subgroup of 52 who smoked more than nineteen cigarettes daily. In this subgroup rates of retinopathy (26-9%) were not significantly higher than in non-smokers, not were rates of proliferative retinopathy 4.
Makino, S., Sasaki, M. S., Fukushima, T Proc. Acad. Jap. 1963, 39, 54.
1. Lancet, 1977, i, 841. 2. Paetkau, M. E., Boyd, T. A. S., 46.
Winship, B., Grace,
M. Diabetes, 1976,
26,
50 CIGARETTE SMOKING AND RISK OF RETINOPATHY
it may be an idiosynwith the XYY sex-chromosome complement, a possibility suggested by the raised levels of prolactin found in others who have not been treated with lactogenic drugs. We would be interested to hear of any patients with this chromosome abnormality who experience the same side-effect on phenothiazine treatment or who are found to have raised prolactin levels when not on any drug therapy. Men with a 47,XYY karyotype at maximum security hospitals are above average height and are admitted in greater than expected numbers. The possibility that prolactin secretion is abnormal in these patients is therefore of interest since it is a hormone known to stimulate growth in some species and its secretion may be related to behaviour. are
given simultaneously. Alternatively,
crasy in
(3.8%). In contrast to the results of Paetkau et al. we found in non-smokers a strong relationship between proliferative retinopathy and duration of diabetes. Among non-smokers who had had diabetes for fifteen years or more, 15% had proliferative lesions (10 of 66). In long-duration cases who were smokers this rate was 9% (3 of 33). Among the 447 nonsmokers there were 166 former smokers. Rates of retinopathy (24-1%) and proliferative retinopathy (3-0%) were the same as in those who had never smoked. Mean duration of known diabetes was seven years in both of these subgroups. More data are needed but our results lend no support to the hypothesis that smoking is a risk factor for diabetic retinopathy. Diabetics should not smoke, because they are already at risk of coronary and peripheral vascular disease. Department of Biostatistics and Epidemiology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma 73190, U.S.A.
KELLY M. WEST JUDY A. STOBER
PROLACTIN SECRETION IN XYY MALES the clinical examination of patients with a at a maximum security hospital, a 27-yearold man was found to have marked gynxcomastial and galactorrhoea. He had been aware of breast enlargement for about two years and during that time he was treated with fortnightly injections of 50 mg fluphenazine decanoate. Intermittent lactation had been occurring for several months. Mild gynscomastia had been noted when the patient had been treated with cestrogens 7 years earlier, but it was not known if this had persisted when treatment was discontinued after about a year. He refuses to provide further blood-samples. Gynaecomastia was not noted in any others with the same karyotype but in three, aged 23, 29, and 43 years, who had not received any drugs, the prolactin levels were 394, 745, and 426 mU/1, respectively, all of which are abnormally high. Several factors such as exercise,2 sleep,3 stress,2 and even venepuncture may raise circulating prolactin levels, but in blood-samples obtained in an identical manner, under similar conditions, from men at the same institution who only had one Y chromosome the prolactin levels were normal. ’Most males with a 47,XYY karyotype are free from physical abnormality, and the patient reported here is the first we have seen with any breast enlargement. We believe that the gynaecomastia and the lactation are complications of treatment with fluphenazine, but the severity seems disproportional to the dose of the drug and raises the possibility of an increased sensitivity. This could be related to the previous oestrogen administration since phenothiazine-stimulated prolactin secretion is augmented by aestrogens,4 but usually when the drugs
SIR,-During
47,XYY karyotype
Price, W. H., Brunton, M , Buckton, K. E., Jacobs, P. A. Clin Genet. 1976, 9, 389. 2. Noel, G. L., Sug, H. K., Stone, J G., Franz, A. G. J. clin. Endocr. Metab 1.
1972, 35, 840. 3. Sassin, J. F., Frantz,
A.
G., Weitz, E. D., Kapen, S. Science, 1972, 177,
1205. 4.
Buckman, M. T., Peake, G. T. J. clin. Endocr. Metab 1973, 37, 977.
men
We thank Dr E. A. Cameron of the regional hormone laboratory for estimations of prolactin and the consultant psychiatrists in charge of the patients at the security hospitals for kind cooperation.
Department of Medicine and M.R.C. Clinical and Population
Cytogenetics Unit, Western General Hospital, Edinburgh EH4 2XU
W. H. PRICE W. B. RENTON W. A. CAMPBELL
PROPRANOLOL THERAPY FOR SECONDARY HYPERPARATHYROIDISM IN URÆMIA
SiR,—The description by Dr Caro and Dr Besarab (April 15, p. 827) of a patient in whom propranolol decreased both raised
raised plasma-parathyroid-horreport the preliminary results of two studies on the interference of antihypertensive drugs with the hormonal control of calcium-phosphate homoeostasis in ursemic patients. In a first study, thirteen hoemodialysed patients were successively treated for 6-week periods with equally antihypertensive regimens of metoprolol, methyldopa, and clonidine. P.T.H. and plasma concentrations of calcitonin, calcium, and phosphate were measured before the first dialysis in the sixth week of each period of treatment. Throughout the study other theraa
mone
plasma-calcium and (P.T.H.) prompts us to
a
peutic measures were kept constant. Variance analysis showed no significant differences between the three treatments except that the predialysis plasma-calcium was lower after metoprolol (8-5 ±0-2 mg/dl) than after clonidine (9-2±0-2). Because a higher P.T.H. was not observed after metoprolol despite the fall in plasma-calcium, metoprolol could have had a greater suppressive effect or a lower stimulating effect on P.T.H. secretion than clonidine. Because the study produced no denmuve conclusion about the absolute effect of these antihypertensive drugs on the hormonal control of calcium phosphate homceostasis, we began a second study to evaluate the acute effects of propranolol and metoprolol on P.T. H. and plasma-calcitonin. Propranolol (blocking &bgr;I and 32 receptors) was given intravenously (priming dose 1 mg given over 5 min and 1 p.g/kg/min given over 85 min) to nine uraemic patients not yet on dialysis and metoprolol (blocking only 31 receptors) was given intravenously (priming dose 1.2mg given over 5 min and 1.2 ug/ kg/min given over 85 min) 15 days later to six of these patients. Venous blood was taken before and 15, 30, 60, and 90 min after starting the injection. P.T.H. and plasma concentrations of total and ionised calcium, phosphate, and calcitonin were measured. The antibody used for P.T.H. was specific for the fragment 1-34 and the native human molecule. There was no significant change at any time in phosphate or total ionised calcium. The significant decrease in heart-rate was of the same magnitude with both drugs, suggesting equally effective 31 receptor blockade. P.T.H. decreased significantly (by 36%) at 30 min with propranolol but did not decrease with metoprolol. Calcitonin also decreased significantly at 60 min after propranolol (by 40%) but did not change after metoprolol. It appears, therefore, that propranolol acutely suppresses
SIR,-Vassilakos
moles
can
undergo malignant transformation. Kajii and Ohama’ have analysed the chromosome heteromorphisms of seven complete moles and the parents. The chroconstitutions were all 46,XX and all 46 chromosomes in origin. The observations could be explained by loss of the maternal haploid complement and fertilisation either by a normal haploid sperm, which then underwent division without cytokinesis resulting in a diploid parthenogenetic zygote or by a diploid sperm formed as a result of failure of the second meiotic division. Either mechanism assumes the loss of the predicted 46,YY class of parthenogenetic zygote before it produced a recognisable pregnancy. Our cytogenetic observations in four cases of trophoblast disease confirm the observations of Kajii and Ohama. mosome were
paternal
The
trophoblast disease in patient A was reported as a hydatidiform
villi are found interspersed with the abnormal ones. This appears to be an exception to the postulated generalisation that in "complete" moles all villi are hydropic. Secondly, while the trophoblast does not have a 46,XX chromosome constitution, it is clearly androgenetic in origin. Thirdly, the distribution of chromosome counts is that classically associated with clinically overt malignancy. In fact our observations are very similar to those reported by Makino et al. on direct preparai tions of a choriocarcinoma. D was While case reported as a possible malignancy with a moderate degree of trophoblast proliferation, there was no evidence of frank malignancy. Thus the cytogenetic observations suggest a degree of severity not matched by the pathological appearance of the tumour. While the discrepancies between Vassilakos’ descriptions of "complete" moles, the appearance of case D, and the cytogenetic results are of considerable interest, they are of secondary importance to the basic observation of Kajii and Ohama,3 confirmed in this report, that the class of moles with malignant propensities are androgenetic in origin. The way is now open for a complete reappraisal of the biology and epidemiology of
ing
case
trophoblast disease. We thank Dr Thomas Kobara for the
and Dr M. Dr T. Tseu for their help in obtaining access to an information from the patients. This work was supported by grant HD 07879 from the National Institutes of Health and grant 6-47 from the National Foundation March of Dimes.
mole, grade I with only slight trophoblastic proliferation while that of
patients B and C was reported grade n with moderate trophoblastic proliferation. Patients A and B are well and their H.C.G. levels returned to normal in 10 and 8 weeks, respectively, without chemotherapy. However, the H.c.G. level in patient C remained high, and 6 weeks after the original diagnosis she had a bleeding episode. A menstrual aspiration specimen soon afterwards showed degenerating decidua which, in some areas of necrosis, contained atypical trophoblastic cells with irregular nuclei and abundant cytoplasm. Chemotherapy started and the H.c.G. level fell to normal in 18 weeks. The trophoblast disease in patient D was reported as possibly malignant. Sections showed a mixture of well-preserved villi of normal appearance and enlarged villi with moderate proliferation of the cytotrophoblast and nuclei showing irregular chromatin distribution and increased mitotic activity. However, there was no evidence of frank malignancy. Patient D had a hysterectomy, her H.c.G. levels returned to normal without chemotherapy in 4 weeks, and she remains well some 6 months later. was
The chromosome constitution of cells cultured from the trophoblast of patients A, B, and C was 46,XX, and Q and C band heteromorphisms clearly demonstrate that the chromosomes were paternal. Patient A had identical heteromorphisms on both chromosomes 3, on both chromosomes 9, and on both chromosomes 13 and these could only have been inherited from the father. Similarly in patient B chromosomes 3, 13, 15, and 22 all appeared identical and paternally derived. The father of patient C was not available: however, the mole had identical chromosomes 1, 21, and 22 which were different from those of the mother and therefore presumed to be paternal. In case D no cell had 46 chromosomes. In the earliest culture we harvested we saw one cell which appeared to be a true 92,XXXX tetraploid while the remaining cells from this and all other cultures were hypotetraploid or aneuploid. There was a wide variety of chromosome-counts with the major mode at 85-86 and a minor cell line in the 55-57 range. Analysis of the chromosomes of the trophoblast and the parents show that all the chromosomes of the trophoblast were paternally derived and the karyotypes we observed had arisen by changes, probably involving tetraploidy and subsequent loss and rearrangement of chromosomes, superimposed on a basic 46,XX pattern. This case is of interest for several reasons. First while the trophoblast is clearly androgenetic in origin, and thus in the "complete" mole category of Vassilakos et al., normal-appear1. 2.
Vassilakos, P., Kajn, T. Lancet, 1976, i, 259. Vassilakos, P., Riotton, G., Kajn, T. Am. J. Obstet. Gynecol. 1977, 127, 3. Kajn, T., Ohama, K. Nature, 1977, 268, 633.
167.
pathology reports
Bautista, Dr G. Li, Dr P. McNamee, and
Department of Anatomy and Reproductive Biology, University of Hawaii School of Medicine, Honolulu, Hawaii 96822, U.S.A.
PATRICIA A. JACOBS TERRY J. HASSOLD AILEEN M. MATSUYAMA IRENE M. NEWLANDS
SMOKING AND DIABETIC RETINOPATHY an editorial last year’ you drew attention to a of Paetkau and her colleagues2 suggesting that the risk of diabetic retinopathy might be enhanced by smoking cigarettes, and you described some mechanisms, such as anoxia, by which smoking might produce adverse effects. Both of these publications cited the need for more data, especially since the association observed might have been affected by confounding variables. Moreover, Paetkau et al. indicated that a significant association between smoking and retinopathy was observed only in diabetes of long duration and only between smoking and proliferative retinopathy. There were 181 patients in that study of whom 65 were long-duration cases (diabetes for twenty years or more). We have examined the relationship between retinopathy and cigarette smoking in a consecutive series of 695 Oklahoma Indians with adult-onset diabetes. Retinal examinations were done on all patients, with pupils dilated, using the standardised procedure of the multinational study of the World Health Organisation. Results are presented in the table. They were strikingly negative both for retinopathy and proliferative
SIR,-In
study
retinopathy. We examined the possibility that one or more confounding variables might have obscured a causal association. The smokers had slightly lower levels of blood-pressure and bloodglucose, but it does not seem likely that these differences would be sufficient to hide an effect of smoking on retinopathy. Duration of diagnosed diabetes, the strongest known. risk factor for retinopathy, was the same in smokers and non-smokers. Data were examined separately for a subgroup of 52 who smoked more than nineteen cigarettes daily. In this subgroup rates of retinopathy (26-9%) were not significantly higher than in non-smokers, not were rates of proliferative retinopathy 4.
Makino, S., Sasaki, M. S., Fukushima, T Proc. Acad. Jap. 1963, 39, 54.
1. Lancet, 1977, i, 841. 2. Paetkau, M. E., Boyd, T. A. S., 46.
Winship, B., Grace,
M. Diabetes, 1976,
26,
50 CIGARETTE SMOKING AND RISK OF RETINOPATHY
it may be an idiosynwith the XYY sex-chromosome complement, a possibility suggested by the raised levels of prolactin found in others who have not been treated with lactogenic drugs. We would be interested to hear of any patients with this chromosome abnormality who experience the same side-effect on phenothiazine treatment or who are found to have raised prolactin levels when not on any drug therapy. Men with a 47,XYY karyotype at maximum security hospitals are above average height and are admitted in greater than expected numbers. The possibility that prolactin secretion is abnormal in these patients is therefore of interest since it is a hormone known to stimulate growth in some species and its secretion may be related to behaviour. are
given simultaneously. Alternatively,
crasy in
(3.8%). In contrast to the results of Paetkau et al. we found in non-smokers a strong relationship between proliferative retinopathy and duration of diabetes. Among non-smokers who had had diabetes for fifteen years or more, 15% had proliferative lesions (10 of 66). In long-duration cases who were smokers this rate was 9% (3 of 33). Among the 447 nonsmokers there were 166 former smokers. Rates of retinopathy (24-1%) and proliferative retinopathy (3-0%) were the same as in those who had never smoked. Mean duration of known diabetes was seven years in both of these subgroups. More data are needed but our results lend no support to the hypothesis that smoking is a risk factor for diabetic retinopathy. Diabetics should not smoke, because they are already at risk of coronary and peripheral vascular disease. Department of Biostatistics and Epidemiology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma 73190, U.S.A.
KELLY M. WEST JUDY A. STOBER
PROLACTIN SECRETION IN XYY MALES the clinical examination of patients with a at a maximum security hospital, a 27-yearold man was found to have marked gynxcomastial and galactorrhoea. He had been aware of breast enlargement for about two years and during that time he was treated with fortnightly injections of 50 mg fluphenazine decanoate. Intermittent lactation had been occurring for several months. Mild gynscomastia had been noted when the patient had been treated with cestrogens 7 years earlier, but it was not known if this had persisted when treatment was discontinued after about a year. He refuses to provide further blood-samples. Gynaecomastia was not noted in any others with the same karyotype but in three, aged 23, 29, and 43 years, who had not received any drugs, the prolactin levels were 394, 745, and 426 mU/1, respectively, all of which are abnormally high. Several factors such as exercise,2 sleep,3 stress,2 and even venepuncture may raise circulating prolactin levels, but in blood-samples obtained in an identical manner, under similar conditions, from men at the same institution who only had one Y chromosome the prolactin levels were normal. ’Most males with a 47,XYY karyotype are free from physical abnormality, and the patient reported here is the first we have seen with any breast enlargement. We believe that the gynaecomastia and the lactation are complications of treatment with fluphenazine, but the severity seems disproportional to the dose of the drug and raises the possibility of an increased sensitivity. This could be related to the previous oestrogen administration since phenothiazine-stimulated prolactin secretion is augmented by aestrogens,4 but usually when the drugs
SIR,-During
47,XYY karyotype
Price, W. H., Brunton, M , Buckton, K. E., Jacobs, P. A. Clin Genet. 1976, 9, 389. 2. Noel, G. L., Sug, H. K., Stone, J G., Franz, A. G. J. clin. Endocr. Metab 1.
1972, 35, 840. 3. Sassin, J. F., Frantz,
A.
G., Weitz, E. D., Kapen, S. Science, 1972, 177,
1205. 4.
Buckman, M. T., Peake, G. T. J. clin. Endocr. Metab 1973, 37, 977.
men
We thank Dr E. A. Cameron of the regional hormone laboratory for estimations of prolactin and the consultant psychiatrists in charge of the patients at the security hospitals for kind cooperation.
Department of Medicine and M.R.C. Clinical and Population
Cytogenetics Unit, Western General Hospital, Edinburgh EH4 2XU
W. H. PRICE W. B. RENTON W. A. CAMPBELL
PROPRANOLOL THERAPY FOR SECONDARY HYPERPARATHYROIDISM IN URÆMIA
SiR,—The description by Dr Caro and Dr Besarab (April 15, p. 827) of a patient in whom propranolol decreased both raised
raised plasma-parathyroid-horreport the preliminary results of two studies on the interference of antihypertensive drugs with the hormonal control of calcium-phosphate homoeostasis in ursemic patients. In a first study, thirteen hoemodialysed patients were successively treated for 6-week periods with equally antihypertensive regimens of metoprolol, methyldopa, and clonidine. P.T.H. and plasma concentrations of calcitonin, calcium, and phosphate were measured before the first dialysis in the sixth week of each period of treatment. Throughout the study other theraa
mone
plasma-calcium and (P.T.H.) prompts us to
a
peutic measures were kept constant. Variance analysis showed no significant differences between the three treatments except that the predialysis plasma-calcium was lower after metoprolol (8-5 ±0-2 mg/dl) than after clonidine (9-2±0-2). Because a higher P.T.H. was not observed after metoprolol despite the fall in plasma-calcium, metoprolol could have had a greater suppressive effect or a lower stimulating effect on P.T.H. secretion than clonidine. Because the study produced no denmuve conclusion about the absolute effect of these antihypertensive drugs on the hormonal control of calcium phosphate homceostasis, we began a second study to evaluate the acute effects of propranolol and metoprolol on P.T. H. and plasma-calcitonin. Propranolol (blocking &bgr;I and 32 receptors) was given intravenously (priming dose 1 mg given over 5 min and 1 p.g/kg/min given over 85 min) to nine uraemic patients not yet on dialysis and metoprolol (blocking only 31 receptors) was given intravenously (priming dose 1.2mg given over 5 min and 1.2 ug/ kg/min given over 85 min) 15 days later to six of these patients. Venous blood was taken before and 15, 30, 60, and 90 min after starting the injection. P.T.H. and plasma concentrations of total and ionised calcium, phosphate, and calcitonin were measured. The antibody used for P.T.H. was specific for the fragment 1-34 and the native human molecule. There was no significant change at any time in phosphate or total ionised calcium. The significant decrease in heart-rate was of the same magnitude with both drugs, suggesting equally effective 31 receptor blockade. P.T.H. decreased significantly (by 36%) at 30 min with propranolol but did not decrease with metoprolol. Calcitonin also decreased significantly at 60 min after propranolol (by 40%) but did not change after metoprolol. It appears, therefore, that propranolol acutely suppresses
