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AFRICA HEALTH. 1993 Mar; 15(3):18-9.Until recently, Africa's fertility rates showed no sign of change in spite of the vast resources committed to decreasing population growth. Now there are early indications of success in parts of Nigeria, Botswana, Zimbabwe, and Kenya. In Kenya, between 1984 and 1989, total fertility fell from 7.7 to 6.7, the crude birth rate fell from 52/1000 to 46/1000, and the contraceptive prevalence rate rose from 17% to 27%. Public awareness of modern contraceptive techniques is above 70% in much of Africa, and in Kenya it is up to 90%. Injectable contraceptives are very popular. In October 1992, they were finally licensed by the United States Food and Drug Administration. Injectable contraceptives were first used in Africa in the late 1960s. They were withdrawn from the Bangladesh family planning program, and they were banned in Zimbabwe in 1981. 2 injectable contraceptives administered by deep intra-muscular injection are widely available. Depo medroxyprogesterone acetate (DMPA) or Depo-Provera is normally given in a dose of 150 mg every 12 weeks. Norethindrone enanthate (NETEN) is given in a dose of 200 mg every 8 weeks. DMPA has been used by more than 10 million women. It is repeatedly endorsed by the WHO and the IPPF and has the lowest failure rate of any method of reversible contraception. Side effects include spotting or amenorrhoea, and rarely, menorrhagia. Injectables are suitable for women who are breast feeding, as they may even increase the quantity of breast milk. Norplant, an implanted device developed by the Population Council, releases progestogen at a low, steady rate for 5 years. There is less progestogen in a 5-year Norplant than in the 3-month dose of DMPA. The implant can be removed at any time and fertility is quickly restored. Norplant is becoming increasingly available throughout Africa.
ENTRE NOUS. 1991 Dec; (19):15.About 8 million women use the long acting injectable contraceptive depot-medroxy-progesterone acetate (DMPA) and norethisterone enanthate (NET-EN). These progesterone only injectables are not dependent on sexual activity and are easy to administer. Yet they are not always well accepted since they can interfere with menstrual bleeding and often induce amenorrhea. Researchers find that adding estrogen to DMPA and NET-EN treats these irregularities. They must use esters with limited action to protect the endometrium from constant estrogens, however, which requires monthly injections. Thus bleeding occurs once a month just like the normal menstrual cycle. Clinical trials in China of Injectable No. 1 (250 mg 17-alpha-hydroxyprogesterone caproate and 5 mg estradiol valerate) show that it has few side effects and is acceptable. Other trials in China are evaluating monthly injectables with NET-EN or megestrol acetate. Numerous developing countries often as WHO's Special Programme of Research in Human Reproduction for effective, safe, and fully studied monthly injectables. WHO operates under a 2 part strategy: optimum improvement of HPR 102 (50 m NET-EN and 5 mg estradiol valerate) and Cyclofem (25 mg DMPA and 5 mg estradiol cypionate) resulting in a reduction of the dose of at least 1 of the hormones and results of a study of the efficacy and side effects of these 2 injectables. It hopes the study provides the impetus to introduce them into national family planning programs. It demonstrates that they are indeed efficacious, effect fewer changes in the menstrual cycle than the progesterone only injectables, and are well accepted, even though women must go to a clinic every 27-33 days for an injection. Other studies are determining their effects on lipid and glucose metabolism, coagulation, and fibrinolysis. They are also looking at the time needed for ovulation to return. 1 study shows that menstruation returned in all women by the 3rd cycle.
Injectable Contraceptives Newsletter. 1982 Apr; (9):1-2.Noristerat is the trade name for a long-acting injectable contraceptive. It is a formulation of Norethisterone enanthate (NET-OEN) in 4 parts of Benzobenzoate and 6 parts of castor oil. The active principle of the drug is Norethisterone which is released from intramuscular depot following hydrolysis of the enanthate side-chain by unspecified tissue. NET-OEN is registered at this time in 36 European, African, Asian, Central and South American countries. Extensive ongoing clinical trials have been and are being carried out by several international organizations including the World Health Organization (WHO). Extended preclinical drug safety testing has been carried out in the U.S. The 1st pilot studies with NET-OEN were performed in 1958; regular clinical studies were started in October 1964. Peru was the 1st country to register and market NET-OEN, followed by Chile, Brazil, and Argentina. When toxicity studies revealed breast and liver tumors in rats NET-OEN was discontinued worldwide. Up to 1973 further toxicological studies had been completed in monkeys. These studies could not demonstrate any pathological effects on the experimental animals. Thus, NET-OEN was released again for further studies in February 1973. Investigations revealed that the development of mammarian and hepatic tumors in rats were not restricted to NET-OEN and could be provoked by administration of other substances. It was concluded that the findings in rats cannot be applied to humans. Schering's toxicological studies on NET-OEN include acute toxicity studies, chronic drug safety studies, and combined drug safety and carcinogenicity studies. With regard to the profile of endocrine activity, NET-OEN has been shown to have progestational and no estrogenic activity in humans. Clinical trials with NET-OEN have been performed in more than 20 different countries, and WHO has conducted 2 multi-center studies on long-acting injectable contraceptives comparing NET-OEN with medroxyprogesterone acetate. The data on use-effectiveness obtained from the 1st WHO study showed a higher failure rate for NET-OEN, i.e., 3.6/100 woman years, but a markedly better tolerance for NET-OEN was found. WHO began a 2nd multicenter trial in February 1976 with a modified application scheme. The results obtained thus far showed that by using these modified application schemes the contraceptive reliability of NET-OEN greatly increased.
Activities of the Special Program of Research, Training and Development in Human Reproduction, World Health Organization in the field of long acting contraceptives.
In: Bangladesh Fertility Research Program. Workshop on Injectable Contraceptives: Noristerat, Dacca, Bangladesh, April 25, 1980. [Dacca, Bangladesh, BFRP, 1980]. 70-80.Following a brief introduction to the World Health Organization (WHO) Special Program of Research, Development and Research Training in Human Reproduction, established in 1972, focus is on what has been achieved thus far with long-acting injectable fertility regulating agents based on steroidal hormones and possessing a duration of action of at least 1 month. Over the last 20-year period, several estrogen-progestin combinations have been developed as monthly injectable contraceptives. The Special Program has initiated a series of clinical pharmacological studies aimed at developing new and improved estrogen progestin injectable formulations. 1 preparation, composed of norethisterone enanthate (50 mg) plus 5 mg of estradiol valerate, has shown promise in preliminary clinical studies. 3 progestogen only preparations with a duration of action of several months have been tested clinically: clormadinone acetate, depo-medroxyprogesterone acetate and norethisterone-enanthate. The 1st clinical trials utilizing the heptanoic acid ester of norethisterone raised considerable hopes, for no pregnancies were observed in 70 highly fertile women given the drug every 90 days. In a WHO trial preliminary data on Depo-Provera (DMPA) bleeding irregularities were responsible for the discontinuation of 9.3 subjects/100 women-years; prolonged amenorrhea accounted for the termination of 11.5 subjects/100 women years. There are several ongoing studies to evaluate the effects of the injectables on users. Norethisterone enanthate, although not possessing the same degree of effectiveness as DMPA, when adminstered every 3 months, remains an attractive injectable because of its lower incidence of amenorrhea.
A preliminary pharmacokinetic and pharmacodynamic evaluation of depot-medroxyprogesterone acetate and norethisterone oenanthate.
Fertility and Sterility. 1980 Aug; 34(2):131-9.2 populations attending WHO centers, one in Sweden and one in India, participated in a comparative, pilot trial of 2 increasingly popular injectable progestin-only female contraceptives, Depo-Provera and Norigest. The purpose of the study was to assess the pharmacokinetic and pharmacodynamic properties of the 2 formulations (depot medroxyprogesterone acetate and norethisterone enanthate). Differences were found between Swedish women and Indian women in their reactions to the 2 drugs: 1) Norigest was detectable in blood samples a significantly shorter time after injection of the agent in Indian women than in Swedish women; this difference was not apparent with Depo-Provera. 2) Although there was no difference at the 2 centers in the time of ovulation return for subjects receiving Norigest, 0 of 4 Swedish women ovulated more than 156 days after Depo-Provera injection, whereas all 4 Indian women ovulated within 73 days of Depo-Provera injection; in the Swedish women, the levels of medroxyprogesterone were undetectable at time of return to ovulation, whereas Indian women had levels of .6 ng/ml when ovulation resumed. 3) In both cultures, Depo-Provera users had significantly more episodes of bleeding and spotting than Norigest users. This preliminary report emphasizes the variety of responses possible to injection of different contraceptive progestins among various populations and points to the need for further culturally comparative studies.
Multinational comparative clinical evaluation of two long-acting injectable contraceptive steroids: norethisterone oenanthate and medroxyprogesterone acetate. 1. Use-effectiveness.
Contraception. 1977 May; 15(5):513-533.A 10-center study of the use-effectiveness of long-acting systemic contraceptive agents is reported. 200 mg of norethisterone enanthate (NET-EN) was administered every 12 weeks + or -5 days to 832 women and 150 mg of depot medroxyprogesterone acetate (DMPA) was administered to 846 women on the same schedule. The cumulative 12-month gross pregnancy rate/100 woman-years was 3.6 + or -.7 for NET-EN and .7 + or -.4 for DMRA. 54% of all the pregnancies in the NET-EN group was contributed by 2 of the 10 centers. 75% of the NET-EN pregnancies occurred during the 1st injection period, primarily in the last 4 years. The admission weight of NET-EN women who became pregnant was significantly lower than those for whom the method was successful. This difference was absent in the DMPA group. The cumulative discontinuation rate for medical reasons at 12 months was 16.9 + or -1.4/100 woman-years for NET-EN and 23.4 + or -1.7 for DMPA. The discontinuation rate for amenorrhea was significantly higher for DMPA than for NET-EN. Differences between the drugs for bleeding irregularities were insignificant as were discontinuations for nonmedical reasons. This study represents a successful attempt at comparing the use-effectiveness of 2 drugs under highly standardized conditions using a large sample drawn from a number of internationally representative settings.
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.
Multinational comparative clinical evaluation of two long-acting injectable contraceptive steroids: norethisterone oenanthate and medroxyprogesterone acetate: 2. bleeding patterns and side effects.
Contraception. 1978 May; 17(5):395-406.A WHO sponsored comparative trail (9 centers) studied the bleeding patterns and side effects experienced by 1678 women using injectable (every 12 weeks) norethisterone enanthate (NOR) and depot-medroxyprogesterone (DMPA). 388.8 women-years of menstrual experience with NOR and 372.5 with DMPA were studied. The percentage of women with total amenorrhea with DMPA was significantly higher than with NOR for all injection intervals. The porportion of women with total amenorrhea increased significantly over time with both drugs (chi-square=33.9 for NOR and 73.4 for DMPA; P < .001). After 1 year, 35% of DMPA and 8.6% of NOR users had total amenorrhea. With NOR, the cycle length distribution changed markedly over time, with the percentage of short cycles under 25 days diminishing as the percentage of long cycles in excess of 46 days increased. In contrast, DMPA held cycle length patterns more or less constant. Length of bleeding and spotting episodes were significantly greater with DMPA. The mean number of bleeding/spotting days decreased over time with both drugs; the difference from the 1st to 4th injection was statistically significant (P < .001). Though the overwhelming majority of women experienced abnormal cycles with both drugs, the percentage of normal cycles remained fairly constant during consecutive intervals. Headache was the most frequently reported complaint: 10.7% of DMPA and 6.9% of NOR users. Other nonmenstrual side effects were reported with similar frequencies in both groups.
Injectable progestogens - officials debate but use increases. Les progestatifs injectables : les autorites en debattent, mas l'usage s'en repand.
Population Reports. Series K: Injectables and Implants. 1975 Mar; (1): p.A report on the status of the injectable contraceptive agents, Depo-Provera (depot medroxyprogesterone acetate) and Norigest is presented. Depo-Provera is distributed in 64 countries, though it is not available in the U.S., the United Kingdom, and Japan. The drug is usually administered in single 150 mg injections every 3 months, and doses of 300-400 mg every 6 months have been studied. The contraceptive effect of Depo-Provera is primarily through its ability to inhibit ovulation. Norigest exerts its effect by altering the cervical mucus. The suppression of ovulation is most likely caused by action on the hypothalamus-pituitary axis, resulting in inhibition of the luteinizing hormone surge. Depo-Provera causes an atrophic endometrium, while Norigest has varying endometrial effects. The reported pregnancy rates for Depo-Provera are usually less than 1%, while those for Norigest are slightly higher. Most method failures occur either shortly after the 1st injection or at the end of an injection interval. Menstrual disorders have been the primary reason for discontinuation. The injectables can cuase shorter or longer cycles, increased or decreased menstrual flow, and spotting. Depo-Provera users experience increased amenorrhea with continued use, while normal cycles increasingly reappear in Norigest users. Cyclic estrogen therapy has been effective in treating excessive or irregular bleeding and amenorrhea. Long-acting estrogen injections have been administered in combination with Depo-Provera or Norigest, though the studies are limited in number. Weight gain of up to 9 pounds has been reported for users of Depo-Provera. Some researchers have found that Depo-Provera raises blood glucose levels, while others have reported it does not. No adverse effects have been reported for injectables on blood clotting, adrenal or liver function, blood pressure, lactation, and metabolic or endocrine functions. The continuation rate for Depo-Provera is reportedly higher than that for oral contraceptives. Generally, 60% of the acceptors will use the method for at least 1 year. Effective counseling on the menstrual alterations resulting from injectables can increase continuation of the method. The return of fertility in Depo-Provera users usually requires 13 months from the time of the last injection, while the afertile period in Norigest users is about 6 months from the time of the last injection. Instances of fetal masculinization as a result of Depo-Provera use have not occurred. The possibility that Depo-Provera can cause cervical carcinoma in situ has not been substantiated by the evidence; doubt about this possible association has prevented its approval as a contraceptive method in the U.S. Although Depo-Provera and Norigest have caused breast nodules in laboratory animals, there is no evidence to suggest that this effect would occur in human. Despite the advantages of injectables, family planning officials have been reluctant to permit its unrestricted use, primarily because it cannot be withdrawn guickly enough if problems arise and because the actual effect on fertility is not yet known. Nonetheless, the use of Depo-Provera has increased in recent years. The IPPF and the U.N. Fund for Population Activities currently supply the drug.