Mesigyna once-a-month combined injectable contraceptive: experience in Latin America.

A phase III clinical study was carried out among 534 fertile Latin American women to evaluate cycle control, side effects, and contraceptive efficacy of a once-a-month combined injectable, Mesigyna, consisting of 50 mg norethisterone enanthate and 5 mg estradiol valerate. The pregnancy rate at 1 year was 0 per 100 woman-years for a total experience of 4688 woman-months. The overall discontinuation rate at one year was 17.9%. Discontinuation rate for bleeding problems was 5.1%. The Colombian women had a significant increase (p <0.001) in bleeding problems compared to other countries. The discontinuation rate for amenorrhea was 1.1%. There were no significant differences between the groups regarding discontinuation for other medical or non-medical reasons. Mean weight gain after one year of use was 1.02 kg. Mesigyna is an appropiate once-a-month injectable contraceptive for Latin American women since it is highly effective and its perception of normal menstrual bleeding is of importance in the Latin American population.

A comparative study on the return to ovulation following chronic use of once-a-month injectable contraceptives.

A comparative study was undertaken involving 21 Mexican women who discontinued the use of medroxyprogesterone acetate 25 mg plus oestradiol cypionate 5 mg (Cyclofem) and norethisterone enanthate 50 mg plus oestradiol valerate 5 mg (Mesigyna) to assess the time required for the return to menses and ovulation. All subjects were exposed to once-a-month injectable contraceptives for two years and were followed for 120 days after the last injection. The urinary concentration of oestrone glucuronide and pregnanediol glucuronide was determined daily in all subjects beginning one month after the last injection. The results disclosed that ovulatory cycles were documented after 120 days of the last injection in six women of each studied group. Similar endometrial bleeding patterns were observed in both groups, indicating that the two drugs have alike pharmacokinetic and pharmacodynamic effects.

PIP: At the family planning clinic of the medical school in Coahuila, Mexico, providers recruited 11 volunteers requesting an injectable contraceptive into Group I (Mesigyna: 50 mg norethisterone enanthate + 5 mg estradiol valerate) and 10 similar volunteers into Group II (Cyclofem: 25 mg medroxyprogesterone acetate + 25 mg estradiol cypionate). After they used the injectables continuously for two years, researchers followed them for 120 days after the last injection. Early morning urine samples were taken every day between day 30 and day 120 after the last injection to measure estrone glucuronide and pregnanediol glucuronide. Researchers also measured the urinary luteinizing hormone level. Normal ovulatory cycles returned within the first to third month after injection in six users from each group. In fact, all but one woman in the Group I had a normal ovulatory cycle during the first month. The other woman had a normal cycle during the second month. During months 1, 2, and 3, the numbers of women in group II who had a normal ovulatory cycle were 3, 2, and 1, respectively. The two groups did not have significant differences in the first bleeding-free interval (51 for Group I vs. 43 for Group II) and in the total number of bleeding/spotting days (11 vs. 14). These findings suggest that long-term use of these injectable contraceptives did not cause chronic inhibition of the hypothalamus-pituitary-ovarian axis and that the ovarian function and the endometrial bleeding patterns returned to normal similarly in both groups. Thus, national family planning programs in developing and developed countries may want to consider offering them as part of the contraceptive mix.

Review of ovulation return upon discontinuation of once-a-month injectable contraceptives.

Once-a-month combined injectable preparations draw their contraceptive efficacy from continuous ovulation suppression. When their use is discontinued, ovulation resumes within a few weeks or a few months, depending on the formulation. After use of the dihydroxyprogesterone acetophenide 150 mg/estradiol enanthate 5 mg combination for one to two years, ovulation returns in most subjects 3-4 months after discontinuation of treatment. Similarly, recent data show that after 2-year use of the depot-medroxyprogesterone acetate 25 mg/estradiol cypionate 5 mg or the norethisterone enanthate 50 mg/estradiol valerate 5 mg combination, approximately 70% women have resumed ovulation by the third month post-treatment. This is shorter than the time for return of ovulation experienced by ex-users of progestogen-only injectable contraceptives.

PIP: This paper reviews the progress made in the determination of ovulation and specifically addresses the effects of returning ovulation after discontinuance of once-a-month injectable contraceptive preparations. Correlation between ovulation and the hormones estrogen, progesterone, and luteinizing hormone (LH) is well documented. It has served as the basis for many studies on determining ovulation mid-point and in evaluating the efficacy, safety, and time of returned ovulation when using various contraceptive methods and preparations. Current monthly injectable contraceptive formulations are discussed and used as comparison for the new generation injectables. New generation contraceptives in this study are preparations (combinations) of several compounds. The depot microcrystalline form of medroxyprogesterone acetate (DMPA) in combination with estradiol cypionate (E2-Cy) was studied. The authors conclude that these initial studies on the new generation combination monthly injectables indicate that these new contraceptives are highly effective in inhibiting ovulation, as well as allowing for predictable return of ovulation.

Long-acting hormonal contraceptives for women.

Following the development and widespread use of oral hormonal contraceptives, it became evident that alternative long-acting delivery systems would be required to improve contraceptive practice in some cultural settings where injectable or subdermal routes of administration are preferred. Nowadays, long-acting contraceptives constitute an important option in family planning services in many parts of the world. Indeed, two long-acting injectable contraceptives containing just a synthetic progestogen (depot-medroxyprogesterone acetate (DMPA) and norethisterone enantate (NET-EN)) have been in clinical practice for more than 20 years. The World Health Organization's (WHO) Special Programme of Research in Human Reproduction, in collaboration with the U.S. National Institute of Child Health and Human Development (NICHD) and universities primarily in developing countries undertook a synthesis programme aimed at producing an improved injectable preparation by developing new derivatives of known steroids. One such compound (levonorgestrel 17-butanoate) is now at the stage of Phase II clinical testing. In addition, the Special Programme has developed and improved once-a-month injectable formulations and assessed their safety and efficacy in different countries worldwide. After large scale clinical testing, at least two progestogen-estrogen combinations have reached the point of introductory trials.

PIP: 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.

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.

[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

Effects of synthetic steroid contraceptives on biliary lipid composition of normal Mexican women.

The effects of two hormonal contraceptives upon the biliary lipid composition of Mexican women were evaluated in a prospective study. Twenty-one healthy volunteers of reproductive age were allocated into three groups (7 subjects each). Group I served as the experimental control (all subjects were bearing a non-medicated IUD), group II received i.m. norethisterone enanthate (NET-e) 200 mg every two months, and group III received an oral combination of 1-norgestrel 150 micrograms and ethinyl estradiol 30 micrograms. The bile lithogenic index as assessed by the relative proportion of cholesterol to bile acids and lecithin was determined in duodenal bile samples obtained before (baseline), during (4 months), and after (12 months) contraceptive administration. The results indicated that NET-e administration resulted in a slight although significant increase of the lithogenic index while the oral formulation did not. The overall data were interpreted as demonstrating that administration of these steroid contraceptives does not constitute a risk factor in terms of gallstone formation in the population studied. The estrogen-like behavior exhibited by NET-e is discussed.

PIP: The effects of 2 hormonal contraceptives upon the biliary lipid composition of Mexican women were evaluated in a prospective study. 21 healthy volunteers of reproductive age were assigned to 3 groups (7 subjects each). Group 1 served as the experimental control (all subjects wore a nonmedicated IUD), group 2 received 200 mg norethisterone enanthate (NET-e) intramuscularly every 2 months, and group 3 received an oral combination of 150 mcg l-norgestrel and 30 mcg ethinyl estradiol. The bile lithogenic index as assessed by the relative proportion of cholesterol to bile acids and lecithin was determined in duodenal bile samples obtained before (baseline), during (4 months), and after (12 months) contraceptive administration. Results indicated that NET-e administration resulted in a slight although significant increase of the lithogenic index while the oral formulation did not. The overall data were interpreted as demonstrating that administration of these steroid contraceptives does not constitute a risk factor in terms of gallstone formation in the population studied. The estrogen-like behavior exhibited by NET-e is discussed.

[Injectable contraceptives. 10 years' clinical experience]. / Anticonceptivos inyectables. Diez años de experiencia clínica.

PIP: 3 parenteral progestogens (medroxyprogesterone acetate, northisterone enanthate, and dehydroxyprogesterone acetophenide with estradiol enanthate, DPA) were studied in 907 women during 14,958 cycles over a 10-year period. The findings are summarized in 9 diagrams. The frequency of the principal side effects - intermenstrual bleeding, amenorrhea, headache, dizziness and nervousness - varied with the different substances. Intermenstrual bleeding and amenorrhea were least serious using DPA. When the injections were administered at the appropriate intervals, the drugs were effective and no pregnancies occurred. After suspending the treatment, the menstrual pattern returned to normal and the endometrium was fully regenerated. To date no fetal abnormalities have been reported after discontinuing the treatment.^ieng

[Histopathological changes of the Fallopian tubes during treatment with norethisterone enanthate]. / Cambios histopatologicos de las trompas de falopio durante el tratamiento con enantato de nor-etisterona.

PIP: Although less distinct than those of the endometrium, the Fallopian tubes show definite changes due to ovarian hormones. The effect of the hormones on the tubes determines certain modifications in their secretions and activities. The estrogens increase the secretions, but progesterone decreases the effect of the estrogens. In the study, a single dose of 200 mgm of norethisterone enanthate was given im on the 6th day of the cycle to 10 patients of fertile age. The effects were studied using conventional histological methods. During the first 6 weeks there was a definite decrease in growth and differentiation of the epithelial cells and gradual recovery toward the end of the 12 weeks of observation. The salpingian mucus in the first 6 weeks indicated a state of rest, similar to that of menopause. This aspect gradually modified itself with the increase in the volume of cells and the appearance of cellular secretions. In the last 2 weeks, cellular hypertrophy, and the appearance of intercalary cells indicated the anatomical and functional recovery of the epithelium. As a possible explanation it was suggested that during the first 6 weeks the action of the estrogens was inhibited, but by the 7th week their proliferative effects became dominant. It is implied that the changes were due to the contraceptive action of norethindrone enanthate.^ieng

[Two years' clinical experience with norethisterone enanthate as a prolonged-action injectable contraceptive]. / Dos anos de experiencia clinica con el enantato de noretisterona como an ticonceptivo inyectable de deposito.

PIP: 1036 patients were treated with norethisterone enanthate as a contraceptive. The drug was found to be highly effective, the failure rate being 1.58/100 woman-years. Protection against unwanted pregnancies lasts for 12 weeks after the injection, and the contraceptive effect is reversible. The menstrual cycle is often affected, especially when the treatment was started during amenorrhea in lactating women. The occurrence of late amenorrhea is relatively rare and always reversible if the treatment is discontinued, while spotting and intermenstrual bleeding tend to decrease after the initial months of treatment. Lactation is generally unimpaired and side effects are minor and usually well tolerated; the drug is well accepted by patients of low socioeconomic level.^ieng

[Mechanism of action of prolonged-action injectable contraceptives]. / Mecanismo de accion de los contraceptivos inyectables de deposito.

PIP: Several parameters were studied to clarify the mechanisms of action of 2 prolonged-action injectable contraceptives: 17alpha-19-hydroxynorprogesterone caproate (with a contraceptive effectiveness of at least 8 weeks) and 19-norethindrone enanthate (effectiveness over 12 weeks). The generally accepted theory of ovulation inhibition was unconvincing. In 14 ovarian biopsies of patients under treatment, taken in the 2nd phase of the cycle, ovulation was evidenced in 11 cases by the presence of corpora lutea. 245 endometrial biopsies showed that the exogenous gestagen effect lasts only 3 weeks; after such period, most endometria could be correlated with the day of the cycle on which they were taken; 2/3 of them suggested biphasic cycles. An evaluation of 240 colpocytograms also confirmed endogenous cyclic activity. In order to explain the prolonged contraceptive effectiveness of the drugs, the cervical mucus was thoroughly studied in 380 cases. A definite, uniform, and constant effect of the progestogen on the mucus was demonstrated, in contrast to the cyclic changes in the other parameters; such effect begins to decline simultaneously with the loss of contraceptive protection. It is suggested that the effectiveness of the 2 drugs is due to changes in the cervical mucus, which affect sperm penetration.^ieng

[Effects of different contraceptives upon the ovulation changes of the morphological study of the ovaries].

PIP: Bilateral ovarian wedges were performed on 46 patients scheduled for laparotomies for medical reasons. Prior to the operation, the patients were divided into 5 groups and treated as follows: 1 for control (5 patients); 1 that was given 1 of 3 different combined oral contraceptives, i.e., Anovlar, Gynovlar, or Engynon (22 patients); 1 that was given Sequens (3 patients); 1 that was injected with 200 mg of norethindrone enanthate (14 cases); and 1 given IUDs (2 cases). It was established that all experienced ovulatory cycles prior to therapy. The laparotomies were done between the 22nd-28th day of the menstrual cycle; hormonal therapy was begun between the 3rd-6th day. All but 1 of the group on combined preparations had anovulatory cycles. Detained follicles Grade 3 or 4 with precocious cystic atresic involution were observed. Of the 3 on the sequential preparation, 2 had involuted cystic corpora lutea and 1 had atresic follicles with thecal luteinization. The patients who received the injectable ovulated. There were no morphological or substantial changes in the corpora lutea of the control and IUD groups.^ieng

[Clinical experience with a prolonged-action injectable hormonal contraceptive]. / Experiencia clinica con un anticonceptivo hormonal inyectable de deposito.

PIP: 207 highly fertile Peruvian women were studied during treatment with a prolonged-action injectable contraceptive, norethindrone enanthate. Using 200 mg doses ever 3 months, there were no pregnancies in 134 patients; in 53 patients receiving the same dose every 4 months 3 pregnancies occurred, which demonstrated the reversibility of the contraceptive action. During the first 3 months, side effects were reported with the usual incidence for oral contraceptives, but they declined to 2.9% after this period of time. Lactation remained unaffected and dysmenorrhea disappeared in most patients. Although the menstrual cycle is often disrupted, there is a spontaneous tendency to return to normalcy.^ieng