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WHO systematic review of prevalence of chronic pelvic pain: a neglected reproductive health morbidity.
BMC Public Health. 2006 Jul 6; 6:177.Health care planning for chronic pelvic pain (CPP), an important cause of morbidity amongst women is hampered due to lack of clear collated summaries of its basic epidemiological data. We systematically reviewed worldwide literature on the prevalence of different types of CPP to assess the geographical distribution of data, and to explore sources of variation in its estimates. We identified data available from Medline (1966 to 2004), Embase (1980 to 2004), PsycINFO (1887 to 2003), LILACS (1982 to 2004), Science Citation index, CINAHL (January 1980 to 2004) and hand searching of reference lists. Two reviewers extracted data independently, using a piloted form, on participants' characteristics, study quality and rates of CPP. We considered a study to be of high quality (valid) if had at least three of the following features: prospective design, validated measurement tool, adequate sampling method, sample size estimation and response rate > 80%. We performed both univariate and multivariate meta-regression analysis to explore heterogeneity of results across studies. There were 178 studies (459975 participants) in 148 articles. Of these, 106 studies were (124259 participants) on dysmenorrhoea, 54 (35973 participants) on dyspareunia and 18 (301756 participants) on noncyclical pain. There were only 19/95 (20%) less developed and 1/45 (2.2%) least developed countries with relevant data in contrast to 22/43 (51.2%) developed countries. Metaregression analysis showed that rates of pain varied according to study quality features. There were 40 (22.5%) high quality studies with representative samples. Amongst them, the rate of dysmenorrhoea was 16.8 to 81%, that of dyspareunia was 8 to 21.8%, and that for noncyclical pain was 2.1 to 24%. There were few valid population based estimates of disease burden due to CPP from less developed countries. The variation in rates of CPP worldwide was due to variable study quality. Where valid data were available, a high disease burden of all types of pelvic pain was found. (author's)
Contraception. 2003 Dec; 68(6):439-446.The present paper combines the estimates of efficacy and side effects of 10 mg mifepristone for emergency contraception obtained from randomized trials. A total of 6083 women participating in 12 randomized trials and receiving 10 mg mifepristone for emergency contraception up to 120 h after intercourse, were analyzed for efficacy. Between 4188 and 5833 women were analyzed for side effects and 3601 for delay of menses of more than 7 days. Prevented fractions, the effect of delay and of further acts of intercourse after treatment administration were analyzed in 3440 women, using individual data. The combined pregnancy rate from all the 12 trials was 1.7% [101/6083, 95% confidence interval (CI): 1.3–2.2]. From the three trials providing individual data, the combined pregnancy rate was 1.3% (45/3440, 95% CI: 0.9 –1.7) and the estimate of pregnancies prevented was 83.4% (95% CI: 77.4–87.8). There was a sharp decline in efficacy when treatment was administered during the 5th day after intercourse compared to administration during the 1st day, the odds of pregnancy increasing by a factor of 5.3 (95% CI: 1.9 –14.9). The relative risk of pregnancy was about 28 times higher among women with unprotected acts of coitus between treatment administration and the onset of next menses, compared with women reporting none [odds ratio (OR) = 27.6, 95% CI: 12.7– 60.2]. The increase in risk for women reporting protected acts of intercourse during this interval was not statistically significant (OR = 1.8, 95% CI: 0.9 –3.8). There was a large heterogeneity among trials in all side effects and delay of menses of more than 7 days (all had p < 0.0001 for the test of homogeneity). The percentage of women with nausea ranged from 0.0–19.4% (highest upper 95% confidence limit: 23.0%), that of vomiting from 0.0–4.3% (highest upper 95% confidence limit: 6.1%), that of lower abdominal pain from 4.3–19.1% (highest upper 95% confidence limit: 22.7%). The percentage of women with delay of menses of more than 7 days ranged from 4.3–25.8% (highest upper 95% confidence limit: 34.1%). We conclude that 10 mg mifepristone is an effective emergency contraception regimen, with an acceptable side-effects profile. Postponing treatment until the 5th day seriously decreases efficacy. The risk of pregnancy is dramatically increased among women having unprotected acts of intercourse between treatment administration and the onset of next menses. This risk may be enhanced for women whose ovulation is postponed by treatment. (author's)
Geneva, World Health Organization, 1965. (Technical Report Series No. 308,) 28 p.This is a report of a World Health Organization (WHO) Expert Committee on the Health Problems of Adolescence which met in Geneva from November 3-9, 1964. Adolescence is characterized by a series of biochemical, anatomical and mental changes that are unique to this group which encompasses the age range of about 10-20. This report deals with the primary importance of the family in the life of the adolescent, the influence of the society, and the influence of socioeconomic factors under 1 heading. Also discussed are anatomical, physiological, mental, and emotional aspects of growth and development (such as the development of conseptual thought, search for a sense of personal identity, acquisition of proper sexual attitudes and behavior, etc.). Health needs such as nutrition, physical and mental fitness, the relation of health with school and employment, and health problems such as veneral disease and menstrual disorders are also discussed. The WHO Expert Committee recommends that further attention be given to the mental problems and needs of youth, ways of effective contribution for the establishment and development of school health services be provided for, and time be devoted to the organizational problems of caring for the physically and mentally handicapped individuals.
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.
CONTRACEPTION. 1988 Aug; 38(2):129-56.Methods of analyzing vaginal bleeding patterns, both of normally menstruating non-contracepting and contracepting women, are reviewed, and the reference period method is described in greater detail. For women using long-acting hormonal methods, the concept of cycle is no longer appropriate. The reference period method adopts the woman as the unit of analysis, divides her menstrual diary into consecutive periods, and summarizes vaginal bleeding patterns within each period. Data are presented in bar plots showing median length of bleeding, 5th and 95th percentiles, means and standard deviations. Natural, oral contraceptive, and IUD patterns are similar, while 3-monthly injections, vaginal rings and minipill patterns are disrupted patterns with no notion of cyclicity. Dealing with events that overlap reference period boundaries is still a problem, and is still being studied by working groups, in particular at WHO and the University of Exeter. For example, the effects of different definitions have not yet been systematically evaluated, and recommendations have not been tested empirically. The WHO has published a set of data on 4817 women's diaries to stimulate statistical research on this topic.
CONTRACEPTION. 1988 Aug; 38(2):157-63.A microcomputer software program called the Menstrual Diary System (MDS) is described which analyzes menstrual diaries by the reference period method, according to WHO guidelines. An IBM compatible microcomputer with floppy or hard disk, at least 256K of memory, and an MS-DOS 2.0 or later operating system is used. Menstrual data consist of entries labeling vaginal bleeding as absent, bleeding or spotting. There are optional parameters for the drive, path, and printer used by the system; user-defined symbols for bleeding patterns; screen characteristics; file management by date and length of data collection (maximum 380 days); and subject identifying information. A data management section permits data entry. The data analysis section follows the reference period method, allowing for within-subject analysis and between-subject analysis. Diary data entered in MDS can be transferred onto standard ASCII file to be used by other packages. Examples of output are provided.
PROGRESS. 1987 May; (2):9.The World Health Organization's Task Force on Long-acting Systemic Agents for Fertility Regulation is currently investigating several injectable steroidal contraceptives with a duration of action from 1-6 months. Nearing completion is a large Phase III clinical trial involving 2 monthly injectable preparations (HRP 102 and HRP 112), both of which involve a synthetic preparation in combination with an estrogen. To date, 2300 women from 17 centers around the world have participated in this trial. Efficacy rates have been high, with no pregnancies occurring in the HRP 112 group and only 2 in the HRP 102 group. Discontinuation rates for reasons related to disturbances of bleeding patterns have been 6.4% for HRP 112 and 7.4% for HRP 102 at 12 months. Compared to progestogen-only injectable preparations, fewer women discontinued because of amenorrhea. The only drawback to these new preparations is that monthly visits to a health center are required. On the other hand, injections are viewed by women in many developing countries as an acceptable, highly effective means of delivering medicines.
Healthright. 1985 Aug; 4(4):9-12.The pattern of reproductive activity displayed by early hunter-gatherer ancestors, before the dawn of civilization, must have been vastly different from today's pattern. In the absence of contraception such women would have spent the greater part of their reproductive lives either pregnant or in lactational amenorrhea. In developing these ideas further it was estimated that a hunter-gatherer woman would have spent about 15 years in lactational amenorrhea, whereas just under 4 years would have been occupied by her 5 pregnancies, and she would only have had about 4 years of menstrual cycles. The total number of menstrual cycles she would experience in her entire life would be no more than about 50. This is in marked contrast to the situation today in a typical Western woman using contraceptives and experiencing menarche at 13 and the menopause at 50. Allowing her 2 years' respite from cycles during her 2 pregnancies, each followed by only a token period of breastfeeding, this leaves 35 years during which she would experience about 420 menstrual cycles. The conclusion is that an excessive number of menstrual cycles is an iatrogenic disorder of communities practicing any form of contraception. Thus, it is important to note that even the condom or vasectomy have important repercussions on the female's reproductive cycle. Since 99.9% of human existence has been spent living a nomadic hunter-gatherer life, this high frequency of menstrual cycles is a new experience, one that humans may be genetically ill-adapted to cope with. In fact, there are a number of "diseases of nulliparity" whose incidence is markedly increased in women with few or no children and who are therefore experiencing an increased number of menstrual cycles. These diseases include carcinoma of the breast, endometrium and ovaries, and endometriosis. As part of the effort to develop contraceptives that promote a healthy state of fertility, it is necessary to ask the question, "is a period really necessary?" To learn if women women accept a contraceptive method that reduced the frequency of menstruation, a clinical trial of an oral contraceptive was conducted. The OC was administered in such a way as to produce a withdrawal bleed only once every 3 months. This was termed the tricycle pill regimen. 196 women attending a family planning clinic in Edinburgh, Scotland, volunteered to participate, although 89 of them subsequently withdrew from the trial for a variety of reasons before it was completed at the end of a year. Overall, 82% of the women positvely welcomed the reduction in the number of periods; 91% of the women who completed the trial even refused to revert to a standard monthly OC regimen thereafter. The findings were in complete contrast to the results of a World Health Organization survey of patterns and perceptions of menstruation. But the WHO sample was highly biased in favor of women having regular menstrual cycles, and hence quite unrepresentative of the population as a whole. In sum, even the most pessimistic estimate of the WHO's menstruation survey shows that a proportion of women in every country investigated were prepared to accept amenorhea as a by-product of contraception. Reversible amenorrhea might become an increasingly popular form of contraception, and it might also confer significant health benefits.
World Health Organization evaluates NORPLANT subdermal implants as effective, reversible, long-term contraceptive. News release.
New York, Population Council, 1985 Feb 22. 5 p.A World Health Organization (WHO) review of animal and human data on Norplant subdermal implants, convened at the request of the United Nations Fund for Population Activities, has determined that this contraceptive system is an "effective and reversible long term method of fertility regulation" and recommended that it be made available through family planning programs. George Zeidenstein, president of the Pouplation Council, which developed the Norplant system, has termed the WHO report "a giant step toward worldwide acceptance and availability." So far, extensive clinical trails have noted no adverse side effects of this contraceptive system, and animal studies on levonorgestrel suggest the drug is safe for use in humans. Clinical trial data on more than 4000 women have indicated continuation rates of 60-95% at the end of the 1st year and about 50% at the end of the 5th year. The annual pregnancy rate is 0.2-1.3/100 women over a 5 year period. Disturbance of the menstrual cycle, including increased frequency and number of bleeding days as well as irregular bleeding or spotting, occurs in the majority of women who use this method; however, bleeding problems tend to diminish with increased duration of use. The Norplant implant system is particularly suitable fo r women who seek extended contraceptive protection but either do not wish to undergo sterilization or who desire a child in the future. Norplant is currently a vailable in Finland and has just been granted registration in Sweden. Over the next 2 years, regulatory approval will be sought in 40 additional countries including the US, where the Norplant system is in clinical trials at 3 sites.
Outlook. 1985 Mar; 3(1):7-8.The World Health Organization (WHO) consultation convened in October 1984 the Special Programme of Reasarch in Human Rreproduction concluded that Norplant provides effective and reversible longterm contraception and should be available in family planning programs for women desiring longterm contraception. The Norplant implant systgem consists of 6 silastic capsules each containing 36 mg of levonorgestrel which is slowly released into the bloodstream. The implants can be left in place for up to 5 years or removed at any time. The consultation report considered the research data adequate to conclude that the method is safe for human use. Acceptability apperas to be high: 1st year continuation rates of 80-90% are roughly equivalent to those of the IUD, and continuation at the end of 5 years is about 50%. Bleeding irregularities are a common side effect, but heavy and prolonged menstrual bleeding is infrequent. The constant slow release of levonorgestrel minimizes the common side effects of contraceptive steroids, and the system exposes the body to less than 100 mg of levonorgestrel over 5 years. Since the method is new and not in widespread use, there have been few studies on longterm use or rare side effects, prompting the WHO consulatation to recommend "appropriate surveillance activities to evaluate its long-term safety." Additional research was also recommended on the effect of the implants on lactation and on the growth and development of children exposed to levonorgestrel in breastmilk. The consultation report pointed out the need for clinic facilities for insertion and removal and for adequate training of providers before introduction of the method into a program. An international pharmaceutical company based in Finland has been licensed by the Population Council, the developer of Norplant, to manufacture and distribute the implants. The Swedish National Board of Health and Welfare has also approved the Norplant system for contraceptive use in Sweden.
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)
People. 1981; 8(1):30.The International Planned Parenthood Federation's (IPPF's) new medical advisory body, the International Medical Advisory Panel, has approved the continued distribution of the injectable contraceptive Depo-Provera (DMPA). The conclusion of the 5-member panel endorses similar recommendations from other bodies, among them the World Health Organization and the United States Food and Drug Administration's Scientific Advisory Committee. IPPF is the largest nongovernmental supplier of DMPA to developing countries. At this time it supplies 400,000 3-monthly injections of the injectable each year to its member family planning associations in Thailand, Sri Lanka, Kenya, Sarawak, Zaire and other countries. 3 characteristics are cited in the Panel's report as being responsible for the high acceptability of injectables over other reversible methods of contraception in developing countries: effectiveness of injections; convenience for use; and acceptability because it is free of the cardiovascular side-effects associated with the oral contraceptive which contains estrogen. The approval of the Panel comes at a time when the controversy surrounding the injectables is becoming more vocal. The controversy has primarily focused on its use in developing countries where agencies are accused of "dumping" harmful drugs on unsuspecting women. The fact that the United States Food and Drug administration has failed to approve DMPA for use in the U.S. lends support to proponents of this view. The Panel found that among an estimated 10 million women who had used DMPA for varying periods in the 15 years it has been in use, there has not been a single causal association. The most disturbing and immediately apparent side-effect from the perspective of the user, is the disruption of the menstrual cycle.
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.
In: Diczfalusy, E., ed. Regulation of human fertility. (Proceedings of the WHO Symposium on Advances in Fertility Regulation, Moscow, USSR, November 16-19, 1976) Copenhagen, Denmark, Scriptor, 1977. p. 253-282This review of combined oral contraceptive (OC) preparations presents formulations, pregnancy rates, biochemical parameter changes, morbidity, and OC indications in 15 tables. The OC preparations are based on 2 different estrogens and 14 progestagens. Though steroid content differs among products, all act primarily to inhibit ovulation by suppression of midcycle release of pituitary gonadotropins. Variable-dose products are associated with higher pregnancy rates than fixed-dose preparations. Side effects of OCs, while difficult to identify, fall into 2 categories: 1) common adverse associations similar to responses to inert placeboes; and 2) serious biochemical and physiological alterations. There is no evidence of any increase in morbidity due to OC use, whereas avoidance of risks associated with pregnancy is beneficial. No convincing evidence of carcinogenic hazard is presented. Some evidence of reduced systemic side effects by lower-dose products is presented, though gynecological side effects, such as irregular bleeding, may increase. Drug interaction with OCs is described; rifampicin causes the most serious of these. OCs induce wide-ranging metabolic changes in many organ systems. These may relate to undesirable side effects (psychological or neurological signs, skin disorders, and blood pressure changes).
In: Diczfalusy, E., ed. Regulation of human fertility. (Proceedings of the WHO Symposium on Advances in Fertility Regulation, Moscow, USSR, November 16-19, 1976) Copenhagen, Denmark, Scriptor, 1977. p. 283-321This review of low-dose gestagen contraception emphasizes the variety of findings from different studies. For example, studies of chlormadinone acetate have found pregnancy rates of 1.1-12/100 woman-years. Results of trials of megestrol acetate suggested that a 500-mcg dose level yielded unacceptable pregnancy rates. No significant difference between various doses of norgestrel which have been studied were found (e.g., 50 and 75 mcg daily of dl-norgestrel or 30 mcg daily of the d-isomer). Pregnancy rate reported for most trials with this gestagen and also norethisterone and quingestanol were within an acceptable range. With 1 exception, pregnancy rates reported in trials of lynestrenol were remarkable low. Cumulative results of trials with various gestagens show Pearl Index rates between 2 and 3, except for lynestrenol. Dose level was the critical variable; i.e., it must be sufficiently high to exert antifertility action and low enough to avoid a high incidence of irregular bleeding. Apart from menstrual irregularities, other side effects from the minipill seem minor and in general less severe than those encountered with combined oral contraceptives.
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.
September 1975. 41 p.Information gathered from knowledgeable sources (e.g., obstetricians, family doctors, pharmacists, nurses, family planning workers, and informal social network representatives) indicated the important position that menstrual bleeding, and the social implication related to it, holds in the life of Egyptian women. Menstrual bleeding is a sign of well-being, youth, fertility, and femininity. The majority of knowledgeable sources agreed that a normal cycle length among Eyptian women ranged from 21-32 days, whereas the normal bleeding interval ranged from 3-5 days. Abnormality, however, is a function of personal experience, i.e., a cycle is abnormal when it deviates from the woman's normal pattern. Egyptian women perceive menstrual blood as bad blood that they must lose every month, the retention is thought to result in bodily poisoning. Egyptian women are aware of specific color, smell, and texture of vaginal bleeding, and any change in quality or quantity is alarming. Illiterate women predict and recall their bleeding episodes by using a lunar calender which indicates national or religious ceremonies. Menarch is reported to be an occasion of joy signifying womanhood, whereas menopause is resented and dreaded, associated with drying or shrinking of the uterus. Menstruation is induced by various folk means, because it is believed that retention of blood causes cramping and that blood flow will alleviate that pain. The cleansing ritual after each cycle has both physical and religious importance.
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.
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.