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Comparative studies on two combination oral contraceptives, one containing synthetic estrogen, the other “natural” estrogens
CONTRACEPTION
COMPARATIVE STUDIES ON TWO COMBINATION ORAL CONTRACEPTIVES, ONE CONTAINING SYNTHETIC ESTROGEN, THE OTHER "NATURAL" ESTROGENS
D.M. Saunders, M.D., M.R.C.O.G., F.R.A.C.S. B. Shuter, M,Sc., B.A. R.P. Shearman, M.D., F.R.C.O.G., D.G.O.
Department of Obstetrics and Gynaecology, IJniversityof Sydney, Sydney, Australia
ABSTRACT Two combined oral contraceptives, one containing ethinyl estradiol and the other micronized estradiol and estriol,were compared by measuring a variety of endocrine and renal parameters over nine months. Significant changes were observed in plasma renin activity (P.R.A.) on the synthetic estrogen. Much larger changes were observed in the total urinary estrogens on patients taking the "natural" estrogens reflecting the amount of estrogens required to be excreted in the urine.
Accepted
for
NOVEMBER
publication
October
1978 VOL. 18 NO. 5
17,
1978
527
CONTRACEPTION
INTRODUCTION Despite the reduction in the amount of ethinyl estradiol in the combined oral contraceptive pill, adverse side effects involving many systems are still causing concern. Widholm -et al. (1) suggested that combined oral contraceptives, using conjugated estrogens with megestrol acetate,might be a suitable alternative. This combination was well tolerated, but had an unacceptable pregnancy rate. Micronised estradiol is a natural estrogen which is readily absorbed orally, and ha? been used as an effective oral contraceptive when combined with norethindrone (2). Oral contraceptives have been shown to induce hypertension in some individuals to a mild degree (3). Many mechanisms have been postulated (4) including changes in the renin-angiotensin-aldosterone system and renal sodium and water handling, but the activation of the renin-angiotensin-aldosterone system with synthetic estrogens has been clearly shown (5). No long-term studies involving "natural" estrogen oral contraceptives have been carried out. A study was undertaken to compare the effect of two combined oral contraceptives, one containing natural estrogens and the other a synthetic estrogen, on a wide variety of endocrine and renal parameters. It was hoped that if significant changes could be observed, then natural estrogens might reduce the incidence of undesirable side effects attributed to estrogens.
MATERIALS AND METHODS Study Subjects Sixteen volunteers (aged 20-35 years), with histories of regular menstrual cycles, and who were requiring contraception, but had not recently been taking oral contraceptives, were selected for this study. Ten patients concluded the study. Those dropping out did so for logistical rather than medical reasons. The oral contraceptives were supplied by the World Health Organisation (W.H.O.). There were 2 types of formulations administered in a double-blind fashion for 21 days each month for 9 months. The "natural" oral contraceptive contained 17@ estradiol 4 mg, estriol 2 mg and norethindrone acetate 3 mg (4 patients). The "synthetic" oral contraceptive contained ethinyl estradiol 5Oyg with norethindrone acetate 3 mg (6 patients). The patients were studied for one month before and two months after therapy.
528
NOVEMBER
1978 VOL. 118NO. 5
CONTRACEPTION
Laboratory
Methods
Tht biochemical
parameters
studied
TABLE Parameters
Follicle-stimulating Luteiniaing Prolactin Free
hormone
shown
Progesterone
(luteal)
activity
Renin
substrate
(RS)
Angiotensin
II (AII)
Aldosterone
(Aldo)
urinary
Urinary-free
(P)
(PRA)
estrogen
Normal
range
0 -
(FSH)
(E2)
I.
studied
(LH)
(luteal)
in Table
I
(hPr1)
estradiol
Renin
Total
hormone
are
11
mIU/ml
5 - 25
mIU/ml
4 - 22
x/ml
550 - 1280
pmol/l
30 - 100
nmol/i
140 - 360
fmol/l/s
380 - 1150
nmol/l
0 - 30 165 - 290 (luteal)
cortisol
22 - 104 000
pmol/l pm0111 pg/24h nmo1/24h
Assays for FSH, LH, hPr1, E, and P were carried out weekly for four weeks in the control cycle 2nd every two weeks for the nine treatment and follow-up months. Assays for the remainder were performed monthly. The samples were taken on any 2 days 2 weeks apart during the 21-day pill regimen and net during the pill-free week. The laboratory methods used were in routine use in the Regional Endocrine Laboratory of Royal Prince Alfred Hospital of Sydney.
RESULTS Both oral contraceptives were tolerated well and there were no pregnancies during the study. Blood pressure was measured at each visit during the study and showed no significant change in any patient. The mean values for the different parameters measured are shown in Table II for the oral contraceptive containing the synthetic estrogen ethinly estradiol, and in Table III for the natural estrogens estriol and estradiol. In the control and follow-up menstrual cycles, values for E 2, P and urinary total estrogens which show natural
NOVEMBER
1978 VOL. 18 NO. 5
529
CONTRACEPTION
530
.
.
.
N
La
+-
.
o\
.
.
N
VI
.
w
.
o\
NOVEMBER
. r-2
197X VOL. 18 NO. 5
11.0 + 83.1 + 16.1 + 127.8 -r 741.0 +
pmol/l
nmol/l
fmol/l/s
i.
1
ng/mi
nm0 1,’
pm01/
pmol/l
pg/ 24h
nmo1/24h
hPrl
E,
P
P.R.A.
R.S.
A.11
AldU
Urinary Estrogen
Urinary Cortisol 160
3.8
59.3
7.1
2.6
41.8
0.9
1.0
0.7
+
5.8
4.1
f 152
28.2 +
380
8.0 'r
16.8 +
mIU/ml
LH
6.8 +
mIU/ml
FSH
Control
f
42.6
0.6
25.4
2.1
0.9
1.4
130
2112
493
74
3.3
+
40
+ 308
+
9.9 +
1089.9 -r 245.5
213
2.1 +
93.0 +
15.7 +
12.4 +
'6.1 +
Treatment
patients)
7.4 +
42.6
1.5
8.8
0.7
143
35
439
f
+
+
9.4 +
44
13
41
2.2
855.0 1 154.3
127.2 + -
16.6 t
86.2 +
11.9 $
0.6
0.6
Follow-up
(4
15.6 +
Mean values (i S.E.M.! before, during and after "natural" estrogen therapy
TABLE III
CONTRACEPTION
variation within the in the luteal phase.
cycle,
With the exception of taking the natural estrogen the normal ranges.
were
only
the urinary preparation,
selected
total all
from
samples
taken
estrogens in the group values fell fairly near
Non-paired Student’s t-tests were carried out comparing the changes for each group between the control and the treatment cycles, the treatment cycles and the follow-up cycles. Where no significant differences were noted, the results were reanalysed using the paired t-test where sufficient control or follow-up values allowed. Al though smaller values of p were obtained in some cases, significance was not Some changes in the parameters for both contrareached (pa.05). ceptives bordered on significance, but the small numbers in the study and the wide range of normal values cast doubt on their acceptance. The only changes within each parameter where a level rose significantly when on the treatment and fell significantly after treatment was for PRA in the synthetic group (significant rise on treatment 0.05, ~~0.01; significant fall off treatment 0.1 >p >0.05) and for urinary estrogens in the “natural” group (rise on treatment 0.01, p \O.OOl; significant fall off treatment 0.01. p> 0.001). There was no significant increase in PRA during treatment in the “natural” group. There was no significant progressive change in any parameter over the 9 months in either group.
DISCUSSION There is no doubt that natural estrogens can be used with success The difficulties in relating a as combination oral contraceptives. variety of biochemical parameters to possible side effects in this study are exaggerated by control values with a wide range of normal It must be admitted that the wide and the necessarily small numbers. scatter of values brought about possibly by the irregular timing of the sample collection in this study may have obscured significant Changes were regarded as significant where there was a rise trends. in the mean values on the contraceptive followed by a fall in the Using these criteria there was a definite increase follow-up months. in PRA on the synthetic pill which was not seen on the natural pill. There were no other changes of significance seen except for the rise in This has been described previously (6) and total urinary estrogens. is not surprising in that it reflects the enormous amount of estrogens being taken and required to be excreted. It is in fact reassuring that no other parameter changed on the natural estrogen pill and suggests that these estrogens may be a useful area for future oral contraceptive research. The results also suggest parameters is not necessarily
532
that measuring different the way of identifying
NOVEMBER
biochemical a causal
1978 VOL. 18 NO. 5
CONTRACEPTION
relationship (if one exists) between estrogens and side effects such as hypertension even over 9 months. As no side effects were observed in either group and in the natural estrogen group in our results question a relationship between biochemical particular, estrogens and side effects. indices,
ACKNOWLEDGEMENTS Laboratory facilities for this study were kindly supplied by Advice about the Professors Lazarus and Turtle and Dr. Tiller. statistics was given by Dr. Heady of the W.H.O. Special Program of Research in Human Reproduction which funded the study.
NOVEMBER
1978 VOL. 18 NO. 5
533
CONTRACEPTION
REFERENCES 1.
Widholm, O., Kaivola, S. and Timonen, S. The use of conjugated oestrogen in oral contraception. Ann. Chir. Gynaecol. Fenn. 63: 180-185, 1974.
2.
Astedt, B., Svanberg, L., Jeppsson, S., Liedholm, P. and Rannevik, G. The natural oestrogenic hormone oestradiol as a new component of combined oral contraceptives. Br. Med. J. 1: 269, 1977.
3.
Greenblatt, D.J. and Koch-Weser, J. A report from the Oral contraceptives and hypertension. Boston Collaborative Drug Surveillance Program. Obstet. Gynecol. 44: 412-417, 1974.
4.
Low, J. and Oparil, S. Oral contraceptive pill hypertension. J. Reprod. Med. 15: 201-208, 1975.
5.
Beckerhoff, R., Vetter, W., Armbruster, H., Luetscher, J.A. and Siegenthaler, W. Plasma aldosterone during oral contraceptive therapy. Lancet 1: 1218-1219, 1973.
6.
Saunders, D.M., Hunter, J.C., Shutt, D.A. and O'Neill, B.J. The effect of oestradiol valerate therapy on coagulation factors and lipid and oestrogen levels in oophorectomised women. Accepted for publication Aust. N.Z. J. Obstet. Gynaecol. 1978.
534
NOVEMBER
1978 VOL. 18 NO. 5
COMPARATIVE STUDIES ON TWO COMBINATION ORAL CONTRACEPTIVES, ONE CONTAINING SYNTHETIC ESTROGEN, THE OTHER "NATURAL" ESTROGENS
D.M. Saunders, M.D., M.R.C.O.G., F.R.A.C.S. B. Shuter, M,Sc., B.A. R.P. Shearman, M.D., F.R.C.O.G., D.G.O.
Department of Obstetrics and Gynaecology, IJniversityof Sydney, Sydney, Australia
ABSTRACT Two combined oral contraceptives, one containing ethinyl estradiol and the other micronized estradiol and estriol,were compared by measuring a variety of endocrine and renal parameters over nine months. Significant changes were observed in plasma renin activity (P.R.A.) on the synthetic estrogen. Much larger changes were observed in the total urinary estrogens on patients taking the "natural" estrogens reflecting the amount of estrogens required to be excreted in the urine.
Accepted
for
NOVEMBER
publication
October
1978 VOL. 18 NO. 5
17,
1978
527
CONTRACEPTION
INTRODUCTION Despite the reduction in the amount of ethinyl estradiol in the combined oral contraceptive pill, adverse side effects involving many systems are still causing concern. Widholm -et al. (1) suggested that combined oral contraceptives, using conjugated estrogens with megestrol acetate,might be a suitable alternative. This combination was well tolerated, but had an unacceptable pregnancy rate. Micronised estradiol is a natural estrogen which is readily absorbed orally, and ha? been used as an effective oral contraceptive when combined with norethindrone (2). Oral contraceptives have been shown to induce hypertension in some individuals to a mild degree (3). Many mechanisms have been postulated (4) including changes in the renin-angiotensin-aldosterone system and renal sodium and water handling, but the activation of the renin-angiotensin-aldosterone system with synthetic estrogens has been clearly shown (5). No long-term studies involving "natural" estrogen oral contraceptives have been carried out. A study was undertaken to compare the effect of two combined oral contraceptives, one containing natural estrogens and the other a synthetic estrogen, on a wide variety of endocrine and renal parameters. It was hoped that if significant changes could be observed, then natural estrogens might reduce the incidence of undesirable side effects attributed to estrogens.
MATERIALS AND METHODS Study Subjects Sixteen volunteers (aged 20-35 years), with histories of regular menstrual cycles, and who were requiring contraception, but had not recently been taking oral contraceptives, were selected for this study. Ten patients concluded the study. Those dropping out did so for logistical rather than medical reasons. The oral contraceptives were supplied by the World Health Organisation (W.H.O.). There were 2 types of formulations administered in a double-blind fashion for 21 days each month for 9 months. The "natural" oral contraceptive contained 17@ estradiol 4 mg, estriol 2 mg and norethindrone acetate 3 mg (4 patients). The "synthetic" oral contraceptive contained ethinyl estradiol 5Oyg with norethindrone acetate 3 mg (6 patients). The patients were studied for one month before and two months after therapy.
528
NOVEMBER
1978 VOL. 118NO. 5
CONTRACEPTION
Laboratory
Methods
Tht biochemical
parameters
studied
TABLE Parameters
Follicle-stimulating Luteiniaing Prolactin Free
hormone
shown
Progesterone
(luteal)
activity
Renin
substrate
(RS)
Angiotensin
II (AII)
Aldosterone
(Aldo)
urinary
Urinary-free
(P)
(PRA)
estrogen
Normal
range
0 -
(FSH)
(E2)
I.
studied
(LH)
(luteal)
in Table
I
(hPr1)
estradiol
Renin
Total
hormone
are
11
mIU/ml
5 - 25
mIU/ml
4 - 22
x/ml
550 - 1280
pmol/l
30 - 100
nmol/i
140 - 360
fmol/l/s
380 - 1150
nmol/l
0 - 30 165 - 290 (luteal)
cortisol
22 - 104 000
pmol/l pm0111 pg/24h nmo1/24h
Assays for FSH, LH, hPr1, E, and P were carried out weekly for four weeks in the control cycle 2nd every two weeks for the nine treatment and follow-up months. Assays for the remainder were performed monthly. The samples were taken on any 2 days 2 weeks apart during the 21-day pill regimen and net during the pill-free week. The laboratory methods used were in routine use in the Regional Endocrine Laboratory of Royal Prince Alfred Hospital of Sydney.
RESULTS Both oral contraceptives were tolerated well and there were no pregnancies during the study. Blood pressure was measured at each visit during the study and showed no significant change in any patient. The mean values for the different parameters measured are shown in Table II for the oral contraceptive containing the synthetic estrogen ethinly estradiol, and in Table III for the natural estrogens estriol and estradiol. In the control and follow-up menstrual cycles, values for E 2, P and urinary total estrogens which show natural
NOVEMBER
1978 VOL. 18 NO. 5
529
CONTRACEPTION
530
.
.
.
N
La
+-
.
o\
.
.
N
VI
.
w
.
o\
NOVEMBER
. r-2
197X VOL. 18 NO. 5
11.0 + 83.1 + 16.1 + 127.8 -r 741.0 +
pmol/l
nmol/l
fmol/l/s
i.
1
ng/mi
nm0 1,’
pm01/
pmol/l
pg/ 24h
nmo1/24h
hPrl
E,
P
P.R.A.
R.S.
A.11
AldU
Urinary Estrogen
Urinary Cortisol 160
3.8
59.3
7.1
2.6
41.8
0.9
1.0
0.7
+
5.8
4.1
f 152
28.2 +
380
8.0 'r
16.8 +
mIU/ml
LH
6.8 +
mIU/ml
FSH
Control
f
42.6
0.6
25.4
2.1
0.9
1.4
130
2112
493
74
3.3
+
40
+ 308
+
9.9 +
1089.9 -r 245.5
213
2.1 +
93.0 +
15.7 +
12.4 +
'6.1 +
Treatment
patients)
7.4 +
42.6
1.5
8.8
0.7
143
35
439
f
+
+
9.4 +
44
13
41
2.2
855.0 1 154.3
127.2 + -
16.6 t
86.2 +
11.9 $
0.6
0.6
Follow-up
(4
15.6 +
Mean values (i S.E.M.! before, during and after "natural" estrogen therapy
TABLE III
CONTRACEPTION
variation within the in the luteal phase.
cycle,
With the exception of taking the natural estrogen the normal ranges.
were
only
the urinary preparation,
selected
total all
from
samples
taken
estrogens in the group values fell fairly near
Non-paired Student’s t-tests were carried out comparing the changes for each group between the control and the treatment cycles, the treatment cycles and the follow-up cycles. Where no significant differences were noted, the results were reanalysed using the paired t-test where sufficient control or follow-up values allowed. Al though smaller values of p were obtained in some cases, significance was not Some changes in the parameters for both contrareached (pa.05). ceptives bordered on significance, but the small numbers in the study and the wide range of normal values cast doubt on their acceptance. The only changes within each parameter where a level rose significantly when on the treatment and fell significantly after treatment was for PRA in the synthetic group (significant rise on treatment 0.05, ~~0.01; significant fall off treatment 0.1 >p >0.05) and for urinary estrogens in the “natural” group (rise on treatment 0.01, p \O.OOl; significant fall off treatment 0.01. p> 0.001). There was no significant increase in PRA during treatment in the “natural” group. There was no significant progressive change in any parameter over the 9 months in either group.
DISCUSSION There is no doubt that natural estrogens can be used with success The difficulties in relating a as combination oral contraceptives. variety of biochemical parameters to possible side effects in this study are exaggerated by control values with a wide range of normal It must be admitted that the wide and the necessarily small numbers. scatter of values brought about possibly by the irregular timing of the sample collection in this study may have obscured significant Changes were regarded as significant where there was a rise trends. in the mean values on the contraceptive followed by a fall in the Using these criteria there was a definite increase follow-up months. in PRA on the synthetic pill which was not seen on the natural pill. There were no other changes of significance seen except for the rise in This has been described previously (6) and total urinary estrogens. is not surprising in that it reflects the enormous amount of estrogens being taken and required to be excreted. It is in fact reassuring that no other parameter changed on the natural estrogen pill and suggests that these estrogens may be a useful area for future oral contraceptive research. The results also suggest parameters is not necessarily
532
that measuring different the way of identifying
NOVEMBER
biochemical a causal
1978 VOL. 18 NO. 5
CONTRACEPTION
relationship (if one exists) between estrogens and side effects such as hypertension even over 9 months. As no side effects were observed in either group and in the natural estrogen group in our results question a relationship between biochemical particular, estrogens and side effects. indices,
ACKNOWLEDGEMENTS Laboratory facilities for this study were kindly supplied by Advice about the Professors Lazarus and Turtle and Dr. Tiller. statistics was given by Dr. Heady of the W.H.O. Special Program of Research in Human Reproduction which funded the study.
NOVEMBER
1978 VOL. 18 NO. 5
533
CONTRACEPTION
REFERENCES 1.
Widholm, O., Kaivola, S. and Timonen, S. The use of conjugated oestrogen in oral contraception. Ann. Chir. Gynaecol. Fenn. 63: 180-185, 1974.
2.
Astedt, B., Svanberg, L., Jeppsson, S., Liedholm, P. and Rannevik, G. The natural oestrogenic hormone oestradiol as a new component of combined oral contraceptives. Br. Med. J. 1: 269, 1977.
3.
Greenblatt, D.J. and Koch-Weser, J. A report from the Oral contraceptives and hypertension. Boston Collaborative Drug Surveillance Program. Obstet. Gynecol. 44: 412-417, 1974.
4.
Low, J. and Oparil, S. Oral contraceptive pill hypertension. J. Reprod. Med. 15: 201-208, 1975.
5.
Beckerhoff, R., Vetter, W., Armbruster, H., Luetscher, J.A. and Siegenthaler, W. Plasma aldosterone during oral contraceptive therapy. Lancet 1: 1218-1219, 1973.
6.
Saunders, D.M., Hunter, J.C., Shutt, D.A. and O'Neill, B.J. The effect of oestradiol valerate therapy on coagulation factors and lipid and oestrogen levels in oophorectomised women. Accepted for publication Aust. N.Z. J. Obstet. Gynaecol. 1978.
534
NOVEMBER
1978 VOL. 18 NO. 5