Gene/Protein Disease Symptom Drug Enzyme Compound
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Endometrial bleeding and alteration in blood coagulation, fibrinolysis, ovarian function and endometrial morphology were studied in twelve normally menstruating women who received the injectable contraceptive norethisterone enanthate (NET-EN) 200mg at 60-day intervals. Levels of clotting factor VII declined significantly during episodes of irregular bleeding compared to those during both normal pretreatment menstruation and the bleeding-free period during treatment. Antithrombin III and fibrinolytic activity, expressed by euglobulin lysis time, showed no marked change. The average level of progesterone during the bleeding-free period was slightly but significantly lower than that during the bleeding period. There were no significant alterations in the mean levels of estradiol and the ratio of estradiol to progesterone. The endometrial biopsies showed considerable individual variation and seem to be independent of the effects of NET-EN on ovarian function.
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PMID:Effect of norethisterone enanthate on endometrial bleeding and changes in coagulation function, ovarian hormones and endometrial histology in Thai women. 189 2

A survey of recent trials of new injectable hormonal contraceptives, progestogen-only, levonorgestrel esters, and once monthly injectables, follows a brief review of all the experimental long-acting contraceptive modalities, injectables, implants, vaginal rings, and hormone-releasing IUDs. Currently medroxyprogesterone acetate (DMPA) and norethisterone enanthate (NET-EN) are being used by 7 million women. WHO is conducting dose reduction trials and studies of bioavailability in various national populations. Even though a dose of 100 mg DMPA every 3 months has been satisfactory for contraception, 150 mg is still recommended until further pharmacodynamic data are available. Some populations, notably Thais and Mexican women, have higher peaks and more rapid elimination rates of DMPA, while Chinese women show slower elimination and higher blood levels of NET-EN. Extensive studies of new synthetic esters of levonorgestrel have proceeded to Phase II clinical trials with levonorgestrel butanoate. This ester is an effective contraceptive for 3 months at 12.5 mg, or 5-6 months at a dose of 25 or 50 mg. Trials of combined estrogen and progestogen injectables once-monthly have been ongoing for 10 years. The ratio of the 2 components is as important as the amounts. 2328 women from 12 countries participated in trials of DMPA 25 mg-estradiol cypionate 5 mg, and NET-EN 50 mg-estradiol valerate 5 mg. The continuation rate was better than that for 3-monthly progestogen-only injectables, because of less irregular bleeding. A combined injectable called Cyclofem, DMPA 25 mg-estradiol cypionate is being introduced in several countries. The steadily increasing demand for long-acting injectables prompts development of better formulations.
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PMID:Long-acting hormonal contraceptives for women. 195 67

In preparation for introducing the injectable contraceptive norethisterone enanthate (NET-EN) into the national family planning program, a field study was conducted in 6 family planning clinics in Bangladesh. 3 of the clinics were located in Dhaka, the capital city, 1 was located in a town approximately 15 kilometers from Dhaka, and the other 2 clinics were located several hundred kilometers from Dhaka. A total of 913 women were chosen to receive injections of NET-EN every 8 weeks for 6 months and every 12 weeks thereafter. The mean age of the subjects was 26.8 years, and the mean number of live births was 3.4. The overall cumulative discontinuation rates were 26.3/100 women at 6 months, 37.3/100 at 12 months, and 42.9/100 at 18 months. The most common reason for discontinuing was a disturbance in bleeding. Heavy and/or prolonged bleeding was the single most frequent reason (6.3/100 women at 12 months), but amenorrhea was not uncommon (5.1/100 women at 12 months), while irregular bleeding or spotting was given as a reason somewhat less frequently (3.9/100 women). 3 women became pregnant during the study, giving a cumulative pregnancy rate of 0.4/100 women at 18 months. A variety of complaints fell within the category of "other medical reasons," the most common being fatigue, headache, and dizziness. The overall discontinuation rates varied markedly by center, as did the reasons for discontinuation. The lowest discontinuation rate of 14.7/100 women at 12 months was seen in the Mohammedpur Fertility Services and Training Center. This rate was considerably lower than that in any other center. The highest discontinuation rate was found by the Bangladesh Association for Voluntary Sterilization -- 52.0/100 women at 12 months. The variation in rate of discontinuation because of bleeding disturbances was most dramatic, with relatively high rates at the Bangladesh Association for Voluntary Sterilization, markedly low rates in the Mohammedpur Fertility Services and Training Centre, and intermediate rates elsewhere. Neither the overall discontinuation rate, nor the individual reasons for discontinuation varied much by age group. The most notable finding regarding discontinuation of NET-EN was the marked difference between centers. This is particularly notable given the lack of any major differences with respect to age, parity, residence, and history of contraception of the subjects. These findings suggest that the specific approach used in each clinic had a considerable impact on continuation rates and acceptance of NET-EN.
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PMID:Introduction of the injectable contraceptive NET-EN into family planning clinics in Bangladesh. 387 43

There have been many reports of late regarding the safety and effectiveness of injectable contraceptives, yet there is still considerable confusion and uncertainty. The attempt is made in this discussion to clarify the issues by outlining the results of recent research in animal and human subjects. The current state of knowledge on injectable hormonal contraceptives is summarized. Attention is directed to the following: injectable preparations available for contraception; animal studies; human studies (pharmacology, effectiveness, bleeding problems, metabolic effects, neoplasia, return of fertility, and effects on progeny). Some data from animal studies have raised concern about the possible carcinogenicity of depot-medroxyprogesterone acetate (DMPA) and norethisterone enanthate (NET-EN), but certain animal models used appear to be inappropriate for studying the effects of these steroids in human subjects. A large number of clinical trials, including multicenter studies organized by the World Health Organization (WHO) have been carried out in many countries with both DMPA and NET-EN. The 2 steroid preparations have a similar mechanism of action in inhibiting gonadotropin production by the pituitary gland, which thus prevents ovulation. They do, however, show certain pharmacological differences. The differences in formulation are reflected in the levels of steroid found in the blood. From both DMPA and NET-EN the continuation rates have been found to vary markedly among different populations, ranging from 15% to nearly 90% at 1 year. Pregnancy rates (method failures) have been consistently low with DMPA, less than 1 pregnancy/100 woman years of use. The pregnancy rate reported with NET-EN has varied according to the interval between injections. A dose of 200 mg every 12 weeks resulted in a pregnancy rate considered to be unacceptably high (3.6/100 woman years) in 1 clinical trial undertaken by WHO. A more frequent administration of NET-EN in the same trial resulted in a pregnancy rate of less than 1/100 woman years at 18 months. The majority of women who receive DMPA or NET-EN experience some disruption of their normal menstrual cycle, defined as a cycle of 26-35 days' duration in which bleeding/spotting lasts for 2-8 weeks. Women frequently report irregular bleeding, spotting, and amenorrhea, but heavy or prolonged bleeding is uncommon. DMPA and NET-EN appear to be acceptable methods of fertility regulation.
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PMID:Facts about injectable contraceptives: memorandum from a WHO meeting. 621 18

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

Irregularity in vaginal bleeding patterns is the most common clinical side effect causing discontinuation of the method reported by the-users of the newer contraceptive methods, especially hormonal ones. An objective assessment of vaginal bleeding pattern is, therefore, critical in evaluation of a new contraceptive method for its acceptance and continued use. The menstrual diary records of women participating in clinical trials of several contraceptive methods undertaken by the Indian Council of Medical Research were analysed. It was observed that the long-acting progestogen-only hormonal contraceptives like levonorgestrel (LNG)-releasing subdermal implants Norplant or intrauterine devices (LNG-IUD) as well as injectable contraceptive NET-EN 200mg given 2 or 3 monthly produced disturbances in bleeding pattern in the majority of their users. Very heavy or prolonged bleeding, a potential health hazard was uncommon and a shift more towards infrequent bleeding was observed. In Norplant-II implants users, 75 to 80% of women had irregularities in bleeding pattern during the first year of use which improved with prolonged use. However, even at 4 years of use, about half of the users of Norplant-II implants continued to have irregular bleeding patterns. The bleeding disturbances occurred in 80% users of 200mg NET-EN injectable contraceptives also during first year of use, however unlike Norplant-II implants users, there was no improvement with prolonged use. Combined monthly injectable contraceptives containing 50mg NET-EN and 5mg estradiol valerate caused less bleeding problems with half of the users experiencing normal pattern during one year of its use. Combined low-dose oral pills, both triphasic and monophasic, produced much better cycle control as compared to any of the other hormonal contraceptive-treated groups; about 90% of combined oral pill users had normal bleeding patterns during one year of method use. The use of copper IUDs was associated with increased bleeding in 18 to 20% of women during the initial period of three months which improved with prolonged use. It was observed that the women having frequent or prolonged bleeding had discontinued the contraceptive method more often as compared to those having delayed bleeding episodes or oligomenorrhoea. However, discontinuation rates due to bleeding irregularities at one year were lower in Norplant-II implants users as compared to other long acting hormonal contraceptive methods such as injectables or IUDs in spite of similar or better bleeding patterns in women using these methods.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Vaginal bleeding patterns of women using different contraceptive methods (implants, injectables, IUDs, oral pills)--an Indian experience. An ICMR Task Force Study. Indian Council of Medical Research. 762 84

Injectable progestogen, norethisterone enanthate (NET-EN, 200 mg/ml) was administered to 122 women at 2 month intervals for more than 1 year. Only a minority of women had consistently normal cycles. Most women experienced some menstrual irregularities: 57% of users experienced irregular bleeding, 32% developed amenorrhea, while only 11% showed regular cyclic bleeding. Important nonmenstrual side effects were weakness and abdominal pain. No appreciable changes in body weight and blood pressure were recorded.
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PMID:Clinical trial of a long-acting injectable contraceptive: NET-EN. 1231 44

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.
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PMID:Statement on injectable contraception. 1233 11