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Serum copper and pregnancy
OBSTETRICS Serum copper and pregnancy STOYAN Sofia,
I.
DOKUMOV,
M.D.,
S.R.O.
Bulgaria
Serum copper was investigated in 300 healthy pregnant women divided into ten groups according to the lunar month of pregnancy and in another 30 women in the first stage of labor. The technique of Callen and Henderson modified by Schmidt was used. From the analysis of the results obtained, it is established that serum copper increases continuously during pregnancy. During the corpus luteum phase of pregnancy, however, this increase is gradual and not very significant. The formation of the placenta is accompanied by a sudden rise in the level of the serum copper. In the second half of pregnancy, serum copper continues to rise gradually and reaches its highest leuel during gestation in the tenth month of pregnancy. The onset of labor brings about a rapid decrease in the content of serum copper. The source of the increased serum copper content during pregnancy and its biologic value are discussed.
importance of the THE BIOLOGIC “trace” elements, especially of iron, copper, zinc, and manganese, can be compared in living organisms only with that of the hormones, vitamins, and ferments. In spite of this, however, their exact mechanism of action as well as their metabolism remains still unsettled and disputable. Copper is of vital necessity and widespread in plants as well as in animals. But while in animals copper deficiency leads to certain well-defined morbid states, in humans it brings about only a decrease in the hemoglobin, in the tissue catalases and cytochrome-oxidases and never a real disease. Copper has a catalytic action on the synthesis of the hemoglobin and in the production of the erythrocytes. Because of its biocatalytic properties, on the cell it also plays an important role in the processes of growing. On the other hand, copper is of
great importance in the defensive reactions of the organism against the different. infections and, particularly, in the production of the specific antibodies. Even the papers of Krebs,‘l Sarata,” and Heilmeyer, Keiderling, and Stiiwe” drew attention to the serum copper content in the pregnant woman. SchindePg and Gorter, Grendel, and Weyers8 as well as Tompsett” disclosed a rapid rise in the serum copper in the third month of pregnancy, a slow increase thereafter, and a peak in the ninth month of pregnancy, followed by a decrease of the serum copper level. But according to Sarata,18 elevated values for serum copper are disclosed only during the first months of gestation. In the second half of pregnancy, however, there is always a return to normal values found in the serum of the nonpregnant woman. The high level of the serum copper described by some investigators8 at the end of the pregnancy is caused, according to Sarata, by the processes of onset of labor. On the other hand, Effkemarm and Rottger” showed that the titer of the
From the Institute for Specialization and Perfection of Physicians (ISUL), Clinic of Endocrinology and Metabolic Diseases.
217
218
Dokumov
cus % 64G Jlc / I JOG 88C 16d
c&J.%
320 WV Jlo JO0
.I 1 I~ I .’ .1.. .I..’.
220 800
140
240
22c
2lO
LOG
200
foe
i**
f60 . I f40 : f29 1: fW' . 80 00
foe f40 I20
0 ‘4 *, . . .
fro 80 lo
40
40
20
w
MA :.
ax
t
Fig. 1. Serum copper levels in the women studied according to the lunar month (ML) and at delivery (D).
Fig. 2. Serum copper levels according to the lunar month of pregnancy and the parity of the women under study. 0, multiparas; 0, primiparas.
serum copper progressively increases in blood serum as pregnancy advances, and it reaches its peak not before the tenth month of pregnancy. Wilken, 23 however, disclosed a rapid increase in the serum copper only in the first half of gestation, and especially during the fourth month, whiIe in the second half of pregnancy the serum copper continues to rise again, but then gradually. According to Hejduk, lo however, the titer of the serum copper increases in the blood continuously from the beginning of pregnancy to the onset of labor. As the literary data are quite various and even contradicting, it is of interest to handle this problem again, particularly in a large series.
normal course of pregnancy with normal blood counts and urine findings were examined. They were divided into ten groups, each one consisting of 30 women, according to the lunar month of pregnancy. Besides them, an additional group of 30 women in the first stage of labor was investigated. The parity of the women under study is best seen in Figs. 2 and 4.
Material Three free of
hundred healthy pregnant any subjective complaints
women in the
Method By repeated examination of the same person, Nielsenl’ disclosed daily fluctuations of the serum copper with morning values lowest and evening values highest. Although this daily fluctuation of the serum copper is rejected by most of the investigators,Bl l3 the blood samples necessary for the examination were always taken at the same timemorning 9:30 A.M. to lo:30 A.M.-from a fasting person through puncture of the
Volume Number
Ill1 ‘2
Serum
copper
and
pregnancy
~‘19
Fig. 3. Mean, maximal, and minimal values of serum copper in the women under study during the course of pregnancy and at delivery. Solid line, mean values; broken line, maximal and minimal values.
Fig. 4. Mean values of serum copper during the course of pregnancy and at delivery according to the parity of the women studied. Solid line, primiparas; broken line, multiparas.
anterior cubital vein by means of needle V,A. To avoid any possible contamination, the blood was collected directly from the needle into a specially treated centrifuge glass test tube. After the coagulation of the blood the serum was separated by means of a centrifugation (1.5 minutes, 3,000 r.p.m.) , poured off into a well-cleaned dry glass and kept in a refrigerator at +4O C. The estimation of the serum copper was further carried out according to the technique of Callan and Henderson, modified by Schmidt. The results are seen in Figs. 1 through 4.
woman. Thus, as early as in the first 2 months of gestation, the serum copper is already increasing but in values near the maximal level found in the woman who are not pregnant (Figs. 1 and 2). With the end of the first trimester, however, and particularly with the beginning of the fourth month of pregnancy, serum copper rises rapidly and abruptly, reaching high values. Thereafter serum copper continues to increase progressively and gradually as pregnancy advances, and it reaches its highest peak during gestation in the tenth lunar month. The onset of labor, however, leads to an abrupt and sharp drop in the serum copper content, but its values remain still very high. The curve expressing the mean values of the serum copper of the examined 300 pregnant women and the 30 in the first
Comment There is no doubt that pregnancy with its considerably increased hormonal and metabolic demands would have an effect on the serum copper content of the pregnant
220
Dokumov
stage of labor (Fig. 3) confirms the same findings. A significant difference in the serum copper level, according to the parity of the patient, was found neither among the pregnant women nor among those in the first stage of labor (Figs. 2 and 4). Source of increased serum copper during pregnancy The rise in the serum copper level early of the in gestation before the formation fetus and its organs, the abrupt and rapid increase in the serum copper IeveI at the end of the first trimester and at the beginning of the second trimester of pregnancy when the formation of the placenta takes place, as well as the abrupt and sharp drop in the serum copper with the onset of labor exclude the fetal origin of the serum copper increase during pregnancy. Moreover, it is well known6> I5 that the blood serum of the umbilical cord of the newborn infant contains half the amount of copper when compared with the value in adult normal women. The mean serum copper level of the umbilical blood of 50 full-term newborn infants discloses 52.8 y per cent copper, while that of 30 healthy women with normal menstrual cycles discloses 114.8 7 per cent copper.4’ 5 On the other hand, Locke and Main,‘” Nielsen,‘” and Hejduk,lD also disclosed low content of copper in the serum of the fetus. Neuweiler,15 in turn, established a lower level of serum copper in the umbilical artery than in the umbilical vein. This finding was supported also by Dokumo+ 5umbilical artery, 40.2 y per cent copper; umbilical vein, 54.9 y per cent copper. Therefore the increase of the serum copper disclosed during pregnancy could hardly be of fetal origin. Biologic value of increased serum copper during pregnancy According to Neuweiler, the biologic value of the increase in serum copper during pregnancy is intimately related to the accelerated development of the growing fetus. The increasing content of the copper in the serum of the mother during gestation continuously
May 15. 1%X Am. J. Ohs. & Gyntc.
supplies a sufficient copper quantity to the developing fetus. The growing fetus needs an increased copper supply because fetal organs, especially the liver and spleen, show an increased copper content when compared with adult organs. 1 Therefore, the rise in the serum copper during pregnancy is regarded as a result of an increased ability of the organism of the pregnant woman to meet the higher demands of the growing fetus for copper. Effkemann and RSttgeP find the explanation for the augmentation of the serum copper during pregnancy in a resistance reaction of the maternal organism against the continuously invading metabolic products front the fetus into the maternal circulation. Besides, during pregnancy a significant rise in the serum copper level is disclosed in most of the infectious diseases as well as in all malignant processes. 14. I5 On the other hand, neoplasms, infectious diseases, and pregnancy lead to an increase in the blood sedimentation rate, to a shift to the left in the leukocyte count, and to an increase in the roughly dispersed serum proteins. The explanation for all these alterations disclosed in the serum is found by Effkemann and RSttger in a significant increase in the circulation of parenteral protein metabolic products derived from disintegrating processes in the tumors by neoplasms, from toxic damage in the tissue by infectious diseases, and during pregnancy from invasion into the maternal circulation of protein metabolic products from the fetus. According to Eisler, Rosdahl, and TheorelJ7 copper, like most of the heavy metals, exerts its biologic effect only as a protein-conjugated compound and never in an organic form. Therefore, copper is a component part of a proteolytic ferment that has to do with the disintegration of the protein bodies which have entered parenterally into the maternal circulation, The fluctuations of the serum copper content found during gestation, however, can be considered also as a consequence of a hormonal adaptation of the maternal organism to the increased metabolic and hormonal demands of pregnancy. If this is true, the
Volume Number
101 2
fluctuation of the serum copper in the pregnant woman during gestation would depend upon and would follow the same regulatory mechanism that determines the elaboration and secretion of hormones which are necessary for the normal pregnancy (chorionic gonadotropins, estrogens, and progesterone). However, the excretion of chorionic gonadotropins in the urine reaches its highest peak of about 250,000 M.U. per 24 hours from the thirty-fifth to the fifty-fifth day of pregnancy then rapidly drops to maintain a titer of 3,000 to 1,000 M.U. per 24 hours about the seventeenth to the twentieth week of pregnancy. Theerfore, with an insignificant fluctuation in its level, the chorionic gonadotropins excreted in the urine remain almost constant throughout the remainder of gestation and the fluctuation found in the excretion of the chorionic gonadotropins in the urine is thoroughly distinguished from the fluctuations of the serum copper level during pregnancy and could hardly be related to it. The excretion of the total estrogens through the urine increases slowly and gradually during the first trimester of pregnancy, fluctuating in values quite near the highest level found in the nonpregnant woman. About the twelfth to the sixteenth week of gestation, however, their excretion through the urine rapidly rises and then increasing continuously reaches its maximal values of 50,000 y per 24 hours at the end of pregnancy. About a week before onset of labor there is a decrease in the excretion of the total estrogens in the urine. During the first 2 months of pregnancy the several metabolites of progesterone, among which the pregnanediol complex has the leading part, hardly rise abolre the usual daily maximum excre-
Serum
copper
and
pregnancy
221
tion disclosed during the corpus lutwn phase in the nonpregnant woman. After tht: one hundred and twentieth day of gestation. however, there is a rapid and abrupt rise in the excretion of the progesterone metabolitcs in the urine which is followed by a further continuous increase. The excretion remains at its peak of 80 to 100 mg. per 24 hours at the two hundred and twentieth to two hundred and fortieth day of gestation. Just prior to the onset of labor there is also a marked fall in the output of the proqestcronc* metabolites in the urine. Therefore, during the course of the normal pregnancy, the fluctuation in the output 01 the total estrogens in the urine as well as that of the progesterone metabolites in tht. urine coincides with the fluctuation of tht serum copper content. This finding suggt,stq the esistence of some relation between dw serum copper level and the estrogenir :Yto progesterone stimulation duririg sponse pregnancy. The highly decreased level of serum copper disclosed in patients with II& mary or secondary hypoestrogenism”, ” as ~~~11 as the highly increased content of s(lrum copper in the hyperestrogenic states rnakr:s the relation between the fluctuation of the. serum copper durin,g pregnancy and thee estrogenic stimulation more probable. On thts other hand, the results obtained after trc;ltmerit with different estrogens”, L‘L’ confilm from the experimental point of view the I*\:istence of this relation between the S~XIIIIL copper level and the estrogenic stimulatiori: every abrupt or prolonged rise of the estrogenie le\rel is accompanied by a simultanc~ous increase in the serum copper content. PIYIgesteronc, however, npvcr leads to any altpr.;ltion in the serum copper levrl.
REFERENCES
1. 2. 3. 4. 5.
Brenner, W.: Ergebn. Inn. Med. Kinderheilk. 4: 806, 1953. Callan, T., and Henderson, J. A.: Analyst 54: 650, 1929. Cartwright, G. E.: Copper Metabolism, Baltimore, 1950. The Johns Hopkins Press. Dokumov, S.: Akush. ginek. 3: 291, 1967. Dokumov, S.: Prdiatria. 4: 304, 1967.
6. 7. 8. 9.
Effkemann, G., and RGttger, II.: Klin. Wchnschr. 13: 216, 1950. Eisler, B., Rosdahl, K. G., and Throrell. II.: Biochem. Ztschr. 286: 435, 1936. Gorter, E., Grendel, F., and Weyrrs, A. M.: Rev. frarq. pkdiat. 7: 747, 1931. Heilmeyer, L., Keiderling, W., and Stiiw(*, G.: Klin. Wchnschr. 17: 925. 1938.
222
10. 1 I. 12. 13.
14. 15. 16.
Dokumov
160: Hejduk, J.: Geburtsh. u. Gynsk. 1963. Krebs, H. A.: Biochem. Ztschr. 234: 1931. Locke, A., and Main, E. R.: J. Infect. 48: 449, 1931. Markowitz, H., Gubler, C. J., Mahoney, P.. Cartwriaht. G. E.. and Wintrobe. M. J. Clin. Invest.‘34: 1498, 1955. ’ Mischel, W.: Geburtsh. u. GynTk. 155: 1960. med. acta 5: Neuweiler, W.: Helvet. 1943. Nielsen, A.: Acta med. scandinav. 118: 1944.
187,
17.
278,
18. 19. 20.
Dis. J. M.:
21. 22.
197, 23.
Russ, E. M., and Raymunt, J.: Proc. Sot. Exper. Biol. & Med. 92: 465. 1956. Sarata, U.: Japan. J. SC. 2:. 305, 1934. Wchnschr. 10: 743. 1931. Schindel. L.: Klin. Schmidt,’ H. G.: Biochem. Ztschr. 302: 256, 1939. Tompsett, S. L.: Biochem. Ztschr. 28: 1544, 1934. Turpin, R., Schmitt-Jubeau, H., and Jerome, H.: Compt. rend. Sot. biol. 144: 352, 1950. Wilken, H.: Arch. GynHk. 194: 158, 1960.
619, 87,
Bud. Sofia
General Christo 3, Bulgaria
Michailov
6
I.
DOKUMOV,
M.D.,
S.R.O.
Bulgaria
Serum copper was investigated in 300 healthy pregnant women divided into ten groups according to the lunar month of pregnancy and in another 30 women in the first stage of labor. The technique of Callen and Henderson modified by Schmidt was used. From the analysis of the results obtained, it is established that serum copper increases continuously during pregnancy. During the corpus luteum phase of pregnancy, however, this increase is gradual and not very significant. The formation of the placenta is accompanied by a sudden rise in the level of the serum copper. In the second half of pregnancy, serum copper continues to rise gradually and reaches its highest leuel during gestation in the tenth month of pregnancy. The onset of labor brings about a rapid decrease in the content of serum copper. The source of the increased serum copper content during pregnancy and its biologic value are discussed.
importance of the THE BIOLOGIC “trace” elements, especially of iron, copper, zinc, and manganese, can be compared in living organisms only with that of the hormones, vitamins, and ferments. In spite of this, however, their exact mechanism of action as well as their metabolism remains still unsettled and disputable. Copper is of vital necessity and widespread in plants as well as in animals. But while in animals copper deficiency leads to certain well-defined morbid states, in humans it brings about only a decrease in the hemoglobin, in the tissue catalases and cytochrome-oxidases and never a real disease. Copper has a catalytic action on the synthesis of the hemoglobin and in the production of the erythrocytes. Because of its biocatalytic properties, on the cell it also plays an important role in the processes of growing. On the other hand, copper is of
great importance in the defensive reactions of the organism against the different. infections and, particularly, in the production of the specific antibodies. Even the papers of Krebs,‘l Sarata,” and Heilmeyer, Keiderling, and Stiiwe” drew attention to the serum copper content in the pregnant woman. SchindePg and Gorter, Grendel, and Weyers8 as well as Tompsett” disclosed a rapid rise in the serum copper in the third month of pregnancy, a slow increase thereafter, and a peak in the ninth month of pregnancy, followed by a decrease of the serum copper level. But according to Sarata,18 elevated values for serum copper are disclosed only during the first months of gestation. In the second half of pregnancy, however, there is always a return to normal values found in the serum of the nonpregnant woman. The high level of the serum copper described by some investigators8 at the end of the pregnancy is caused, according to Sarata, by the processes of onset of labor. On the other hand, Effkemarm and Rottger” showed that the titer of the
From the Institute for Specialization and Perfection of Physicians (ISUL), Clinic of Endocrinology and Metabolic Diseases.
217
218
Dokumov
cus % 64G Jlc / I JOG 88C 16d
c&J.%
320 WV Jlo JO0
.I 1 I~ I .’ .1.. .I..’.
220 800
140
240
22c
2lO
LOG
200
foe
i**
f60 . I f40 : f29 1: fW' . 80 00
foe f40 I20
0 ‘4 *, . . .
fro 80 lo
40
40
20
w
MA :.
ax
t
Fig. 1. Serum copper levels in the women studied according to the lunar month (ML) and at delivery (D).
Fig. 2. Serum copper levels according to the lunar month of pregnancy and the parity of the women under study. 0, multiparas; 0, primiparas.
serum copper progressively increases in blood serum as pregnancy advances, and it reaches its peak not before the tenth month of pregnancy. Wilken, 23 however, disclosed a rapid increase in the serum copper only in the first half of gestation, and especially during the fourth month, whiIe in the second half of pregnancy the serum copper continues to rise again, but then gradually. According to Hejduk, lo however, the titer of the serum copper increases in the blood continuously from the beginning of pregnancy to the onset of labor. As the literary data are quite various and even contradicting, it is of interest to handle this problem again, particularly in a large series.
normal course of pregnancy with normal blood counts and urine findings were examined. They were divided into ten groups, each one consisting of 30 women, according to the lunar month of pregnancy. Besides them, an additional group of 30 women in the first stage of labor was investigated. The parity of the women under study is best seen in Figs. 2 and 4.
Material Three free of
hundred healthy pregnant any subjective complaints
women in the
Method By repeated examination of the same person, Nielsenl’ disclosed daily fluctuations of the serum copper with morning values lowest and evening values highest. Although this daily fluctuation of the serum copper is rejected by most of the investigators,Bl l3 the blood samples necessary for the examination were always taken at the same timemorning 9:30 A.M. to lo:30 A.M.-from a fasting person through puncture of the
Volume Number
Ill1 ‘2
Serum
copper
and
pregnancy
~‘19
Fig. 3. Mean, maximal, and minimal values of serum copper in the women under study during the course of pregnancy and at delivery. Solid line, mean values; broken line, maximal and minimal values.
Fig. 4. Mean values of serum copper during the course of pregnancy and at delivery according to the parity of the women studied. Solid line, primiparas; broken line, multiparas.
anterior cubital vein by means of needle V,A. To avoid any possible contamination, the blood was collected directly from the needle into a specially treated centrifuge glass test tube. After the coagulation of the blood the serum was separated by means of a centrifugation (1.5 minutes, 3,000 r.p.m.) , poured off into a well-cleaned dry glass and kept in a refrigerator at +4O C. The estimation of the serum copper was further carried out according to the technique of Callan and Henderson, modified by Schmidt. The results are seen in Figs. 1 through 4.
woman. Thus, as early as in the first 2 months of gestation, the serum copper is already increasing but in values near the maximal level found in the woman who are not pregnant (Figs. 1 and 2). With the end of the first trimester, however, and particularly with the beginning of the fourth month of pregnancy, serum copper rises rapidly and abruptly, reaching high values. Thereafter serum copper continues to increase progressively and gradually as pregnancy advances, and it reaches its highest peak during gestation in the tenth lunar month. The onset of labor, however, leads to an abrupt and sharp drop in the serum copper content, but its values remain still very high. The curve expressing the mean values of the serum copper of the examined 300 pregnant women and the 30 in the first
Comment There is no doubt that pregnancy with its considerably increased hormonal and metabolic demands would have an effect on the serum copper content of the pregnant
220
Dokumov
stage of labor (Fig. 3) confirms the same findings. A significant difference in the serum copper level, according to the parity of the patient, was found neither among the pregnant women nor among those in the first stage of labor (Figs. 2 and 4). Source of increased serum copper during pregnancy The rise in the serum copper level early of the in gestation before the formation fetus and its organs, the abrupt and rapid increase in the serum copper IeveI at the end of the first trimester and at the beginning of the second trimester of pregnancy when the formation of the placenta takes place, as well as the abrupt and sharp drop in the serum copper with the onset of labor exclude the fetal origin of the serum copper increase during pregnancy. Moreover, it is well known6> I5 that the blood serum of the umbilical cord of the newborn infant contains half the amount of copper when compared with the value in adult normal women. The mean serum copper level of the umbilical blood of 50 full-term newborn infants discloses 52.8 y per cent copper, while that of 30 healthy women with normal menstrual cycles discloses 114.8 7 per cent copper.4’ 5 On the other hand, Locke and Main,‘” Nielsen,‘” and Hejduk,lD also disclosed low content of copper in the serum of the fetus. Neuweiler,15 in turn, established a lower level of serum copper in the umbilical artery than in the umbilical vein. This finding was supported also by Dokumo+ 5umbilical artery, 40.2 y per cent copper; umbilical vein, 54.9 y per cent copper. Therefore the increase of the serum copper disclosed during pregnancy could hardly be of fetal origin. Biologic value of increased serum copper during pregnancy According to Neuweiler, the biologic value of the increase in serum copper during pregnancy is intimately related to the accelerated development of the growing fetus. The increasing content of the copper in the serum of the mother during gestation continuously
May 15. 1%X Am. J. Ohs. & Gyntc.
supplies a sufficient copper quantity to the developing fetus. The growing fetus needs an increased copper supply because fetal organs, especially the liver and spleen, show an increased copper content when compared with adult organs. 1 Therefore, the rise in the serum copper during pregnancy is regarded as a result of an increased ability of the organism of the pregnant woman to meet the higher demands of the growing fetus for copper. Effkemann and RSttgeP find the explanation for the augmentation of the serum copper during pregnancy in a resistance reaction of the maternal organism against the continuously invading metabolic products front the fetus into the maternal circulation. Besides, during pregnancy a significant rise in the serum copper level is disclosed in most of the infectious diseases as well as in all malignant processes. 14. I5 On the other hand, neoplasms, infectious diseases, and pregnancy lead to an increase in the blood sedimentation rate, to a shift to the left in the leukocyte count, and to an increase in the roughly dispersed serum proteins. The explanation for all these alterations disclosed in the serum is found by Effkemann and RSttger in a significant increase in the circulation of parenteral protein metabolic products derived from disintegrating processes in the tumors by neoplasms, from toxic damage in the tissue by infectious diseases, and during pregnancy from invasion into the maternal circulation of protein metabolic products from the fetus. According to Eisler, Rosdahl, and TheorelJ7 copper, like most of the heavy metals, exerts its biologic effect only as a protein-conjugated compound and never in an organic form. Therefore, copper is a component part of a proteolytic ferment that has to do with the disintegration of the protein bodies which have entered parenterally into the maternal circulation, The fluctuations of the serum copper content found during gestation, however, can be considered also as a consequence of a hormonal adaptation of the maternal organism to the increased metabolic and hormonal demands of pregnancy. If this is true, the
Volume Number
101 2
fluctuation of the serum copper in the pregnant woman during gestation would depend upon and would follow the same regulatory mechanism that determines the elaboration and secretion of hormones which are necessary for the normal pregnancy (chorionic gonadotropins, estrogens, and progesterone). However, the excretion of chorionic gonadotropins in the urine reaches its highest peak of about 250,000 M.U. per 24 hours from the thirty-fifth to the fifty-fifth day of pregnancy then rapidly drops to maintain a titer of 3,000 to 1,000 M.U. per 24 hours about the seventeenth to the twentieth week of pregnancy. Theerfore, with an insignificant fluctuation in its level, the chorionic gonadotropins excreted in the urine remain almost constant throughout the remainder of gestation and the fluctuation found in the excretion of the chorionic gonadotropins in the urine is thoroughly distinguished from the fluctuations of the serum copper level during pregnancy and could hardly be related to it. The excretion of the total estrogens through the urine increases slowly and gradually during the first trimester of pregnancy, fluctuating in values quite near the highest level found in the nonpregnant woman. About the twelfth to the sixteenth week of gestation, however, their excretion through the urine rapidly rises and then increasing continuously reaches its maximal values of 50,000 y per 24 hours at the end of pregnancy. About a week before onset of labor there is a decrease in the excretion of the total estrogens in the urine. During the first 2 months of pregnancy the several metabolites of progesterone, among which the pregnanediol complex has the leading part, hardly rise abolre the usual daily maximum excre-
Serum
copper
and
pregnancy
221
tion disclosed during the corpus lutwn phase in the nonpregnant woman. After tht: one hundred and twentieth day of gestation. however, there is a rapid and abrupt rise in the excretion of the progesterone metabolitcs in the urine which is followed by a further continuous increase. The excretion remains at its peak of 80 to 100 mg. per 24 hours at the two hundred and twentieth to two hundred and fortieth day of gestation. Just prior to the onset of labor there is also a marked fall in the output of the proqestcronc* metabolites in the urine. Therefore, during the course of the normal pregnancy, the fluctuation in the output 01 the total estrogens in the urine as well as that of the progesterone metabolites in tht. urine coincides with the fluctuation of tht serum copper content. This finding suggt,stq the esistence of some relation between dw serum copper level and the estrogenir :Yto progesterone stimulation duririg sponse pregnancy. The highly decreased level of serum copper disclosed in patients with II& mary or secondary hypoestrogenism”, ” as ~~~11 as the highly increased content of s(lrum copper in the hyperestrogenic states rnakr:s the relation between the fluctuation of the. serum copper durin,g pregnancy and thee estrogenic stimulation more probable. On thts other hand, the results obtained after trc;ltmerit with different estrogens”, L‘L’ confilm from the experimental point of view the I*\:istence of this relation between the S~XIIIIL copper level and the estrogenic stimulatiori: every abrupt or prolonged rise of the estrogenie le\rel is accompanied by a simultanc~ous increase in the serum copper content. PIYIgesteronc, however, npvcr leads to any altpr.;ltion in the serum copper levrl.
REFERENCES
1. 2. 3. 4. 5.
Brenner, W.: Ergebn. Inn. Med. Kinderheilk. 4: 806, 1953. Callan, T., and Henderson, J. A.: Analyst 54: 650, 1929. Cartwright, G. E.: Copper Metabolism, Baltimore, 1950. The Johns Hopkins Press. Dokumov, S.: Akush. ginek. 3: 291, 1967. Dokumov, S.: Prdiatria. 4: 304, 1967.
6. 7. 8. 9.
Effkemann, G., and RGttger, II.: Klin. Wchnschr. 13: 216, 1950. Eisler, B., Rosdahl, K. G., and Throrell. II.: Biochem. Ztschr. 286: 435, 1936. Gorter, E., Grendel, F., and Weyrrs, A. M.: Rev. frarq. pkdiat. 7: 747, 1931. Heilmeyer, L., Keiderling, W., and Stiiw(*, G.: Klin. Wchnschr. 17: 925. 1938.
222
10. 1 I. 12. 13.
14. 15. 16.
Dokumov
160: Hejduk, J.: Geburtsh. u. Gynsk. 1963. Krebs, H. A.: Biochem. Ztschr. 234: 1931. Locke, A., and Main, E. R.: J. Infect. 48: 449, 1931. Markowitz, H., Gubler, C. J., Mahoney, P.. Cartwriaht. G. E.. and Wintrobe. M. J. Clin. Invest.‘34: 1498, 1955. ’ Mischel, W.: Geburtsh. u. GynTk. 155: 1960. med. acta 5: Neuweiler, W.: Helvet. 1943. Nielsen, A.: Acta med. scandinav. 118: 1944.
187,
17.
278,
18. 19. 20.
Dis. J. M.:
21. 22.
197, 23.
Russ, E. M., and Raymunt, J.: Proc. Sot. Exper. Biol. & Med. 92: 465. 1956. Sarata, U.: Japan. J. SC. 2:. 305, 1934. Wchnschr. 10: 743. 1931. Schindel. L.: Klin. Schmidt,’ H. G.: Biochem. Ztschr. 302: 256, 1939. Tompsett, S. L.: Biochem. Ztschr. 28: 1544, 1934. Turpin, R., Schmitt-Jubeau, H., and Jerome, H.: Compt. rend. Sot. biol. 144: 352, 1950. Wilken, H.: Arch. GynHk. 194: 158, 1960.
619, 87,
Bud. Sofia
General Christo 3, Bulgaria
Michailov
6