J Neural Transm [GenSect] (1992) 87:125-131
Journal of Neural Transmission 9 Springer-Verlag 1992 Printed in Austria
Dexamethasone suppression of the calcitonin induced ~-endorphin, ACTH and cortisol secretion Z. Oberman 1, E. Graft 1, R. Chayen 2, N. Grazas 2, A. Burstein 2, and L. Laurian 2 ~Laboratory of Chemical Pathology and 2 Endocrinology Department, Ichilov Medical Center, Tel Aviv University Medical School, Tel Aviv, Israel
Accepted August 23, 1991
Summary.Our previous observations have shown that calcitonin (CT) stimulates ]3-endorphin, ACTH, and cortisol secretion. In order to give further information on the supposed hypothalamic pituitary involvement in this effect, we studied the influence of dexamethasone on this stimulative influence of CT. Six healthy women aged 50-65 years were investigated. All the subjects received 100 U CT salmon (Sandoz) i.v. at 0800 (0 time). Plasma J3-endorphin, ACTH, and cortisol were estimated every 30rain from - 30 to 120min by specific radioimmunoassays. The same subjects were evaluated a second time, at the same intervals, when 1 mg dexamethasone was administered per os at 11 PM the previous night and CT i.v. at 0800 the next morning. [3-endorphin, ACTH, and cortisol levels (mean • SEM) rose significantly after 100U CT from 5.6 • 0.17 to 16.75 • 1.Spmol/L (p < 0.001); from 39.6 • 6 to 88.0 • 3.1 pg/ml (p < 0.0001) (from 8.7 • 1.3 to 19.4 • 0.7pmol/ L); and from 13.1 • 1.6 to 23.8 • 3.0~tg/dl (p < 0.0001) [374 • 45 to 680 • 85 nmol/L], respectively. Dexamethasone suppressed almost completely the stimulatory effect of CT ]3-endorphin rose from 4.9 • 0.12 to 6.3 • 1.3pmol/L (n.s.), ACTH from 38.6 • 5.1 to 42.6 • 6.2pg/ml (n.s.) (from 8.5 -4- 1.1 to 9.4 • 0.9pmol/L) and cortisol from 0.88• to 0.88• (n.s.) (from 25.1 • to 25.0 4- 5.1 nmol/L). [3-endorphin and cortisol rose significantly after 50 and 25 U CT but less than after 100 U CT. 50 U CT increased the ]3-enorphin and cortisol levels from 4.8 • 0.49 to 7.98 • 0.4pmol/L (p < 0.05)and from 10.46 • 1.48 to 16.4 • 3.3/ dl (p < 0.05) (from 299 • 42 to 468 • 95 nmol/L), respectively. 25 U CT increased the ]3-endorphin and cortisol levels from 4.6 • 0.58 to 5.9 • 0.88pmol/L (p < 0.05) and from 10.90 • 1.00 to 15.35 • 1.8~tg/dl (p < 0.05) (from 311 • 28 to 438 • 51 nmol/L). Dexamethasone is known to inhibit the hypothalamic-pituitary-adrenal axis.
126
Z. Oberman et al.
The inhibition of the CT stimulative effect on [3-endorphin, A C T H , and cortisol observed in this study enforces our idea that CT exerts this effect by stimulating the hypothalamic-pituitary-adrenal axis.
Keywords: Calcitonin, dexamethasone, beta-endorphin, A C T H , hypothalamus. Introduction Most of the studies concerning calcitonin (CT) function have focused on the effect of CT on calcium homeostasis (Munson, 1976). However recent reports have indicated a broader range of CT action namely on the C N S central nervous system (Freed et al., 1979; MacIntyre and Stevenson, 1988; Morley et al., 1981). It was also shown that CT exerts stimulatory or inhibitory action on the secretion of m a n y a d e n o h y p o p h y s e a l h o r m o n e s in basal condition or in response to appropriate stimuli (Cantalamessa etal., 1978; Pecile et al., 1981). In a previous study (Laurian etal., 1986), we observed that CT induces a concurrent increase of [3-endorphin, A C T H , and cortisol secretion. A similiar effect was recently reported by others (Ceda et al., 1989). A n increase of A C T H levels after i.v. or intra cerebroventricular injection of CT has also been observed in rats (Rapisarda et al., 1984). Since A C T H and [3-endorphin derive from a c o m m o n pituitary precursor P O M C (proopiomelanocortin) (Naganishi etal., 1979) we assumed that CT m a y play a role as a m o d u l a t o r of the anterior pituitary function. The present investigation was initiated to get further i n f o r m a t i o n about the h y p o t h a l a m i c pituitary adrenal involvement in this response. We examined the influence of dexamethasone on the CT induced [3-endorphin, A C T H , and cortisol secretion.
Material and methods Six healthy women aged 50-65 were investigated. Informed consent was obtained from all of them. All the subjects in fasting condition received 100 IU Salmon Calcitonin (Sandoz) i.v. at 8.0AM (0 time). Blood samples were collected at - 30, 0, 30, 60, 90, and 120rains. via an indwelling i.v. canula kept open with a diluted 10% solution of heparin; plasma [3endorphin, ACTH, and cortisol were estimated. The same patients were investigated a second time at the same intervals when 1mg Dexamethasone was administered per os at 11.0 PM the previous night and 100 U CT i.v. at 8.0 am next morning The response of [3-endorphin and cortisol to 50 U and 25 U CT were also studied. Plasma [3-endorphin and cortisol were estimated, using commercial radioimmunoassay kits. The kits for [3-endorphin and ACTH were supplied by INCSTAR Corporation, Minnesota, U.S.A. The procedure for [3-endorphin estimation utilizes a preliminary extraction of J3-endorphin by specific affinity particles made by coupling [3-endorphin to sepharose followed by elution, and neutralization and a 17-hours radioimmunoassay procedure. The antibody to [3-endorphin cross reacts 100% with human J3-endorphin (Des-Tyr) human 13endorphin (2-Me-Ala) and N acetyl [3-endorphin and exhibits a 5% cross reactivity with J3 lipotropin. The kit for ACTH was not sensitive for levels less than approximately 40 pg/ml., and the kit' for [3-endorphin was not sensitive for levels less than approximately 5 pmol/1).
Dexamethasone and calcitonin on ~-endorphin, ACTH and cortisol
127
The estimation of cortisol was done with the Diagnostic Product Corporation kit. The statistical evaluation was done with analysis of variance and covariance and repeated measurements and paired Student's t-test. Results A significant increase of ]3-endorphin and cortisol was observed after 100, 50, 25 U CT although the increase was higher after 100 U. The 13-endorphin (pmol/1) levels increased from 5.6 4- 0.17 to 16.75 4- 1.8, (p < 0.0001), from 4.8 4- 0.49 to 7.98 4- 0.4 (p < 0.05), and from 4.6 4- 0.58 to 5.9 4- 0.88 (p < 0.05) respectively. The cortisol (Ixg/dl) levels increased (mean 4- S.E.) from 10.58 4- 1.4 (p < 0.0001) (from 302 + 40 to 559 4- 60nmol/L), from 10.46 4- 1.48 to 16.4 4- 3.3 (p < 0.05) (from 298 4- 43 to 468 4- 94nmol/L), and from 10.9 4- 1.0 to 15.35 4- 1.8 (p < 0.05) respectively (from 311 4- 28 to 438 4- 51 nmol/L). A C T H levels (gg/ml) increased after 100U CT from 39.6 4- 6.0 to 88.0 4- 3.1 (p < 0.0001) (from 8.7 4- 1.3 to 19.4 4- 0.68 pmol/L). Marked increase of all parameters with time (30-60 min after CT administration) was highly significant (p < 0.0001). A significant difference in the increase of the two parameters (f3-endorphin and cortisol) was observed between 100U CT and 5 0 U CT (p < 0.05) and between 100 U CT and 25 U CT (p < 0.05). N o significant difference in the increase of the two parameters (]3-endorphin and cortisol) was observed between 50 U CT and 25 U CT administration. After dexamethasone administration, the response of 13-endorphin, ACTH, and cortisol was almost completely inhibited. ]3-endorphin rose from 4.9 -4- 0.12
20 18 84 .-A
16-
~c~14~12~ L~ 10 -
c~.
--"O'--
8
-30
Calcitonin +
Dexamethasone
6
41
Calcitonin
.......
.
, 0
.
, 30
.
, 60
.
, 90
.
I , 120
Time (min)
F i g . 1. L e v e l s o f 1 3 - e n d o r p h i n ( p m o l / L )
a f t e r 100 U c a l c i t o n i n , a n d a f t e r 100 U o f c a l c i t o n i n
preceded by 1 mg dexamethasone. Area under the curve -- 51.55 (calcitonin). Area under the curve = 34.1 (calcitonin + dexamethasone)
128
Z. Oberman et al. 100 90
8O
~- 70 1I-o,
Journal of Neural Transmission 9 Springer-Verlag 1992 Printed in Austria
Dexamethasone suppression of the calcitonin induced ~-endorphin, ACTH and cortisol secretion Z. Oberman 1, E. Graft 1, R. Chayen 2, N. Grazas 2, A. Burstein 2, and L. Laurian 2 ~Laboratory of Chemical Pathology and 2 Endocrinology Department, Ichilov Medical Center, Tel Aviv University Medical School, Tel Aviv, Israel
Accepted August 23, 1991
Summary.Our previous observations have shown that calcitonin (CT) stimulates ]3-endorphin, ACTH, and cortisol secretion. In order to give further information on the supposed hypothalamic pituitary involvement in this effect, we studied the influence of dexamethasone on this stimulative influence of CT. Six healthy women aged 50-65 years were investigated. All the subjects received 100 U CT salmon (Sandoz) i.v. at 0800 (0 time). Plasma J3-endorphin, ACTH, and cortisol were estimated every 30rain from - 30 to 120min by specific radioimmunoassays. The same subjects were evaluated a second time, at the same intervals, when 1 mg dexamethasone was administered per os at 11 PM the previous night and CT i.v. at 0800 the next morning. [3-endorphin, ACTH, and cortisol levels (mean • SEM) rose significantly after 100U CT from 5.6 • 0.17 to 16.75 • 1.Spmol/L (p < 0.001); from 39.6 • 6 to 88.0 • 3.1 pg/ml (p < 0.0001) (from 8.7 • 1.3 to 19.4 • 0.7pmol/ L); and from 13.1 • 1.6 to 23.8 • 3.0~tg/dl (p < 0.0001) [374 • 45 to 680 • 85 nmol/L], respectively. Dexamethasone suppressed almost completely the stimulatory effect of CT ]3-endorphin rose from 4.9 • 0.12 to 6.3 • 1.3pmol/L (n.s.), ACTH from 38.6 • 5.1 to 42.6 • 6.2pg/ml (n.s.) (from 8.5 -4- 1.1 to 9.4 • 0.9pmol/L) and cortisol from 0.88• to 0.88• (n.s.) (from 25.1 • to 25.0 4- 5.1 nmol/L). [3-endorphin and cortisol rose significantly after 50 and 25 U CT but less than after 100 U CT. 50 U CT increased the ]3-enorphin and cortisol levels from 4.8 • 0.49 to 7.98 • 0.4pmol/L (p < 0.05)and from 10.46 • 1.48 to 16.4 • 3.3/ dl (p < 0.05) (from 299 • 42 to 468 • 95 nmol/L), respectively. 25 U CT increased the ]3-endorphin and cortisol levels from 4.6 • 0.58 to 5.9 • 0.88pmol/L (p < 0.05) and from 10.90 • 1.00 to 15.35 • 1.8~tg/dl (p < 0.05) (from 311 • 28 to 438 • 51 nmol/L). Dexamethasone is known to inhibit the hypothalamic-pituitary-adrenal axis.
126
Z. Oberman et al.
The inhibition of the CT stimulative effect on [3-endorphin, A C T H , and cortisol observed in this study enforces our idea that CT exerts this effect by stimulating the hypothalamic-pituitary-adrenal axis.
Keywords: Calcitonin, dexamethasone, beta-endorphin, A C T H , hypothalamus. Introduction Most of the studies concerning calcitonin (CT) function have focused on the effect of CT on calcium homeostasis (Munson, 1976). However recent reports have indicated a broader range of CT action namely on the C N S central nervous system (Freed et al., 1979; MacIntyre and Stevenson, 1988; Morley et al., 1981). It was also shown that CT exerts stimulatory or inhibitory action on the secretion of m a n y a d e n o h y p o p h y s e a l h o r m o n e s in basal condition or in response to appropriate stimuli (Cantalamessa etal., 1978; Pecile et al., 1981). In a previous study (Laurian etal., 1986), we observed that CT induces a concurrent increase of [3-endorphin, A C T H , and cortisol secretion. A similiar effect was recently reported by others (Ceda et al., 1989). A n increase of A C T H levels after i.v. or intra cerebroventricular injection of CT has also been observed in rats (Rapisarda et al., 1984). Since A C T H and [3-endorphin derive from a c o m m o n pituitary precursor P O M C (proopiomelanocortin) (Naganishi etal., 1979) we assumed that CT m a y play a role as a m o d u l a t o r of the anterior pituitary function. The present investigation was initiated to get further i n f o r m a t i o n about the h y p o t h a l a m i c pituitary adrenal involvement in this response. We examined the influence of dexamethasone on the CT induced [3-endorphin, A C T H , and cortisol secretion.
Material and methods Six healthy women aged 50-65 were investigated. Informed consent was obtained from all of them. All the subjects in fasting condition received 100 IU Salmon Calcitonin (Sandoz) i.v. at 8.0AM (0 time). Blood samples were collected at - 30, 0, 30, 60, 90, and 120rains. via an indwelling i.v. canula kept open with a diluted 10% solution of heparin; plasma [3endorphin, ACTH, and cortisol were estimated. The same patients were investigated a second time at the same intervals when 1mg Dexamethasone was administered per os at 11.0 PM the previous night and 100 U CT i.v. at 8.0 am next morning The response of [3-endorphin and cortisol to 50 U and 25 U CT were also studied. Plasma [3-endorphin and cortisol were estimated, using commercial radioimmunoassay kits. The kits for [3-endorphin and ACTH were supplied by INCSTAR Corporation, Minnesota, U.S.A. The procedure for [3-endorphin estimation utilizes a preliminary extraction of J3-endorphin by specific affinity particles made by coupling [3-endorphin to sepharose followed by elution, and neutralization and a 17-hours radioimmunoassay procedure. The antibody to [3-endorphin cross reacts 100% with human J3-endorphin (Des-Tyr) human 13endorphin (2-Me-Ala) and N acetyl [3-endorphin and exhibits a 5% cross reactivity with J3 lipotropin. The kit for ACTH was not sensitive for levels less than approximately 40 pg/ml., and the kit' for [3-endorphin was not sensitive for levels less than approximately 5 pmol/1).
Dexamethasone and calcitonin on ~-endorphin, ACTH and cortisol
127
The estimation of cortisol was done with the Diagnostic Product Corporation kit. The statistical evaluation was done with analysis of variance and covariance and repeated measurements and paired Student's t-test. Results A significant increase of ]3-endorphin and cortisol was observed after 100, 50, 25 U CT although the increase was higher after 100 U. The 13-endorphin (pmol/1) levels increased from 5.6 4- 0.17 to 16.75 4- 1.8, (p < 0.0001), from 4.8 4- 0.49 to 7.98 4- 0.4 (p < 0.05), and from 4.6 4- 0.58 to 5.9 4- 0.88 (p < 0.05) respectively. The cortisol (Ixg/dl) levels increased (mean 4- S.E.) from 10.58 4- 1.4 (p < 0.0001) (from 302 + 40 to 559 4- 60nmol/L), from 10.46 4- 1.48 to 16.4 4- 3.3 (p < 0.05) (from 298 4- 43 to 468 4- 94nmol/L), and from 10.9 4- 1.0 to 15.35 4- 1.8 (p < 0.05) respectively (from 311 4- 28 to 438 4- 51 nmol/L). A C T H levels (gg/ml) increased after 100U CT from 39.6 4- 6.0 to 88.0 4- 3.1 (p < 0.0001) (from 8.7 4- 1.3 to 19.4 4- 0.68 pmol/L). Marked increase of all parameters with time (30-60 min after CT administration) was highly significant (p < 0.0001). A significant difference in the increase of the two parameters (f3-endorphin and cortisol) was observed between 100U CT and 5 0 U CT (p < 0.05) and between 100 U CT and 25 U CT (p < 0.05). N o significant difference in the increase of the two parameters (]3-endorphin and cortisol) was observed between 50 U CT and 25 U CT administration. After dexamethasone administration, the response of 13-endorphin, ACTH, and cortisol was almost completely inhibited. ]3-endorphin rose from 4.9 -4- 0.12
20 18 84 .-A
16-
~c~14~12~ L~ 10 -
c~.
--"O'--
8
-30
Calcitonin +
Dexamethasone
6
41
Calcitonin
.......
.
, 0
.
, 30
.
, 60
.
, 90
.
I , 120
Time (min)
F i g . 1. L e v e l s o f 1 3 - e n d o r p h i n ( p m o l / L )
a f t e r 100 U c a l c i t o n i n , a n d a f t e r 100 U o f c a l c i t o n i n
preceded by 1 mg dexamethasone. Area under the curve -- 51.55 (calcitonin). Area under the curve = 34.1 (calcitonin + dexamethasone)
128
Z. Oberman et al. 100 90
8O
~- 70 1I-o,
