of Endocrinology and Metabolism, Veterans Administration Hospital, Washington University School of Medicine. Washington D. C, USA
Department George
PARADOXICAL EFFECT OF SALMON CALCITONIN ON SERUM CALCIUM: STUDIES IN INTACT AND THYROPARATHYROIDECTOMIZED MEN AND DOGS
By Mahmood Mohamadi, Kenneth L. Becker and Leonard E. Bivins ABSTRACT Total serum calcium of normal men, a hypoparathyroid man, two thyroparathyroidectomized men, and intact and thyroparathyroidectomized dogs were studied at multiple intervals following the acute administration of synthetic salmon calcitonin. Calcitonin produced marked fluctuations in serum calcium in one normal man and a biphasic hypocalcaemic response in another. In four of five intact dogs, calcitonin caused absolute or relative hypercalcaemia. In contrast, administration of calcitonin to thyroparathyroidectomized dogs caused a hypocalcaemia with less fluctuations and with no periods of hypercalcaemia. It is possible that some of the paradoxical responses of serum calcium induced by exogenous calcitonin are due to overcompensation by parathyroid hormone. However, other mechanisms may be involved. Our findings indicate that when the disturbing influence is sufficiently great, the control of serum calcium is not as well modulated as previously suspected. In addition, our findings of paradoxically hypercalcaemic responses to calcitonin indicates that the pathophysiologic interpretation of serum calcium at any single moment in time following the administration of this hormone to either intact or thyroparathyroidectomized men or dogs is a precarious endeavour.
It has been assumed that the effect of calcitonin in man and laboratory animals is "hypocalcaemic'. The hypocalcaemic action of this hormone has been attri¬ buted principally to decreased bone résorption (Copp 1970; Martin et al. 1966; Milhaud et al. 1965).
Several clinical and/or physiological studies have appeared in the literature in which the serum calcium response to calcitonin in either man or the labora¬ tory animal has been evaluated at specific periods of time following adminis¬ tration (Bijvoet et al. 1968; Caniggia Sc Gennari 1969). Occasionally, the erratic and variable hypocalcaemic effect of calcitonin has been apparent (Care Sc Duncan 1967; Cooper 1968; Kammerman Sc Canfield 1970). The purpose of this study is to investigate, in detail, the effects of calcitonin on serum calcium.
MATERIALS AND METHODS
I. Human studies Three normal male volunteers, one man with idiopathic hypoparathyroidism, and with surgically-induced hypoparathyroidism following total thyroidectomy for carcinoma of the thyroid were studied. These three patients were taking 100 000 units of vitamin D> daily in order to maintain a normal serum calcium. The two patients with hypothyroidism were maintained on levothyroxine, 0.3 mg daily. The study of each subject consisted of a control day and a day during which synthetic salmon calcitonin11' in 16% gelatin, 16 MRC units per kg of body weight, was administered intramuscularly. The study periods were separated by a one-week interval. The subjects were fasted after midnight prior to the study, and during the study period. At 8 a.m., a butterfly needle #21, with reseal injection site, was placed in an antecubital vein, blood being drawn into vacuum tubes without the use of a tourniquet. After obtaining baseline specimens, whenever possible, the frequency of blood sampling was as follows: every 5 min during the first hour, every 15 min during the second and third hours, and every 30 min during the following three hours. The subjects remained supine throughout the study. An identical procedure was followed during the control day with prior injection of the 16% gelatin, in order to determine the range of normal fluctuations of serum calcium in each respective person. two men
II. Animal studies Five intact adult male mongrel dogs, weighing 13-20 kg, were studied during a control period and, on another day, after calcitonin administration. Four of these animals were re-studied in an identical fashion following thyroparathyroidectomy. A. Intact dogs. The dogs were fasted overnight and were lightly anaesthetized with sodium Nembutal one-half hour prior to the experiment. A butterfly needle #21, with reseal injection site, was placed into the median vein of the leg, blood being drawn without the use of a tourniquet. After obtaining blood for baseline determina¬ tions, salmon calcitonin in 16% gelatin, 16 MRC units per kg body weight, or the gelatin vehicle alone was administered intravenously. Thereafter, blood was drawn at intervals of 2, 5, 10, 15, 20, 25, 30, 40, 50 and 60 min. The sequence of the studies was randomized among the six dogs. -
*
The salmon calcitonin
was
tories, Kankakee. Illinois.
kindly supplied by
Dr.
James
B.
Lesh, Armour Labora¬
Thyroparathyroidectomized dogs. Thyroparathyroidectomy was performed upon dogs. In order to be sure that the removal of parathyroid tissue was nearly com¬ plete, the serum calcium was allowed to fall to tetanic levels. Then the dogs were treated with vitamin D2, 50 000 units daily, intramuscularly, until the serum calcium returned to normal values. Subsequently, the aforementioned control and calcitonin . four
-
studies were repeated. In all of the human and animal studies, the blood samples were allowed to clot and the serum was separated immediately and analyzed in duplicate for calcium by atomic absorption spectrophotometry using the Perkin-Elmer Model 403 (Fernandez Se Kahn 1971), and for total proteins and albumin and globulin by the biuret method (Cornali et al. 1949). RESULTS
The coefficient of variation for interassay determinations of serum calcium in our laboratory is 0.6 %, for serum albumin 2 %>, and for serum globulin 4 °/o. ACALCIUM
(itkj%)
-¡Û
/
7
\
er (ER)
-12
*2r
-a ^
IAV V
CT
-/e'¬ I
2
3 TIME (hrtû
Fig.
4
5
6
i.
Effect of salmon calcitonin (CT) on serum calcium in intact men. The dotted lines indicate the maximum excursions of serum calcium from the baseline on the control day.
2
3
TIME (fri)
Fig. Effect of salmon calcitonin two
4
2. calcium in
a hypoparathyroid thyroparathyroidectomized patients. on serum
and
I. Human studies A. Normal subjects. The fluctuation of serum calcium among the normal subjects on the control day never exceeded 0.1 mg/100 ml from the baseline values. Consequently, only deviations from the baseline greater than this were considered to be meaningful. Calcitonin administration to normal subjects (Fig. 1), caused an initial de¬ crease of serum calcium followed by marked fluctuations before ultimately re¬ turning to or near the baseline at about the sixth hour. In two subjects, these fluctuations were so marked that it caused serum calcium to return to normal baseline values between 15 to 20 min after the administration of calcitonin, subsequently decreasing again to relative hypocalcaemia. -
. Hypoparalhyroid and thyroparathyroidectomized subjects. The oscilla¬ tions in serum calcium among one hypoparathyroid and two thyroparathyroid¬ ectomized persons on the control day did not exceed 0.2 mg/100 ml from the baseline. Administration of calcitonin to all three patients (Fig. 2), caused a reduction of serum calcium with subsequent fluctuations. In two of the patients, the serum calcium had not returned to the baseline by the sixth hour. Except for one patient (C. G), the maximum drop in serum calcium was not appreciably greater in these patients than among the normal subjects. In none of the aforementioned control studies or calcitonin studies in man or dog were there any significant changes in total protein, albumin or globulin during the experiment. A study of the calcitonin-induced changes of total cal¬ cium revealed no significant correlation with the concomitant total protein, albumin or globulin. -
.
25 10 15202530
40 TIME (min)
Fig. Eflect of salmon calcitonin
50
60
3.
on serum
calcium in intact
IL Animal studies A. Intact animals. The serum calcium of intact dogs did not vary from baseline values on the control day by more than 0.15 mg/100 ml. The administration of calcitonin to intact dogs (Fig. 3), caused absolute or relative hypercalcaemia in four of the five animals. The elevation of serum calcium was preceded by a detectable decreased value in three of these four dogs. The hypercalcaemia occurred at different times among the animals. In one dog, calcitonin caused an increase of serum calcium of 1.2 mg/100 ml at 40 min. Two dogs still had elevated calcium values one hour following ad¬ ministration of calcitonin. In one calcitonin-treated animal, serum calcium re¬ mained at above baseline values throughout the experiment. -
B. Thyroparathyroidectomized dogs. The serum calcium of vitamin D treated thyroparathyroidectomized dogs did not vary from baseline by more than 0.2 mg/100 ml during the control day. -
CALCI UM
(mg%) +.2
I
CT
I/Kl f :
(thyroparathX dog)
III
I-1-1
*.
- —r
CT (thyroparathX dog)
O -.2
-1-1-1-1-1-1-1
I
CTÏthyroparathXdog)
JA
40 TIME (min)
25 10 6 202530
50
60
Fig. 4. Effect of salmon calcitonin
on serum
calcium in
thyroparathyroidectomized dogs.
The administration of calcitonin to thyroparathyroidectomized dogs (Fig. 4), produced hypocalcaemia in all animals, the serum calcium usually not re¬ turning definitively to the baseline by the end of the experiment. Moderate oscillations of serum calcium levels which transiently returned to or towards the baseline were noted in two of the dogs.
DISCUSSION
In
experiments, the response to salmon calcitonin in intact men and intact dogs demonstrated extremely variable and unpredictable responses when serum our
calcium
determined at
frequent intervals. One normal man exhibited a strikingly biphasic hypocalcaemic response, maximal at | h and again at 3 h. Interestingly, there was a clearly hypercalcaemic response to intravenous cal¬ citonin in four of the five intact dogs. A clearly hypercalcaemic response to calcitonin was not noted in the thyro¬ parathyroidectomized men, the hypoparathyroid man, or any of the thyropara¬ thyroidectomized dogs. Nevertheless, there often appeared to be a relatively was
fluctuation in serum calcium values. The fact that calcitonin produces a variable hypocalcaemic response in ani¬ mals and man has been previously known (Care 8c Duncan 1967; Cooper 1968; Sitai et al. 1971). Bijvoet et al. (1968) stated that the hypocalcaemic response to porcine calcitonin appeared to be proportional to the prevailing rate of bone résorption. Stekolnikov et al. (1971) have reported a biphasic hypocalcaemic response to porcine calcitonin in rabbits, and they attributed the first decrease to central nervous system mechanisms. Our finding that calcitonin can produce hypercalcaemia in intact animals has not been widely appreciated, although scattered suggestions have appeared in the literature indicating that such a phenomenon is not unknown. For example, Aldred el al. (1970) noted a late hypercalcaemic response to porcine calcitonin in both intact and parathyroidectomized rats. Is the biphasic hypocalcaemic response or the hypercalcaemic response to calcitonin due to compensation or overcompensation by endogenous parathyroid hormone^ It is well known that chronic calcitonin administration induces a secondary hyperparathyroidism (Becker 1972; Eindeck 8c Jowsey 1971), and it is conceivable that, in our experiment, the acute hypocalcaemia induced by calcitonin is the stimulus for release of parathyroid hormone. In most of our intact dogs, a prior hypocalcaemic nadir was noted. However, one intact dog had no detectable hypocalcaemia prior to manifesting persistent hypercal¬ caemia for one hour. Of course, it is possible that even more frequent serum calcium determinations might have elucidated a very early hypocalcaemic dip in this animal. In addition, perhaps an early hypocalcaemic nadir is not neces-
large
sary, because Fischer et al (1971) have demonstrated that calcitonin per se can stimulate parathyroid hormone release independently of its hypocalcaemic action. Although none of the thyroparathyroidectomized dogs which were given calcitonin became hypercalcaemic, three of the four animals had marked belowbaseline fluctuations of serum calcium which, in the case of one animal, ascended to the baseline before descending again. Conceivably, even though enough parathyroid tissue had been removed in these animals to induce tetany, a remnant of parathyroid tissue might have been sufficient to produce these compensatory fluctuations. It is uncertain to what extent therapy with vita¬ min D may have played a role in these thyroparathyroidectomized dogs, al¬ though the serum calcium had remained relatively stable during the control
day. In our study, the multiple sampling of blood specimens has revealed that, if the exogenous perturbing influence is great enough, the homoeostatic control of serum calcium is not well-modulated. There were no discernible changes in serum proteins which would explain these fluctuations. Apparently, com¬ pensatory processes which arise secondary to exogenous calcitonin administra¬ tion can produce violent and overcompensatory fluctuations. Further studies are needed to elucidate the nature of these compensatory mechanisms, which, conceivably, might involve various contributions from endogenous parathyroid hormone, as well as other factors. In addition, the comparative effects of synthetic calcitonin of other species (human, porcine, etc.) should be evaluated. Our studies in men are not strictly comparable to those in dogs, because of the different route of administration of the calcitonin. Nevertheless, the results reveal a relative crudity of blood calciostasis in the face of a sufficiently great disturbing signal. In addition, the demonstration of paradoxical respon¬ ses of serum calcium to calcitonin indicate that the pathophysiologic inter¬ pretation of serum calcium levels in man or the laboratory animal at any single specific period of time following administration of this hormone is a precarious endeavour.
REFERENCES Aldred J. P., Stubbs R. K. Se Hermann W. R.: Acta endocr. (Kbh.) 65 (1970) 737. Becker K. L.: Fed. Proc. 31 (1972) 251. Bijvoet O. L. M., Van der Sluys Veer J. 8c Jansen A. P.: Lancet 1 (1968) 876. Caniggia A. Se Gennari C: Panminerva Med. 11 (1969) 303. Care A. D. 8- Duncan T.: J. Endocr. 37 (1967) 107. Cooper C. W.: Endocrinology cS2 (1968) 1015. Copp H. D. In: Talmage R. V. and Langer L. F. B., Eds. Parathyroid and Thyrocalcitonin (Calcitonin). Parathyroid hormone, calcitonin and calcium homeostasis. Excerpta med., New York (1970) pp 25.
Eindech M. Se Jowsey J.: Endocrinology 88 (1971) 1489. Fernandez F. J. Se Kahn K. L.: Clin. News Letter 3 (1971) 24. Fischer J. ., Oldham S. B. Se Sizemore G. W.: Horm. Metab. Res. 3 (1971) 323. Gornall A. G., Bardawill G J. Se David M. M.: J. biol. Chem. 777 (1949) 751. Kammerman S. Se Canfield R. E.: J. clin. Endocr. 31 (1970) 70. Martin T. J., Robinson C. J. & Maclntyre I.: Lancet 1 (1966) 900. Milhaud M. G., Perault A. M. 8c Mouktar M. D.: C. R. Acad. Sci. (Paris) 267 (1965) 813.
Shai F., Baker R. K. & Wallach S.: J. clin. Invest. 50 (1971) 1927. Stekolnikov L. L, Briskin A. I. 8- Katkovsky S. B.: Byull. eskp. biol. med. 77
(1971)
Received
on
18.
June 14th,
1974.
(Moscow)
Department George
PARADOXICAL EFFECT OF SALMON CALCITONIN ON SERUM CALCIUM: STUDIES IN INTACT AND THYROPARATHYROIDECTOMIZED MEN AND DOGS
By Mahmood Mohamadi, Kenneth L. Becker and Leonard E. Bivins ABSTRACT Total serum calcium of normal men, a hypoparathyroid man, two thyroparathyroidectomized men, and intact and thyroparathyroidectomized dogs were studied at multiple intervals following the acute administration of synthetic salmon calcitonin. Calcitonin produced marked fluctuations in serum calcium in one normal man and a biphasic hypocalcaemic response in another. In four of five intact dogs, calcitonin caused absolute or relative hypercalcaemia. In contrast, administration of calcitonin to thyroparathyroidectomized dogs caused a hypocalcaemia with less fluctuations and with no periods of hypercalcaemia. It is possible that some of the paradoxical responses of serum calcium induced by exogenous calcitonin are due to overcompensation by parathyroid hormone. However, other mechanisms may be involved. Our findings indicate that when the disturbing influence is sufficiently great, the control of serum calcium is not as well modulated as previously suspected. In addition, our findings of paradoxically hypercalcaemic responses to calcitonin indicates that the pathophysiologic interpretation of serum calcium at any single moment in time following the administration of this hormone to either intact or thyroparathyroidectomized men or dogs is a precarious endeavour.
It has been assumed that the effect of calcitonin in man and laboratory animals is "hypocalcaemic'. The hypocalcaemic action of this hormone has been attri¬ buted principally to decreased bone résorption (Copp 1970; Martin et al. 1966; Milhaud et al. 1965).
Several clinical and/or physiological studies have appeared in the literature in which the serum calcium response to calcitonin in either man or the labora¬ tory animal has been evaluated at specific periods of time following adminis¬ tration (Bijvoet et al. 1968; Caniggia Sc Gennari 1969). Occasionally, the erratic and variable hypocalcaemic effect of calcitonin has been apparent (Care Sc Duncan 1967; Cooper 1968; Kammerman Sc Canfield 1970). The purpose of this study is to investigate, in detail, the effects of calcitonin on serum calcium.
MATERIALS AND METHODS
I. Human studies Three normal male volunteers, one man with idiopathic hypoparathyroidism, and with surgically-induced hypoparathyroidism following total thyroidectomy for carcinoma of the thyroid were studied. These three patients were taking 100 000 units of vitamin D> daily in order to maintain a normal serum calcium. The two patients with hypothyroidism were maintained on levothyroxine, 0.3 mg daily. The study of each subject consisted of a control day and a day during which synthetic salmon calcitonin11' in 16% gelatin, 16 MRC units per kg of body weight, was administered intramuscularly. The study periods were separated by a one-week interval. The subjects were fasted after midnight prior to the study, and during the study period. At 8 a.m., a butterfly needle #21, with reseal injection site, was placed in an antecubital vein, blood being drawn into vacuum tubes without the use of a tourniquet. After obtaining baseline specimens, whenever possible, the frequency of blood sampling was as follows: every 5 min during the first hour, every 15 min during the second and third hours, and every 30 min during the following three hours. The subjects remained supine throughout the study. An identical procedure was followed during the control day with prior injection of the 16% gelatin, in order to determine the range of normal fluctuations of serum calcium in each respective person. two men
II. Animal studies Five intact adult male mongrel dogs, weighing 13-20 kg, were studied during a control period and, on another day, after calcitonin administration. Four of these animals were re-studied in an identical fashion following thyroparathyroidectomy. A. Intact dogs. The dogs were fasted overnight and were lightly anaesthetized with sodium Nembutal one-half hour prior to the experiment. A butterfly needle #21, with reseal injection site, was placed into the median vein of the leg, blood being drawn without the use of a tourniquet. After obtaining blood for baseline determina¬ tions, salmon calcitonin in 16% gelatin, 16 MRC units per kg body weight, or the gelatin vehicle alone was administered intravenously. Thereafter, blood was drawn at intervals of 2, 5, 10, 15, 20, 25, 30, 40, 50 and 60 min. The sequence of the studies was randomized among the six dogs. -
*
The salmon calcitonin
was
tories, Kankakee. Illinois.
kindly supplied by
Dr.
James
B.
Lesh, Armour Labora¬
Thyroparathyroidectomized dogs. Thyroparathyroidectomy was performed upon dogs. In order to be sure that the removal of parathyroid tissue was nearly com¬ plete, the serum calcium was allowed to fall to tetanic levels. Then the dogs were treated with vitamin D2, 50 000 units daily, intramuscularly, until the serum calcium returned to normal values. Subsequently, the aforementioned control and calcitonin . four
-
studies were repeated. In all of the human and animal studies, the blood samples were allowed to clot and the serum was separated immediately and analyzed in duplicate for calcium by atomic absorption spectrophotometry using the Perkin-Elmer Model 403 (Fernandez Se Kahn 1971), and for total proteins and albumin and globulin by the biuret method (Cornali et al. 1949). RESULTS
The coefficient of variation for interassay determinations of serum calcium in our laboratory is 0.6 %, for serum albumin 2 %>, and for serum globulin 4 °/o. ACALCIUM
(itkj%)
-¡Û
/
7
\
er (ER)
-12
*2r
-a ^
IAV V
CT
-/e'¬ I
2
3 TIME (hrtû
Fig.
4
5
6
i.
Effect of salmon calcitonin (CT) on serum calcium in intact men. The dotted lines indicate the maximum excursions of serum calcium from the baseline on the control day.
2
3
TIME (fri)
Fig. Effect of salmon calcitonin two
4
2. calcium in
a hypoparathyroid thyroparathyroidectomized patients. on serum
and
I. Human studies A. Normal subjects. The fluctuation of serum calcium among the normal subjects on the control day never exceeded 0.1 mg/100 ml from the baseline values. Consequently, only deviations from the baseline greater than this were considered to be meaningful. Calcitonin administration to normal subjects (Fig. 1), caused an initial de¬ crease of serum calcium followed by marked fluctuations before ultimately re¬ turning to or near the baseline at about the sixth hour. In two subjects, these fluctuations were so marked that it caused serum calcium to return to normal baseline values between 15 to 20 min after the administration of calcitonin, subsequently decreasing again to relative hypocalcaemia. -
. Hypoparalhyroid and thyroparathyroidectomized subjects. The oscilla¬ tions in serum calcium among one hypoparathyroid and two thyroparathyroid¬ ectomized persons on the control day did not exceed 0.2 mg/100 ml from the baseline. Administration of calcitonin to all three patients (Fig. 2), caused a reduction of serum calcium with subsequent fluctuations. In two of the patients, the serum calcium had not returned to the baseline by the sixth hour. Except for one patient (C. G), the maximum drop in serum calcium was not appreciably greater in these patients than among the normal subjects. In none of the aforementioned control studies or calcitonin studies in man or dog were there any significant changes in total protein, albumin or globulin during the experiment. A study of the calcitonin-induced changes of total cal¬ cium revealed no significant correlation with the concomitant total protein, albumin or globulin. -
.
25 10 15202530
40 TIME (min)
Fig. Eflect of salmon calcitonin
50
60
3.
on serum
calcium in intact
IL Animal studies A. Intact animals. The serum calcium of intact dogs did not vary from baseline values on the control day by more than 0.15 mg/100 ml. The administration of calcitonin to intact dogs (Fig. 3), caused absolute or relative hypercalcaemia in four of the five animals. The elevation of serum calcium was preceded by a detectable decreased value in three of these four dogs. The hypercalcaemia occurred at different times among the animals. In one dog, calcitonin caused an increase of serum calcium of 1.2 mg/100 ml at 40 min. Two dogs still had elevated calcium values one hour following ad¬ ministration of calcitonin. In one calcitonin-treated animal, serum calcium re¬ mained at above baseline values throughout the experiment. -
B. Thyroparathyroidectomized dogs. The serum calcium of vitamin D treated thyroparathyroidectomized dogs did not vary from baseline by more than 0.2 mg/100 ml during the control day. -
CALCI UM
(mg%) +.2
I
CT
I/Kl f :
(thyroparathX dog)
III
I-1-1
*.
- —r
CT (thyroparathX dog)
O -.2
-1-1-1-1-1-1-1
I
CTÏthyroparathXdog)
JA
40 TIME (min)
25 10 6 202530
50
60
Fig. 4. Effect of salmon calcitonin
on serum
calcium in
thyroparathyroidectomized dogs.
The administration of calcitonin to thyroparathyroidectomized dogs (Fig. 4), produced hypocalcaemia in all animals, the serum calcium usually not re¬ turning definitively to the baseline by the end of the experiment. Moderate oscillations of serum calcium levels which transiently returned to or towards the baseline were noted in two of the dogs.
DISCUSSION
In
experiments, the response to salmon calcitonin in intact men and intact dogs demonstrated extremely variable and unpredictable responses when serum our
calcium
determined at
frequent intervals. One normal man exhibited a strikingly biphasic hypocalcaemic response, maximal at | h and again at 3 h. Interestingly, there was a clearly hypercalcaemic response to intravenous cal¬ citonin in four of the five intact dogs. A clearly hypercalcaemic response to calcitonin was not noted in the thyro¬ parathyroidectomized men, the hypoparathyroid man, or any of the thyropara¬ thyroidectomized dogs. Nevertheless, there often appeared to be a relatively was
fluctuation in serum calcium values. The fact that calcitonin produces a variable hypocalcaemic response in ani¬ mals and man has been previously known (Care 8c Duncan 1967; Cooper 1968; Sitai et al. 1971). Bijvoet et al. (1968) stated that the hypocalcaemic response to porcine calcitonin appeared to be proportional to the prevailing rate of bone résorption. Stekolnikov et al. (1971) have reported a biphasic hypocalcaemic response to porcine calcitonin in rabbits, and they attributed the first decrease to central nervous system mechanisms. Our finding that calcitonin can produce hypercalcaemia in intact animals has not been widely appreciated, although scattered suggestions have appeared in the literature indicating that such a phenomenon is not unknown. For example, Aldred el al. (1970) noted a late hypercalcaemic response to porcine calcitonin in both intact and parathyroidectomized rats. Is the biphasic hypocalcaemic response or the hypercalcaemic response to calcitonin due to compensation or overcompensation by endogenous parathyroid hormone^ It is well known that chronic calcitonin administration induces a secondary hyperparathyroidism (Becker 1972; Eindeck 8c Jowsey 1971), and it is conceivable that, in our experiment, the acute hypocalcaemia induced by calcitonin is the stimulus for release of parathyroid hormone. In most of our intact dogs, a prior hypocalcaemic nadir was noted. However, one intact dog had no detectable hypocalcaemia prior to manifesting persistent hypercal¬ caemia for one hour. Of course, it is possible that even more frequent serum calcium determinations might have elucidated a very early hypocalcaemic dip in this animal. In addition, perhaps an early hypocalcaemic nadir is not neces-
large
sary, because Fischer et al (1971) have demonstrated that calcitonin per se can stimulate parathyroid hormone release independently of its hypocalcaemic action. Although none of the thyroparathyroidectomized dogs which were given calcitonin became hypercalcaemic, three of the four animals had marked belowbaseline fluctuations of serum calcium which, in the case of one animal, ascended to the baseline before descending again. Conceivably, even though enough parathyroid tissue had been removed in these animals to induce tetany, a remnant of parathyroid tissue might have been sufficient to produce these compensatory fluctuations. It is uncertain to what extent therapy with vita¬ min D may have played a role in these thyroparathyroidectomized dogs, al¬ though the serum calcium had remained relatively stable during the control
day. In our study, the multiple sampling of blood specimens has revealed that, if the exogenous perturbing influence is great enough, the homoeostatic control of serum calcium is not well-modulated. There were no discernible changes in serum proteins which would explain these fluctuations. Apparently, com¬ pensatory processes which arise secondary to exogenous calcitonin administra¬ tion can produce violent and overcompensatory fluctuations. Further studies are needed to elucidate the nature of these compensatory mechanisms, which, conceivably, might involve various contributions from endogenous parathyroid hormone, as well as other factors. In addition, the comparative effects of synthetic calcitonin of other species (human, porcine, etc.) should be evaluated. Our studies in men are not strictly comparable to those in dogs, because of the different route of administration of the calcitonin. Nevertheless, the results reveal a relative crudity of blood calciostasis in the face of a sufficiently great disturbing signal. In addition, the demonstration of paradoxical respon¬ ses of serum calcium to calcitonin indicate that the pathophysiologic inter¬ pretation of serum calcium levels in man or the laboratory animal at any single specific period of time following administration of this hormone is a precarious endeavour.
REFERENCES Aldred J. P., Stubbs R. K. Se Hermann W. R.: Acta endocr. (Kbh.) 65 (1970) 737. Becker K. L.: Fed. Proc. 31 (1972) 251. Bijvoet O. L. M., Van der Sluys Veer J. 8c Jansen A. P.: Lancet 1 (1968) 876. Caniggia A. Se Gennari C: Panminerva Med. 11 (1969) 303. Care A. D. 8- Duncan T.: J. Endocr. 37 (1967) 107. Cooper C. W.: Endocrinology cS2 (1968) 1015. Copp H. D. In: Talmage R. V. and Langer L. F. B., Eds. Parathyroid and Thyrocalcitonin (Calcitonin). Parathyroid hormone, calcitonin and calcium homeostasis. Excerpta med., New York (1970) pp 25.
Eindech M. Se Jowsey J.: Endocrinology 88 (1971) 1489. Fernandez F. J. Se Kahn K. L.: Clin. News Letter 3 (1971) 24. Fischer J. ., Oldham S. B. Se Sizemore G. W.: Horm. Metab. Res. 3 (1971) 323. Gornall A. G., Bardawill G J. Se David M. M.: J. biol. Chem. 777 (1949) 751. Kammerman S. Se Canfield R. E.: J. clin. Endocr. 31 (1970) 70. Martin T. J., Robinson C. J. & Maclntyre I.: Lancet 1 (1966) 900. Milhaud M. G., Perault A. M. 8c Mouktar M. D.: C. R. Acad. Sci. (Paris) 267 (1965) 813.
Shai F., Baker R. K. & Wallach S.: J. clin. Invest. 50 (1971) 1927. Stekolnikov L. L, Briskin A. I. 8- Katkovsky S. B.: Byull. eskp. biol. med. 77
(1971)
Received
on
18.
June 14th,
1974.
(Moscow)
