Clinical experience with triphasic oral contraceptive (Triquilar) in 527 women in China

From October 1987 to May 1989, a total number of 527 women completed a total of 6,291 treatment cycles in 6 centers in China for the study of a triphasic oral contraceptive - Triquilar. The mean age of subjects was 30.21 +/- 2.84 years. There were 7 pregnancies during the study period. Among them, five were patient failures because of missed pill or incorrect intake; one had taken barbiturates along with Triquilar. Only one woman became pregnant in the 11th treatment cycle without any reason being found. In most cases, menstrual flow decreased and dysmenorrhea improved as treatment continued. Of the total treatment cycles, the incidence of missed withdrawal bleeding was 0.25%, spotting 0.97%, and breakthrough bleeding 0.48%. Nausea and vomiting was the most common side effect and accounted for 6.4% of the total treatment cycles. This was followed by breast tenderness (3.7%), dizziness (2.4%) and headache (1.6%). Most of the side effects occurred during the first few cycles and were alleviated later. By the end of one year, the total dropout was 64 cases. The reasons for discontinuing treatment were: pregnancy 1.33 (per hundred women), menstrual disturbances 0.76, side effects 3.80, other medical reasons 2.09, and personal reasons 4.18. The results confirm that Triquilar is an effective oral contraceptive with good cycle control and low incidence of side effects. No serious reaction has been reported. It has been well accepted by the Chinese women. However, due to the low dosage of steroids, it is of utmost importance to avoid errors in its use.(ABSTRACT TRUNCATED AT 250 WORDS)     

Pituitary and ovarian function and clinical performance during the use of a levonorgestrel-releasing intracervical contraceptive device

A levonorgestrel-releasing intracervical device (ICD) was inserted postmenstrually to twenty-one voluntary women. Eight subjects gave blood samples twice a week during the initial three months of use of the ICD and during the seventh and twelfth months of use. Clinical performance was studied; plasma concentrations of levonorgestrel were measured by radioimmunoassay and the effects of the treatment on pituitary and ovarian function were determined by assaying plasma concentrations of LH, FSH, estradiol and progesterone. The results of the first year are presented. Dysmenorrhea, menstrual flow and the number of days of bleeding decreased during the first treatment year. Three spontaneous expulsions occurred; two at the very beginning of the treatment and one after six months of use. Side-effects were few. The plasma level of levonorgestrel remained fairly constant during the observation time of 12 months. Thirty-one of the 36 cycles were ovulatory as judged by plasma progesterone elevations. No pregnancies occurred during the study period of one year.     

Intracervical release of levonorgestrel for contraception

Twenty-one women used a levonorgestrel-releasing intracervical contraceptive device, which was designed to release 20 μ/day. The devices were inserted after cessation of menstrual bleeding. Patterns of bleeding and clinical performance were evaluated and plasma concentrations of levonorgestrel, estradiol and progesterone in selected subjects were measured by radioimmunoassay. The results of the initial 90-day treatment are presented. Levonorgestrel was detected in peripheral plasma by 30 minutes after insertion of the device. Considerable variation of plasma levonorgestrel concentrations was observed between subjects, but within each subject, the plasma level of levonorgestrel was very stable with time. Of 24 cycles monitored by blood sampling, 19 were ovulatory. One subject did not ovulate at all. During the first 30-day period of treatment, frequent intermenstrual bleeding or spotting periods occurred. Two spontaneous expulsions occurred 9 and 22 days after insertion. Both of these subjects were nulligravidas. Side-effects were few and no pregnancies occurred during the study period.     

The role of matching menstrual data with hormonal measurements in evaluating effectiveness of postcoital contraception

The effectiveness of postcoital contraception can only be estimated. The most commonly used method of calculation compares the expected pregnancy rate in the exposed population to the resultant pregnancies after treatment. Estimation of the fertile period and the day of ovulation are critical to calculate the expected pregnancies. The aim of this study was to improve the accuracy of calculations by evaluating the hormonal status on the day of contraceptive treatment. A total of 483 consecutive women requesting postcoital contraception was included in a prospective observational trial. A blood sample was obtained at the moment of consultation to measure serum luteinizing hormone, estradiol, and progesterone concentrations. An ethinylestradiol-levonorgestrel combination (100 micrograms/500 mg for two doses, 12 h apart) was then prescribed. The fertile period was estimated according to previous hormonal studies in the normal cycling population. Of 483 women, 64 (13.25%) women were excluded because they presented irregular menstrual cycles and 37 (7.6%) women were lost to follow-up. Two pregnancies occurred in the remaining 382 women. Following Wilcox's and Trussell's methods, 21.1 and 17.75 pregnancies should be expected, yielding an overall treatment effectiveness of 90.52% (95% confidence interval [CI] 62.58%-97.6%) and 88.73% (95% CI 55.93%-97.12%), respectively. Hormonal data were available in 356 women; 303 of whom presented with regular cycles. Hormonal information in this group restricted the number of exposed cases to 88 women. Of the women included in Trussell's method of analysis, only 51 (51.5%; p < 0.05) were at risk using hormonal data. Fifty-six percent (95% CI 34.9%-75.6%) of women with luteinizing hormone levels > 20 IU/L were not between days-1 and +1 of the cycle. Hormonal studies suggest that methods based on pregnancy risk calculated by cycle day do not faithfully reflect the real exposure.     

Postcoital contraception with dl-norgestrel/ethinyl estradiol combination: six years experience in a student medical clinic

Postcoital contraception with ethinyl estradiol/dl-norgestrel in combination has been available to women students attending the University of British Columbia since 1974. This paper reports on the side effects, cycle control and efficacy, for a six-year period (1979-1985). In this sample of women 50% reported side effects of nausea alone or nausea with vomiting. Length of the menstrual cycle was shortened in women who took the medication prior to the expected day of ovulation. The number of pregnancies reported was significantly (p less than 0.002) less than the number expected had the medication not been taken. Some women took the medication even though there was a possibility of conception earlier in the cycle and this might account for four of the failures. The mode of action of the postcoital medication remains unsolved making it difficult to understand possible reasons for the other 14 failures.     

Evaluation of a new triphasic oral contraceptive in private practice

We evaluated the clinical and metabolic effects of a new triphasic regimen developed in the continuing attempt to reduce the dose of estrogen and progestogen in oral contraceptives. A combination of ethinyl estradiol (EE) and levonorgestrel (LNg) was used (six tablets with 30 micrograms EE + 50 micrograms LNg, five tablets with 40 micrograms EE + 75 micrograms LNg, and 10 tablets with 30 micrograms EE + 125 micrograms LNg), also known as Triphasil (Wyeth). In a private practice, 409 subjects participated in 7,286 treatment cycles. Three pregnancies occurred, all due to subject failure. Menstrual regulation was excellent and the incidence of side effects extremely low. Withdrawals from the study for possibly drug-related medical reasons totaled 9.0% through 56 cycles of treatment. Metabolic changes also were evaluated in 14 of these women over a 6-month period. The only statistically significant increase in carbohydrate values occurred at 6 months. The mean glucose level at 30 minutes of the oral glucose tolerance test was above the baseline mean value, but serum insulin levels showed no statistically significant deviation. Lipid values presented are total lipids, total cholesterol, triglycerides, alpha-, beta-, and pre-beta-lipoproteins, and high density and low density lipoprotein cholesterol. There was no statistically significant difference between the mean values at baseline and those during treatment for any lipid variable. These results indicate that this triphasic oral contraceptive has a high degree of efficacy, a low incidence of side effects, excellent cycle control, and high subject compliance, and would seem to indicate a minimal influence on the metabolism of lipids and carbohydrates in the small number of subjects studied.     

Contraceptive efficacy of emergency contraception with levonorgestrel given before or after ovulation

Background

The contraceptive efficacy of emergency contraceptive pills containing levonorgestrel (LNG-EC) has been estimated in most previous studies by judging the day of ovulation from presumptive menstrual cycle data, thus providing poorly reliable estimates.

Methods

In the present study, the efficacy of LNG-EC was determined in 393 cycles by dating ovulation on the basis of reliable hormonal and ovarian parameters validated by a database constructed in a separate study. In addition, the efficacy was determined separately for cycles in which LNG-EC was given before or after ovulation.

Results

For the 148 women who had sexual intercourse during the fertile days, the overall accumulated probability of pregnancy was 24.7, while altogether 8 pregnancies were observed. Thus, the overall contraceptive efficacy of LNG-EC was 68%. Among the 103 women who took LNG-EC before ovulation (days −5 to −1), 16 pregnancies were expected and no pregnancy occurred (p<.0001). Among the 45 women who took LNG-EC on the day of ovulation (day 0) or thereafter, 8 pregnancies occurred and 8.7 were expected (p=1.00). These findings are incompatible with the inhibition of implantation by LNG-EC in women. The same cases were also analyzed using the presumptive menstrual cycle data, and important discrepancies were detected between the two methods.

Conclusion

The efficacy of LNG-EC has been overestimated in studies using presumptive menstrual cycle data. Our results confirm previous similar studies and demonstrate that LNG-EC does not prevent embryo implantation and therefore cannot be labeled as abortifacient.     

Menstrual cycle variability and the likelihood of achieving pregnancy

The menstrual cycle is an important indicator of underlying hormonal function. Although menstrual cycle variability (sometimes referred to as 'regularity') is associated with a variety of demographic, behavioral, occupational, and environmental factors, as well as with several chronic diseases, few studies have examined its association with fecundity. We investigated whether a woman's menstrual cycle variability was associated with the likelihood of her achieving pregnancy. In this prospective study, we analyzed 3,536 menstrual cycles from 401 women (aged 19-41) recruited from 1990-1994. The women provided daily diaries recording menstrual bleeding, intercourse, and birth control use. Urine samples were assayed for human chorionic gonadotropin to identify early pregnancies during each menstrual cycle. Each woman's menstrual cycle variability was defined by the standard deviation of her cycle lengths during followup. The median follow-up was eight cycles. The outcome was her per-cycle probability of pregnancy. We found that women with high menstrual cycle variability had a reduced (51% lower) per cycle probability of pregnancy (fecundity ratio: 0.49; 95% confidence interval: 0.31, 0.77) compared with women with minimal variability. This relationship was independent of a woman's age and her mean cycle length. Thus, researchers and clinicians using menstrual cycle characteristics as indicators of endocrine or reproductive health should include measures of cycle variability in addition to the more commonly examined cycle length.     

Scanning electron microscopic (SEM) changes of the endometrium in women taking high doses of levonorgestrel as emergency postcoital contraception

Endometrial surface changes by scanning electron microscope were studied in three women who intentionally took high doses of levonorgestrel as an emergency postcoital contraceptive. Based upon findings of a close link between endometrial receptivity and surface integrity, significant alterations of the uterine lining structure may represent a drug effect accomplishing endometrial contraception. High doses of levonorgestrel (4–6 times more than recommended) caused detectable changes on the surface regardless of the menstrual cycle phase when the medication was taken. Cycle classification was based on estradiol and progesterone hormone levels, which corresponded to the menstrual diary. Comparison to control specimens displayed marked restructuralization of the endometrium. As a main feature, the number of ciliated cells were reduced, and cilia disappeared in the proliferative and periovulatory phase. In the secretory phase, pinopodia disappeared and the endometrial integrity broke down. The contraceptive effect of levonorgestrel seems to be accomplished by alteration of the endometrial surface and, therefore, receptivity.     

Levonorgestrel plasma concentrations and hormone profiles after insertion and after one year of treatment with a levonorgestrel-IUD

Plasma concentrations of levonorgestrel, progesterone, estradiol, FSH and LH were measured in seven volunteers who had a levonorgestrel-releasing IUD inserted postmenstrually. Blood samples were collected twice weekly during a mean of 93 days immediately postmenstrually and during a mean of 41 days over the twelfth to fifteenth month of treatment. Patterns of bleeding were studied during the first year of treatment. The IUDs used were designed to release 25 micrograms/day of levonorgestrel. The mean +/- SD plasma concentration of levonorgestrel for all subjects during the first three months was 260 +/- 68 pg/ml, and 129 +/- 28 pg/ml after one year of treatment. During the initial period of blood sampling only two of the subjects ovulated, while only two did not ovulate after one year of treatment. Intermenstrual spotting occurred during the first sixty days of treatment. Three subjects developed amenorrhea at the end of the first year. All the subjects continued the use of the IUD and no pregnancies occurred.     

Bleeding patterns after use of levonorgestrel emergency contraceptive pills

OBJECTIVE: The objective of this study was to describe bleeding after use of an emergency contraceptive pill (ECP) regimen consisting of 1.5 mg of levonorgestrel in a single dose. METHODS: We asked 120 women who had been treated with the regimen to keep daily bleeding diaries for 9 weeks. We compared bleeding patterns observed after treatment with usual patterns reported by the participants and with patterns observed in a prior study on women who had not taken ECPs. RESULTS: Treatment in the first 3 weeks of the menstrual cycle significantly shortened that cycle as compared both with the usual cycle length and with the cycle duration in a comparison group. The magnitude of this effect was greater the earlier the pills were taken. In contrast, the duration of the first menstrual period after treatment increased significantly with cycle week of treatment and was longer in women who used the treatment than in those who did not. Intermenstrual bleeding occurred in only 5% of women in the first cycle after treatment. CONCLUSIONS: The effect of the single-dose levonorgestrel ECP regimen on the timing and duration of the next menstrual period depends on when during the cycle the pills are taken. Intermenstrual bleeding following treatment is uncommon.     

Realignment and multiple imputation of longitudinal data: an application to menstrual cycle data

Reproductive hormone levels are highly variable among premenopausal women during the menstrual cycle. Accurate timing of hormone measurement is essential, especially when investigating day- or phase-specific effects. The BioCycle Study used daily urine home fertility monitors to help detect the luteinising hormone (LH) surge in order to schedule visits with biologically relevant windows of hormonal variability. However, as the LH surge is brief and cycles vary in length, relevant hormonal changes may not align with scheduled visits even when fertility monitors are used. Using monitor data, measurements were reclassified according to biological phase of the menstrual cycle to more accurate cycle phase categories. Longitudinal multiple imputation methods were applied after reclassification if no visit occurred during a given menstrual cycle phase. Reclassified cycles had more clearly defined hormonal profiles, with higher mean peak hormones (up to 141%) and reduced variability (up to 71%). We demonstrate the importance of realigning visits to biologically relevant windows when assessing phase- or day-specific effects and the feasibility of applying longitudinal multiple imputation methods. Our method has applications in settings where missing data may occur over time, where daily blood sampling for hormonal measurements is not feasible, and in other areas where timing is essential.     

Menstrual cycle characteristics: associations with fertility and spontaneous abortion

BACKGROUND: Epidemiologists often use menstrual cycle patterns as indicators of endocrine function in environmental and occupational studies, yet few studies have considered whether menstrual cycle characteristics are associated with fertility or pregnancy outcome. METHODS: We prospectively studied 470 women to determine whether cycle length or bleed length were associated with fertility or spontaneous abortion. Women completed daily diaries with information on menstrual bleeding, intercourse, birth control use, and covariates. For each menstrual cycle, women collected at least 2 urine samples, which were assayed for human chorionic gonadotropin to define early pregnancies. Women were followed for 1 year or until the end of a clinical pregnancy. RESULTS: Cycles with lengths of 30 to 31 days preceded cycles with the highest fecundity. Shorter cycles were less likely to be followed by conception (fecundity ratio [FR] = 0.6; 95% confidence interval [CI] = 0.4-1.0). Compared with 30- to 31-day cycles, conceptions after shorter and longer cycles were more likely to be spontaneously aborted (for shorter cycles, odds ratio [OR] = 3.0 [95% CI = 0.9-9.6] and for longer cycles, OR = 3.0 [0.9-10.6]). Cycles with 5 days of menstrual bleeding had the highest fecundity. Cycles with up to 4 days of bleeding had lower fecundity (for bleed lengths of 4 days, FR = 0.5 [0.3-0.8] and for bleed lengths less than 4 days, FR = 0.6 [0.3-0.9]). Spontaneous abortion was less likely after bleeds greater than 5 days (OR = 0.4 [0.1-1.1]) when compared with 5-day bleeds. CONCLUSIONS: Menstrual cycle characteristics appear to be associated with fertility and spontaneous abortion.     

Desogestrel and ethinyloestradiol

The effectiveness and side effects of Marvelon (0.150 mg desogestrel and 30 mcg ethinyl estradiol) were evaluated in a multicenter study of 1570 women for a total of 22,158 menstrual cycles. Half the women in the study were under age 25. Only 1 pregnancy was reported, and this was due to patient failure. The frequency of spotting and breakthrough bleeding decreased steadily from 22.3% in the 1st treatment cycle, 14.9% in the 2nd, 8.4% in the 6th, 5.6% in the 12th, to 2.8% in the 21st and then rose slightly from 3.6% in the 24th cycle. This pattern of irregular bleeding during the early cycles is common to all oral contraceptive preparations. Changes in body weight were almost negligible and restricted to women under age 20. There was no change in average blood pressure when compared with pretreatment values. Superficial thrombophlebitis occurred in 7 women. Side effects, including nausea, headache, nervousness, depression, and breast tenderness, declined to negligible levels as treatment progressed. Levels of plasma protein sex-hormone-binding globulin (SHBG) appear to be higher with Marvelon than with a similar preparation containing levonorgestrel and ethinyl estradiol. Other studies have noted significantly higher serum high density lipoprotein (HDL) cholesterol levels with Marvelon than with combined levonorgestrel and ethinyl estradiol. This is attributed to the lack of androgenicity of desogestrel in the clinical dosage used in this study. SHBG and serum HDL levels are increased by estrogens and decreased by androgens.     

Susceptibility to nausea and motion sickness as a function of the menstrual cycle.

PURPOSE: The present study examined whether susceptibility to nausea and other symptoms of vection-induced motion sickness vary as a function of phase of the menstrual cycle, as research findings in this area are sparse and contradictory. DESIGN: Ninety young women (42 current users of oral contraceptives) were exposed to a rotating optokinetic drum during the peri-menses or peri-ovulatory phase of the menstrual cycle in an independent-groups, quasi-experimental design. Nausea and motion sickness symptoms were assessed using the Nausea Profile (NP) and the Subjective Symptoms of Motion Sickness (SSMS) questionnaire. RESULTS: Among women not on oral contraceptives, reports of nausea and motion sickness by women in the peri-menses phase were more severe than reports by women in the peri-ovulatory phase. By contrast, among women taking oral contraceptives, reports of nausea and motion sickness did not differ by the same categorical phase of the menstrual cycle. CONCLUSIONS: We speculate that fluctuating estrogen levels over the course of the menstrual cycle may influence the experience of or susceptibility to nausea and motion sickness during illusory self-motion and other nauseogenic contexts.     

Timing of insertion affects expulsion in patients using the levonorgestrel 52 mg intrauterine system for noncontraceptive indications

ObjectiveTo evaluate levonorgestrel 52 mg intrauterine system (IUS) expulsion risk by menstrual cycle day of insertion (days 1–8 vs days 9 and beyond) in women using the IUS for noncontraceptive indications.Study designWe performed a retrospective cohort study of patients with a levonorgestrel IUS inserted for the management of noncontraceptive, gynecologic conditions at Kaiser Permanente-Hawaii between January 2009 and December 2010. We used multivariable logistic regression models to estimate the likelihood of IUS expulsion adjusting for demographic and clinical factors and a Kaplan-Meier curve for survival analysis.ResultsOf 176 patients identified, insertion occurred in 42 patients in cycle days 1 to 8 and 87 patients after day 8. Patient follow-up within the Kaiser system ranged from 1 to 71 months. Thirty-nine (22%) patients experienced expulsion, 16 (38%) and 15 (17%) for the 2 timing groups, respectively. Expulsion was more likely if the IUS placement occurred during the menstrual cycle days 1 to 8 (adjusted odds ratio 3.57 [95% confidence interval 1.13, 11.31]), which was consistent with the Kaplan-Meier analysis (p = 0.008).ConclusionLevonorgestrel IUS expulsion among women using the IUS for noncontraceptive indications occurred more frequently if insertion occurred during the first eight days of the menstrual cycle.ImplicationsIn women planning to use the levonorgestrel IUS to treat gynecologic conditions such as abnormal uterine bleeding, dysmenorrhea, and endometrial hyperplasia, providers should consider waiting until after cycle day 8 to perform insertion.     

A five-year clinical trial of levonorgestrel silastic implants (Norplant™)

Silastic implants containing the progestin, levonorgestrel, were tested as a long-term contraceptive system in 101 women. During five full years of use, no pregnancies occurred. The 5-year continuation rate was 54%. Menstrual irregularities were the most frequent reason for termination of use but only during the first year. More than half of the terminations for this reason were in the first year. Some of the subjects elected to continue use of the implants beyond 5 years, allowing release rate data to be obtained through 6 years.From the second through the sixth year of use, the implants delivered a constant 30 micrograms per day of levonorgestrel to the subjects, and even after six years 57% of the original steroid content remained in the capsules.Return of fertility following removal was essentially immediate and not related to time of use. Medical reasons for removal were infrequent and no pattern was discernible.     

Menstrual problems and side effects associated with long-term TCu 380A IUD use in perimenopausal women

The study assessing menstrual problems and side effects associated with long-term TCu 380A intrauterine device (IUD) use in perimenopausal women is reported. Fifty perimenopausal TCu 380A IUD acceptors who had IUD inserted after age 40 and used IUD at least 36 months were recruited. The mean age of acceptors at time of insertion was 44.2 years with an average parity of two live births. The mean body weight at insertion was 62.13 kg. Most of the bleeding patterns were regular cycles. Intermenstrual bleeding and pelvic pain were the side effects most often reported. No pregnancies, pelvic inflammatory disease, or IUD expulsions occurred during the follow-up period. This study suggests that the use of TCu 380A IUD in perimenopausal women is safe and effective.     

Comparative evaluation of the effectiveness and safety of two regimens of levonorgestrel for emergency contraception in Nigerians

Emergency contraception was introduced in Nigeria over two decades ago, but few women have used this method even in emergency situations because of the side effects. To find an acceptable levonorgestrel regimen for emergency contraception in our community, the two-dose regimen 0.75-mg levonorgestrel 12 h apart (group A) and the single dose 1.5-mg levonorgestrel (group B) were studied in 1118 volunteers. Mild side effects such as nausea, vomiting, lower abdominal pains, menorrhagia, dizziness, headache, and breast tenderness were reported. Significantly more women in the high-dose group reported headache, breast tenderness, and heavy menstrual flow. Eleven pregnancies (1.0%) were reported (7 in group A and 4 in group B). The crude relative risk of pregnancies was similar in the two groups (RR = 0.71, 95% CI = 0.32-1.55; p > 0.05) [corrected]. On the other hand, the estimated effectiveness rate of 86.80% in group A was significantly lower than the 92.99% for group B (p < 0.05). The pregnancy rates increased with delay in starting treatment and if further acts of unprotected sexual intercourse took place after treatment. It was concluded that both regimens were effective and safe.     

Accuracy of the peak day of cervical mucus as a biological marker of fertility

The (PD) peak day of cervical mucus is an important biologic marker for the self-determination of the optimal time of fertility in a woman's menstrual cycle. The purpose of this article is to provide evidence (literature and empiric) for the accuracy of the PD of cervical mucus as a biologic marker of peak fertility and the estimated day of ovulation. An analysis of data from four published studies that compared the self-determination of the PD of cervical mucus with the urinary luteinizing hormone (LH) surge was conducted. The four studies yielded 108 menstrual cycle charts from 53 women participants. The 108 cycles ranged in length from 22 to 75 days (mean 29.4 SD 6.0). Ninety-three of the 108 cycles had both an identified PD and LH surge. Data charts showed that 97.8% of the PD fell within +/-4 days of the estimated day of ovulation. Use of a standardized mucus cycle scoring system indicated that the peak in cervical mucus ratings was highest on the day of the LH surge. Self-determination of the PD of cervical mucus is a very accurate means of determining peak fertility and a fairly accurate means of determining the day of ovulation and the beginning of the end of the fertile time.