S. Holck

Multinational comparative clinical trial of long-acting injectable contraceptives: Norethisterone enanthate given in two dosage regimens and depot-medroxyprogesterone acetate. Final report: Who special programme of research, development and research training in human reproduction*

Final results are presented from a two-year WHO multinational comparative trial of three regimens: depot-medroxyprogesterone acetate (DMPA) given at 90-day intervals, norethisterone enanthate (NET-EN) given at 60-day intervals for the entire study period (NET-EN (60-day)), and NET-EN given at 60-day intervals for six months and thereafter at 84-day intervals (NET-EN (84-day)). 1587 DMPA subjects were observed for 20,550 woman-months, 789 NET-EN (60-day) subjects were observed for 10,361 woman-months, and 796 NET-EN (84-day) subjects were observed for 10,331 woman-months. This clinical trial represents the largest clinical trial undertaken on injectable contraceptives. After two years, the pregnancy rate with NET-EN (84-day) was 1.4 (+/- 0.6 S.E.) per 100 women, as compared with the two-year rates of 0.4 (+/- 0.3 S.E.) per 100 women observed with DMPA and 0.4 (+/- 0.2 S.E.) with NET-EN (60-day). Both discontinuation rates for amenorrhea and the prevalence of amenorrhea lasting more than 90 days were significantly higher with DMPA than with either NET-EN regimen. Terminations for bleeding problems were similar with the three treatments, despite a better cyclic pattern for the first six months with the NET-EN regimens. The three treatments were comparable with respect to discontinuation rates for other medical or personal reasons, and for all reasons combined. For family planning programs, NET-EN (60-day) has the advantage of low pregnancy rates compared to NET-EN (84-day), and a schedule of administration that does not change. Both NET-EN regimens produce less amenorrhea than DMPA. However, the NET-EN (60-day) regimen has the logistic and economic disadvantage of requiring more frequent injections. All three injectable regimens compare favourably with oral contraceptives in terms of pregnancy and total continuation rates observed in clinical trial settings.

A randomized double-blind study of the effects of two low-dose combined oral contraceptives on biochemical aspects: report from a seven-centred study. WHO Special Programme of Research Development and Research Training in Human Reproduction. Task Force on Oral Contraceptives.

A comparative study of the metabolic effects of two combined oral contraceptive preparations was undertaken in seven WHO Collaborating Centres for Research in Human Reproduction. A total of 847 subjects were randomly allocated to one of two pill groups - norethisterone lmg/ethinyl estradiol 35 micrograms (NET/EE) or levonorgestrel 150 micrograms/ethinyl estradiol 30 micrograms (LNG/EE). An additional 195 women using an IUD served as a comparison group. Blood samples were taken on admission, and at 3 and 12 months thereafter. Both pills induced changes in fasting and 2-hour glucose, triglycerides, total cholesterol, HDL-cholesterol, bilirubin, alkaline phosphatase, albumin, and total protein, but not aspartate aminotransferase. The most dramatic and probably most clinically important changes were an increase in triglycerides and a decrease in HDL-cholesterol. The NET/EE preparation appeared to induce a greater increase in triglycerides, but no significant difference was found between the two pill preparations with respect to HDL-cholesterol changes.

Lipid and biochemical changes after low-dose oral contraception

A randomized double-blind study of the metabolic effects of 2 low-dose combined oral contraceptives was carried out in Singaporean women. The subjects comprised 58 women randomly allocated to two treatment groups (29 each): norethisterone 1 mg/ethinyl estradiol 35 micrograms (NET/EE) or levonorgestrel 150 micrograms/ethinyl estradiol 30 micrograms (LNG/EE) and a control group of 23 women using intra-uterine devices (IUD). Blood samples were taken on admission and at 3 and 12 months after pills or insertion of IUDs. Fasting glucose levels were decreased while 2h glucose and triglyceride were increased throughout the treatment period in NET/EE group [corrected]. LNG/EE group only showed significant increase of 2h glucose at 12 months and decrease of LDL cholesterol at 3 months while total cholesterol was significantly suppressed at 3 and 12 months [corrected]. The atherogenic index, LDL/HDL cholesterol was significantly reduced by 12 months. Both groups had no change in hemoglobin, hematocrit and total protein levels but alkaline phosphatase, bilirubin and aspartate transaminase (SGOT) were suppressed. While NET/EE suppressed albumin significantly, this was not observed with LNG/EE group. However, these differences observed with use of each pill preparations, were not so obvious between treatment groups and control. Changes in total, HDL and LDL cholesterol and SGOT were not significantly different than the IUD group. Furthermore, except for 2h glucose, there was no increase in the number of abnormal parameters after treatment. On the contrary, there was a reduction of abnormal values in most liver function parameters. Thus, except for glucose intolerance, the observed changes in metabolic parameters may not constitute any clinical significance.(ABSTRACT TRUNCATED AT 250 WORDS)

A multicentre comparative study of serum lipids and lipoproteins in four groups of oral combined contraceptive users and a control group of IUD users

A prospective clinical trial was conducted in three centres to assess the effects of the type and dose of progestogen, the dose of estrogen and the progestogen-to-estrogen ratio of oral contraceptives on lipid metabolism. The preparations selected contained levonorgestrel 250 micrograms + ethinyl estradiol 50 micrograms (Neogynon), levonorgestrel 250 micrograms + ethinyl estradiol 30 micrograms (Eugynon 30), levonorgestrel 150 micrograms + ethinyl estradiol 30 micrograms (Microgynon) or norethisterone acetate 1 mg + ethinyl estradiol 50 micrograms (Minovlar). Four-hundred-and-seven premenopausal women were randomly assigned to one of the four pill groups and compared to a control group of 119 users of a CuT220c intrauterine device. Total cholesterol, HDL-cholesterol, LDL-cholesterol and total triglycerides were monitored and the analysis includes the data of those who were followed over 48 weeks, 241 OC users and 87 IUD users. 250 micrograms of levonorgestrel were found to induce more unfavourable lipid changes in terms of atherosclerotic risk than 1mg of norethisterone acetate. Levonorgestrel was found to have a dose-effect on HDL-cholesterol and LDL-cholesterol serum levels, while ethinyl estradiol had a dose-effect on serum triglycerides. HDL-cholesterol was related to the progestogen-to-estrogen ratio. Most of these findings were consistent across centres. Finally, some comments are made on the implications of the study results on the design of future lipid studies.

Phase IV study of the injection norigest in Pakistan

A field study of the injectable contraceptive, norethisterone enanthate (NET-EN), was conducted in family planning clinics in Sind and Punjab provinces of Pakistan, to determine the acceptability and feasibility of providing NET-EN in government family planning clinics staffed by Family Welfare Visitors (FWVs). A total of 2147 women were recruited to the study, of whom approximately three-fourths had never previously used contraception. The overall discontinuation rate at one year was 78 per 100 women; the most common reason for discontinuation was bleeding disturbances, including amenorrhea, although returning to the clinic too late for an injection also accounted for a substantial proportion of the discontinuations. Given adequate training, FWVs were shown to be capable of providing NET-EN in family planning clinics, including managing the bleeding disturbances common with this method of contraception. No pregnancies were reported, demonstrating that the method is highly effective when used in a usual family planning clinic situation.