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Excretion of estriol and pregnanediol in Chinese women during pregnancy
hinese PING
YES
PEI
CHUAN
TZU
YAO
JUI Taipei,
ncY WEI,
OUYANG, LEE,
SAN
CHEN,
Taiwan>
M.D.
Republic
M.D.
M.D. M.D. of China
The excretion pattern of estriol and firegnanediol of Chinese women during pregnancy is not well known. The urinary excretion values of 56 normal and 41 pathologic pregnancies were determined by the method of Frandsen and the thin-layer chromatographic method of Waldi with a total of 628 determinations. The discrepancy in pattern of pregnanediol excretion between the reported (Caucasian) and our results (Chinese) awaits further investigation. Estriol excretion: values were lower in threatened abortion and premature delivery and further lower in hydatidiform mole and intrauterine fetal death than in normal pregnancy, but pregnanediol excretion values were dispersed widely and less informative.
I T MCA s B E E pi noted that changes in the output of urinary estriol and pregnanediol might assess the placental function and the prognosis of the pregnancy since the quantitative determination of pregnanediol by Venning21, 22and estriol by Cohen, Marrian, and Watsok5 The present study is concerned with the determination of estriol and pregnanediol excretion in Chinese women during normal and pathologic pregnancies. aterial
and
Twenty-four-hour urine was collected lor determinations in each case. Estriol excretion values were determined by the method of FrandserP and pregnanediol excretion values by the thin-layer chromatographic method of Waldi.23y 24
methods
Material studied included 61 subjects admitted to the National Taiwan University Hospital from April, 1964, to May, 1966, and 36 normal subjects admitted to the Taipei MCH Center for a special research purpose from February to July, 1966. The duration of pregnancy was calculated from the first day of the last menstrual period.
From The Department of Obstetrics and Gynecology, National Taiwan University Medical College and the Hospital. Supported by Grants M63-126 M65-121 from the Population Inc., New York, New York.
and Council,
Week of pregnancy Fig. 1. Mean values for excretion of e&al week of pregnancy before 16 weeks. Full represents data of Fran&en.“’
per line
Volume Number
102 1
Estriol
and
pregnanediol
excretion
in pregnancy
9
70 c
32' 28. AZ24 :202 E 16.
z a : g g ‘i
512. : r8~ Id 4
40. 55. 50. 25. 20. IS-
IO-
.
5.
I
6
24
23
28 30 Week
32 34 36 38 of
40
Pregnancy
Fig. 2. Mean values for the excretion per week of pregnancy after 27 weeks. represents data of Frandsen.ll
[;I
of estriol Full
IO I2 14 I6 16 202224262630323436364042
42
line
,<,
Week
12
14
Week
of
pregnancy
16
I6
20
pregnancy
Fig. 3. Mean value for the excretion of pregnanediol per week of pregnancy. Full line represents mean excretion curve and fiducial limits of Shearman.
pJ/
8 10
of
,kF; 2022242626303’2.3436364042
Week
of
pregnancy
4. Pregnanediol/estriol ratio in (A) early pregnancy and (B) in late pregnancy line) . Full line represents ratio of mean value from Klopper and Billewiczl4 Fig.
Results
and
comment
Urinary e:xcretion of estriol and pregnanediol during normal pregnancy. Estriol. The mean excretion values for estriol per week in 139 determinations from 26 subjecti before 16 weeks and 147 determinations from 30 subjects after 27 weeks of gestation are shown in Figs. 1 and 2. The mean values and the pattern of the excretion in later pregnancy were quite similar to those and Coyle and Brown7 ; howof Frandsen’l
(broken
ever, the weekly increment of the mean value in early pregnancy was less than they reported. Similar to the results of Frandsen,l’ no prebirth drops> 12r 2o in excretion of estriol was observed. Pregnanediol. The mean excretion values for pregnanediol per week in 221 determinations from 26 subjects before 16 weeks and 66 determinations from 25 subjects after 28 weeks of gestation are shown in Fig. 3. Considerably greater individual and day-to-day
Septemar 1, 1968 Am. J. Obst, & Gym.
variations were observed than those in estriol excretion. The mean values in early pregnancy were higher than or at the upper limit of those reported,i4l I@ whereas they were much lower than those reported in later pregnancy. Ratio
of pregnanediol
and
estriot
excre-
tion. According to Klopper and Billewicz,14 the ratio is about 100: 1 in early pregnancy, then it falls to about 3: 1 by 20 weeks of gestation and about 1: 1 at the term. Table I and Fig. 4 show our resultsin comparison with those of others.**’ l7 The discrepancy is causedby lower estriol and higher pregnanediol values in early pregnancy and lower pregnanedio1 values in later pregnancy in our series.
Table I. Ratio of excretion of pregnanediol and estriol in earIy pregnancy Week of pregnancy 15 11 i2 !3 14 15 1s
Ratio
_I Present
series
/ Macnaughton”
75.1 102.0 43.1 46.4 44,.9
46.6 36.4 37.8 34.6 22.0 7.5 5.2
34.2
Threatened abortion. The values in 12 determinations of estriol and pregnanediol excretion from 11 patients are shown in Table II. They were generally at the Iower end of our normaP range or at subnormal levels. The values did not predict the outcome, asreported by others.17s l8 Hydatidiform mole. The values in 8 determinations from 8 patients are shown in Table III. The values for estriol were much lower and those for pregnanediol were either norma1 or lo,wer than the values for the appropriate stage of normal pregnancy, as previousIy reported.15*I69I* Intrauterine fetal death. The values in 15 determinations from 9 patients with proved intrauterine death are listed in Table IV. The estriol values were much lower than those for the comparable stage of normal gestation, but the pregnanediol values were dispersed in a rather wide range, though also generally low. The estrio1value in a caseof an anencephalit infant was very low, as reported by ten Xergel and Frandsen and Stakemann.1oTen Berge’s results were in a case of toxemic pregnancy as were ours, but Frandsen’s patients were not toxemic. Coyle, Grieg, and Walker6 reported that
TahIe II. Estriol and pregnanediol excretion in threatened abortion of gestation Week
Specimen No. 6 17 70 83 98 133 141" '55" 202 204 276 279
Estriol
13 14 13 10 16 14
*From the same patient. tNot determined, may be less than
1
(w.)
1
(mg.) 0.!7 0.13 0.20 0.27 0.16 0.17 5.32 0.10 f 0.35 f 0.12
2": 8 17 14 15 40 fig per 24 hours
according
l_ll~-
Pregnanediol 1.0 5.3 21.3 3.0 0.2 9.4 6.1 9.4 7.9 3.1 18.6 14.5 to Frandsen.
...---.
Outcome
of gestation
Improved Aborted Aborted Aborted Aborted Improved 3 Aborted Improved Improved Aborted Improved
Volume Number
102 1
Estriol and pregnanediol
Table III. Estriol in hydatidiform
3 9 11 14 27 206 216 277 *Less
and pregnanediol mole
23 17 19 22 16 12 18 23 than
40 jog per
20.1 7.7 10.2 2.4 0.3 1.1 17.8 22.4
24 hours.
Table IV. Estriol and pregnanediol in intrauterine fetal death Specimen NO.
Week of gestation
3% 79* 146 228 249 148 151 156 157 138 142 143 224 231 40 ‘A
Table V. Estriol Specimen No.
1Pregnanediol
8.7 2.0 5.4 3.3 5.2 3.3 2.8 3.9 4.2 2.4 4.4 3.6 2.3 1.7 2.5 with
21.0 10.8 4.4 17.8 14.0 9.8 3.5 4.6 9.5 11.0 9.3 5.4 12.0 2.6 10.8
hydmmnios
and
and pregnanediol
1 z;fiii
19 31 33 34 36 71 131 254 264 from
1
time
the
toxemic
excretion
7;;
33 29 33 34 31 34 31 34 35 the
excretion
(mg.)
29 32 32 32 32 33 33 33 33 36 36 36 36 36 39
case of anencephaly
*Days
1 7::
specimen
was
in premature
1 PreF;;diol
6.3 3.8 8.7 6.0 4.2 8.3 5.8 5.5 8.0 taken
7.7 10.7 6.0 15.0 9.1 8.3 12.3 11.8 17.2 to the
in pregnancy
11
urinary pregnanediol levels were of less immediate prognostic value than were levels of estriol for fetal death from severe preeclampsia. Premature delivery. The values in 9 determinations from 8 patients, as well as some related data, are shown in Table V. The estriol values were lower than those in normal pregnancy, but slightly higher than those in fetal death at each comparable period. The pregnanediol values, again, showed a considerable dispersion. It is accepted that estrogens are produced by the placenta,* and Brown4 reported the correlation between the excretion level and weight of the placenta. Meanwhile, Frandsen and Stakemann reported that estriol excretion was more closely related to birth weight of the newborn ,than weight of the placenta. Our results did not show any of these correlations existed. Multiple pregnancy. The values in 11 determinations from 4 subjects bearing twins and one bearing triplets are shown in Table VI. Higher estriol excretion values than in single pregnancy were reported,2’ 3, Bl I31 25 but our results showed them to be within normal range. The pregnanediol values, as reported by Shearman, I0 did not show any elevation in single pregnancy, but, again, a wide dispersion of the values. The estriol values in 2 determinations made at the thirty-second and thirty-third weeks in a triplet pregnancy
excretion
0.32 a.20 0.20 0.19 0.11 + * *
excretion
delivery.
delivery
1 ;;;f;*
1 :
27 25 1 1 11 7 7
place~~t~~~;;;n 400 350 280 280 300 350 40’0 500 500
2,080 1,280 1,380 1,380 1,400 1,820 1,660 2,200 2,300
September I, !96S Am. J. Obst. B Gynec.
VI. &trio;
Table Multifile
births
and pregnanediol /
Specimen No.
excretion / Week
in multiple of gestation
10 61 145 150 440 144 149 147 153
Twins
TripletS
pregnancy
28 32
were at the lower margin of normal range. The triplets included 2 females and a male. One of the females was an 880 gram anencephalic and macerated infant. Low estriol values in pregnancy with an anencephalic
Estriol
40
(mg.j
1 Pregnanediol
(mg.)
7.0 27.1 6.1
37
10.5 17.0 8.7 22.7 14.0 35.0 11.2 11.7 13.0
32 33
11.0 7.3
22.8 22.5
33 40 40 36 36 37 37
infant have fetal death. We
and
wish
Hou-Tar
2.2
7.6 20.3 13.1 17.1
7.9
been mentioned to thank
Chien,
Cheng-Ghang
in intrauterine Wang,
B.S., for their
B.S.,
technical
assistance.
REFERENCES
ten Berge, B. S.: Gynaecologia (Basel) 149: 40, 1960. 2. Borth, R., Lunenfeld, B., Stamm, O., and de Watteville, H.: Acta obst. et gynec. scandinav. 38: 417, 1959. 3. Breitner, J.: Arch, GynBk. 185: 258, 1954. 4. Brown, J. B. : J. Endocrinok 16: 202, 1957. 5. Cohen, S. L., Marrian, G. F., and Watson, M. C.: Lancet 1: 674, 1935. 6. Coyle, M. G., Greig, M., and Walker, J.: Lancet 2: 275, 1962. 7 . Goyle, M. G., and Brown, J. B.: J, Obst. & Gynaec. Brit. Comm. 70: 225, 1963. 8. Diczfalusy, E. : Acta endocrinol. Suppl. 50: __ 129, 1960: V. A., and Stakemann, G.: Danish 9. Frandsen, M. Bull. 7: 95. 1960. Cited by Frandsen, V. A.: The Excretion of Oestriol in Normal Human Pregnancy, Copenhagen, 1963, Ejnar Munksgaards Forlag. 10. Frandsen, V. A., and Stakemann, G.: Acta Endocrinol. 38: 383, 1961. 11. Erandsen, V. A.: The Excretion of Oestriol in Normal. Human Pregnancy, Copenhagen, 1963, Ejnar Munksgaards Forlag. 12. Taylor, E. S., Bruns, P. D., Anker, R. M., and Drose, V. E.: AXI, J. OBST. & CYNEC. 70: 894, 1955. 1.
13.
14. 15. 16. 17. 18.
19. 20. 21. 22. 23. 24. 25.
Keliar, R., Matthew, G. D., MacKay, R., Brown, J. B., and Roy, E.: J. Obst. & Gynaec. Brit. Emp. 66: 804, 1959. Klopper, A., and Billewicz, W.: J. Obst. & Gynaec. Brit. Comm. 70: 1024, 1963. MacDonald, P. C., and Siiteri, P. K.: J. Clin. Endocrinol. 24: 685, 1964. Macnaughton, M. C.: J. Obst. & Gynaec. &it. Comm. 72: 249, 1965. Macnaughton, M. C.: J. Obst. & Gynaec. Brit. Comm. 73: 290, 1966. Russell, C. S., Paine, C. G., CoyIe, M. G., and Dewhurst, C. J.: J. Obst. & Gynaec. Brit. Emp. 64: 649, 1957. Shear-man, R. P.: J. Obst. & Gynaec. Brit. Emp. 66: 1, 1959. Smith, 0. W., Smith, 6. V. S., and Schiller, S.: J. Clin. Endocrinol. 1: 461, 1941. Venning, E. H.: Jo Biol. Chem. 119: 473, 1937. Venning, E. H.: J. BioI. Chem. .I%: 595, 1938. Waldi, D., Munter, E., and Wolpert, E.: Med. ExDer. 3: 45. 1960. Waldi, D.: Klin. Wchnschr. 40: 827, 1962. Zondek, B., and Pfeiffer, V.: Acta obst. et gynec. scandinav. 38: 742, 1959.
YES
PEI
CHUAN
TZU
YAO
JUI Taipei,
ncY WEI,
OUYANG, LEE,
SAN
CHEN,
Taiwan>
M.D.
Republic
M.D.
M.D. M.D. of China
The excretion pattern of estriol and firegnanediol of Chinese women during pregnancy is not well known. The urinary excretion values of 56 normal and 41 pathologic pregnancies were determined by the method of Frandsen and the thin-layer chromatographic method of Waldi with a total of 628 determinations. The discrepancy in pattern of pregnanediol excretion between the reported (Caucasian) and our results (Chinese) awaits further investigation. Estriol excretion: values were lower in threatened abortion and premature delivery and further lower in hydatidiform mole and intrauterine fetal death than in normal pregnancy, but pregnanediol excretion values were dispersed widely and less informative.
I T MCA s B E E pi noted that changes in the output of urinary estriol and pregnanediol might assess the placental function and the prognosis of the pregnancy since the quantitative determination of pregnanediol by Venning21, 22and estriol by Cohen, Marrian, and Watsok5 The present study is concerned with the determination of estriol and pregnanediol excretion in Chinese women during normal and pathologic pregnancies. aterial
and
Twenty-four-hour urine was collected lor determinations in each case. Estriol excretion values were determined by the method of FrandserP and pregnanediol excretion values by the thin-layer chromatographic method of Waldi.23y 24
methods
Material studied included 61 subjects admitted to the National Taiwan University Hospital from April, 1964, to May, 1966, and 36 normal subjects admitted to the Taipei MCH Center for a special research purpose from February to July, 1966. The duration of pregnancy was calculated from the first day of the last menstrual period.
From The Department of Obstetrics and Gynecology, National Taiwan University Medical College and the Hospital. Supported by Grants M63-126 M65-121 from the Population Inc., New York, New York.
and Council,
Week of pregnancy Fig. 1. Mean values for excretion of e&al week of pregnancy before 16 weeks. Full represents data of Fran&en.“’
per line
Volume Number
102 1
Estriol
and
pregnanediol
excretion
in pregnancy
9
70 c
32' 28. AZ24 :202 E 16.
z a : g g ‘i
512. : r8~ Id 4
40. 55. 50. 25. 20. IS-
IO-
.
5.
I
6
24
23
28 30 Week
32 34 36 38 of
40
Pregnancy
Fig. 2. Mean values for the excretion per week of pregnancy after 27 weeks. represents data of Frandsen.ll
[;I
of estriol Full
IO I2 14 I6 16 202224262630323436364042
42
line
,<,
Week
12
14
Week
of
pregnancy
16
I6
20
pregnancy
Fig. 3. Mean value for the excretion of pregnanediol per week of pregnancy. Full line represents mean excretion curve and fiducial limits of Shearman.
pJ/
8 10
of
,kF; 2022242626303’2.3436364042
Week
of
pregnancy
4. Pregnanediol/estriol ratio in (A) early pregnancy and (B) in late pregnancy line) . Full line represents ratio of mean value from Klopper and Billewiczl4 Fig.
Results
and
comment
Urinary e:xcretion of estriol and pregnanediol during normal pregnancy. Estriol. The mean excretion values for estriol per week in 139 determinations from 26 subjecti before 16 weeks and 147 determinations from 30 subjects after 27 weeks of gestation are shown in Figs. 1 and 2. The mean values and the pattern of the excretion in later pregnancy were quite similar to those and Coyle and Brown7 ; howof Frandsen’l
(broken
ever, the weekly increment of the mean value in early pregnancy was less than they reported. Similar to the results of Frandsen,l’ no prebirth drops> 12r 2o in excretion of estriol was observed. Pregnanediol. The mean excretion values for pregnanediol per week in 221 determinations from 26 subjects before 16 weeks and 66 determinations from 25 subjects after 28 weeks of gestation are shown in Fig. 3. Considerably greater individual and day-to-day
Septemar 1, 1968 Am. J. Obst, & Gym.
variations were observed than those in estriol excretion. The mean values in early pregnancy were higher than or at the upper limit of those reported,i4l I@ whereas they were much lower than those reported in later pregnancy. Ratio
of pregnanediol
and
estriot
excre-
tion. According to Klopper and Billewicz,14 the ratio is about 100: 1 in early pregnancy, then it falls to about 3: 1 by 20 weeks of gestation and about 1: 1 at the term. Table I and Fig. 4 show our resultsin comparison with those of others.**’ l7 The discrepancy is causedby lower estriol and higher pregnanediol values in early pregnancy and lower pregnanedio1 values in later pregnancy in our series.
Table I. Ratio of excretion of pregnanediol and estriol in earIy pregnancy Week of pregnancy 15 11 i2 !3 14 15 1s
Ratio
_I Present
series
/ Macnaughton”
75.1 102.0 43.1 46.4 44,.9
46.6 36.4 37.8 34.6 22.0 7.5 5.2
34.2
Threatened abortion. The values in 12 determinations of estriol and pregnanediol excretion from 11 patients are shown in Table II. They were generally at the Iower end of our normaP range or at subnormal levels. The values did not predict the outcome, asreported by others.17s l8 Hydatidiform mole. The values in 8 determinations from 8 patients are shown in Table III. The values for estriol were much lower and those for pregnanediol were either norma1 or lo,wer than the values for the appropriate stage of normal pregnancy, as previousIy reported.15*I69I* Intrauterine fetal death. The values in 15 determinations from 9 patients with proved intrauterine death are listed in Table IV. The estriol values were much lower than those for the comparable stage of normal gestation, but the pregnanediol values were dispersed in a rather wide range, though also generally low. The estrio1value in a caseof an anencephalit infant was very low, as reported by ten Xergel and Frandsen and Stakemann.1oTen Berge’s results were in a case of toxemic pregnancy as were ours, but Frandsen’s patients were not toxemic. Coyle, Grieg, and Walker6 reported that
TahIe II. Estriol and pregnanediol excretion in threatened abortion of gestation Week
Specimen No. 6 17 70 83 98 133 141" '55" 202 204 276 279
Estriol
13 14 13 10 16 14
*From the same patient. tNot determined, may be less than
1
(w.)
1
(mg.) 0.!7 0.13 0.20 0.27 0.16 0.17 5.32 0.10 f 0.35 f 0.12
2": 8 17 14 15 40 fig per 24 hours
according
l_ll~-
Pregnanediol 1.0 5.3 21.3 3.0 0.2 9.4 6.1 9.4 7.9 3.1 18.6 14.5 to Frandsen.
...---.
Outcome
of gestation
Improved Aborted Aborted Aborted Aborted Improved 3 Aborted Improved Improved Aborted Improved
Volume Number
102 1
Estriol and pregnanediol
Table III. Estriol in hydatidiform
3 9 11 14 27 206 216 277 *Less
and pregnanediol mole
23 17 19 22 16 12 18 23 than
40 jog per
20.1 7.7 10.2 2.4 0.3 1.1 17.8 22.4
24 hours.
Table IV. Estriol and pregnanediol in intrauterine fetal death Specimen NO.
Week of gestation
3% 79* 146 228 249 148 151 156 157 138 142 143 224 231 40 ‘A
Table V. Estriol Specimen No.
1Pregnanediol
8.7 2.0 5.4 3.3 5.2 3.3 2.8 3.9 4.2 2.4 4.4 3.6 2.3 1.7 2.5 with
21.0 10.8 4.4 17.8 14.0 9.8 3.5 4.6 9.5 11.0 9.3 5.4 12.0 2.6 10.8
hydmmnios
and
and pregnanediol
1 z;fiii
19 31 33 34 36 71 131 254 264 from
1
time
the
toxemic
excretion
7;;
33 29 33 34 31 34 31 34 35 the
excretion
(mg.)
29 32 32 32 32 33 33 33 33 36 36 36 36 36 39
case of anencephaly
*Days
1 7::
specimen
was
in premature
1 PreF;;diol
6.3 3.8 8.7 6.0 4.2 8.3 5.8 5.5 8.0 taken
7.7 10.7 6.0 15.0 9.1 8.3 12.3 11.8 17.2 to the
in pregnancy
11
urinary pregnanediol levels were of less immediate prognostic value than were levels of estriol for fetal death from severe preeclampsia. Premature delivery. The values in 9 determinations from 8 patients, as well as some related data, are shown in Table V. The estriol values were lower than those in normal pregnancy, but slightly higher than those in fetal death at each comparable period. The pregnanediol values, again, showed a considerable dispersion. It is accepted that estrogens are produced by the placenta,* and Brown4 reported the correlation between the excretion level and weight of the placenta. Meanwhile, Frandsen and Stakemann reported that estriol excretion was more closely related to birth weight of the newborn ,than weight of the placenta. Our results did not show any of these correlations existed. Multiple pregnancy. The values in 11 determinations from 4 subjects bearing twins and one bearing triplets are shown in Table VI. Higher estriol excretion values than in single pregnancy were reported,2’ 3, Bl I31 25 but our results showed them to be within normal range. The pregnanediol values, as reported by Shearman, I0 did not show any elevation in single pregnancy, but, again, a wide dispersion of the values. The estriol values in 2 determinations made at the thirty-second and thirty-third weeks in a triplet pregnancy
excretion
0.32 a.20 0.20 0.19 0.11 + * *
excretion
delivery.
delivery
1 ;;;f;*
1 :
27 25 1 1 11 7 7
place~~t~~~;;;n 400 350 280 280 300 350 40’0 500 500
2,080 1,280 1,380 1,380 1,400 1,820 1,660 2,200 2,300
September I, !96S Am. J. Obst. B Gynec.
VI. &trio;
Table Multifile
births
and pregnanediol /
Specimen No.
excretion / Week
in multiple of gestation
10 61 145 150 440 144 149 147 153
Twins
TripletS
pregnancy
28 32
were at the lower margin of normal range. The triplets included 2 females and a male. One of the females was an 880 gram anencephalic and macerated infant. Low estriol values in pregnancy with an anencephalic
Estriol
40
(mg.j
1 Pregnanediol
(mg.)
7.0 27.1 6.1
37
10.5 17.0 8.7 22.7 14.0 35.0 11.2 11.7 13.0
32 33
11.0 7.3
22.8 22.5
33 40 40 36 36 37 37
infant have fetal death. We
and
wish
Hou-Tar
2.2
7.6 20.3 13.1 17.1
7.9
been mentioned to thank
Chien,
Cheng-Ghang
in intrauterine Wang,
B.S., for their
B.S.,
technical
assistance.
REFERENCES
ten Berge, B. S.: Gynaecologia (Basel) 149: 40, 1960. 2. Borth, R., Lunenfeld, B., Stamm, O., and de Watteville, H.: Acta obst. et gynec. scandinav. 38: 417, 1959. 3. Breitner, J.: Arch, GynBk. 185: 258, 1954. 4. Brown, J. B. : J. Endocrinok 16: 202, 1957. 5. Cohen, S. L., Marrian, G. F., and Watson, M. C.: Lancet 1: 674, 1935. 6. Coyle, M. G., Greig, M., and Walker, J.: Lancet 2: 275, 1962. 7 . Goyle, M. G., and Brown, J. B.: J, Obst. & Gynaec. Brit. Comm. 70: 225, 1963. 8. Diczfalusy, E. : Acta endocrinol. Suppl. 50: __ 129, 1960: V. A., and Stakemann, G.: Danish 9. Frandsen, M. Bull. 7: 95. 1960. Cited by Frandsen, V. A.: The Excretion of Oestriol in Normal Human Pregnancy, Copenhagen, 1963, Ejnar Munksgaards Forlag. 10. Frandsen, V. A., and Stakemann, G.: Acta Endocrinol. 38: 383, 1961. 11. Erandsen, V. A.: The Excretion of Oestriol in Normal. Human Pregnancy, Copenhagen, 1963, Ejnar Munksgaards Forlag. 12. Taylor, E. S., Bruns, P. D., Anker, R. M., and Drose, V. E.: AXI, J. OBST. & CYNEC. 70: 894, 1955. 1.
13.
14. 15. 16. 17. 18.
19. 20. 21. 22. 23. 24. 25.
Keliar, R., Matthew, G. D., MacKay, R., Brown, J. B., and Roy, E.: J. Obst. & Gynaec. Brit. Emp. 66: 804, 1959. Klopper, A., and Billewicz, W.: J. Obst. & Gynaec. Brit. Comm. 70: 1024, 1963. MacDonald, P. C., and Siiteri, P. K.: J. Clin. Endocrinol. 24: 685, 1964. Macnaughton, M. C.: J. Obst. & Gynaec. &it. Comm. 72: 249, 1965. Macnaughton, M. C.: J. Obst. & Gynaec. Brit. Comm. 73: 290, 1966. Russell, C. S., Paine, C. G., CoyIe, M. G., and Dewhurst, C. J.: J. Obst. & Gynaec. Brit. Emp. 64: 649, 1957. Shear-man, R. P.: J. Obst. & Gynaec. Brit. Emp. 66: 1, 1959. Smith, 0. W., Smith, 6. V. S., and Schiller, S.: J. Clin. Endocrinol. 1: 461, 1941. Venning, E. H.: Jo Biol. Chem. 119: 473, 1937. Venning, E. H.: J. BioI. Chem. .I%: 595, 1938. Waldi, D., Munter, E., and Wolpert, E.: Med. ExDer. 3: 45. 1960. Waldi, D.: Klin. Wchnschr. 40: 827, 1962. Zondek, B., and Pfeiffer, V.: Acta obst. et gynec. scandinav. 38: 742, 1959.