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Serotonin and the menopausal flush
SEROTONIN
AND
THE
MENOPAUSAL ROBERT
(Fro? the University)
Department
of
Pharmacology,
A. College
FLUSH* MUNSICK,
of
Physicians
M.D.,** and
NEW
Surgeons,
YORK,
N. Y. Columbia
INCE GlaeveckeP suggestion in 1889 that the hot flush of the menopause S is probably due to an imbalance of the autonomic nervous system, there has been considerable controversy concerninBe the actual mechanism of the flush and the etiology of the autonomic imbalance if it exists. A review of the literature indicates that an adequate experimentally provecl explanation of the menopausal vasomotor phenomena has not as yet been given. 111 view of the striking flushes sun in patients wit,h the malignant carcinoid syndrome and the absence of a study of serotonin metabolism in menopausal womrn as a group, it seemed worth while to investigate the possibility that serotonin, 5-hydroxytryptamine (5HT), might be the mediator of the hot flush. The reader is referred to the articles of Sjocrdsma and associatrsi, b 8 concerning aspects of the malignant carcinoid syndrome, and to the reviews of Page5 and Erspamer2 regarding the physiologic and pharmacologic actions of 5HT and its metabolites. Thorson has described in detail the hetnodyna,mic changes which occur in the carcinoid flush. Since it, has been demonstrated that 5hydroxyindoleacctic acid (5HIAA) is one of the principal metabolites of 5-HT,7 and because the excretion of 5HIAA roughly parallels the severity and frequency of flushes in patients with the malignant carcinoi(1 syndrome,’ the 24 hour urinary (lxcretion of 5HIAA was t,he criterion used to test the possibility of srrotonin mediation of flushcls in the menopause. &ccbnt reports of large quantities of 5-IiT in bananas11 and of increased 5-HIAA (Lxcretion after ingestion of bananas’. ” prompted the author t,o confirJJ1 these fin(~ings. Recovclry and stability experiments and the excretion of 5-JHAA in one paGc>nt with the malignant earGnoid syndrome will also 1~ r(Jported. Materials
and Methods
Assays for urinary 5-HIAA were performed 1)~ thp method of Udenfriend and associates.l” Pure 5HlAA was used as a standard in all experiments. All determinations were performed in cluplicat,c.
SEROTONIN
AND
MENOPAUSAL
FLUSH
149
These investigators stated that losses during t,hc extraction are due iu part to salting out by urinary solutes of some 5-HIAA into chloroform. The author agrees on the basis of three findings. The first is a 44 per cent loss of 5-HIAA from aqueous solution when an excess of sodium chloride was added prior to the chloroform extraction, compared to a 100 per cent recovery in the presence of the same amount of sodium chloride but with omission of the chloroform extraction. The s~ond is thp finding of 89, 105, 104, and 110 per cent recoveries from urine which was diluted 1 part with 4 parts water. The third confirmatory finding is t,h(> (xomparison of 24 hour urine volume, including the amount of 2N HCl diluent added, with milligrams of 5-HL4A per 24 hours. In 19 sepa,ratc urines of’ I 1 norma,l in(lividuals, the correlation POefficient was 0.7, P = < 0.01 (Fig. 1). Gcncrally, then, the greater the 24 hour urine VO~UIIIC, the lower wilt be the solute concentration, and the greater will be the recovery. The employment of a mean recovery factor of 100/74 will give accurate mean values for LHIAA excretion, but for individual urines the figure is meaningless! and
.
l
l .
# .*
. .
. . . .
a 2 IA
. 2
.
.
I
J---n-71 07
I.1
I.5
LITERS
Fig.
I.-Correlation
of
urine
.
URINE
volume
/ 24
with
HOURS
5-HIAA
recovery
from
urine.
recovery experiments should bc performed on each urine specimen if accurate quantitative results are desired. Despite this criticism, all results expressed 100 as milligrams of 5-HIAA per 24 hours have been corrected by the recov74 cry factor, unless otherwise stated. B. BaWty.-In a single experiment, the urine of G. M. was assayed on the day of collection and again 3 and 9 days later. The urine was collected and Values for micrograms of 5-HIAA per 6 ml. stored as previously described. were respectively 17.2, 18.2, and 20.3; in terms of optical density, the figures The discrepancies between optical were 0.141, 0.146, and 0.141, respectively. density and micrograms per 6 ml. are probably due to small errors in weighing of the 5-HIAA standard and unavoidable differences in extraction of standard and of unknown. L’. BanaTta IngestioTL.--The effect of banana ingestion 011 5-HIAA excretion on the first 2 control days, 5-IHAA excretion was 5.8 and 5.9 was as follows: mg. per 24 hours, respectively; during the 24 hour period in which 2 bananas were eaten, the excretion rose to 12.0 mg. per 24 hours; the excretion ou the following 2 control days was 5.9 and 5.5 mg. per 24 hours, respectively. If
150
Volume
number
78
1
SEROTONIN
AND
MENOPAUSAL
151
FLUSH
after e,strogen inhibition of flushes, arc strong evidence against the implication of serotonin in menopausal vasomotor phenomena. Just as important to the clinician with whom the responsibility lies for the differentiation of the menopause from the malignant carcinoid syndrome, an increase in 5-HlAA excretion above normal is now known not to occur in the menopausal syndrome. Summary
and Conclusions
1. 5-Hydroxyincloleacetic acid (5-HIAA) excretion is not increased in the menopausal syndrome. 2. In the opinion of the author, the rcportcd findings arc strong cvidencc against any part played by scrotonin in the menopausal flush. :l. The effects of banana feeding on 5-HIAA excretion arc confirmed, Information relevant to the duration of elevated 5-HlAA cxcrction after cating bananas has been rcportcd. 4. some significant findings regarding the recovery of 5-HIAA from urine arc reported and discussed. The author wishes to express his appreciation to Prof. H. B. van Dyke for his kind criticism and suggestions, to the house staff and attenlling staff of the Sloane Hospital for Women for their cooperation in obtaining the menopausal patients and to these patients whose personal interest and cooperation were so gratifying. sample
Appreciation of pure
is also expressed 5hy~lroxyindoleacetic
to 1). acid.
A.
Shepherd
of
the
Upjohn
Company
for
the
References 1. Anflerson, ., Erspamer, i: Glaevecke: 4. Macfarlane,
J. A., Ziegler, M. R., antI Doetlen, I).: Science 127: 236, 195% X7. : Pharmacol. Rev. 6: 425, 1!>54. Arch. Gyn%k. 35: 1, lS89. P. S., Dalgliesh, C. E., Dutton, R. W., Lennox, B., Nyhus, L. M., Smith, A. N.: Scottish M. *J. 1: 148, l$JX. 5. Page, I. H.: Physiol. Rev. 38: 2X, 1958. 6. Scandrett, F. .J.: Lancet 1: 967, 1956. A., Weissbach, H., and V~lenfriend, S.: 7. Sjoedsma, Am. J. Med. 20: 520, 1956. A., Weisshach, H., Terry, 8. Sjoertlsma, L. L., and Udenfriend, S.: A4m. ,J. iWe(l. .5, 1957. Thorson, ,%. H.: Am. Heart J. 52: 444, 1956. 1:: Udenfriend, S., Titus, E., and Weissbach, H.: J. Biol. Chem. 216: 499, 1955. T. P., Sjoerdsma, A., Creveling, cl. R., Weissbach, H., and Udenfrientl, 11. Waalkes, Science 127: 64s. 1958.
an11
23:
S.:
AND
THE
MENOPAUSAL ROBERT
(Fro? the University)
Department
of
Pharmacology,
A. College
FLUSH* MUNSICK,
of
Physicians
M.D.,** and
NEW
Surgeons,
YORK,
N. Y. Columbia
INCE GlaeveckeP suggestion in 1889 that the hot flush of the menopause S is probably due to an imbalance of the autonomic nervous system, there has been considerable controversy concerninBe the actual mechanism of the flush and the etiology of the autonomic imbalance if it exists. A review of the literature indicates that an adequate experimentally provecl explanation of the menopausal vasomotor phenomena has not as yet been given. 111 view of the striking flushes sun in patients wit,h the malignant carcinoid syndrome and the absence of a study of serotonin metabolism in menopausal womrn as a group, it seemed worth while to investigate the possibility that serotonin, 5-hydroxytryptamine (5HT), might be the mediator of the hot flush. The reader is referred to the articles of Sjocrdsma and associatrsi, b 8 concerning aspects of the malignant carcinoid syndrome, and to the reviews of Page5 and Erspamer2 regarding the physiologic and pharmacologic actions of 5HT and its metabolites. Thorson has described in detail the hetnodyna,mic changes which occur in the carcinoid flush. Since it, has been demonstrated that 5hydroxyindoleacctic acid (5HIAA) is one of the principal metabolites of 5-HT,7 and because the excretion of 5HIAA roughly parallels the severity and frequency of flushes in patients with the malignant carcinoi(1 syndrome,’ the 24 hour urinary (lxcretion of 5HIAA was t,he criterion used to test the possibility of srrotonin mediation of flushcls in the menopause. &ccbnt reports of large quantities of 5-IiT in bananas11 and of increased 5-HIAA (Lxcretion after ingestion of bananas’. ” prompted the author t,o confirJJ1 these fin(~ings. Recovclry and stability experiments and the excretion of 5-JHAA in one paGc>nt with the malignant earGnoid syndrome will also 1~ r(Jported. Materials
and Methods
Assays for urinary 5-HIAA were performed 1)~ thp method of Udenfriend and associates.l” Pure 5HlAA was used as a standard in all experiments. All determinations were performed in cluplicat,c.
SEROTONIN
AND
MENOPAUSAL
FLUSH
149
These investigators stated that losses during t,hc extraction are due iu part to salting out by urinary solutes of some 5-HIAA into chloroform. The author agrees on the basis of three findings. The first is a 44 per cent loss of 5-HIAA from aqueous solution when an excess of sodium chloride was added prior to the chloroform extraction, compared to a 100 per cent recovery in the presence of the same amount of sodium chloride but with omission of the chloroform extraction. The s~ond is thp finding of 89, 105, 104, and 110 per cent recoveries from urine which was diluted 1 part with 4 parts water. The third confirmatory finding is t,h(> (xomparison of 24 hour urine volume, including the amount of 2N HCl diluent added, with milligrams of 5-HL4A per 24 hours. In 19 sepa,ratc urines of’ I 1 norma,l in(lividuals, the correlation POefficient was 0.7, P = < 0.01 (Fig. 1). Gcncrally, then, the greater the 24 hour urine VO~UIIIC, the lower wilt be the solute concentration, and the greater will be the recovery. The employment of a mean recovery factor of 100/74 will give accurate mean values for LHIAA excretion, but for individual urines the figure is meaningless! and
.
l
l .
# .*
. .
. . . .
a 2 IA
. 2
.
.
I
J---n-71 07
I.1
I.5
LITERS
Fig.
I.-Correlation
of
urine
.
URINE
volume
/ 24
with
HOURS
5-HIAA
recovery
from
urine.
recovery experiments should bc performed on each urine specimen if accurate quantitative results are desired. Despite this criticism, all results expressed 100 as milligrams of 5-HIAA per 24 hours have been corrected by the recov74 cry factor, unless otherwise stated. B. BaWty.-In a single experiment, the urine of G. M. was assayed on the day of collection and again 3 and 9 days later. The urine was collected and Values for micrograms of 5-HIAA per 6 ml. stored as previously described. were respectively 17.2, 18.2, and 20.3; in terms of optical density, the figures The discrepancies between optical were 0.141, 0.146, and 0.141, respectively. density and micrograms per 6 ml. are probably due to small errors in weighing of the 5-HIAA standard and unavoidable differences in extraction of standard and of unknown. L’. BanaTta IngestioTL.--The effect of banana ingestion 011 5-HIAA excretion on the first 2 control days, 5-IHAA excretion was 5.8 and 5.9 was as follows: mg. per 24 hours, respectively; during the 24 hour period in which 2 bananas were eaten, the excretion rose to 12.0 mg. per 24 hours; the excretion ou the following 2 control days was 5.9 and 5.5 mg. per 24 hours, respectively. If
150
Volume
number
78
1
SEROTONIN
AND
MENOPAUSAL
151
FLUSH
after e,strogen inhibition of flushes, arc strong evidence against the implication of serotonin in menopausal vasomotor phenomena. Just as important to the clinician with whom the responsibility lies for the differentiation of the menopause from the malignant carcinoid syndrome, an increase in 5-HlAA excretion above normal is now known not to occur in the menopausal syndrome. Summary
and Conclusions
1. 5-Hydroxyincloleacetic acid (5-HIAA) excretion is not increased in the menopausal syndrome. 2. In the opinion of the author, the rcportcd findings arc strong cvidencc against any part played by scrotonin in the menopausal flush. :l. The effects of banana feeding on 5-HIAA excretion arc confirmed, Information relevant to the duration of elevated 5-HlAA cxcrction after cating bananas has been rcportcd. 4. some significant findings regarding the recovery of 5-HIAA from urine arc reported and discussed. The author wishes to express his appreciation to Prof. H. B. van Dyke for his kind criticism and suggestions, to the house staff and attenlling staff of the Sloane Hospital for Women for their cooperation in obtaining the menopausal patients and to these patients whose personal interest and cooperation were so gratifying. sample
Appreciation of pure
is also expressed 5hy~lroxyindoleacetic
to 1). acid.
A.
Shepherd
of
the
Upjohn
Company
for
the
References 1. Anflerson, ., Erspamer, i: Glaevecke: 4. Macfarlane,
J. A., Ziegler, M. R., antI Doetlen, I).: Science 127: 236, 195% X7. : Pharmacol. Rev. 6: 425, 1!>54. Arch. Gyn%k. 35: 1, lS89. P. S., Dalgliesh, C. E., Dutton, R. W., Lennox, B., Nyhus, L. M., Smith, A. N.: Scottish M. *J. 1: 148, l$JX. 5. Page, I. H.: Physiol. Rev. 38: 2X, 1958. 6. Scandrett, F. .J.: Lancet 1: 967, 1956. A., Weissbach, H., and V~lenfriend, S.: 7. Sjoedsma, Am. J. Med. 20: 520, 1956. A., Weisshach, H., Terry, 8. Sjoertlsma, L. L., and Udenfriend, S.: A4m. ,J. iWe(l. .5, 1957. Thorson, ,%. H.: Am. Heart J. 52: 444, 1956. 1:: Udenfriend, S., Titus, E., and Weissbach, H.: J. Biol. Chem. 216: 499, 1955. T. P., Sjoerdsma, A., Creveling, cl. R., Weissbach, H., and Udenfrientl, 11. Waalkes, Science 127: 64s. 1958.
an11
23:
S.: