Ione Cristina Barbosa

Multicenter clinical trial on the efficacy and acceptability of a single contraceptive implant of nomegestrol acetate, Uniplant

Uniplant, a single Silastic implant containing nomegestrol acetate, provides contraceptive efficacy for one year. Uniplant use for one year was studied in 1,803 healthy women of reproductive age, enrolled from 10 centers in 9 countries, after informed consent. Implants were placed subdermally either in the upper arm or in the gluteal region. Two-hundred-seventy-six subjects discontinued prior to completing one year of study. Cumulative discontinuation rate at 12 months was 15.72%. Medical reasons for discontinuation were principally menstrual-related. Fifteen pregnancies occurred during the one year study period, resulting in a 12-month net cumulative pregnancy rate of 0.94%. Approximately 56% of subjects using Uniplant had bleeding patterns similar to normal menstruation. Results from this study confirm that Uniplant is an efficient, well tolerated, 12-month contraceptive implant, with the advantage of easier insertion and removal of the single implant compared to other multiple implant methods.

Comparative study on intermittent versus continuous use of a contraceptive pill administered by vaginal route.

A multicenter, international, randomized, comparative trial was conducted to assess the acceptability, efficacy and safety of two different schedules of a contraceptive pill, containing 250 micrograms levonorgestrel and 50 micrograms ethinyl estradiol, administered by the vaginal route. One schedule of daily administration for 21 days with a seven-day interruption to allow withdrawal bleeding was compared to daily administration without interruption for bleeding. A total of 900 women were recruited in three countries, Brazil, Egypt and China; 7,090 women-months of vaginal pill use were recorded (3,364 using the pills intermittently and 3,726 continuously). Four undesired pregnancies occurred, one in Egypt and three in China, all four in women using the pills intermittently. There was a statistically significant difference (p = 0.486) in pregnancy rate between the two groups. There were no other significant differences in discontinuation rates despite marked differences in bleeding patterns, amenorrhea predominating in the continuous use group. Hemoglobin levels increased significantly in the two groups but hematocrit was significantly higher in the continuous use group.

Evaluation of the endometrial cavity during menopause

Objective: To compare transvaginal sonography (TVS), hysteroscopy and suction curettage in the evaluation of uterine bleeding during the menopause. Methods: Forty‐seven patients who presented with either postmenopausal bleeding (31 cases) or sonographic endometrial abnormalities at menopause (16 cases) were evaluated using TVS, hysteroscopy, and curettage with a Karman curette. Results: When endometrial thickness measured by TVS was <4 mm, there was no endometrial pathology. However TVS could not differentiate accurately between hyperplasia, polyps or endometrial carcinoma. In these cases, endometrial thickness was invariably greater than 5 mm. Conclusion: Hysteroscopy proved superior to curettage in the diagnosis of endometrial polyps.

A randomized,open-label study of conjugated equine estrogens plus medroxyprogesterone acetate versus tibolone: effects on symptom control, bleeding pattern, lipid profile and tolerability

Objective: To compare the effects of continuous combined conjugated equine estrogens plus medroxyprogesterone acetate (CEE/MPA) with those of tibolone on symptom control, bleeding pattern, lipid profile and tolerability in postmenopausal women. Methods: This was a randomized, open-label, parallel-group, multicenter study. Generally healthy postmenopausal women with an intact uterus and no contraindications to hormone replacement therapy (HRT) or tibolone were enrolled. Each subject was randomly assigned to receive CEE/MPA 0.625 mg-5.0 mg or tibolone 2.5 mg daily for 13 treatment cycles, each of 28 days. Results: A total of 85 subjects were enrolled and received at least one dose of study medication, of which 76 (89.4%) subjects completed the study (n = 40, CEE/MPA; n = 36, tibolone). The incidence of postmenopausal symptoms decreased significantly over time in both treatment groups, compared with baseline, including significant decreases in the incidence of urogenital and sexual health symptoms. Significant differences in symptom control (other than hot flushes) were observed between treatment groups in a few different cycles for different symptoms, but no consistent or clinically significant trends were observed. No statistically significant differences in the incidence of bleeding were observed between treatment groups after cycle 4. Significant decreases in total cholesterol (5.6%) and low-density lipoprotein (LDL) cholesterol (7.5%) were observed at cycle 13, compared with baseline, in the CEE/MPA group, and significant decreases in high-density lipoprotein (HDL) cholesterol (8.5%) and triglycerides (13.7%) were observed at cycle 13, compared with baseline, in the tibolone group. Significant weight gain was observed at cycle 13 in the tibolone group (3.05 kg), compared with the CEE/MPA group (0.96 kg). The incidences of adverse events were similar in both treatment groups. Conclusions: Women treated with CEE/MPA or tibolone showed significant improvement of postmenopausal symptoms, including urogenital and sexual health symptoms, and had similar bleeding patterns after four cycles of therapy. CEE/MPA and tibolone each induced a different mix of changes in the lipid profile.

The effects of nomegestrol acetate subdermal implant (uniplant) on carbohydrate metabolism, serum lipoproteins and on hepatic function in women

This study was undertaken to assess possible variations in body weight, blood pressure, fasting glucose, HbA1C, insulin, total cholesterol, HDL-C, LDL-C, triglycerides, SGPT, SGOT, GGT and bilirubin in women bearing a single subdermal Silastic implant containing 55 mg (10%) of nomegestrol acetate during two years. A total of eighteen volunteers of reproductive age who desired to avoid conception were enrolled in this study. Subjects were healthy women with no contraindications to hormonal contraception. All women were investigated before starting treatment and were followed up for one year. At the end of one year the capsules were removed and a new capsule was inserted. Fasting blood samples were drawn at 8:00 to 8:30 am twice prior to implant insertion and then at the first, third, sixth and twelfth months and every six months thereafter. Body weight increased from 54.9 +/- 1.5 kg at admission to 55.3 +/- 2.0 kg at 12 months of use (p < 0.05) and to 56.0 +/- 2.7 kg at 24 months of use. A slight increase in both systolic and diastolic blood pressure was recorded at month 12 (p < 0.01). At month 24, blood pressure was not significantly different from admission values. All levels were within the normal range. Insulin, HbA1C, LDL-C and GGT remained unchanged during twenty-four months of Uniplant use. A significant decrease in total cholesterol (p < 0.05) was observed in the third month while a significant decrease in HDL-C (p < 0.01) was observed only in the sixth month of Uniplant use.(ABSTRACT TRUNCATED AT 250 WORDS)

Use of a single implant of elcometrine (ST-1435), a nonorally active progestin, as a long acting contraceptive for postpartum nursing women.

Because of its unique features, the contraceptive effectiveness and tolerance during breast-feeding of 16-methylene-17 alpha-acetoxy-19-nor-4-pregnene-3,20-dione (elcometrine), delivered within a single subdermal capsule of medical grade polydimethylsiloxane, was investigated. Unlike other progestational steroids, elcometrine has no affinity for androgen and estrogen receptors and is inactive by the oral route. A total of 66 breast-feeding women receiving elcometrine by the subdermal route were enrolled in the study, and 69 women who elected to use Copper-T380 intrauterine devices (IUD) served as control subjects. The women and their infants were observed until the end of the first postpartum year. There were no significant differences in growth and development measurements among the infants in the elcometrine and control groups. The percentage of infants continuing to breast-feed at 3 and 6 months was significantly higher in the elcometrine group. There were no significant differences between the concentration of elcometrine in the mothers blood and milk. At 75 days, blood levels of elcometrine in the infants were near the undetectable and were significantly lower than the levels in maternal blood or milk (p < 0.01). In 15 of 25 infants, blood levels of elcometrine were at the limit of assay sensitivity or undetectable. Two pregnancies occurred in women using IUD, whereas none occurred in those using implants. There were menstrual bleeding irregularities in both groups. A single elcometrine capsule placed subcutaneously at 6-monthly intervals appears to be an effective method of contraception for lactating women and results in blood concentrations of nursing infants at or near undetectable levels.

Ovulation suppression in women following vaginal administration of oral contraceptive tablets.

A preliminary trial was conducted to test the possibility of using intravaginally a contraceptive tablet manufactured for oral use to achieve ovulation suppression. 12 women who could not continue with oral contraceptives (OCs) because of gastrointestinal complaints and/or nausea volunteered to participate. All subjects discontinued oral use of tablets for at least 2 months prior to the vaginal administration. Condoms were provided for use during the interim period. Patients were instructed to manually place in the vagina either 1 (4 subjects) or 2 tablets (8 subjects) daily for 21 days. Progesterone blood levels remained at preovulatory levels, below 2 ng/ml, throughout the treatment period, indicating that ovulation was suppressed in all subjects. Levels of 17beta-estradiol (32) which showed considerable variation during the control cycle remained low during the treatment cycle. Withdrawal bleeding occurred 2-5 days following the last tablet and lasted 3-5 days, as in normal menstruation. In patients inserting 1 tablet, intermenstrual spotting was common, but in those inserting 2 tablets daily no spotting occurred. 5 of 6 subjects who complained of nausea during OC use reported no nausea during the period of vaginal administration. These patients requested vaginal administration as a regular contraceptive method.

Inhibition of Ovulation in Marmoset Monkeys by Indomethacin

The effect of indomethacin on human menopausal gonadotropin/human chorionic gonadotropin-induced ovulation was studied in marmoset monkeys. Indomethacin was effective in preventing follicular rupture and ovum extrusion when administered simultaneously with gonadotropin. The production of progesterone and luteinization of the granulosa cells were not affected by indomethacin treatment. Histologic examination of corpora lutea from indomethacin-treated animals revealed the presence of entrapped oocytes surrounded by luteal cells. These results suggest that prostaglandin synthesis is required for ovulation in this species, but not for luteinization and progesterone production.

Ovulation inhibition following vaginal administration of pills containing norethindrone and mestranol

Plasma levels of estradiol and progesterone were investigated in women using daily vaginal pills containing 1 mg norethindrone and 50 mcg mestranol. Of 13 treatment cycles in ten women using one vaginal pill daily, six were ovulatory and seven anovulatory. All 12 cycles in ten women using two vaginal pills daily were anovulatory.

Temporal relationship between uniplant insertion and changes in cervical mucus

This study was undertaken to determine the time required by a single implant containing nomegestrol acetate to affect cervical mucus production and sperm penetration in women. All subjects were investigated and, if necessary, treated for any kind of cervicitis or vaginitis prior to starting cervical mucus study. The subjects had not used hormonal contraception for at least three months prior to investigation. They were counseled to use condoms during this study and also to refrain from intercourse during the period of cervical mucus sampling. Follicular development and endometrial thickness were analyzed by transvaginal sonography. Cervical mucus examination, sperm penetration test, and transvaginal sonography were performed during the control cycle and during the first cycle of Uniplant use. Blood samples were taken for the measurement of estradiol, LH, and progesterone. Cervical mucus and sperm penetration tests were evaluated according to the World Health Organization (WHO) criteria. In the treated cycle, when cervical mucus reached a score of 8-10, Uniplant was inserted, independent of the day of the cycle. Cervical mucus was then collected at 0, 4, 8, 12, 24, 48, and 96 h later until a marked change in volume, consistency, ferning spinnbarkheit, and cellularity was observed. All samples were also used for sperm penetration test. Preovulatory estradiol and LH peak decreased significantly compared to pre-implant insertion. Progesterone levels were within the normal limit. Cervical mucus and sperm penetration tests were not affected by Uniplant in the first 12 h. Twenty-four hours after Uniplant insertion, cervical mucus and sperm penetration tests were affected in 70.6% of the women. Forty-eight hours after implant insertion, the women were affected. Follicular rupture occurred in the majority of the women 48 h after implant insertion. Based on these results, it is possible to conclude that Uniplant can affect estradiol and LH preovulatory peaks and disrupt the process of cervical mucus production and sperm penetration, but it was unable to prevent ovulation when inserted in the preovulatory phase.