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Hormonal contraceptive eligibility for women at high risk of HIV. Guidance statement. Recommendations concerning the use of hormonal contraceptive methods by women at high risk of HIV.
Geneva, Switzerland, WHO, 2017. 20 p. (WHO/RHR/17.04)The World Health Organization (WHO) convened a technical consultation during 1-2 December 2016 to review new evidence on the risk of HIV acquisition with the use of hormonal contraception. The issue was recognized as a critical one, particularly for sub-Saharan Africa, where women have a high lifetime risk of acquiring HIV, hormonal contraceptives constitute a significant component of the contraceptive method mix and unintended pregnancy is a common threat to the well-being and lives of women and girls. A wide range of stakeholders were present at this meeting, and serving on the Guideline Development Group (GDG) was global representation from experts in family planning and HIV, representatives from affected populations, clinicians, epidemiologists, researchers, programme managers, policy-makers and guideline methodologists. The GDG considered the following factors in making their determination for each contraceptive method: quality of the evidence (GRADE profile); values and preferences of contraceptive users and health care providers; balance of benefits and harms; priority of the problem; equity and human rights; acceptability; and feasibility. Through consensus, the GDG arrived at new recommendations for progestogen-only injectables. The recommendations for use of progestogen-only injectables among women at high risk of HIV changed from category 1 to category 2, with an accompanying clarification, in the Medical eligibility criteria for contraceptive use (MEC). Recommendations for all other methods of hormonal contraception remained unchanged. (Excerpts)
Hormonal contraception and risk of HIV acquisition: a difficult policy position in spite of incomplete evidence.
Reproductive Health Matters. 2012 Dec; 20(39 Suppl):14-7.Injectable hormonal contraceptives are the most widely used modern contraceptive method in many countries, and are especially popular in sub-Saharan Africa. Some studies have suggested that women using injectable contraception are at a higher risk of acquiring HIV infection that non-users, although other studies have not shown any significant increase in risk. In settings where the risk of HIV infection is high, these conflicting findings present a difficult choice. Modern contraceptive methods, including injectable hormonal contraceptives, are critically important for preventing unintended and mistimed pregnancies, reducing maternal mortality and avoiding the consequences of unsafe abortion. Women and contraceptive providers who advise women in settings where there is a risk of HIV infection are faced with a complex balance of risks regarding contraceptive choice, complicated by the fact that the evidence of whether or not there is an increased risk is far from certain. Furthermore, although additional research has been promised, it may not resolve the question in the near future.
Training and reference guide for a screening checklist to initiate use of DMPA (or NET-EN). Second edition.
Research Triangle Park, North Carolina, Family Health International [FHI], 2009. 79 p. (USAID Cooperative Agreement No. GPO-A-00-05-00022-00)This training and reference guide was developed for family planning service providers interested in using the Checklist for Screening Clients Who Want to Initiate DMPA (or NET-EN), commonly referred to as the "DMPA Checklist". Designed to serve as both a training and reference tool, the guide is composed of two parts: a training module and a collection of essential, up-to-date reference materials. The guide is part of a series to train on other checklists. The DMPA Checklist was developed to assist service providers in screening clients who have already been counseled about contraceptive options and who have made an informed decision to use either of two popular injectable contraceptive methods: depot-medroxyprogesterone acetate (DMPA) or norethisterone enantate (NET-EN). This simple job aid is based on the technical guidance provided by the World Health Organization (WHO) in its Medical Eligibility Criteria for Contraceptive Use (2004, updated 2008). The checklist supports the application of these guidelines -- known as the WHO MEC -- into service delivery practice. (Excerpts)
[Research Triangle Park, North Carolina], FHI, 2009.  p.Clients should be scheduled for NET-EN reinjections every 8 weeks. According to the 2008 WHO guidelines, a client can receive a reinjection if she is up to 2 weeks early or 2 weeks past her scheduled reinjection date, without ruling out pregnancy. Clients arriving after the reinjection window may also be eligible if pregnancy can be ruled out. The steps in this aid should be followed for clients who are returning for reinjection. For clients who want an injection for the first time, "Checklist for Screening Clients Who Want to Initiate NET-EN" should be used.
IPPF MEDICAL BULLETIN. 1992 Apr; 26(2):4.At a meeting in November 1991, the International Medical Advisory Panel (IMAP) of the International Planned Parenthood Federation (IPPF) was asked by the South Asia Region of IPPF to consider a report by the Bangladesh Family Planning Program concerning the operational implications of using more than one formulation of injectable contraceptive in a geographic area. The report states that depot medroxyprogesterone acetate (DMPA) and norethisterone enanthate (NET-EN) are very similar in terms of continuation rates, use-effectiveness levels, and reported side effects. However, they differ in administration schedule (DMPA is given at three month intervals; the other is given at two) and viscosity (NET-EN is more viscous and requires a larger bore needle than the other), which can lead to delivery problems for outreach programs. 50% of the contraceptive methods offered and used in these programs are injectables. Maintaining both types of injectables can lead to fieldworker confusion and error, disruption of fieldworker work routines, managerial burden, and supply shortages. IMAP recommends that family planning program managers select one progestogen-only injectable formulation and keep to it, to ensure that only one formulation is used in a particular geographic area. DMPA and NET-EN should not be considered medically interchangeable. They have different formulations and different periods of effectiveness. There is no data on the medical consequences of women receiving the two interchangeably because of program problems or errors.
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.
MARHIA - MEDIUM FOR THE ADVANCEMENT AND ACHIEVEMENT OF REPRODUCTIVE RIGHTS, HEALTH INFORMATION AND ADVOCACY. 1989 Jul-Sep; 2(3):1, 3-9.4 major contraceptives are being examined by health care professionals throughout the world. They are: injectables, the IUD, condoms and the pill. This article discusses the advantages and disadvantages of all four. Injectable contraceptive are most commonly either Depo-provera or Noristerat. Depo-provera is approved for use as a contraceptive in 90 countries. Noristerat is approved for use in 40 countries. Detractors of Depo-provera say that is produces breast tumors in beagle dogs, possible tetratogenecity upon failure concern that abnormal bleeding might lead to additional estrogen therapy, and that the simple nature of this type of drug might lead to abuse of informed consent. However, World Health Organization studies have shown no cancerous effects of the drug and a failure rate of 1 in 100 women. When failure occurs, tetratogenecity is very low. It must be looked at in the context of risk assessment before judgement is passed on it. In countries where pregnancy can mean a decrease in the quality of life for the mother or the family, this is an easy method of birth control. The IUD has many questions surrounding its use: infection, expulsion, tubal infertility, ectopic pregnancy and uterine laceration. While it is an effective method of birth control, not an abortifacient, it does have certain disadvantages that must be considered. Condoms have the added benefit of preventing the spread of disease as well as preventing pregnancy. However, in many countries there is a cultural bias against using a condom. Men complain about reduced sensitivity. Also, they break with a certain frequency that is unavoidable in a mass produced product (about 1 in 10,000). Their biggest weakness is most users do not use them consistently. This is where injectables, the IUD and the pill have an advantage over the condom. Use patterns also increase their failure rate in terms of contraception. The pill is the most popular and widely used form of hormonal contraception. It has been proven safe at lower doses and is very effective. It is however, incapable of preventing the spread of disease. Also, women who smoke and use the pill run a higher risk of breast cancer.
British Journal of Family Planning. 1990 Jan; 15(4 Suppl):27-9.The long-acting injectable contraceptives, once-a-month injectables, vaginal rings, and implants, either in use or being clinically tested, are reviewed briefly. About 6 million women now use injectables, 4 million use Depo-Provera, and 1 million use norethisterone enanthate (NET-EN) in a once-monthly schedule. Other once-monthly injectables are being developed by WHO, such as a dihydroxy-progesterone acetophenide-estradiol enanthate being tested in Mexico. These injections are highly effective and acceptable, despite frequency, because they cause regular withdrawal bleeding. Other combinations already tested by WHO are HRP 102 (norethisterone enanthate 50 mg-estradiol valerate 5 mg), and HRP 112 (depo-medroxyprogesterone acetate 25 mg-estradiol cypionate 5 mg). Continuation rates for these methods were 64.5 and 63.2%. Lower doses were not as effective in cycle control. Depo-Provera (depo- medroxyprogesterone acetate, DMPA) is available in 85 countries, and accounts for 65% of injectables, while NET-EN is available in over 40 countries and makes up 15%. Recent studies with DMPA have shown that efficacy can be affected by variations in particle size of the microcrystals, as well as by the population using it. Vaginal rings containing levonorgestrel have reached Phase II trials; failures have been reported due to inconsistent quality. Besides the well-known Norplant, an implant called Capronor is being developed. It is a polycaprolactone tube 4 cm long containing levonorgestrel in ethyl oleate vehicle. IT has a zero order release and biodegrades after 2 years.
Lancet. 1985 May 4; 1(8436):1046.As part of a study on acute febrile pelvic inflammatory disease and IUDs, reported elsewhere, a significantly lower risk of PID was observed in women using injectable contraceptives. The World Health Organization coordinated the multinational case-control study in 1979-79. Diagnostic criteria were fever, suprapubic tenderness with guarding, cervical or adnexal tenderness or a pelvic mass. 319 cases and 639 matched controls were matched for age, parity, marital status and hospital status. Data were taken from questionnaires. 10 cases (3.1%) currently used injectable contraceptives, mainly Depo-Provera, compared to 38 controls (6.0%). Thus the risk of getting PID was half as great among injectable users, similar in magnitude to risks reported for women using oral contraceptives, barrier methods and sterilization in developing countries.
In: Zatuchni GL, Goldsmith A, Shelton JD, Sciarra JJ, ed. Long-acting contraceptive delivery systems. Philadelphia, Pa., Harper and Row, 1984. 1-19. (PARFR Series on Fertility Regulation)Depo-Provera (depomedroxy-progesterone acetate, or DMPA) and NORPLANT (the Population Council's registered trade name for subdermal implants) are focused on in this literature review. Over the past 17 years, more than 1 million individual doses of Depo-Provera have been supplied in Thailand. Currently 6,000 women a month use the method. Depo-Provera has proved outstandingly successful in Bangladesh for years. The basic disadvantage of long-acting steroid systems is that return to fertility is slow and unpredictable. Other disadvantages include menstrual distrubances and weight gain. Acceptability of injectable contraceptives has been studied primarily by the World Health Organization (WHO). In 1976, the Task Force on Acceptability of Research and Family Planning explored preferences among 3 routes of contraceptive administration: 1)oral; 2)intravaginal; and 3)injection. The study was conducted in Indonesia, Korea, Pakistan, and Thailand. Although the oral route was generally preferred by most women, many respondents still chose the injectable. A WHO III multicentered trial comparing the use, effectiveness, side effects and bleeding patterns of Depo-Provera and norethisterone enanthate (NET-EN) was terminated after only 1 year because of excessively high pregnancy rates with NET-EN. A total sample of about 250 women in Manila and Alexandria were interviewed. Results indicated that the 2 most important considerations were effectiveness and menstrual bleeding. Depo-Provera did not affect menstruation. Various types of subdermal implants releasing a contraceptive Silastic implant, is placed beneath the skin of the forearm or upper arm and provides 5 or more years' protection against pregnancy. The 6 capsules are not biodegradable and require surgical removal under local anesthesia.
In: United States. Food and Drug Administration. Depo-Provera Public Board of Inquiry. Official transcript of proceedings, Food and Drug Administration. Depo-Provera Board of Inquiry. Vol. 3. January 12, 1983. Arlington, Virginia, TIW Reporting Group, . 7-13.Dr. S. Holck, a member of the World Health Organization (WHO) Secretariat, described WHO's Special Program of Research and Human Reproduction and introduced the representative of the program who will address specific questions raised by the board in this inquiry. The program was eastblished in 1972 for the purpose of promoting family planning research and development. 1 area of research which the program focuses on is assessing the safety and effectiveness of existing contraceptives. The program helps developing countries conduct large scale studies through a network of WHO centers. The use of the same protocal for collecting inforamtion in all centers facilitates interpopulation comparison ans ensures that data is collected on large population samples. The safety of Depo-Provera has been assessed by the program on a continuing bases. In 1978 the program convened a meeting of its Toxicology Review Panel, scientist, and members of drug regulatory agencies to examine the findings of animal and human studies in the 2 currently available injectable contraceptives. i.e., Depo-Provera and norethisndrone enanthate. The members concluded that the findings did not substantiate that there were serious associated with Depo-Provera for humans; however, they noted that there was a need to continue monitoring Depo-Provera in order to assess whether prolonged use of the drug produced serious adverse affects. In 1981 the program convened another meeting to assess injectable contraceptives in light of the findings of more recent animal and human studies. The participants saw no reason to reverse their earlier decision regarding Depo-Provera. Depo-Provera has been used for 15 years and there is no evidence that the drud is associated eith any more adverse than other hormonal contraceptives. The program is continuing to conduct extensive research on injectable contraceptives. Studies include: 1) phase 3 and phase 4 clinic trial; 2) a large comparative study of the 2 injectables; 3) a case control study of neoplasia and steroid contraceptives, including Depo-Provera; 4) an investigation of the effects of Depo-Provera on exposed infants; 5) several investigations to identify any longterm effects of Depo-Provera; and 6) several studies on the drug's metabolic, lipid and protein effects and pharmocology.
[Some facts concerning injectable contraceptives: memorandum of a World Health Organization meeting] Quelques faits concernant les contraceptifs injectables: memorandum sur une reunion de l'OMS.
Bulletin of the World Health Organization. 1982; 60(4):535-48.This memorandum seeks to clarify issues concerning the safety of injectable contraceptives and to recommend areas for further research. Depo-Provera and norethindrone enanthate, 2 long-acting progestagen preparations, offer the important advantages in contraception of high efficacy, prolonged effect, and reversibility. Depo-Provera has been used since 1950 to treat a wide variety of complaints without serious side effects. It is estimated to have been used by about 10 million women for contraception and is currently used by about 1.5 million in 84 countries. Norethindrone enanthate has been much less widely used since its appearance in 1966 and is currently available in 40 countries. The Group on Toxicologic Evaluation, reviewing the results of longterm use of the 2 steroids in mice, rats, and rhesus monkeys, found no reason to modify their earlier position that the 2 substances were sufficiently safe for use in contraceptive programs. The Group also concluded that beagle dogs are inappropriate models for observation of the effects of the 2 steroids in women because of the predisposition of beagles to mammary tumors and acromegaly and because of differences in the specificity of their progesterone receptors. Some of the dosage levels used in the beagle studies were also questioned. Results of a large number of trials on women in numerous countries were reviewed regarding consequences of the different pharmacological properties of the 2 preparations, their effectiveness at different dosage levels, the nature and consequences of bleeding problems, current knowledge concerning their effects on lipid and glucose metabolism and liver function, possible carcinogenic effects, return of fertility, and effects of exposure in utero or through the mother's milk. None of the clinical or epidemiological studies was able to demonstrate life-threatening secondary effects. The most frequent secondary effect is the disturbance of menstrual cycles which is observed in the majority of women and is the most common cause of discontinuation. Although no serious short or longterm effects have been noted, the substances have been in use for a relatively short time. Research should proceed on the effects of longterm use of both steroids on lipid and glucose metabolism, on the appearance of neoplasms, and on the later development of the fetus or nursing child exposed to them. The study group concluded that Depo-Provera and norethindrone enanthate are acceptable methods of fertility regulation.
Multinational comparative clinical trial of long-acting injectable contraceptives: norethisterone enanthate given in two dosage regimens and depot-medroxyprogesterone acetate. A preliminary report.
Contraception. 1982 Jan; 25(1):1-11.A multicenter phase 3 clinical trial compared norethisterone enanthate (NET-EN) given by 2 different treatment regimens and depot-medroxyprogesterone acetate (DMPA). After 18 months of observation, preliminary findings are reported for 790 women who received NET-EN 200 mg every 60 days; for 796 women who recieved NET-EN every 60 days (200 mg) for 6 months, then 200 mg every 84 days, and for 1589 women who received DMPA 150 mg every 90 days. Overall discontinuation rates and discontinuation for bleeding and personal reasons were similar for all 3 groups after 18 months observation (61.8-63.5/100 women). Terminations due to amenorrhea were significantly higher among DMPA users (12.1 and 17.4/100 women at 12 and 18 months) than among both NET-EN groups (6.8-8.2/100 women at 12 months and 10.4-10.9/100 women at 18 months). The only significant difference in pregnancy rates observed among the 3 groups was a higher rate at 18 months among NET-EN (84 days) users (1.6/100 women), than among DMPA users (0.2/100 women). There was no overall significant difference between the 2 NET-EN groups, although between the 6 and 18 month follow-ups when the 2 NET-EN regimens diverged, the NET-EN (84 days) users' pregnancy rates rose significantly, whereas in the NET-EN (60 days) group, the pregnancy rate did not change. Weight gain was significantly higher in those subjects using NET-EN at 60 day intervals than at 84-day intervals. (author's modified)
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.
British Medical Journal. February 3, 1979; 1(6154):343.The World Health Organization's Special Program of Research, Development and Research Training in Human Reproduction is presently conducting a multinational randomized comparative controlled clinical trial of depot-medroxyprogesterone acetate (DMPA) and norethisterone oenanthate (NET-OEN) in 11 countries. The injections of NET-OEN are given at 8 weekly intervals for the first 6 months of therapy, and then 50% of the NET-OEN subjects are randomly assigned to a 12 weekly injection schedule; the remaining 50% continue on the 8 weekly regimen. By August 1, 1978, 1186 subjects had received NET-OEN and 13,344 women months of experience had been accumulated. There have been a number of pregnancies among women receiving NET-OEN at 8 week intervals in contrast to the results presented by Giwa-Osagie and colleagues. In addition the termination rates for amenorrhea among subjects receiving 8 weekly NET-OEN injections is substantially higher than that reported by Giwa-Osagie et al. and higher than the rates observed in a previous World Health Organization trial.
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.
CRP Population Research. 1978 Nov; 33-34.The Contraceptive Development Branch (CDB) program conducts research in 2 areas: 1) reproductive processes and 2) product development. Research on reproductive processes improved the understanding of gamete transport and has better identified corpus luteum functions and the role of prostaglandins. The biology and biochemistry of the ovum has been studied, and in vitro fertilization investigated. The mechanism of spermatogenesis, sperm maturation, and subsequent fertilization have been observed. Moreover, CDB has participated in the distribution of a variety of reagents to the scientific community, to stimulate research on the antipregnancy vaccine. In the area of product development, the CDB continues experimenting with the synthesis of new chemicals to regulate human fertility, the issue of safety being the primary motivation of the program. Approximately 1100 new chemicals have been synthesized and tested on laboratory animals. A drug testing program was initiated in 1972, providing feedback of biological data, and representing the major drug testing effort in the U.S. Considerable progress has been made in the area of implantable and oral contraceptives, and in the area of devices for fertility regulation, and for sexual sterilization. Clinical studies sponsored by CDB are ongoing.
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.
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.