Ini J Gynaecol Obsiet 16; 61-64. 1978

The Monthly Injectable Contraceptive: A Two-Year Clinical Trial S. Koetsawang 1 , S. Srisupandit 1 , O. Kiriwat 1 and A. Koetsawang 2 Family Planning Research Unit, Department of Obstetrics and Gynecology, Faculty of Medicine, Siriraj Hospital, Mahidol University, Bangkok, Thailand ' Pathological Unit, Department of Obstetrics and Gynecology, Faculty of Medicine, Siriraj Hospital, Mahidol University, Bangkok, Thailand

ABSTRACT

accepted and highly effective (5, 6, 7). However, because it is associated with unpredictable bleeding Koetsawang S, Srisupandit, S, Kiriwat 0, Koetsawang A patterns and the possibility of delayed ovulation (Family Planning Research Unit and Pathological Unit, after medication is discontinued, it is suitable only Dept of Obstetrics and Gynecology, Faculty of Medicine, in certain groups of women. Siriraj Hospital, Mahidol University, Bangkok, Thailand). Scommegna et al (9) tried giving an I M injection The monthly injectable contraceptive: a two-year clinical of 50 mg of M P A and another injection of 10 mg of trial. estradiol cypionate every five weeks, for a total of IntJ Gynaecol Obstei 16: 61-64, 1978 1155 cycles in 90 women. T h e regimen appeared A contraceptive regimen of monthly intramuscular injeceffective, well accepted and safe. There was a 14% tions of a combination of 25 mg of medroxyprogesterone incidence of amenorrhea and 15% incidence of poacetate and 5 mg of estradiol cypionate (Cyclo-Provera, lymenorrhea during treatment. Coutinho and de Upjohn Co, Kalamazoo, MI, USA) was studied in 111 Souza (2) administered 25 mg of M P A and 5 mg of Thai women through 2356 cycles. During the first two estradiol cypionate (mixed in the same syringe) I M years of treatment, more than 80% of the patients had only at 28- to 32-day intervals in 104 patients for 634 one bleeding episode per cycle. The incidence of amenorrhea cycles. After nine months, fewer than 5% of the ranged from 3.6% to 14.9%>. Average cycle length and patients dropped out of the study. Cyclic bleeding duration of bleeding were similar to the pretreatment values. similar to menstruation occurred in 85% of the High continuation rates (79% at 12 months) indicated good cycles. No contraceptive failure or serious side effects patient acceptance of the method. There were no contraceptive were observed. failures or serious side effects. Return offertility was relaThis paper presents results of a study of 111 tively prompt. Among 21 patients who had discontinued nonlactating Thai women treated with a mixture of treatment in order to plan pregnancy, 10 were pregnant 25 mg of M P A and 5 mg of estradiol cypionate in within six months, and 3 others conceived during the suca 0.5 ml aqueous suspension (Cyclo-Provera, Upceeding three months. In five volunteers, serum medroxypro- j o h n Co, Kalamazoo, M I , USA) through 2356 cygesterone acetate levels were below 5 ng/ml (with one cles. exception) after a single injection of Cyclo-Provera given at intervals up to 56 days. MATERIALS A N D M E T H O D S INTRODUCTION Suppression of ovulation by monthly injection of contraceptives has been studied (2, 3, 8-12) in the hope that this method will provide better cycle control and a relatively rapid return of ovulation. The most popular injectable contraceptive preparation available is the aqueous suspension of medroxyprogesterone acetate (MPA), 150 mg administered by intramuscular (IM) injection every three months or 12 weeks. This preparation has been well

Between July 1973 and July 1974, 111 healthy Thai women volunteered to use monthly IM injections of Cyclo-Provera for contraception. T h e majority were using the method to space pregnancies. A full medical history was taken and a complete medical and gynecologic examination, including breast examination and Papanicolaou smear, was performed on each patient. Each patient was given a menstrual diary card and instructed in its proper use. T h e first injection of Cyclo-Provera was given

IntJ Gynaecol Obsiet 16

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Koetsawang et al

during the first five days of the menstrual cycle. Later injections were given at 28-day intervals. Shortly before each month's scheduled injection, the patient's menstrual history, blood pressure (BP) and body weight were recorded, and the patient was asked nonspecific questions concerning side effects. A breast examination was performed every six months and a Papanicolaou smear was taken once a year, unless other examinations were indicated. Hematocrit was determined at the initial examination and repeated at six months and one year. Liver function tests and blood urea nitrogen (BUN) and serum cholesterol determinations were performed in 32 women initially and at six and 12 months. In 20 women, endometrial histology was studied before initiation of therapy and 28-30 days after the 23rd-35th injections. In five volunteers who were not among the 111 patients in the clinical trial, M P A concentrations were determined before treatment and at intervals u p to 56 days after a single injection of CycloProvera. T h e assays were performed in the laboratories of the Upjohn Co in Kalamazoo, MI, USA, using the radioimmunoassay method described by Cornette et al (l).

RESULTS T h e majority of patients were 20-29 years old (83%) and had one or two living children (81%); 47% h a d previously used oral contraceptives. At the cutoff date for the study, J u n e 30, 1976,

Cyclo-Provera had been used for 2356 months, excluding months for which complete data were not available. Cumulative continuation rates were 89.2% at 6 months, 79.3% at 12 months, 56.7% at 18 months and 44.1% at 24 months. There were no contraceptive failures among the 111 cases with 2356 months of use. Most women expressed satisfaction with this contraceptive method. Only six women (5.4%) discontinued because of medical reasons. Twenty-four patients requested the same method after subsequent childbirth or when clinic visits could be resumed regularly. If one bleeding episode occurred during a treatment interval, we considered it as menstrual bleeding for our analysis purposes. If more than one episode was reported, bleeding which occurred at the time most similar to a normal cycle was considered as menstruation, while other episodes in that treatment interval were considered breakthrough bleeding or spotting. A cycle was classified as amenorrheal if no bleeding occurred during a treatment interval. As indicated in Fig. 1, more than 80% of the patients had only one bleeding episode during the treatment interval; this is similar to the normal menstrual pattern. T h e incidence of amenorrheal cycles, which increased gradually and continuously, ranged from 3.6% to 14.9% in the first two years. For all cycles beyond the two-year period, the incidence of amenorrhea was 25%. However, prolonged amenorrhea over a three-month period occurred in only 7.2% of the total patients. Prolonged bleeding of more than 10 days occurred in two patients, one

Number of Bleeding Episodes 100

0 1 2 3

0 I

90 80|70 60 50 40 h 30 20 10 CYCLE N

L_a2

Control 1 111 111

*A

3 4 5 6 7 111 109 109 106 103 99

8 98

9 96

10 94

11 92

12 90

18 65

24 >2S 51 353

Fig. 1. Number of bleeding episodes in the month after injection of Cyclo-Provera (N = number of patients). Prolonged bleeding occurred in 0.9% of the patients in Cycle 1 and in 0.3% of the patients in cycles beyond 24 months. IntJ Gynaecol Obstei 16

Monthly injectable contraceptive

after the first injection and another after the 30th injection. Fig. 1 excludes a few cycles for which adequate information was not available. Table I shows that the mean cycle length was shortened after the first injection, when bleeding occurred approximately 18-20 days after injection, but then became regular and closer to the pretreatment mean. T h e mean duration of bleeding ranged from 4.4 to 5.3 days. T h e majority of patients had light or moderate bleeding (Table II); less than 5% reported heavy bleeding. No patients required treatment for bleeding. After 12 months of treatment, 24.4% of the patients had an increase of 2.5 kg or more in body weight. After 24 months, 41.2% of the patients showed a weight gain, and the mean weight was significantly higher than the pretreatment mean (analysis of variance, p25

111 95 93 95 93 87 90 78 79 78 73 72 73 46 33 220

Mean ± SD 30.6 22.4 27.5 27.0 27.8 27.2 26.7 28.4 27.3 27.9 28.0 28.3 27.5 28.0 28.4 28.3

± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ±

5.0 4.0 4.8 4.8 5.2 4.1 5.2 3.7 4.7 4.4 4.4 4.6 4.6 4.5 3.7 4.4

N 111 95 107 98 102 91 92 85 90 85 80 80 80 52 42 261

Mean ± SD 3.9 5.5 4.8 5.2 4.9 5.3 4.6 4.7 4.9 4.7 5.0 4.4 5.1 4.6 4.9 4.4

± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ±

" Excluded were amenorrhea! cycles, one cycle prolonged bleeding, cycles following amenorrhea prolonged bleeding and a few cycles for which quate information was not available. " Excluded were amenorrhea! cycles, two cycles prolonged bleeding and a few cycles for which quate information was not available.

1.2 2.4 2.4 2.1 1.8 2.2 2.2 1.5 2.3 2.0 2.2 2.3 2.2 2.4 1.9 2.0 with and adewith ade-

63

Table I I . Character of bleeding during the month after injection (N = number of patients). Patients with Bleeding (%)

Cycle Control 1 2 3 4 5 6 7 8 9 10 .11 12 18 24 >25

N 111 111 111 109 109 106 103 99 98 96 94 92 90 65 51 353

None 0.0 13.5 3.6 10.1 6.4 14.2 10.7 14.1 8.2 11.5 14.9 13.0 11.1 20.0 17.7 25.8

Scanty 0.9 6.3 11.7 14.7 7.3 6.6 11.7 7.1 12.2 14.6 10.6 12.0 14.4 15.4 7.8 9.1

Light 59.5 55.0 59.5 52.3 65.1 61.3 66.6 68.7 67.4 62.5 67.0 65.2 56.7 55.4 62.7 57.8

Moderate Heavy 2.7 36.9 20.7 4.5 4.5 20.7 21.2 1.8 20.2 0.9 15.1 2.8 10.7 0.9 9.1 1.0 10.2 2.0 10.4 1.0 7.5 0.0 7.6 2.2 15.6 2.2 7.7 1.5 11.8 0.0 5.4 1.9

Twenty endometrial specimens obtained 28-30 days after the 23rd-35th injections showed nonfunctioning endometrium. T h e endometrial glands were narrow, nontortuous and widely separated with edematous pseudodecidual stroma. Follow-up information was obtained for all 21 patients who discontinued treatment in order to plan pregnancy. Three patients decided to return to contraception, and the other 18 discontinued medication for 1-24 months. Seven women became pregnant within three months and fourteen within 18 months. O n e patient was lost to follow-up after the third month and another after the 12th month. Among the 14 patients who became pregnant by the end of the study, five had delivered healthy infants at term, one had prematurely delivered an infant weighing 2420 gm, one had an ectopic pregnancy two months after discontinuing medication, and seven were currently pregnant. All pretreatment control values were zero in the radioimmunoassay in the five volunteers tested. Serum M P A levels after a single dose of Cyclo-Provera were, with one exception, less than 5 n g / m l (Table III). T h e levels at seven days after treatment ranged from 2.3 to 3.3 n g / m l and at 28 days after treatment from 1.4 to 3.5 n g / m l . DISCUSSION Monthly injections of Cyclo-Provera appear to be an effective and safe contraceptive method. This method produces better bleeding patterns than those of 150 mg of M P A injected every three months. While a gradual and continuous increase

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Koetsawang et al

TABLE III. Serum medroxyprogesterone acetate (MPA) concentration after a single injection of Cyclo-Provera in five volunteers. MPA Level (ng/ml) by Posttreatment Day Subject

Number

3

1 2 3 4 5

1.9 2.1 1.8

4

7

14

21

28

42

3.6 2.7 2.5 4.3 2.3 0.7 2.3 1.4 2.3 3.0 1.2 2.8 2.6 2.8 2.4 1.2 5.3 3.3 3.0 1.9 1.4 1.1 2.7 2.6 2.9 3.5 1.5

56 0.8 0.6 0.7 0.9 0.8

in amenorrhea occurred among the Cyclo-Provera users, the incidence of amenorrhea was much lower than that found for depomedroxyprogesterone acetate (DMPA) administered every three months. T h e incidence of amenorrhea in the D M P A study was 12.6% after the first injection, increasing to 46.0% after the 16th injection (5). T h e serum M P A level after a single Cyclo-Provera injection was much lower than that observed after treatment by the standard three-month D M P A injection (4). T h e range of the serum M P A level at seven days postinjection of Cyclo-Provera was 2.3-3.3 n g / m l compared to 9.4-38.5 ng/ml at seven days postinjection of the three-month D M P A . However, even for Cyclo-Provera, the data show a slow decline of serum M P A level from day 28 to day 56, suggesting a gradual cumulative increase in serum M P A level which may have some relation to the gradually increasing amenorrhea observed. In this study, the high continuation rate (79%) after 12 months indicates that this method was well accepted. T h e drop in continuation rates after 12 months largely reflected planning for pregnancy. Clinical and laboratory examination did not suggest adverse effects of the treatment. Blood pressure did not change significantly. There was a gain in average body weight; but because there was no control group in this study, it is not possible to attribute the weight change to the method. Only one patient discontinued treatment because of weight gain. T h e absence of any contraceptive failures among the 111 cases in 2356 months of use seems to indicate that monthly injections of Cyclo-Provera are a highly effective contraceptive method. The chances of the rapid return of fertility after discontinuation of the method also seem favorable. However, much larger studies are required to establish both the high efficacy and rapid return of fertility after discontinuation of this method. This preparation should provide a good alternative for women who cannot tolerate the side effects of oral contraceptive pills or intrauterine devices

InlJ Gynaecol Obstet 16

and who desire a highly effective method which offers good cycle control and a relatively rapid return of fertility after discontinuation of treatment. It is particularly suitable for spacing the pregnancy interval in urban women who can attend a clinic regularly. ACKNOWLEDGMENT Cyclo-Provera was supplied by the Upjohn Co, Kalamazoo, MI, USA. REFERENCES 1. Cornette J C , Kirton K T , Duncan, G W : Measurement of medroxyprogesterone acetate (Provera) by radioimmunoassay. J Clin Endocrinol M e t a b 33:459, 1971. 2. Coutinho E M , de Souza J C : Conception control by monthly injections of medroxyprogesterone suspension and a long-acting oestrogen. J Reprod Fértil 7.5:209, 1968. 3. Felton H T , Hoelscher E W , Swartz D P : Evaluation of use of an injectable progestin-estrogen for contraception. Fértil Steril /6>665, 1965. 4. Koetsawang S: Injected long-acting medroxyprogesterone acetate: effect on h u m a n lactation and concentration in milk. J M e d Assoc T h a i 60:57, 1977. 5. Koetsawang S, Srisupandit S, Srivannaboon S, Bhiraleus S, Rachawat D, Kiriwat O, Koetsawang A: Intramuscular depomedroxyprogesterone acetate for contraception. J Med Assoc Thai 57:396, 1974. 6. McDaniel EB, Pardthaisong T : R e t u r n of menstruation and fertility in T h a i women after contraceptive injections. J Biosoc Sci 3:209, 1971. 7. McDaniel EB, Zelenik J S : Field trial results of long-acting injectable medroxyprogesterone acetate as an injectable contraceptive in 1730 patients. In Proceedings of the VI World Congress of Fertility and Sterility, Tel Aviv, Israel, 1968, p 209. Israel Academy of Sciences a n d Humanities, Jerusalem, 1970. 8. Rizkallah T H , T a y m o r M L : Ovulation inhibition with a long-acting injectable: II. T h e cycling effects of varying progestogen-estrogen combinations. Am J Obstet Gynecol 34:161, 1966. 9. Scommegna A, Lee AW, Borushek S: Evaluation of an injectable progestin-estrogen as a contraceptive. Am J O b stet Gynecol /07.-1147, 1970. 10. de Souza, J C , Coutinho E M : Control of fertility by monthlyinjections of a mixture of norgestrel a n d a long-acting estrogen: a preliminary report. Contraception 5:395, 1972. 11. Statzer D E : Injectable estrogen-progestin as a contraceptive. Adv Plann Parent 1 8 1 , 1968. 12. T a y m o r M L , Yussman M A : Pituitary gonadotropin effects of a long-acting estrogen-progestogen combination. Adv Plann Parent ¿ 1 3 2 , 1969. Address for reprints: S. Koetsawang Family Planning Research Unit Department of Obstetrics and Gynecology Faculty of Medicine Siriraj Hospital Mahidol University Bangkok 7 Thailand