Contraception, Modern Methods of

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CONTRACEPTION, MODERN METHODS OF

Human reproduction is regulated by a synchronized series of events that result in the production of mature sperm and eggs and the preparation of the woman's reproductive tract to establish and maintain a pregnancy. With a growing understanding of the links in the chain of reproductive events, opportunities to advance contraceptive technology have also increased.

Throughout human history, most societies and cultures have understood that sexual intercourse introduces the male factor responsible for fertilization. Consequently, for centuries people attempted to prevent pregnancy by the simple and direct procedure of withdrawing the penis prior to ejaculation. This practice, termed withdrawal or coitus interruptus, has a slang name in virtually every language. In relatively recent times, mechanical barriers or chemicals introduced into the vagina in various formulations have been employed to thwart the sperm. Sperm have been confronted with vulcanized roadblocks or been plunged into creams, ointments, gels, foams, or effervescent fluids containing mercurial compounds, weak acids, soaps, or biological detergents. Strange concoctions used or recommended have ranged from crocodile dung in antiquity to Coca Cola in the twentieth century. Post-coital douching also became popular early in history.

Contraceptive technology finally caught up with modernity when hormones were discovered and scientists turned their attention to the woman's ovulatory cycle. The principle of periodic abstinence timed to avoid coitus near the day of ovulation was the first method of fertility regulation that relied on this new knowledge. This contraceptive method was developed in the 1920 when, independently, two scientists, a Japanese, Kyusaka Ogino, and an Austrian, Herman Knaus, in 1925 recognized that a woman should avoid sex around the middle of a menstrual month if she did not intend to become pregnant.

The Ogino-Knaus method was based on emerging understanding about the endocrinology of the ovarian cycle in women, establishing that ovulation occurs about fourteen days before the first day of the next expected menstrual flow. These pioneer endocrinologists understood when the egg would be released although they did not know how long it remained fertilizable, or how long sperm survive in the fallopian tube. Scientists now estimate that the egg remains viable for one day after its release from the ovary and that the sperm retains its viability in the female tract for six or seven days.

Hormonal Contraceptives for Women

It was several decades before the necessary knowledge was marshaled to develop effective means to prevent ovulation medically and launch the era of hormonal contraception.

The pill. Gregory Pincus, Director of the Worcester Foundation for Experimental Biology in Massachusetts, led the scientific effort that resulted in the first oral contraceptive, recognized around the world simply as the pill. Before the pill, twentieth century couples had a limited choice of contraceptive methods, largely ineffective unless used with great diligence. A 1935 survey revealed that contraceptive use in the United States was evenly divided among the condom, douche, rhythm, and withdrawal. Failure rates must have been high, forcing many women to choose between high fertility or illegal and unsafe abortions. Since 1960, when the U.S. Food and Drug Administration (FDA) first approved the pill, more than 130 million women have used the method, avoiding multitudes of unwanted pregnancies and abortions.

Oral contraceptives suppress ovulation using a combination of estrogen and progestin. By 2000, over 50 products with different progestins, lower doses, and various schedules of administration had supplanted the original pill. Some products offer a change in dose over the month, attempting to mimic the hormonal levels of the ovarian cycle. The main modification has been a significant lowering of the amounts of both hormones delivered. Modern oral contraceptives contain less than one-twentieth of the dose of the original pill, which results in a lower incidence of side effects.

The pill has been the subject of greater post-marketing surveillance for safety than any other pharmaceutical product. A study published in 1999 reported on 25 years of follow-up of over 45,000 women. Countless other studies have documented not only the safety but also the non-contraceptive health benefits of oral contraceptives: decreased risk of endometrial and ovarian cancer; decreased risk of colon cancer; decreased anemia; decreased dysmenorrhea; and maintenance of bone density. Oral contraception use also reduces the incidence of benign breast disease (cysts) and does not increase the overall risk of breast cancer, but there are uncertainties regarding long-term use for those who start using the method when they are teenagers. If there is an added health risk, it appears to be small and may be offset by careful surveillance.

Since it was first introduced, the pill has been marketed as a three-week-on and one-week-off method, thus creating a monthly pseudomenstruation. Over the years, some doctors have counseled women to take the pill continuously to avoid menstruation, both for convenience and for medical reasons. Seasonale®, the first product designed for longer uninterrupted use (for three months at a time) was undergoing final testing for FDA approval in 2003.

Beyond the pill, hormonal contraception has evolved to include the continuous use of a progestin alone by oral administration (the minipill), by injection, or by sub-dermal implants. New delivery systems for estrogen/progestin contraception have created a birth control skin patch and a vaginal ring contraceptive.

Contraceptive injections. Elsimar Coutinho, a Brazilian gynecologist, was the first to demonstrate that injections of 150 mg of the synthetic progestin medroxyprogesterone acetate (Depo-Provera®) can inhibit ovulation for three-month durations. After several decades of use for other gynecological purposes, Depo-Provera® was approved as a contraceptive in the United States in 1993. It offers a high level of effectiveness in preventing pregnancy (99.7%) and the ability to suppress menstruation. An injection every three months replaces the need to remember to take a pill every day. By not having a monthly period, women can avoid monthly cramps, and reduce their risk for endometriosis and uterine fibroids. Although it is as effective as surgical sterilization, the method is reversible; women who wish to become pregnant after stopping the drug usually do so within a year. Because it has no estrogen, this method does not maintain normal bone density, hence it could lead to the development of osteoporosis. An alternative system that addresses this problem combines Depo-Provera® with ethinylestradiol, the estrogen found in many oral contraceptives, taken as a monthly injection. With this system, a woman has a monthly menstruation, and maintains bone density.

Contraceptive implant. Another drug delivery system that provides acontinuous dose of progestin is the sub-dermal implant. The first contraceptive implant was NORPLANT®, developed by scientists at the Population Council in New York. It consists of six flexible tubes of Silastic® containing the progestin levonorgestrel. The contraceptive steroid is released at a slow and relatively constant rate for 5 years. This long-acting characteristic is the main advantage of this and other implant systems. In the case of NORPLANT®, one visit to a clinic for the simple insertion procedure replaces taking a pill daily for five years. Ovulation-suppression is the main mechanism of action. During the first two years of use 80 percent to 90 percent of cycles are clearly anovulatory (no eggs are released). By the fifth year about 50 percent of cycles are ovulatory. The high level of contraceptive protection (99.8%) covering the entire five-year span depends on an additional mechanism of action: the prevention of sperm from ascending into the female reproductive tract, so that fertilization cannot occur. This is achieved through an effect on the woman's cervical mucus. In a normal cycle, the mucus becomes less viscous and more abundant at about mid-cycle, facilitating sperm transport when ovulation is about to occur. In Norplant® users, the mucus remains scanty, thick, and impenetrable to sperm.

Other implant systems have been developed that last for one year or three years, and have the advantage of reducing the number of implants, thus simplifying the insertion and removal procedure. The first single implant method, a three-year system, is IMPLANON®, which contains the progestin etonorgestrel, a so-called third-generation progestin. Another three-year system, JADELLE®, contains the contraceptive hormone levonorgestrel. By 2002, JADELLE® had received FDA approval; IMPLANON® is used in many European countries.

Vaginal ring contraceptive. Nuva Ring® is the first monthly vaginal ring for contraception. A woman using the vaginal ring inserts and removes it herself so that it is not a clinic-dependent method. This novel contraceptive was approved for marketing in the United States in 2001. It is based on the combined release of a low dose of progestin and estrogen over a 21-day period of use. The steady flow of hormones (etonorgestrel and ethinyl estradiol) prevents ovulation as its main mechanism of action. Women begin using Nuva Ring® around the fifth day of their menstrual period, and leave it in place for three weeks. The ring is removed for a week so that a menstrual flow can occur, and a new ring in placed in the vagina for the next cycle. Since it is not a barrier method, the exact positioning of the ring is not important for its effectiveness (about 99%).

Birth control patch. The ORTHO EVRA™ birth control patch was approved by the FDA in 2001. This transdermal system delivers the combination of a progestin and estrogen (norelgestromin/ethinyl estradiol) in a one-time weekly dose. The system is 99 percent effective. The thin, beige patch delivers continuous levels of the two hormones through the skin into the bloodstream. A new patch is used weekly for three consecutive weeks. The fourth week is patch-free so that a menstrual-like bleeding can occur. Like other hormonal contraceptives, the primary mechanism of action is ovulation suppression. Other contraceptive patches are being developed. One of these employs a transparent material to make the patch less evident, particularly for women with darker skin.

Progestin-releasing intrauterine system. Late in 2000, the FDA approved a levonorgestrelreleasing intrauterine system that had been available in Europe for 10 years. Developed by Population Council scientists, MIRENA® is a long-acting contraceptive that lasts for five years, and is more than 99 percent effective. In addition to its ease of use for women, it has the advantage that menstrual periods tend to become shorter and lighter. Some women experience an absence of menstrual bleeding after one year. Studies suggest several mechanisms that prevent pregnancy: thickening of cervical mucus, which prevents the passage of sperm, inhibition of sperm motility, and suppression of endometrial growth. Approximately eight out of every ten women who want to become pregnant will establish a pregnancy in the first year after MIRENA® is removed. Insertion and removal of MIRENA® is a short procedure done by a trained health care professional.

Emergency Contraception

Post-coital contraception that could prevent a pregnancy from becoming established has been possible for several decades. During the 1960s, orally active estrogenic products were shown to initiate menstrual-like bleeding when taken within a few days of unprotected intercourse. Bleeding and sloughing of the uterine lining means that pregnancy cannot take place even if a fertilized egg is present. In the 1960s, the product used most frequently to cause this was diethylstilbestrol (DES). Subsequently, it was demonstrated that a high dose of the conventional pill, a combination of estrogen and progestin, when taken up to 72 hours after intercourse can prevent pregnancy from becoming established. Now referred to as "emergency contraception," several products have been sold in European countries for many years and two were introduced in the United States in 1999. Prevens® consists of four high-dose oral contraceptive pills all to be taken within 48 hours. A second product, marketed initially in Hungary, is a progestin-only product that causes far fewer of the transient side effects of the combination pill. It is distributed in the United States under the name Plan B®.

Emergency contraception does not work by terminating an early pregnancy. Its action is prior to implantation.

Nonhormonal Intrauterine Devices (IUDs)

Modern inert IUDs. The most widely used reversible contraceptive by global count in 2001 is not any of the hormonal methods but the intrauterine device. The IUD is little used in the United States, but has 120 million users in the developing countries. (It accounts for more than half of all couples using reversible contraception in China, Cuba, Turkey, and Vietnam.) The IUD is also commonly used in Europe: For example, it is used by 30 percent of contracepting women in Sweden and Norway. Its appeal lies in simplicity of use, ease of reversibility, absence of medical side effects, low cost, and high effectiveness.

Modern IUD research began at about the same time that the final stages of research on oral contraceptives were in progress. Despite intensive research, scientists do not fully understand why the presence of a foreign body in the uterus prevents pregnancy. The evidence clearly indicates that the IUD is a prefertilization method: The presence of fertilized eggs in IUD users cannot be demonstrated.

Copper-releasing IUDs. The Lippes loop and other plastic IUDs of the 1960s were highly effective compared to other contraceptive methods, but the real breakthrough in effectiveness occurred when copper-releasing IUDs were developed. This started as a small laboratory research project by Jaime Zipper in Santiago, Chile. It is not known why the release of copper in the uterus is so effective in preventing pregnancy. There is evidence from animal studies that the copper ions released from the copper wire attached to the plastic IUD act to stop most sperm before they reach the fallopian tube, but there are probably other mechanisms of action, as well, that account for the high level of effectiveness in preventing pregnancy. In a seven-year study, the World Health Organization found that the contraceptive effectiveness of the Copper T-380A is equal to that of surgical sterilization. The device maintains its effectiveness for 10 to 12 years. It can be realistically described as reversible sterilization.

Table 1 compares the contraceptive effectiveness of the major modern contraceptive methods in use in 2002, and updated from Hatcher (1998), for which there are adequate data based on a variety of studies.

TABLE 1

The fertility transition in less developed countries will have to be accomplished essentially using the present armamentarium of contraceptive devices in combination with other methods of birth control. New contraceptives will need to offer broader product profiles. Couples will be looking for non-contraceptive health benefits, particularly for the prevention of sexually transmitted diseases. High priority is being given to developing a vaginal gel that is microbicidal and spermicidal so that women, on their own initiative, can use a contraceptive that will protect them from sexually transmitted disease including HIV/AIDS. New products have been designed that emphasize menstruation suppression. This option provides health benefits and gives women control not only of when they will have a pregnancy, but if and when they will menstruate.

Contraceptives Used by Men

The development of methods of contraception that would be used by men is promising. The condom and the vasectomy operation are effective because they prevent sperm from entering the female without interfering with the male libido or potency. The development of a medical method that would stop sperm production would be easy; however, most approaches either inhibit the man's production of testosterone or elevate levels to an unsafe height. This problem can be overcome by the use of a testosterone-like compound, MENT®, that acts as a substitute for testosterone in many beneficial ways while suppressing sperm production and protecting the prostate gland against hyper-stimulation. MENT® is being studied in Europe for possible use as hormone replacement therapy in aging men but once on the market for that purpose, possibly in 2003, its use as a male contraceptive would be evident. There is also considerable basic research on approaches that would not inhibit sperm production but would interfere with the final maturation processes of the sperm once they leave the testis. This would make the sperm unable to fertilize eggs.