Metabolic effects of the contraceptive skin patch and subdermal contraceptive implant in Mexican women: a prospective study.

BACKGROUND: The contraceptive skin patch (CSP) accepted by the U.S. FDA in 2001 includes ethinylestradiol and norelgestromine, whereas the subdermal contraceptive implant (SCI) has etonogestrel and is also approved by the FDA. In Mexico, both are now widely used for contraception but their effects on Mexican population are unknown. The objective of the study was to evaluate if these treatments induce metabolic changes in a sample of indigenous and mestizo Mexican women. METHODS: An observational, prospective, longitudinal, non-randomized study of women between 18 and 35 years of age assigned to CSP or SCI. We performed several laboratory tests: clinical chemistry, lipid profile, and liver and thyroid function tests. Also, serum levels of insulin, C-peptide, IGF-1, leptin, adiponectin, and C reactive protein were assayed. RESULTS: Sixty-two women were enrolled, 25 used CSP (0 indigenous; 25 mestizos) and 37 used SCI (18 indigenous; 19 mestizos). Clinical symptoms were relatively more frequent in the SCI group. Thirty-four contraceptive users gained weight without other clinical significant changes. After 4 months of treatment, significant changes were found in some biochemical parameters in both treatment groups. Most were clinically irrelevant. Interestingly, the percentage of users with an abnormal atherogenic index diminished from 75% to 41.6% after follow-up. CONCLUSIONS: The CSP slightly modified the metabolic variables. Most changes were nonsignificant, whereas for SCI users changes were more evident and perhaps beneficial. Results of this attempt to evaluate the effects of contraceptives in mestizo and native-American populations show that clinical symptoms are frequent in Mexican users of CSP and SCI. Although these medications may affect some metabolic variables, these changes seem clinically irrelevant. Induction of abnormalities in other physiological pathways cannot be ruled out.

[Combined hormonal contraception in cycles artificially extended]. / Anticoncepción con hormonales combinados en ciclos extendidos artificialmente.

OBJECTIVE: To compare the bleeding patterns, satisfaction and tolerability of 3 different contraceptive in an extended regimens in the service of Family Planning of the North Central Hospital of PEMEX. MATERIAL AND METHODS: Healthy, adult women with desire of contraception for one year (N 120) were randomly assigned to receive oral contraceptive drospirenone/ethinyl E2 (group1), the norelgestromin/ethinyl E2 transdermal patch (group 2) and vaginal ring etonogestrel/ ethinyl E2 (group 3) in an extended regimen (42 consecutive days, 1 hormone-free week). Study assessments were conducted at scheduled visits at the time of initial screening, at baseline after 1, 3, 6, and 12 months. Subjects recorded menstrual associated symptoms bleeding data and completed satisfaction questionnaires. Subjects and investigators provided overall assessments of the regimens. RESULTS: Extended use of 3 different contraceptive resulted in fewer bleeding days in every group (66.6%, 55% and 58.3% P 0.0024), and less mastalgia and menstrual pain. Subjects were highly satisfied with three regimens (93.3%, 96.6% and 91.6% P 0.00421). Although not mayor adverse events were reported with this regimen, there was an increase in spotting days; it decreased with each successive cycle of therapy. Efficacy and safety were similar to those reported for traditional cycle. CONCLUSION: Extended-contraceptive regimen delays menses and reduces bleeding, a profile that may be preferred by women who seek flexibility with their contraceptive method.

Contraception in hereditary angioedema.

OBJECTIVE: To report a case of successful use of a transdermal contraceptive in a patient with hereditary angioedema. DESIGN: Case report. SETTING: University medical center. PATIENT(S): A patient who had used oral contraceptives contracted SC and submucosal tumefaction every 1 or 2 months. She was diagnosed with type I hereditary angioedema. It was determined that she was complement C4 deficient and C1-inhibitor quantitative deficient but functional C1-inhibitor normal. After she was diagnosed, the use of oral contraceptives was contraindicated. INTERVENTION(S): Oral contraceptives were suspended, and a hormonal transdermal contraceptive was started. MAIN OUTCOME MEASURE(S): The absence of symptoms after 26 months using a transdermal contraceptive. RESULT(S): After 26 months of using this treatment, the patient has not experienced any symptoms of the hereditary angioedema. CONCLUSION(S): The use of hormonal contraceptives transdermally can be an alternative in patients with hereditary angioedema.

[Emergency contraception: a simple, safe, effective and economical method for preventing undesired pregnancy]. / Anticoncepción de emergencia: un método simple, seguro, efectivo y económico para prevenir embarazos no deseados.

In the following article, the most recent knowledge on emergency contraception (EC) is reviewed. EC is defined as those contraceptive methods that may be used to prevent an unwanted pregnancy up to 3 days after unprotected intercourse, contraceptive failure or rape. In case of non-hormonal methods (IUD), the time window for pregnancy prevention goes up to 5 days after intercourse. The different regimens now available, hormonal and non-hormonal methods, indications, contraceptive effectiveness, side effects and safety profile, possible mechanisms of action and counseling strategies will be reviewed. The potential benefits on reproductive health of wide-spread knowledge and easy, non-restrictive access to this methodology are emphasized. An extensive list of recent references is enclosed.

[Endometrial interference of synthetic estrogens in fertility regulation.Is it necessary to interfere with the antiovulatory mechanism at the central nervous system level in order to obtain contraception?]. / Interferencia endometrial de los estrógenos sintéticos en la regulación de la fertilidad. Es necesario el mecanismo antiovulatorio a nivel del sistema nervioso central, para obtener la anticoncepción?

For some time the anti-ovulatory activity of certain estrogen/progestagen preparations was the main approach in fertility control. Up to date a drastic dosage reduction of both steroid hormones has been accomplished ameliorating the side effects on the one hand, and being active compounds as contraceptives, in the other. Currently, there are a wide variety of oral contraceptives available with a variety of estrogen doses combined with different progestagens. The estrogen content is a high as 80 micrograms and as low as 20 micrograms, moreover, such formulations are prescribed beginning the 1st or the 5th day of the menstrual cycle. By studying plasma and endometrial samples simultaneously obtained from chronic oral contraceptive users taking either 30 micrograms or 50 in such pills; a 17-beta-estradiol pattern was attained as that seen during follicular maturation in the ovulatory cycle only women under the lower dose of synthetic estrogen. However, in the endometrium such a cyclicity did not take place; in parallel circulating progesterone in both groups never reach levels greater than 5.0 ng/ml. Results offer to find a local critical period during the ovulatory menstrual cycle to achieve with much lower hormonal dosages a different approach in future methods of contraception.

A multicenter comparative trial of triphasic and monophasic, low-dose combined oral contraceptives.

A comparative multicenter clinical trial of two combined oral contraceptives (OCs) was conducted at clinics located in the Sudan, Sri Lanka, Chile, the Dominican Republic and Ecuador. The trial was designed to determine if there were differences in efficacy, safety and acceptability between a triphasic and a low-dose monophasic OC. This report includes analysis of 1088 women. At each center, subjects were randomly allocated to one of the two OCs. Follow-up visits were scheduled at 1, 4, 8 and 12 months after admission. There were two accidental pregnancies attributed to user failure reported during the study period; one in the triphasic group and one in the monophasic group. Adverse experiences were mainly minor with headaches and dizziness being the most common complaints; frequency of reports was similar in both groups. Cycle control was good in both groups with women in the triphasic group reporting fewer complaints of intermenstrual bleeding. Both OCs were safe and effective.

PIP: Researchers compared the efficacy, safety, and acceptability of a triphasic oral contraceptive (OC), Triquilar, with those of a monophasic OC, Lo-Femenal, among 1088 women attending clinics in Chile, the Dominican Republic, Ecuador, Sri Lanka, and the Sudan. Both OCs contained levonorgestrel and ethinyl estradiol. 90% of women in each group exhibited good user compliance. Only 1 unplanned pregnancy occurred in each group, and both pregnancies were attributed to user failure. The gross cumulative efficacy rates at 11 months were 0.3/100 woman-years for the triphasic OC and 0.2/100 woman-years for the monophasic OC. The continuation rate at 11 months was lower for Lo-Femenal than it was for Triquilar (80.8% vs. 84.6%), but the difference was not significant. The leading side-effect-related reason for discontinuation in both groups was headache. Another key reason for OC discontinuation in both groups was personal reasons, such as planning a pregnancy. Most women in both groups did not have menstrual complaints (78.8% for the Triquilar group and 77.1% for the Lo-Femenal group). Intermenstrual bleeding rates were low (7.6% for the Triquilar group and 9% for the Lo-Femenal group). Significant intercenter differences for women reporting intermenstrual bleeding and side effects (e.g., headaches) existed (p .05). Women from both groups at the clinic in the Sudan always had lower reports of intermenstrual bleeding than those at the other clinics. In fact, no woman discontinued OC use because of intermenstrual bleeding in the Sudan. Women in Sri Lanka reported fewer side effects than those in other countries, suggesting they could better tolerate OCs than the other women. This multicenter study's findings indicates that both Triquilar and Lo-Femenal are effective and safe. In addition, they exhibit good cycle control.

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.

[Levonorgestrel releasing subcutaneous implants. 1st year's experience]. / Implantes subdérmicos liberadores de levonorgestrel. Primer año de experiencia.

This multicentric study was done in order to know the contraceptive efficacy and side effects of subdermal implants liberating levonorgestrel, in Mexican women. Results analysis, at one year, of 246 women, at four medical centers of Mexican Institute of Social Security (IMSS), showed that this contraceptive is highly efficacious, as there were no pregnancies in 2326 months of observation. The main side effects were: menstrual disorders in 34.8% of women; soreness in implantation site in 3.6%; headache in 13.4% and nausea, dizziness and vomiting in 11.6%. The most frequent causes for implant retirement were menstrual cycle alterations, and soreness at implantation site, with 7.3 and 3.5 respectively. The continuity rate at one year was 84.3, which was higher to what has been seen at the Institution with other temporal contraceptive methods, so the implants may be considered as one more alternative in family planning methods.

[Long acting hormonal contraception]. / Anticoncepción hormonal de acción prolongada.

Long-acting hormonal contraception has been widely accepted in different cultures, where the use of injectables and implants is preferred over other methods of fertility control. The administration of synthetic progestogens in combination with estrogens as injectables suppresses ovulation, allowing the control of the endometrial bleeding too. The use of injectables containing only progesterone constitutes a 2 to 6 months contraceptive method with high effectiveness and easy administration, although its major disadvantage is the alteration of the endometrial bleeding pattern, which is the most common cause of discontinuation. The group of long-acting injectables includes the development of microencapsulated steroids, whose structure gives them the property of maintaining controlled liberation of the drug. Recently subdermal contraceptive implants (Norplant) have appeared, based on the subcutaneous sustained liberation of levonorgestrel. The daily drug dose is enough to inhibit ovulation in the initial months of use and modifies the cervical mucus in the subsequent months. Norplant has been shown to be efficient in preventing pregnancy, but main secondary effect is bleeding pattern disturbance during the menstrual cycle. The Capronor constitutes a new system of contraceptive implant which is different from Norplant, where the capsules containing levonorgestrel are of unbiodegradable material, and Capronor is formed by a biodegradable polimerus. Finally, among the contraceptive methods that have been developed to date there are the vaginal rings; these rings are silastic made and allow a continuous release of levonorgestrel or progestins.

Assessing the acceptability of NORPLANT implants in four countries: findings from focus group research.

In 1986-87, a qualitative research project was conducted in the Dominican Republic, Egypt, Indonesia, and Thailand to expand understanding of the acceptability of NORPLANT contraceptive implants beyond inferences made on the basis of continuation rates. In each of the four study sites, focus group discussions or in-depth interviews were held with potential acceptors, current NORPLANT users, discontinuers, husbands of women in these three groups, and service providers. Nonclinical participants generally had little formal education and lived primarily in urban or semi-urban areas where NORPLANT has been available for at least five years. The study focused on attitudes, perceptions, and experiences of each group regarding NORPLANT implants. Results suggest that factors having an impact on the acceptability of NORPLANT implants fall into three general categories: medical/technical, cultural/religious, and informational/educational. This article discusses each of these categories, including programmatic implications of the findings, and puts forward recommendations for enhancing NORPLANT introduction efforts on the basis of these findings.

PIP: In 1986-87, a qualitative research project was done in Thailand, Egypt, Indonesia, and the Dominican Republic to expand knowledge of the acceptability of NORPLANT contraceptive implants beyond continuation rates. In each of the 4 studies, in-depth interviews or focus group discussions were held with current NORPLANT users, potential acceptors, discontinuers, husband of women in the 3 groups, and service providers. The 4 countries were chosen because of their diverse cultures and religions. Most participants favored family planning. Many had used other contraceptives. Men and women in all countries were worried that oral female contraceptive agents (the pill) caused cancer. There were many objections to the IUD. In all countries but Thailand, there was little knowledge of NORPLANT. In the Dominican Republic, NORPLANT was used mostly as a child spacing method. In Indonesia, it was used for child spacing and termination of childbearing. Perceived advantages were alike in all countries. Pain during insertion and removal was a big concern of potential users. Men and women in all countries said that religion and traditional beliefs did not influence their family planning decisions. But many said that religion influenced their tolerance of side effects. In Egypt and Indonesia sterilization is unpopular because it is seen as violating Islamic law. Irregular bleeding was the major side effect and the main reason for discontinuation. Many satisfied users felt that the advantaged outweighed the side effects. Primary reasons for removal in all countries were irregular bleeding, amenorrhea, and the desire to give birth. The need for information was mentioned in all countries. In Egypt, Indonesia, and Thailand services providers reported the need for more thorough training in insertion and removal as well as continuing education sessions.

Seguimiento a largo plazo de mujeres tratadas con implantes anticonceptivos de Levonorgestrel Norplant / Long-term follow up of women treated with contraceptive implants of norplant levonorgestrel

Este trabajo describe el seguimiento a largo plazo de 376 mujeres que recibieron los implantes Norplant durante el período comprendido entre octubre de 1974 y mayo de 1979. En ciento diez de estos casos, se reemplazaron los implantes luego de diferentes plazos de uso del primer set. Los niveles promedios de levonorgestrel plasmático declinaron en forma paulatina a través de ocho años de uso continuo de las cápsulas Norplant (r=937). Los valores fueron 0,35 ng/ml, 0,29 ng/ml y 0,22 ng/ml durante el primer, quinto y octavo año de tratamiento, respectivamente. Luego de la extracción de Norplant y su reemplazo con un segundo set de implantes, los niveles de levonogestrel plasmático fueron similares a aquellos observados después de la primera inserción, tanto cuando se colocaron en el mismo lugar que el primer set como cuando se ubicaron en un área diferente. Se estableció que la vida media del levonorgestrel en plasma después del retiro de los implantes es de 42 ñ 16 h (x ñ D. S) y que sólo quedaban cantidades mínimas en circulación después de 96 h. Durante 18.530 meses-mujer de uso del primer set de implantes se produjeron diecinueve embarazos, once de ellos entre el sexto y octavo año de tratamiento. El índice de Pearl para los primeros cinco años de uso de implantes Norplant fue 0,63. En los 5.020 meses-mujer observadas durante el tratamiento con un segundo set de cápsulas no se ha producido ningún embarazo. Cincuenta y seis mujeres (14,9%) de las 376 usuarias del primer implante, y doce (10,9%) de las 110 mujeres que aceptaron el reemplazo de los implantes se retiraron del estudio por razones médicas, principalmente efectos secundarios asociados frecuentemente con la contracepción hormonal..

Treatment with Norplant subdermal implants inhibits sperm penetration through cervical mucus in vitro.

Attempts were made to collect several samples of cervical mucus in each of thirty-three cycles of women using NORPLANT subdermal implants, in seven cycles from NORPLANT-2 rod users, and in 33 control cycles. The attempts to collect a mucus sample were successful on 20 of 77 and 7 of 14 occasions in NORPLANT capsule and rod users, respectively, due to the scanty amount and stickiness found in the majority. All 59 attempts in control subjects were successful. The distance travelled by the fastest sperm and by the bulk of spermatozoa through the cervical mucus in vitro was assessed after 10 min of incubation with a normal semen sample. The best score for each cycle was considered for the comparison between treated and control cases. Sperm penetration was greatly impaired in mucus samples of implant users with penetration by the fastest sperm exceeding 10 mm in only two instances and exceeding 20 mm in none. In 30 of 33 control samples, the fastest sperm travelled 21 mm or more and in 28, the bulk of spermatozoa travelled further than 10 mm. Unsuccessful attempts to collect mucus and poor sperm migration were observed in NORPLANT implant users even when circulating estradiol levels were comparable to those seen in the late follicular phase of the normal menstrual cycle. These results suggest that the principal mechanism by which NORPLANT implants prevent pregnancy is by interference of sperm migration through cervical mucus.

Early chorionic activity in women bearing inert IUD, copper IUD and levonorgestrel-releasing IUD.

Early chorionic activity was assessed in the premenstrual days by means of serum HCG beta-fraction. As control, a group of women with no contraceptive use was studied; early chorionic activity was detected in 31.8% of the cycles. In the group bearing an inert IUD the incidence was 20%, which did not differ from the control; while in the medicated IUD groups (Cu-IUD and LNG-IUD) the incidences were 4.8% and nil, respectively. Both medicated IUD groups showed a significant difference when compared with the control, as well as the inert IUD groups. The meaning of these findings, pointing out differences in the main mechanism of action between inert and medicated IUDs, is discussed.

PIP: Early chorionic activity was compared in 100 IUD users (inert device, copper IUD, and a levonorgestrel-releasing IUD) and 22 controls through measurement of the serum human chorionic gonadotropin (hCG) beta-fraction. In the control group, 7 (32%) of the 22 women had hCG beta-fraction values indicative of chorionic activity (i.e., 5mIU/ml). In the group of women wearing an inert IUD (Lippes Loop), 8 (20%) were positive for early chorionic activity. In contrast, the incidence of premenstrual chorionic activity signs was very low among women with medicated IUDs: 5% among acceptors of the copper IUD and zero among women in the levonorgestrel-releasing IUD group. In general, elevated premenstrual hCG values are indicative of failed implantation. The high incidence of hCG activity recorded among Lippes Loop acceptors in this study is consistent with the anti-implantation effect postulated for inert devices. In contrast, medicated IUDs appear to act by preventing rather than interrupting implantation and therefore should not be regarded as abortifacient contraceptive agents.

Long-term follow-up of women treated with Norplant implants.

This report describes the long-term follow-up of 376 women who received NORPLANT implants in the period October 1974 through May 1979. One-hundred-and-ten subjects received replacement implants after variable lengths of use of the first set. The average levonorgestrel plasma levels declined steadily through eight years of use of NORPLANT capsules (r = -.937). Values were 0.35 ng/ml, 0.29 ng/ml and 0.22 ng/ml at treatment years 1, 5 and 8, respectively. Levonorgestrel plasma levels after replacement with a second set of implants were similar to those observed after the first insertion, either when placed in the same site as the first set or in a different area. Nineteen pregnancies occurred during 18,530 woman-months of use of the first set of implants, eleven of them during years 6 through 8 of treatment. The Pearl Index for the first 5 years of NORPLANT implants use was 0.63. No pregnancy has occurred in 4194 woman-months observed during treatment with a second set of capsules. Fifty-six women (14.9%) out of 376 acceptors of the first implant and 10 (9.1%) out of 110 acceptors of the replacement implants were terminated for other medical reasons, mainly bleeding problems and side effects commonly associated with hormonal contraception. Two women died while using NORPLANT implants, one of a cardiac arrest after surgery for a gallbladder disease and one because of endocranial hypertension originating from the rupture of an aneurism of the median cerebral artery. The bleeding pattern observed in the three months after NORPLANT capsules replacement was similar to that observed in the 90 days before replacement and different from that experienced by the same women in the first 90 days of implant use. This finding can be interpreted as an indicator of adaptive changes experienced by the target organs during long-term continuous administration of levonorgestrel. The prompt recovery of fertility after removal of NORPLANT implants suggests that these changes are reversible.

Recovery of fertility and outcome of planned pregnancies after the removal of Norplant subdermal implants or Copper-T IUDs.

The recovery of fertility after discontinuation of NORPLANT implant use was assessed in ninety women who stated a desire for a new child at the time of removal. Three subjects were lost to follow-up after removal. The cumulative probability of conception in the remaining 87 women was 25, 49, 73 and 86 percent at one, three, six and twelve months after removal, respectively. Nine observations were censored either because of the use of a contraceptive method soon after removal of the implants (n = 7) or separation (n = 2). All other cases were pregnant at the end of two years with exception of three subjects where a male factor for infertility was present. There was no significant correlation between the length of NORPLANT use and the length of the interval from removal to conception. A significantly higher frequency of intervals longer than 6 months was observed among women older than 30 years as compared to younger women. Pathology during pregnancy was cholestasia (n = 5), hypertension (n = 1) and gestational diabetes (n = 1). The outcome was term delivery in 59 cases, premature delivery in 4 cases, and spontaneous abortion in 7 cases. One woman is still pregnant and the outcome is unknown in 4 cases. One premature infant died. A contemporary control group of Copper T users enrolled under the same criteria as NORPLANT implant users provided 44 women who had the device removed to become pregnant. The cumulative probability of pregnancy was 27, 69, 84 and 89 at one, three, six and twelve months and all were pregnant by the end of the second year. Six censored observations occurred because of the use of another contraceptive method after removal (n = 3) or loss to follow-up (n = 3). The outcome of pregnancy was term delivery in 23 cases and abortion in 7 cases. Recovery of fertility occurred at a normal rate after NORPLANT implant removal and the incidence of problems detected in the ensuing pregnancy were within the expected range for Chilean women.

Two-year prospective study in Colombia of Norplant implants.

A clinical trial of levonorgestrel-releasing Norplant implants used for contraception was undertaken in two cities in Colombia. Through two years in which 389 women had accumulated 594 years of use, there were no pregnancies. In a comparison group of copper intrauterine device acceptors, the one-year pregnancy rate was 1.1 per 100. Menstrual disturbances associated with progestin-only administration were the principal side-effects, and the major reason for cessation of use. Continuation among users of the implants was at the same or at a higher rate than observed among users of the intrauterine device. Advantages and disadvantages of alternate sites for implant placement are discussed.