In search of a second contraceptive revolution

Hormonal agents 

Many of the contraceptive methods in use today have a long history, though most methods have been improved over the years. The first full reports on the use of depot-medroxyprogesterone acetate as a long-acting injectable contraceptive for women appeared in 1966.9, 10 Other steroids were tested for greater effectiveness around the same time, with norethisterone enanthate (NET-EN) emerging as a possible alternative.11 This steroid is an approved contraceptive in many countries, but it is still not approved in the United States, meaning that no centers in the US will be able to participate in the upcoming Phase III study of testosterone undecanoate and NET-EN for long-acting contraception in men.

The first animal studies of steroids released from Silastic (silicone) implants were published in 1968,12 and this was quickly followed by a contraceptive efficacy study in women using implants containing megestrol acetate.13 Other steroids (such as NET) were evaluated but, except for norgestrel, were less effective.14 The Population Council was responsible for the development of both the 6-rod and 2-rod systems for releasing levonorgestrel. The 6-rod system is no longer marketed, but the second-generation implant system of 2 rods (Jadelle) is available in 20 countries, and will soon be available in the US.

The first studies to use a vaginal ring for contraception were reported in 1970.15 The initial device was a 70- to 80-mm ring impregnated with medroxyprogesterone acetate. There have been many subsequent iterations of this basic design, including different ring sizes, different steroids, and different release rates. Some intravaginal rings are designed to be used on a 3-week-in and 1-week-out schedule, while other rings are meant to be worn continuously.

The first pilot study using large doses of estrogen to prevent pregnancy after mid-cycle unprotected intercourse was reported in 1967.16 Preliminary reports of successful clinical trials then followed.17, 18 Later, in a large-scale trial of 4,631 women studied for 41,802 cycles, d-norgestrel was found to be an effective contraceptive when given in doses from 150 to 400 mg within 2 hours of intercourse. At the highest dose, the failure rate was 3.5 per 100 women-years.19

Intrauterine devices 

One of the most notable early reports on IUDs involved the eponymous Graefenberg silver ring, which was tested in 600 women in the early 20th century.20 This was followed in the 1930s by the evaluation of a modified Graefenberg ring designed by Ota, which appeared more effective than the original ring.21 Yet, despite the apparent efficacy of these IUDs, medical opinion at the time was against this approach to contraception and work ceased until 1959, when reports of good success with other vaginal rings were published.22, 23

Since then, a variety of different IUD designs have been tested, starting with alternative inert components and evolving to the first copper-24 and hormone-releasing devices.25 Although IUDs are widely used outside the US, the bad experience with the Dalkon Shield26 tarnished the image of all IUDs for decades, especially in this country.

On a more promising note, the pioneering work of the Population Council has led to the development of new and improved IUDs. The Copper T 380A and the levonorgestrel-releasing IUD (Mirena) are now available in the US, leading to a resurgence of interest in the IUD.

Barrier methods 

Cervical barrier methods also have a long history. In the 1920s, the diaphragm was the most widely prescribed contraceptive method in this country. The eventual and dramatic decline in barrier method use can be traced to the advent of the OC pill, which dissociated the practice of contraception from coitus. Fairly recently, in 1993, a conference in the Dominican Republic led to an extensive treatise on the status and prospects of barrier contraceptives, focusing on their safety, acceptability, and effectiveness.27

The cervical cap was first approved as a contraceptive in the US in 1988; current products include FemCap and Lea's Shield. Then, in 1993, came the female condom (Reality), which is applied by the woman before intercourse.

Natural skin male condoms had been available during the early part of the 20th century, though more robust and reliable condoms were possible only after the vulcanization of latex rubber. This and other improved manufacturing processes in the 1950s permitted high-quality condoms to be produced at low cost.28

Barrier methods are generally used with a spermicide, such as nonoxynol-9 (N-9). The possibility that a spermicide could induce vaginal lesions necessitated the development of an animal model to assess the irritation potential of new spermicidal agents. The original rabbit vaginal irritation test, first described in 1969,29 is still the gold standard today, though it is being improved through additional testing of the vaginal lavages for proinflammatory cytokines.

Surprisingly, N-9 was never subjected to the modern standards of toxicology and was approved by the Food and Drug Administration (FDA) by monograph in 1978.30 It was known that N-9 could have some effect in preventing venereal diseases, as well as conception, but a key animal study in 1980 reported significant vaginal irritation from N-9 delivered by vaginal sponge.31 This adverse reaction likely explains why the over-frequent use of COL-1492, a low-dose N-9 vaginal gel, was recently shown to have a detrimental rather than beneficial effect on HIV transmission among female sex workers.32

Other approaches 

Other forms of contraception include sterilization by vasectomy or tubal ligation, or by various chemicals or plugs. Apart from condom use, vasectomy, abstinence, and withdrawal, no other options specifically enable men to share the burden of family planning. However, a promising lead is that a hormonal method based on a progestin and a testosterone ester could be effective and developed in the not too distant future.

IOM Report, 1996 

The IOM committee published 11 recommendations in 1996 and addressed 3 key questions41:

The committee was convinced of the need for new contraceptive methods and endorsed the woman-centered agenda (Recommendation 1). It also concluded that modern scientific methods could identify the genes involved solely in reproduction, thus providing specificity to the target tissue (Recommendation 2). Key objectives for both women and men were identified and placed in short-, medium-, and long-term frameworks. Because medium- and long-term forecasting is inexact, let us consider solely the short-term predictions.

Targets specific to women: New contraceptive methods for women that might soon be available include those acting by spermiostatic rather than spermicidal means. One such vaginal gel, cellulose sulfate (Ushercell), is already in a Phase II effectiveness trial, with results expected to be published in 2006. An interim analysis indicates that the product is effective. Cellulose sulfate does not kill sperm or affect sperm motility, but inhibits acrosomal enzymes and, by binding to sperm, may block sperm-egg interaction. Another contraceptive approach involves administering combinations of steroid hormone inhibitors to induce menses. However, because of the moral sensitivity of using an intervention so late in the menstrual cycle, funding for this research is low and thus little work in this area is being done.

Targets specific to men: The only male method likely to be available in the short term is an androgen/progestin regimen designed to suppress spermatogenesis but maintain libido. Under the auspices of the World Health Organization (WHO) and CONRAD, a Phase II study of testosterone undecanoate and NET-EN will soon be started. In the trial, separate injections—4 mL of testosterone undecanoate and 1 mL of NET-EN—will be given intramuscularly every 8 weeks. If the results are positive, it should be possible to combine both drugs in a single injection, formulated in a 4-mL aliquot of oil, making the regimen more acceptable.

In the private sector, Schering AG and Organon are collaborating to test the combination of Organon's etonogestrel (a progestin-releasing implant known as Implanon) with testosterone undecanoate (given IM). A WHO study had already shown that administration of testosterone enanthate (T-EN) alone could produce satisfactory contraception as long as sperm counts were suppressed to less than 3 million/mL.42 This regimen, however, was not practical for widespread application because T-EN had to be administered weekly. It is now 9 years since the IOM report made this specific forecast, and though we know the principle works, a safe, effective, and marketable product is still not at hand.

Immunologic-based targets: The 1996 IOM report showed considerable enthusiasm for immunologic approaches to contraception for both men and women. Work on immunocontraceptives has been a priority of the WHO since 1973, and an advanced approach has been developed, based on the C-terminal fragment of β-human chorionic gonadotropin (β-hCG), which is not present in β-luteinizing hormone. Yet even this most advanced formulation has for a variety of reasons still not been tested clinically for efficacy. A contraceptive efficacy trial in India used whole β-hCG conjugated to tetanus toxoid.43 In this trial, contraception occurred if antibody levels were above a certain threshold, but the response of different individuals to the same antigens was variable. Research on the use of other antigens has waned over the years.

Other recommendations: The1996 IOM report also highlighted perceived constraints to the advancement of contraception in general. These included third-party payment for contraceptives, a need for collaboration between public and private sectors to catalyze contraceptive research and development, a lack of government standards to help companies defend against unanticipated and unknowable side effects, and a need for more balanced, accurate, and intelligible package inserts for consumers.

Some of these issues remain of large concern. For example, the WHO Commission on Intellectual Property Rights, Innovation, and Public Health is currently conducting a global forum discussion to address the issue of getting safe medicines to consumers in resource-poor countries. The goals are to develop these medications more cheaply and efficiently and to provide them at an appropriate cost for various diseases, especially those of little or no commercial interest to the developed world.44, 45 The Web site for the forum can be accessed directly at www.who.int/intellectualproperty/forum/welcome.

IOM: Fast-forward to 2004 

In the years following the IOM's 1996 report, science moved beyond the study of genes (genomics) to the study of proteins (proteomics), lipids (lipidomics), and carbohydrates in cells (glycomics) and how they vary with differing physiological states. The Bill & Melinda Gates Foundation believed these areas should be explored in the interest of stimulating the development of new contraceptives. An IOM committee was again commissioned to examine contraceptive research goals, and its deliberations were published in 2004.46 The recommendations of the committee were this time confined to 2 issues:

Unlike in 1996, the 2004 committee purposely eschewed dividing the potential targets on the basis of short-, medium-, or long-term success. The 2004 IOM report was organized into 4 chapters encompassing 13 recommendations.

Chapter 1: Target selection and validation. Recommendation 1: “Identify and characterize all genes—expressed in the testis, ovary, and reproductive tissues.” In addition to the use of genomics for this task, the IOM recommended that a lipidome and glycome of reproductive tract tissues and mature gametes be undertaken (Recommendation 2). This sort of basic research is well supported by the National Institutes of Health and the Medical Research Council, among others; it is a long-term endeavor that will require additional funds and personnel. Once targets have been selected, they need to be validated (Recommendation 3), and this could be accomplished by forward and reverse genetic approaches.

Chapter 2: Here, the focus was on product identification and development, where the challenges are great. Of all Investigational New Drug applications submitted to the FDA for permission to conduct Phase I safety studies, only about 20% make it to the New Drug Application stage or are approved for marketing. This figure, which is applicable to therapeutic categories for curing diseases, is likely to be even lower for the testing of contraceptives, in that healthy people are being treated for long periods of time.

To facilitate this progression, a number of suggestions were made: Make use of high-throughput screening (Recommendation 4); implement mechanisms to promote and support translational research (Recommendation 5); develop new drug delivery systems and formulation capacities (Recommendation 6); and identify new surrogate markers for contraceptive efficacy, to speed the transition from Phase I safety studies to Phase II efficacy studies and thus reduce costs (Recommendation 7).

A key to success is to focus on targets that are “druggable.” Such targets would include enzymes, ion channels, receptors, and ligands for these receptors, which might be inhibited by small molecules and thus be suitable for high-throughput screening. (When a molecule of interest has been identified, a search is then made for small molecules that can inhibit the activity of the target. This is usually accomplished by high-throughput screening, which depends on an in vitro assay robust enough to determine the potential activity of a large number of compounds very rapidly.)

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Margaret Sanger, a nurse, established the first birth control clinic in the U.S. in 1916 and later founded the Planned Parenthood Federation of America. Her mother had 18 pregnancies and gave birth to 11 children. Reprinted with permission from Planned Parenthood® Federation of America, Inc. © 2005 PPFA. All rights reserved.

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In September of this year, the FDA approved new labeling for the Copper-T380A IUD (ParaGard), recommending it for women age 16 through menopause who are in stable relationships and thus not at high risk of sexually transmitted diseases or HIV. IUDs were previously recommended for women in mutually monogamous relationships who have at least one child.

Chapter 3: Recommendations 8 and 9 are concerned with research to improve both the access and acceptability of contraceptives and to seek other health benefits in addition to contraception. One such example might be the reduction of prostate cancer with long-term use of a male contraceptive method, as was the case with oral contraceptives and reduction of breast cancer in women. While recognizing that it may be difficult to develop these benefits a priori, the IOM stressed the need to identify such benefits proactively during the clinical trial phase.

Chapter 4: The key point of the report is presented in this chapter and deals with the capitalization of recent scientific advances. The merits of public/private partnerships are again recognized (Recommendation 10). These collaborations should include scientists from developing countries as well as organizations in all stages of research and development (Recommendation 11).

To carry out these ambitious plans and bring new contraceptives to the market, it will be necessary to recruit new talent to the field. This in itself may pose unique challenges. For many, basic research is more exciting than translational research and is certainly more conducive to academic progress, as translational research is a long-term activity not lending itself to high publication rates. New mechanisms for supporting training and career advancement must therefore be sought to increase recruitment (Recommendation 12). To promote interest and communication among those already working in the contraceptive field, as well as to engage new talent, the IOM suggested establishing an organization to act as a clearing-house for information (Recommendation 13).