[Current status of contraceptive vaginal rings]. / Etat actuel des anneaux vaginaux contraceptifs.

PIP: Vaginal administration of contraceptive steroids has several advantages over oral administration, including avoidance of the digestive tract and the 1st passage effect, continuous release of the active principle allowing lower doses and fewer side effects, independence of the method from sexual relations, and possibility of application directly by the user. An early vaginal ring containing medroxyprogesterone acetate in silastic inhibited ovulation but released the progesterone in large initial bursts followed by rapid decline, offering no advantage over parenteral administration. The problem was resolved through development of a vaginal ring with an inert core covered with a fine layer of a mixture of silastic and progesterone, in turn covered by a fine layer of silastic. The speed of release of the new ring was proportional to t he surface of the ring and inversely proportional to the thickness of the outer layer. This method was used to release variable quantities of levonorgestrel over 3-6 cycles, which inhibited ovulation in 85% of users but provided only mediocre cycle control. The World Health Organization at about the same time was sponsoring research focussed on development of a vaginal ring releasing small doses of progestins with a minimal blocking of ovulation but a major contraceptive effect at the level of the cervical mucus and endometrium. Several progestins were evaluated and dose-response tests were conducted on a number of them. A ring releasing 20 mcg/day of levonorgestrel was found to cause fewer cycle problems and to have a moderate affect on ovarian function. The Population Council in New York developed a method adding estrogen to the progestin to resolve the problem of irregular bleeding and obtain better cycle control. Development was halted despite promising results because of difficulties of mass production and the results of metabolic studies that indicated the method had undesirable effects on lipoprotein levels. But large scale multicountry trails with the levonorgestrel-releasing ring continued to give positive results. Bleeding problems, when they arose, were less serious than those with low-dose oral progestins. The efficacy was at least equal. A detailed study of social acceptability found the level of acceptability of the vaginal ring to be high, with women appreciating their ability to remove the ring themselves. Despite the favorable results, marketing of the levonorgestrel vaginal ring was delayed by problems in mass production and in procuring adequate supplies of silastic. Recent developments have included new lightweight plastics and a model that allows the ring to be divided into sections. A multicenter study is underway of a ring releasing 120 mcg of desogestrel and 30 mcg of ethinyl estradiol. Results have been very favorable. A vaginal ring is likely to be commercially available by 1995.^ieng

Serum pharmacokinetics of orally administered desogestrel and binding of contraceptive progestogens to sex hormone-binding globulin.

Serum levels of 3-ketodesogestrel and ethinyl estradiol were analyzed by radioimmunoassay in a balanced crossover study with two tablet formulations containing desogestrel (0.150 mg) and ethinyl estradiol (0.030 mg) in 25 women under steady-state conditions after 21 days of treatment. The pharmacokinetic properties of desogestrel were characterized by the following parameters: (1) maximum serum concentration, (2) time to maximum serum concentration, (3) total area under the serum concentration versus time curve, and (4) serum half-life of elimination. The interindividual variation in these parameters was comparable with that observed with other contraceptive combinations containing ethinyl estradiol and norethisterone, levonorgestrel, or gestodene. The serum distribution of contraceptive progestogens is known to be determined by their affinity to sex hormone-binding globulin and the concentration of sex hormone-binding globulin. We analyzed the structural features that determine binding to sex hormone-binding globulin. The 18-methyl group increased and the 11-methylene group weakened the binding to sex hormone-binding globulin. The double bond at C-15 reinforced the binding only when combined with an 18-methyl group. Therefore, the binding of levonorgestrel (the 18-methyl derivative of norethisterone) and gestodene (the delta-15,18 methyl derivative of norethisterone) to sex hormone-binding globulin was much stronger than that of 3-keto-desogestrel and norethisterone.

PIP: Serum levels of 3-ketodesogestrel and ethinyl estradiol (EE) were analyzed by radioimmunoassay in a balanced crossover study with 2 tablet formulations containing desogestrel (0.150 mg) and EE (0.030 mg) in 25 women under steady-state conditions after 21 days of treatment. The pharmacokinetic properties of desogestrel were characterized by the following parameters: maximum serum concentration, time to maximum serum concentration, total area under the serum concentration vs time curve, and serum 1/2 life of elimination. The interindividual variation in these parameters was comparable with that observed with other contraceptive combinations containing EE and norethisterone, levonorgestrel, or gestodene. The serum distribution of contraceptive progestogens is known to be determined by their affinity to sex hormone- binding globulin (SHBG) and the concentration of SHBG. The authors analyzed the structural features that determine binding to SHBG; the 18- methyl group increased and the 11-methylene group weakened the binding to SHBG. The double bond at C-15 reinforced the binding only when combined with an 18-methyl group. Therefore, the binding of levonorgestrel (the 18-methyl derivative of norethisterone) and gestodene (the delta-15, 18 methyl derivative of norethisterone) to SHBG was much stronger than that of 3-ketodesogestrel and norethisterone.

Clinical performance and endocrine profiles of contraceptive vaginal rings releasing 3-keto-desogestrel and ethinylestradiol.

The clinical performance and endocrine profiles of contraceptive vaginal rings (CVR) with an in vitro daily release rate of 15 micrograms of ethinylestradiol combined with 75, 100 or 150 micrograms 3-keto-desogestrel were evaluated. Two studies were performed; one with 11 volunteers, consisting of a control cycle, a cycle with an oral preparation (Marvelon), followed by two CVR treatment cycles, and a second study with 12 volunteers, having the same design but one CVR treatment cycle. A dose-response relationship was seen in the endocrine and clinical performance of the CVR. With CVR 75/15, ovulation occurred in two subjects, and increases in serum estradiol concentrations were seen in two additional subjects. With CVR 100/15, slight estradiol increases were seen in four subjects, but progesterone remained low. With CVR 150/15, both estradiol and progesterone serum concentrations remained low. With CVR 75/15 extra bleeding was common, but with CVR 150/15 this did not occur. No major side effects occurred, and no abnormal Papanicolaou smears or histological findings of the endometrium were found. All volunteers completed all cycles, and the three-week CVR use was generally well accepted. In conclusion, the release rate of CVR 75/15 was insufficient. A vaginal ring with a daily release rate between 100 and 150 micrograms of 3-keto-desogestrel in combination with 15 micrograms of ethinylestradiol seems suitable for contraceptive purposes, and will be further tested in larger clinical studies.

The clinical acceptability of a non-medicated vaginal ring.

In an open study the acceptability of a newly designed vaginal ring was evaluated. The ring, being developed for contraceptive purposes, was made of Silastic and did not contain any medication. Three groups of 10 healthy female volunteers were selected after informed consent. The 6 nulliparous and 24 parous women were equally distributed over the 3 groups. The volunteers were instructed to insert the ring as high in the vagina as possible. In each group a ring of a different stiffness was used for 3 cycles. The first cycle started with the insertion of the ring on day 5 of the menstrual cycle or on the day oral contraception was started. Each cycle consisted of 21 days of vaginal ring use, followed by a 7-day ring-free interval. Expulsions, reasons for removal and complaints were recorded. Vaginal cultures were obtained before insertion and after the third cycle. The vaginal ring was well accepted. There were no differences between the three groups of women using rings of different stiffness. Twenty-two women completed all 3 cycles. Four women (3 nulliparous) stopped after one day. One of the nulliparous women who stopped after one day complained of expulsions, the only one in the study. The 4 women who stopped after a longer period were all parous. In the first cycle several women complained of vaginal discharge, coital problems or foreign body feeling. The complaints decreased in the second cycle and almost disappeared in the third. The rings had no influence on the vaginal flora.

An oral contraceptive particularly suitable for women over 35.

PIP: Fertility control for women aged 35 and over is a concern that requires consideration of specific needs and technologies. Orally active steroids are considered the best method available among all the methods of contraception. The steroids are highly beneficial as they are effective and reversible. As well, they prevent the onset of osteoporosis and regulate menstrual bleeding. However, they do hide the symptoms of menopause and along with them come adverse side effects. A study of 434 women by 70 general practitioners and gynecologists was conducted to determine the cycle control and side effects of a combined oral contraceptives (OC). The women, aged 30 and older, were given one tablet containing 0.150 mg desogestrel and 0.020 mg ethinyl estradiol for 21 consecutive days. The results demonstrated the high effectiveness of this combination of desogestrel and ethinyl estradiol as a contraceptive (no pregnancies were recorded). It also proved an acceptable method of cycle control. Formerly, estrogens have been denounced for their side effects, but new compounds have proven effective, safe and beneficial.^ieng