Pharmacodynamic effects of once-a-month combined injectable contraceptives

Abstract

The pharmacology and clinical assessment of existing first generation once-a-month combined injectable contraceptives, mainly Deladroxate and Chinese Injectable No. I, are reviewed. Although these two types of monthly injectables have been used in some million women in China and Latin America, Deladroxate needs in-depth re-evaluation of its long-term toxicity and possible accumulation. For Injectable No. 1, its disadvantage of being administered on an erratic schedule will cause significant confusion in family planning practice. When used in a strict once-a-month schedule, it is not sufficiently effective for contraception. In order to attain predictable menstrual cycle control as well as high efficacy with a 30-day injection schedule, two improved once-a-month injectable formulations, Cyclofem and Mesigyna, were developed. Pharmacokinetic/pharmacodynamic study on estrogenic components suggested that estradiol valerate and cypionate were suitable estrogen esters to give elevated plasma estrogen levels for 7 to 11 days. After a single injection of Cyclofem and Mesigyna, both formulations showed equal contraceptive effect with inhibition of follicle maturation for some 30 days and ovulation, corpus luteum formation for some 60 days. Multicentre studies on the optimization of dosages of progestogens and estrogens in once-a-month injectables confirmed that the full doses of Cyclofem (DMPA 25 mg/estradiol cypionate 5 mg) and Mesigyna (NET-EN 50 mg/estradiol valerate 5 mg) are suitable for large scale clinical trials. Pharmacodynamics and progestogen/estrogen ratio study indicated the importance of not only the absolute amounts of the progestogen and estrogen but also of their ratio. Reduction of estrogen dose resulted in breakthrough ovulation with both Cyclofem and Mesigyna. Also, it is important to note that the second part of the injection cycle is dominated by the progestogen component of both monthly formulations. A longitudinal study indicated that there is no accumulation of norethisterone after 12 months of treatment with NET-EN 50 mg and estradiol valerate 5 mg.