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Contraception. 2005; 71:235-238.Recognizing that the currently available contraceptive options represent a limited choice for women, contraceptive research and development programs have identified the process of implantation as a promising area for investigation. Contraceptive methods that prevent implantation and can be taken on a once-a-month basis appear to be an attractive option for many women in a variety of settings. A recently completed 5-year, international, collaborative research programme—conducted by the World Health Organization with financial support from the Rockefeller Foundation—has identified a number of promising leads for once-a-month method development and the more promising of these leads are being actively followed up in collaboration with the pharmaceutical industry. (author's)
The global eradication of smallpox. Final report of the Global Commission for the Certification of Smallpox Eradication, Geneva, December 1979.
Geneva, Switzerland, WHO, 1980. 122 p. (History of International Public Health No. 4)The Global Commission for the Certification of Smallpox Eradication met in December 1978 to review the program in detail and to advise on subsequent activities and met again in December 1979 to assess progress and to make the final recommendations that are presented in this report. Additionally, the report contains a summary account of the history of smallpox, the clinical, epidemiological, and virological features of the disease, the efforts to control and eradicate smallpox prior to 1966, and an account of the intensified program during the 1967-79 period. The report describes the procedures used for the certification of eradication along with the findings of 21 different international commissions that visited and reviewed programs in 61 countries. These findings provide the basis for the Commission's conclusion that the global eradication of smallpox has been achieved. The Commission also concluded that there is no evidence that smallpox will return as an endemic disease. The overall development and coordination of the intensified program were carried out by a smallpox unit established at the World Health Organization (WHO) headquarters in Geneva, which worked closely with WHO staff at regional offices and, through them, with national staff and WHO advisers at the country level. Earlier programs had been based on a mass vaccination strategy. The intensified campaign called for programs designed to vaccinate at least 80% of the population within a 2-3 year period. During this time, reporting systems and surveillance activities were to be developed that would permit detection and elimination of the remaining foci of the disease. Support was sought and obtained from many different governments and agencies. The progression of the eradication program can be divided into 3 phases: the period between 1967-72 when eradication was achieved in most African countries, Indonesia, and South America; the 1973-75 period when major efforts focused on the countries of the Indian subcontinent; and the 1975-77 period when the goal of eradication was realized in the Horn of Africa. Global Commission recommendations for WHO policy in the post-eradication era include: the discontinuation of smallpox vaccination; continuing surveillance of monkey pox in West and Central Africa; supervision of the stocks and use of variola virus in laboratories; a policy of insurance against the return of the disease that includes thorough investigation of reports of suspected smallpox; the maintenance of an international reserve of freeze-dried vaccine under WHO control; and measures designed to ensure that laboratory and epidemiological expertise in human poxvirus infections should not be dissipated.
BULLETIN OF THE WORLD HEALTH ORGANIZATION. 1993; 71(6):669-76.Depot-medroxyprogesterone acetate (DMPA) is a highly effective long-acting progestational contraceptive, which is administered by injection. DMPA has been widely used in Thailand and New Zealand. The licensing, acceptability, and prevalence of use have been influenced by concern that DMPA may increase the risk of cancer, in particular cancer of the breast. The results of toxicological tests in animals and epidemiological studies in humans concerning the carcinogenicity of DMPA are reviewed. Animals injected with DMPA were exposed to far greater concentrations of the progestogen than were animals tested with orally administered 19-nortestosterone derivatives. In beagle dogs, a unique response to DMPA led to increased serum growth hormone, which was probably responsible for the tumorigenic effect of DMPA on the mammary gland. However, women taking contraceptive doses of DMPA have no significant elevation of serum growth hormone. Available toxicological data do not seem to indicate that DMPA is different from other progestogens in its tumorigenic potential. Epidemiological studies reassure that use of DMPA does not increase breast cancer risk overall. Elevated risks in the same or similar subgroups were observed in the WHO and New Zealand studies, consistent with an acceleration in detection of pre-existing cancer. The data were not compatible with DMPA as an initiating agent. Research is needed on the biological mechanisms of action of progestogens on the human breast. Findings from studies of DMPA and invasive cervical cancer showed no overall increase in risk of cervical cancer and no association between DMPA and cervical cancer. Data from the WHO study provided evidence that DMPA protects against endometrial cancer and that DMPA use was not associated with either an increased or decreased risk of ovarian cancer. Therefore, restriction of DMPA use as contraceptive on the grounds of risk of neoplasia is not recommended.
CONTRACEPTION. 1994 Mar; 49(3):185-8.Depot-medroxyprogesterone acetate (DMPA) is currently used for contraception by about nine million women in more than 90 countries. DMPA injected intramuscularly at a dose of 150 mg every 3 months, is among the most effective reversible contraceptive methods. The reluctance of the US Food and Drug Administration (FDA) to approve DMPA in 1992 was attributed to the occurrence of mammary neoplasia in beagle dogs and of endometrial cancer in two of sixteen rhesus monkeys after long-term DMPA treatment. The beagle dog responds to DMPA with a release of growth hormone which is probably the cause of the tumorigenic effect of DMPA on the mammary gland. Around 1990 findings were published from a WHO multicenter study in Kenya, Mexico and Thailand and studies from Costa Rica and New Zealand. In 1993, a WHO meeting of experts reviewed the available data on use of DMPA and cancer risk in women as well as recent toxicology data. DMPA exerts a protective effect against endometrial cancer. The epidemiological studies report no association between the risk of ovarian cancer and the use of DMPA. There was a lack of an association between cervical cancer and DMPA. Two well-designed epidemiological studies did not provide evidence for an increase in overall risk of breast cancer among women having used DMPA. However, both studies reported a weak association between current and recent use of DMPA and breast cancer although there was no evidence of increased risk for women who had stopped using DMPA several years ago. Women who were less than 35 years old at diagnosis, an age at which breast cancer is rare, also showed a slightly increased risk. DMPA can cause an irregular bleeding pattern, it is not immediately irreversible, and there is a relatively slow return of fertility after discontinuation. Yet for women who wish for medium- or long-term contraception, DMPA is one of the alternatives to be considered.
WORLD HEALTH FORUM. 1993; 14(1):90-1.The WHO Special Program of Research, Development, and Research Training in Human Reproduction has developed a prototype antifertility vaccine. The vaccine is directed against human chorionic gonadotrophin (hCG) and consists of a conjugate immunogen, formed from a synthetic fragment of the beta subunit of hCG joined to diphtheria toxoid and mixed with an immunostimulant. After 4 years of extensive preclinical safety and efficacy studies, the Program conducted a Phase I clinical trial between 1986 and 1988, using the vaccine in sterilized women to assess its safety. Teratology studies were carried out in rats and rabbits in case it failed to prevent pregnancy; the results showed that the WHO prototype vaccine had no adverse effects either on the pregnant animals or on the fetuses. The Program is now planning to conduct Phase II clinical trials to assess the effectiveness of the vaccine. The studies done so far have shown that the prototype anti-hCG vaccine is well tolerated, safe, and immunogenic in humans, but this version requires at least 2 injections, at an interval of several weeks, to elicit an anti-hCG immune response lasting for 3-6 months. Therefore, the Program has been developing an advanced prototype vaccine designed to elicit effective levels of immunity which will last for 12-18 months following a single injection. The advanced prototype anti-hCG vaccine consists of the same immunogen conjugate and immunostimulant used in the prototype version, but they are incorporated into a polymer designed to release the vaccine slowly over an extended and predetermined period of time. Dose-response and toxicity studies are currently under way in rabbits and baboons to determine the optimal dose of the vaccine and to see if this vaccine is safe for testing in humans.
BMJ. British Medical Journal. 1993 Apr 10; 306(6883):947-8.Extensive studies in experimental animal models and phase I and II clinical trials in humans provide some grounds for optimism about developing a vaccine for AIDS. Over 200 monkeys have been protected by simple inactivated vaccines against infection with a lethal challenge dose of simian immunodeficiency virus (SIV). Passive transfer of the antibody to SIV has been shown to prevent infection. Recent vaccination with attenuated, live SIV protected against a challenge with 1000 monkey infectious doses of virus. Studies in chimpanzees have been limited to the unrepresentative IIIB strain of HIV-1. Purified recombinant envelope protein either as the gp 120 surface unit or as the entire gp 160 protein has protected a proportion of chimpanzees against infection. Several experimental immunogens have been tested in phase I and II clinical trials in human volunteers. 5 different recombinant HIV envelope subunits, live recombinant vaccinia virus expressing HIV envelope, and synthetic peptides or virus-like particles derived from yeast, but expressing HIV core proteins, have been used for vaccines that have proved safe. However, large quantities of the subunit HIV antigens are required, and the humoral immune responses are short-lived. Trials with the live recombinant vaccinia virus expressing HIV envelope represent the first use of live recombinant virus in humans. Further studies are under way in France with an avian poxvirus vector, which is host restricted and therefore potentially safer. STudies with combinations of live recombinant virus vaccines followed by immunization with purified subunits indicate that this approach may stimulate both cellular immunity and neutralizing antibodies at higher concentrations than previously observed. The WHO has identified sites in Brazil, Rwanda, Thailand, and Uganda for large scale trials of the efficacy of AIDS vaccines that will probably begin within 5 years.
PROGRESS IN HUMAN REPRODUCTION RESEARCH. 1992; (22):4-5.During 1986-1988, the WHO Special Programme of Research, Development and Research Training in Human Reproduction used the diphtheria toxoid as a carrier for a fragment of the human chorionic gonadotropin (hCG) molecule (a conjugate immunogen) and an immunostimulant in a phase I clinical trial of this prototype antifertility vaccine in sterilized women. Between 1990 and 1991, it conducted teratology studies in rats and rabbits to determine whether the vaccine causes fetal abnormalities. The vaccine did not adversely affect either the animals or their fetuses. Clinical trials of the vaccine's effectiveness (phase II trials) are scheduled for 1992. At least 2 injections several weeks apart, are needed to produce an anti-hCG immune response which is only effective for 3-6 months, however. So the same components of the original vaccine were placed in a polymer to deliver the vaccine slowly over a prolonged and predetermined time frame. WHO hoped that this advanced vaccine would raise effective immunity levels long enough to last for at least 1 year after 1 injection. WHO is conducting dose-response and toxicity studies of this prototype vaccine in rabbits and baboons to identify the optimal dose which would elicit an effective immunity level over a desired period of time and would be safe for testing in humans. WHO hopes to begin a phase I clinical trial with this advanced anti-hCG vaccine in late 1992. WHO anticipates that the preclinical and clinical trials will reveal a need for further modifications and improvements. WHO is supported multicenter research on antitrophoblast vaccines which target membrane cells of the preimplantation embryo since 1985. It uses monoclonal antibodies (MABs) and recombinant DNA technology to identify and isolate surface molecules. So far this research has tested 15,000 MABs but is centering on 9 MAbs. A study in baboons showed that 1 MAB reduced fertility, even though researchers could only use minute amounts of the protein in the injection.
CONTRACEPTION. 1992 Aug; 46(2):103-4.WHO formed its Task Force on Methods for the Regulation of Male Fertility in 1972. Its charge is developing safe, effective, reversible, and affordable contraceptive methods for developing countries. The research focus is on suppression of sperm production. The research strategy consists of 3 parts: suppression of secretion of the pituitary gonadotropin hormones, recouping circulating androgen to physiological levels without prompting spermatogenesis, and determining the functional ability of residual sperm if treatment does not bring about azoospermia in all cases. A task Force study reveals that men of various ethnic groups respond to testosterone contraceptives differently. Other clinical research involved an androgen with a progestogen such as DMPA. Since steroids are basically inexpensive to produce they may prove to be beneficial and affordable to national family planning programs in developing countries. Gonadotropin releasing hormone (GnRH) antagonists proved to be relatively effective in suppressing gonadotropins and sperm production in animals. Scientists working on developing GnRH antagonists should strive to formulate a reversible contraceptive with no side effects which requires limited injections. The Task Force carried out a study in bonnet monkeys with the GnRH agonist buserelin in which buserelin suppressed spermatogenesis for 3 years and, after treatment, testicular function was entirely restored. Subsequent mating trials indicated they were fertile. The Task Force planned to follow the study with a GnRH antagonist. The 1st international gathering on GnRH analogues in China served to bring together scientists the world over to meet and to collaborate in developing new drugs for contraceptive use.
JOURNAL OF PEDIATRICS. 1987 Sep; 111(3):475-6.Experiments directed at finding the most effective oral rehydration solutions for children with diarrhea, by using a jejunally perfused healthy rat model may not be relevant. The experiments predicted that 110 mM glucose and 60 mEq/L Na+ would maximize water absorption and maintain isotonicity. In rats with artificially induced diarrhea, persistent net Na+ secretion and reduced absorption of bicarbonate and water were observed during perfusion of glucose-saline solutions. Thus the relevance of the healthy rat model to human diarrheal disease therapy requires validation before advancing to therapeutic recommendations. In most pediatric patients with diarrhea, the gastrointestinal luminal fluid contains 60 mEq/L Na+ and no glucose other than what is ingested. The WHO recommended oral formula contains 90 mEq/L Na+ and 111 mmol/L glucose. In some studies patients are given 90 mEq/L Na+ for 2 hours (8 oz/hr), followed by water for 1 hour, then 90 mEq/L Na+ for 2 more hours. This regimen produced greater initial Na+ absorption than a mixture of 60 mEq/L Na+, and causes less hyponatremia. The most efficiently absorbed solution is the WHO solution alone with no extra water, according to numerous studies.
ECONOMIC AND POLITICAL WEEKLY. 1986 Jun 14; 21(24):1079-80.NET-EN was marketed initially in 1967 and almost 15 years following its use the Twelfth Annual Report of the World Health Organization (WHO), published in 1983, states that questions exist regarding the effectiveness and safety of DMPA and NET-EN that call for more research. Yet, in 1982, the Toxicology Review Panel of WHO had found NET-EN to be a safe contraceptive and had recommended its use in family planning programs. According to Iris Kapil, studies by WHO have failed thus far to identify any health risk associated with the use of Depo Provera and have shown no adverse effect on the composition or yield of breast milk. In 1983, however, the Federal Health Office of West Germany, where the parent company manufacturing NET-EN is based, revised its ruling with specific reference to the use of NET-EN and DMPA during lactation. If Kapil would not be so awed by the WHO and the ICMR and would take the time to identify their own admissions, she too would question the basis on which the injectables are being declared safe. Factors governing the rate of metabolism of contraceptive hormones are not well understood. The rate of decline of circulating norethisterone in patients having multiple injection was significantly slower, suggesting a decrease in the metabolism of the steroid. In the WHO multicenter trial of 1977 no systematic differences in factors could be identified to account for the high failure rate. Little is known about the basic mechanisms of bleeding disturbances especially those related to steroidal contraceptions. A satisfactory approach to the management of prolonged or heavy bleeding due to the injectable contraceptive has not been developed as yet. Nothing is known about whether synthetic progestogens have any effects on normal hormonal changes in the early infant which may in turn affect the latter's sexual development. Little information from human studies is available on long acting injectable contraceptives and the risk of neoplasia. Other important aspects such as immuno-supressive effect of the injectable on the woman and her breastfed infant, the possibility of irreversible pituitary ovarian and endometrial atrophy have not been studied. Kapil cities a "well-reported" project from South India to support her case. What is apparent is that the list of disadvantages identified appear to be written from the perspective of how it would affect continuation rates. Nowhere does it appear to stem from a concern for the health of the women involved.
Weekly Epidemiological Record / Releve Epidemiologique Hebdomadaire. 1980 Feb 1; 55(5):33-4.At its final meeting in December 1979, the Global Commission for the Certification of Smallpox Eradication concluded that smallpox eradication has been achieved on a worldwide basis and there is no evidence that smallpox will return as an endemic disease. The 65th session of the WHO's Executive Board, held on January 25, 1980, endorsed these conclusions and made 19 recommendations covering the areas of vaccination policy, reserve stocks of vaccine, investigation of suspected smallpox cases, laboratories retaining variola virus stocks, human monkeypox, laboratory investigations, documentation of the smallpox eradication program, and WHO headquarters staff. Sufficient freeze-dried smallpox vaccine to vaccinate 200 million people will be maintained by WHO in refrigerated depots in 2 countries. WHO will ensure that appropriate publications are produced describing smallpox and its eradication, with special emphasis on the principles and methods that are applicable to other programs.
In: Wood C, Rue Y, ed. Health policies in developing countries. London, England, The Royal Society of Medicine, 1980. 167-72. (Royal Society of Medicine. International Congress and Symposium Series; No. 24)Research is the tool which can help accelerate control of filariasis including the most important, river blindness and elephantiasis. The principles for control include eliminating the vectors and changing the way of life of the people. However these methods do not take into account the different ecologies of the land, cultures of the people and technical and political differences of the endemic areas. The WHO Onchocerciasis Control Program in the Volta Basin has been highly successful, but reinvasion of vectors is possible and there is concern that unacceptable levels of pollution will occur. Several successful limited programs of control are cited, but the absence of suitable drugs to kill the parasites is evident. One of the areas of research is centering on the characterization of the parasites and their vectors. More studies of isoenzyme markers are needed to distinguish different species of filarial parasites. An important advance in the diagnosis of filariasis has been the application of membrane filtration techniques for detecting light infection. Some of the current vector research is noted. This is particularly important because the main vectors of filariasis in Africa are also the main vectors of malaria. WHO is encouraged to stimulate collaborative research in this area. Chemotherapy is currently the most encouraging aspect of research. WHO is supporting 4 major centers where old and new filaricides are being evaluated. Some experiments are indicating the possibility that resistance to the disease can be stimulated by using irradiated larvae as appear in a cat model. Testing is now underway in a bovine onchocerciasis model. The new laboratory developments must continue so they can be applied clinically.
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.
Sequelae of vasectomy. Report of a Meeting on Vasectomy, organized by the Special Programme of Research, Development and Research Training in Human Reproduction held at WHO, Geneva, 3-6 August 1981.
Contraception. 1982 Feb; 25(2):119-23.In response to enquiries received by the World Health Organization (WHO) from several countries, the WHO Special Program of Research, Development and Research Training in Human Reproduction convened a meeting of experts in Geneva during August 1981 to review the available animal, clinical, and epidemiological data on vasectomy, with particular emphasis on clinical implications of longterm sequelae of vasectomy in cardiovascular disease. The occurrence of circulating antibodies to sperm antigens has been demonstrated after vasectomy in all animal species studied thus far by various techniques. Prospective clinical studies of vasectomized and nonvasectomized men have been conducted at 4 centers in the U.S. involving clinical and laboratory evaluation of subjects before surgery and at intervals thereafter. A total of 412 vasectomized men were enrolled in these studies; most were followed for 2, 3, or 4 years. The only significant finding was the development of antibody to sperm antigens. Alexander and Clarkson first reported that vasectomy increases the extent and severity of diet-induced atherosclerosis in cynomolgus monkeys. In a 2nd study, Clarkson and Alexander extended their previous findings to evaluate the effects of vasectomy on naturally occurring atherosclerosis in rhesus monkeys. The mechanism by which vasectomy exacerbates atherosclerosis in monkeys has not been defined. At present epidemiological data which have been published come from observations in the U.S. and United Kingdom and in particular from 2 studies involving 4830 and 1764 vasectomized men studied at about 5-6 years after surgery. No health risks of vasectomy were detected in these early years. Other epidemiological projects are in progress in the U.S. Various options were discussed for further epidemiological studies which might be conducted in developing countries where large numbers of men have been vasectomized. The cohort approach and the case control method, the 2 main study options, are briefly reviewed.
INTERNATIONAL JOURNAL OF GYNAECOLOGY AND OBSTETRICS. 1979; 17(3):297-9.A report in Family Planning Perspectives (11:47, 1979) that 2 of 12 rhesus monkeys given 50 times the human dose of depot medroxyprogesterone acetate (DMPA) by body weight for 10 years had developed endometrial carcinoma (CA) instigated a retrospective survey of all hospital admissions for proven endometrial CA in 2 Thai provinces where DMPA contraceptive injections have been used since 1965. From 1974-78, 16 women were hospitalized with endometrial CA. None of the 9 women followed up had previously used injectable or oral contraceptives. The recorded incidence of endometrial CA has not increased in these provinces. The McCormick Hospital's Family Planning Department has administered 864,692 DMPA injections (150 mg. into the deltoid muscle every 12 weeks usually) to 86,511 acceptors for a total of 207,694 years usage. Over 300 women have used DMPA continuously for 10-13 years. This study concludes that the monkey dosage and incidence rates of CA do not apply to women taking normal dosage for long periods of time. DMPA should continue to be used and will be recommended to the Toxicology Review Panel of the World Health Organization's Special Programme of Research, Development and Research Training in Human Reproduction.
[Unpublished] October 30, 1978. 7 p.The available evidence does not indicate a risk of adverse effects associated with the injectable contraceptive Depo-Provera or depo-medroxyprogesterone acetate (DMPA) which would preclude the use of the drug as a contraceptive. To meet the need for information concerning DMPA, the Special Programme of Research, Development, and Research Training in Human Reproduction of the World Health Organization (WHO) has placed high priority on gathering such information and on research into the efficacy and safety of the drug. Although the U.S. Food and Drug Administration has denied approval to the Upjohn Company for the marketing of DMPA in the U.S., their negative assessment of the risk/benefit ratio associated with DMPA use may not be relevant to the assessment of the potential benefits or problems associated with the use of the drug in other countries. Assessment of DMPA by the Toxicology Review Panel of the WHO Special Programme of Research in Human Reproduction concludes that on the basis of the data available, there were no toxicological reasons why the drug could not be used for family planning. WHO study results have shown that DMPA is an effective contraceptive with a pregnancy rate of less than 1 per 100 woman-years, and that in many societies women appear to accept the menstrual disturbances associated with this drug. However, as relatively uncommon complications may not be detected until a drug has been used on a large scale for prolonged periods of time, there is a need to monitor the safety of DMPA on an ongoing basis, and the Special Programme will continue to place high priority on such research.
In: McDaniel EB, ed. Second Asian Regional Workshop on Injectable Contraceptives. Oklahoma City, Oklahoma, World Neighbors, 1982. 62-5.Discussion focus is on the history and present legal and registration status of Noristerat--the trade name for a long-acting injectable contraceptive. The drug is a formulation of Norethisterone enanthate in 4 parts of benzo-benzoate and 6 parts of castor oil. The active priniciple of the drug is Norethisterone, which is released from the intramuscular depot following hydrolysis of the enanthate side chain by unspecified tissue. The 1st pilot studies with Norethisterone enanthate were performed by 1958. Regular clinical studies were initiated in October 1964. In 1971 Peru was the 1st country to register and market Noristerat, followed by Chile, Brazil, and Argentina. When toxicity studies revealed breast and liver tumors in rats, Noristerat 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 Noristerat could be released again for further studies in February 1973. It was concluded that the findings in rats could not be transferred to humans. Subsequent to the 1973 studies, Noristerat was registered again in Colombia and Peru in 1974, in Mexico in 1975, and in 1976 in Rhodesia, South Africa, Pakistan, and Nigeria, followed by an increasing number of countries in the subsequent years. Regarding the toxicological status of Norethisterone enanthate, Schering's toxicological studies on Noristerat include acute toxicity studies, chronic drug safety studies, and combined drug safety and carcinogenicity studies. It was concluded that in the 4 animal species used for the toxicological and carcinogenic assessment of Norethisterone enanthate, no unexpected findings occurred. Clinical trials with NET-EN have been performed in more than 20 different countries. The data on the use-effectiveness obtained from the 1st World Health Organization (WHO) study showed a higher failure rate for Noristerat, i.e., 3.6/100 woman years, but a markedly better tolerance of Noristerat was found. The results obtained from a 2nd WHO study showed that by using modified application schemes, the contraceptive reliability is greatly increased. Similar to the results of the previous WHO studies, more DMPA than Noristerat users were discontinuing treatment because of menstrual irregularities and other medical reasons. As of mid 1981 Noristerat has been registered for contraceptive use in more than 36 countries.
IPPF Medical Bulletin. 1982 Dec; 16(6):3-4.Injectable hormonal contraception with 2 longacting steroidal preparations--norethisterone enanthate (NET-EN) and depot medroxyprogesterone acetate (DMPA)--provides an effective means of fertility regulation and has become an important method of family planning. DMPA and NET-EN have several advantages which make them particularly appropriate for some women and acceptable in family planning programs. A single injection can provide highly effective contraception for 2 or more months, delivery is simple, independent of coitus, and ensures periodic contact with medical or other trained health personnel. Currently, DMPA is registered as a therapeutic agent in nearly all countries and as a contraceptive agent in over 80 developed and developing countries. NET-EN is registered as a contraceptive in 40 countries. Administered by intramuscular injection in an aqueous microcrystalline suspension, DMPA exerts its contraceptive effect primarily by suppression of ovulation, but its effects on the endometrium, the uterine tubes, and the production of cervical mucus may also play a role in reducing fertility. DMPA as a contraceptive agent is generally given at a dosage of 150 mg every 90 days. NET-EN when administered as an intramuscular injection of an oil preparation at a dose of 200 mg inhibits ovulation. It should be administered at 8 weekly intervals for the 1st 6 months of use, then at intervals of 8 or 12 weeks. Longterm animal studies with DMPA have been completed mainly on beagle bitches and rhesus monkeys, and similar studies with NET-EN are nearing completion. None of the findings in beagles is considered applicable to human populations because the beagle responds differently than humans to steroidal hormones. None of the deaths among rhesus monkeys was attributable to effects of the drug. Endometrial carcinoma was found in 2 of the replacement monkeys but the number of animals was too small for statistically significant studies, and it is not possible to conclude whether DMPA or NET-EN caused these cancers or instead failed to prevent them. Despite more than 18 years of use and an estimated 13 million women who have ever used DMPA or NET-EN, no case has been recorded of an endometrial malignancy in women so exposed. There is no evidence at this stage of a causal association, either anecdotal or scientific. No evidence of an increased risk of malignant and premalignant disease of the uterine cervix has been found in DMPA users. There is sufficient evidence from investigations in several countries that DMPA and NET-EN may increase both milk production and the duration of lactation. The only clinical metabolic effect attributed to DMPA is weight gain. NET-EN and DMPA are associated with disruption of the menstrual cycle and irregular bleeding.
In: McDaniel EB, ed. Second Asian Regional Workshop on Injectable Contraceptives. Oklahoma City, Oklahoma, World Neighbors, 1982. 39-44.The best available data on the possible side effects of Depot Medroxyprogesterone Acetate (DMPA) are examined so that physicians and health officials can decide for themselves whether DMPA is appropriate for use in their countries. Several evaluations of the scientific evidence on the safety of DMPA have taken place in the last few years. The US Food and Drug Administration (FDA) announced in 1978 that it would not approve DMPA for use in the US. Subsequently, the World Health Organization's (WHO) Toxicology Review Panel conducted a review and found no reason to recommend that DMPA be withdrawn from use. In 1980 an Ad Hoc Consultative Panel presented its findings and recommendations to the US Agency for International Development (USAID). The Panel recommended that USAID make DMPA available to national family planning programs upon request. This recommendation was based on careful consideration of the medical and ethical issues involved by Panel members with expertise in the fields of obstetrics and gynecology, animal physiology and toxicology, epidemiology, pathology, law, and health policy. DMPA is currently approved for contraceptive use in more than 80 developed and developing countries. Each of the 6 reasons for FDA's denial of approval of DMPA are reviewed: studies using beagle dogs showed an increased incidence of mammary tumors associated with DMPA use; the availability of a number of alternative methods of contraception in the US and the lack of clear evidence that a significant patient population in need of DMPA exists in the US; the possibility that bleeding disturbances caused by the drug may lead to the administration of estrogen, thus decreasing the benefits of a progestogen only contraceptive; the possibility that exposure of fetuses to DMPA, if pregnancy occurs, poses a risk of congenital malformation; and reservations about the ability of the post marketing study for breast and cervical carcinoma. As a result of species differences in reactions to DMPA, the WHO Toxicology Review Panel, the Ad Hoc Panel, and the UK Commission on Safety of Medicines have stated that it is not possible to conclude from the beagle studies that DMPA poses any increased risk of breast cancer to women. The Ad Hoc Panel found little information on the effects of progestogen alone and concluded that the data fail to suggest that DMPA poses more of a threat of fetal malformation than do other hormonal contraceptives. Thorough discussion of menstrual changes with prospective DMPA users and supportive patient counseling are the best methods of dealing with concerns about irregular bleeding and amenorrhea. Regarding endometrial cancer, preliminary evidence suggests that progestogens may even protect against endometrial cancer.
Evaluation of the work of the Task Force on Indigenous Plants for Fertility Regulation of the Special Programme of Research in Human Reproduction.
In: Assessment of the WHO Special Programme of Research, Development and Research Training in Human Reproduction [HRP]. II. Task Force reports. Country reports, [compiled by] Sweden. Swedish Agency for Research Cooperation with Developing Countries [SAREC]. Stockholm, Sweden, SAREC, 1983 Apr.  p..This report describes and evaluates the work of the Task Force on Indigenous Plants for Fertility Regulation of the Special Programme of Research in Human Reproduction at WHO. The goal of the project is to set up a network of collaborating centers to train personnel, design bioassays, isolate and test plant substances that are safe and effective by oral route for "morning after" pills or anti-implantation agents or male contraceptives. Plants chosen for assay were selected by a literature search including ethnomedical sources. All data were computerized, weighted and rank ordered. 300 of the 4500 species fell into the high priority group. 4 research centers now participate: Chinese University of Hong Kong, Seoul National University, University of Peradeniya, Sri Lanka and University of Illinois. In 1980-1981 the literature surveillance component of the Task Force provided bi-annual literature updates on the assigned plants. Primate studies are planned for 1982 and phase I human trials are anticipated in 1985 for the 1st compound. Zoapatle (Montanoa tomentosa) is a plant used for centuries in Mexico to terminate early pregnancy. An active compound, zoapatanol, and another more stable analogue are in pre-phase I trials. 4 plants from India are being examined for sperm agglutination activity, the spermatogenesis inhibiting effect of Koenchai (Chinese celery) and the mechanism of action of gossypol are being researched.