Division of Clinical and Experimental Endocrinology, Department of Obstetrics and Gynaecology, University of Hamburg, FRG
EFFECT OF POST-OVULATORY ADMINISTERED OESTROGENS ON CORPUS LUTEUM FUNCTION
By F. Lehmann, I.
Just-Nastansky, B. Behrendt, P.-J. Czygan and G. Bettendorf ABSTRACT
The effect of
orally given diethylstilboestroldiphosphate (DES) and 17\g=a\\x=req-\ ethinyl-oestradiol-3-methylether (EEM) on plasma progesterone levels was studied. Both compounds were administered for 5 days to 5 women in daily doses of 60 mg (DES) and 30 mg (EEM). The fully informed volunteers were found to have a normal menstrual cycle before the study. The mean corpus luteum phase (corpus luteum phase days between LH surge and onset of menstruation) of all control cycles lasted 12.8 days. Daily plasma samples were collected for radioimmunoassay (RIA) of progesterone, immunoreactive oestrogens and LH. After a control cycle =
the first treatment was carried out with DES. The third and the fifth cycle were control cycles again. The EEM-treatment was done in the fourth cycle. Although the effect of the two compounds was different, a dependence of the age of the corpus luteum (CL) could be demonstrated for both. DES-treatment lowered plasma progesterone levels during administration. This effect was only demonstrable if the treatment was begun on the day of the LH-peak. The length of the CL-phase remained unaltered. EEM-treatment if started on the day of the LH surge, suppressed corpus luteum function in the late luteal phase. If the treatment was started later, the effect was less pronounced. The administration of both compounds did not shorten the time between ovulation and the next
preliminary report was given at the IX Acta Endocrinologica Congress in Oslo 1973. Diethylstilboestroldiphosphate (Cyren B®) was supplied by Bayer and 17a-ethinyloestradiol-3-methylether (Mestranol®) by Merck, both FRG. A
bleeding.
After DES-treatment this interval
was
not altered. After EEM\x=req-\
subsequent bleeding was even delayed depending decreasing levels of plasma oestrogens.
treatment the
on
slowly
well documented that the post-coital administration of high doses of oestrogens interfere with implantation in women (Morris Sc Van Wagenen 1969; Haspels 1970; Kuchera 1971). The possible modes of action include: 1. Rapid expulsion of the ovum from the tube and uterus, 2. Alterations of endometrial enzyme activity, particularly carbonic anhydrase levels (Makler 8c Morris 1971), 3. Interference with corpus luteum function. In non-primate species (Akbar et al. 1971; Blatchley et al. 1971), in monkeys (Auletta et al. 1972; Karsh et al. 1972) and also recently in women (Gore et al. 1973; Board et al. 1973; Lehmann et al. 1973), post-ovulatory administered oestrogens have been shown to reduce levels of circulating progesterone. The present study was designed to determine how a treatment with an oestradiol derivative as EEM influences the progesterone production of the CL, compared to a DES-treatment, as other investigators (Gore et al. 1973; Board et al. 1973) restricted their observations to the effect of DES. It
was
MATERIAL AND METHODS
Five normal healthy women, ovulating regularly, volunteered for this study. Each volunteer registered the basal body temperature during three control cycles and during the two treatment cycles. Blood was obtained daily throughout all five cycles. The midcycle LH-peak was detected by RIA-procedure. The assay is described in details elsewhere (Czygan et al. 1972). The oestrogen peak at midcycle was located by the measurement of immunoreactive oestrogens in a RIA utilizing an antiserum against oestradiol-17/?, which cross-reacts with oestrone (37°/o) and oestriol (7 %>) (Lehmann et al. 1972). Plasma progesterone levels were determined by RIA using a specific antiserum with negligible cross-reactions (Hoffmann et al. 1973). Sixty mg DES was given daily for 5 days in the first treatment cycle and 30 mg EEM was administered daily for 5 days in the second treatment cycle. Both compounds were given after a rapid 8 hour determination of the plasma oestrogen pattern to determine that ovulation occurred at the appropriate day.
RESULTS
in which DES was administered only a slight suppression of plasma progesterone levels was found. Furthermore this weak effect was ex¬ clusively seen when the drug administration was started on the day of ovula¬ tion (Table 1). In addition DES-treatment lowered plasma progesterone levels
In all five
cycles
Table 1. The effect of 60 mg DES per day on the length of the luteal phase (in terms of days with progesterone plasma levels > 0.5 ng/ml) and the sum of daily levels of plasma progesterone summarized from the day of the LH surge to the day of the onset of menstruation in one treatment as compared to two control cycles. Treated cycle
Control cycle
Substance: DES
mg per number start days luteal doy of days after U4 peak phase
Difference
Control cycle
luteal
luteal
prog ng
luteal
phase
prog ng
phase
prog, ng
15
183.5
12
80.5
12
133.5
60
13
152.0 13
116.5
U
177.0
60
13
129.5
99.0
13
149.5
60
12
phase
prog ng
Subject
-103 5_
K.H.
-53 5
_3_5.5
6Q5 -30.5
5Ô.5 D.I. 43
-
13
60
170.0
12
127.0
12
156.0 -
12
60 mean
1.4
Ml.5
12
159.5
12
D.E.
172.5
13.2 155.3 12.2 116.5 12.6 157.7 -0.7
"29"
Z.G.
13
Sch.F
40.0
mIU/ml 50 LH
D,E
ÖESmg/die I I I I I
60 60 60
progesterone
ng/ml
20
1 23-56789 10 1112 13
1 3 20
Fig.
25
WZL WrCC ZZZtc .
..
1.
Plasma levels of progesterone during the luteal phase of two control cycles (cc 1.3) as compared to levels during treatment with 60 mg diethylstilboestroldiphosphate (DES) daily for 5 days starting on the day of the LH surge (tc 2).
mIU/ml 50
DES mg /die 60 60 60
progesterone 20
ng/ml
1 2 3 4 5 6 7 8 9101112
1,3
10
20
Fig
25
ce '///////. T777Z te
2.
Plasma levels of progesterone during the luteal phase of two control cycles (cc 1.3) as compared to levels during treatment with 60 mg DES for 5 days starting 4 days after the LH surge (tc 2).
only during days of administration (Fig. 1). If this therapy was started later in the luteal phase, no effect on plasma progesterone pattern could be detected (Fig. 2). No real shortening in the length of the CL-phase was observed. Plasma LH and plasma oestrogens were not different as compared to the con¬ trol cycles. In the other five treatment cycles (EEM administration) a decrease in plasma progesterone occurred not earlier than 4 to 5 days after start of therapy. In two of these cycles in which the treatment was started on the day of the LHsurge, the differences were as evident as in one cycle in which treatment was started one day after the LH-peak (Fig. 3). In another cycle in which the oestrogen administration started one day after the ovulation the differences were less pronounced (Table 2, D. I.). If the treatment was started on day 3 after ovulation, the decline of the plasma progesterone levels occurred only 1 to 2 days earlier as compared to the control cycles (Fig. 4). Plasma LH-levels were not altered in all cycles studied. There was no shortening of the length of the cycle. In contrast to the experience with the DES-administration after EEM-treatment, the next bleeding was delayed. Fig. 5 shows the increasing plasma levels of immuno¬ reactive oestrogens following the EEM-treatment. Peak levels of about 4 to 5
mIU/ml 50 LH
D.E
EEM
mg/die lililí 30 30
progesterone 20
ng/ml
15 10 5 1 2 3 4 5 6 7 8 9 1011 12
14
3,5 ce
4
10
15
25
20
fig.
bleeding
42 days after
ovulation
3.
Plasma levels of progesterone during the luteal phase of two control cycles (cc 3.5) as compared to levels during treatment with 30 mg 17a-ethinyl-oestradiol-3-methylether (EEM) daily for 5 days starting on the day of the LH surge (tc 4).
Table 2. The effect of 30 mg EEM per day on the length of the luteal phase (in terms of days with progesterone plasma levels > 0.5 ng/ml) and the sum of daily levels of plasma progesterone summarized from the day of onset of menstruation in one treatment cycle as
compared
Control cycle
Substance: EEM
mg per number start days luteal day of days after LH peak phase
12
30
prog.
to two control
Treated cycle luteal
phase
133.5
cycles.
Control cycle luteal
prog ng
phase
prog ng
89.0
12
164.5
Difference luteal
phase 3
prog ng
Subject
zk'tk. KH -75 5
30
U
177.0
69.0
14
30
13
M9.5
65.5
13
1605 -__66" -108_0 91.5" D.E. -_84_0 159.5 '--_J_ "- 940 D.I. 7
30
12
156.0
116.0
12
138.0
z^Q.O
145.5
- 2-0 Sch.F 15. Ö"
-
-
10
-
22.0m
-
30
12
172.5
11
130.5
12
-
mean
1.2
126 157.7
8.8
94.0
12.6
153.6
3ß
-61.5
Z.G.
mIU/ml
EEM mg/die
30 30 30
progesterone
ng/ml
6 7 8 9 101112
20
Fig.
2S
hum bleeding
ovulation
cc
44 days after
4.
Plasma levels of progesterone during the luteal phase of two control cycles as compared to levels during treatment with 30 mg EEM daily for 5 days 3 days after the LH surge (tc 4).
(cc 3.5) starting
pg/mt immunoreactive estrogens 30 303030X
prior to the next ovutaltor
ELH1 2345678 910111213
Fig.
5.
Plasma levels of immunoreactive oestrogens during the EEM treatment (30 mg daily for 5 days) as compared to a control cycle. (E midcycle oestrogen peak, LH day of the LH surge). All cycles are synchronized on day 1 as starting point for drug administration. =
=
ensuing menstrual bleeding after this treatment occurred days after the LH surge and 16, 24, 40 and 41 days after the start of the treatment, respectively. All subjects had a normal ovulatory cycle following the EEM-treatment, though one had no bleeding between the EEM-treatment and the following spontaneous cycle. The treatment in this woman started on the day of the LH-peak.
ng
were
reached. The
19, 24. 42 and 44
DISCUSSION
explanations for the antifertility effect of post-coital administered oestrogens are: changes in the endometrial content of carbonic anhydrase (Board 1970) and upset in the mechanisms of tubai transport of ova (Chang Sc Yanagimachi 1965). High doses of ethinyloestradiol have been shown to be ineffective in interfering with early pregnancy, when treatment was started 7 or more days after ovulation (Bacie et al. 1970). This observation fits in well with the assumption that a disruption in the normal hormone sequence after ovulation is important for the antifertility effect (Gore et al. 1973). Several investigators were able to demonstrate an effect of post-ovulatory oestrogens on plasma progesterone levels (Gore et al 1973; Board et al. 1973; Lehmann et al. 1973); other investigators did see minor changes after 10 mg oestradiolbenzoate im for 5 days which might be beyond the minimal effective doses (Cortes et al. 1973). Comparable minor changes were reported by Johansson 8c Gemzell (1971) who administered 0.2 mg ethinyloestradiol per day for 8 days. Another explanation as mentioned above has also to be taken into considera¬ tion: The imbalance between oestrogenic and progestogenic activity in plasma may lead to an inadequate secretory transformation of the endometrium. This might be of more importance in preventing implantation, than suppression of plasma progesterone levels alone, since both drugs have similar effects in pre¬ venting implantation and different effects on the corpus luteum function. Time dependence in the success of the therapy supports this conclusion, as endogenous progesterone levels may already lead to a sufficient secretory
Possible
transformation of the endometrium if the treatment is started too late in the luteal phase. ACKNOWLEDGMENTS The skilful technical assistance of Miss E. Adloff is acknowledged. We are grateful to Dr. A. Hoffmann for providing the specific antiserum for the progesterone RIA and to Dr. I. Dyrenfurth supplying us with the oestradiol- 17/?-antiserum. The study was supported by Deutsche Forschungsgemeinschaft Sonderforschungs¬ bereich 34 Endokrinologie. -
-
REFERENCES Akbar . ., Rowe . E. Se Stormshak F.: J. Animai. Sci. 33 Auletta F. ]., Caldwell B. V., van Wagenen G. Sc Morris
(1972)
(1971) 426. J. Ai.: Contraception
6
411.
Bacie Ai., Wesselins de
(1970) 531. Blatchley F. R.,
Casparis
A. 8c
Diczfalusy
E.: Amer.
J. Obstet. Gynec.
107
Donovan B. T., Poyser N. L., Horton E. W., Thompson C. J. Se Los M.: Nature (Lond.) 230 (1971) 243. Board J. .: Obstet, and Gynec. 36 (1970) 347. Board J. ., Bhatnagar A. S. 8e Bush C. W.: Fértil, and Steril. 24 (1973) 95. Chang M. C. Se Yanagimachi R.: Fértil, and Steril. 16 (1965) 281. Cortes ]., Bagzgoitia ]., Ruiz M. C. Sc Oriol-Bosch .: Acta endocr. (Kbh.) Suppl. 177
(1973) 133. Czygan P.-]., Lehmann F., (1972) 417.
Breckwoldt M. Se
Bettendorf G.:
Acta endocr.
(Kbh.)
70
Gore . ., Caldwell B. W. Se Speroff E.: J. clin. Endocr. 36 (1973) 615. World Congress of Gynaecology and Obstetrics, New York
Haspels . .: Proc. VI (Abstract) (1970) 9.
Hoffmann B., Kyrein H. J.
Sc Ender Ai. L.: Hormone Res. 4 (1973) 302. E. D. B. Se Gemzell C: Acta endocr. (Kbh.) 68 (1971) 551. Karsli F. ]., Weick R. F., Dierschke D. J., Krey L. J., Hotchkiss J., Yamaji T. Se Knobil E.: Proc. IV Intern. Congr. Endocr. Washington, Abstract (1972) 63. Kuchera L. K.: J. Amer. med. Ass. 218 (1971) 562. Lehmann F., Bettendorf G., Peters F. 8c Czygan P.-J.: Acta endocr. (Kbh.) Suppl. 177 (1973) 135. Lehmann f., Gordis /., Neale C. Se Bettendorf G. In: Kaiser E., Ed. Fortschritte der klinischen Chemie, Enzyme und Hormone. Verlag der Wiener Medizinischen Aka¬ demie (1972) 501. Makler A. 8c Morris J. M.: Fértil, and Steril. 22 (1971) 204. Morris J. M. Se van Wagenen G. In: Sobrero A. J. and Lewit S., Eds. Advances in Planned Parenthood, vol. 4. Excerpta med. (Amst.) (1969) 125.
Johansson
Received
on
August 13th,
1974.
EFFECT OF POST-OVULATORY ADMINISTERED OESTROGENS ON CORPUS LUTEUM FUNCTION
By F. Lehmann, I.
Just-Nastansky, B. Behrendt, P.-J. Czygan and G. Bettendorf ABSTRACT
The effect of
orally given diethylstilboestroldiphosphate (DES) and 17\g=a\\x=req-\ ethinyl-oestradiol-3-methylether (EEM) on plasma progesterone levels was studied. Both compounds were administered for 5 days to 5 women in daily doses of 60 mg (DES) and 30 mg (EEM). The fully informed volunteers were found to have a normal menstrual cycle before the study. The mean corpus luteum phase (corpus luteum phase days between LH surge and onset of menstruation) of all control cycles lasted 12.8 days. Daily plasma samples were collected for radioimmunoassay (RIA) of progesterone, immunoreactive oestrogens and LH. After a control cycle =
the first treatment was carried out with DES. The third and the fifth cycle were control cycles again. The EEM-treatment was done in the fourth cycle. Although the effect of the two compounds was different, a dependence of the age of the corpus luteum (CL) could be demonstrated for both. DES-treatment lowered plasma progesterone levels during administration. This effect was only demonstrable if the treatment was begun on the day of the LH-peak. The length of the CL-phase remained unaltered. EEM-treatment if started on the day of the LH surge, suppressed corpus luteum function in the late luteal phase. If the treatment was started later, the effect was less pronounced. The administration of both compounds did not shorten the time between ovulation and the next
preliminary report was given at the IX Acta Endocrinologica Congress in Oslo 1973. Diethylstilboestroldiphosphate (Cyren B®) was supplied by Bayer and 17a-ethinyloestradiol-3-methylether (Mestranol®) by Merck, both FRG. A
bleeding.
After DES-treatment this interval
was
not altered. After EEM\x=req-\
subsequent bleeding was even delayed depending decreasing levels of plasma oestrogens.
treatment the
on
slowly
well documented that the post-coital administration of high doses of oestrogens interfere with implantation in women (Morris Sc Van Wagenen 1969; Haspels 1970; Kuchera 1971). The possible modes of action include: 1. Rapid expulsion of the ovum from the tube and uterus, 2. Alterations of endometrial enzyme activity, particularly carbonic anhydrase levels (Makler 8c Morris 1971), 3. Interference with corpus luteum function. In non-primate species (Akbar et al. 1971; Blatchley et al. 1971), in monkeys (Auletta et al. 1972; Karsh et al. 1972) and also recently in women (Gore et al. 1973; Board et al. 1973; Lehmann et al. 1973), post-ovulatory administered oestrogens have been shown to reduce levels of circulating progesterone. The present study was designed to determine how a treatment with an oestradiol derivative as EEM influences the progesterone production of the CL, compared to a DES-treatment, as other investigators (Gore et al. 1973; Board et al. 1973) restricted their observations to the effect of DES. It
was
MATERIAL AND METHODS
Five normal healthy women, ovulating regularly, volunteered for this study. Each volunteer registered the basal body temperature during three control cycles and during the two treatment cycles. Blood was obtained daily throughout all five cycles. The midcycle LH-peak was detected by RIA-procedure. The assay is described in details elsewhere (Czygan et al. 1972). The oestrogen peak at midcycle was located by the measurement of immunoreactive oestrogens in a RIA utilizing an antiserum against oestradiol-17/?, which cross-reacts with oestrone (37°/o) and oestriol (7 %>) (Lehmann et al. 1972). Plasma progesterone levels were determined by RIA using a specific antiserum with negligible cross-reactions (Hoffmann et al. 1973). Sixty mg DES was given daily for 5 days in the first treatment cycle and 30 mg EEM was administered daily for 5 days in the second treatment cycle. Both compounds were given after a rapid 8 hour determination of the plasma oestrogen pattern to determine that ovulation occurred at the appropriate day.
RESULTS
in which DES was administered only a slight suppression of plasma progesterone levels was found. Furthermore this weak effect was ex¬ clusively seen when the drug administration was started on the day of ovula¬ tion (Table 1). In addition DES-treatment lowered plasma progesterone levels
In all five
cycles
Table 1. The effect of 60 mg DES per day on the length of the luteal phase (in terms of days with progesterone plasma levels > 0.5 ng/ml) and the sum of daily levels of plasma progesterone summarized from the day of the LH surge to the day of the onset of menstruation in one treatment as compared to two control cycles. Treated cycle
Control cycle
Substance: DES
mg per number start days luteal doy of days after U4 peak phase
Difference
Control cycle
luteal
luteal
prog ng
luteal
phase
prog ng
phase
prog, ng
15
183.5
12
80.5
12
133.5
60
13
152.0 13
116.5
U
177.0
60
13
129.5
99.0
13
149.5
60
12
phase
prog ng
Subject
-103 5_
K.H.
-53 5
_3_5.5
6Q5 -30.5
5Ô.5 D.I. 43
-
13
60
170.0
12
127.0
12
156.0 -
12
60 mean
1.4
Ml.5
12
159.5
12
D.E.
172.5
13.2 155.3 12.2 116.5 12.6 157.7 -0.7
"29"
Z.G.
13
Sch.F
40.0
mIU/ml 50 LH
D,E
ÖESmg/die I I I I I
60 60 60
progesterone
ng/ml
20
1 23-56789 10 1112 13
1 3 20
Fig.
25
WZL WrCC ZZZtc .
..
1.
Plasma levels of progesterone during the luteal phase of two control cycles (cc 1.3) as compared to levels during treatment with 60 mg diethylstilboestroldiphosphate (DES) daily for 5 days starting on the day of the LH surge (tc 2).
mIU/ml 50
DES mg /die 60 60 60
progesterone 20
ng/ml
1 2 3 4 5 6 7 8 9101112
1,3
10
20
Fig
25
ce '///////. T777Z te
2.
Plasma levels of progesterone during the luteal phase of two control cycles (cc 1.3) as compared to levels during treatment with 60 mg DES for 5 days starting 4 days after the LH surge (tc 2).
only during days of administration (Fig. 1). If this therapy was started later in the luteal phase, no effect on plasma progesterone pattern could be detected (Fig. 2). No real shortening in the length of the CL-phase was observed. Plasma LH and plasma oestrogens were not different as compared to the con¬ trol cycles. In the other five treatment cycles (EEM administration) a decrease in plasma progesterone occurred not earlier than 4 to 5 days after start of therapy. In two of these cycles in which the treatment was started on the day of the LHsurge, the differences were as evident as in one cycle in which treatment was started one day after the LH-peak (Fig. 3). In another cycle in which the oestrogen administration started one day after the ovulation the differences were less pronounced (Table 2, D. I.). If the treatment was started on day 3 after ovulation, the decline of the plasma progesterone levels occurred only 1 to 2 days earlier as compared to the control cycles (Fig. 4). Plasma LH-levels were not altered in all cycles studied. There was no shortening of the length of the cycle. In contrast to the experience with the DES-administration after EEM-treatment, the next bleeding was delayed. Fig. 5 shows the increasing plasma levels of immuno¬ reactive oestrogens following the EEM-treatment. Peak levels of about 4 to 5
mIU/ml 50 LH
D.E
EEM
mg/die lililí 30 30
progesterone 20
ng/ml
15 10 5 1 2 3 4 5 6 7 8 9 1011 12
14
3,5 ce
4
10
15
25
20
fig.
bleeding
42 days after
ovulation
3.
Plasma levels of progesterone during the luteal phase of two control cycles (cc 3.5) as compared to levels during treatment with 30 mg 17a-ethinyl-oestradiol-3-methylether (EEM) daily for 5 days starting on the day of the LH surge (tc 4).
Table 2. The effect of 30 mg EEM per day on the length of the luteal phase (in terms of days with progesterone plasma levels > 0.5 ng/ml) and the sum of daily levels of plasma progesterone summarized from the day of onset of menstruation in one treatment cycle as
compared
Control cycle
Substance: EEM
mg per number start days luteal day of days after LH peak phase
12
30
prog.
to two control
Treated cycle luteal
phase
133.5
cycles.
Control cycle luteal
prog ng
phase
prog ng
89.0
12
164.5
Difference luteal
phase 3
prog ng
Subject
zk'tk. KH -75 5
30
U
177.0
69.0
14
30
13
M9.5
65.5
13
1605 -__66" -108_0 91.5" D.E. -_84_0 159.5 '--_J_ "- 940 D.I. 7
30
12
156.0
116.0
12
138.0
z^Q.O
145.5
- 2-0 Sch.F 15. Ö"
-
-
10
-
22.0m
-
30
12
172.5
11
130.5
12
-
mean
1.2
126 157.7
8.8
94.0
12.6
153.6
3ß
-61.5
Z.G.
mIU/ml
EEM mg/die
30 30 30
progesterone
ng/ml
6 7 8 9 101112
20
Fig.
2S
hum bleeding
ovulation
cc
44 days after
4.
Plasma levels of progesterone during the luteal phase of two control cycles as compared to levels during treatment with 30 mg EEM daily for 5 days 3 days after the LH surge (tc 4).
(cc 3.5) starting
pg/mt immunoreactive estrogens 30 303030X
prior to the next ovutaltor
ELH1 2345678 910111213
Fig.
5.
Plasma levels of immunoreactive oestrogens during the EEM treatment (30 mg daily for 5 days) as compared to a control cycle. (E midcycle oestrogen peak, LH day of the LH surge). All cycles are synchronized on day 1 as starting point for drug administration. =
=
ensuing menstrual bleeding after this treatment occurred days after the LH surge and 16, 24, 40 and 41 days after the start of the treatment, respectively. All subjects had a normal ovulatory cycle following the EEM-treatment, though one had no bleeding between the EEM-treatment and the following spontaneous cycle. The treatment in this woman started on the day of the LH-peak.
ng
were
reached. The
19, 24. 42 and 44
DISCUSSION
explanations for the antifertility effect of post-coital administered oestrogens are: changes in the endometrial content of carbonic anhydrase (Board 1970) and upset in the mechanisms of tubai transport of ova (Chang Sc Yanagimachi 1965). High doses of ethinyloestradiol have been shown to be ineffective in interfering with early pregnancy, when treatment was started 7 or more days after ovulation (Bacie et al. 1970). This observation fits in well with the assumption that a disruption in the normal hormone sequence after ovulation is important for the antifertility effect (Gore et al. 1973). Several investigators were able to demonstrate an effect of post-ovulatory oestrogens on plasma progesterone levels (Gore et al 1973; Board et al. 1973; Lehmann et al. 1973); other investigators did see minor changes after 10 mg oestradiolbenzoate im for 5 days which might be beyond the minimal effective doses (Cortes et al. 1973). Comparable minor changes were reported by Johansson 8c Gemzell (1971) who administered 0.2 mg ethinyloestradiol per day for 8 days. Another explanation as mentioned above has also to be taken into considera¬ tion: The imbalance between oestrogenic and progestogenic activity in plasma may lead to an inadequate secretory transformation of the endometrium. This might be of more importance in preventing implantation, than suppression of plasma progesterone levels alone, since both drugs have similar effects in pre¬ venting implantation and different effects on the corpus luteum function. Time dependence in the success of the therapy supports this conclusion, as endogenous progesterone levels may already lead to a sufficient secretory
Possible
transformation of the endometrium if the treatment is started too late in the luteal phase. ACKNOWLEDGMENTS The skilful technical assistance of Miss E. Adloff is acknowledged. We are grateful to Dr. A. Hoffmann for providing the specific antiserum for the progesterone RIA and to Dr. I. Dyrenfurth supplying us with the oestradiol- 17/?-antiserum. The study was supported by Deutsche Forschungsgemeinschaft Sonderforschungs¬ bereich 34 Endokrinologie. -
-
REFERENCES Akbar . ., Rowe . E. Se Stormshak F.: J. Animai. Sci. 33 Auletta F. ]., Caldwell B. V., van Wagenen G. Sc Morris
(1972)
(1971) 426. J. Ai.: Contraception
6
411.
Bacie Ai., Wesselins de
(1970) 531. Blatchley F. R.,
Casparis
A. 8c
Diczfalusy
E.: Amer.
J. Obstet. Gynec.
107
Donovan B. T., Poyser N. L., Horton E. W., Thompson C. J. Se Los M.: Nature (Lond.) 230 (1971) 243. Board J. .: Obstet, and Gynec. 36 (1970) 347. Board J. ., Bhatnagar A. S. 8e Bush C. W.: Fértil, and Steril. 24 (1973) 95. Chang M. C. Se Yanagimachi R.: Fértil, and Steril. 16 (1965) 281. Cortes ]., Bagzgoitia ]., Ruiz M. C. Sc Oriol-Bosch .: Acta endocr. (Kbh.) Suppl. 177
(1973) 133. Czygan P.-]., Lehmann F., (1972) 417.
Breckwoldt M. Se
Bettendorf G.:
Acta endocr.
(Kbh.)
70
Gore . ., Caldwell B. W. Se Speroff E.: J. clin. Endocr. 36 (1973) 615. World Congress of Gynaecology and Obstetrics, New York
Haspels . .: Proc. VI (Abstract) (1970) 9.
Hoffmann B., Kyrein H. J.
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Johansson
Received
on
August 13th,
1974.
