Treatment of endometriosis by vaginal administration of gestrinone.

The effectiveness and acceptability of gestrinone administered by vaginal route was evaluated in a group of 110 patients with endometriosis. Patients were divided into four groups. The first three groups were treated by vaginal route. Group I (n = 17) received two 2.5-mg tablets weekly; group II (n = 31) received three 2.5-mg tablets weekly; group III (n = 35) received two 5.0-mg tablets weekly. Group IV consisted of 27 patients who received 2.5 mg of gestrinone orally twice weekly. Ninety-eight women completed the 6- to 8-month treatment period. Amenorrhea developed in all treatment groups, including group I (34%). The disappearance of both dyspareunia and dysmenorrhea occurred in most patients in all treatment groups soon after the second month of therapy. Patients treated by vaginal route had significantly less seborrhea and acne than those treated by oral route. Weight gain was also significantly less in vaginally treated women than in those treated orally. Pregnancy rate following discontinuation was not significantly different for the various groups.

Intravaginal contraception with the synthetic progestin, R2010.

Four women used polysiloxane vaginal rings of core design containing 50 mg of norgestrienone (17 alpha-ethynyl-17 beta-hydroxy-estra-4,9,11,trien-3-one). The treatment was given in three-week cycles, leaving one treatment-free week between the cycles. The patterns of bleeding were registered and plasma norgestrienone (R2010), estradiol, progesterone, and gonadotropins were determined. Altogether twelve cycles were studied. The patterns of bleeding were unsatisfactory; only one subject had regular bleedings, and two of these were preceded by a luteal phase. The mean plasma concentration of norgestrienone (R2010) produced by the rings was 0.9 ng/ml. Ovulation was observed in 25% of cycles studied. Some follicular activity was present in every subject as judged by estradiol peaks. Excluding LH peaks in subjects who ovulated, mild pituitary suppression was achieved by this treatment. The only side-effect complained of was acne in one subject. The ring was regarded as easy to use.

PIP: The clinical performance as well as effects on gonadal and pituitary functions were analyzed during use of a contraceptive vaginal ring (CVR) impregnated with R2010, a synthetic progestin. 4 regularly menstruating women aged 25-29 years, who were parous and married, volunteered, and treatment was given in 3-week periods, leaving 1 treatment-free week. The CVR was a polysiloxane ring of core design and contain 50 mg of norgestrienone. Bleeding patterns were registered along with plasma R2010, progesterone, estradiol, and gonadotropins (luteinizing and follicle stimulating hormones). A total of 12 cycles were studied for this investigation. Bleeding patterns were unsatisfactory. Only 1 of 4 subjects had regular, simulated menstrual bleedings; 2 of these bleedings were preceded by a luteal phase (according to hormone assays). Mean plasma concentration of the progestin produced by the rings was .9 ng/ml. In 25% of the cycles ovulation was observed; in addition, some follicular activity was present in all 4 subjects, based on measurement of estradiol peaks. Mild pituitary suppression was achieved in the 3 subjects who did not ovulate. An acne flare-up constituted the only reported side effect.

Release of contraceptive steroids from sustained release dosage forms and resulting plasma levels.

The correlations of plasma levels of levonorgestrel, megestrol acetate and norgestrienone with the doses delivered from subdermal implants and contraceptive rings have been examined. Differences in plasma levels as large as three-fold between different subjects receiving nearly identical doses were observed with all three steroids. The relative plasma levels seen from one subject to another showed high consistency over time. Part of the explanation may lie in differing levels of sex hormone binding globulin, but additional factors must be operative since megestrol acetate binds only weakly with this carrier.

Clinical trial with subdermal implants containing norgestrienone.

Norgestrienone implants delivering approximately 225 microgram/ day were tested clinically for contraceptive effectiveness and acceptability in 145 women. Five pregnancies occurred in 2259 woman-months of use, one in the 11th month, one in the 15th and three in the 16th month of use. Continuation rate at 12 months was 86.7. The number of bleeding runs and bleeding days was increased in approximately 12% of the subjects. Ten percent of the patients had no bleeding in the first 90 days of treatment. Changes in bleeding pattern led to closures in four cases. Headache and signs of mild androgenicity were among the leading side effects. Blood and urine analysis throughout the study showed normal values of 17 different parameters, but a tendency to lower cholesterolemia not associated with changes in thyroid hormone levels, was observed in several patients. Cortisol was found slightly under the lower normal range in one subject without clinical manifestations of hypoadrenalism. It is concluded that norgestrienone implants should be replaced every twelve months for maximal contraceptive effect and because of their efficacy and good acceptability, evaluation of their long term use is warranted.

Eighteen months contraception following subdermal insertion of silastic capsules containing norgestrienone.

PIP: The contraceptive effect of 6 subdermal silastic implants containing norgestrienone was investigated in 659 women of reproductive age for a period of 2 years. 402 subjects completed 1 year of use, 315 women completed 18 months of use, and 283 completed 2 years of use. A total of 8942 woman-months were recorded. 20 pregnancies occurred. 12 pregnancies occurred after 18 months of use. Only 4 pregnancies occurred during the 1st year of use when 7022 woman-months were recorded. The Pearl Index for the 1st year was .6. For 18 months, the Pearl Index rose to 1.2 and for the 2nd year to 2.6. Most important side effects were bleeding irregularities. 23% of subjects missed the 1st expected period following the insertion of the capsules and approximately 20% of all subjects had at least 1 nonbleeding interval longer than 45 days. The incidence of amenorrhea diminished towards the end of the treatment to attain 10% at 1 year and only 5% at 18 months. 361 women (54%) had regular bleeding episodes with mean interval of 29.5 days (standard deviation 1 /SD/ 1 = 3.9) and a duration of 2-6 days (mean 4 SID = 1.9). Intermenstrual bleeding was reported by 8% of the subjects during the 1st month, but only 2% after the 3rd month of use.^ieng

[Preliminary trials of an oral chemical contraceptive for men]. / Premiers essais d'une contraception chimique par voie orale chez l'homme

PIP: R 2323 (13-ethyl, 17 alpha-ethyl, 18-hydroxy-gona-4,9,11-trien-3-one) was administered orally, 50, 75, or 100 mcg/week in 2 or 3 divided doses with or without 3 100 mg testosterone implants to arrest spermatogenesis, to 20 healthy men 25-35 years of age with at least 2 children. There were 3 dropouts, 1 for a high triglyceride level. 7 men became azoospermic within 2-3 months after the combined treatment and 8 after receiving 75 or 100 mg/week of R 2323 only. No abnormal sperm forms appeared. Side effects were weight gain of 2-8 kg chiefly with the combined schedule. Libido declined in 3, erective capacity decreased in 2, and coital frequency fell in 8. 1 case of gynecomastia appeared after 4 months. 1 man had a superficial thrombosis in the left arm at the site of a biopsy for polyadenopathy. Testosterone fell from 5 to .5 ng/ml and follicle stimulating hormone and luteinizing hormone from 5-1 mIU/ml in both groups. The only remarkable change in a biological parameter was an increase in transaminase, especially SGPT, 25-50%. Testosterone and gonadotropins returned to normal within 1 month after stopping steroids, and sperm counts within 3-4 months. The testosterone implants failed to prevent plasma testosterone levels from falling, and seemed to cause more side effects such as weight gain and loss of libido than did R 2323 alone.^ieng

Contraceptive effectiveness of Silastic implants containing the progestin R-2323.

PIP: The long-term contraceptive effectiveness of subdermal silastic implants containing 30-40 mg of the progestin R-2323 (13-ethyl-17 alpha ethinyl-17 hydroxy-gona-4, 9,11-trien-3-one), was studied in 531 women. 98 women received 2 capsules (Group A), 180 received 3 capsules (Group B), 181 received 4 capsules (Group C) and 68 received 5 capsules (Group D). There were 5 pregnancies reported for Group A over 610 months of use, 3 pregnancies for 2124 months of use in Group B, 4 pregnancies for 2128 months of use in Group C, and Group D had 3 pregnancies over 732 months of use. All of the pregnancies in Group A occurred in the first 4 months while pregnancies in the other 3 groups generally occurred between Months 6-12 of use. Amenorrhea was most frequent during Months 2-6. The frequency of spotting and breakthrough bleeding was minimal.^ieng