Vaginal contraceptive rings: Option for the new millennium

Combination and progestin-only rings now under advanced research

Think of your challenging family planning cases: the patient who forgets to take her birth control pill; the woman who likes a long-acting method but doesn't want to come in for injections; and the nursing mother who needs reliable, safe contraception. With advanced research trials now under way, clinicians in the next few years may see the introduction of vaginal contraceptive rings that will address the needs of those women.

The Center for Biomedical Research, the research arm of the nonprofit Population Council of New York City, has spent 20 years developing ring formulations. One ring, using a combination of 20 mcg ethinyl estradiol and 1 mg of norethindrone acetate, has been passed on to an undisclosed commercial partner for further studies leading toward market introduction, says Theodore Jackanicz, PhD, senior scientist with the council.

An even more promising development lies in another Population Council-designed ring, which combines an even lower dose of estrogen with its own trademarked NESTORONE progestin. "With our new potent progestin, we have been able to reduce the ethinyl estradiol level from 20 to 15 mcg, and perhaps to 10 mcg," Jackanicz says.

Organon of West Orange, NJ, is in phase III trials with a ring utilizing 15 mcg of ethinyl estradiol and the progestin etonogestrel. It expects to complete its research by mid-1999, says Joel Krasnow, MD, associate director of medical services.

With the introduction of the vaginal ring, a simple, long-acting, woman-controlled method will be added to the list of contraceptive choices.

"Implants and IUDs are good methods, but some women want their method literally in their own hands," Jackanicz says. "They don't want to have to depend on a health facility to discontinue it."

Look at ring design

The contraceptive ring is a flexible, lightweight, doughnut-shaped device that is inserted in the vagina. Offered in one size, the ring is smaller than most diaphragms and does not require fitting, Jackanicz says. "A diaphragm must protect the cervix from the onslaught of the sperm. The ring is a platform from which the drug is released and is absorbed by the vaginal tissues."

Diaphragms range in size from 50 to 95 mm, while the rings developed by the Population Council are 58 mm by 8.4 mm in cross section and weigh about 10 g, Jackanicz says.

Once a woman receives instruction on proper use, she can insert and remove the ring herself. Combination estrogen/progestin rings now under development call for three weeks of use and one week of rest. Prototype progestin-only rings have employed three-month, six-month, and even yearlong schedules.

Women grasp the three week/one week concept because it is similar to the birth control pill schedule, Jackanicz says. The schedule is easy to remember, he says, because a woman will take the ring out on a given day, then reinsert it on the same day of the week seven days later. An alternate four-day schedule is being examined, which would reduce the number of bleeding days per month. That schedule would call for more adherence to a calendar, however, because the ring would be taken out on one day and reinserted on a different day of the week, Jackanicz says.

While the composition of the ring may vary (the Population Council-designed rings are made of a silicone rubber polymer, while Organon is testing a non-silicone model), the design offers a slow, gradual release of hormones that is easily absorbed, Krasnow says.

"Instead of having a pill, where you get a large amount of hormone then nothing for the rest of the day, you get a continual release, which is much more physiologic, more like the actual way that hormones tend to be secreted like the ovary would secrete them," he notes.

Krasnow sees the low dose of estrogen used in the combination vaginal rings as a distinct benefit of the method. "The Food and Drug Adminis tration's recommendation to go to the lowest- dose contraceptive regimen possible is able to be pushed even more because of the fact that you don't have a first pass effect," he says. "You're dealing with 15 mcg of ethinyl estradiol, which is lower than the lowest dose pill."

One of the biggest advantages of using the combination ring is the maintenance of regular menstrual cycles, Jackanicz says. The amount of breakthrough bleeding while the ring is in place is low, he reports. Dose-finding studies demonstrated that a ring with 20 mcg of ethinyl estradiol and 1 mg of norethindrone acetate provided better cycle control than a combined oral contraceptive delivering one-third more of the same progestin and estrogen.1 Subjects using NESTORONE/ ethinyl estradiol rings delivering either 15 or 20 mcg of estrogen had excellent menstrual patterns, and a 10 mcg ethinyl estradiol ring is now under investigation.

Cycle control plays a large role in acceptability of any contraceptive method. Studies of progestin-only vaginal rings have found that poor cycle control plays a large factor in discontinuation of the method.2,3

Women who have participated in clinical trials of the combination rings like the simplicity of the method, Jackanicz and Krasnow agree. The most common side effect found with the Population Council's ethinyl estradiol/norethindrone acetate ring was nausea, usually within 24 hours of insertion of a new ring.4 This has not been a problem with the NESTORONE/ethinyl estradiol ring, Jackanicz says.

"The side effects we are seeing are similar to those with any hormonal contraceptive," Krasnow says. "You have the usual incidence of general aches and pains, bloating, headaches, things like that. Our expectations are that it compares favorably with other alternatives."

Researchers are investigating both combination and progestin-only rings for potential vaginal irritation. Investigators at one research site reported instances of vaginal erythematous areas in users of a levonorgestrel (progestin-only) vaginal ring.5 The Population Council found no marked or untoward problems with its combination and progestin- only rings, Jackanicz says. Population Council researchers have standardized their interpretation of colposcopic observation so data can be compared between research sites.

It's important to remember that the condition of the vagina and cervix is not static, Jackanicz notes. Irritation may appear one month, only to vanish by the next. This irritation can occur in women who use vaginal rings or birth control pills or who are sterilized. Vaginal irritation is one of the variables Organon is examining in its phase III trial, Krasnow says. As those data come in, "we'll be able to tell, but clearly, when you have a foreign body, there's a potential for concern."

Next in the research and development pipeline is the progestin-only ring. It offers excellent contraception for nursing mothers because it contains no estrogens that can be passed through breast milk to the infant. A study comparing nursing mothers using progesterone-only rings and IUDs found that the two groups had comparable success in pregnancy prevention and ability to continue nursing their infants.6 This ring has been licensed to Laboratorios Silesia, SA, a company in Santiago, Chile, that will manufacture and distribute the ring in Latin America.

A study is in progress with a NESTORONE-only ring in lactating women. "The woman can use the NESTORONE ring for as long as she's nursing, say five to eight months," Jackanicz notes. "After weaning, she can continue using it, or she could switch to something else without a big effort on her part."

Organon has chosen to focus first on a com bination estrogen/progestin ring, Krasnow says. With more women using a combined hormonal approach to contraception, the company is moving to meet that need in the marketplace, he adds.

References

1. Ballagh SA, Mishell DR Jr., Jackanicz TM, et al. Dose-finding study of a contraceptive ring releasing norethindrone acetate/ethinyl estradiol. Contraception 1994; 50:535-549.

2. Buckshee K, Kumar S, Saraya L. Contraceptive vaginal ring - a rising star on the contraceptive horizon. Adv Contracept 1990; 6:177-183.

3. Koetsawang S, Ji G, Krishna U, et al. Microdose intravaginal levonorgestrel contraception: a multicentre clinical trial. II. Expulsions and removals. World Health Organiza tion. Task Force on Long-Acting Systemic Agents for Fertility Regulation. Contraception 1990; 41:125-141.

4. Weisberg E, Fraser IS, Lacarra M, et al. Effect of different insertion regimens on side effects with a combination contraceptive vaginal ring. Contraception 1997; 56:233-239.

5. Bounds W, Szarewski A, Lowe D, et al. Preliminary report of unexpected local reactions to a progestogen- releasing contraceptive vaginal ring. Eur J Obstet Gynecol Reprod Biol 1993; 48:123-125.

6. Sivin I, Diaz S, Croxatto HB, Miranda P, et al. Contraceptives for lactating women: a comparative trial of a progesterone-releasing vaginal ring and the copper T 380A IUD. Contraception 1997; 55:225-232.