Forearm bone density in users of Depo-Provera as a contraceptive method.

OBJECTIVE: To determine the influence of depot medroxyprogesterone acetate (MPA) on bone mineral density when used as a contraceptive method. DESIGN: Cross-sectional study. SETTING: Academic tertiary-care hospital. PATIENT(S): Fifty premenopausal women who had used depot MPA as a contraceptive method for > or =1 year and 50 women who had never used hormonal contraceptive methods. INTERVENTION(S): Bone mineral density was evaluated at the midshaft and at the distal radius of the nondominant forearm using single x-ray absorptiometry. MAIN OUTCOME MEASURE(S): Bone mineral density. RESULT(S): Bone mineral density at the midshaft of the forearm was lower in depot MPA users than in women who had never used hormonal contraceptive methods, but the difference was not statistically significant. At the distal portion, bone mineral density was significantly lower in the study group. The duration of depot MPA use was not related to bone mineral density. CONCLUSION(S): Women > or =35 years of age presented with a lower bone mineral density only at the distal portion of the forearm after the use of depot MPA for > or =1 year. However, this decrease was not related to the duration of depot MPA use. It is not possible to conclude that women who use depot MPA are at risk of osteoporosis.

PIP: The impact of depot medroxyprogesterone acetate use on bone mineral density was assessed in a cross-sectional study of 100 women recruited from a teaching hospital in Campinas, Brazil, during 1996-98. Bone mineral density, as evaluated at the midshaft and distal radius of the nondominant forearm by single x-ray absorptiometry, was compared in 50 women 35-45 years of age who had been using Depo-Provera for contraception for 1 year or more (mean duration, 46.4 +or- 38.6 months) but had never used any other hormonal method and 50 age- and weight-matched women who had never used any form of hormonal contraception. Although mean bone mineral density at the midshaft of the forearm was lower in Depo-Provera users than nonusers of hormonal contraception (0.459 +or- 0.042 vs. 0.474 +or- 0.049 g/sq. cm), the difference was not statistically significant. At the distal portion, bone mineral density was significantly lower in Depo-Provera users than nonusers of hormonal methods (0.362 +or- 0.040 vs. 0.392 +or- 0.049 g/sq. cm, p 0.001). The duration of Depo-Provera use was not related to bone mineral density, even when women had used the method for more than 5 years. Multiple regression analysis indicated that 4 pregnancies, White race, and Depo-Provera use were significantly associated with lower bone mineral density at the midshaft section of the forearm; at the distal section of the forearm, these variables were Depo-Provera use, more than 4 pregnancies, White race, older age at menarche, and habitual coffee drinking. These findings do not provide sufficient evidence to conclude that Depo-Provera users are at increased risk of osteoporosis.

Multicenter, double-blind, comparative clinical study on the efficacy and acceptability of a monthly injectable contraceptive combination of 150 mg dihydroxyprogesterone acetophenide and 10 mg estradiol enanthate compared to a monthly injectable contraceptive combination of 90 mg dihydroxyprogesterone acetophenide and 6 mg estradiol enanthate.

Healthy, regularly menstruating women, aged 14-38 years, were enrolled in a comparative, double-blind, phase III, clinical trial to evaluate the contraceptive efficacy and acceptability of a combination of 90 mg dihydroxyprogesterone acetophenide with 6 mg estradiol enanthate compared to the commercially available contraceptive combination of 150 mg dihydroxyprogesterone acetophenide with 10 mg estradiol enanthate. Subjects received the contraceptive combination intramuscularly, between the 7th and 10th day of each menstrual cycle, during 12 consecutive menstrual cycles. Approximately 60% of the subjects in both groups completed the study. Principal reasons for discontinuation were personal, nonmedical reasons. Principal medical reasons for discontinuation were menstrual-related, irregular bleeding being the most frequent. Differences in menstrual patterns between the two groups did not lead to differences in discontinuation rates. Three contraceptive failures occurred during the trial, one in Group A (90/6 mg) and two in Group B (150/10 mg), indicating that the lower dose formulation is at least as efficient as the higher dose.

Results of a user satisfaction study carried out in women using Uniplant contraceptive implant.

A study of the acceptability of Uniplant, a 12-month single implant of nomegestrol acetate, included 819 women from Africa, Latin America, and China, participating in a clinical trial of Uniplant. A standard, pre-coded questionnaire was specially designed for this purpose and applied at the moment of removal of implant, either at the end of 12 months of use or at the time of discontinuation for whatever reason. The level of satisfaction proved high when users' comparison with their previous contraceptive method, users' recommendation of Uniplant to others, users' intention to use the method in the future, and service satisfaction were taken into consideration. Uniplant was considered easy to use, safe (low risk of pregnancy), and also to cause fewer side effects than other methods. When asked about the least liked feature of Uniplant, almost half the respondents said that there was nothing that they disliked and about one-third mentioned the changes in their menstrual pattern. However, according to the clinical trial, over half of the Uniplant users have bleeding patterns similar to untreated cycles. The majority of respondents did not feel any discomfort during the procedure of insertion and removal of the implant. About 70% of patients in the study stated that they required contraception for more than one year and most of these women said that they did not mind having to change the implant every year.

[Contraceptive use in women with heart disease]. / Uso de contraceptivos em portadoras de cardiopatia.

PURPOSE: To analyse efficacy, tolerance and adverse events of reversible contraceptives in women with cardiac disease. METHODS: We studied prospectively during 24-39 (mean = 29) months, 89 women with heart disease with a mean age of 25.6 (16-42) years. Rheumatic heart disease was present in 73 (82%) cases, congenital heart disease in 11 (11%), coronary artery disease in 2 (2%) and cardiomyopathy in 3 (3%) case. The patients were divided in three groups: GCO--35 patients taking combined oral contraceptives (30 micrograms ethinyl estradiol and 75 micrograms gestodene--COs); GIT--27 using injectable progestagens (depot medroxyprogesterone acetate-DMPA) and GUID--27 with intrauterine device (IUD). RESULTS: In GCO occurred 4 (11.4%) cases of arterial hypertension, 1 (2.8%) of a transient cerebral isquemic attack, 3 (8.5%) of spotting, 1 (2.8%) of amnorrhea e 1 (2.8%) pregnancy. Interruption of this method occurred in 4 (11.4%) cases due to hypertension (2), pregnancy (1) and amenorrhea (1). In group GIT there were 2 (7.4%) cases of arterial hypertension, 18 (66.6%) of amenorrhea, and 3 (11.1%) of spotting. Interruption of use occurred in 5 (18.5%) due to amnorrhea (2), weight gain (2) and headache (1). In GUID there was 1 (3.7%) case of infeccion, 1 (3.7%) pregnancy and 1 (3.7%) spontaneous expulsion of IUD. Interruption of use took place in 3 (11.1%) cases due to infeccion, pregnancy and expulsion. The comparation between the groups demonstrated a difference in the incidence of amenorrhea (p < 0.005) and descontinuation of use of the method (p < 0.025). CONCLUSION: Use of reversible contraceptives in heart disease women was associated with an acceptable cardiovascular risk. Efficacy and side effects of the methods were comparable in the groups, however intolerance was more observed in GIT.

PIP: The aim of this study was to analyze efficacy, tolerance, and adverse events of reversible contraceptives in women with cardiac disease. The authors studied prospectively, during a period of 24-39 (mean = 29) months, 89 women with heart disease of mean age 25.6 (16-42) years. Rheumatic heart disease was present in 73 cases (82%), congenital heart disease in 11 (11%), coronary artery disease in 2 (2%), and cardiomyopathy in 3 (3%). The patients were divided into three groups: GCO--35 patients taking combined oral contraceptives (30 mcg ethinyl estradiol and 75 mg gestodene); GIT--27 patients using injectable progestagens (depot medroxyprogesterone acetate); and GUID--27 patients with IUDs. In the GCO group were found 4 cases (11.4%) of arterial hypertension, 1 (2.8%) of a transient cerebral ischemic attack, 3 (8.5%) of spotting, 1 (2.8%) of amenorrhea, and 1 (2.8%) of pregnancy. Interruption of this method occurred in 4 cases (11.4%): 2 due to hypertension, 1 due to pregnancy, and 1 due to amenorrhea. In the GIT group there were 2 cases (7.4%) of arterial hypertension, 18 (66.6%) of amenorrhea, and 3 (11.1%) of spotting. Interruption of use occurred in 5 cases (18.5%): 2 due to amenorrhea, 2 due to weight gain, and 1 due to headache. In the GUID group there was 1 case (3.7%) of infection, 1 (3.7%) of pregnancy, and 1 (3.7%) of spontaneous expulsion of the IUD. Interruption of use took place in 3 cases (11.1%): 1 due to infection, 1 due to pregnancy, and 1 due to expulsion. The comparison between the groups demonstrated a difference in the incidence of amenorrhea (p 0.005) and method discontinuation (p 0.025). Use of reversible contraceptives in women with heart disease was associated with an acceptable cardiovascular risk. Efficacy and side effects of the methods were comparable in the groups; however, intolerance was observed more in the GIT group. (author's modified)

Bleeding complaints during the first year of norplant implants use and their impact on removal rate.

The frequency of bleeding complaints during the first year of use and their influence on removal rate were analyzed in a retrospective cohort study of 491 Norplant implants acceptors. Removal rates were significantly higher in women having menstrual complaints (1.98% and 29.23% in the first and fourth trimester) than in those who did not mention them (0.79 and 5.07% in the same periods). In all periods of observation, most women who mentioned menstrual problems decided to continue using the method. Two possible explanations for this are that 1) the complaints did not persist for very long, and 2) the most frequent complaint mentioned was bleeding irregularity, which was not as strongly associated with removals as increased or decreased bleeding. The authors conclude that bleeding problems are the most important factor limiting the acceptability of Norplant implants, either being the main reason for removal (3.9 per 100 women) or influencing the rate of removal for other reasons. Adequate counseling appears to be critical for reducing the impact of bleeding problems on removal rates, and thereby increasing the acceptability of the method. The importance of research aimed at preventing or treating menstrual problems to improve the acceptability of the method is emphasized.

NORPLANT: levonorgestrel-releasing contraceptive implant.

NORPLANT is the newest contraceptive system to be introduced world-wide, with nearly a million current users. It consists of six Silastic capsules containing levonorgestrel (LNg), which are inserted under the skin in the arm. Release of the steroid commences immediately so that, after several weeks, circulating levels of LNg stabilize between 0.3 and 0.4 ng/ml of plasma, and they persist elevated with a minor decline for over 5 years. The gross cumulative pregnancy rate at 5 years is 2.6 per 100 woman-years. In the majority of women it produces no abnormalities in a variety of clinical chemistry, metabolic, haematological and coagulation parameters. The most common side-effect is disruption of the menstrual bleeding pattern; this is reported by two-thirds of the users in the first months and by one-third by the fifth year. Because it is the most disturbing side-effect for many users, counselling prior to insertion is of paramount importance. NORPLANT exerts varying degrees of gonadotrophin and ovarian inhibition, including anovulation and luteal insufficiency. Endometrial development is irregular and, irrespective of oestrogen levels, cervical mucus is thick and scanty at all times due to the strong antioestrogenic effect of LNg. Inhibition of sperm penetration fully accounts for the antifertility effect of NORPLANT in ovulatory cycles. The high contraceptive efficacy, lack of serious side-effects, reversibility and the convenience of long-term unattended use explain the high acceptability of NORPLANT.

Are Norplant, Depo-Provera good options for nursing mothers?

PIP: Family planning providers do not agree on whether it is good clinical practice to administer Norplant or Depo-Provera to mothers shortly after delivery. Manufacturers of both contraceptives recommend that providers not prescribe them before 6 weeks postpartum for lactating mothers. The hormones enter the breast milk, but the amount is minimal, and no studies show the small amount of hormones to be harmful. Some providers point to this lack of data as a reason to prescribe them to mothers immediately after delivery because progestin-only pills do neat adversely affect breast feeding. Some providers even claim Norplant should be inserted no later than 3 weeks. On the other hand, other providers, like a physician from Chile, stress that the lack of studies does not mean it is safe, just that there have not been enough studies. The Chilean physician is investigating the effect of hormones on infant health and central nervous system development. A nurse midwife at the University Medical Center in Jacksonville, Florida, reports that no woman using Depo-Provera has complained of breast-feeding problems. More than 50% of postpartum women leave this hospital after receiving an injection of Depo-Provera and those who do not come back for their 3-month injection are those who did not receive proper prenatal counseling about its side effects. The most upsetting side effect is bleeding which becomes less stressful with adequate counseling. Depo-provera extends the normal postpartum bleeding by a month. A director of services at a family planning clinic in San Marcos, Texas, notes that proper counseling, both before insertion and before removal, is also the key to proper management of Norplant acceptors. Providers at this clinic insert it 6 weeks postpartum. Hispanic women in San Marcos are concerned about bleeding because their partners do not want to have sex with a bleeding partner. Another side effect concerning clients is weight gain.^ieng

A comparative study of a progestin-only oral contraceptive versus non-hormonal methods in lactating women in Buenos Aires, Argentina.

A non-randomized comparative clinical trial of the progestin-only oral contraceptive (POC), Ovrette (75 mcg norgestrel) (Wyeth), versus non-hormonal methods was conducted at two clinics in Buenos Aires, Argentina. The trial was designed to assess the breast-feeding patterns of women choosing progestin-only oral contraception and non-hormonal methods of contraception, and to study the relationship between lactation and the clinical performance of a POC. Five-hundred women were allocated to either the progestin-only pill group (n = 250) or to the non-hormonal group (n = 250) and were followed up monthly for six months after admission. Measurements in mean infant weight, mean infant length, and mean head circumference were similar throughout the follow-up period. Non-hormonal users reported significantly more self-perceived decreases in milk production at the 5th and 6th month follow-up intervals. Acceptance and continued use of the pill were excellent, with only one woman discontinuing because of a pregnancy which was attributed to user failure. The principal side effect reported by women in both groups was intermenstrual bleeding.

PIP: A nonrandomized, comparative, clinical trial of the progestin only oral contraceptive (OC) Ovrette (75 mcg norgestrel) vs. nonhormonal methods was conducted at 2 clinics in Buenos Aires, Argentina. The trial was designed to assess breast-feeding patterns of women choosing progestin- only OCs and nonhormonal methods of contraception and to study the relationship between lactation and the clinical performance of the OC. 500 women were allocated to either the progestin-only pill group (n=250) or t o the nonhormonal group (n=250) and were followed monthly for 6 months after admission. Measurements in mean infant weight, mean infant length, and mean head circumference were similar throughout the follow- up period. Nonhormonal users reported significantly more self-perceived decreases in milk production at the 5th an 6th month follow-up intervals. Acceptance and continued use of the pill were excellent, with only 1 women discontinuing because of a pregnancy which was the result of user failure. The principal side effect reported by women in both groups was intermenstrual bleeding.

Ovulatory dysfunction during continuous administration of low-dose levonorgestrel by subdermal implants.

OBJECTIVE: To study the endocrinologic profile of regularly menstruating users of levonorgestrel subdermal implants. DESIGN: Observational, prospective, case-controlled comparative study. SETTING: The Family Planning Clinic of PROFAMILIA, in Santo Domingo, Dominican Republic. PATIENTS, PARTICIPANTS: Thirty one regularly cycling Norplant users and 12 nonhormonal contraceptors who volunteered to participate. INTERVENTIONS: Norplant contraceptive implants were inserted in 31 subjects between 13 and 77 months before this study. MAIN OUTCOME MEASURES: Follicle-stimulating hormone, luteinizing hormone, estradiol (E2), and progesterone (P) were serially assayed for one menstrual cycle. RESULTS: Almost half of the cycles among Norplant users were anovulatory; all the rest (55%) had some form of dysfunction: diminished gonadotropin surge, luteal phase insufficiency (low P levels and shortened luteal phase), and E2 profiles different from normal controls. CONCLUSIONS: Anovulation is clearly one of the main mechanisms of action of Norplant, but even in presumptive ovulatory cycles, the dysfunctions described possibly contribute to the high contraceptive effectiveness of Norplant.

PIP: The study sought to examine the endocrinologic profile of regularly menstruating users of levonorgestrel subdermal implants. This observational, prospective, case-controlled, comparative study occurred at the Family Planning Clinic of PROFAMILIA in Santo Domingo, Dominican Republic. 31 subjects agreed to receive Norplant contraceptive implants between 13-77 months prior to this study and there were 12 nonhormonal contraceptors who also volunteered to participate. Follicle stimulating hormone, luteinizing hormone, estradiol (E2), and progesterone (P) were serially assayed for 1 menstrual cycle, and almost 1/2 of the cycles of norplant acceptors were anovulatory: the remainder (55%) had some form of dysfunction such as diminished gonadotropin surge, luteal phase insufficiency (low P levels and shortened luteal phase), and E2 profiles different from controls. Anovulation is clearly 1 of the main mechanisms of Norplant action, but even in presumptive ovulatory cycles, the dysfunctions described could have contributed to the high contraceptive effectiveness of Norplant.

[Effectiveness and safety of a new combined oral contraceptive containing 75 micrograms gestodene and 30 micrograms ethinyl estradiol in Mexican women]. / Efectividad y seguridad de un nuevo preparado anticonceptivo oral combinado 75 mcg gestodeno mas 30 mcg etinilestradiol en mujeres mexicanas.

PIP: 69 healthy Mexican women using a new oral contraceptive (OC) containing 75 mcg of gestodene and 30 mcg of ethanol estradiol participated in a prospective study of the safety and efficacy of the method. All participants were evaluated on the s cycle day before beginning use and were questioned monthly about side effects and menstrual bleeding. 10 of the women were evaluated for cholesterol and triglyceride levels before use and after 4 and 8 months. The average age of the participants at admission into the study was 23.4 years. There were no pregnancies in 613 woman-months of use. The average blood pressure was 113.8 + or - 6.9 over 76.7 + or - 7.0 before use and 112.6 + or - 9.2 over 73.8 + or - 7.8 after 12 months of use. The average weight was 55.9 + or - 9.6 kg before use and 55.5 + or - 8.8 after 12 months of use. In the 1st treatment cycle 8 women reported spotting and 3 reported intermenstrual bleeding; the number reporting these signs gradually declined. The number reporting side effects was small and declined after the 1st treatment cycle. Dysmenorrhea declined significantly after the 1st cycle. The crude rate of termination was 44.9% after 1 year. 8 women (11.6%) terminated method use for reasons related to the method, including 2 for nausea and vomiting, 1 for nausea and dizziness, 2 for amenorrhea, and 1 each for intermenstrual bleeding, spotting, and increased blood pressure. Among the 10 women whose lipid and lipoprotein levels were tested, the average levels before and after 8 months respectively were 162.5 + or - 27.0 and 182.3 + or - 35.8 for total cholesterol, 86.5 + or - 29.5 and 120.0 + or - 45.0 for triglycerides, 45.7 + or - 9.3 and 60.6 + or - 6.5 for HDL cholesterol. In general these changes were not significant despite the tendency to increase especially of the triglycerides. The method thus appears to offer advantages for temporary fertility control among Mexican women.^ieng

Mini-pill in lactating women.

A non-comparative study of the progestogen-only oral contraceptive, norgestrel 0.075 mg, in breast-feeding women was conducted at the Centro de Investigaciones Regionales, Merida, Yucatan, Mexico. The study was designed to evaluate the overall acceptability and contraceptive efficacy of norgestrel in breast-feeding women. This report includes a survey of 200 women, all of whom were less than 26 weeks postpartum at admission; 113 were interval patients and 87 were postpartum. Follow-up visits were scheduled at 2, 6 and 12 months after admission. Overall, women experienced an increase in intermenstrual bleeding, amenorrhea, vaginal discharge and breast discomfort. The discontinuation rate at 12 months was 32.5 and the corresponding lost to follow-up rate was 22.5; this is a measure of acceptability. The 12-month life-table rate for pregnancy was 3.4 with a standard error of 2.0. Three women discontinued use of the mini-pill due to accidental pregnancy. One pregnancy was attributed to user failure and the woman conceived 9 months after entering into the study; the other two were attributed to method failure, one woman conceived 3 months after admission and the other conceived 6 months after admission.

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.

Cervical cancer risk and use of depot-medroxyprogesterone acetate in Costa Rica.

The relationship between cervical cancer and the use of depot-medroxyprogesterone acetate (DMPA) was examined in a nationwide case-control study in Costa Rica. Cases were women ages 25-58 years of age with invasive squamous cell cancer (N = 149) or carcinoma in situ (CIS, N = 415) reported by the National Tumor Registry during 1982-84. Controls (N = 764) were randomly selected during a nationwide household survey. Using logistic regression, we adjusted for known risk factors for cervical cancer. DMPA use was associated with a risk of CIS of 1.1 (95% confidence interval 0.6-1.8) and a risk of invasive cancer of 1.4 (95% confidence interval 0.6-3.1). The slightly elevated risks observed may be the result of chance or a detection bias. One limitation of this study is that few women had used DMPA for longer than two years.

PIP: A nationwide case-control study was conducted in Costa Rica in 1984-85 to examine the association between depot-medroxyprogesterone acetate (DMPA) and cervical cancer. Cases, restricted to women 25-58 years of age at the time of diagnosis, were women with invasive squamous cell cancer (n = 149) or carcinoma in situ (CIS, n=415) reported by the National Tumor Registry during 1982-84. The 764 controls were randomly selected during a nationwide household survey. On average, the CIS cases were younger than controls; the invasive cases were older than controls. Both case groups were more likely than controls to be of low socioeconomic status, to have become sexually active at a young age, to report a history of a sexually transmitted disease or pelvic inflammatory disease, and to report having 3 or more partners in their lifetime. Ever users of DMPA had a risk of CIS of 1.1 when compared with never users. Women who 1st used DMPA before age 30 had a CIS risk of 0.6 whereas users who began use after age 39 had a risk of 2.0. Both of these risk estimates were based on small numbers of users. Ever users of DMPA had a risk of invasive cancer of 1.4 when compared with never users, but all estimates for invasive cancer were based on only 10 cases who reported use of DMPA. Few of the women had used DMPA for longer than 2 years.

Norethisterone contraceptive microspheres.

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.

[Oral contraceptives and metabolic changes]. / Anticonceptivos orales y alteraciones metabólicas.

PIP: Sufficient evidence has accumulated to relate oral contraceptives (OCs) to various cardiovascular diseases in which metabolic alterations play a role. Although epidemiological studies have shown OC users to be at greater risk of venous thrombosis than nonusers, blood coagulation studies of OC users have yielded conflicting results due to variations in the methodologies used, the factors studied, the different formulations and doses of OCs, and the duration of use. Moreover, no satisfactory method exists of measuring coagulability in its totality, which is the sum of the effects of individual variations in coagulation factors, fibrinolysis, and platelet function. Numerous studies have shown that OC users have increased levels of several coagulation factors, which are believed to indicate hypercoagulability and increased risk of thrombosis, but the pathogenesis of venous thrombosis is complex. Accompanying changes in the fibrinolytic system can be interpreted as attempts to equilibrate the hypercoagulability induced by OCs. Further, there is no proof that in vitro changes are related to thrombosis in vivo. The alterations appear to be dose-related, produced primarily by estrogens, unrelated to duration of use, and to disappear a few months after termination of OC use. OC users have been shown repeatedly to have elevated levels of glucose and insulin, which are especially pronounced in glucose tolerance tests. The changes vary in intensity according to the dose and progestational components and the existence of other risk factors for diabetes. Deterioration of glucose tolerance appears related to duration of OC use, but serum insulin levels maintain the same initial elevations. The estrogens have been shown to have few effects on carbohydrate metabolism in the lower doses currently used. Norgestrel has the most marked effects on glucose and insulin levels, ethynodiol diacetate has moderate effects, and norethindrone has the least effect. The combination of .15 mg levonorgestrel and 30 mcg ethinyl estradiol has no effect on oral glucose tolerance and little effect on insulin secretion. It is hypothesized that OCs affect carbohydrate metabolism by decreasing the number and affinity of insulin receptors in target tissues. The mechanisms by which OCs produce undesirable effects on the cardiovascular system are not completely understood, but are believed to be related to alterations in lipid metabolism. The majority of laboratory studies have shown that OC users had elevated levels of cholesterol, triglycerides, and the (LDL) fractions, and a diminution of the high density lipoprotein (HDL) fraction, which has antiatherogenic properties. The changes are atherogenic in nature and produce a lipid profile similar to that of men and postmenopausal women, who are at greater risk of thrombotic cardiovascular disease that premenopausal women who are protected by estrogens. .^ieng

Invasive cervical cancer and depot-medroxyprogesterone acetate. WHO Collaborative Study of Neoplasia and Steroid Contraceptives.

Preliminary results of a study of the possible relationship of depot-medroxy-progesterone acetate (DMPA) to invasive cervical cancer are presented. The findings are based on data from three participating centres in Thailand and one in Mexico. A relative risk for cervical cancer of 1.2 was observed in women who had ever used DMPA; this was not statistically significant. No consistent increase in risk with duration of use was observed, although a relative risk of 2 was found in women who had used DMPA for more than 5 years. This observed increase in risk was confined to women who were aged under 46 years or who had first been exposed to DMPA before 30 years of age. These findings are based on small numbers of subjects, and may not represent a causal relationship.

Breast cancer and depot-medroxyprogesterone acetate. WHO Collaborative Study of Neoplasia and Steroid Contraceptives.

The preliminary results of a study of the incidence of breast cancer in relation to use of depot-medroxyprogesterone acetate (DMPA) are presented. The findings are based on data from three participating centres in Thailand, and one each in Kenya and Mexico. A relative risk for breast cancer of 0.7 was observed in women who had ever used DMPA; this was not statistically significant. Although no consistent decrease in risk with duration of use was observed, the lowest relative risk (0.5) was observed in women who had used DMPA for three or more years. These findings are based on small numbers and must be considered preliminary. However, they provide no evidence that DMPA increases the risk of breast cancer, and suggest that it may exert a protective effect, particularly in long-term users.

[Injectable contraception using depot progestagens]. / Anticoncepción inyectable con progestágenos de depósito.

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

[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

[Prolonged use of medroxyprogesterone acetate for contraception]. / Uso prolongado del acetato de medroxiprogesterona en la anticoncepcion.

PIP: 1025 women who had used Depo-Provera 150 mg injections for contraception for 3-8 1/2 years were studied to assess the effects of prolonged use. 24.4% were aged 25-29, 33.7% were 30-34, 25.1% were 35-39, 11.2% were 40-44, and the rest were 24 and under. 47.2% had had 5-8 pregnancies and 36.3% had had 9 or more. 78.3% had had at least 5 births. 93.4% had menstrual cycles averaging 26-32 days before treatment. 74% had used no previous contraception, 18.9% used oral contraceptives (OCs), .9% used a monthly injectable, 2.9% used another trimonthly injectable, 3.1% used IUD, and .1% each used condoms and rhythm. 58.6% had amenorrhea while using Depo-Provera and 73.5% of the others had short bleeding episodes of 1-2 days. 62% of 92 endometrial biopsies indicated varying degrees of endometrial atrophy. 5 cases of benign breast adenomas were confirmed by biopsy. 71 women complained of moderate breast tenderness. No cases of breast cancer were observed. 73% gained and 9.2% lost at least 1 kg in weight. No significant changes in blood pressure were noted. The proportion of women reporting inorgasmic sexual response increased from 50.3% at the beginning of use to 75.3% after 12-38 doses of Depo-Provera. 3 pregnancies occurred, 2 possibly resulting from faulty injection technique. A follow-up study of 80 former users for 1 year showed that 39 of 58 cases of amenorrhea resumed menses in an average time of 8-9 months, and 19 did not resume menstruation. 10 of 48 with weight changes did not return to the former weight. Nervousness, amenorrhea, and acne were the symptoms requiring the longest time to disappear. 29 of 46 women complaining of frigidity and 2 of 15 complaining of dyspareunia failed to improve. 11.2% of the 80 women terminated use to achieve pregnancy. Other factors were amenorrhea (72.5%), weight gain (60%), edema (50%), nervousness (45%), sexual problems (81.2%), and hypertension (3.7%).^ieng