A preliminary pharmacokinetic and pharmacodynamic evaluation of depot-medroxyprogesterone acetate and norethisterone oenanthate.

PIP: 2 populations attending WHO centers, one in Sweden and one in India, participated in a comparative, pilot trial of 2 increasingly popular injectable progestin-only female contraceptives, Depo-Provera and Norigest. The purpose of the study was to assess the pharmacokinetic and pharmacodynamic properties of the 2 formulations (depot medroxyprogesterone acetate and norethisterone enanthate). Differences were found between Swedish women and Indian women in their reactions to the 2 drugs: 1) Norigest was detectable in blood samples a significantly shorter time after injection of the agent in Indian women than in Swedish women; this difference was not apparent with Depo-Provera. 2) Although there was no difference at the 2 centers in the time of ovulation return for subjects receiving Norigest, 0 of 4 Swedish women ovulated more than 156 days after Depo-Provera injection, whereas all 4 Indian women ovulated within 73 days of Depo-Provera injection; in the Swedish women, the levels of medroxyprogesterone were undetectable at time of return to ovulation, whereas Indian women had levels of .6 ng/ml when ovulation resumed. 3) In both cultures, Depo-Provera users had significantly more episodes of bleeding and spotting than Norigest users. This preliminary report emphasizes the variety of responses possible to injection of different contraceptive progestins among various populations and points to the need for further culturally comparative studies.^ieng

Serum phospholipid fractionation after the use of long-acting progestational contraceptives.

The effect of the two long-acting progestational contraceptive injection, depot-medroxyprogesterone acetate (DMPA) and norethisterone onenathate (NET-OEN), on blood phospholipid fractions were studied in eighteen women. The post-injection results showed a significant increase in total serum phospholipids, serum lecithin and serum cephalins. Serum lysolecithin was significantly decreased while serum sphingomyelin showed no significant change. The mechanisms responsible for these phospholipid changes remain somewhat unclear. However deranged liver function may share in its explanation.

PIP: Depot-medroxyprogesterone (DMPA) and norethisterone enanthate (NET-OEN) were compared in this study of 18 women using the long-acting injectables for contraceptive purposes. The parameters studied were liver function tests and measurements of serum phospholipid concentrations. Postinjection, a significant increase in total serum phospholipids, serum lecithin, and serum cephalins was reported. However, the investigators were unable to elucidate the mechanisms of these changes; liver function tests were radically altered, and this may provide the key to the serum phospholipid alterations seen in this study (specifically, clearance of bromosulphthalein dye excretion).

Effect of norethisterone enanthate on the blood count and endometrial histology of Indian women.

Endometrial histology and the haematological indices were studied in women receiving 200 mg of norethisterone enanthate (NET-EN) at 60-day intervals for 24 months as a method of contraception. Significant elevations occurred in the haemoglobin concentration and red blood cell counts during one year of therapy, while eosinophil counts showed a transient increase at 4 months of trial. The changes in the haematological indices seem to be due to stimulation of the erythropoietic system by NET-EN and may also be attributable to diminished blood loss due to amenorrhoea during the course of therapy. The endometrial histology revealed proliferative glands at 2 months which turned quiescent at 6-12 months of NET-EN therapy. Long-term use of 18 months showed atrophic changes with few glands, narrow lumina and stromal oedema.

A survey of different approaches to management of menstrual disturbances in women using injectable contraceptives.

This report summarises 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 of these contraceptives. A wide range of approaches are described. The most frequently emphasised aspect of management is thorough pre-treatment counselling with further support and counselling at follow-up visits. Oestrogens in various forms are widely used for the treatment of prolonged, frequent or heavy episodes of bleeding, but nowadays are not usually used for the induction of withdrawal bleeding in women with amenorrhoea. Heavy or "severe" bleeding appears to be very uncommon and figures of 1-2% were frequently mentioned. Anecdotal information suggests that intramuscular doses or longer courses (14-21 days) of oral oestrogen, including the combined pill, are more likely to successfully stop an episode of bleeding than short courses. However, there are no hard data to show that a course of oestrogen treatment has any beneficial effect on long-term 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 very little risk associated with the short-term oestrogen regimens currently used. Dilatation and curettage is almost never necessary to stop an episode of bleeding, but may occasionally be recommended for diagnostic reasons. It is clear that the bleeding disturbances associated with DMPA and NET-EN use are poorly understood and that urgent research is necessary to clarify pathophysiological mechanisms and improve management.

PIP: 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.

Effect of injectable norethisterone oenanthate (Norigest) on blood lipid levels.

Lipid concentrations were measured in 74 blood samples from 61 women who had been using the injectable contraceptive Norigest (norethisterone oenanthate) for between 2 to 4-1/2 years. There were no significant changes in the concentrations of total cholesterol, total triglycerides and low density and very low density lipoprotein cholesterol but high density lipoprotein cholesterol was significantly reduced. The reduction in serum HDL-C levels was not correlated with either the serum norethisterone concentrations or the length of use of Norigest nor was it affected by obesity or smoking.

Serium protein-bound carbohydrate and seromucoid levels during long-acting progestational contraceptive therapy.

PIP: The effect of 2 long-acting injectables on the plasma protein-bound carbohydrate components and serumucoid when taken for different periods, was illustrated in 100 women of childbearing age. 40 acted as controls, 30 took depot-medroxyprogesterone acetate (DMPA), and 30 took norethisterone enanthate (NET-EN). DMPA was given in a dose of 150 mg and NET-EN in a dose of 200 mg im. The 1st injections were given on Day 5 of the menstrual cycles. Repeat injections were given every 84 + or -5 days for a total of 850 cycles. Serum samples were taken while the women were fasting and immediately before the next injection. There was no statistical difference between any group of women using the injectable contraceptives for different periods of 2-8 injections and the controls for protein-bound carbohydrate components. The seromucoid showed a significant decrease in all the groups, as compared with controls.^ieng

Norethisterone enanthate as an injectable contraceptive in puerperal and non-puerperal women.

Norethisterone enanthate (NET-EN) was intramuscularly administered to 5 puerperal women and 20 non-puerperal women for a total of 366 months. Contraceptive effectiveness and side effects of the drug were evaluated. Basal levels of LH, FSH, prolactin (PRL), estradiol 17 beta (E2) and progesterone (P) were measured in blood samples collected from 5 non-puerperal women, while LH, FSH, PRL and norethisterone (NET) plasma levels were evaluated in puerperal women. NET was also assayed in plasma from breast-fed newborns. No woman became pregnant. Side effects consisted of only menstrual abnormalities. Ovulation (P plasma levels higher than 2000 pg/ml) was achieved in 3 patients during the first month of NET-EN treatment but luteal function appeared to be insufficient. In puerperal women, NET plasma levels showed a course similar to the one observed outside puerperium. Lactation was not inhibited, and NET transfer to newborn through milk was negligible, since NET was undetectable in newborn plasma when maximal levels were measured in the mother. It was concluded that NET-EN is an effective contraceptive drug, deprived of major side effects, and particularly useful in women affected by metabolic diseases or during puerperium.

PIP: 5 puerperal and 20 nonpuerperal were treated with intramuscular injections of norethisterone enanthate (NET-EN) for a total of 366 months. Basal hormonal levels were measured in blood samples, and NET was also assayed in plasma from breastfed newborns. There were no pregnancies and only minor menstrual disorders. Lactation was not inhibited in breastfeeding women, and NET transfer to newborn was negligible, even when maximal levels were measured in the mothers. Ovulation was achieved in 3 patients, but with insufficient luteal function. NET-EN seems therefore to be an effective contraceptive, deprived of major side effects, and particularly advisable during puerperium.

A clinical and metabolic study of norethisterone oenanthate in Thai women.

PIP: Norethisterone oenanthate (NET-OEN), an injectable contraceptive preparation containing 200 mg of steroid in 1 ml oily solution, was administered to 126 healthy Thai women of proven fertility (age, 18 to 35) at 8-week and then 12-week intervals. Vaginal bleeding, weight, blood pressure and menstrual bleeding were recorded during each visit, as were complaints and adverse effect. The 12-month continuation rate was 63/100 women-years with 5 accidental pregnancies. There were 2 pregnancies during the 2nd injection interval and 3 other pregnancies during the 3rd, 4th, and 5th injection intervals. Most frequent complaints were spotting, 32.4% and amenorrhea, 26.2%. 3.8% experienced heavy bleeding while 11.2% reported vertigo, nausea and vomiting. There were 11/100 women-years of amenorrhea, and 25/100 women-years of heavy bleeding. A statistically significant increase in the serum glucose tolerance test (p 0.05) was noted after 12 months of use, but the increase was within normal limits. The significant transient decrease in total cholesterol and triglyceride levels observed at the 3rd month of study returned to normal after 6 months.^ieng

Phase IV study of the injection Norigest in Pakistan.

A field study of the injectable contraceptive, norethisterone enanthate (NET-EN), was conducted in family planning clinics in Sind and Punjab provinces of Pakistan, to determine the acceptability and feasibility of providing NET-EN in government family planning clinics staffed by Family Welfare Visitors (FWVs). A total of 2147 women were recruited to the study, of whom approximately three-fourths had never previously used contraception. The overall discontinuation rate at one year was 78 per 100 women; the most common reason for discontinuation was bleeding disturbances, including amenorrhea, although returning to the clinic too late for an injection also accounted for a substantial proportion of the discontinuations. Given adequate training, FWVs were shown to be capable of providing NET-EN in family planning clinics, including managing the bleeding disturbances common with this method of contraception. No pregnancies were reported, demonstrating that the method is highly effective when used in a usual family planning clinic situation.

Multinational comparative clinical evaluation of two long-acting injectable contraceptive steroids: noresthisterone oenanthate and medroxyprogesterone acetate. 2. Bleeding patterns and side effects.

PIP: A WHO sponsored comparative trail (9 centers) studied the bleeding patterns and side effects experienced by 1678 women using injectable (every 12 weeks) norethisterone enanthate (NOR) and depot-medroxyprogesterone (DMPA). 388.8 women-years of menstrual experience with NOR and 372.5 with DMPA were studied. The percentage of women with total amenorrhea with DMPA was significantly higher than with NOR for all injection intervals. The porportion of women with total amenorrhea increased significantly over time with both drugs (chi-square=33.9 for NOR and 73.4 for DMPA; P .001). After 1 year, 35% of DMPA and 8.6% of NOR users had total amenorrhea. With NOR, the cycle length distribution changed markedly over time, with the percentage of short cycles under 25 days diminishing as the percentage of long cycles in excess of 46 days increased. In contrast, DMPA held cycle length patterns more or less constant. Length of bleeding and spotting episodes were significantly greater with DMPA. The mean number of bleeding/spotting days decreased over time with both drugs; the difference from the 1st to 4th injection was statistically significant (P .001). Though the overwhelming majority of women experienced abnormal cycles with both drugs, the percentage of normal cycles remained fairly constant during consecutive intervals. Headache was the most frequently reported complaint: 10.7% of DMPA and 6.9% of NOR users. Other nonmenstrual side effects were reported with similar frequencies in both groups.^ieng

A clinical trial of norethisterone oenanthate (Norigest) injected every two months.

A clinical trial was carried out in which Norigest (200 mg norethisterone oenanthate) was administered by intramuscular injection every 56 days into 383 women studied for 5,521 woman-months of use. No pregnancies occurred. Continuation rates at the end of one, two and three years were 76.6%, 63.7% and 33.8%. Only minor side-effects were recorded. After one year of use, 20.1% women had gained more than 2 kg in weight and 14.8% had lost more than 2 kg. There was marked disruption of the menstrual pattern and irregular bleeding was the major cause of discontinuation. In 38% of the injection intervals analysed, women were amenorrhoeic. Norigest proved an effective and acceptable method of fertility control.

Estrogen-progestogen once-a-month injectable contraceptives and serum prolactin.

To assess the effect of hormonal monthly injectable contraceptives upon the serum values of immunoreactive prolactin (Prl), three groups of women of reproductive age exposed to different estrogen-progestogen injectable formulation for a minimum of one year were studied. The first group (n = 10) received dihydroxyprogesterone acetophenide 150 mg and estradiol enanthate 10 mg (DHPA/E2-EN), Group 2 (n = 21) received medroxyprogesterone acetate 25 mg and estradiol cypionate 5 mg (MPA/E2-C) and Group 3 (n = 19) was exposed to norethisterone enanthate 50 mg and estradiol valerate 5 mg (NET-EN/E2-V). A group of IUD users (n = 16) served as the control group. Serum Prl and 17 beta-estradiol (E2) concentration were determined in blood samples (0 and 15 min.) on days 0 (day of last injection), 10, 20 and 30 after last contraceptive injection. The results demonstrated a slight though not significant increase (p greater than 0.05) in serum Prl in the three experimental groups as compared with the IUD control group. This increase in Prl levels observed on day 10 post-last injection never exceeded the upper limits of the normal range (20 ng/ml). Overall, the data demonstrated that the chronic administration of these estrogen/progestogen once-a-month injectable contraceptives does not affect the Prl baseline secretion in women.

Hemostatic changes in women using a monthly injectable contraceptive for one year.

The effect of consecutively injecting a one-a-month contraceptive (norethisterone enantate 50 mg with estradiol valerate 5 mg) for one year on haematological parameters was evaluated in 42 Chinese women. The healthy volunteers were randomly allocated to either the treatment group (22) or a control group (20). Blood samples were collected in the follicular and luteal phases of a pretreatment cycle, on days 28 +/- 3 after the 1st, 3rd, 6th, 12th injections and in the luteal phase of the post-treatment cycle. The results showed that in both groups, prothrombin time and fibrinogen fluctuated significantly, and leucocyte count was not significantly changed during the whole course. Factor VIII-related antigen and antithrombin III (AT-III) antigen showed minor changes, although in the 3rd treatment cycle, the differences between the two groups in both parameters reached statistical significance. A progressive and significant decrease in Factor X and AT-III functional activity occurred with the monthly injectable treatment, decreasing by about 14% and 20%, respectively, after 12 months of treatment. Haemoglobin levels were increased in the treatment group after the 3rd injection and remained at the higher level during the study period. It is doubtful whether these changes are likely to be of clinical relevance.

Contraception with progestagens in systemic lupus erythematosus.

To test the efficacy and tolerance of progestagens as contraceptives in systemic lupus erythematosus (SLE), 200 mg IM norethisterone enanthate was administered to 10 patients, 0.03 mg/day oral levonorgestrel to 15 patients and they were compared with 18 control patients. There were 4 episodes of active SLE in 48 patient-months on norethisterone enantate and 6 episodes in 122 patient-months on levonorgestrel as compared with 9 episodes of active disease in 298 control patient-months (p = ns). There were no pregnancies and intermenstrual bleeding led to discontinuation of medication in 30% of patients. Progestagens may be an alternative contraceptive method in SLE.

PIP: To test the efficacy and tolerance of progestagens as contraceptives in systemic lupus erythematosus (SLE), 200 mg intramuscular norethisterone enanthate was administered to 10 patients, .03 mg/day oral levonorgestrel to 15 patients; they were compared with 18 controls. There were 4 episodes of active SLE in 48 patient-months on norethisterone enanthate and 6 in 122 patient-months on levonorgestrel as compared with 9 episodes of active disease in 298 control patient-months (p=ns). There were no pregnancies, and intermenstrual bleeding led to discontinuation of medication in 30% of the patients. Progestagens may be an alternative contraceptive method in SLE.

Effect of norethisterone enanthate on endometrial bleeding and changes in coagulation function, ovarian hormones and endometrial histology in Thai women.

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.

The effects of long-acting injectable contraceptives on carbohydrate metabolism.

Carbohydrate metabolism, as assessed by the intravenous glucose tolerance test (i.v.-GTT), was studied in 19 healthy, non-lactating women who received injectable contraceptives containing either medroxyprogesterone acetate (DMPA) (10 subjects) or norethisterone enanthate (Net-En) (9 subjects). Tests were made prior to treatment and at intervals over a period of 15 months thereafter. Results obtained indicate that carbohydrate metabolism is not impaired by either of the two progestogens, and neither pyruvate nor cortisol concentrations changed significantly over the period of observation. However, the insulin release in response to glucose loading underwent interesting alterations during treatment. These abnormalities returned promptly to normal after withdrawal of treatment.

[Use and effectiveness of norethisterone enanthate for family planning in a rural area]. / Uso y efectividad del enantato de noretisterona para la planificación familiar en el área rural.

PIP: The objective of this study was to analyze the acceptability, effectiveness, and continuation of long-acting progestagens in certain sectors of the population where its advantages are more obvious by virtue of certain socioeconomic, cultural, and geographic characteristics, and by lack of availability of family planning services, as in rural areas and urban marginal zones. The study was performed using females of reproductive age residing in rural areas of the Mexican States of Hidalgo, Puebla, and Yucatan between July 1981 and September 1982. Originally the investigation included a total of 462 women, of whom 94 were lost to follow-up, leaving a total of 368 patients (79.6%) with effective follow-up. The contraceptive used was 19-Nor progestagen, norethisterone enanthate (NET), in 200 mg doses administered intramuscularly. The 1st dose was applied between the 1st to the 5th day of the menstrual cycle and each 60 calendar days thereafter. Of a total of 94 discontinuations, 2/3 occurred during the 1st 6 months of the study. The final discontinuation rate was 14.46%. The studied population showed a continuation rate of 85.54% after 12 months of use. Observing rates by reasons for discontinuation, the principal causes in descending order were nonmedical reasons, amenorrhea, pregnancy, bleeding and other secondary effects. The greatest number of discontinuations, considering each particular reason, occurred predominantly during the 1st 6 months of the study. Distribution of users by age group show that more than 2/3 (71.8%) were between 20 and 34 years old. Distribution by number of previous pregnancies show 56.5% with 5 or more gestations. To analyze behavior of menstrual cycles, "cycles" were defined as period of 30 calendar days. Under this concept, more than 2/3 (70.9%) of the users had from 1 to 7 days of bleeding per cycle. On the basis of the results of the study, it is possible to conclude the following: 1) Continuation of NET use is greater than that observed with other long-lasting progestagens. This seems to be especially so when employed in areas where limitations exist for the utilization of other contraceptive means. 2) Contraceptive effectiveness is greater when administration is scheduled at 60 day intervals rather than longer intervals. 3) Unlike other long-acting progestagens, NET conserves the normal menstrual pattern in the majority of users, which favorably influences its continuation.^ieng

[3 months contraception with norethisteronönantate. Clinical and biochemical studies]. / Zur 3-Monats-Kontrazeption mit Norethisteronönanthat. Klinische und biochemische Untersuchungen.

PIP: Clinical experiences and biological parameters with injections of no rethisterone enanthate (200 mg) given at intervals of 84 days in 10 women aged 20-38 years are reported. Total gonadotropin excretion was decreased in 9 patients and urinary pregnanediol decreased by 50% in all patients. Basal temperature levels remained about .5 degrees C higher for 4-6 weeks after injections. Endometrial biopsies revealed proliferation and secretion phases and slight evidence of an anti-estrogenic effect, but atrophic or hyperplastic changes were not seen. The antiestrogenic effect was also observed in the vaginal epithelium. Other biological parameters were considered normal (plasma cortisol rise after ACTH, oral glucose tolerance, protein-bound iodine, serum cholesterol and total lipids, and liver tests). Side effects included cycle irregularities, spotting, breakthrough bleeding, and weight changes of less than 3 kg. No pregnancies occurred.^ieng

Hormonal contraceptive methods.

PIP: This discussion identifies the risks and benefits of each of the hormonal methods of contraception -- combined estrogen-progesterone oral contraceptive (OCs), progestogen-only pills, and depot progestogen injections. It also explains the use of a profile of risk factors in considering the appropriate prescription for each individual in relation to her contraceptive needs. Information regarding medical risks has come from the consideration of mortality rates in large cohort studies. Looking at categories of the causes of 249 deaths in ever-users of the pill and controls, Layde and colleagues were able to show that there was an excess mortality in the pill group of 40% and that the extra risk was concentrated in cardiovascular causes: myocardial infarctions, cerebral thrombosis, and cerebral hemorrhage constituted the largest proportions. A small proportion of combined OC users may develop clinical hypertension but more suffer a reduction in the high-density lipoprotein (HDL) cholesterol fraction of the blood lipids. Both of these effects tend to increase the risk of cardiovascular complications and both are positively related to the dose of the progestogen components. In prescribing combined OCs, attention needs to be paid to further moves away from the norm towards the extremes: the presence of cardiovascular risk factors and the use of certain longterm medications or the presumptive designation as a "rapid metabolizer." An analysis of progestogen only pill (POP) users in the Oxford-Family Planning Association study confirmed the reasonably low rates of accidental pregnancy in POP users. There is a marked reduction with increasing age, and it is significant that many prescribers are now giving POP to older women for whom combined OCs are contraindicated because of cardiovascular risks. It also seems reasonable to use them in women with some medical disorders, for example, recurrent pulmonary embolism, hypertension, and diabetes. Initially, depot injections of progesterone were developed to provide a long-acting or sustained-release type of drug administration to assist users of the progestogen-only method which, unlike combined OCs, does not make use of regular drug-free intervals. In practice it has been found that the effectiveness against pregnancy is enhanced and the side-effects are increased in giving progestogen by depot injection. The 2 preparations currently licensed in Britain are Depo-Provera (medroxyprogesterone acetate) and Noristerat (norethisterone enanthate). In some cases proper and clear information may not have been given to the patient and proper consent not obtained before giving the drug. This problem is magnified because of the occurrence in some women of disturbed bleeding patterns, especially if given immediately after childbirth or an abortion. Also, in a small proportion of users anovulatory amenorrhea may supervene for some months or even as long as 2 years following depot injection.^ieng

Influence of nor-ethisterone enanthate on the structure of ovary, particularly corpus luteum.

PIP: Injectable nor-ethisterone enanthate was studied for it's effect on the ovary in 50 women. 200mg was given between the fifth and seventh day of the menstrual cycle. Endometrial biopsy and cervical mucus study were done on each woman throughout treatment. Ovulation was suppressed in 7 cases. In 10 cases 1 aporotomized in the first month of treatment, all 10 had ovulated. In the second and third months, out of 40 women, 34 had a corpus luteum. The antiovulatory effect of the drug was very weak. The corpora lutea were poorly developed.^ieng