Suporn Koetsawang

Microdose intravaginal levonorgestrel contraception: A multicentre clinical trial

A multicentre clinical trial, including 19 centres in 13 countries, assessed the contraceptive efficacy and clinical acceptability of a Silastic 382 vaginal ring releasing 20 micrograms of levonorgestrel for at least 90 days. A total of 1005 women entered the study and 8176.74 woman-months of experience was gathered. The rate of intrauterine pregnancy at one year of use was 3.6 per 100 women (95% confidence interval 2.2-5.0), and of ectopic pregnancy, 0.2% (one case). The principal reasons for discontinuation were menstrual disturbances (17.2% at one year), vaginal symptoms (6.0%) and repeated expulsion of the ring (7.1%). The pregnancy rate with this 20 micrograms levonorgestrel-releasing vaginal ring compares favourably with that of a low estrogen combination oral contraceptive tested by WHO and is less than half that of a progestogen-only oral contraceptive in a WHO randomized study. It is concluded that the WHO intravaginal ring releasing an average of 20 micrograms of levonorgestrel per 24 hours is an effective method of contraception for at least one year of use.

Multinational comparative clinical evaluation of two long-acting injectable contraceptive steroids: Norethisterone oenanthate and medroxyprogesterone acetate

Abstract The present paper reports the bleeding patterns and side effects experienced by women using norethisterone oenanthate (NET-OEN) and depot-medroxyprogesterone acetate (DMPA) in a WHO-sponsored comparative trial. Only a small minority of women had consistently normal cycles: the vast majority experienced some menstrual abnormality, with 47% of NET-OEN and 70.6% of DMPA users not having any normal cycles. Amenorrhoea was significantly more frequent with DMPA than with NET-OEN and its incidence increased with time. At the end of one year 35% of DMPA and 8.6% of NET-OEN users had total amenorrhoea. There were only minor differences between the two drugs with respect to the frequency or duration of bleeding episodes, but DMPA caused significantly more spotting than NET-OEN. With both treatments there were large individual variations and the bleeding pattern was totally unpredictable. Headache, the most important nonmenstrual side effect, was reported by 6.9% of the NET-OEN and 10.7% of the DMPA users. In the case of DMPA its incidence increased with time. Other complaints such as abdominal discomfort and nervousness were reported with similar frequency on both drugs. There was, with both treatments, a slight increase in body weight and a decrease in blood pressure.

Contraceptives for lactating women: A comparative trial of a progesterone-releasing vaginal ring and the Copper T 380A IUD

From approximately one week before normal ovulation resumes, lactating women require protection against pregnancy by a contraceptive that is safe for both infant and mother in a multicenter one-year study, the natural hormone, progesterone, delivered vaginally by a sequence of four contraceptive rings designed for continuous use, was evaluated as a contraceptive for nursing mothers in comparison with the Copper T 380A IUD. Individual rings release in effective average dose of 10 mg day for a 3 month period. Evaluation included measures of lactational performance as well as of contraceptive efficacy and safety to mother and child. Nine participating clinics enrolled 802 ring users and 734 IUD acceptors between postpartum days 29 and 63. Life table analyses were performed with parallel decrements for ring and IUD subjects. Continuation in the study and analysis required that subjects not stop breastfeeding. The ring, with a one-year pregnancy rate of 1.5 per 100, did not differ significantly from the IUD with respect to contraceptive effectiveness (p > 0.05). More than half of the ring subjects were continuing at 6 months post admission and a quarter (23.5 per hundred) were still using the ring and breastfeeding one year after admission. Women with the IUD, however, had higher continuation rates (p < 0.001) at both time points. The largest single decrement for each method was that for weaning. Ring users had more complaints of vaginal problems but had fewer vaginal disorders on examination. At 12 months postpartum, 46 per 100 continuing ring users remained in amenorrhea. Lactation performance and the health and weight gain of the infants were similar among users of either regimen.

Clinical performance of a new two-rod levonorgestrel contraceptive implant : A three-year randomized study with Norplant® implants as controls

In a randomized three-year clinical trial at seven clinics, the performance of levonorgestrel rod (LNG ROD) implants used by 600 women was compared with that of soft tubing NORPLANT implants used by 598 women. No pregnancies occurred in either group of women and, accordingly, body weight did not affect the efficacy of either type of implant. There were neither statistically significant nor important differences in termination rates for any reason over the three years. Complaint and illness rates during use of either of the two implant types were statistically indistinguishable and were attributable to the same set of conditions. Seventy-one per 100 of the women using each implant regimen continued to the three-year point, for an average annual continuation rate of 89 per 100. Removals of LNG ROD implants were accomplished in about half the time required for removal of Norplant capsule implants (p < 0.001).

Pharmacokinetic study of different doses of Depo Provera

Doses of DepoProvera of 25, 50, 100 and 150mg were administered to four groups of women. The mean time for the return of follicular and luteal activity increased with increasing dose of DepoProvera. Luteal activity was suppressed for a longer period than follicular activity. None of the women receiving the two higher doses of DepoProvera showed a return of luteal function within 100 days of injection. The period for which medroxyprogesterone acetate (MPA) was detectable in serum increased with increasing dose but the values for the 100 and 150mg doses were not significantly different. There was a significant correlation between the concentration of MPA in blood and the return of follicular and luteal function. It is suggested that in the population studied, 100mg DepoProvera would be as effective as the usual 150mg dose and that injection of 50mg DepoProvera would provide a contraceptive effect for two months. The dose of MPA in the monthly injectable CycloProvera could be substantially reduced without loss of effectiveness.

A multicentred phase III comparative study of two hormonal contraceptive preparations given once-a-month by intramuscular injection: I. Contraceptive efficacy and side effects

Two once-a-month injectable contraceptive formulations, HRP112 (depot-medroxyprogesterone acetate, 25mg and estradiol cypionate, 5 mg) and HRP102 (norethisterone enantate, 50 mg and estradiol valerate, 5 mg) were compared in two groups of women with regard to effectiveness, reported complaints and reasons for discontinuation. A total of 2328 women were recruited into a seventeen-centre, randomized clinical trial. Follow-up was for a period of one year and resulted in a total of 10,969 women-months of experience of HRP112 and 10,608 women-months of experience with HRP102. The study showed little difference in efficacy and side-effects between the two formulations. Two pregnancies occurred in women receiving HRP102, giving a cumulative life-table pregnancy rate at 12 months of 0.18 per 100 woman-years. None occurred in the group receiving HRP112. There was no difference in the overall continuation rates between the two groups at one year, being 64.5% in the HRP112 group and 63.2% in the HRP102 group. The rates for all medical and non-medical reasons given for discontinuation were comparable between the two treatment groups. Discontinuations for bleeding irregularities were low, being 6.3% and 7.5% for HRP112 and HRP102 respectively, as well as for amenorrhea, the respective figures being 2.1% and 1.6%. There were, however, marked centre-to-centre differences. Both products were shown to be highly effective contraceptive preparations, which gave rise to few discontinuations due to menstrual cycle disturbances when compared with progestogen-only injectable contraceptives. As such it is expected that they will have an important role in family planning programmes in many countries throughout the world.

Pharmacokinetics of ethynyloestradiol in women from different populations

The pharmacokinetics of a dose of 50 microgram ethynyloestradiol administered orally was studied in fourteen centres. Absorption was rapid and the highest serum concentrations of total ethynyloestradiol were found in most subjects at 1 h and by 24 h concentrations were less than 250 pg/ml. Calculation of the half-lives for absorption, distribution and elimination showed wide variations between subjects, the half-life of elimination varying from 2.5 h to more than 30 h. Bioavailability as measured by the area under the serum ethynyloestradiol concentration-time curve also showed more than a ten-fold variation. Intra-centre differences in the various parameters measured were as large as the inter-centre differences.

Microdose intravaginal levonorgestrel contraception: A multicentre clinical trial: II. Expulsions and removals

This paper investigates the relationship between expulsions and removals, and demographic characteristics of 1005 women from 19 centres using a vaginal ring releasing 20 micrograms levonorgestrel per 24 hours. Emphasis is placed on discontinuations of method use due to expulsions, on the number and rate of expulsions, and the time at which the first expulsion occurred. The overall life-table discontinuation rate due to expulsion was 7.1% at one year. Life-table discontinuation rates increased with parity and were highest in Asian and lowest in European women. In respect to the number of expulsions experienced by women (expulsions did not necessarily lead to discontinuation), the women of high parity and those from Asia and Europe have the highest rates. The life-table first expulsion rate is 29% at one year. Such rates are highest in Chinese and Asian women. Following a first expulsion, the second expulsion rate is 45% by the end of the subsequent six months. The majority of first expulsions occur at defaecation (134 or 57% of 234 women), urination (12%) and during menstruation (17%). Rings were removed by 121 (12%) women on 201 occasions and for a variety of reasons. The main medical reasons were vaginal discharge and irritation, bleeding pain and dyspareunia. Others removed the ring during defaecation, intercourse or because the ring came out of place. Women also removed rings for curiosity, to show their husbands and to clean.

Transfer of contraceptive steroids in milk of women using long-acting gestagens

Levels of norethisterone and medroxyprogesterone acetate were measured in serum and milk of women receiving the injectable contraceptive formulations Norigest and DepoProvera, respectively, throughout complete injection intervals. In 5 of 10 women receiving Norigest, serum norethisterone levels were undetectable by 8 weeks after injection and only 2 women had detectable levels of norethisterone in milk at this time. In contrast, 8 of 10 women receiving DepoProvera had detectable levels of medroxyprogesterone acetate in both serum and milk 12 weeks after injection. The ratio of the milk:serum concentrations of norethisterone varied from 0.12 to 0.92 (mean 0.34) and for medroxyprogesterone acetate from 0.12 to 2.60 (mean 0.88). It is unlikely that these differences between the two formulations are due entirely to differences between the binding of norethisterone and medroxyprogesterone acetate to serum proteins. The area under the curve of serum steroid concentrations plotted against time was only 50% higher for women injected with DepoPovera than for those injected with Norigest but the area under the curve for milk values was 400 times higher. Assuming the infant ingests 600 ml daily, the daily intake of steroids in the first week after injection would be 0.5 to 2.4 micrograms for norethisterone and 1 to 13 micrograms for medroxyprogesterone acetate. By 8 weeks after injection, the amount of norethisterone ingested would be small but that of medroxyprogesterone acetate would still be significant.

Microdose intravaginal levonorgestrel contraception: A multicentre clinical trial: III. The relationship between pregnancy rate and body weight

This paper investigates the relationship between pregnancy rates and body weight of 1005 women using a vaginal ring releasing 20 micrograms levonorgestrel per 24 hours. While the overall pregnancy rate at one year was 3.7%, it was found that women have an increasing risk of pregnancy with increasing body weight. For example, a woman of 40 kg has an estimated pregnancy rate of 1.7% in contrast to 9.8% for a woman of 80 kg weight.