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The use of a large-scale surveillance system in Planned Parenthood Federation of America clinics to monitor cardiovascular events in users of combination oral contraceptives.
International Journal of Fertility and Women's Medicine. 1999 Jan-Feb; 44(1):19-30.In response to studies reporting an excess of thrombotic events in women who used oral contraceptives (OCs) containing third-generation progestins, the Planned Parenthood Federation of America (PPFA) launched a retrospective review of clients at all PPFA-affiliated centers during 1993-95. During the 3-year study period, 2,265,087 woman-years of OC use were recorded in clinic drug sale records. All OCs prescribed in this period contained 30 or 35 mcg of estrogen and either norgestimate (21.0%), desogestrel (8.9%), norethindrone (46.6%), or levonorgestrel (23.6%) as the progestin. 70 major thrombotic events among clients using OCs (3 vascular complications per 100,000 woman-years of OC use) were reported to PPFA's risk management division during 1993-95; these included 25 cases of deep vein thrombosis, 20 cases of pulmonary embolism, 22 cerebrovascular accidents, and 3 myocardial infarctions. There were 5 deaths (0.22/100,000 woman-years of use), all from pulmonary emboli. The thrombotic event rates were calculated as the relative risk of complication, comparing the risk of each event for one progestin relative to the other three classes of progestins. The overall risk varied from a low of 1.895 events/100,000 woman-years for norgestimate OC users to a high of 3.969 events/100,000 woman-years for desogestrel OC users, but these differences were not statistically significant. In the progestin comparison, desogestrel users showed elevated risks for pulmonary emboli and fatalities, norgestrel use was associated with an increased risk of deep vein thrombosis, and norgestimate an increased risk of deep vein thrombosis and pulmonary embolism. Generally, these four groups of low-dose OCs appear safer than any previously published study has indicated. In part, this may reflect PPFA's careful prescribing guidelines. In addition to following US Food and Drug Administration contraindications, PPFA affiliates do not provide OCs to women over 35 years of age who smoke more than 15 cigarettes a day.
ADVANCES IN CONTRACEPTION. 1990 Sep; 6(3):169-76.Clinical trials of vaginal rings containing progestins or ethinyl estradiol and progestins by WHO, the Population Council and private firms are reviewed. Contraceptive steroids can be formulated into Silastic vaginal rings because they are released continuously from this material (zero-order kinetics). Vaginal rings have the advantage of avoiding the 1st pass effect on the liver, as well as self- administration, unrelated to the timing of coitus and regulation of withdrawal bleeding with removal for 7 days per cycle. The shell vaginal ring, with an inert core, a layer of Silastic containing the progestogen, and an outer Silastic layer is designed to regulate release by the thickness of the outer layer. The WHO tested rings releasing 200 mcg norethisterone/day resulting in too many menstrual side effects; and 50 mcg/day with too high a failure rate. A ring releasing 20 mcg levonorgestrel is expected to perform well. The Population Council designed rings releasing 152 mcg ethinyl estradiol and 252 mcg levonorgestrel, and 183 mcg ethinyl estradiol and 293 mcg levonorgestrel. These resulted in pregnancy rates of 2/100 woman years, and continuation rates of 50%, but unacceptably adverse lipid effects. Women discontinued for vaginal symptoms. Compared to a similar combined oral pill, the rings offered no advantage. WHO subsequently introduced a ring releasing 20 mcg levonorgestrel: efficacy was 3.8 and continuation over 50%. A new segmented ring with desogestrel is causing fewer androgenic effects and bleeding complaints. Another ring in current trials gives off 120 mcg desogestrel and 30 mcg ethinyl estradiol with no pregnancies and good acceptability in 100 women to date. Availability of Silastic material and quality control in manufacture are seen as obstacles to overcome for mass production of these vaginal rings.
Steroids. 1983 Mar; 41(3):243-53.The great demand for improved longacting injectabe steroid contraceptives, particularly in developing countries, and the relative lack of interest from the pharmaceutical industry to develop such products stimulated the World Health Organization to launch a synthetic and screening program to find improved, safe, and acceptable injectable preparations. More than 210 esters of norethisterone (17alpha-ethynyl-17beta-hydroxyestr-4-en-3-one) and levonorgestrel (D-(-)-13beta-ethyl-17alpha-ethynyl-17beta-hydroxygon-4-en-3-one) have been prepared in university-based research laboratories situated mainly in developing countries, and then screened by NICHHD in animal models. The following 3 compounds levonorgestrel butanoate, cyclopropylcarboxylate, and cyclobutylcarboxylate, proved to be particularly longacting when administered as microcrystalline suspensions. The overall strategy of this research and development program is described. (author's modified)
JOURNAL OF STEROID BIOCHEMISTRY. 1979 Jul; 11(1B):461-7.This report succinctly summarizes Phase I and II clinical trials of intravaginal and intracervical delivery systems for fertility control agents (both steroidal and spermicidal) performed at World Health Organization (WHO) Centres internationally. The WHO Special Programme has conceived of and developed a number of vaginal rings (silastic), which are capable of achieving constant release rates of progestogenic steroid for periods of 90 or more continuous days of use. The local administration rules out the possibility of systemic side effects while the constant release is capable of inhibiting sperm migration through the cervical mucus efficacy of these devices incorporating norethisterone, levonorgestrel, and progesterone is in progress. The vaginal ring has also been incorporated with nonoxynol-9, a potent spermicidal agent. Constant daily release of this spermicidal agent also inhibits sperm migration in the cervical mucus, and use-effectiveness studies are underway. An inert intracervical device, designed and manufactured by WHO, is described (figures depict its manufacturer), and though it is suitable for constant release contraception, no such studies have been performed as yet. Numerous tables report particular release rate data for the vaginal rings impregnated with various dosages of progestogen or spermicide.
Contraception. 1979 Jan; 19(1):39-45.The metabolism rate of orally administered norethisterone (Nor) was compared in 14 WHO Collaborating Centres by measuring plasma steroid levels by radioimmunoassay at varying times after a 1-mg oral dose. Peak plasma concentration was reached between 1 and 2 hours after ingestion in all Centres except Singapore and Seoul. After the peak, a marked decrease in serum Nor concentration occurred, but even after 24 hours, significant amounts were still present in serum, with mean values ranging from 275 pg (Stockholm) to 935 pg/ml (Mexico). As expected, a highly significant decrease (p < .001) of serum Nor values occurred with time, the mean correlation coefficient varying from .8 (Los Angeles) to .96 (Stockholm). Ratios of Nor metabolism were compared in different Centres; mean value for Stockholm was significantly higher than that of all other Centres, and that for Canada (.048) was significantly higher than that of Bangkok and other Centres with a value less than .043. Calculated steroid half-lives for the period 8-24 postadministration were within a range from 9.7-18.9, more consistent than values for the 2-8 hour period. In general, inter-Centre differences were of the same order as the intra-Centre ones. Variations in steroid metabolism did not appear to be caused by body size variations.
In: Diczfalusy, E., ed. Regulation of human fertility. (Proceedings of the WHO Symposium on Advances in Fertility Regulation, Moscow, USSR, November 16-19, 1976) Copenhagan, Denmark, Scriptor, 1977. p. 323-360Long-acting systemic contraceptives inhibit fertility either at a central or peripheral level. In some instances, a mixed reaction is likely to be working: during the 1st portion of the drug's life-span the contraceptive effect is exerted at a hypothalamic central level, whereas later on--when ovulation is restored--the action is on the cervix or uterus. The most important factor holding back utilization of long-acting agents is serious interference with regularity of the menstrual cycle, and delivery systems must be devised with zero-order release rates to improve cycle control and acceptability. Monthly injectables consisting of synthetic progestins alone proved unsuitable for contraception because of frequent and prolonged amenorrhea. Addition of an estrogenic substance helped cycle control, and a dihydroxyprogesterone acetophenide plus estradiol enanthate combination seems most worthy of clinical investigation; so far, 15,000 woman-months of experience have yielded no unwanted pregnancies. Few bleeding pattern irregularities were reported, but premenstrual tension, dysmenorrhea, and libido changes occurred. Reversibility of drug-induced anovulation has been shown by spontaneous ovulation resumption 12-42 weeks after cessation. Tri-monthly injections of Depo Provera resulted in pregnancy rates averaging .5/100 woman-years of use. Biannual injectable and sustained release systems are discussed and data are presented.
In: Gabelnick, H.L., ed. Drug delivery systems. (Proceedings of a Workshop sponsored by Contraceptive Development Branch, Center for Population Research, National Institute of Child Health and Human Development, Bethesda, Maryland, August 2-3, 1976) Bethesda, Maryland, U.S. Department of Health, Education, and Welfare, 1977. 339-413. (NIH 77-1238)The main drug delivery systems in which WHO is conducting research are for vaginal, cervical, uterine, nasal, and systemic delivery; these are summarized. For vaginal drug delivery, rings with progestational steroid have been developed but lack patient acceptability. In addition to progesterone (d-norgestrel and norethisterone are also being studied), spermicidal agents, specifically nonoxynol, are being tested in vaginal rings. For cervical drug delivery, studies of a cervical device with 2 prongs and a reservoir are underway using spermicidal agents rather than progestational steroids. Clinical acceptance studies underway indicate no problem with the inert device. Variable expulsion rates do pose a problem, hopefully one which can be resolved through better insertion techniques. Nonoxynol is a pH-dependent agent, so quinine is now being tested for efficacy because it is not pH dependent. A local histological study of the cervix will follow clinical trials. IUDs designed for developing countries are of interest to WHO, and to this end an IUD which is coated with some kind of rapidly degrading polymer, causing the device to shrink, would allow for postabortion and postpartum insertion. The problems of IUD acceptability and continuation rate in developing countries are being studied, and hopefully collaborative work will overcome pain and bleeding side effects. A systemic delivery system (study initiated 3.5 years ago) is designed to deliver drugs at a zero-order rate but problems with biodegradable material and inhibitory levels of progestational agents remain to be worked out.