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This report summarizes a survey of the management of menstrual disturbances occurring during injectable progestogen use (depot-medroxyprogesterone acetate, DMPA and norethisterone enanthate, NET-EN) by 35 investigators from 20 countries with ongoing experience with these contraceptives. A wide range of approaches are described. The most frequently emphasized aspect of management is thorough pretreatment counseling with further support and counseling at follow-up visits. Estrogens in various forms are widely used for the treatment of prolonged, frequent, or heavy bleeding episodes, but now are not usually used for induction of withdrawal bleeding episodes in women with amenorrhea. Heavy or severe bleeding appears very uncommon and figures of 1-2% are mentioned. Anecdotal information suggests that intramuscular doses or longer courses (14-21 days) of oral estrogen, including the combined pill, are more likely to successfully stop an episode of heavy bleeding than short courses. However, there are no hard data to show that a course of estrogen treatment has any beneficial effect on longterm bleeding patterns. Nevertheless, temporary cessation of spotting or light bleeding may be sufficiently reassuring to the patient to ensure continued use of the method. There appears to be little risk associated with short-term estrogen regimens currently in use. Dilatation and curettage is almost never necessary to stop an episode of bleeding, but may occasionally be recommended for diagnostic reasons. Clearly, bleeding connected with DMPA and NET--EN use are poorly understood and research is necessary to clarify pathophysiological mechanisms and improve management.
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PMID:A survey of different approaches to management of menstrual disturbances in women using injectable contraceptives. 623 Feb 12

A total of 2388 subjects, 1181 for 60 +/- 5-day and 1207 for 90 +/- 5-day treatment regimen with norethisterone oenanthate (NET OEN) 200 mg injection, were observed for 24 months, constituting 28,513 woman-months. This clinical trial represents the largest clinical trial undertaken on NET OEN. The observations indicated that NET OEN given at 60 +/- 5-day intervals provides adequate contraceptive protection. However, as compared to the published studies elsewhere, higher method failures were seen during the first six months of NET OEN usage, when all women were receiving the drug at 60 +/- 5-day intervals. The reasons for this discrepant observation in the present study cannot be explained. The higher method failures reported with 90 +/- 5-day regimen were mainly during the third month following the injection, suggesting reduced contraceptive efficacy of the drug during this period. Thin build women (body weight less than or equal to 40 kg) were at higher risk of involuntary pregnancy. Disrupted menstrual pattern was the major reason for discontinuation ranging between 42-43 per 100 users at the end of 24 months. Amongst these, amenorrhoea was the commonest reason for discontinuation. No change in blood pressure was observed during contraceptive usage. The majority of NET OEN users did not show any change in body weight. The overall continuation rates with NET OEN were lower than those observed in similar conditions with Cu-T 200 mm2 IUCD.
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PMID:Comparative evaluation of contraceptive efficacy of norethisterone oenanthate (200 mg) injectable contraceptive given every two or three monthly. Indian Council of Medical Research Task Force on Hormonal Contraception. 639 28

This comparative trial of norethindrone enanthate (NET-ENT) and depo-medroxyprogesterone acetate (DMPA) was conducted in a randomized, single blind manner in a clinic in Bangladesh to assess discontinuation rates, reasons for discontinuation, and variablility of side effects between these 2 injectable contraceptives. Of a total of 239 women, 106 received NET-ENT (200 mg) and 133 received DMPA (150 mg). DMPA was given every 12 weeks after the first injection and NET-ENT was given every 10 weeks after initial injection. Oral estrogen therapy was made available to women in this study based on the following criterion: 1) spotting/bleeding lasting more than 7 days; 2) heavy bleeding; or 3) 3 or more months of amenorrhea if this disturbed the subject. For menstrual pattern variability, a larger proportion of women reported irregular bleeding when given NET-ENT than did those with DMPA. On the other hand, on all follow-up visits the proportion of women reporting amenorrhea was higher for DMPA compared with NET-ENT users. However, by the 4th injection, fewer than 15% of clients in both experimental groups still reported regular cyclic bleeding (4 of 26 in DMPA group and 4 of 28 in NET-ENT). 11 pregnancies occurred during treatment, 5 in the DMPA group and 6 in the NET-ENT group. Continuation after 1 year totaled 28 clients, 14 from each group. The primary reasons for discontinuation were pregnancy; medical reasons, including symptoms and fear of symptoms; nonmedical reasons such as desire for more children, or death of husband; or loss to follow-up: the number of clients in the DMPA group discontinuing for these reasons were 5, 48, 17, and 49, respectively, and the respective numbers among NET-ENT users were 6, 34, 24, and 28.
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PMID:A randomized, single blind comparative trial of norethindrone enanthate and depo-medroxyprogesterone acetate in Bangladesh. 644 42

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.
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PMID:WHO special programme of research, development and research training in human reproduction. Task force on long-acting agents for the regulation of fertility. 646 May 93

Clinical trials of norethisterone enanthate (NET-EN), a long-acting, injectable progestogen, have demonstrated its short-term safety and effectiveness as a method of contraception in a controlled trial setting. Family planning programs interested in providing NET-EN need information on its efficacy and acceptability under usual field conditions. This first field study of NET-EN was conducted in family planning clinics in rural areas of Mexico. Women admitted to the study were followed up at two-month intervals to receive an injection of 200 milligrams of NET-EN, and to be asked about possible side effects of the drug. Among the 5,792 women recruited, the overall life-table discontinuation rate was 57.0 per 100 women at 12 months and 69.0 at 18 months. The single most common reason for discontinuation was amenorrhea, followed by bleeding problems. Women who were older and who already had several children were most likely to continue using NET-EN. Nine pregnancies were reported during the study, with a cumulative pregnancy rate of 0.3 per 100 women at 18 months. NET-EN appears to be an effective method of contraception that is acceptable to a substantial proportion of women from rural areas in Mexico who choose to use it, when it is provided through a national family planning program.
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PMID:A clinical study of norethisterone enanthate in rural Mexico. 674 Jul 31

A randomized comparative trial of 832 women receiving (NET-EN) norethisterone enanthate and 846 women receiving (DMPA) depot medroxyprogesterone acetate injections at 12 week intervals was conducted in 10 centers. The pregnancy rate with NET-EN was significantly higher than with DMPA. The termination rate for amenorrhea was substantially lower with NET-EN than DMPA, whereas the discontinuation rates for bleeding problems were similar with the 2 drugs. Analysis of bleeding patterns among continuing and discontinuing users suggests that women tolerated frequent bleeding episodes, but found prolonged bleeding or prolonged bleeding-free intervals unacceptable. Bleeding for more than 30 days during an injection interval and complete amenorrhea for a whole injection interval were jointly associated with 43.7% of all terminations among NET-EN users and 64.5% of all terminations among DMPA users. In future efforts to improve the acceptability of long acting injectable contraceptives, more attention should be given to the control of prolonged amenorrhea and prolonged bleeding.
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PMID:Vaginal bleeding disturbances associated with the discontinuation of long-acting injectable contraceptives. From the World Health Organization Special Programme for Research, Development, and Research Training in Human Reproduction; Task Force on Long-acting Systemic Agents for the Regulation of Fertility. 700 25

Depot-medroxyprogesterone acetate (DMPA) in a dose of 1-2 g per injection has been administered up to 3 times a week i.m. since the early 1960s for the prevention of miscarriage, but this therapy has proven unsuccessful. However, its use for contraception proved effective. Depot-norethindrone enanthate (NET-EN) was combined with DMPA in the late 1960s. NET-EN was injected every two months. In Germany, DMPA preparations made by the Upjohn Co. (Depot-Clinovir) and NET-EN made by the Schering Co. (Noristerat) are available for contraceptive purposes. Injectable gestagens are used in more than 80 countries worldwide, except for the US, because in studies on beagle dogs breast tumors developed. Injectables occupy a high share of contraceptives in developing countries: 8% in Kenya, 12% in Thailand, and almost 20% in Jamaica, while in central Europe the three-month injectable represents only 1% of contraceptive agents. In terms of pharmacokinetics, the maximum concentration of NET-EN is reached after an injection of 1 mg/kg i.m., averaging 2-5 ng/ml, which is over the 1 ng/ml dose required for contraceptive effectiveness. The bioavailability is 100% when so applied, while the elimination half-time is 15-20 days. A 1977 WHO study revealed a continuation rate of 70-75% after 12 months. About 10% complained of bleeding disorders. Within the first 6 months of DMPA use amenorrhea sets in in one-third of the cases; it occurs in over 60% of cases after 1-1.5 years of use. Bleeding disorders often cause discontinuation, which can be treated with estrogen-gestagen combination preparations. Dihydroxyprogesterone acetophenid is combined with estradiol enanthate (E2-EN), MPA with estradiol cypionate (E2-Cyp), NET-EN with estradiol valerate (E2-Val), and 17-alpha-hydroxyprogesterone caproate with E2-Val. The rate of continuation with the DMPA/estrogen combination was more than 60%, while it varied between 26.5% and 44.1% with NET-EN plus E2-Val after 1 year of use.
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PMID:[Depot gestagens]. 857 39

This review covers the appropriateness of the use of hormonal contraceptive methods while breast feeding. The introduction notes that exclusive breast feeding is associated with a pregnancy rate of less than 2% during the first 6 months postpartum. While infertility associated with amenorrhea may be extended by breast feeding on demand continually during the day and night, this is often impractical for women in developed countries. Research on progestin-only contraceptives indicates that use of norgestrel may enhance lactation and is associated with no difference in milk content from controls. Use of levonorgestrel was associated with decreased milk volume but no differences in length, weight, or head circumference of subject infants. Injections of NET-EN or depot medroxyprogesterone at 1 and 6 weeks postpartum led to no adverse effects on infants or lactation. In addition, Norplant implants after the 4th week postpartum had no affect other than passing on a small dose to the infant, which is associated with no health risk. Use of a progestin-releasing IUD in comparison with a copper IUD was associated with a slight decrease in milk volume. Nearly all studies have concluded that combined oral contraceptives decrease milk volume and impair a woman's ability to breast feed exclusively. Thus, hormonal contraceptives can be used immediately postpartum and progestin-only contraceptives are preferable during the first 6 months because they have no apparent deleterious effect on breast feeding.
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PMID:Hormonal contraception and lactation. 902 49

Persistent and/or unpredictable bleeding is a common reason for discontinuation of hormonal contraceptive methods. An open-label, nonrandomized, parallel, controlled study compared the efficacy, safety, and cycle control of the new, highly efficacious monthly injectable contraceptive containing 25 mg medroxyprogesterone acetate (MPA) and 5 mg estradiol cypionate (E(2)C) (MPA/E(2)C) (Lunelle Monthly Contraceptive Injection) with that of the frequently used norethindrone 0.5, 0.75, 1.0 mg/0.035 mg ethinyl estradiol (NET/EE) triphasic oral contraceptive (Ortho-Novum 7/7/7). This report directly compares the bleeding patterns of women on MPA/E(2)C to those of women on NET/EE and untreated women. Overall, breakthrough bleeding occurred less frequently in women using MPA/E(2)C than in women using NET/EE (p < or =0.01). However, more women using MPA/E(2)C experienced amenorrhea/missed periods than those on NET/EE (p < or =0.01). In addition, the percentage of women experiencing breakthrough bleeding or amenorrhea while using other oral contraceptives is compared to that of women using MPA/E(2)C. A rapidly reversible method, MPA/E(2)C, combines the high contraceptive efficacy of surgical sterilization with the convenience of monthly administration. These data suggest that, for a large proportion of women, MPA/E(2)C offers predictability in bleeding patterns comparable to or greater than that experienced by ovulatory untreated women or those using combination oral contraceptives.
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PMID:Bleeding patterns of women using Lunelle monthly contraceptive injections (medroxyprogesterone acetate and estradiol cypionate injectable suspension) compared with those of women using Ortho-Novum 7/7/7 (norethindrone/ethinyl estradiol triphasic) or other oral contraceptives. 1123 15

A comparison of cycle control, efficacy and tolerability of two oral contraceptive preparations containing 20 microg ethinylestradiol combined with either 100 microg levonorgestrel (EE/LNG 20/100) or 500 microg norethisterone (EE/NET 20/500) was conducted. These results were compared to a standard reference preparation, containing 30 microg ethinylestradiol combined with 150 microg levonorgestrel (EE/LNG 30/150). Efficacy data from 8,544 treatment cycles were obtained from 767 women. Good cycle control and effective contraception was achieved with the two LNG preparations, however, the cycle control results were less favorable with EE/NET 20/500. The cumulative incidence of women with at least one episode of intermenstrual bleeding from cycles 2 to 7 (primary target variable) was 43.9% for EE/LNG 20/100, 72.7% for EE/NET 20/500, and 15.7% for the standard EE/LNG 30/150. The difference between the 2 20 microg of EE preparations, which favored EE/LNG 20/100, was statistically significant (p = 0.001). The overall spotting rates (cycles 1-13) were 9.3% for EE/LNG 20/100, 21.7% for EE/NET 20/500, and 3.3% for the standard EE/LNG 30/150. Amenorrhea was reported in 7.1% (EE/LNG 20/100), 20.6% (EE/NET 20/500), and 0.9% (standard EE/LNG 30/150), respectively. Intermenstrual bleeding episodes were shorter with EE/LNG 20/100 and EE/LNG 30/150 of the 13 treatment cycles. The study Pearl indices were 0.9 for EE/LNG 20/100, 1.9 for EE/NET 20/500, and 0.0 for EE/LNG 30/150. All three treatments were well tolerated. However, tolerability was somewhat less favorable with EE/NET 20/500. A total of 160 women prematurely discontinued the study for various reasons (EE/LNG 20/100: 7%; EE/NET 20/500: 18%; EE/LNG 30/150: 4%). The overall adverse event incidence rate during the trial was low in all groups. Blood pressure remained largely unaffected. Thirteen serious adverse events were recorded for all treatment groups, all but one were assessed as not related to the treatments. There were no remarkable treatment related differences in mean body weight throughout the study and the laboratory values were largely unaffected in all three treatments groups.
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PMID:Multicenter, comparative study of cycle control, efficacy and tolerability of two low-dose oral contraceptives containing 20 microg ethinylestradiol/100 microg levonorgestrel and 20 microg ethinylestradiol/500 microg norethisterone. 1153 6


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