Gene/Protein Disease Symptom Drug Enzyme Compound
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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

Final results are presented from a two-year WHO multinational comparative trial of three regimens: depot-medroxyprogesterone acetate (DMPA) given at 90-day intervals, norethisterone enanthate (NET-EN) given at 60-day intervals for the entire study period (NET-EN (60-day)), and NET-EN given at 60-day intervals for six months and thereafter at 84-day intervals (NET-EN (84-day)). 1587 DMPA subjects were observed for 20,550 woman-months, 789 NET-EN (60-day) subjects were observed for 10,361 woman-months, and 796 NET-EN (84-day) subjects were observed for 10,331 woman-months. This clinical trial represents the largest clinical trial undertaken on injectable contraceptives. After two years, the pregnancy rate with NET-EN (84-day) was 1.4 (+/- 0.6 S.E.) per 100 women, as compared with the two-year rates of 0.4 (+/- 0.3 S.E.) per 100 women observed with DMPA and 0.4 (+/- 0.2 S.E.) with NET-EN (60-day). Both discontinuation rates for amenorrhea and the prevalence of amenorrhea lasting more than 90 days were significantly higher with DMPA than with either NET-EN regimen. Terminations for bleeding problems were similar with the three treatments, despite a better cyclic pattern for the first six months with the NET-EN regimens. The three treatments were comparable with respect to discontinuation rates for other medical or personal reasons, and for all reasons combined. For family planning programs, NET-EN (60-day) has the advantage of low pregnancy rates compared to NET-EN (84-day), and a schedule of administration that does not change. Both NET-EN regimens produce less amenorrhea than DMPA. However, the NET-EN (60-day) regimen has the logistic and economic disadvantage of requiring more frequent injections. All three injectable regimens compare favourably with oral contraceptives in terms of pregnancy and total continuation rates observed in clinical trial settings.
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PMID:Multinational comparative clinical trial of long-acting injectable contraceptives: norethisterone enanthate given in two dosage regimens and depot-medroxyprogesterone acetate. Final report. 622 88

Medroxyprogesterone acetate (MPA; 5 micrograms/g body wt) or norethisterone oenanthate (NET-OEN; 4 micrograms/g body wt) was given to lactating female rats by subcutaneous injection 1 day after parturition. Each female suckled ten female pups which had been randomly allocated to her and at 21 days of age the pups were weaned. In this way female pups were exposed to either MPA or NET-OEN via milk during suckling. The patterns of LH and progesterone secretion at pro-oestrus were investigated using radioimmunoassay. When these pups reached adulthood it was found that neonatal exposure to MPA via milk significantly reduced the pro-oestrous LH peak by 45% as well as the total amount (by 27%) of LH secreted during pro-oestrus. Neonatal exposure via milk to NET-OEN had no effect on LH secretion during pro-oestrus. Pro-oestrous progesterone secretion was unaffected by either MPA or NET-OEN treatment.
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PMID:Neonatal exposure to a progestin via milk alters subsequent LH cyclicity in the female rat. 622 92

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

The action of theophylline derivatives (-)-7-2-(2-hydroxy-1-methyl-2-phenyl-ethylamino)-ethyl-theophyl-line (cafedrine) and 7-2-2-(3,4-dihydroxy-phenyl-2-hydroxy-ethylamino)-ethyl-theophylline (theodrenaline) on free fatty acids (FFA) levels in rat blood serum and on cyclic AMP (cAMP) accumulation and FFA mobilization in isolated fat cells has been studied and compared to the action of a noradrenaline plus aminophylline mixture (NAA). A significant in vivo increase of FFA appeared 15 min after NAT and 90 min after NET i.p. administration. NAA was active at both times. Unlike NET, NAT stimulated in vitro FFA mobilization and cAMP accumulation: NAA action was however stronger. NAT-mediated cAMP accumulation, but not that which was NAA-induced, was totally inhibited by timolol. Our results suggest the existence of a beta-adrenergic mechanism for NAT and a tyraminic mechanism for NET. A theophyllinic action dos not seem to apply to either drug.
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PMID:Differences in the lipolytic and cyclic AMP accumulative action of noradrenaline-theophylline and norephedrine-theophylline. 625 57

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

10 Egyptian women who were using the injectable contraceptive norethisterone enanthate (NET-EN) for at least 6 months were monitored weekly for a period of 12 weeks by measuring 3 pituitary hormones (FSH, LH, prolactin) and 2 ovarian hormones (estradiol 17-B and progesterone). It was concluded that NET-EN is a strong ovulation inhibitor, at least after its use for 6 months. Prolactin levels were depressed and this is in contrast to the findings in rats.
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PMID:Blood hormone levels in egyptian women on norethisterone oenanthate. 641 60

In a double-blind randomized trial, 25 women (8-9 weeks pregnant) received 20 mg norethisterone acetate (NET-AC) and 0.04 mg ethinylestradiol (EE2), 25 women receiving placebo. The patients were followed by ultrasound and the products at curettage studied macroscopically and microscopically. In an open trial, ten patients (5-9 weeks pregnant) received NET-AC + EE2, 11 serving as controls. The concentrations of plasma progesterone, estradiol-17 beta, 17 alpha-hydroxyprogesterone, norethisterone, and FSH were followed. The frequency of intrauterine hemorrhage in early pregnancy was not affected by NET-AC + EE2. Ultrasound was not reliable when studying the occurrence of decidual hemorrhages during early pregnancy. The pharmacokinetics and bioavailability of NET remain unchanged during early pregnancy. The treatment with NET-AC + EE2 had no effect on the heights and the time courses of the mean plasma values of progesterone, estradiol-17 beta, 17 alpha-hydroxyprogesterone, and FSH. No differences were found between treated and nontreated patients in the pathology of the placenta or decidua as determined by both macroscopic and microscopic examinations. The hypothesis of Papp and Gardo, that decidual hemorrhages may be induced in early pregnancy as a consequence of a "withdrawal effect" of hormonal pregnancy tests, is not supported by the results of this investigation.
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PMID:Norethisterone acetate and ethinylestradiol in early human pregnancy. 642 76

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


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