LONG-ACTING HORMONAL CONTRACEPTIVE METHODS FOR WOMEN
The need for long-acting hormonal methods of contraception became apparent when experience with oral preparations showed the difficulty of maintaining a daily intake of medication. Injectable formulations, taken every two or three months, were the first alternatives to become available. Later, technological advances made it possible to deliver steroidal hormones continuously at a very low dose, thereby avoiding the unnecessary excess exposure which follows each administration. A major breakthrough was achieved in 1983 with the registration of the first implantable device, NorplantR, which offers contraceptive protection for five years. Current research aims at improving injectables and implants and also at developing long-acting hormonal methods which offer more flexibility of use for women, such as the contraceptive vaginal rings.
Injectable contraceptive formulations
In 1991, the United Nations Population Fund (7) estimated that injectable contraceptives were used by close to 13 million women in the developing world. They include approximately 10 million users of the three-monthly preparation, depot-medroxyprogesterone acetate (DMPA), 2 million users of the two-monthly preparation norethisterone enanthate (NET-EN) and 1 million users of once-a-month injectable preparations.
Progestogen-only injectable preparations
DMPA and NET-EN are the two progestogen-only injectable preparations currently available. DMPA is an aqueous microcrystalline suspension given at a dose of 150 mg every 3 months. NET-EN is an oily solution administered at a dose of 200 mg every 2 months.
Table 1 summarizes the results of several Phase III clinical trials of these methods. Both are extremely effective with one-year life-table pregnancy rates generally below 1%. This is due to a combined effect of ovulation inhibition, cervical mucus thickening and endometrial suppression. Their most undesirable side-effect is disruption of the menstrual cycle; they induce a pattern of irregular and prolonged bleeding which, in time, changes to amenorrhea. After one year of DMPA use, close to 50% women experience at least 90 consecutive days of amenorrhea (11) and this percentage increases with continued use. Many women do not tolerate this unpredictable pattern, as shown by the discontinuation rates for bleeding and amenorrhea which, combined, account for about half of the reasons for discontinuation. Other side-effects include weight gain (10) and a delay in return to fertility after discontinuation of use (2).
DMPA has been the subject of much controversy over the past 20 years, centered around potential breast carcinogenicity suggested by toxicological studies. It was then shown that the animal models used were not good predictors of human safety (4). More importantly, the results of a multinational case-control study conducted in three countries (17) provided reassurance that women who used DMPA for a long time and who initiated use many years previously were not at increased risk of breast cancer.
Research for new progestogen-only injectables aims at obtaining an improved pharmacokinetic profile with a decreased peak blood level following injection and a longer duration of action. Approaches under investigation include:
These last two approaches have led to the development of a levonorgestrel ester, levonorgestrel butanoate, as an injectable contraceptive.
Combined once-a-month injectable preparations
As estrogens were known to be an effective treatment for menstrual disturbances induced by progestogens, investigators considered the possibility of developing combined estrogen/progestogen preparations which would induce a more regular bleeding pattern. Short-acting estrogen esters were selected in order to avoid continuous exposure of the subjects to high levels of estrogen. This imposed a more frequent administration of the injection but offered the possibility of inducing a cyclic monthly pattern. The first injection is given between days 1 and 5 of a menstrual period, to ensure that treatment is not initiated when the woman is pregnant. It is soon followed by a rise in progestogen and estrogen blood levels. When the estrogen level decreases, i.e. approximately two weeks later, depending on the estrogen ester, a bleeding episode occurs which reflects this estrogen withdrawal. With monthly administration of the preparation, this phenomenon recurs on a monthly basis, giving the woman the experience of a first short cycle followed by regular monthly cycles.
A large number of contraceptive preparations were developed, however only two are used currently to any large extent, estimated as 1 million women world-wide:
Because of the need to develop alternatives which would be safe, effective and acceptable once-a-month preparations, the Special Programme of Research, Development and Research Training in Human Reproduction carried out, in collaboration with industry, the development of two products:
In comparison to the two progestogen-only injectables, DMPA and NET-EN, once-a-month preparations are equally effective but are better accepted as shown by lower discontinuation rates at one year for all reasons combined (Table 1). This is mostly a reflection of lower one-year discontinuation rates for amenorrhea and for bleeding with these preparations.
The detailed analysis of the menstrual diaries collected during these trials shows a considerable improvement in the bleeding patterns experienced by users of Mesigyna and Cyclofem over those experienced by users of DMPA or NET-EN. Between 50 and 70% of users of once-a-month preparations experience a regular monthly bleed, compared to only 3 to 9% among DMPA users (WHO, unpubl.).
Introductory trials of Cyclofem were undertaken in Chile, Indonesia, Jamaica, Mexico, Thailand and Tunisia, and are being planned in Brazil, Colombia and Peru. Cyclofem is being manufactured in Indonesia, Mexico and Thailand and is expected to be registered in these countries in 1993.
Mesigyna is a product of the Schering company which plans to launch the product in 1994. Its registration was approved in Argentina and is in process in Brazil and Mexico.
The only implant currently available is the non-biodegradable NorplantR implant (6). It consists of six Silastic capsules, each containing 36 mg of levonorgestrel and having a diameter of 2.4 mm and a length of 3.4 cm. These capsules are inserted subcutaneously in a fan-like manner in the upper arm. They release levonorgestrel at a rate of 80µg per 24h during the first 6-10 months of use. This rate declines to 30µg/24h over the next few months and is maintained at that level until the end of the five year life of the implant.
This system is highly effective with a 5-year cumulative pregnancy rate of 3.9% (3). During the first year of use, ovulations are suppressed in the majority of women; in subsequent years, about half of the women have ovulatory-like cycles but contraceptive efficacy is maintained through cervical mucus thickening. Like other progestogen-only methods, it induces menstrual irregularities, particularly during the first year. With prolonged use, the bleeding pattern improves, reflecting the return of ovulation. Other side-effects with this method include headaches, dizziness, nervousness or breast tenderness, however, these occur mostly during the first year of use and are infrequent. Return to the previous level of fertility is prompt after removal of the implants. NorplantR is manufactured and distributed by the Leiras company and is currently registered in 26 countries world-wide (3).
A second-generation system, NorplantRII, is being developed. It consists of only two rods in which levonorgestrel is homogeneously dispersed within a Silastic matrix and covered by a layer of Silastic. It will also probably offer five-year contraceptive protection.
Single implant systems are being developed, releasing a progestogen: 3-keto-desogestrel, over three years; nomegestrol acetate for one year; or ST.1435, over two years. These will have the advantage of being more easily inserted and removed than the current NorplantR system.
Biodegradable systems are also being developed, which dissolve in the body and do not require removal. Capronor II consists of 2 rods of poly(e-caprolactone) each containing 18 mg of levonorgestrel. Capronor III is a single capsule of copolymer (caprolactone and trimethylenecarbonate) filled with 32 mg of levonorgestrel. It releases the drug and biodegrades more rapidly than Capronor II. With both systems, the implant remains intact during the first year of use, thus could be removed if needed. Over the second year, it biodegrades to carbon dioxide and water, which are absorbed by the body.
Norethisterone pellets, made of 90% drug and 10% pure cholesterol, are also being developed as biodegradable systems.
It had been recognized since 1918 that the vagina is a suitable site for the administration of drugs that will reach the systemic circulation but it was not until 1968 that a patent was issued to Dr Gordon Duncan of Upjohn Ltd., which describes a vaginal ring composed of a silicone polymer which could release a number of progestational steroids for contraceptive purposes.
A number of rings are being developed, the most advanced being the levonorgestrel-releasing vaginal ring. It consists of a core containing 5 mg of levonorgestrel which is molded and then enclosed by two half rings. The thickness of the outer layer of the Silastic determines the release rate, which has been set at 20µg/day. The ring has an outside diameter of 55.6 mm and a cross-section of 9.5 mm. This device is placed in the vagina and worn continuously for 90 days, at which time it is replaced with a new one. Its effectiveness is due to a combination of effects on the cervical mucus, the endometrium and the ovarian function. Clinical trials (13-16) have shown that it is not quite as effective as the combined oral contraceptives, but is more effective than the progestogen-only pills. Approximately half of the users experience an irregular bleeding pattern, but the total menstrual blood loss is reduced compared to pre-treatment values.
This form of contraception offers a number of specific advantages:
A number of other progestogen-only rings are being developed, which release: levonorgestrel, megestrol acetate, progesterone, or ST.1435.
Other rings have been designed to deliver two hormones, a progestogen and an estrogen. They are inserted for three weeks, then removed for one week and can be used for a total of six months. A withdrawal bleeding episode occurs during the week when the ring is not used, thereby giving a regular bleeding pattern. The devices currently being tested release: norethisterone acetate/ethinyl estradiol; ST.1435/ethinyl estradiol; or 3-keto-desogestrel/ethinyl estradiol.
Long-acting hormonal methods of contraception offer new perspectives to women for the control of their fertility. They facilitate compliance and ensure prolonged contraceptive protection. New systems allow the delivery of the minimum dose required for effectiveness and thereby reduce the level of unwanted side-effects. However, their novelty also implies novel approaches in their introduction into family planning programmes, with particular attention to counselling of potential acceptors, training of health care providers and adequate support of health services.
Edited by Aldo Campana,