Clinical Endocrinology (1991) 34, 299-304
ADONIS
0300066491000558
The effects on anterior pituitary hormone secretion of salmon calcitonin in healthy volunteers P. J. Trainer, J. M. W. Kirk, L. McLoughlin, R. J. Touzei, L. Perry, L. H. Rees and G. M. Besser Departments of Endocrinology, Chemical Endocrinology and Reproductive Physiology, St Bartholomew's Hospital, London, UK (Received 16 August 1990; returned for revision 7 September 1990; finally revised 28 November 1990; accepted 13 December 1990)
tion, and whether basal levels of the hormone were studied or those after increased secretion following exogenous releasing hormone administration. We therefore designed a placebocontrolled study to compare changes in basal anterior pituitary hormone secretion following single doses of subcutaneous (the usual therapeutic route) and intravenous salmon calcitonin (the route of administration used in most published studies). Patients and methods
Summary The reports of the effect of calcitonin on pituitary function are confusing and often refer to uncontrolled studies. We have now carried out a double-blind placebotontrolled trial of Intravenous and subcutaneous salmon calcitonin on anterior pituitary function in 17 healthy volunteers. Visual analogue scores lor the nausea and vomiting seen after salmon calcltonin correlated with the rise In ACTH and, secondarily, cortisol. Calcitonin had no effect on growth hormone, prolactin, thyrotrophin, iuteinlzing hormone or follicle stimulating hormone. It is concluded that the stlmulatlon of ACTH secretlon following a single dose of salmon calcitonin is probably the result of the stress of nausea rather than a direct effect on the pituitary.
The only accepted physiological role of calcitonin in the adult human is the conservation of skeletal calcium at times of high physiological calcium demand such as pregnancy, lactation and growth, probably by inhibiting osteoclastic activity (Stevenson et af., 1979). The therapeutic uses of calcitonin in the treatment of hypercalcaemia, Paget's disease, bone pain and osteoporosis are increasing. Synthetic salmon calcitonin, a potent analogue with a prolonged halflife of action is the most widely prescribed form of calcitonin. Acute suppression of growth hormone, prolactin, thyrotrophin and gonadotrophin secretion from the anterior pituitary by single doses of calcitonin have all been reported (Looij et al., 1988; Cantalamessa et al., 1978; Isaac et al.. 1980; Leicht et af., 1974); however, other published data contradict these findings (Stevenson et al., 1977; Ceda et al., 1982). The situation is further confused by the different varieties of calcitonin used, different routes of administraCorrespondence: Professor G. M . Besser, Department of Endocrinology, St Bartholomew's Hospital, West Smithfield. London EClA 7 B E . UK.
Seventeen healthy male volunteers (age range 20-33 years, mean 25.6) were studied double-blind on three occasions, at least 7 days apart, in a randomized order determined by two replicated Latin squares. Venous cannulae were inserted after overnight fasting at 0800 h, and at 0900 h they received simultaneously in 1 ml diluent subcutaneous (s.c.) or intravenous (i.v.) injections of either 100 IU synthetic salmon calcitonin (Rorer Health Care Ltd, Eastbourne, UK) or its diluent alone as placebo. Thus the treatments were: S.C. calcitonin and i.v. placebo; S.C.placebo and i.v. calcitonin; S.C. placebo and i.v. placebo. Blood samples for plasma adrenocorticotrophic hormone (ACTH), serum cortisol, growth hormone, prolactin, luteinizing hormone, follicle stimulating hormone and thyroid stimulating hormone were taken 30 min and just prior to the injections, and thereafter at 15-min intervals for 2 h and then at 30-min intervals for a further 2 h. Blood glucose and serum calcium were measured at baseline and hourly thereafter. At the same times as blood sampling, subjects completed a linear visual analogue scale (VAS) for nausea: 0 corresponding to 'no nausea' and 10 to 'never felt more nauseated'. Subjects were not allowed to compare their visual analogue scores between different time points. Any other side-effects volunteered by the subjects were recorded. Assays
Plasma ACTH was measured using an immunoradiometric assay (Novo Biolabs Ltd). Coefficients of variation at 25.9 and 120 ng/l were 11.9 and 5.6% respectively (ACTH ng/ I x 0.23 = pmol/l). Serum cortisol was measured by our own non-extracted, non-chromatographic radioimmunoassay. The coefficients of variation at both 100 and 1000 nmol/l were 6% (Cunnah et al., 1987). Human growth hormone was measured by radioimmunoassay against NlBSC standard 66/217, coefficients of variation at 4.5 and 33.5 mU/l were 6.2 299
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changes in LH, FSH, TSH, GH, prolactin, glucose, calcium and VAS for nausea were performed in the same manner. Correlation coefficients between VAS for nausea and cortisol were calculated by Pearson's product moment correlation coefficient.
and 7.6% respectively. Serum levels of TSH were measured using an immunoradiometric assay, using North East Thames Regional Immuno-Assay Service (NETRIA) reagents, results being expressed in terms of NIBSC preparation 80/558.Coefficients of variation at 1.1 and 28 mU/I were 7.3 and 4.7% respectively. Prolactin was measured by radioimmunoassay using NETRIA reagents and NIBSC standard 83/562. At 133 and 1313 mU/l the coefficients of variation were 11.7 and 5.7% respectively. Serum gonadotrophins were measured by radioirnmunoassay using reagents purchased from Chelsea Kits and Reagents, results being expressed for LH in terms of NIBSC preparation 68/40 and for FSH preparation 78/549. The coefficient of variation for LH was 7.0 and 5.7% at 4 and 29.5 U/I respectively and for FSH, 13.2 and 3.4% at 1.8 and 15.5 U/I respectively. Blood glucose was measured by the glucose oxidase method and serum calcium by the cresolphthalein complexone colour reaction.
Results Adverse reactions
Adverse reactions were common. Calcitonin made all subjects feel unwell; nausea occurred in 13 of 17 subjects following i.v. calcitonin and eight of 16 following S.C. calcitonin, severe enough to cause one subject to withdraw following the i.v. limb. Vomiting occurred in seven of 17 with i.v. and two of 16 with S.C. calcitonin; five subjects reported paraesthesiae, two flushing, two dizziness, and two taste disturbance during the i.v. limb. Four of the subjects who vomited after i.v. calcitonin and both who vomited after S.C. calcitonin did so after the completion of venous sampling and the visual analogue scales.
Statistical analysis
The primary analysis was performed for ACTH and cortisol by comparing mean changes in circulating ACTH and cortisol at each time point over the 4 h post dose for each of the three treatment limbs. Means were compared using the paired Student's r-test. Analysis of variance was used to assess any order or carry-over effects. Secondary analyses for
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0
30
60
Hormonal changes
Plasma ACTH rose after the i.v. and S.C. doses of salmon calcitonin (P=O.OOOI) compared to placebo (Fig. I). There was no significant difference between the ACTH responses
90
120
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210
240
Time post dose ( m i n )
Flg. 1 a. Mean visual analogue score; b. plasma ACTH and c. serum cortisol following the administration of 100 IU of salmon calcitonin. The bars represent one standard error of mean. Conversion ACTH ng/l x 0.23=pmol/l. Placebo; . .. s.c.; - - -, i.v.
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Calcitonin and the pituitary
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Time p o s t dose ( m a n )
Fig. 2 Mean S e r m LH, FSH, prolactin, GH and TSH following the administration of 100 IU of salmon calcitonin. The bars represent Placebo; . ., s.c.; - - -, i.v. one standard error of mean. -,
FIg. 3 a, Mean serum glucose and b, calcium following the administration of 100 IU of salmon calcitonin. The bars represent one Placebo; . . ., s.c.; - - -, i.v. standard error of mean. -,
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after i.v. and S.C. administrations. Similarly, significant differences (P< 0.001) occurred in serum cortisol following both the i.v. and S.C. salmon calcitonin, but there was no difference between the two routes of administration (Fig. 1). There were no significantchanges in serum GH, LH, FSH, TSH and prolactin following either subcutaneous or intravenous calcitonin compared to placebo (Fig. 2). Blood glucose levels rose significantly (P
ADONIS
0300066491000558
The effects on anterior pituitary hormone secretion of salmon calcitonin in healthy volunteers P. J. Trainer, J. M. W. Kirk, L. McLoughlin, R. J. Touzei, L. Perry, L. H. Rees and G. M. Besser Departments of Endocrinology, Chemical Endocrinology and Reproductive Physiology, St Bartholomew's Hospital, London, UK (Received 16 August 1990; returned for revision 7 September 1990; finally revised 28 November 1990; accepted 13 December 1990)
tion, and whether basal levels of the hormone were studied or those after increased secretion following exogenous releasing hormone administration. We therefore designed a placebocontrolled study to compare changes in basal anterior pituitary hormone secretion following single doses of subcutaneous (the usual therapeutic route) and intravenous salmon calcitonin (the route of administration used in most published studies). Patients and methods
Summary The reports of the effect of calcitonin on pituitary function are confusing and often refer to uncontrolled studies. We have now carried out a double-blind placebotontrolled trial of Intravenous and subcutaneous salmon calcitonin on anterior pituitary function in 17 healthy volunteers. Visual analogue scores lor the nausea and vomiting seen after salmon calcltonin correlated with the rise In ACTH and, secondarily, cortisol. Calcitonin had no effect on growth hormone, prolactin, thyrotrophin, iuteinlzing hormone or follicle stimulating hormone. It is concluded that the stlmulatlon of ACTH secretlon following a single dose of salmon calcitonin is probably the result of the stress of nausea rather than a direct effect on the pituitary.
The only accepted physiological role of calcitonin in the adult human is the conservation of skeletal calcium at times of high physiological calcium demand such as pregnancy, lactation and growth, probably by inhibiting osteoclastic activity (Stevenson et af., 1979). The therapeutic uses of calcitonin in the treatment of hypercalcaemia, Paget's disease, bone pain and osteoporosis are increasing. Synthetic salmon calcitonin, a potent analogue with a prolonged halflife of action is the most widely prescribed form of calcitonin. Acute suppression of growth hormone, prolactin, thyrotrophin and gonadotrophin secretion from the anterior pituitary by single doses of calcitonin have all been reported (Looij et al., 1988; Cantalamessa et al., 1978; Isaac et al.. 1980; Leicht et af., 1974); however, other published data contradict these findings (Stevenson et al., 1977; Ceda et al., 1982). The situation is further confused by the different varieties of calcitonin used, different routes of administraCorrespondence: Professor G. M . Besser, Department of Endocrinology, St Bartholomew's Hospital, West Smithfield. London EClA 7 B E . UK.
Seventeen healthy male volunteers (age range 20-33 years, mean 25.6) were studied double-blind on three occasions, at least 7 days apart, in a randomized order determined by two replicated Latin squares. Venous cannulae were inserted after overnight fasting at 0800 h, and at 0900 h they received simultaneously in 1 ml diluent subcutaneous (s.c.) or intravenous (i.v.) injections of either 100 IU synthetic salmon calcitonin (Rorer Health Care Ltd, Eastbourne, UK) or its diluent alone as placebo. Thus the treatments were: S.C. calcitonin and i.v. placebo; S.C.placebo and i.v. calcitonin; S.C. placebo and i.v. placebo. Blood samples for plasma adrenocorticotrophic hormone (ACTH), serum cortisol, growth hormone, prolactin, luteinizing hormone, follicle stimulating hormone and thyroid stimulating hormone were taken 30 min and just prior to the injections, and thereafter at 15-min intervals for 2 h and then at 30-min intervals for a further 2 h. Blood glucose and serum calcium were measured at baseline and hourly thereafter. At the same times as blood sampling, subjects completed a linear visual analogue scale (VAS) for nausea: 0 corresponding to 'no nausea' and 10 to 'never felt more nauseated'. Subjects were not allowed to compare their visual analogue scores between different time points. Any other side-effects volunteered by the subjects were recorded. Assays
Plasma ACTH was measured using an immunoradiometric assay (Novo Biolabs Ltd). Coefficients of variation at 25.9 and 120 ng/l were 11.9 and 5.6% respectively (ACTH ng/ I x 0.23 = pmol/l). Serum cortisol was measured by our own non-extracted, non-chromatographic radioimmunoassay. The coefficients of variation at both 100 and 1000 nmol/l were 6% (Cunnah et al., 1987). Human growth hormone was measured by radioimmunoassay against NlBSC standard 66/217, coefficients of variation at 4.5 and 33.5 mU/l were 6.2 299
300
P. J . Trainer et al.
changes in LH, FSH, TSH, GH, prolactin, glucose, calcium and VAS for nausea were performed in the same manner. Correlation coefficients between VAS for nausea and cortisol were calculated by Pearson's product moment correlation coefficient.
and 7.6% respectively. Serum levels of TSH were measured using an immunoradiometric assay, using North East Thames Regional Immuno-Assay Service (NETRIA) reagents, results being expressed in terms of NIBSC preparation 80/558.Coefficients of variation at 1.1 and 28 mU/I were 7.3 and 4.7% respectively. Prolactin was measured by radioimmunoassay using NETRIA reagents and NIBSC standard 83/562. At 133 and 1313 mU/l the coefficients of variation were 11.7 and 5.7% respectively. Serum gonadotrophins were measured by radioirnmunoassay using reagents purchased from Chelsea Kits and Reagents, results being expressed for LH in terms of NIBSC preparation 68/40 and for FSH preparation 78/549. The coefficient of variation for LH was 7.0 and 5.7% at 4 and 29.5 U/I respectively and for FSH, 13.2 and 3.4% at 1.8 and 15.5 U/I respectively. Blood glucose was measured by the glucose oxidase method and serum calcium by the cresolphthalein complexone colour reaction.
Results Adverse reactions
Adverse reactions were common. Calcitonin made all subjects feel unwell; nausea occurred in 13 of 17 subjects following i.v. calcitonin and eight of 16 following S.C. calcitonin, severe enough to cause one subject to withdraw following the i.v. limb. Vomiting occurred in seven of 17 with i.v. and two of 16 with S.C. calcitonin; five subjects reported paraesthesiae, two flushing, two dizziness, and two taste disturbance during the i.v. limb. Four of the subjects who vomited after i.v. calcitonin and both who vomited after S.C. calcitonin did so after the completion of venous sampling and the visual analogue scales.
Statistical analysis
The primary analysis was performed for ACTH and cortisol by comparing mean changes in circulating ACTH and cortisol at each time point over the 4 h post dose for each of the three treatment limbs. Means were compared using the paired Student's r-test. Analysis of variance was used to assess any order or carry-over effects. Secondary analyses for
-30
0
30
60
Hormonal changes
Plasma ACTH rose after the i.v. and S.C. doses of salmon calcitonin (P=O.OOOI) compared to placebo (Fig. I). There was no significant difference between the ACTH responses
90
120
150
180
210
240
Time post dose ( m i n )
Flg. 1 a. Mean visual analogue score; b. plasma ACTH and c. serum cortisol following the administration of 100 IU of salmon calcitonin. The bars represent one standard error of mean. Conversion ACTH ng/l x 0.23=pmol/l. Placebo; . .. s.c.; - - -, i.v.
-.
Calcitonin and the pituitary
4 r
-30
0
30
60
90
120
150
180
210
240
Time p o s t dose ( m a n )
Fig. 2 Mean S e r m LH, FSH, prolactin, GH and TSH following the administration of 100 IU of salmon calcitonin. The bars represent Placebo; . ., s.c.; - - -, i.v. one standard error of mean. -,
FIg. 3 a, Mean serum glucose and b, calcium following the administration of 100 IU of salmon calcitonin. The bars represent one Placebo; . . ., s.c.; - - -, i.v. standard error of mean. -,
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after i.v. and S.C. administrations. Similarly, significant differences (P< 0.001) occurred in serum cortisol following both the i.v. and S.C. salmon calcitonin, but there was no difference between the two routes of administration (Fig. 1). There were no significantchanges in serum GH, LH, FSH, TSH and prolactin following either subcutaneous or intravenous calcitonin compared to placebo (Fig. 2). Blood glucose levels rose significantly (P
