Original Paper Gynecol Obstet Invest 1992;33:98-101
Ron Teppera Joseph Pardo h Jardena Ovadiah Yoram Beytha Department of Obstetrics and Gynecology ‘A’, Sapir Medical Center, Kfar Saba; Department of Obstetrics and Gynecology, Beilinson Medical Center, Petach Tikva, Israel
Key Words Calcitonin (3-Endorphins Hot flush
Menopausal Hot Flushes, Plasma Calcitonin and Beta-Endorphin A Preliminary Report
Abstract
The association between plasma calcitonin and (3-endorphin has been shown in various studies with analgesic and thermoregulatory effects. In the present study, we sought a similar association between those chemicals and physiolog ical menopausal hot flush. Plasma calcitonin and (3-endorphin levels were measured in 5 women in physiologic menopause who suffered from frequent episodes of hot flushes. An increase in plasma calcitonin levels was noted dur ing the hot flushes, although it was not significant. In contrast, plasma (3endorphin levels fell significantly at onset of the hot flush, as compared to their levels 5-20 min earlier (p < 0.005), and rose 5-15 min following the hot flush episode.
Material and Methods
Introduction
Five normal women, aged between 50 and 56 years (mean = 54)
Received: April 23,1991 Accepted: August 6. 1991
Ron Tepper. MD Department of Gynecology and Obstetrics ‘A* Sapir Medical Center Kfar Saba 44281 (Israel)
€> 1992 S. Kargcr AG, Basel 0378-7346/92/0322-0098 $2.75/0
Downloaded by: Univ. of California Santa Barbara 128.111.121.42 - 3/5/2018 9:04:21 PM
Calcitonin plays a role in the regulation of calcium and and complaining of hot Hushes, were randomly selected from the phosphate metabolism. In addition to its main physio menopausal outpatient clinic of the Department of Obstetrics and logic effect in lowering serum calcium levels, calcitonin Gynecology. The patients were healthy and had been in physiologic has analgetic effects that are independent of its bone menopause for more than 1 year. The percent ideal weight of a sub action [1,2]. The analgetic effects that have been demon ject was calculated by dividing her actual weight by her ideal weight (obtained from the Metropolitan Life insurance table) and multi strated clinically in patients with bone metastases after plied by 100. None of the patients smoked, consumed alcohol or had injection of calcitonin by the subarachnoid route, are taken any medications during the 6 months preceding the study. associated with an increase in the secretion of (3-endor Informed written consent was obtained from all volunteers and phins [2], Previous studies [3-7] have demonstrated that the study was approved by the local ethical committee. Subjects were (3-endorphin levels change significantly at the beginning hospitalized at the clinical research center on the days of the study and put on an unrestricted diet, except for caffeine-containing sub of a hot flush. In view of this sequence of events, this stances. The room temperature was maintained at 20-23 °C, and the study was designed to measure plasma calcitonin and 13- study always began between 8.00 and 9.00 PM. All the women were seated throughout the study. An indwelling antecubital intravenous endorphin levels before and during hot flushes.
Table 1. Percent of change in serum P-endorphin and calcitonin levels at the onset of a hot flush (time 0) and 5, 10 and 15 min later compared to plasma levels before a hot flush (100%) P-Endorphin
Calcitonin
mean
± SEM
mean
± SEM
Onset of flush
(-) 37.00
3.3
(+) 2.71
1.75
5 min later
(-) 48.50*
8.51
(+) 8.42
3.10
10 min later
(-) 41.70**
4.35
(+) 13.28**** 4.20
15 min later
(-) 19.42*** 5.14
(+) 11.28
3.87
* p = 0.014, 5 vs. 15 min; * * p = 0 .001, 10 vs. 15 min; * * * p = 0 .003. 15 min vs. ‘onset of hot flush’; **** p = 0 .063, 10 min vs. ‘on set of hot flush’ (not significant). (-), (+) = Direction of change.
Results
Nine hot flushes were monitored in 5 subjects. Table 1 represents plasma P-endorphin levels (pg/ml) during and after the hot flush (mean ± SEM) and plasma calcitonin levels as a percent of change in plasma levels before a hot flush. p-Endorphin levels at point zero (the beginning of the hot flush) were significantly lower when compared to the pre-hot flush basal plasma P-endorphin levels, and sig
Fig. 1. Percent of change in P-endorphin (•) and calcitonin ( a ) plasma levels as a function of time, in relation to levels before the hot flush.
nificantly higher levels were recorded 15 min later. The average of basal plasma P-endorphin concentrations, cal culated from 24 blood samples collected from the 5 sub jects, is 5.3 ± 0.5 pg/ml. Thirty-five minutes after a hot flush, plasma P-endorphin levels almost reached basal values. The tendency towards elevated plasma calcitonin levels at onset of the hot flushes, and 5, 10 and 15 min later, relative to plasma calcitonin levels before the hot flush, was not significant. Figure 1 represents the percent of change in p-endorphin and calcitonin plasma levels as a function of time in relation to levels before the hot flush. Because the timing of the hot flush was unpredictable, a blood specimen before the objective appearance of the hot flush was taken 5-20 min before its start. Discussion
P-Endorphins, derived from pro-opiomelancortin and P-lipotropin precursor molecule, are the most potent opioid peptides. An opioid-dependent central-mecha nism influence on the pathogenesis of hot flushes has been suggested by Leslie [8]. He has also demonstrated that a metenkephalin analog (FK33.824) is capable of inducing post-menopausal flushes, and opiate antagonists, such as
99
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catheter (flushed with heparinized saline) was inserted 30 min before blood sampling. Blood samples of 7 ml [with ethylene diamine tetraacetic acid (EDTA)] were withdrawn at 20-min intervals until the beginning of a hot flush. Finger temperature was recorded for 4 h over the dorsal surface of the proximal phalanx of the third finger of the nondominant hand using a YSI banjo thermister connected to the recording paper monitor. A hot flush was defined as an elevation of 0.5 °C or more in finger temperature. A blood sample was taken within 1 min of the temperature increase, then 5, 10, and 15 min later. Subsequently, samples were drawn every 20 min until the next hot flush. The study continued during and following the second hot flush as described above. The specimens were centrifuged imme diately at 4 °C at 3.000 rpm for 10 min, and plasma was separated and stored at - 20 ° C until assayed. All plasma samples for each sub ject were measured in a single assay (plasma P-endorphin and plasma calcitonin) by radioimmunoassay (Immune Nuclear Corp., Inc., Stillwater. Minn., USA). Results were expressed by the mean ± SEM for P-endorphin lev els, and percent change was calculated for calcitonin measurement, either preceding or following the temperature rise by using the hor mone base levels before the onset of hot flushes as a reference point. The relationship of each sample to the onset of the hot flushes was calculated and statistically analyzed by paired Student’s t test.
naloxone, are capable of reducing flushing [6]. Tepper et al. [3] found significantly lower levels of plasma (3-endor phin at the onset of hot flushes and a significant rise in plasma [3-endorphin levels a few minutes later. Calcito nin, the hypocalcemizing hormone, is a primary peptide hormone produced by the parafollicular cells of the thy roid gland. It was evident that calcitonin extended a posi tive effect on bone pain [9-12]. A modulatory role of cal citonin on the hypothalamo-pituitary-adrenal axis was suggested by Lauria et al. [13]. Further, calcitonin may induce an analgetic effect by acting as a neurotransmitter [14] by inhibiting prostaglandin and thromboxane syn thesis [15] or by affecting the (3-endorphin-releasing mechanism [16]. These observations gave rise to the hypothesis that cal citonin could have a direct analgetic effect. The localiza tion of immunoreactive calcitonin in the human pituitary gland and in the cerebrospinal fluid [17, 18] may be related to the neuroendocrine and analgetic effects of this hormone. The presence of binding sites of calcitonin in the human brain support this hypothesis. It has been sug gested that the analgetic effect of calcitonin [1,2, 19] may involve the endogenous P-endorphin system. Gennari et al. [19] have shown a rapid increase in circulatory (3endorphin levels in man after intravenous infusion of sal mon calcitonin [2], ensuing in an analgetic effect, which can be reversed by injecting naloxone [20]. The evidence for this is contradictory. Braga [ 14] failed to demonstrate any significant antagonism by a naloxone. p-Endorphin in the hypothalamus functions as a neurotransmitter pep tide in the central thermoregulatory and analgetic path
ways [21]. Camargo [22] reported that synthetic human calcitonin, which is effective in patients who fail to respond to salmon calcitonin, causes flushing in as many as 20% of treated patients. The present study was undertaken to investigate the interaction between calcitonin and P-endorphin in the induction of hot flushes. A significant change in plasma p-endorphin levels during hot flushes is shown to be asso ciated with a slight rise in plasma calcitonin levels when hormonal levels were evaluated before the onset of a hot flush and during the first 15 min thereof. The changes in the P-endorphin level during a hot flush, as demonstrated in this study with menopausal women, might explain a possible involvement of p-endorphin in the hypothalamic thermoregulatory processes. According to the results of this study, the internal secretion of calcitonin and [3endorphin is independent. These hormones most proba bly are not dependent upon one another in the process of menopausal hot flush. There is no evidence to suggest a possible role of calcitonin secretion during hot flush epi sodes.
References
100
5 Aleem FA, McIntosh TK: Menopausal syn drome: Plasma levels of p-EP in post-meno pausal women measured by specific radioim munoassay. Maturitas 1985;7:329-334. 6 Lightman SL, Jacobs HS, Maguire AK, McGarrick G, Jeffcoate SL: Climacteric flush ing: Clinical and endocrine response to infu sion of naloxone. Br J Obstet Gynaecol 1981 ; 88:919-924. 7 Pettibone DJ, Mueller GP: Alpha-adrenergic stimulation by clinodine increases plasma con centrations in immunoreactive P-endorphin in rats. Endocrinology 1981;109:798-802. 8 Leslie RDG, Pyke DA, Stubbe WA: Sensitivity to enkephalin as a case of non-insulin-depen dent diabetes. Lancet 1979;i:341—343.
T epper/Pardo/Ovadia/Beyth
9
Bijvoet OLM, Vab der Sluys Veer J, Jansen AP: Effects of calcitonin on patients with Paget’s disease, thyrotoxicosis or hypocalcemia. Lan cet 1968;i:876—881. 10 Kanis JA, Horn DB, Scott RDM, Strong JA: Treatment of Paget's disease o f bone with syn thetic salmon calcitonin. Br Med J 1974:3: 727-731. 11 Martin TJ, Jerums G, Melik RS, Xipell JM, Arnott R: Clinical biochemical and histological observations on the effect of porcine calcitonin in Paget’s disease of bone. Aust NZ J Med 1977,7:36-43. 12 DeRose J, Singer FR, Avramides A, Flores A, Dziadin R, Baker RK, Wallach S: Response of Paget's disease to porcine and salmon calcito nins: Effects of long-term treatment. Am J Med 1974;56:858-866.
Menopause, Hot Flush, Calcitonin and ß-Endorphin
Downloaded by: Univ. of California Santa Barbara 128.111.121.42 - 3/5/2018 9:04:21 PM
1 Weiss L, Gilbert HA (eds): Bone Metastasis. Boston, Hall Medical Publications, 1981, p 348. 2 Fraioli F, Fabbri A, Gnessi L, Moretti C, San toro C, Felici M: Subarachnoid injection of sal mon calcitonin inducer analgesia in man. Eur J Pharmacol 1982;78:381-382. 3 Tepper R, Neri A, Kaufman H, Schoenfeld A, Ovadia J: Menopausal hot flashes and plasma P-endorphins. Obstet Gynecol 1987;70:150— 152. 4 Genazzoni AR, Petraglia F, Facchinetti F, Facchini V, Volpe A, Alessandrini G: Increase of proopiomelanocortin-related peptides during subjective menopausal flushes. Am J Obstet Gynecol 1984;149:775-779.
serotonergic inhibition of calcitonin-induced increase of (3-endorphin, ACTH and cortisol secretion. J Neurol Transm 1988;73/3:167— 176. 14 Braga PC. Ferri S, Santagostino A, Olginti VR, Pecile A: Lack of opiate receptor involvement in centrally induced calcitonin analgesia. Life Sci 1978;22:971-978. 15 Cesarani F, Columbo M, Olgiati VR, Pecile A: Calcitonin and prostaglandin system. Life Sci 1979;25:1851-1856.
16 Gennari C. Montagnani M, Francini G, Orlandini G, Nami R, Maioli E: II razionale dell’impiego della calcitonina nelle osteolisis tumorali; in Canigga A (ed): Calcitonina e Osteolisi Neoplastiche. Siena, Université degli studi. 1980: 182-187. 17 Cooper CW, Peng TC, Obie JF, Garner SC: Calcitonin-like immunoreactivity in rat and human pituitary gland histochemical, in vitro and in vivo slides. Endocrinology 1980; 107: 98-107. 18 Palvinac DM, Lenhard LW, Parthemore JG, Deftor LJ: Immunoreactive calcitonin in hu man cerebrospinal fluid. J Clin Endocr Metab 1980:50:717-720.
19 Gennari C: Calcitonin and bone métastasés of cancer; in Pecile A (ed): Calcitonin 1980. Am sterdam, Excerpta Medica, 1981, p 277. 20 Bates RFL, Buckley GA, Eglen RM. Strettle RJ: The interaction of naloxone and calcitonin in the production of analgesia in the mouse. London, Proc Br Pharmacol Soc, 1981, p 279. 21 Blatteis CM: The newer putative central neurotransmittors: Roles in thermoregulation. Fed Proc 1981:40:2735-2740. 22 Camargo AC, Kolb OF: Endocrine disorders; in Schroeder AS, Krupp AM, Tierney JR (eds): Current Medical Diagnosis and Treatment. Norwalk Appleton-Lange, 1988, p 722.
101
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13 Laurion L, Oberman Z, Hoerer E, GrafE: Anti-
Ron Teppera Joseph Pardo h Jardena Ovadiah Yoram Beytha Department of Obstetrics and Gynecology ‘A’, Sapir Medical Center, Kfar Saba; Department of Obstetrics and Gynecology, Beilinson Medical Center, Petach Tikva, Israel
Key Words Calcitonin (3-Endorphins Hot flush
Menopausal Hot Flushes, Plasma Calcitonin and Beta-Endorphin A Preliminary Report
Abstract
The association between plasma calcitonin and (3-endorphin has been shown in various studies with analgesic and thermoregulatory effects. In the present study, we sought a similar association between those chemicals and physiolog ical menopausal hot flush. Plasma calcitonin and (3-endorphin levels were measured in 5 women in physiologic menopause who suffered from frequent episodes of hot flushes. An increase in plasma calcitonin levels was noted dur ing the hot flushes, although it was not significant. In contrast, plasma (3endorphin levels fell significantly at onset of the hot flush, as compared to their levels 5-20 min earlier (p < 0.005), and rose 5-15 min following the hot flush episode.
Material and Methods
Introduction
Five normal women, aged between 50 and 56 years (mean = 54)
Received: April 23,1991 Accepted: August 6. 1991
Ron Tepper. MD Department of Gynecology and Obstetrics ‘A* Sapir Medical Center Kfar Saba 44281 (Israel)
€> 1992 S. Kargcr AG, Basel 0378-7346/92/0322-0098 $2.75/0
Downloaded by: Univ. of California Santa Barbara 128.111.121.42 - 3/5/2018 9:04:21 PM
Calcitonin plays a role in the regulation of calcium and and complaining of hot Hushes, were randomly selected from the phosphate metabolism. In addition to its main physio menopausal outpatient clinic of the Department of Obstetrics and logic effect in lowering serum calcium levels, calcitonin Gynecology. The patients were healthy and had been in physiologic has analgetic effects that are independent of its bone menopause for more than 1 year. The percent ideal weight of a sub action [1,2]. The analgetic effects that have been demon ject was calculated by dividing her actual weight by her ideal weight (obtained from the Metropolitan Life insurance table) and multi strated clinically in patients with bone metastases after plied by 100. None of the patients smoked, consumed alcohol or had injection of calcitonin by the subarachnoid route, are taken any medications during the 6 months preceding the study. associated with an increase in the secretion of (3-endor Informed written consent was obtained from all volunteers and phins [2], Previous studies [3-7] have demonstrated that the study was approved by the local ethical committee. Subjects were (3-endorphin levels change significantly at the beginning hospitalized at the clinical research center on the days of the study and put on an unrestricted diet, except for caffeine-containing sub of a hot flush. In view of this sequence of events, this stances. The room temperature was maintained at 20-23 °C, and the study was designed to measure plasma calcitonin and 13- study always began between 8.00 and 9.00 PM. All the women were seated throughout the study. An indwelling antecubital intravenous endorphin levels before and during hot flushes.
Table 1. Percent of change in serum P-endorphin and calcitonin levels at the onset of a hot flush (time 0) and 5, 10 and 15 min later compared to plasma levels before a hot flush (100%) P-Endorphin
Calcitonin
mean
± SEM
mean
± SEM
Onset of flush
(-) 37.00
3.3
(+) 2.71
1.75
5 min later
(-) 48.50*
8.51
(+) 8.42
3.10
10 min later
(-) 41.70**
4.35
(+) 13.28**** 4.20
15 min later
(-) 19.42*** 5.14
(+) 11.28
3.87
* p = 0.014, 5 vs. 15 min; * * p = 0 .001, 10 vs. 15 min; * * * p = 0 .003. 15 min vs. ‘onset of hot flush’; **** p = 0 .063, 10 min vs. ‘on set of hot flush’ (not significant). (-), (+) = Direction of change.
Results
Nine hot flushes were monitored in 5 subjects. Table 1 represents plasma P-endorphin levels (pg/ml) during and after the hot flush (mean ± SEM) and plasma calcitonin levels as a percent of change in plasma levels before a hot flush. p-Endorphin levels at point zero (the beginning of the hot flush) were significantly lower when compared to the pre-hot flush basal plasma P-endorphin levels, and sig
Fig. 1. Percent of change in P-endorphin (•) and calcitonin ( a ) plasma levels as a function of time, in relation to levels before the hot flush.
nificantly higher levels were recorded 15 min later. The average of basal plasma P-endorphin concentrations, cal culated from 24 blood samples collected from the 5 sub jects, is 5.3 ± 0.5 pg/ml. Thirty-five minutes after a hot flush, plasma P-endorphin levels almost reached basal values. The tendency towards elevated plasma calcitonin levels at onset of the hot flushes, and 5, 10 and 15 min later, relative to plasma calcitonin levels before the hot flush, was not significant. Figure 1 represents the percent of change in p-endorphin and calcitonin plasma levels as a function of time in relation to levels before the hot flush. Because the timing of the hot flush was unpredictable, a blood specimen before the objective appearance of the hot flush was taken 5-20 min before its start. Discussion
P-Endorphins, derived from pro-opiomelancortin and P-lipotropin precursor molecule, are the most potent opioid peptides. An opioid-dependent central-mecha nism influence on the pathogenesis of hot flushes has been suggested by Leslie [8]. He has also demonstrated that a metenkephalin analog (FK33.824) is capable of inducing post-menopausal flushes, and opiate antagonists, such as
99
Downloaded by: Univ. of California Santa Barbara 128.111.121.42 - 3/5/2018 9:04:21 PM
catheter (flushed with heparinized saline) was inserted 30 min before blood sampling. Blood samples of 7 ml [with ethylene diamine tetraacetic acid (EDTA)] were withdrawn at 20-min intervals until the beginning of a hot flush. Finger temperature was recorded for 4 h over the dorsal surface of the proximal phalanx of the third finger of the nondominant hand using a YSI banjo thermister connected to the recording paper monitor. A hot flush was defined as an elevation of 0.5 °C or more in finger temperature. A blood sample was taken within 1 min of the temperature increase, then 5, 10, and 15 min later. Subsequently, samples were drawn every 20 min until the next hot flush. The study continued during and following the second hot flush as described above. The specimens were centrifuged imme diately at 4 °C at 3.000 rpm for 10 min, and plasma was separated and stored at - 20 ° C until assayed. All plasma samples for each sub ject were measured in a single assay (plasma P-endorphin and plasma calcitonin) by radioimmunoassay (Immune Nuclear Corp., Inc., Stillwater. Minn., USA). Results were expressed by the mean ± SEM for P-endorphin lev els, and percent change was calculated for calcitonin measurement, either preceding or following the temperature rise by using the hor mone base levels before the onset of hot flushes as a reference point. The relationship of each sample to the onset of the hot flushes was calculated and statistically analyzed by paired Student’s t test.
naloxone, are capable of reducing flushing [6]. Tepper et al. [3] found significantly lower levels of plasma (3-endor phin at the onset of hot flushes and a significant rise in plasma [3-endorphin levels a few minutes later. Calcito nin, the hypocalcemizing hormone, is a primary peptide hormone produced by the parafollicular cells of the thy roid gland. It was evident that calcitonin extended a posi tive effect on bone pain [9-12]. A modulatory role of cal citonin on the hypothalamo-pituitary-adrenal axis was suggested by Lauria et al. [13]. Further, calcitonin may induce an analgetic effect by acting as a neurotransmitter [14] by inhibiting prostaglandin and thromboxane syn thesis [15] or by affecting the (3-endorphin-releasing mechanism [16]. These observations gave rise to the hypothesis that cal citonin could have a direct analgetic effect. The localiza tion of immunoreactive calcitonin in the human pituitary gland and in the cerebrospinal fluid [17, 18] may be related to the neuroendocrine and analgetic effects of this hormone. The presence of binding sites of calcitonin in the human brain support this hypothesis. It has been sug gested that the analgetic effect of calcitonin [1,2, 19] may involve the endogenous P-endorphin system. Gennari et al. [19] have shown a rapid increase in circulatory (3endorphin levels in man after intravenous infusion of sal mon calcitonin [2], ensuing in an analgetic effect, which can be reversed by injecting naloxone [20]. The evidence for this is contradictory. Braga [ 14] failed to demonstrate any significant antagonism by a naloxone. p-Endorphin in the hypothalamus functions as a neurotransmitter pep tide in the central thermoregulatory and analgetic path
ways [21]. Camargo [22] reported that synthetic human calcitonin, which is effective in patients who fail to respond to salmon calcitonin, causes flushing in as many as 20% of treated patients. The present study was undertaken to investigate the interaction between calcitonin and P-endorphin in the induction of hot flushes. A significant change in plasma p-endorphin levels during hot flushes is shown to be asso ciated with a slight rise in plasma calcitonin levels when hormonal levels were evaluated before the onset of a hot flush and during the first 15 min thereof. The changes in the P-endorphin level during a hot flush, as demonstrated in this study with menopausal women, might explain a possible involvement of p-endorphin in the hypothalamic thermoregulatory processes. According to the results of this study, the internal secretion of calcitonin and [3endorphin is independent. These hormones most proba bly are not dependent upon one another in the process of menopausal hot flush. There is no evidence to suggest a possible role of calcitonin secretion during hot flush epi sodes.
References
100
5 Aleem FA, McIntosh TK: Menopausal syn drome: Plasma levels of p-EP in post-meno pausal women measured by specific radioim munoassay. Maturitas 1985;7:329-334. 6 Lightman SL, Jacobs HS, Maguire AK, McGarrick G, Jeffcoate SL: Climacteric flush ing: Clinical and endocrine response to infu sion of naloxone. Br J Obstet Gynaecol 1981 ; 88:919-924. 7 Pettibone DJ, Mueller GP: Alpha-adrenergic stimulation by clinodine increases plasma con centrations in immunoreactive P-endorphin in rats. Endocrinology 1981;109:798-802. 8 Leslie RDG, Pyke DA, Stubbe WA: Sensitivity to enkephalin as a case of non-insulin-depen dent diabetes. Lancet 1979;i:341—343.
T epper/Pardo/Ovadia/Beyth
9
Bijvoet OLM, Vab der Sluys Veer J, Jansen AP: Effects of calcitonin on patients with Paget’s disease, thyrotoxicosis or hypocalcemia. Lan cet 1968;i:876—881. 10 Kanis JA, Horn DB, Scott RDM, Strong JA: Treatment of Paget's disease o f bone with syn thetic salmon calcitonin. Br Med J 1974:3: 727-731. 11 Martin TJ, Jerums G, Melik RS, Xipell JM, Arnott R: Clinical biochemical and histological observations on the effect of porcine calcitonin in Paget’s disease of bone. Aust NZ J Med 1977,7:36-43. 12 DeRose J, Singer FR, Avramides A, Flores A, Dziadin R, Baker RK, Wallach S: Response of Paget's disease to porcine and salmon calcito nins: Effects of long-term treatment. Am J Med 1974;56:858-866.
Menopause, Hot Flush, Calcitonin and ß-Endorphin
Downloaded by: Univ. of California Santa Barbara 128.111.121.42 - 3/5/2018 9:04:21 PM
1 Weiss L, Gilbert HA (eds): Bone Metastasis. Boston, Hall Medical Publications, 1981, p 348. 2 Fraioli F, Fabbri A, Gnessi L, Moretti C, San toro C, Felici M: Subarachnoid injection of sal mon calcitonin inducer analgesia in man. Eur J Pharmacol 1982;78:381-382. 3 Tepper R, Neri A, Kaufman H, Schoenfeld A, Ovadia J: Menopausal hot flashes and plasma P-endorphins. Obstet Gynecol 1987;70:150— 152. 4 Genazzoni AR, Petraglia F, Facchinetti F, Facchini V, Volpe A, Alessandrini G: Increase of proopiomelanocortin-related peptides during subjective menopausal flushes. Am J Obstet Gynecol 1984;149:775-779.
serotonergic inhibition of calcitonin-induced increase of (3-endorphin, ACTH and cortisol secretion. J Neurol Transm 1988;73/3:167— 176. 14 Braga PC. Ferri S, Santagostino A, Olginti VR, Pecile A: Lack of opiate receptor involvement in centrally induced calcitonin analgesia. Life Sci 1978;22:971-978. 15 Cesarani F, Columbo M, Olgiati VR, Pecile A: Calcitonin and prostaglandin system. Life Sci 1979;25:1851-1856.
16 Gennari C. Montagnani M, Francini G, Orlandini G, Nami R, Maioli E: II razionale dell’impiego della calcitonina nelle osteolisis tumorali; in Canigga A (ed): Calcitonina e Osteolisi Neoplastiche. Siena, Université degli studi. 1980: 182-187. 17 Cooper CW, Peng TC, Obie JF, Garner SC: Calcitonin-like immunoreactivity in rat and human pituitary gland histochemical, in vitro and in vivo slides. Endocrinology 1980; 107: 98-107. 18 Palvinac DM, Lenhard LW, Parthemore JG, Deftor LJ: Immunoreactive calcitonin in hu man cerebrospinal fluid. J Clin Endocr Metab 1980:50:717-720.
19 Gennari C: Calcitonin and bone métastasés of cancer; in Pecile A (ed): Calcitonin 1980. Am sterdam, Excerpta Medica, 1981, p 277. 20 Bates RFL, Buckley GA, Eglen RM. Strettle RJ: The interaction of naloxone and calcitonin in the production of analgesia in the mouse. London, Proc Br Pharmacol Soc, 1981, p 279. 21 Blatteis CM: The newer putative central neurotransmittors: Roles in thermoregulation. Fed Proc 1981:40:2735-2740. 22 Camargo AC, Kolb OF: Endocrine disorders; in Schroeder AS, Krupp AM, Tierney JR (eds): Current Medical Diagnosis and Treatment. Norwalk Appleton-Lange, 1988, p 722.
101
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13 Laurion L, Oberman Z, Hoerer E, GrafE: Anti-
