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A multicentred, two-year, phase III clinical trial of norethisterone enanthate 50 mg plus estradiol valerate 5 mg as a monthly injectable contraceptive
CONTRACEPTION
A HULTICENTRED, TEO-YEAR, PEASE III CLINICAL TRIAL OF NORETHISTERONE ENANTEATE 50 MG PLUS ESTRADIOL VALERATE 5 MG AS A MONTHLY INJECTABLE CONTRACEPTIVE E. v.
S. Aydinlik**, J. Kaufmann ***
*
First Gynecological Clinic, University of Buenos Aires, Argentina (monitoring clinical center of the trial)
**
Clinical Germany
Research
***
Institute
of Biometrics,
Department,
Schering
A.G.
Berlin,
Schering A.G. Berlin, Germany
Abstract Norethisterone enanthate (NET-EN) 50 mg combined with estradiol valerate (EV) 5 mg was studied as a once-a-month injectable contraceptive with regard to effectiveness, cycle control, adverse events and acceptability. In eight Family Planning from 5 Latin American 652 Centres countries, fertile women were followed-up for a period of 24 months, providing a total of 10,689 woman-months of experience. Only 1 pregnancy occurred, in the first treated month a few days before the second injection (failure rate 0.11 per 100 woman-years). Under first treatment, the cycle was drastically shortened in most cases, but thereafter cycles tended to recover to pre-treatment patterns. There was a significant decrease of hypermenorrhea and dysmenorrheic cycles. Intracyclic bleeding and spotting appeared in 1.2% and 2.4%, respectively, and amenorrhea in 2.5% of cycles. Incidence of other adverse events was very low with the exception of weight gain of 2 Kg (28%). Continuation rate at 12 months was 64.7%. The cumulative discontinuation rate due to bleeding problems was 7.4% and 10.7% due to adverse events at 24 months.
Address for correspondence: Mrs. Semiramis Aydinlik, Schering A.G., Postfach 65 03 FAX: 0049 304 691 6612 11, D-1000 Berlin 65, Germany Submitted for publication September 19, 1991 Accepted for publication October 8, 1991
DECEMBER 1991 VOL. 44 NO. 6
669
CONTRACEPTION
effective The treatment was shown to be a highly contraceptive method that offers fairly good cycle control, that makes it good tolerance and a continuation rate suitable fur use in family planning programmes in the Latin American area. Introduction contraception based Long-acting parenteral being used E," progestogen-only preparations is currently family planning some 5 million women in programmes throughout the world (1). Currently, only two progestogens are in use, one of which is norethisterone enanthate (NETA major drawback of progestogen-only contraception is EN). amenorrhea and poor cycle control, i.e., intracyclic bleeding (2,3). This led in the 1960's to the investigation of progestogen-estrogen combinations. It became evident that the best results are achieved by adding estrogen esters whose action lasts a shorter period than that of the progestogen component, a measure which results in a more llnormalllmenstrual bleeding pattern; once-a-month injectable preparations have been developed (4-6). After multiple pharmacokinetic and pharmacodynamic studies of the different steroids (7,8), investigation was focused on ascertaining In the case of NET-EN, these the optimal dosage ratios. studies showed the optimal combination to be NET-EN 50 mg plus estradiol valerate 5 mg (g-10). two-year, The present study is a Phase III, multicentric trial with the above combination as a monthly injectable contraceptive, aimed at ascertaining its effectiveness, safety, tolerance and acceptability. Material
and Methods
The study was carried out in 8 Family Planning Centres in 5 Latin American countries (Argentina, Brazil, Peru, Uruguay and Venezuela). Six hundred and fifty-two women were recruited for monthly injectable treatment which began in 1987 and was designed to last 24 months. All subjects were healthy women with proven fertility, non-lactating, with regular menstrual cycles and who had not received longlast six months. acting steroids for the The age distribution was 9.7% between 18 and 20 years, 62.9% between 21 and 30 years, and 27.5% between 31 and 35 years. No post-partum amenorrheic, hypertensive or diabetic women or women with abnormal gynecological, breast or Pap smear findings were admitted to the study. 58.5% of the subjects were using methods: contraceptive 27.5% IUDs, 15% oral steroids and the others, condoms, barrier or other methods. All participants gave their informed consent.
I590
DECEMBER 1991 VOL. 44 NO. 6
CONTRACEPTION
studied consisted of The preparation 50 mg norethisterone enanthate plus 5 mg estradiol valerate as a 1 ml oily solution (manufactured by Schering A.G. Berlin, Germany). The first injection was administered five days of the cycle, the subsequent every 30 + 3 days.
within the doses were
first given
In a previous study to determine effective dosage (lo), all 3 pregnancies observed occurred before the second injection. In the present study, the women were therefore advised to use additional contraceptive protection (condom or vaginal barrier) during the first month of treatment. The patients underwent monthly gynecological examination, at which time bodya weight blood pressure, cycle pattern, incidence of side effe'cts intercurrent diseases and additional medication were rekorded. If a patient failed to attend the control appointment, a social worker tried to contact her to discover the reason for the discontinuation of treatment. Results
In this study, the two-year accumulated was 10,689 women-months.
total
experience
There was only one pregnancy in the entire study. It occurred in the first month of treatment, a few days before administration of the second iniection. Thus, the failure rate was 0.11 per 100 women-year&. in Table Cycle patterns are shown I. The first bleeding interval under treatment was notably shortened; only 24.4% of the women had a first cycle of 26 to 30 days. The shortening of cycles decreased sharply from the second injection. Thereafter, the cycle distribution tended to recover to pre-treatment patterns, although with a greater incidence of cycles of 30 or more days. As regards the amount of bleeding (Table II), heavy bleeding decreased throughout the study, while scanty bleeding increased proportionally. Duration of menstrual flow is shown in Table III. Although the proportion of women with 6 or more days increased slightly in the first cycle, it had reverted by the end of the treatment. The incidence of amenorrhea totalled 2.5% of the cycles and was more frequently observed in women with short periods (4-5 days or less) before treatment.
DECEMBER 1991 VOL. 44 NO. 6
691
CONTRACEPTION
Table
Length
I.
of cycle; percentage
16.25 days %
11-15 days %
of women
26-30 days %
more than 30days 96
ql?lWl? treatment
0.3
5.4
08.4
4.5
Cycle 3
0.2
9.9
62.9
25.3
Cycle 12
0.2
3.1
67.5
27.2
Table
II.
Intensity
of bleeding;
scanty no.(%)
692
Beforethe lstinjection
27 (4.2)
Cycle 6
165 (32.4)
Cycle 12
101 (28.3)
Cycle25
41 (22.0)
percentage
normal no.(%)
of women
heavy no. (%)
114 (17.8)
Total no. of women 641
14 (2.8)
306 (73.9)
DECEMBER 1991 VOL. 44 NO. 6
CONTRACEPTION
Table III.
of flow (women with at percentage of women
Duration cycles);
Before treatment
6 - 7 days or more no. (“7)
During treatment
6-7 days or more
4-5 days or less
Cycle 1
16 (42.1%)
22 (57.9%)
Cycle 24
5 (13.2%)
33 (86.8%)
38
least 24
4 - 5 days or less
151
no. (“7)
6-7 days or more
4-5 days or less
38
28 (18.7%)
122 (81.3%)
150
38
5 (4.2%)
138 (95.8%)
144
Breakthrough bleeding occurred in 1.2% of all cycles and spotting in 2.1%. Body weight fluctuations of up to + 2 Kg were regarded as physiological. Most of the women remained within these limits; however, the incidence of weight gain increased during the study (Table IV). On the other hand, no variations in blood pressure were registered. The evolution of subjective side effects is shown in Table V. Progressive diminution of the incidence of dysmenorrhea was observed during the treatment, while headache increased slightly. The remaining side effects did not show variation. Some of the adverse events often encountered with oral contraceptives, depression, e.g., vomiting, loss of libido, etc., were totally absent in the present study. Similarly, there were no cases of thrombophlebitis or hepatopathies. Only one woman treatment interrupted because of chloasma and four women due to varicosis. A total of 422 women (64.7%) completed 12 months of the study. Life table cumulative discontinuation rate due to bleeding problems was 5.8% (32 women) and due to adverse events was 6.7% (40 women) at 12 months; these rates were 7.4% (37 women) and 10.7% (51 women) at 24 months, respectively. One pregnancy (0.2%) was registered during the study. Fifty-five women withdrew from the study for personal reasons (desired pregnancy, etc.); 84 left the study area.
DECEMBER 1991 VOL. 44 NO:6
693
CONTRACEPTION
Table
IV.
Body
weight
gain
(2 Kg);
percentage
of women
Before the 4th injection
11.5 %
Before the 12th injection
25.9 %
Before the 25th injection
28.0 %
Table
V.
Subjective
last untreated cycle %
side
effects;
percentage
of cycles
Cycle 1-3
Cycle 4-12
%
%
%
26.8 4.2
:::
:::
::S
Headache
0.8
3.3
2.3
1.6
Nausea
_
0.5
0.1
0.1
Dizziness
0.2
0.3
0.2
_
Breast tenderness
0.2
1.2
0.3
0.2
0.7
0.7
0.6
Dysmenorrhoea mild severe
Nervousness
Cycle 13-25
DECEMBER 1991 VOL. 44 NO. 6
CONTRACEPTION
652 610 528
No. of
189
cycls 3
-t
cycle6
-I
cycle 12
t
cycle 1s
Cycles
Fig. 1.
Number
of women completing
Figure 1 shows the continuation study period.
cycles of therapy,
rates over the 24-month
Discussion The WHO Special Programme of Research, Development and Research Training in Human Reproduction has published (11) a multicentre, Phase III trial comparing the (NET-EN + EV) preparation which we used in the present study, with another monthly combination. The NET-EN + EV-treated group of that study has a greater number of women (1152) than our material (652); on the other hand, the WHO study lasted 12 months, of ours 24 months, which makes the number of woman-months experience in the WHO study and ours very similar: 10,608 and 10,680, respectively. Despite the above-stated differences in design, the two studies nevertheless offer some points for comparison.
DECEMBER 1991 VOL. 44 NO. 6
CONTRACEPTION
First of all, the high contraceptive effectiveness. We had one pregnancy (failure rate 0.11) and the WHO study two This compares favourably with the most effective (0.18). hormonal contraceptive regimens. We advised our patients to use additional contraception in the first month. The pregnancy occurred in the first month despite the woman claiming that she had practised coitus condomatus during that period. It should be stressed that of the 6 pregnancies registered with this preparation (two in the WHO study, 3 in our previous study (10) and one in this study), all but one occurred in the first month of treatment, a few days before the second dose and after a very shortened first cycle. The notable shortening of the first bleeding interval had already been observed by Saxena et al. (9) and also in our previous study (10). The reason is the shorter duration of the effect of EV than that of NET-EN (1,7,8). However, the noticeable tendency for the bleeding patterns to second normalise from the cycle onwards continued to increase over the entire 24 months. We agree with the conclusion from the WHO study that this good cycle control with predictable bleeding may have contributed to the high acceptability of the method. Indeed, our drop-out rate for problems was remarkably bleeding low (5.7%). The continuation rate of 62% at 24 months is higher than that observed with the NET-EN progestogen-only method (12) and also with an oral contraceptive method (13), both of which were studied in the same Latin American area. It is comparable only to our experience with IUDs (14). The inconvenience of the monthly visits to the clinic did not seem to play a negative role in the continuation rate. The significant improvement of dysmenorrhea as well as the intensity and decrease of bleeding duration have may contributed to the good acceptance. The incidence of subjective and objective side effects was quite low, similar to the WHO experience. The only exception was the incidence of body weight gain. To summarize, this study supports the view that the NET-EN + EV monthly injectable is a highly effective, well tolerated and acceptable contraceptive method suitable for family planning programmes in Latin American countries. Acknowledgement We are greatly indebted to the principal investigators of the collaborative centres involved in this study: Prof. It. Tozzini, Rosario, Argentina; Prof. J. Polto, Montevideo, Uruguay; Dr. A. LarraEaga, Lima, Peru; Dr. N. Mello, S6o Paulo, Brazil; Dr. S. Lagrosa Garcia, S&o Paulo, Brazil; Dr. P. Guzman Llovet (dec.), Puerto Cabello, Venezuela; and Dr. W. Szczedrin, Caracas, Venezuela.
596
DECEMBER 1991 VOL. 44 NO. 6
CONTRACEPTION References 1.
injectable formulations. In: Hall PE. Long-acting Diczfalusy E, Bygdeman M, eds. Fertility regulation, today and tomorrow. Raven Press: New York, 1987:119-41.
2.
Gray RH. Patterns of bleeding associate with the use of steroidal contraceptives. In: Diczfalusy E, Fraser IS, Webb FTG, eds. bleeding and Endometrial steroidal contraception. Pitman Press: Bath, 1980:14-44.
3.
World Health Organization (WHO). Facts about injectable contraceptives. Bull, WHO 1982;60:199-210.
4.
Benagiano G. Long-acting systemic contraceptives. In: Regulation of Diczfalusy E, ed. human fertility. Scriptor: Copenhagen, 1977:323-60.
5.
Toppozada M. The clinical use contraceptive preparations. 1977;32:335-47.
6.
Hall PE, Fraser IS. Monthly injectable contraceptives. In: Mishell DR Jr, ed. Long-acting steroid contraception. Raven Press: New York, 1983:65-88.
7.
Oriowo MA, Landgren B-M, Stenstrijm B, Diczfalusy E. A comparison of the pharmacokinetic properties of three estradiol esters. Contraception 1980;21:415-24.
8.
Aedo A-R, Landgren B-M, Johannisson E, Diczfalusy E. Pharmacokinetic and pharmacodynamic investigations with monthly injectable contraceptive preparations. Contraception 1985;31:453-69.
9.
Saxena BN et al. Monthly injectables: NET and estradiol valerate/cypionate. In: Zatuchni GI, Shelton Sciarra JJ, eds. Long-acting delivery system. JD, Harper & Row: Philadelphia, 1983:537-42.
10.
Kesserc E, Tozzini R. Monthly injectable contraception with norethisterone enanthate plus estradiol valerate. In: Runnebaum B, Rabe T, Kiesel L, eds. Female contraception. Springer-Verlag: Berlin-Heidelberg 1988:221-26.
11.
World Health Organization Special Programme of Research, Development and Research Training in Human Reproduction. A multicentred phase III comparative study of two hormonal contraceptive preparations given once-a-month intramuscular injection. I. by Contraceptive efficacy and side effects. Contraception 1988;37:1-20.
DECEMBER 1991 VOL. 44 NO. 6
of monthly injectable Obstet Gynecol Surv
597
CONTRACEPTION
12.
KesserG E et al. Fertility control with norethisterone Acta enanthate, a long-acting parenteral progestogen. Eur Fertil 1973;4:203-21.
13.
Etchepareborda JJ et al. Clinical trial of a new progestogen compound (Gestoden) as a triphasic oral contraceptive formulation. 12th World Congress on Fertility and Sterility, Singapore. Soon TE, Ratnam SS, Min LS, eds. Handbook of abstracts. 1986:338.
14.
Five-year comparative study with Kesserii E et al. 12th Congress on Nova-T, copper-T and Lippes IUDs. Fertility and Sterility, Singapore. Soon TE, Ratnam 1986:23. SS, Min LS, eds. Handbook of abstracts.
DECEMBER 1991 VOL. 44 NO. 6
A HULTICENTRED, TEO-YEAR, PEASE III CLINICAL TRIAL OF NORETHISTERONE ENANTEATE 50 MG PLUS ESTRADIOL VALERATE 5 MG AS A MONTHLY INJECTABLE CONTRACEPTIVE E. v.
S. Aydinlik**, J. Kaufmann ***
*
First Gynecological Clinic, University of Buenos Aires, Argentina (monitoring clinical center of the trial)
**
Clinical Germany
Research
***
Institute
of Biometrics,
Department,
Schering
A.G.
Berlin,
Schering A.G. Berlin, Germany
Abstract Norethisterone enanthate (NET-EN) 50 mg combined with estradiol valerate (EV) 5 mg was studied as a once-a-month injectable contraceptive with regard to effectiveness, cycle control, adverse events and acceptability. In eight Family Planning from 5 Latin American 652 Centres countries, fertile women were followed-up for a period of 24 months, providing a total of 10,689 woman-months of experience. Only 1 pregnancy occurred, in the first treated month a few days before the second injection (failure rate 0.11 per 100 woman-years). Under first treatment, the cycle was drastically shortened in most cases, but thereafter cycles tended to recover to pre-treatment patterns. There was a significant decrease of hypermenorrhea and dysmenorrheic cycles. Intracyclic bleeding and spotting appeared in 1.2% and 2.4%, respectively, and amenorrhea in 2.5% of cycles. Incidence of other adverse events was very low with the exception of weight gain of 2 Kg (28%). Continuation rate at 12 months was 64.7%. The cumulative discontinuation rate due to bleeding problems was 7.4% and 10.7% due to adverse events at 24 months.
Address for correspondence: Mrs. Semiramis Aydinlik, Schering A.G., Postfach 65 03 FAX: 0049 304 691 6612 11, D-1000 Berlin 65, Germany Submitted for publication September 19, 1991 Accepted for publication October 8, 1991
DECEMBER 1991 VOL. 44 NO. 6
669
CONTRACEPTION
effective The treatment was shown to be a highly contraceptive method that offers fairly good cycle control, that makes it good tolerance and a continuation rate suitable fur use in family planning programmes in the Latin American area. Introduction contraception based Long-acting parenteral being used E," progestogen-only preparations is currently family planning some 5 million women in programmes throughout the world (1). Currently, only two progestogens are in use, one of which is norethisterone enanthate (NETA major drawback of progestogen-only contraception is EN). amenorrhea and poor cycle control, i.e., intracyclic bleeding (2,3). This led in the 1960's to the investigation of progestogen-estrogen combinations. It became evident that the best results are achieved by adding estrogen esters whose action lasts a shorter period than that of the progestogen component, a measure which results in a more llnormalllmenstrual bleeding pattern; once-a-month injectable preparations have been developed (4-6). After multiple pharmacokinetic and pharmacodynamic studies of the different steroids (7,8), investigation was focused on ascertaining In the case of NET-EN, these the optimal dosage ratios. studies showed the optimal combination to be NET-EN 50 mg plus estradiol valerate 5 mg (g-10). two-year, The present study is a Phase III, multicentric trial with the above combination as a monthly injectable contraceptive, aimed at ascertaining its effectiveness, safety, tolerance and acceptability. Material
and Methods
The study was carried out in 8 Family Planning Centres in 5 Latin American countries (Argentina, Brazil, Peru, Uruguay and Venezuela). Six hundred and fifty-two women were recruited for monthly injectable treatment which began in 1987 and was designed to last 24 months. All subjects were healthy women with proven fertility, non-lactating, with regular menstrual cycles and who had not received longlast six months. acting steroids for the The age distribution was 9.7% between 18 and 20 years, 62.9% between 21 and 30 years, and 27.5% between 31 and 35 years. No post-partum amenorrheic, hypertensive or diabetic women or women with abnormal gynecological, breast or Pap smear findings were admitted to the study. 58.5% of the subjects were using methods: contraceptive 27.5% IUDs, 15% oral steroids and the others, condoms, barrier or other methods. All participants gave their informed consent.
I590
DECEMBER 1991 VOL. 44 NO. 6
CONTRACEPTION
studied consisted of The preparation 50 mg norethisterone enanthate plus 5 mg estradiol valerate as a 1 ml oily solution (manufactured by Schering A.G. Berlin, Germany). The first injection was administered five days of the cycle, the subsequent every 30 + 3 days.
within the doses were
first given
In a previous study to determine effective dosage (lo), all 3 pregnancies observed occurred before the second injection. In the present study, the women were therefore advised to use additional contraceptive protection (condom or vaginal barrier) during the first month of treatment. The patients underwent monthly gynecological examination, at which time bodya weight blood pressure, cycle pattern, incidence of side effe'cts intercurrent diseases and additional medication were rekorded. If a patient failed to attend the control appointment, a social worker tried to contact her to discover the reason for the discontinuation of treatment. Results
In this study, the two-year accumulated was 10,689 women-months.
total
experience
There was only one pregnancy in the entire study. It occurred in the first month of treatment, a few days before administration of the second iniection. Thus, the failure rate was 0.11 per 100 women-year&. in Table Cycle patterns are shown I. The first bleeding interval under treatment was notably shortened; only 24.4% of the women had a first cycle of 26 to 30 days. The shortening of cycles decreased sharply from the second injection. Thereafter, the cycle distribution tended to recover to pre-treatment patterns, although with a greater incidence of cycles of 30 or more days. As regards the amount of bleeding (Table II), heavy bleeding decreased throughout the study, while scanty bleeding increased proportionally. Duration of menstrual flow is shown in Table III. Although the proportion of women with 6 or more days increased slightly in the first cycle, it had reverted by the end of the treatment. The incidence of amenorrhea totalled 2.5% of the cycles and was more frequently observed in women with short periods (4-5 days or less) before treatment.
DECEMBER 1991 VOL. 44 NO. 6
691
CONTRACEPTION
Table
Length
I.
of cycle; percentage
16.25 days %
11-15 days %
of women
26-30 days %
more than 30days 96
ql?lWl? treatment
0.3
5.4
08.4
4.5
Cycle 3
0.2
9.9
62.9
25.3
Cycle 12
0.2
3.1
67.5
27.2
Table
II.
Intensity
of bleeding;
scanty no.(%)
692
Beforethe lstinjection
27 (4.2)
Cycle 6
165 (32.4)
Cycle 12
101 (28.3)
Cycle25
41 (22.0)
percentage
normal no.(%)
of women
heavy no. (%)
114 (17.8)
Total no. of women 641
14 (2.8)
306 (73.9)
DECEMBER 1991 VOL. 44 NO. 6
CONTRACEPTION
Table III.
of flow (women with at percentage of women
Duration cycles);
Before treatment
6 - 7 days or more no. (“7)
During treatment
6-7 days or more
4-5 days or less
Cycle 1
16 (42.1%)
22 (57.9%)
Cycle 24
5 (13.2%)
33 (86.8%)
38
least 24
4 - 5 days or less
151
no. (“7)
6-7 days or more
4-5 days or less
38
28 (18.7%)
122 (81.3%)
150
38
5 (4.2%)
138 (95.8%)
144
Breakthrough bleeding occurred in 1.2% of all cycles and spotting in 2.1%. Body weight fluctuations of up to + 2 Kg were regarded as physiological. Most of the women remained within these limits; however, the incidence of weight gain increased during the study (Table IV). On the other hand, no variations in blood pressure were registered. The evolution of subjective side effects is shown in Table V. Progressive diminution of the incidence of dysmenorrhea was observed during the treatment, while headache increased slightly. The remaining side effects did not show variation. Some of the adverse events often encountered with oral contraceptives, depression, e.g., vomiting, loss of libido, etc., were totally absent in the present study. Similarly, there were no cases of thrombophlebitis or hepatopathies. Only one woman treatment interrupted because of chloasma and four women due to varicosis. A total of 422 women (64.7%) completed 12 months of the study. Life table cumulative discontinuation rate due to bleeding problems was 5.8% (32 women) and due to adverse events was 6.7% (40 women) at 12 months; these rates were 7.4% (37 women) and 10.7% (51 women) at 24 months, respectively. One pregnancy (0.2%) was registered during the study. Fifty-five women withdrew from the study for personal reasons (desired pregnancy, etc.); 84 left the study area.
DECEMBER 1991 VOL. 44 NO:6
693
CONTRACEPTION
Table
IV.
Body
weight
gain
(2 Kg);
percentage
of women
Before the 4th injection
11.5 %
Before the 12th injection
25.9 %
Before the 25th injection
28.0 %
Table
V.
Subjective
last untreated cycle %
side
effects;
percentage
of cycles
Cycle 1-3
Cycle 4-12
%
%
%
26.8 4.2
:::
:::
::S
Headache
0.8
3.3
2.3
1.6
Nausea
_
0.5
0.1
0.1
Dizziness
0.2
0.3
0.2
_
Breast tenderness
0.2
1.2
0.3
0.2
0.7
0.7
0.6
Dysmenorrhoea mild severe
Nervousness
Cycle 13-25
DECEMBER 1991 VOL. 44 NO. 6
CONTRACEPTION
652 610 528
No. of
189
cycls 3
-t
cycle6
-I
cycle 12
t
cycle 1s
Cycles
Fig. 1.
Number
of women completing
Figure 1 shows the continuation study period.
cycles of therapy,
rates over the 24-month
Discussion The WHO Special Programme of Research, Development and Research Training in Human Reproduction has published (11) a multicentre, Phase III trial comparing the (NET-EN + EV) preparation which we used in the present study, with another monthly combination. The NET-EN + EV-treated group of that study has a greater number of women (1152) than our material (652); on the other hand, the WHO study lasted 12 months, of ours 24 months, which makes the number of woman-months experience in the WHO study and ours very similar: 10,608 and 10,680, respectively. Despite the above-stated differences in design, the two studies nevertheless offer some points for comparison.
DECEMBER 1991 VOL. 44 NO. 6
CONTRACEPTION
First of all, the high contraceptive effectiveness. We had one pregnancy (failure rate 0.11) and the WHO study two This compares favourably with the most effective (0.18). hormonal contraceptive regimens. We advised our patients to use additional contraception in the first month. The pregnancy occurred in the first month despite the woman claiming that she had practised coitus condomatus during that period. It should be stressed that of the 6 pregnancies registered with this preparation (two in the WHO study, 3 in our previous study (10) and one in this study), all but one occurred in the first month of treatment, a few days before the second dose and after a very shortened first cycle. The notable shortening of the first bleeding interval had already been observed by Saxena et al. (9) and also in our previous study (10). The reason is the shorter duration of the effect of EV than that of NET-EN (1,7,8). However, the noticeable tendency for the bleeding patterns to second normalise from the cycle onwards continued to increase over the entire 24 months. We agree with the conclusion from the WHO study that this good cycle control with predictable bleeding may have contributed to the high acceptability of the method. Indeed, our drop-out rate for problems was remarkably bleeding low (5.7%). The continuation rate of 62% at 24 months is higher than that observed with the NET-EN progestogen-only method (12) and also with an oral contraceptive method (13), both of which were studied in the same Latin American area. It is comparable only to our experience with IUDs (14). The inconvenience of the monthly visits to the clinic did not seem to play a negative role in the continuation rate. The significant improvement of dysmenorrhea as well as the intensity and decrease of bleeding duration have may contributed to the good acceptance. The incidence of subjective and objective side effects was quite low, similar to the WHO experience. The only exception was the incidence of body weight gain. To summarize, this study supports the view that the NET-EN + EV monthly injectable is a highly effective, well tolerated and acceptable contraceptive method suitable for family planning programmes in Latin American countries. Acknowledgement We are greatly indebted to the principal investigators of the collaborative centres involved in this study: Prof. It. Tozzini, Rosario, Argentina; Prof. J. Polto, Montevideo, Uruguay; Dr. A. LarraEaga, Lima, Peru; Dr. N. Mello, S6o Paulo, Brazil; Dr. S. Lagrosa Garcia, S&o Paulo, Brazil; Dr. P. Guzman Llovet (dec.), Puerto Cabello, Venezuela; and Dr. W. Szczedrin, Caracas, Venezuela.
596
DECEMBER 1991 VOL. 44 NO. 6
CONTRACEPTION References 1.
injectable formulations. In: Hall PE. Long-acting Diczfalusy E, Bygdeman M, eds. Fertility regulation, today and tomorrow. Raven Press: New York, 1987:119-41.
2.
Gray RH. Patterns of bleeding associate with the use of steroidal contraceptives. In: Diczfalusy E, Fraser IS, Webb FTG, eds. bleeding and Endometrial steroidal contraception. Pitman Press: Bath, 1980:14-44.
3.
World Health Organization (WHO). Facts about injectable contraceptives. Bull, WHO 1982;60:199-210.
4.
Benagiano G. Long-acting systemic contraceptives. In: Regulation of Diczfalusy E, ed. human fertility. Scriptor: Copenhagen, 1977:323-60.
5.
Toppozada M. The clinical use contraceptive preparations. 1977;32:335-47.
6.
Hall PE, Fraser IS. Monthly injectable contraceptives. In: Mishell DR Jr, ed. Long-acting steroid contraception. Raven Press: New York, 1983:65-88.
7.
Oriowo MA, Landgren B-M, Stenstrijm B, Diczfalusy E. A comparison of the pharmacokinetic properties of three estradiol esters. Contraception 1980;21:415-24.
8.
Aedo A-R, Landgren B-M, Johannisson E, Diczfalusy E. Pharmacokinetic and pharmacodynamic investigations with monthly injectable contraceptive preparations. Contraception 1985;31:453-69.
9.
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