British Journal of Obstetrics and Gynaecolbgy September 1979. Vol. 86. pp 732-736
CLINICAL TRIAL OF A NEW ORAL CONTRACEPTIVE PILL CONTAINING THE NATURAL OESTROGEN 17P-OESTRADIOL BY
S. JEPPSSON P. LIEDHOLM G. RANNEViK AND
L. SVANBERG Department of Gynaecology and Obstetrics University of Lund, Malmo"Allmanna Sjukhus, S-214 01 Malmo, Sweden
Summary The natural oestrogen, 17P-oestradiol, has been shown not to depress fibrinolysis and apparently has less influence on liver function and lipid metabolism than ethinyl oestradiol, the synthetic oestrogen in conventional 'combined' oral contraceptive tablets. A triple-blind study was therefore made of 215 women during 2051 treatment cycles with oral contraceptives containing either (i) 4 mg of micronized 17p-oestradiol and 3 mg norethisterone (Netagen 403), (ii) 4 mg 17P-oestradiol plus 2 mg of oestriol and 3 mg norethisterone (Netagen 423) or (iii) 50 pg ethinyl oestradiol and 3 mg norethisterone (Netasyn). There were no pregnancies or thrombotic incidents. The numbers discontinuing treatment were about the same in the three groups, the main reasons being intermenstrual spotting in those on Netagen 423, amenorrhoea and weight gain in those on Netagen 403 and nausea and weight gain in those on Netasyn. The natural oestrogen showed promise as a new and safe component of the 'combined' pill. in most of the women with phlebographically proven deep vein thrombosis during oral contraceptive usage (Astedt et al, 1973). Ethinyl oestradiol has been shown to depress the fibrinolytic activator content of the vessel wall (Astedt, 1971). The natural oestrogen, 17Poestradiol, does not have this effect when given in biologically equivalent doses ( h t e d t and Jeppsson, 1974). It has also been shown that 17P-oestradiol impairs liver function less than ethinyl oestradiol (Jeppsson and Rannevik, 1976). Thus 17P-oestradiol is considered to be a safer component of combined oral contraceptives (Astedt, 1975) and the use of the hormone
THROMBOEMBOLISM, the most serious of the side effects ascribed to the use of oral contraceptives (Jordan, 1961; Vessey and Doll, 1968; Vessey and Doll, 1969), has been ascribed to the oestrogenic component of the pill (Grant, 1969; Inman et al, 1970; McQueen, 1970). Only two synthetic oestrogens, ethinyl oestradiol and mestranol, have been used in oral contraceptives, and several studies have been done to clarify their thrombogenic effect. In recent years a defect in the fibrinolytic activator content of vessel walls has been found in the majority of patients suffering from recurrent idiopathic thrombosis (Isacson and Nilsson, 1972) and also 732
TRIAL OF NATURAL OESTROGEN
has been studied in a small pilot series ( h t e d t et al, 1977). We now report controlled triple-blind study of 2051 cycles using combined oral contraceptives. All preparations had the same progestogen, but the oestrogen was either 17p-oestradiol, 17Poestradiol with oestriol or ethinyl oestradiol.
METHODS Patients were allocated in random and double-blind fashion to the taking of tablets containing: either (i) 4 mg of micronized 17p-oestradiol and 3 mg of norethisterone (Netagen 403); or (ii) 4 mg 17P-oestradiol with 2 mg of oestriol and 3 mg of norethisterone (Netagen 423) ; or (iii) 50 pg of ethinyl oestradiol and 3 mg of norethisterone (Netasyn). Tablets were taken for 21 days out of 28 in consecutive cycles. The study was approved by the Swedish Medical and Social Welfare Boards. The volunteers were 215 apparently healthy and normally menstruating women who gave their informed and full consent: 73 of them had used combined oral contraceptives or continuous low dose progestogens within 6 months of entering the study. Most of the women had expressed side effects with previous oral contraceptive therapy. Patients were seen and examined at 3, 6 and 12 months after entering the trial. Questions were asked about amenorrhoea, irregular bleeding, dysmenorrhoea, premenstrual tension, nausea and emotional disturbances and notes were made of weight gain in excess of 2 kg and/or diastolic pressures which had increased more than 20 mm Hg or were above 90 mm Hg (Weir et ai, 1971). The code was broken after volunteers had dropped out or had taken their tablets for one year.
RFBULTS No pregnancies and no thrombotic incidents occurred during the study (2051 cycles). The number of drop-outs was 31 out of 71 (44 per cent) for those taking Netagen 423, 39 out of 74 (53 per cent) for those taking Netagen 403 and 35 out of 70 (50 per cent) for those taking Netasyn. The number of cycles studied was 696 for Netagen 423, 655 for Netagen 403 and 700 for Netasyn. The distribution of women who had used oral contraceptives within 6 months of
entering the study was about the same in the three groups. The main reasons for drop-out and the interval between entering the study and drop-out are given in Table I. The main causes were spotting in those on Netagen 423, amenorrhoea and weight gain in those on Netagen 403 and nausea and weight gain in those on Netasyn. Table I1 gives the reasons for drop-out in 142 women who had not taken oral contraceptives in the 6 months preceding our study. The pattern was the same as that seen in Table I. No noteworthy side effects were observed among those who continued the trial. No patient had a diastolic blood pressure which rose by more than 20 mm Hg or exceeded 90 mm Hg.
DISCUSSION The most potent natural oestrogen hormone produced by the ovary is 17p-oestradiol and the hormone can also be obtained from soyabeans. It has been available for many years, but has hitherto proved unsuitable for oral use because it is not readily absorbed, a problem that has been solved by the use of the micronizing technique (Lebech and Svendsen, 1969; Lebech and Olsen, 1970; Gad et al, 1971) which leads to 90 per cent absorbtion (Lebech, 1978). We used 17p-oestradiol in a relatively large dose because it is metabolized so rapidly (Lebech, 1978). In a pilot study of 25 women on Netagen 403, no predominant side effect was noted (Astedt et al, 1977). The present study shows that the frequency of drop-out (44 per cent) was lowest in the Netagen 423 group. The corresponding figures for the Netagen 403 and the Netasyn groups were 53 per cent and 50 per cent respectively. The high frequency for drop-outs in all three groups is possibly due to the fact thst many of the women entered the study because of side effects experienced with the earlier oral contraceptives used. In the Netagen 403 group amenorrhoea was a common and unacceptable side effect, indicating that the relative content of norethisterone was too high. The addition of 2 mg of oestriol in the Netagen 423 reduced the frequency of amenorrhoea. In various conventional oral contraceptives, 50 pg of ethinyl oestradiol is balanced by 1 to 3 mg of norethisterone. Lowering of the norethisterone
ASTEDT, JEPPSSON, LIEDHOLM, RANNEVIK AND SVANBERG
TABLE I Main reasons for drop-out for all patients and months of administration before withdrawal Group 4 mg 17p-oestradiol
+2 mg oestriol +3 mg norethisterone (Netagen 423)
4 mg 17P-oestradiol
+ 3 mg norethisterone
0.05 mg ethinyl oestradiol t 3 mg norethisterone
Months of administration Reason for drop-out
Amenorrhoea Spotting Weight gain Depression Nausea Non-medical causes Unknown causes Miscellaneous
2 3 2 1
1 3 1
1 2 1
1 2 1
5 1 2
1 6 1
1 3 3
1 4 1 6 1 1 2
1 1 1
5 1 1
TABLE I1 Main reasons for drop-out in 142 women not using oral contraceptives during the 6 months preceding the study Group 4 mg 17P-oestradiol
Reason for drop-out Amenorrhoea spotting Weight gain Depression Nausea Non medical Unknown Miscellaneous Total
+2 mg oestriol +3 mg norethisterone (Netagen 423) 3 6 -
4 mg 17!3-0estradiol $3 mg norethisterone
0.05 mg ethinyl oestradiol +3 mg norethisterone
7 2 6
1 1 2
1 4 3
3 5 2
3 4 1
content of Netagen 403 would probably reduce the frequency of amenorrhoea. Weir et al(1971 and 1974) found an increase in the diastolic blood pressure in oral contraceptive users after four years but not after one year; thus the absence of significant rises in diastolic pressure in our patients may have been associated with too short an observation time.
Because of the suspected thrombogenic effect of oestrogens, the British Committee on Safety of Drugs recommended that the oestrogen content of oral contraceptives should not exceed 50 pg. This recommendation has been followed by most countries and in the British experience a decrease in the frequency of thrombosis seems to have occurred (Royal College of General
TRIAL. OF NATURAL OESTROGEN
Practitioners, 1974). The oestrogen content of some oral contraceptive preparations is as low as 30 pg; below this level adequate control of cyclical bleeding can probably not be achieved. Replacement of the synthetic oestrogens by l7p-oestradiol should be safer, because of its lack of depressive effect on the fibrinolytic defence system against thrombosis. The synthetic oestrogenic component of oral contraceptives appear to have an adverse effect on liver function (Rannevik et al, 1972). In women who had previously had hepatosis of pregnancy Jeppsson et al (1976) found that mestranol impaired liver function more than a biologically equivalent dose of 17P-oestradiol. It would also appear that Netagen 403 which contains 17P-oestradiol has less influence on lipid metabolism than does Netasyn, which contains ethinyl oestradiol (Samsioe, 1979). Administration of 17P-oestradiol might cause endometrial hyperplasia, however, the high frequency of amenorrhoea in the Netagen 403 group suggests the contrary. Oestrone and oestriol are metabolites of 17p-oestradiol. The reason why oestriol was added to one of the preparations was because oestrone appears to be mitogenic (Rubin et al, 1972; Siiteri et al, 1974; Siiteri, 1975) and oestriol is said to exert a protective effect (Lemon, 1973) by competing with oestrone for receptor binding sites (Siiteri, 1975). But 17P-oestradiol also has a higher affinity for oestrogen receptor sites than oestrone (Siiteri, 1975) and thus the value of adding oestriol is questionable. High levels of oestrone and oestrone sulphate have been found after the administration of 17P-oestradiol valerate (Anderson et al, 1978) or micronized 17Poestradiol (Dada et al, 1978). There is room for further study of serum levels of 17p-oestradiol and its metabolites before making adjustments to the components of Netagen. Brown and Blair (1960) found ethinyl oestradiol in the urine of women receiving norethisterone but Fotherby et a1 (1968) detected only minute amounts. We agree with Breuer (1970) who suggested that this may represent an artifact of chemical analysis rather than conversion of norethisterone to ethinyl oestradiol. The avoidance of thrombotic complications and adverse influences on liver function and
lipid metabolism form the main reasons for replacing synthetic oestrogens by 17P-oestradiol in oral contraceptives and with further adjustment of the balance between 17P-oestradiol and norethisterone there is promise of a new and convenient form of oral contraceptive therapy.
ACKNOWLEDGEMENTS The study was supported by grants from the Swedish Medical Research Council (B79-17X04523-05B). The coded series of Netagen 403, Netagen 423 and Netasyn were provided by Novo Pharmaceuticals, Denmark. REFERENCES Anderson, A. B. M., Sklovsky, E., Sayers, L., Steele, P. A., and Turnbull, A. C. (1978): British Medical Journal, 1,140. Astedt, B. (1971): Acta obstetricia et gynecologica Scandinavica, 50,279. Astedt, B. (1975): American Heart Journal, 90,l. Astedt, B., Isacson, S., Nilsson, I. M., and Pandolfi, M. (1973) :British Medical Journal, 4,63 1. Astedt, B., and Jeppsson, S. (1974): Journal of Obstetrics and GynaecoIogy of the British Commonwealth, 81, 719. Astedt, B., Svanberg, L., Jeppsson, S., Liedholm, P., and Rannevik, G. (1977): British Medical Journal, 1,269. Breuer, H. (1970):Lancet, 2,615. Brown, J. B., and Blair, H. A. F. (1960): Proceedings of the Royal Society of Medicine (London),53,433. Dada, 0.A., Laumas, V., Landgren, B-M., Cekan, S. Z., and Diczfalusy, E. (1978) : Acta endocrinologica, 88, 754. Fotherby, K., Kamyab, S., Littleton, P., and Klopper, A. I. (1968): Journal of Reproduction and Fertility. Supplement 5,51. Gad, C., Fischer, S., Lebech, P., and Wiese, J. (1971): Acta obstetricia et gynecologica Scandinavica, 50, Supplement 9,27. Grant, E. C. G. (1969): British MedicalJournal, 4,73. Inman, W. H. W., Vessey, M. P., Westerholm, B., and Engelund, A. (1970) : British Medical Journal, 2,203. Isacson, S., and Nilsson, I. M. (1972): Acta chirurgica Scandinavica, 138,3 1 3. Jeppsson, S., and Rannevik, G. (1976): British Journal of Obstetrics and Gynaecology,83,567. Jordan, W. M. (1961):Lancet, 2,1146. Lebech, P . E., and Svendsen, P. (1969): Acta endocrinoIogica, Supplement 138,227. Lebech, P. E., and Olsen, C. E. (1970): New Developments in GynaecoIogicaI Endocrinology, 2nd International Symposium of the R.C. Hospital, Sittard, The Netherlands.
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Lebech, P. E. (1978): International Symposium on Hormonal Contraception. Utrecht, The Netherlands. Excerpta Medica p. 33. Lemon, H. M. (1973): Lancet, 1,546. McQueen, E. G. (1970): New Zealand Medical Journal, 71,317. Rannevik, G., Jeppsson, S., and Kullander, S . (1972): Journal of Obstetrics and Gynaecology of the British Commonwealth,79,1128. Royal College of General Practitioners (1974): Oral contraceptives and health. An interim report from the oral contraceptive study of the Royal College of GeneralPractitioners. Pitman Medical, 1974. Rubin, B. L., Gusberg, S. B., Butterfly, J., Han, T. C., and Maralit, M. (1972): American Journal of Obstetricsand Gynecology,114,660.
Samsioe, G. (1979): Gynecologic and Obstetric Investigation, In press. Siiteri, P. K. (1975): Frontiers of Hormone Research (Basel), 3,40. Siiteri, P. K., Schwarz, B. E., and MacDonald, P. C. (1974): Gynecologic Oncology,2,228. Vessey, M. P., and Doll, R. (1968): British Medical Journal, 2,199. Vessey, M. P.. and Doll, R. (1969): British Medical Journal, 2,651. Weir, R. J., Briggs, E., Mack, A., Taylor, L., Browning, J., Naismith, L., and Wilson, E. (1971): Lancet, 1, 467. Weir, R. J., Briggs, E., Mack, A., Naismith, L., Taylor, L., and Wilson, E. (1974): British Medical Journal, 1,533.