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The effect of weekly administration of an oral progestogen -R 2323- on the ovarian function
The Effect of Weekly Administration of an Oral Progestogen - R 2 3 2 3 - on the Ovarian Function
Arne Victor and Elof D.B. Johansson Department of Obstetrics and Gynecology, University Hospital, Uppsala, Sweden
ABSTRACT An oral progestogen - R 2 3 2 3 - was given in the dose of 10 mg as a weekly contraceptive pill. The effect on the ovarian function was followed by measuring the plasma levels of progesterone and estradiol. Seventeen cycles were studied and, in three of these, ovulation occurred. In all other cycles, progesterone and estradiol were depressed to early follicular phase levels. Intermenstrual bleeding or spotting was noticed in all cycles except the ovulatory ones. It is concluded that R 2 3 2 3 in this dosage probably gives a better contraceptive effect than lower dosages. The occurrence ,of intermenstrual bleeding and spotting seems to be related to the timing of drug intake.
Accepted for publication May 16, 1975
JULY 1975
VOL. 12 NO. 1
89
CONTRACEPTION The use of continuous low dose gestagens for anticonceptional purpose though advantageous as far as diminishing serious side effects has some drawbacks. One of them is the increased risk for pregnancy once a pill is forgotten and the complications arising for the patient having to abstain from intercourse for some time or use additional contraceptives. From this point of view, it would be favourable if one could achieve an intermittent but regular dosage where one day's forgetfullness would not matter. The gestagen used in this study is 13-ethyl-17-hydroxy-18,19-dinor-17~-pregna4,9,11,-trien-20-yn-3-one (R 2323) 1. The structural formula is shown in Fig. 1. This steroid was found to possess a very strong antiprogesterone activity, a very low estrogenic activity, average progestomimetic and anti-estrogenic activity and a marked pituitary inhibitory activity in animal experiments (1). Furthermore, it possesses an hitherto unexplained inhibitory effect on implantation (1).
"'C=CH 0 Fig. I. Structural formula of R 2323.
R 2323 has been used in clinical trials in 2.5 and 5.0 mg doses given weekly (2). In the lower dosage, the pregnancy rate was unacceptably high, with a pregnancy rate resulting from method failure of 13.1 per hundred women years. In the 5.0 mg dosage, it had a moderate contraceptive effect with a total pregnancy rate of 8.7 in the first year of use of which 3.7 was attributed to method failure. Eighteen out of 33 cycles studied (55 %) in women treated with 2.5 or 5.0 mg R 2323 weekly were ovulatory (2, 3). The aim of this study was to investigate the effect on ovarian function using a higher dosage of 10 mg R 2323 administered once weekly.
MATERIAL
AND
METHODS
Nine healthy women with regular menstrual cycles volunteered for the study. Their ages ranged from 19 to 25 years and they were all hospital employees. No other contraceptives were used during the treatment period. Ten mg of R 2323 was given every Saturday for eight weeks, starting on the first Saturday following the beginning of the last menstrual bleeding. If the menstrual bleeding oc1Supplied by Roussel Uclef, Paris. France.
90
JULY 1975 VOL. 12 NO. 1
CONTRACEPTION curred on a Saturday, medication was started on the following Saturday. One patient was treated only four weeks because of technical difficulties with the blood sampling. Her recovery cycle was the second following medication. Blood samples for the estimation of progesterone and estradiol were obtained every Tuesday and Friday during the luteal phase of a control cycle preceding treatment, during treatment and during the rec:overy cycle following treatment. The one exception is mentioned above. Progesterone in plasma was determined by a competitive protein binding method (4). Estradiol in plasma was determined by radioimmunoassay (5)° excluding the thin layer chromatography step (6).
RESULTS All women had ovulatory control cycles before treatment as judged from their progesterone and estradiol levels. The lowest peak progesterone value for a single patient was 6.4 ng/ml. The cycle length of these control cycles was 2 9 - 3 7 days with a mean of 33.5 days, omitting two patients who could not remember the exact day of their last menstrual period. During the treatment all patients but one, had regular menstruation-like bleedings with an interval of 2 2 - 3 5 days (mean 27.4 days). One patient had irregular spotting during the entire treatment period. Excluding this patient, seven out of eight women experienced intermenstrual bleeding or spotting for 1-9 days during the treatment period (mean 3.5 days/patient). Out of a total of 33 bleeding episodes during or immediately after treatment, four appeared four days after medication, 21, five days after medication and seven, six days after medication. Intermenstrual bleeding or spotting occurred during all 17 treatment cycles except those three which were ovulatory. On three occasions, ovulation was recorded during treatment. One patient (Fig. 2) ovulated twice with peak progesterone values of 18.7 and 13.2 ng/ml, and one patient during her second treatment cycle with a peak progesterone value of 12.9 ng/ml. Ovulation thus occurred in three out of 17 treatment cycles (18 %). In all the other cycles of treatment, progesterone and estradiol were depressed to levels comparable to those found in the early follicular phase of the menstrual cycle. Fig. 3 shows the progesterone, estradiol and bleeding pattern typical for those women who did not ovulate during treatment. Excluding the patient with irregular spotting during the entire treatment period, the length of the recovery cycle varied between 15 and 42 days (mean 27.4 days) as measured from the last bleeding in connection with treatment. Measuring from the day of the last pill intake to the occurrence of bleeding, the cycle length was 2 0 - 4 0 days with an average of 29.2 days. No pregnancy occurred in this series and no patient complained of any more pronounced systemic side effects that could be related to treatment. The recovery cycle was ovulatory in all women.
JULY 1975 VOL. 12 NO. 1
91
CONTRACEPTION
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J U L Y 1975
V O L . 12 N O . 1
CONTRACEPTION
DISCUSSION The frequency of ovulation recorded in this study is lower (3/17 or 18 %) than what is reported in earlier studies using 2.5 or 5.0 mg R 2 3 2 3 weekly (2, 3). Out of 17 cycles studied using the 2.5 mg dosage, 11 (65 %) were ovulatory and out of 16 cycles using the 5.0 mg dosage, 7 (44 %) were ovulatory. The differences are statistically significant when tested with ),'Z-analysis (P <0.01 ). The number of ovulations found in this study compares favourably even to th~ rates found by Larsson-Cohn et a/. using 0.5 mg of norethindrone daily (7) which was about 30 per cent and is much lower than what is found for 0.3 mg of norethindrone daily (8), which is commonly used in low dose gestagen contraceptives, where the ovulation rate was about 65 per cent. The contraceptive effect of gestagens depends not only on ovulation inhibition but also on local effects in the reproductive tract. Measurement of the plasma levels of R 2 3 2 3 after oral intake of 5.0 mg has shown that the levels decline from peak levels of 1 6 - 3 4 ng/ml on the day of intake to 0 . 0 - 0 . 3 6 ng/ml on day 5 - 6 (9). One of the reasons for the high pregnancy rate in w o m e n using 2.5 or 5.0 mg R 2 3 2 3 as a weekly contraceptive pill might be that the levels of R 2 3 2 3 at the end of the treatment week are too low to exhibit the local effects. This proposition is further supported by the fact that the ovulatory rate in w o m e n using 2.5 mg R 2 3 2 3 is about the same as that for w o m e n using 0.3 mg norethindrone daily whereas the pregnancy rate in the former group is much higher.
There are t w o reasons to believe that the pregnancy rate would decrease if the weekly amount of R 2 3 2 3 is increased from 2.5 or 5 mg to 10 mg. The first reason is that the ovulation rate is significantly decreased. The second reason is that one might assume, that with the higher dosage the chance is greater to maintain plasma levels of R 2 3 2 3 high enough to exert local action in the reproductive tract at the end of the treatment week. This would decrease the risk for conception in cases where ovulation occurs. The incidence of intermenstrual bleeding or spotting was disturbingly high in this study. In the study by Mora et al. (2) using 5 mg of R 2 3 2 3 weekly, intermenstrual bleeding or spotting occurred in 33 per cent of the cycles during the first three months of treatment. In this study we found intermenstrual bleeding or spotting in 82 per cent of the cycles. This difference is hard to explain, but it is interesting to note that a majority of these bleedings occurred 5 - 6 days after taking the pills. It is likely that this represents a withdrawal bleeding from the drug. The high frequency of intermenstrual bleeding and spotting found in this study indicates that R 2 3 2 3 in the dosage used would make it unacceptable for many w o m e n as a weekly contraceptive. In clinical studies with prolonged use of 10 mg however, a high frequency of amenorrhoea is found (10). In conclusion, it might be said that 10 mg of R 2 3 2 3 probably would yield a better protection against pregnancy than 2.5 or 5.0 mg and that bleeding and spotting during treatment is related to the timing of drug intake.
JULY 1975
VOL. 12 NO. 1
93
CONTRACEPTION
ACKNOWLEDGEMENTS This study was supported by the Ford Foundation, the Swedish Medical Research Council and the International Committee for Contraception Research of the Population Council.
REFERENCES 1. Sakiz, E. and Azadian-Boulanger, G. R 2323 - an original contraceptive compound. Hormonal steroids. Proceedings of the Third International Congress. Excerpta Med Int Congr Series No. 2 1 9 : 8 6 5 - 8 7 1 (1970). 2. Mora, G., Fa~ndes, A. and Pastore, U. Clinical evaluation of an oral progestin contraceptive, R 2323, 5 mg, administered at weekly intervals. Contraception 10: 1 4 5 - 1 5 8 (1974). 3. Tredway, D.R. and Mishell, D.R., Jr. Effect of a once weekly oral contraceptive upon gonadotrophin and gonadal steroid levels. Contraception 1 0 : 1 5 9 - 1 7 0 (1974). 4. Johansson, E.D.B. Progesterone levels in peripheral plasma during the iuteal phase of the normal human menstrual cycle measured by a rapid competitive protein binding technique. Acta endocr (Kbh) 6 1 : 5 9 2 - 6 0 6 (1969). 5. Hotchkiss, J., Atkinson, L.E. and Knobil, E. Time course of serum estrogen and luteinizing hormone (LH) concentrations during the menstrual cycle of the rhesus monkey. Endocrinology 8 9 : 1 7 7 - 1 8 3 (1971). 6. Edqvist, LE. and Johansson, E.D.B. Radioimmunoassay of estrone and estradiol in human and bovine peripheral plasma. Acta endocr (Kbh) 7 1 : 7 1 6 - 7 3 1 (1972). 7. Larsson-Cohn, U., Johansson, E.D.B. and Gemzell, C. Effects of continuous daily administration of 0.5 mg of norethindrone on the plasma levels of progesterone and on the urinary excretion of luteinizing hormone and total estrogens. Acta endocr (Kbh) 6 3 : 2 1 6 - 2 2 4 (1970). 8. Larsson-Cohn, U., Johansson, E.D.8. and Gemzell, C. Effects of continuous administration of 0.3 mg of norethindrone on the plasma levels of progesterone and on the urinary excretion of pregnanediol and total estrogens. Acta endocr (Kbh) 64: 3 8 - 4 6 (1970). 9. Johansson, E.D.B. and Luukkainen, T. Personal communication. 10. Mora, G. Personal communication.
94
JULY 1975 VOL. 12 NO. 1
Arne Victor and Elof D.B. Johansson Department of Obstetrics and Gynecology, University Hospital, Uppsala, Sweden
ABSTRACT An oral progestogen - R 2 3 2 3 - was given in the dose of 10 mg as a weekly contraceptive pill. The effect on the ovarian function was followed by measuring the plasma levels of progesterone and estradiol. Seventeen cycles were studied and, in three of these, ovulation occurred. In all other cycles, progesterone and estradiol were depressed to early follicular phase levels. Intermenstrual bleeding or spotting was noticed in all cycles except the ovulatory ones. It is concluded that R 2 3 2 3 in this dosage probably gives a better contraceptive effect than lower dosages. The occurrence ,of intermenstrual bleeding and spotting seems to be related to the timing of drug intake.
Accepted for publication May 16, 1975
JULY 1975
VOL. 12 NO. 1
89
CONTRACEPTION The use of continuous low dose gestagens for anticonceptional purpose though advantageous as far as diminishing serious side effects has some drawbacks. One of them is the increased risk for pregnancy once a pill is forgotten and the complications arising for the patient having to abstain from intercourse for some time or use additional contraceptives. From this point of view, it would be favourable if one could achieve an intermittent but regular dosage where one day's forgetfullness would not matter. The gestagen used in this study is 13-ethyl-17-hydroxy-18,19-dinor-17~-pregna4,9,11,-trien-20-yn-3-one (R 2323) 1. The structural formula is shown in Fig. 1. This steroid was found to possess a very strong antiprogesterone activity, a very low estrogenic activity, average progestomimetic and anti-estrogenic activity and a marked pituitary inhibitory activity in animal experiments (1). Furthermore, it possesses an hitherto unexplained inhibitory effect on implantation (1).
"'C=CH 0 Fig. I. Structural formula of R 2323.
R 2323 has been used in clinical trials in 2.5 and 5.0 mg doses given weekly (2). In the lower dosage, the pregnancy rate was unacceptably high, with a pregnancy rate resulting from method failure of 13.1 per hundred women years. In the 5.0 mg dosage, it had a moderate contraceptive effect with a total pregnancy rate of 8.7 in the first year of use of which 3.7 was attributed to method failure. Eighteen out of 33 cycles studied (55 %) in women treated with 2.5 or 5.0 mg R 2323 weekly were ovulatory (2, 3). The aim of this study was to investigate the effect on ovarian function using a higher dosage of 10 mg R 2323 administered once weekly.
MATERIAL
AND
METHODS
Nine healthy women with regular menstrual cycles volunteered for the study. Their ages ranged from 19 to 25 years and they were all hospital employees. No other contraceptives were used during the treatment period. Ten mg of R 2323 was given every Saturday for eight weeks, starting on the first Saturday following the beginning of the last menstrual bleeding. If the menstrual bleeding oc1Supplied by Roussel Uclef, Paris. France.
90
JULY 1975 VOL. 12 NO. 1
CONTRACEPTION curred on a Saturday, medication was started on the following Saturday. One patient was treated only four weeks because of technical difficulties with the blood sampling. Her recovery cycle was the second following medication. Blood samples for the estimation of progesterone and estradiol were obtained every Tuesday and Friday during the luteal phase of a control cycle preceding treatment, during treatment and during the rec:overy cycle following treatment. The one exception is mentioned above. Progesterone in plasma was determined by a competitive protein binding method (4). Estradiol in plasma was determined by radioimmunoassay (5)° excluding the thin layer chromatography step (6).
RESULTS All women had ovulatory control cycles before treatment as judged from their progesterone and estradiol levels. The lowest peak progesterone value for a single patient was 6.4 ng/ml. The cycle length of these control cycles was 2 9 - 3 7 days with a mean of 33.5 days, omitting two patients who could not remember the exact day of their last menstrual period. During the treatment all patients but one, had regular menstruation-like bleedings with an interval of 2 2 - 3 5 days (mean 27.4 days). One patient had irregular spotting during the entire treatment period. Excluding this patient, seven out of eight women experienced intermenstrual bleeding or spotting for 1-9 days during the treatment period (mean 3.5 days/patient). Out of a total of 33 bleeding episodes during or immediately after treatment, four appeared four days after medication, 21, five days after medication and seven, six days after medication. Intermenstrual bleeding or spotting occurred during all 17 treatment cycles except those three which were ovulatory. On three occasions, ovulation was recorded during treatment. One patient (Fig. 2) ovulated twice with peak progesterone values of 18.7 and 13.2 ng/ml, and one patient during her second treatment cycle with a peak progesterone value of 12.9 ng/ml. Ovulation thus occurred in three out of 17 treatment cycles (18 %). In all the other cycles of treatment, progesterone and estradiol were depressed to levels comparable to those found in the early follicular phase of the menstrual cycle. Fig. 3 shows the progesterone, estradiol and bleeding pattern typical for those women who did not ovulate during treatment. Excluding the patient with irregular spotting during the entire treatment period, the length of the recovery cycle varied between 15 and 42 days (mean 27.4 days) as measured from the last bleeding in connection with treatment. Measuring from the day of the last pill intake to the occurrence of bleeding, the cycle length was 2 0 - 4 0 days with an average of 29.2 days. No pregnancy occurred in this series and no patient complained of any more pronounced systemic side effects that could be related to treatment. The recovery cycle was ovulatory in all women.
JULY 1975 VOL. 12 NO. 1
91
CONTRACEPTION
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J U L Y 1975
V O L . 12 N O . 1
CONTRACEPTION
DISCUSSION The frequency of ovulation recorded in this study is lower (3/17 or 18 %) than what is reported in earlier studies using 2.5 or 5.0 mg R 2 3 2 3 weekly (2, 3). Out of 17 cycles studied using the 2.5 mg dosage, 11 (65 %) were ovulatory and out of 16 cycles using the 5.0 mg dosage, 7 (44 %) were ovulatory. The differences are statistically significant when tested with ),'Z-analysis (P <0.01 ). The number of ovulations found in this study compares favourably even to th~ rates found by Larsson-Cohn et a/. using 0.5 mg of norethindrone daily (7) which was about 30 per cent and is much lower than what is found for 0.3 mg of norethindrone daily (8), which is commonly used in low dose gestagen contraceptives, where the ovulation rate was about 65 per cent. The contraceptive effect of gestagens depends not only on ovulation inhibition but also on local effects in the reproductive tract. Measurement of the plasma levels of R 2 3 2 3 after oral intake of 5.0 mg has shown that the levels decline from peak levels of 1 6 - 3 4 ng/ml on the day of intake to 0 . 0 - 0 . 3 6 ng/ml on day 5 - 6 (9). One of the reasons for the high pregnancy rate in w o m e n using 2.5 or 5.0 mg R 2 3 2 3 as a weekly contraceptive pill might be that the levels of R 2 3 2 3 at the end of the treatment week are too low to exhibit the local effects. This proposition is further supported by the fact that the ovulatory rate in w o m e n using 2.5 mg R 2 3 2 3 is about the same as that for w o m e n using 0.3 mg norethindrone daily whereas the pregnancy rate in the former group is much higher.
There are t w o reasons to believe that the pregnancy rate would decrease if the weekly amount of R 2 3 2 3 is increased from 2.5 or 5 mg to 10 mg. The first reason is that the ovulation rate is significantly decreased. The second reason is that one might assume, that with the higher dosage the chance is greater to maintain plasma levels of R 2 3 2 3 high enough to exert local action in the reproductive tract at the end of the treatment week. This would decrease the risk for conception in cases where ovulation occurs. The incidence of intermenstrual bleeding or spotting was disturbingly high in this study. In the study by Mora et al. (2) using 5 mg of R 2 3 2 3 weekly, intermenstrual bleeding or spotting occurred in 33 per cent of the cycles during the first three months of treatment. In this study we found intermenstrual bleeding or spotting in 82 per cent of the cycles. This difference is hard to explain, but it is interesting to note that a majority of these bleedings occurred 5 - 6 days after taking the pills. It is likely that this represents a withdrawal bleeding from the drug. The high frequency of intermenstrual bleeding and spotting found in this study indicates that R 2 3 2 3 in the dosage used would make it unacceptable for many w o m e n as a weekly contraceptive. In clinical studies with prolonged use of 10 mg however, a high frequency of amenorrhoea is found (10). In conclusion, it might be said that 10 mg of R 2 3 2 3 probably would yield a better protection against pregnancy than 2.5 or 5.0 mg and that bleeding and spotting during treatment is related to the timing of drug intake.
JULY 1975
VOL. 12 NO. 1
93
CONTRACEPTION
ACKNOWLEDGEMENTS This study was supported by the Ford Foundation, the Swedish Medical Research Council and the International Committee for Contraception Research of the Population Council.
REFERENCES 1. Sakiz, E. and Azadian-Boulanger, G. R 2323 - an original contraceptive compound. Hormonal steroids. Proceedings of the Third International Congress. Excerpta Med Int Congr Series No. 2 1 9 : 8 6 5 - 8 7 1 (1970). 2. Mora, G., Fa~ndes, A. and Pastore, U. Clinical evaluation of an oral progestin contraceptive, R 2323, 5 mg, administered at weekly intervals. Contraception 10: 1 4 5 - 1 5 8 (1974). 3. Tredway, D.R. and Mishell, D.R., Jr. Effect of a once weekly oral contraceptive upon gonadotrophin and gonadal steroid levels. Contraception 1 0 : 1 5 9 - 1 7 0 (1974). 4. Johansson, E.D.B. Progesterone levels in peripheral plasma during the iuteal phase of the normal human menstrual cycle measured by a rapid competitive protein binding technique. Acta endocr (Kbh) 6 1 : 5 9 2 - 6 0 6 (1969). 5. Hotchkiss, J., Atkinson, L.E. and Knobil, E. Time course of serum estrogen and luteinizing hormone (LH) concentrations during the menstrual cycle of the rhesus monkey. Endocrinology 8 9 : 1 7 7 - 1 8 3 (1971). 6. Edqvist, LE. and Johansson, E.D.B. Radioimmunoassay of estrone and estradiol in human and bovine peripheral plasma. Acta endocr (Kbh) 7 1 : 7 1 6 - 7 3 1 (1972). 7. Larsson-Cohn, U., Johansson, E.D.B. and Gemzell, C. Effects of continuous daily administration of 0.5 mg of norethindrone on the plasma levels of progesterone and on the urinary excretion of luteinizing hormone and total estrogens. Acta endocr (Kbh) 6 3 : 2 1 6 - 2 2 4 (1970). 8. Larsson-Cohn, U., Johansson, E.D.8. and Gemzell, C. Effects of continuous administration of 0.3 mg of norethindrone on the plasma levels of progesterone and on the urinary excretion of pregnanediol and total estrogens. Acta endocr (Kbh) 64: 3 8 - 4 6 (1970). 9. Johansson, E.D.B. and Luukkainen, T. Personal communication. 10. Mora, G. Personal communication.
94
JULY 1975 VOL. 12 NO. 1