A 12-month comparative clinical investigation of a levonorgestrel-releasing intracervical device situated in the uterine cavity or cervical canal.

A randomized study was performed in two clinics in order to compare the efficacy, safety and acceptability of a new model of a levonorgestrel-releasing intracervical device situated either in the cervical canal (group I) or in the uterine cavity (group II). Group I included 151 women (age 18-43) and group II, 147 women (age 19-43). The number of nulliparous women was 145. The total expulsion rate was 9.1%. The expulsion rate was lower among nulliparous women (4.8%) than among parous women (13.1%). There was also a significant difference in the expulsion rates between the two clinics. Two pregnancies occurred in both groups and two of these were ectopic, one in each group. The other two occurred after unnoticed expulsion. These figures give 12-month cumulative pregnancy rates of 1.3% and 1.4% in groups I and II, respectively. Total infection rate was 0.3%. The continuation rates were 82.1% in group I and 85.0% in group II after the first year. At three-month follow-up there were significantly fewer menstrual problems in group I than in group II (p = 0.0266). It is concluded that expulsion is still a problem with a small device but it may be diminished by intrauterine insertion and by selecting the users carefully.

Subcutaneous goserelin versus intranasal buserelin for pituitary down-regulation in patients undergoing IVF: a randomized comparative study.

One-hundred women undergoing ovarian stimulation with gonadotrophin-releasing hormone agonist (GnRH-a) and a human menopausal gonadotrophin (HMG) for in-vitro fertilization (IVF) participated in this randomized comparative study. The effectiveness of long-acting s.c. goserelin (Zoladex depot; 49 patients) and intranasally (i.n.) administered buserelin acetate (Suprefact; 51 patients) for pituitary down-regulation was compared. Treatment with s.c. goserelin (3.6 mg) or i.n. buserelin acetate (200 micrograms; 6 times/day) was started on day 21-23 of the cycle. Stimulation with 150 IU of HMG/day was started after at least 11 days of GnRH-a treatment. There were no differences in the time required for follicular development nor in the clinical outcome between groups treated with either goserelin or buserelin. The number of oocytes recovered in the goserelin group was 6.7 +/- 5.0 versus 6.3 +/- 4.9 in the buserelin group. There were 11 pregnancies after the use of goserelin (22.4%) and 12 pregnancies in those given buserelin (24.0%). The number of HMG ampoules needed for follicular maturation was higher in the goserelin group (27.9 +/- 7.8) than in the buserelin group (24.6 +/- 7.8, P < 0.05). The patients given buserelin suffered significantly more from tiredness, depression, headache and abdominal pain than those receiving goserelin, whereas there were no differences between the groups in experiencing mental irritability, nausea and swelling. Subcutaneous goserelin depot injection offers a useful alternative for pituitary down-regulation in IVF stimulation.

Measurements of salivary progesterone throughout the menstrual cycle in women suffering from unexplained infertility reveal high frequency of luteal phase defects.

Forty-five women suffering from unexplained infertility collected saliva for progesterone (P) measurements every morning during 1 to 3 complete cycles. A total of 27 cycles analyzed were unstimulated, 19 were stimulated by clomiphene citrate (CC), and 7 with CC, human menopausal gonadotropin (hMG), and human chorionic gonadotropin (hCG). Compared with reference profiles of salivary P from 27 normal cycles, the length and magnitude of P secretion were significantly lower in the infertility group. Luteal P concentrations were normalized during CC stimulation and significantly elevated during the CC-hMG-hCG stimulation. The other abnormalities found in the salivary P profiles of these patients included preovulatory P peaks, interruption of P secretion during luteal phase, and high P level at the beginning of menstruation. The results suggest that patients with prolonged unexplained infertility represent a heterogenous population with common luteal phase defects. The disturbance is effectively corrected with treatments stimulating gonadotropin secretion.

Clinical performance of a levonorgestrel-releasing intracervical contraceptive device during the first two years of use.

One-hundred-and-ninety-eight women used a levonorgestrel-releasing intracervical contraceptive device (LNG-ICD) designed to release 20 micrograms levonorgestrel/day. Clinical performance during the first two years of LNG-ICD use was evaluated. A total of seven pregnancies occurred during the study period, all of them during the first year. Six pregnancies were after unnoticed expulsion of the device. One pregnancy occurred in an epileptic women using carbamazepine, with the LNG-ICD remaining in situ. Eighteen spontaneous expulsions occurred, 16 during the first year and 2 during the second year. Three pelvic infections were observed, all of them during the first year. Bleeding problems, hormonal side effects and other medical reasons were the most common side effects resulting in removal of the device. The continuation rate was 72.6 per cent after one year and 57.1 per cent after two years.

Plasma levonorgestrel levels and ovarian function during the use of a levonorgestrel-releasing intracervical contraceptive device.

Levonorgestrel, estradiol and progesterone plasma concentrations were measured over four years of use of a 20 micrograms/day levonorgestrel-releasing intracervical device (LNG-ICD). The mean levonorgestrel concentration showed a slight decline, being 142 + 46 (SD) pg/ml in the third month and 81 +/- 22 pg/ml in the 48th month of LNG-ICD use. However, considerable interindividual variation in levonorgestrel plasma levels between study subjects was observed. In 77% of the monitored cycles, ovulation or a luteinized follicle was observed when judged by a plasma progesterone elevation of over 5 ng/ml. Some follicular function was also noted in anovulatory cycles. Inhibition of ovulatory ovarian function is not the mode of contraceptive action of the LNG-ICD.

PIP: Levonorgestrel, estradiol and progesterone plasma concentrations were measured over 4 years of use of a 20 mcg/day levonorgestrel-releasing intracervical device (LNG-ICD). The mean levonorgestrel concentration showed a slight decline, being 142 +or- 46 (SD) pg/ml in the 3rd month and 81 +or- 22 pg/ml in the 48th month of LNG-ICD use. However, considerable inter-individual variation in levonorgestrel plasma levels between study subjects was observed. In 77% of the monitored cycles, ovulation or a luteinized follicle was observed when judged by a plasma progesterone elevation over 5 ng/ml. Some follicular function was also noted in anovulatory cycles. Inhibition of ovulatory ovarian function is not the mode of contraceptive action of the LNG-ICD.

Acceptability of an experimental intracervical device: results of a study controlling for selection bias.

We analyzed baseline and 12-month follow-up interview data from 98 women who had volunteered to use an experimental intracervical device (ICD) and from 155 women who had been randomly assigned to two control groups, the levonorgestrel-releasing intrauterine device (LNG-IUD; N = 86) and the copper Nova-T IUD (N = 69). All participants were clinic patients in Helsinki, Finland. Initial analysis of 12-month discontinuation data indicated that a significantly higher percent of ICD users (22.4) discontinued their device than did either LNG-IUD (7.0) or Nova-T (8.7) users. However, we were no longer able to detect significant differences in discontinuation after controlling for baseline variables that assessed predisposition to be dissatisfied with contraception in general. Adjusted probabilities of discontinuing the ICD, LNG-IUD, and Nova-T were 11.8%, 6.2% and 7.9%, respectively. These data indicate that the ICD is likely to be acceptable to Helsinki clinic patients; moreover, they suggest a definite place for hormonal intrauterine devices in the contraceptive armamentarium. Most importantly, the methodology used here can be generalized to acceptability studies of other contraceptive devices and drugs undergoing Phase I and early Phase II clinical trials (in situations where randomization may not be feasible) in order to identify and control for the bias introduced by nonrandom assignment procedures.

PIP: 253 women aged 18-38 participated in comparative and clinical studies of 3 contraceptive devices in Helsinki during 1983 and 1985. The newest and most experimental device was the intracervical device. (ICD), currently in Phase II clinical trials. The ICD is placed in the cervical canal with its horizontal arm resting in the lower part of the uterus. On its vertical arm is a Silastic rod containing 50% levonorgestrel covered by Silastic tubing. The device releases 20mcg levonorgestrel/day. The advantages of the ICD are that it is independent of the size of the uterus, and its insertion does not require trained medical personnel. The levonorgestrel improves contraceptive efficacy, reduces pain and bleeding, and minimizes risk of infection. The control devices were the Nova-T copper IUD and the levonorgestrel-releasing IUD. The Nova-T is a plastic device with its vertical arm bound with copper wire with a silver Nova-T containing 50% levonorgestrel, released at 20mcg /day. It is currently completing Phase III clinical trials. The final study sample consisted of 98 volunteers using the ICD, 86 randomly selected women using the levonorgestrel IUD, and 69 randomly selected women using the Nova-T. All of the women were previous users of some form of effective contraception; 70-80% had used nonhormonal IUDs, and 1-8% had used hormonal IUDs. The dependent variable was the discontinuation rate during the 12-month test period. At 1st analysis, it appeared that a significantly higher proportion of ICD users (22.4%) discontinued than levonorgestrel IUD users (8.7%). However, these results reflect severe selection bias,since the 98 volunteer were self-selected and predisposed to be dissatisfied with contraceptive methods in general and IUDs in particular. 9 specific variables associated with discontinuation were identified and used to construct and IUD attitude index representing negative attitudes toward prior methods. After adjustment for these group differences through logistic regression analysis, the estimated probability of discontinuing became 11.8% for the ICD, 6.2% for the levonorgestrel IUD, and 7.9% for the Nova-T. These low probabilities of discontinuation indicate that the ICD is likely to be accepted by women and that hormonal IUDs in general are more acceptable than nonhormonal IUDs. The study also showed the importance of attitude, and therefore of counseling, in contraceptive decision-making. The most important implication of the study, however, is meaningful data can be extracted from an experimental study participants were not selected randomly.

Patterns of bleeding and body iron stores during the use of a levonorgestrel-releasing intracervical device.

A levonorgestrel-releasing intracervical device (LNG-ICD) was inserted in 198 women. The subjects registered bleeding and spotting days on special cards, which were analyzed after one year of treatment. Bleeding and spotting days gradually declined from sixteen during the first month to seven during the seventh month, and they remained under that level until the end of the first year. There were more days of spotting than bleeding. Eleven per cent of the subjects experienced at least 90 days non-bleeding interval during the first year of LNG-ICD use. There were no significant changes in blood hemoglobin concentrations during the first four years of LNG-ICD use. The mean serum ferritin concentration increased from 38 micrograms/l at the beginning to 97 micrograms/l at the end of the fourth year.

Clinical performance of a levonorgestrel-releasing intracervical contraceptive device during the first year of use.

One-hundred-and-ninety-eight women used a new type of levonorgestrel-releasing intracervical contraceptive device (LNG-ICD) designed to release 20 micrograms levonorgestrel/day. The insertion took place within 7 days of menstruation. Clinical performance during the first year of LNG-ICD use was evaluated. Seven pregnancies occurred during the study period; one in an epileptic woman using carbamazepine, 300 mg/day, and the other six in healthy women after unnoticed expulsion of the ICD. Sixteen spontaneous expulsions occurred. The most common reasons for removal were side effects, including bleeding disturbances, hormonal side effects and other medical reasons. The continuation rate was 72.6 per cent after one year. Three pelvic infections were observed.

PIP: 198 healthy, regularly menstruating women between 18-38 years of age volunteered for this study designed to evaluate a new type of levonorgestrel-releasing intracervical contraceptive device (LNG-ICD) which releases 20 mcg levonorgestrel/day. The insertion of the ICD occurred within 7 days of menstruation. Followup visits were 3 and 12 months following insertion. Subjects were asked to make additional visits if they experienced any problems with the ICD. Bimanual examination was performed, and blood pressure and body weight were measured at every visit. During the 12-month visit, a cervicovaginal smear was obtained. Life-table analysis of pregnancy and discontinuation rates were carried out according to the method of Potter. The observation period covered 1957 woman-months. The insertion of the ICD was considered to be easy by the majority of participants and by the doctor. No or minimal pain was felt by 56% and severe pain by 6% of the women. In 10% of the cases, the doctor considered the insertion to be difficult. In most of these cases, the internal os of the cervical canal was so tight that insertion was not possible without dilatation up to Hegar 4. 7 pregnancies occurred during this observation period, a net rate of 3.5. 6 of these 7 pregnancies occurred after an unnoticed expulsion of the device. 16 expulsions or partial expulsions occurred during the observation period. The primary reasons for termination were bleeding problems (4.6%), hormonal side effects (4.6%, and other medical reasons (2.6%). There was no termination because of amenorrhea. Additional reasons for termination were pain (2 subjects) and planning pregnancy (2 subjects). In 3 cases the ICD was removed because of an infection. No major changes in blood pressure were observed after 1 year of use of ICD. Cervicovaginal smears did not reveal any malignant or premalignant changes.

Vaginal contraception with gossypol: a clinical study.

A clinical study concerning the vaginal contraceptive efficacy of gossypol acetic acid was performed. Fifteen women who had undergone tubal sterilization volunteered for the study. The effect of vaginal gossypol-containing gel on spermatozoa was determined by postcoital tests performed in subjects without and after using gossypol gel. After gossypol application, the number of spermatozoa found in cervical mucus was greatly decreased and, in eleven of the fifteen women, all spermatozoa seen were immobilized. In four cases a few poorly motile spermatozoa were seen but they showed no forward progression. We have previously reported that gossypol has an inhibitory effect on herpes simplex virus type 2 in vitro. This anti-viral property of gossypol makes it particularly attractive as a topical barrier contraceptive. The present study shows that gossypol is also promising as a vaginal contraceptive agent in human in vivo experiments.

PIP: 15 women who had undergone tubal sterilization participated in a study of the vaginal contraceptive efficacy of a gel containing gossypol acetic acid. The women were aged 35 on average and had 2-3 children each. Postcoital tests (PCT) were performed 2 weeks before expected menstruation, 1 test after gossypol application, and another after a control application of the vehicle gel without gossypol in the following cycle. The gel was applied about 1 hour before coitus and the PCT was performed about 8 hours later. Gossypol treatment greatly decreased the number of spermatozoa seen in cervical mucus in 13 of 15 test subjects, and all spermatozoa seen were immobilized in 11 of the 15. Poor motility with no forward progress was seen in the other 4 test cases. In control PCTs, 11 of the 15 showed 20 or more spermatozoa per visual field with motility between 20-70%. In 3 of the control PCTs, only 2-15 spermatozoa were seen but the motility was good. The PCTs performed after application of the vehicle gel alone showed 5-30 spermatozoa per visual field and good motility indicating that gel alone had no spermicidal effect. Gossypol gel was well accepted. An in vitro test of the effect of gossypol gel on spermatozoa in cervical mucus demonstrated gradual immobilization within 3-5 minutes. In addition to its antifertility effect, gossypol has antiviral and antigonococcal properties.