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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.

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Two formulations of polylactic and polyglycolic acid microcapsules containing 75 and 100 mg of NET respectively were studied for a 90-day period of anticipated contraceptive effect in two groups of five women. A 200 mg dose of NET preparation was also studied for a 180-day period of anticipated contraceptive effect in 19 women. Alteration in menstrual cycle, with tendency to short bleeding episodes, spotting days, and amenorrhea were the most important collateral effects. In the majority of cases, ovulation was inhibited. No cases of pregnancy were presented. The obtained NET circulating levels were very stable during the period of anticipated contraceptive effect.

PIP: At the Institute of Scientific Investigation of Juarez University of Durango State in Mexico, clinical researchers compared three delivery systems of norethisterone (NET) contraceptive microspheres (biodegradable polymers [e.g., polyglycolic or polylactic acid] containing micronized crystals of NET). In the 6-month system, they injected 800 mg of microspheres containing 200 mg NET intramuscularly into 19 women and then monitored the women for various effects and side effects. Soon after injection, the mean NET level in serum rose to a peak value of about 3 ng/ml and then fell gradually until it was below 0.5 ng/ml at 25 weeks. No pregnancies occurred during this period. Estradiol levels remained well below 100 pg/ml, suggesting inhibition of follicular activity. However, one patient showed an elevation in estradiol at week 16. By 24 weeks, 4 of the 19 women showed signs of the return of follicular activity. Rises in progesterone levels, indicative of ovulation, were not seen in most women during the 6-month period. However, 4 women showed progesterone peaks followed by menstruation in weeks 4, 7, 17, and 23, suggesting that their cycles had begun to return before the end of the 6-month period. 35% of women reported dizziness and nausea. 26% reported nausea. A more serious concern was the disruption seen in the menstrual pattern. 13 women had bleeding and spotting, which continued for 8-30 days in 8 women. In the 3-month system, microspheres containing either 75 or 100 mg NET were injected, each into 5 women. NET levels rose to between 1 and 2 ng/ml and fell to 0.5 ng/ml by week 15. At week 25, they were undetectable. Levels of estradiol remained low for at least 15 weeks as did serum progesterone. No pregnancies occurred. One woman ovulated in week 17. Although no headache, dizziness, and nausea were reported, many of the same disruptions in the menstrual cycle reported in the 6-month study were observed, particularly prolonged cycles, amenorrhea, and spotting. Based on these findings, the researchers deemed the 100 mg for 3 months to be the most safe and effective formulation.

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PIP: After 20 years of clinical experience, injectable hormonal contraceptives such as norethisterone enanthate (NET) and medroxyprogesterone acetate (MPA) remain one of the most controversial methods currently used for temporary control of fertility in women. Since December 1980 this controversy has been accentuated in Mexico with issuing of regulations by the Secretary of Health and Welfare which initially did not permit promotion of long-acting injectable hormones for contraception purposes, and later, in June 1981, a reconsideration which exclusively authorized use of NET as an injectable contraceptive. Undeniably these official measures and the scientific information, occasionally contradictory, have created confusion about the indications and risks of using these formulations in clinical work. This paper presents an anlysis of the basic pharmacological aspects of long-acting contraceptive progestagens, potential risks for side effects, and some clinical rules for safe use. The authors conclude that injectable contraceptives will continue holding a definite place among hormonal methods of temporary fertility control, particularly with the advent of new administration schemes for NET which have elevated its contraceptive efficacy without appreciably increasing complications. The more rapid metabolism of NET, manifested in the absence of significant effects on body weight, less alteration of the menstrual cycle, and more rapid return of fertility after discontinuation, has considerably increased its popularity, and the possibility exists that with time and an increase in clinical experience, it may replace MPA as the injectable contraceptive of choice. Nevertheless, while investigative studies have not clearly defined the possibilities of potential risk of using these contraceptives, its clinical use must be governed by appropriate selection and careful follow-up of patients.^ieng

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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

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PIP: Since recent recommendations advocate that smaller doses of estrogen should be used, a combination of .5 mg of norethindrone and .015 mg ethinyl estradiol was tested on 198 patients for a total of 2546 cycles, the longest usage being over 2 years. The women ranged from 15 to 45 years of age, the average age being 28, and the average number of pregnancies, 5.2. The medication was taken daily for 21 days and then stopped for 7. The group was controlled for secondary effects, bleeding, weight changes, and nucleal or hormonal changes. 14.2% stopped taking it because of secondary problems like spotting, nausea, transhormonal bleeding, and depression. The only pregnancy was due to inadequate attention to the prescription by the patient. Tolerance of the medication was quite good overall and no severe difficulties resulted.^ieng

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PIP: The use of oral contraceptive appears to be associated with alterations in glucose tolerance and slight increases of plasma free fatty acids and triglycerides. In this study, the glucose disappearance constant and the plasma levels of nonesterified fatty acids were studied in 63 women, carefully selected with respect to age (20-30 years), parity (less than 4), normal body weight for height and age, absence of obstetric or family precedents suggesting diabetes mellitus, and absence of other pathological conditions. The oral contraceptive (Norlestrin, Parke Davis) was administered during 1 year, starting between the 7th and 9th week of puerperium. Clinical and laboratory tests were performed before the administration of the drug, and after 3, 6, and 12 months. The number of patients was reduced to 36 at the 1st control, 30 at the 2nd, and 24 at the 3rd. A progressive deterioration of the glucose disappearance constant was observed, with significant differences (p less than .001) between the values before and 12 months after treatment. Diabetic-level values were absent. The plasma nonesterified fatty acids showed a progressive and significant increase, interrupted only during the glucose tolerance tests. There was an average increase in body weight of 4 kg at the 1st control, followed by normalization at the 12th month of treatment. The study discusses the possible causes of such alterations, emphasizing the role of many functi ons that maintain metabolic homeostasis.^ieng

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PIP: The authors observed the changes produced in the endometrium of 20 women who took a daily dose of 350 mcg of norethindrone uninterruptedly, starting on the 1st day of the menstrual cycle. It was found that this dose of norethindrone prevents endometrial development and the endometrium does not reach the stage of full secretion.^ieng

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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

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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

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