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Contraception Report. 1999 Jan; 9(6): p..A recent WHO-sponsored study has demonstrated that the progestin levonorgestrel, used alone, is a highly effective and well-tolerated form of emergency contraception. With the proportion of pregnancies prevented up to 95% - depending on the timeliness of administration - the levonorgestrel regimen proved more effective than the most commonly used regimen, the Yuzpe method. The Yuzpe method employs a dual-hormone (ethinyl estradiol plus levonorgestrel) approach to preventing pregnancy. Despite the Yuzpe regimen's 75% efficacy rate (a weighted average from 10 studies) the method has been associated with drawbacks. About 50% of users experience nausea and 20% report vomiting, which can reduce patient compliance. (excerpt)
Contraception. 2006 May; 73(5):443-444.Steroid hormonal contraceptives, including oral contraceptives, injectables and implants, are highly effective and widely used. These contraceptives have important health benefits, including contraceptive and noncontraceptive benefits, and some health risks. For most women, the health benefits of use clearly exceed the health risks. Questions have been raised regarding the association between use of one particular hormonal contraceptive, depot medroxyprogesterone acetate (DMPA) and the risk of bone loss. In response, WHO convened a consultation in Geneva, on June 20-21, 2005, to assess current evidence on the relationship between the use of steroid hormonal contraceptives and bone health. (excerpt)
Geneva, Switzerland, WHO, 1978. (World Health Organization Technical Report Series No. 619) 54 pStudies on steroid contraception (SC) and risk of neoplasia are reviewed. Methodological issues in neoplasia etiology studies include: 1) possibility of a latent period between exposure to cause and disease development; 2) cumulative effects of prolonged or repeated SC exposure; 3) discontinued drugs or dosage schedules; 4) time of exposure (adolescence or prenatal, e.g.); 5) isolation of specific causes among multiple risks; and 6) variations in neoplasma diagnoses. The 4 epidemiological approaches to SC-associated neoplasia studies have inherent shortcomings, but cohorts yield significant associations. Relative risk (ratio of disease incidence among exposed vs. nonexposed persons) is an index of association only, not evidence of cause and effect. Benign breast neoplasia risk was reduced by current SC use of >2 years, and weak evidence points to a residual protective effect, apparently associated with progestogen dose. Aggregated breast cancer data show no clear adverse or beneficial effect of SC use; however, evidence suggests SCs may increase breast cancer risk in population subgroups (e.g., young women). Only short-term evidence is available; hence, no inference of long-term SC breast cancer effects is possible. No beneficial effect of SCs on uterine fibroids is evident, but sequential SCs, no longer marketed, may have increased risk to endometrial carcinoma. Inconclusive data suggest SCs may decrease ovarian cancer risk. Increased risk of cervical dysplasia and carcinoma in situ is associated with SC use, especially long-term use by women with predisposing factors. Risk of hepatocellular adenoma of the liver increases with prolonged SC exposure, especially high dose. Relevance of existing data from more developed countries to disease risk in less developed ones is discussed, and recommendations made.
The use of a large-scale surveillance system in Planned Parenthood Federation of America clinics to monitor cardiovascular events in users of combination oral contraceptives.
International Journal of Fertility and Women's Medicine. 1999 Jan-Feb; 44(1):19-30.In response to studies reporting an excess of thrombotic events in women who used oral contraceptives (OCs) containing third-generation progestins, the Planned Parenthood Federation of America (PPFA) launched a retrospective review of clients at all PPFA-affiliated centers during 1993-95. During the 3-year study period, 2,265,087 woman-years of OC use were recorded in clinic drug sale records. All OCs prescribed in this period contained 30 or 35 mcg of estrogen and either norgestimate (21.0%), desogestrel (8.9%), norethindrone (46.6%), or levonorgestrel (23.6%) as the progestin. 70 major thrombotic events among clients using OCs (3 vascular complications per 100,000 woman-years of OC use) were reported to PPFA's risk management division during 1993-95; these included 25 cases of deep vein thrombosis, 20 cases of pulmonary embolism, 22 cerebrovascular accidents, and 3 myocardial infarctions. There were 5 deaths (0.22/100,000 woman-years of use), all from pulmonary emboli. The thrombotic event rates were calculated as the relative risk of complication, comparing the risk of each event for one progestin relative to the other three classes of progestins. The overall risk varied from a low of 1.895 events/100,000 woman-years for norgestimate OC users to a high of 3.969 events/100,000 woman-years for desogestrel OC users, but these differences were not statistically significant. In the progestin comparison, desogestrel users showed elevated risks for pulmonary emboli and fatalities, norgestrel use was associated with an increased risk of deep vein thrombosis, and norgestimate an increased risk of deep vein thrombosis and pulmonary embolism. Generally, these four groups of low-dose OCs appear safer than any previously published study has indicated. In part, this may reflect PPFA's careful prescribing guidelines. In addition to following US Food and Drug Administration contraindications, PPFA affiliates do not provide OCs to women over 35 years of age who smoke more than 15 cigarettes a day.
Family Planning Perspectives. 1999 Jan-Feb; 31(1):49-50.The World Health Organization Collaborative Study of Cardiovascular Disease and Steroid Hormonal Contraception found no evidence of increased cardiovascular risk in women who used oral or injectable progestogen-only contraceptive methods. The analyses were based on 3697 women with cardiovascular disease from 21 centers in 17 countries in Africa, Asia, Europe, and Latin America. Women with a history of hypertension were at increased risk of stroke, regardless of their use of a hormonal contraceptive, but this pattern did not apply to venous thromboembolism or heart attack. Use of progestogen-only methods was associated with small but nonsignificant increases in cardiovascular risk among smokers. Many of the risk estimates in this study had wide confidence intervals because of the small numbers of users of progestogen-only methods enrolled at the various study centers. The interaction between progestogen-only contraceptives and hypertension merits further assessment, especially because women with a history of high blood pressure use progestogen-only pills more frequently than combined oral contraceptives.
SEXUALIDADE E PLANEAMENTO FAMILIAR. 1995 Jul-Sep; (7):17-8.The Portuguese Association of Family Planning has learned about a study of the World Health Organization that associated certain types of combined oral contraceptives (OCs) with an increased risk of cardiovascular diseases, notably deep venous thrombosis. The position of the International Medical Advisory Panel (IMAP) of the IPPF, however, was that such conclusions were not definitive and new studies should be conducted to confirm or refute these conclusions. Furthermore, since the risk is rare, those using OCs should have regular medical examinations. For the majority of OC users the benefits outweigh the risks. The author of one of the two studies that hinted at the cardiovascular risks of third-generation progestagens stated that the British authorities incorrectly interpreted the data, which were preliminary. In fact, these data suggest that the new generation of OCs protects against cardiac attack and associated mortality. Even the WHO took the position that these results should be confirmed by independent studies. The polemic mounted when the British authorities issued an alert about the possible negative effects of seven types of OCs containing progestagens which putatively doubled the risk of venous thrombosis. This was based on the findings of three studies: two of them were incomplete, one was done at the initiative of the WHO, one was carried out in Europe, and the third one was done in the UK. At the meeting of the Committee of Pharmaceutical Specialties of the European Agency of Medicaments in October 1995 in London the position was taken that it is not appropriate to withdraw such OCs; investigators should analyze these data in depth and perform new studies; the three companies that manufacture such OCs should submit more information by the end of 1995; and physicians should take into account thromboembolic risk factors when prescribing such OCs.
[Sexual abstinence or thrombosis? Comment on the controversy regarding the "third generation pill"] Enthaltsamkeit oder Thrombose? Stellungnahme zur Kontroverse um "Pille der dritten Generation".
FORTSCHRITTE DER MEDIZIN. 1995 Nov 30; 113(33):18, 20.In October 1995 the WHO published the alarming results of an international study about oral contraceptives (OCs) and the risk of venous thrombosis stating that with the use of the third generation of OCs or micropills containing gestodene and desogestrel the risk increases twofold compared with OCs containing other gestagens. However, the Zurich discussion group, composed of German and Swiss hormone researchers, declared that this statement should be taken with a grain of salt. The study reported that 3 cases of thrombosis occur for 100,000 woman years when no OCs are used. When OCs without the above two gestagens are used the incidence of thrombosis increases to 8 cases/100,000 woman years. With the use of these micropills the incidence rose to 17 cases/100,000. The experts interpretation of the differentials was that the common risk factors for thrombosis (obesity, smoking, age, and duration of OC use) were not sufficiently taken into consideration. The original higher dose OCs already produced side effects early on, such as thrombosis, stroke, and heart infarction. Therefore, in the late 1980s the introduction of the new generation of OCs with lower doses seemed to be a welcome solution. The micropill, Femovan by Schering, was put on the market containing .03 mg of ethinyl estradiol (EE) and .075 mg of gestodene, a synthetic, very effective gestagen. The Organon Company introduced another preparation (Marvelon) that contained the same dose of EE and .15 mg of desogestrel. The considerable attention to the putative higher risk of thrombosis posed by these agents was not shared by the European Drug Commission, which did not see any reason for removal of these OCs from the market. The third generation OCs also provide benefits: reduction of bleeding anomalies and cardioprotective effects. Even the increased thrombosis risk is significantly lower than the thrombosis risk posed by pregnancy, delivery, and puerperium.
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.
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.
In: Issues in reproductive technology I: an anthology, edited by Helen Bequaert Holmes. New York, New York, Garland Publishing, 1992. 11-30. (Garland Reference Library of Social Science Vol. 729)The progestin, levonorgestrel, suppresses ovulation and thickens the cervical mucus. The 1-year pregnancy rate is 0.2/100 users and the 5-year rate is 3.9/100 users. Contraindications of Norplant include abnormal bleeding, cardiovascular conditions, liver tumors, and breast cancer. The most frequent side effect is changes in bleeding patterns. A main concern of women's health advocates is that women are dependent on the medical establishment for insertion and removal of Norplant which affects the provider-client relationship. Family planning programs that do not recognize a woman's right to free choice of existing contraceptives and her right to have Norplant removed at any time may abuse Norplant. Health workers still do not know the long term effects of Norplant and Norplant's effect on the fetus in case of method failure or insertion while pregnant. Most acceptability studies occurred at university-based health clinics or at clinics in urban areas. The clinic environment may affect women's answers. These studies should occur in the community and home of users and nonusers. Another bias of these studies was clinic staff chose women who would tend to continue using Norplant. Thus subjects were not representative of the population. Researchers did not attempt to understand the women's perception of reproduction physiology and mode of action, the women's cost benefit analysis used to determine what method to use, or the consequences of menstruation changes. They also did not report on the information women received about contraceptive choices. The issue of abuse has arisen in Kansas where a state legislator proposed paying any mother on welfare US$500 if she uses Norplant. In California, a judge ordered a woman convicted of child abuse to use Norplant after release from jail and throughout her probation period.
WASHINGTON MEMO. 1992 Nov 12; (17):2-3.In October 1992, the US Food and Drug Administration (FDA) approved Depo-Provera for contraceptive use thus increasing the number of available contraceptives to women. Yet USAID has distributed it through its family planning programs in developing countries for many years. It has been available in the US since 1969 for noncontraceptive purposes such as endometrial cancer treatment. More than >30 million women around the world have used it to prevent conception. Today about 9 million women in 90 countries use it. A reason FDA did not approve Depo-Provera is that some studies revealed a link between it and breast tumors and cervical cancer in animals. More recent research conducted by WHO shows no connection with cervical cancer or ovarian cancer. In fact, it demonstrates Depo-Provera may protect against endometrial cancer. Yet it does indicate an insignificant increased risk of breast cancer in younger women. Some research suggests Depo-Provera may decrease bone density leading to osteoporosis and may increase the risk of having a low birth weight infant if the child is conceived before an injection. Evidence exists that it may lead to longer delays in becoming pregnant than other forms of contraception. Still 70% do conceive within 12 months after the last injection. Each Depo-Provera injection delivers a progestin in a water-based solution over 12 weeks resulting in suppressed ovulation. Its failure rate is <.5%/year, so Depo-Provera is one of the most effective reversible contraceptive available. The most common side effects are menstrual changes and weight gain (5-15 lbs.). Some contraindications include pregnancy, heart or liver disease, and breast cancer. As of November 1992, the FDA had not announced the cost or whether there would be a reduced price for family planning and public health clinics. Women's health and rights advocates plan on monitoring introduction of Depo-Provera to make sure that women have received comprehensive information and were not coerced to use it.
SCIENCE. 1992 Jun 26; 256:1754.Depo-Provera (DP) was unanimously recommended for approval as a contraceptive by a Food and Drug Administration (FDA) advisory committee. This had happened once before in the mid-1970s, but Congress raised concerns about DP's possible link to cervical cancer. DP has been in use for 20 years as a treatment for uterine cancer. DP is an injectable progesterone analog that induces infertility for 3 months in 99% of the women who use it. It is already in use in 90 countries and has annual sales of US$100 million. The 4 annual shots cost US$120 and is an economical alternative to Norplant. There are still many unanswered questions about its safety. A recent WHO study found that it increased breast cancer by 21%, which was almost statistically significant. However, in the <34 age group breast cancer was twice as common, which is statistically significant. DP was found to increase the number of breast cancer cases by 5.6/100,00; but, it reduced the number of uterine cancer cases by 19.2/100,000. A New Zealand Hospital study found that DP use reduced bone density by 7.5% in the lumber spine and 6.5% in the neck of the femur. Critics charge that Upjohn has had 20 years to compile data but has failed to do so. There is little or no data about its effect on developing fetuses, osteoporosis, or the mechanism that causes breast cancer. All these areas were recommended for follow-up study by the FDA advisory committee.
SOUTH AFRICAN MEDICAL JOURNAL. 1992 May 2; 81(9):444-5.The advantages and side effects of the injectable contraceptive, Depo-Provera, are highlighted. It has been available to women in South Africa and in about 90 developing and developed countries for 20 years. It is an effective and convenient contraceptive with no serious side effects. Its failure rate is 0.2-0.6/100 woman years. Nevertheless there is still concern that it may cause breast cancer because original tests of Depo-Provera using beagles indicated that it may increase breast cancer risk. WHO and the UK Committee on Safety of Medicines have since dropped the requirement of testing of beagles since they cannot predict the effects of steroids on women. A 12-year WHO multinational, hospital-based case-control study on neoplasia and hormonal contraceptives reassures Depo-Provera's safety. For example, the risk of breast cancer did not increase with duration or in women who had used it for >5 years. The risk was higher, however, among women who had used it for <4 years, particularly <35-year old women. The same holds true for oral contraceptive (OC) users. It has been suggested that this slight increase is because Depo-Provera and OCs may accelerate growth of some existing, previously undetected breast tumors. The WHO study verifies that the benefits of Depo-Provera surpass the side effects which include disturbed bleeding patterns, weight gain, and headaches. For example, it decreases the risk of ovarian and endometrial cancer. It is even more beneficial in developing countries where women often suffer from anemia because it increases hemoglobin levels. Further since women in developing countries cannot always comply and take their OCs, Depo-Provera can grant them the protection they need against pregnancy thus saving many lives. Depo-Provera should be available in developed as well as in developing countries.
International Family Planning Perspectives. 1992 Jun; 18(2):75-7.The main points of a study from the WHO Special Program of Research, Development and Research and Training in Human Reproduction on menstrual bleeding patterns and contraceptive use are presented. 1875 users of oral contraceptives, 1822 users of monthly injectables, 546 users of vaginal rings, and 1109 depot-medroxyprogesterone acetate (DMPA) users kept diaries of full bleeding and days of spotting during the 1st year a method was started. This information was compared with data from the 1930s and 1960s on bleeding patterns among nonusers of contraceptive methods. Monthly data were excluded in which pregnancy occurred of following a pregnancy, and when there were menstrual disorders or gynecological surgery. Data were then limited to women aged 18-34 years which left 3893 woman years of menstrual cycles. The results revealed that women who used hormonal contraceptives such as the vaginal ring or monthly injectables tended to have shorter periods of menstrual bleeding and more regular predictable periods than women on longterm injectables. Most women have variable bleeding patterns during the year, even when not using hormonal methods. Nonusers, pill users, and vaginal ring users had a median of just more than 3 bleeding or spotting day episodes during a 90-day period vs. 3 days among injectable users and <2 days for DMPA users. However, when the average duration of bleeding or spotting episodes was examined, the median was 4 days for pill users, 5 days for vaginal ring users, and 6 days for DMPA users. Menstrual cycle average length was lowest at 26 days for vaginal ring users, 28 days for nonusers, 29 days for injectable users, and 36 days for DMPA users. The median value for difference between the longest and the shortest cycle within 12 months was around 10 days for nonusers and pill users and 24 days for injectable or vaginal ring users vs. 55 days for DMPA users. The median for the longest episode of bleeding or spotting was 5 days for pill users, 7 days among nonusers, monthly injectable users, or vaginal ring users, and 12 days among DMPA users, of which 25% bled for at least 21 days and 1 in 29 bled for 55 days or more. The shortest bleeding-free intervals was the median for vaginal ring users at 21 days, and longest for DMPA users at 27 days. Other methods were similar to the intervals for the vaginal ring. 25% of DMPA users had a minimum bleeding-free interval of only 2 days, and 25% had an interval of at least 20 days. The myth is debunked that normal women have normal and regular cycles of 25-35 days.
Family Planning Perspectives. 1992 Jan-Feb; 24(1):43-4.1 hospital in Nairobi, Kenya; Mexico City, Mexico, and Chiang Mai, Thailand and 2 hospitals in Bangkok, Thailand took part in a WHO sponsored collaborative study to examine the association between depomedroxyprogesterone acetate (DMPA) and breast cancer. The researchers compared 1979-1988 data on 869 hospitalized women with breast cancer with 11,890 hospitalized women with unrelated conditions. 12.5% of cases and 12.2% of controls had ever had an injection of DMPA. Overall ever users had no significant increased risk of breast cancer (relative risk [RR], 1.2) In addition, risk did not rise with duration. Nevertheless current users who began receiving DMPA within the past 4 years did have a significantly higher risk (RR 2.6). On the other hand, current users who began receiving DMPA >5 years earlier were not at increased risk at all. For example, the RR for those who began 8-12 years earlier was 0.8 and for those who began >12 years earlier was 0.5. Further even though the current users <35 years old who began receiving DMPA within the past 4 years were >2 times as likely to have breast cancer than their corresponding counterparts who did not use DMPA (RR 2.2), the risk according to duration was not significant. The researchers listed some possible reasons for the discrepancies. They concluded that there is only a weak association between DMPA and breast cancer--comparable to that between oral contraceptives and breast cancer. In New Zealand, a case control study of 30 25-51 year old women who used DMPA for at least 5 years showed that long term use of DMPA significantly reduced bone density. For example, for DMPA users, the spine and femoral neck bone densities were 8% and 7% respectively lower than the premenopausal controls. The researchers found the same effect even when they restricted the analysis to nonsmokers.
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.
CONTRACEPTIVE TECHNOLOGY UPDATE. 1992 Jan; 13(1):15-6.A recent World Health Organization (WHO) study found that women using Depo-Provera have only a slight increased risk of breast cancer. WHO examined case-control data from 5 hospitals in Africa, Mexico, and Thailand. The study revealed a 1.21 relative risk of breast cancer among all women in the study who had used Depo-Provera (a relative risk of 1.0 means that there is neither an increased or decreased likelihood to develop the disease in question). A relative risk of 1.21 indicates that there is a 21% increased likelihood of developing the disease, but any relative risk of less than 2.0 is considered slight. The study also found that among the diagnosed breast cancer cases, 12.5% had ever used Depo-Provera, compared to 12.2% among the control patients. Although an increased risk of breast cancer among women--especially women under 35--within the first 4 years of exposure to Depo-Provera was found, the risk did not increase with the duration of use, and it did not increase among women who had used the drug for more than 5 years. WHO explains that the risk of breast cancer among Depo-Provera user is similar to that found among oral contraceptives users, whose relative risk ranges from 1.0-1.42. Based on their findings, WHO investigators estimate that there would be 7-8 new cases of breast cancer per 100,000 Depo-Provera users annually, compared to 5 new cases annually among women who had not used the drug. As a recent commentary by Family Health International (FHI) points out, this increased risk of breast cancer must be weighted against the benefits provided by Depo-Provera. FHI concludes that there is a net gain for women using Depo-Provera, since despite the slight risk of breast cancer, it would result in a higher life expectancy compared to women not using contraception.
A randomized comparative study of interval insertion of three intrauterine devices: the copper T 220c, the Nova T and the WHO levonorgestrel 2 ug IUD.
[Unpublished] 1985 May. 5 p. (Project: 82901)The objective is to compare the effectiveness and acceptability of 3 IUDs inserted in 300 health women, aged 24-38. All have had at least 1 full-term delivery. Subjects were randomly allocated to 1 of the 3 IUDS: the Copper T 220C (Tcu 220c), the Nova T, and the World Health Organization levonorgestrel 2 ug IUD. Insertion was done from the 3rd to the 5th day of menstruation between Feb. and Sept. 1984 and followed up at 48 hours, 3, 6, 12, and 24 months after IUD insertion. 12 month data was collected for cumulative rates, based on life table procedures and analyzed with log-rank test. There was no loss to follow up and no insertion failure. All levonorgestrel IUDs have been removed because the levonorgestrel-releasing IUD has a relatively high risk of ectopic pregnancy. The use-related discontinuation rates of Tcu 220c, Nova T, and levonorgestrel IUD during 12 months of use, were 11.1, 2.4, and 12.7, respectively. The difference between Tcu 220c and Nova T were statistically significant (p.<0.01). The continuation rates of Tcu 220c, Nova T, and levonorgestrel during 6 months of use were 94.0, 99.0, and 96.0, respectively. During 12 months of use, they were 88.9, 97.6, and 87.3 respectively. 1 ectopic pregnancy occurred with the levonorgestrel IUD after 7 months of use. No pregnancy occurred in Nova T users. The pregnancy rates of Tcu 220c and levonorgestrel IUD during 12 months of use were 1.0 and 1.3, respectively. Removal rates for bleeding with Tcu 220c and levonorgestrel IUD during 12 months of use were 3.1 and 1.0, respectively. The removal rate for pain with Tcu 220c during 12 months of use was 2.0. The duration of bleeding and spotting with 3 IUDs, 3, 6, 9, and 12 months of use are illustrated. Preliminary results show that the Nova T is superior to Tcu 220c and levonorgestrel IUDs. Expulsion is the main event in both Nova T and Tcu 220c. More attention should be paid to the insertion technique. The duration of bleeding and spotting of levonorgestrel IUD were longer in the last 3 months after insertion, but was shortest at 1 year of use when compared with Tcu 220c and Nova T.
Effective interception with the levonorgestrel-20-IUD contrarily to WHO advocated Lng-2-microdose IUD. Reply to letter to the editor [letter]
CONTRACEPTION. 1988 Jun; 37(6):644-6.This letter is a response to Professor Haspels' letter criticizing the World Health Organization Special Programme of Research, Development and Research Training in Human Reproduction's clinical study of a 20 mcg microdose levonorgestrel IUD for Contraception (Contraception 1987;35: 363-79). The Population Council's International Committee for Contraceptive Research was provided with the results of the study prior to publication. The feasibility of an IUD that released a dose of progestational steroid that was pharmacologically active only on the endometrium was confirmed in a study conducted between 1980-1982 in 7 centers, only 3 of which were in developing countries. There was no evidence of effects on ovulation and no ectopic pregnancies in this study. The study itself resulted in only 8 ectopic pregnancies (6 with the levonorgestrel device and 2 with copper devices) out of 17,064 woman-years of experience. Nevertheless, the study was terminated and the results published. The polymeric delivery system used in the 2 mcg levonorgestrel IUD had undergone extensive animal toxicological studies in the US and the UK before human use. Moreover, the ethical acceptability of the study was approved by the World Health Organization as well as by local institutional ethic committees and appropriate national authorities.
Effective interception with the levonorgestrel-20-IUD contrarily to WHO advocated Lng-2-microdose IUD [letter]
CONTRACEPTION. 1988 Jun; 37(6):643.The World Health Organization's Special Program of Research, Development, and Research Training in Human Reproduction has investigated microdose administration of levonorgestrel to the uterine cavity and concluded that this approach is not safe or effective. In contrast to the excellent results obtained with 20 mcg of levonorgestrel release per 24 hours, the results of application of only 2 mcg release per 24 hours have been disappointing. There was a 6.7 increased relative risk of ectopic pregnancy with the levonorgestrel 2 IUD compared with the copper IUD, making this an unacceptable form of fertility control. On the other hand, the 12-month pregnancy rate for the levonorgestrel 20 IUD is 0.1/100 woman and the 12-month continuation rate is 80%. Removal rates for menstrual problems with this IUD are only 7.5%, and blood hemoglobin concentrations actually increase among users of the levonorgestrel 20 model.
IPPF MEDICAL BULLETIN. 1987 Apr; 21(2):1-2.Within the past 25 years, steroidal preparations have become available that allow the user contraceptive protection over extended periods of time. There are only 2 injectable preparations presently used at all widely within family planning programs throughout the world: 1) depot medroxyprogesterone acetate (DMPA), and 2) norethisterone enanthate (NET-EN). 1 of the major side effects of progestagen-only contraception has been disruption of normal menstrual bleeding, giving rise to both irregular bleeding and amenorrhea. Several extensive reports on the clinical use of monthly injectables appeared in 1970, but few studies have been reported subsequently. In response to the demand from certain populations to have safe, well-investigated, once-a-month injectable contraceptives with high efficacy and little menstrual bleeding disturbance, the World Health Organization's (WHO) Special Programme of Research in Human Reproduction developed a strategy for the development of a once-a-month contraceptive which involves: 1) the assessment of use-effectiveness and side-effects of HRP102 (NET-EN, 50 mg., plus oestradiol valerate, 5 mg) and Clyloprovera (DMPA, 25 mg., plus estradiol cypionate, 5 mg.); and 2) the optimum improvement of these 2 combined formulas by reduction of the progestagen content. Results from a pharmacokinetic/pharmacodynamic study show that many of the women receiving reduced progestagen dose preparations ovulated during the 3rd treatment month; thus the 2 original preparations, Cycloprovera and HRP102 appear to be the optimal formulations for these combinations of steroids. Plans are being developed to make 1 or both of these available for introduction into certain family planning programs in developing countries early in 1988.
BMJ. British Medical Journal. 1985 May 25; 290(6481):1587.The recent World Health Organization (WHO) report on oral contraceptives (OCs) and cervical cancer suggests a relative risk of contracting cervical cancer among users and former users of OCs ranging from 1.1-1.7 depending on which variables are controlled. For women who had used OCs for 2-5 years the relative risk was 1.46 (not controlling for other risk factors). OC use carries both risks and benefits and these need to be kept in perspective. It is important to remember that the risk attributable to OC use is small even for those diseases which have been associated with OC use. Life expectancy was calculated using mortality rates that have been modified to incorporate all known risks and benefits of OC use. To illustrate the effect of an increased risk of cervical cancer life expectancy was calculated with no increased risk of cervical cancer (relative risk = 1) and again with a relative risk of 1.46 (the relative risk reported by WHO for women with 2-5 years of OC use). Relative risks for other diseases were kept constant. The risks for women taking OCs were calculated when the women were 20-24 and for women taking pills when they were 30-34. The expectation of life for American women never taking OCs is 77.34 years. A table shows the expectation of life for OC users. Young women using OCs benefit very slightly in terms of life expectancy, and older women taking pills lose very slightly. That part of the difference which is contributed by cervical cancer is also extremely small. The maximum change in life expectancy that could be attributed to an increased risk of cervical cancer is 0.03 years or 11 days. By contrast, a women who smokes 1-10 cigarettes a day during her 30s reduces her life expectancy by about 4 years.
Invasive cervical cancer and combined oral contraceptives. WHO Collaborative Study of Neoplasia and Steroid Contraceptives.
BMJ. British Medical Journal. 1985 Mar 30; 290(6473):961-5.This paper presents the preliminary results of a multicenter case-control study conducted under the auspices of the World Health Organzation to determine whether combined oral contraceptives (OCs) increase the risk of malignant neoplasms of the breast, cervix, endometrium, ovary, and liver. Initial results on the relationship between combined OCs and invasive cervical carcinoma in 726 cases and 5246 controls indicate a relative risk of 1.19 (95% confidence interval, 0.99-1.44) in women who had ever used OCs. The risk increased to 1.53 after 5 years of OC use. The analysis made adjustments for various potentially confounding variables, including age, center, number of pregnancies, age at 1st intercourse, number of sexual relations, and history of vaginal discharge. The relative risk obtained in this study, of borderline significance, could be explained on the basis of incomplete control for the confounding effect wf sexual variables. In addition, the implications of these findings for women who are currently using combined OCs are uncertain; most wf the women in this study were exposed to preparations containing higher doses of estrogen and progestogens than products now in use. Future analyses of data from this investigation, bases on lager numbers of patents, will include controls for smoking and infection by sexually transmitted agents.
Breast cancer, cervical cancer, and depot medroxyprogesterone acetate. [WHO Collaborative Study of Neoplasia and Steroid Contraceptives] [letter].
Lancet. 1984 Nov 24; 2(8413):1207-8.This letter presents the preliminary findings of a collaborative, multinational, hospital-based, case-control study being conducted under the auspices of the World Health Organization to assess the influence of depot medroxyprogesterone acetate (DMPA) on risks of mammary, gynecological, and hepatobiliary malignancies. The frequency of ever-use of DMPA was greater in breast cancer cases (15/246, or 6,0%) than in controls (381/4162, or 9.2%). When adjusted for age, center, age of birth of 1st child, and nulliparity, the relative risk in women who had ever used DMPA was 0.7. The lowest risk was noted in women who had used DMPA for 3 or more years, but no decreasing trend in risk with duration of use was evident. The reducton in risk of breast cancer in DMPA users was largely confined to women with 1st exposure after age 30 years. In terms of cervical cancer, a history of DMPA use was reported by slightly more cases (67/469, or 14.3%) than controls (269/2704, or 9.9%). Use of oral contraceptives, number of cervical smears, and number of pregnancies were the variables most strongly related to cervical or having the greatest influence on relative risk estimates for users of DMPA. When controlled for these 4 factors and age and center, the relative risk in DMPA was 1.13. The highest relative risk was found in longterm users, although there was no clear trend of increasing risk with duration of DMPA use. These preliminary findings provide no evidence that DMPA increases the risk of breast cancer. The relative risk for cervical cancer for DMPA users obtained in this study could be due to chance or to incomplete control for the confounding effect of sexual variables. Although the absence of a trend of increasing risk with duration of use tends to rule out a causal connection between DMPA use and cervical cancer, the doubling of risk in women who used DMPA for 5 years or more is of potential concern.
Science. 1982 Jul 30; 217(4558):424-8.The record of the U.S. Food and Drug Administration's (USFDA) actions regarding Depo-Provera, a medroxyprogesterone acetate, as an injectable contraceptive and the international implications are reviewed. In September 1982 a special panel of scientists began deliberations to recommend whether Depo-Provera should be approved for use as an injectable contraceptive. The U.S. Agency for International Development (USAID) has been asked by developing countries to furnish the drug but will not export drugs that are not approved by USFDA. More than 80 countries have approved the drug. Advocates for USFDA approval include the Upjohn Company (manufacturer of the drug), World Health Organization, International Planned Parenthood Federation, Population Crisis Committee, and the American College of Obstetrics and Gynecology. The opposition includes the Health Research Group affiliated with Ralph Nader, the National Women's Health Network, and several right-to-life groups. Hesitation by USFDA is related to laboratory animal studies which suggest that Depo-Provera is a potential human carcinogen. Upjohn conducted a 7 year study with 16 beagles and a 10 year study with Rhesus monkeys; both of the test animals developed more tumors than the controls. Questions were raised about using the animals since the response of these two species to the drug and the human response are not necessarily comparable. Limited approval has been recommended twice by expert advisory committees in 1974 and 1975, but USFDA refused both times. It is suspected that Korea, Taiwan, Egypt, Jordan, and Yemen reversed their approval as a result of the latest USFDA rejection. This final decision will have major economic and social implications and will assume international importance.