3
Contraceptive Technology and the State of the Science: Current and Near-future Methods

Introduction

This chapter first speaks briefly about those contraceptive options that are available today. It then turns to options that are-all things being equal-likely to be developed or become available sometime during the decade that is beginning now, that is, between 1996 and the year 2006. The term "all things being equal" refers to the fact that the entry into the market of any new contraceptive method is not just a function of scientific innovation. It is also a function of the contextual dynamics addressed in other chapters in this report. Those dynamics encompass the character of the need and demand for contraception; the various economic and political factors that may prevail as a product advances from bench to shelf; and the social, cultural, religious, and personal variables that, in market terms, shape the need and demand for contraceptives and the extent to which they are, or are not, supplied. Chapter 4 deals with the science landscape in a more distant future, and with the concepts and mechanisms that are the most probable antecedents of very new and innovative contraceptive alternatives, for women and for men. These new possibilities are affected by some of the same dynamics that affect today's contraceptive methods; those are discussed in Chapter 6 and Chapter 7.

Because of the varying states of development of the technologies under consideration, Chapters 3 and 4 are organized differently. Chapter 3 is based on presentations made at the December 1994 Institute of Medicine workshop on Contraceptive Research and Development and the Frontiers of Contemporary Science, conducted as part of this study activity (Institute of Medicine [IOM] 1995). It consists of two parts, as follows:



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--> 3 Contraceptive Technology and the State of the Science: Current and Near-future Methods Introduction This chapter first speaks briefly about those contraceptive options that are available today. It then turns to options that are-all things being equal-likely to be developed or become available sometime during the decade that is beginning now, that is, between 1996 and the year 2006. The term "all things being equal" refers to the fact that the entry into the market of any new contraceptive method is not just a function of scientific innovation. It is also a function of the contextual dynamics addressed in other chapters in this report. Those dynamics encompass the character of the need and demand for contraception; the various economic and political factors that may prevail as a product advances from bench to shelf; and the social, cultural, religious, and personal variables that, in market terms, shape the need and demand for contraceptives and the extent to which they are, or are not, supplied. Chapter 4 deals with the science landscape in a more distant future, and with the concepts and mechanisms that are the most probable antecedents of very new and innovative contraceptive alternatives, for women and for men. These new possibilities are affected by some of the same dynamics that affect today's contraceptive methods; those are discussed in Chapter 6 and Chapter 7. Because of the varying states of development of the technologies under consideration, Chapters 3 and 4 are organized differently. Chapter 3 is based on presentations made at the December 1994 Institute of Medicine workshop on Contraceptive Research and Development and the Frontiers of Contemporary Science, conducted as part of this study activity (Institute of Medicine [IOM] 1995). It consists of two parts, as follows:

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--> Current Options: This section sets the stage for discussion of new approaches to reversible contraception over the next decade and beyond. The section is organized by categories of methods that are presently available, that is, existing, named formulations that work through a variety of mechanisms and delivery systems. Table 3-1 summarizes these methods, their mechanisms of action, failure rates under typical and perfect use, advantages, disadvantages, side effects, and potential complications. Contraceptive Options in the Next Decade, 1995-2005: This section focuses on approaches that are at least in phase I of trials. For the most part, these are either improvements or novel applications of approaches that are already well known. These, too, are considered as methods and are organized in the same way as current options, in order to point more clearly to where improvements are under way. We recognize that, in some categorical instances, the boundary between prospects for the next decade and prospects for the years beyond is often blurred. This is a function of technology and of the degree of advance. In the first instance, a technology that seems promising disappoints in trials. In the second, there may be one or two advances that have become "available methods," but the contraceptive category to which it belongs is otherwise largely empty; good examples are barrier and postcoital methods and contraceptives for men. Chapter 4 and its appendixes constitute the committee's efforts to respond to its charge to review the state of the relevant basic science and identify a range of potential areas and targets that would provide a foundation for fresh endeavor in contraceptive research and development. The chapter is based not only on the December 1994 workshop but on a set of authored papers found in the appendixes to this report. The chapter has three sections: (1) areas of inquiry or specific targets in the development of contraceptive methods for women, that is, "female methods"; (2) areas of inquiry or specific targets in the development of contraceptive methods for men, that is, "male methods"; and (3) an area that holds promise for the development of various contraceptive methods for both females and males, "immunocontraception," which subsumes the topic of "mucosal immunity'' and its potential for generating new anti-infective and/or contraceptive barrier methods. The internal organization of each of these categories was determined by physiology and by the stage of scientific understanding. Because the stages of the female reproductive cycle are critical from both the technologic and policy perspectives, this particular section is organized according to that cycle. Because of the diversity in the levels of scientific advance, the sections of Chapter 4 that deal with methods for males and with immunocontraception are, necessarily, a mix of specific molecular targets and modes of action. Current Options The reversible contraceptive options that are available today, almost all of

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--> TABLE 3-1 Current Reversible Contraceptive Options, Mode of Action, Rates of Failure,a Advantages and Disadvantages Method Mode of Action Unintended Pregnancy Rate Disadvantages and Advantages Side Effects Dangers Typical Use Perfect Use Female Hormonal Methods           Oral Contraceptives             Combined Suppression of ovulation, changes in cervical mucus and endometrium 3% 0.1% Protection against ovarian/endometrial cancer, pelvic inflammatory disease (PID), fibrocystic breast disease, ovarian cysts, iron-deficiency anemia, dysmenorrhea Nausea, headaches, dizziness, spotting, weight gain, breast tenderness, chloasma Cardiovascular (stroke, heart attack, blood clots, hypertension), depression, hepatic adenomas Progestin-only Changes in cervical mucus and endometrium, possible ovulation suppression 4% 0.5% Protection against PID, iron-deficiency anemia, dysmenorrhea Menstrual irregularities Unknown Implants Levonorgestrel subdermal implants (Norplant) Similar to progestin-only 0.09% 0.09% Effective for 5 years Site tenderness, removal problems, menstrual irregularities, headache, weight gain, acne Infection at implant site

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--> Method Mode of Action Unintended Pregnancy Rate Disadvantages and Advantages Side Effects Dangers Typical Use Perfect Use Female Hormonal Methods           Injectables             Depomedroxyprogesterone acetate (Depo-Provera) Suppression of ovulation, changes in cervical mucus and endometrium 0.3% 0.3% Effective for 3 months Reduced risk of endometrial cancer, PID Menstrual irregularities, headache, weight gain, delayed return to fertility None proven Intrauterine Devices (IUD):           Progesterone T (Progestasert) Inhibition of sperm migration, fertilization and ovum transport (progesterone is responsible for primary mode of action) 2% 1.5% Diminished menstrual blood loss and relief of dysmenorrhea Requirement for removal and reinsertion on an annual basis; increased cramping and menstrual flow Ectopic pregnancy Copper T 380A (ParaGard) Copper is responsible for primary mode of action 0.8% 0.6% Protection against ectopic pregnancy; 10-year useful approved life; decreased menstrual blood flow, possible decrease in fibroids Increased menstrual blood loss, cramping, spotting, dysmenorrhea Uterine perforation (rare), PID limited to 20-30 days postinsertion, anemia Levonorgestrel T (Mirena) Development of an endometrium with lessened sensitivity to circulating estradiol as result of high tissue concentration of progestin inhibiting synthesis of estradiol receptor 0.1% 0.1% Reduced incidence of myomas, arrested development of endometriosis, prevention of progression of STDs to endometritis and PID   STD risks

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--> Method Mode of Action Unintended Pregnancy Rate Disadvantages and Advantages Side Effects Dangers Typical Use Perfect Use Barrier Methods:             Spermicide alone Inactivation of sperm 6% 21% May protect against bacterial STDs Vaginal irritation None proven Cervical cap with Spermicide Mechanical barrier; inactivation of sperm 18% 11.5% Protection against STDs Cervical irritation, vaginal discharge, pelvic pressure, Pap smear abnormalities Toxic shock syndrome Diaphragm with Spermicide Mechanical barrier; inactivation of sperm 18% 6% Protection against STDs Cervical irritation Toxic shock syndrome, urinary tract infections Condom Mechanical barrier           Male   12% 3% Protection against STDs Latex allergies None Female   21% 5% Protection against STDs, including external genitalia Difficult to insert None

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--> Method Mode of Action Unintended Pregnancy Rate Disadvantages and Advantages Side Effects Dangers Typical Use Perfect Use Non-Commodity-Based Methods Lactational Amenorrhea Method (LAM) Based on enhancement of lactational physiology and identification of period of lactational infertility using three criteria 1-2% (6-mo. rate) 0-1% No commodities necessary; enhances breastfeeding practices. Only applicable during the first 6 months postpartum Side effects are a result of the enhanced breastfeeding behaviors, including improved maternal and child health Provides no protection against STDs Periodic Abstinence Methods: Avoidance of coitus during days when fertilization might occur using a mathematical method (CM), a cervical mucus-based method (OM), or a combination of temperature shift and other signs (STM) 20% 0-1% No commodities necessary; enhances breastfeeding practices. Another method should be started whenever any of the three criteria are no longer met   Provides no protection against STDs Calendar Method (CM) 9%     Ovulation Method (OM) 3%     Symptothermal Method (STM) 2% No commodities necessary, except a thermometer with STM; said to enhance couple communication; periods of abstinence required; provides no protection against STDs; requires daily observation and interpretation of fertility signs    

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--> Method Mode of Action Unintended Pregnancy Rate Disadvantages and Advantages Side Effects Dangers Typical Use Perfect Use Non-Commodity-Based Methods             Fertility Awareness Methods (FAM) Avoidance of coitus and/or use of a barrier method during days when fertilization might occur 10%b 10%b Combines understanding of fertility with use of barrier methods, potentially increasing efficacy Those associated with the barrier method only Provides limited protection against STDs Coitus Interruptus Withdrawal of the penis from the vagina prior to ejaculation 18% 4% No commodity necessary, no advance planning or charting   Provides no protection against STDs Emergency Contraception           Emergency Contraceptive Pills (ECPs) (combined oral contraceptive pills containing combination of estrogen and progestin) 2 Ovral pills initially, 2 more 12 hours later; or 75%   Relatively easy to obtain Nausea, vomiting Side effects may be severe 4 Lo/Ovral, Nordette, or Levlen initially, 4 more 12 hours later; or          

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--> Method Mode of Action Unintended Pregnancy Rate Disadvantages and Advantages Side Effects Dangers Typical Use Perfect Use Emergency Contraception             4 Triphasil or Tri-Levlen (yellow only) initially, 4 more 12 hours later           Minipills (progestin-only oral contraceptive pills) 20 Ovrette pills (.75 mg) initially, 20 more 12 hours later   75% Contains no estrogen so can be used by women who cannot tolerate combined OCs     Mifepristone (a drug, also known as RU 486, that can function as an emergency contraceptive before pregnancy begins) 1 dose (Note: not yet available)   ~99% Less nausea and vomiting than ECP, and is more effective     IUD Clinician inserts a copper T-shaped intrauterine device into the uterus   ~99% Can serve as a long-term contraceptive after the "emergency"; greater window of time than with ECPs and is most effective     a Rates are for U.S. women and were determined from: C Ellerton, Expanding access to emergency contraception in developing countries, Studies in Family Planning 26(5):251-262, 1995, and J Trussell, C Ellerton, Efficacy of emergency contraception, Fertility Control Reviews 4(2):8-11, 1995. b D Rogow et al. A year's experience with a fertility awareness program: A report. Advances in Planned Parenthood 15(1):27-33, 1980. Other studies in Germany have shown FAM to be more efficacious than PAM, while other studies are equivocal.

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--> which are for women, fall into the following broad categories: oral contraceptives, including emergency contraception; implants; and injectables; intrauterine devices; barrier methods; and non-commodity-based methods. Although the past decade has seen the introduction of levonorgestrel subdermal implants (Norplant) and depo-medroxyprogesterone acetate (Depo-Provera or DMPA), these are technical variations of existing hormonal methods; they have new and/or different advantages and disadvantages, but they do not represent truly new physiologic concepts. The same can be said for some of the new female barrier methods, which, while their configurations are novel and represent a great deal of research, are still not manifestations of completely new ways of thinking about contraceptive technology. Currently available methods of emergency contraception, while receiving fresh attention, use existing products, although expansion of their availability and utilization would be, in itself, an important novelty. Oral Contraceptives Combination Oral Contraceptives Beyond new delivery systems and minor modifications in active ingredients, hormonal methods of contraception have changed little since the birth control pill was first introduced, although research on lower-dose formulations has been a steady theme in the field. Today's hormonal contraceptives—consisting of various combinations of estrogens and progestins—can be delivered in the following ways: as pills taken orally, as implants, and as injectables. Hormonal contraceptive methods work through a variety of mechanisms. The dual action of estrogen and progestin in combined oral contraceptives (COCs) serves both to suppress ovulation and change the nature of cervical mucus, making it less permeable to sperm. A fact that is very imperfectly recognized is that COCs have definite non-contraceptive advantages, including protection against ovarian and endometrial cancer, fibrocystic breast disease, benign ovarian cysts, ectopic pregnancies, and symptomatic pelvic inflammatory disease. And, with lower doses of estrogen, their disadvantages are infrequent. Because of their established and good record of safety and efficacy, particularly in the modem formulations, there would seem to be scant incentive to improve OCs (Hatcher et al. 1994). However, the appearance of the injectable methods spurred competitive response in the market, as did the perception of needs in special subpopulations (e.g., older women) for whom some reformulation might be attractive (Hatcher et al. 1994). Taken conscientiously, oral contraceptives seldom fail.

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--> Progestin-only Pills (POPs) The marketing of progestin-only pills (POPs, often referred to as minipills1) began about 10 years after combined oral contraceptives were introduced. Although there are now a number of these preparations employing a variety of progestins, they account for a small portion of the OC market (Hatcher et al. 1994). Progestin-only products are members of a family of progestin-only contraceptives which, in addition to being administered orally, may be administered by injection, implants, intrauterine devices, and vaginal rings. They prevent pregnancy through several modes of action: by inhibiting ovulation; thickening and decreasing the amount of cervical mucus (making it more difficult for sperm to penetrate; creating a thin, atrophic endometrium; and/or premature luteolysis (McCann and Potter 1994). Like regular oral contraceptives, progestin-only methods provide little or no protection against sexually transmitted infections, including HIV. Given perfect use, progestin-only pills have slightly higher rates of unintended pregnancy than combined OCs and cause sporadic bleeding in some women (Hatcher et al. 1994). Implants The first implant introduced onto the world market was Norplant, developed through a long process of intersectoral collaboration. When initially introduced, Norplant was remarkably successful. This long-acting contraceptive slowly and steadily diffuses a small amount of progestin through six slim, flexible rods inserted subcutaneously in a woman's upper arm and produces in most women the same cessation of ovulation and other physiologic changes that are associated with all progestin-based methods. Despite the somewhat cumbersome need to insert the rods, the method's long-term convenience (five years of protection in its present formulation) and low unintended pregnancy rates led initially to its quick adoption by many women in many countries, including the United States. As with all contraceptives, Norplant has side effects for some women, primarily menstrual irregularities and, in some instances, weight gain. Experience of these sequelae led some women to request discontinuation within the first year of use. However, if not inserted properly, removal of the implants can be difficult in some instances, so that there were cases of difficult removals. As a consequence of adverse publicity about those experiences, as well as an alleged (but totally unproven) effect from the silicone in the rods, there was a widely publicized series of class action suits. Choice of this method dropped precipitously and requests for removal mounted, even in women who had been satisfied with the method (White 1995). These issues are discussed in Chapter 7 in the context of legal and regulatory issues.

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--> Injectables The underlying mechanism for the injectable contraceptive, Depo-Provera, is similar to that of progestin-only hormonal methods. It does not, however, have to be taken every day, but is effective for three months. For women who may wish to change their minds, this time commitment may or may not be a disadvantage, depending on the urgency with which they wish to reestablish fertility. For women who wish to continue with an injectable method, the need for quarterly injections can also be a problem if there are constraints on access to an appropriate health provider, although the method is somewhat forgiving since it has a variable grace period. Its contraceptive efficacy is very high and, again, like all progestin-only methods, Depo-Provera can be used by lactating women. The method is approved for use in over 90 countries, including the United States where it was finally approved in late 1992, its approval having been delayed because of its effect on dogs (Hatcher et al. 1994) (see Chapter 7). Several other injectables are available outside the United States, for example, Noristerat and Cyclofem. Intrauterine Devices (IUDs) Two intrauterine devices are currently available in the United States, the progesterone T (Progestasert System), which must be inserted and removed annually, and the Copper T 380A (CU T380, or ParaGard), which is effective for at least 10 years.2 The levonorgesterol IUD (LNg IUD), not yet licensed in the United States, has a manufacturer-recommended duration rate of five years. There are also other IUDs available outside the United States, for example, Multiload and Nova-T. All newer IUDs have very low failure rates (1 percent or less, equal to sterilization), and fewer side effects (bleeding and pain) than earlier devices. Although the exact mechanism of action of the IUD has been uncertain until quite recently, it now seems that fertilization and implantation rates are both decreased. All IUDs that have been tested experimentally or clinically induce a local inflammatory reaction in the endometrium that changes the cellular and humoral components of the fluid contents of the uterine cavity; in humans, the entire genital tract then appears to be affected by the inflammatory fluids from the uterine lumen. This in turn affects the function and viability of gametes, thus decreasing the rate of fertilization, either in the altered tubal milieu or in the uterine cavity (Bardin 1996).3

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--> levonorgestrel butanoate (WHO 1995a) and, as mentioned above, norethisterone microspheres. Some of these products do contain estrogen as well as progestin, thereby overcoming the bleeding side effect. While ranking high in efficacy, one problem with all implants on the market and most that are under development today is that they contain only progestin (as opposed to a combination of estrogen and progestin). In many users, progestinonly products cause irregular uterine bleeding as a side effect (particularly in the early stages of use), which limits their acceptability. Although research on implants and injectables has focused on developing products for women (as has most contraceptive research), there are a few products that fall into this category that are now under development for men. These are discussed below in the context of new contraceptive methods for males. Better Barrier Methods Mechanical Barriers The barrier methods of contraception that are now available are either mechanical (male and female condoms, diaphragms, and cervical caps), chemical (spermicides and other formulations), or some combination of both, all of which are inadequate to needs. Recognition of this inadequacy has motivated movement toward research to correct it, involving efforts by a number of public sector entities, including the World Health Organization's Special Programme of Research, Development and Research Training in Human Reproduction (WHO/ HRP) and the Human Immunodeficiency Network (HIV/NET); the NICHD's Center for Population Research; and Family Health International and the Contraceptive Research and Development (CONRAD) Program, both supported by the U.S. Agency for International Development (USAID). The driving objectives of these efforts are to improve product safety and efficacy, formulations, and configurations; to widen the spectrum of barrier methods that women can control and use discreetly (Mauck et al. 1994, Stewart 1994); and to determine acceptability prior to decisions about market launch. One especially active area of research is in efforts to combine contraceptives with effective mechanical barriers to sexually transmitted diseases (STDs). Included in this category are methods developed for contraception, some of which may provide protection against STDs. These include Lea's Shield and FemCap. Lea's Shield is a "one size fits all" device that blocks the cervix but has a valve that allows passage of cervical secretions and facilitates insertion. FemCap is a new cervical cap with a design that increases apposition to the cervix and vaginal wall and is sized based on parity. Both devices could become available within a few years. Their efficacy against pregnancy or infection is still unknown and their present costs would be prohibitive for many women. The usefulness in

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--> much of the developing world of any such coitus-dependent method that is both costly and dependent on access to privacy and clean water remains questionable. In addition, manufacturers have developed a new vaginal sponge, Protectaid, which incorporates three spermicides that have a synergistic spermicidal and microbicidal effect and is designed to provide STD protection without irritating the vaginal epithelium (Psychoyos et al. 1994). The sponge contains a compound spermicide, microbicide, and virucide that, in laboratory studies, has inactivated HIV as well as chlamydia and trichomonas. With the withdrawal from the market of the Today sponge in 1995, there is no other comparable product available in any market. Chemical Barriers The spermicides that are now on the market are not very effective against either sperm or pathogenic organisms. This may be due to weaknesses in certain characteristics of these products. Due to their short period of activity and messiness, many of these formulations are not seen by users as particularly desirable. While some spermicides, specifically nonoxynol-9, can kill HIV and bacteria in laboratory studies, there is concern that, as a detergent, it may also kill cells and irritate the vaginal epithelium, thereby possibly elevating susceptibility to HIV transmission. This has led many researchers to suggest that research should now focus on noncytotoxic rather than cytotoxic methods of stopping sexually transmitted pathogens. Any potential new barrier method should not compromise natural defenses and, if possible, should strengthen them. Defense mechanisms include a thick epithelial lining and mucus secretion during certain stages of the menstrual cycle, both of which provide a physical barrier. The vagina and cervix are also equipped to mount antibody and cell-mediated immune responses against pathogens, and secretions from these areas contain several nonspecific antibacterial and antiviral defense agents, including lysozyme, polyamines, zinc, hydrogen peroxide, lactoferrin, and B-defensins. Finally, the natural flora of the vagina, that is, lactobacilli, keep the vaginal pH low (Larsen 1993), creating yet another deterrent to microbes. Current research focuses on developing a chemical barrier that would be nontoxic and nonirritating to these beneficial microbes and at the same time capable of killing or disabling invading pathogens. Researchers at Johns Hopkins University are working with the support of the NICHD and the National Institute of Allergy and Infectious Disease and, most recently, with the HIV/NET component of the Global Programme on AIDS, on development of buffer gels5 that can maintain vaginal acidity even in the presence of semen and cervical mucus. The gels are created with nonmetabolizable polymers that should produce only minimal perturbation of the normal vaginal flora. Because the cell membranes and the vaginal epithelium are not permeable to polymers, they can provide high buffer capacity without producing the toxicity

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--> or irritation caused by high concentrations of membrane-permeable weak acids (e.g., lactic and acetic acids). Indeed, the gel simply increases the buffer capacity of vaginal fluids sufficiently to overcome the neutralizing action of semen and cervical mucus. Furthermore, compared with other broad-spectrum microbicides, an acidic buffer is less likely to irritate or disturb normal vaginal microflora. This combination of characteristics suggests that the gels can be used to create new methods for vaginal protection against pregnancy and STDs and could also serve as drug-delivery vehicles for vaginal therapy (e.g., during menses and menopause, for vaginal bacteriosis). They may also help prevent the onset or relapse of vaginal and urinary tract infections. More specifically, the Reprotect gel formulation also has excellent qualities as a sexual lubricant; is inexpensive, colorless, and odorless; and its constituents are in products already approved by the FDA for vaginal use or that are generally recognized as safe. Pilot experiments using the mouse/HSV-2 model demonstrate that the gel's acidic-buffer action blocks vaginal and genital skin transmission of genital herpes infections, which suggests that it might also be effective against HIV infections. The gel will go into phase I trials in Boston, Malawi, India, Zimbabwe, and Thailand in 1996 (K Whaley, personal communication, February 1996). Another vaginal gel formulation, PC 213, comprised of sulphated polysaccharides, has completed Phase I vaginal irritation studies, under the aegis of the Population Council (Stein 1995). Another possibility is a vaginal product containing squalamine, a natural substance that appears to be spermicidal as well as microbicidal. Isolated from animals, squalamine is thought to protect them from a wide range of diseases. Further animal studies are being conducted prior to doing safety studies in women, under a Cooperative Research and Development Agreement between NICHD and Magainin Pharmaceuticals (N Alexander, personal communication, 1995; Russell 1996a). There is other research that builds on compounds derived from plants that have exhibited spermicidal and virucidal properties. The National Institute of Immunology in India has isolated oils from the neem tree (Azadirachta indica). One formulation, Praneem polyherbal cream, combines neem seed extract with soapnut extract (Sapindus mukerossi) , and is said to induce local cell-mediated immunity. Phase II trials are reported to be under way in India. Other plant extracts being studied for their potential ability to kill sperm, bacteria, and viruses include papain from papaya and gossypol from cottonseed oil. One unresolved and quite urgent issue concerning combination contraceptive cum anti-STD agents in the United States is how they will fare in the FDA approval processes. Guidelines from the agency will be utterly essential for research and development in this area if new methods are to make their way into a very needy market. At the time of this writing, there are no FDA guidelines for

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--> research and development activities with respect to products in this combined category. New Postcoital Methods Antiprogestins A rich and novel area of work in recent years has been around the antiprogestins (sometimes referred to as antiprogestogens), steroid antihormones with a unique ability to block the action of progesterone at the cellular level through binding to the progesterone receptor in target tissues (Van Look and von Hertzen 1993). Progesterone exerts well-documented effects throughout the reproductive system (including the uterus, cervix, breast, and pituitary-hypothalamic system) and plays a key role in both establishing and maintaining pregnancy. It also exerts less well-defined actions on tissues outside the reproductive system (e.g., brain, vascular endothelial cells) and on lipid metabolism (Baulieu 1993; IOM 1993). The first antiprogestin was discovered fortuitously by scientists searching for an antiglucocorticoid, a compound that would interfere with the action of adrenal gland hormones, glucocorticoids, that are involved in the physiologic regulation of virtually all tissues in the body (IOM 1993). While several hundred antiprogestins have been synthesized, only three have been given to humans (mifepristone, lilopristone, and onapristone). Just one of those, mifepristone—RU 486—has been extensively studied in humans, most widely as a means of nonsurgical termination of early pregnancy (Van Look and von Hertzen 1993).6 The compound has been licensed for that purpose in France, Sweden, and the United Kingdom, and is being manufactured in China. In the United States, RU 486 is in phase III clinical trials under the aegis of the Population Council (IOM 1993). One of the most promising potential uses of antiprogestins is as a postcoital emergency contraceptive that would reduce the chance of undesired pregnancy after unprotected intercourse around the time of ovulation. Because of the critical role progesterone plays in early transformation of the endometrium (and its possible role in follicular maturation and ovulation), researchers hypothesized that mifepristone might act as an effective postcoital contraceptive. Studies in England and Scotland have supported this hypothesis (Baird et al. 1988). Researchers have also experimented with antiprogestins as expected menses inducers (EMIs, taken regularly just before the onset of expected menstruation) and missed menses inducers (MMIs, taken only when the menstrual period does not occur). Perhaps most promising has been work combining an antiprogestin (mifepristone) with a prostaglandin (gemeprost). In a recent study, researchers working in six countries demonstrated that a combination of mifepristone followed two days later by gemeprost-induced menstruation in 98 percent of a group

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--> of women who were up to 10 days late getting their periods (Van Look and von Hertzen 1993). The potential of the antiprogestins goes well beyond emergency contraception. Their role in human health and disease could be large, given their applicability to a variety of reproductive and nonreproductive conditions. Research has suggested that antiprogestins may have clinical value in treating endometriosis, uterine leiomyomas (fibroid tumors), and endometrial and breast cancers. They also appear to offer value for obstetrics and fertility regulation. The antiprogestins also have potential for use as antifertility agents by inhibiting ovulation, preventing or disrupting implantation, and/or inducing luteal regression. During the early luteal phase, mifepristone may prove to be not only an effective postcoital agent used under circumstances of emergency but as a once-a-month pill or menses-inducer. The role of antiprogestins as ovulation inhibitors could be particularly attractive, since this is already a widely accepted category of contraceptive. Antiprogestins may also have clinical utility for the treatment of several other conditions, most importantly including meningioma (tumors arising from membranes surrounding the brain) and, because of their antiglucocorticoid effects, in palliative treatment of hypercortisolism due to Cushing's syndrome, some forms of depression and glycoma, and wound healing (Baird 1993; Croxatto et al. 1993; IOM 1993; Van Look and von Hertzen 1993). There is much research to be done in all these areas and, from this broader perspective, the antiprogestin compounds should be highly attractive to industry. However, perhaps the most striking aspect of the antiprogestins, as seen in the history of RU 486, is the extent to which medical and economic decisions about their development, clinical testing, marketing, and use are being shaped by social and political forces, centering on strongly held, powerful secular and religious values either favoring or opposing abortion (Swazey 1992). The core issue in the controversy is the use of RU 486 or future antiprogestins as abortifacients (Banwell and Paxman 1992; Swazey 1992). The range of actions of the antiprogestins, together with incomplete understanding of their mechanisms (IOM 1993), can blur distinctions between contraception and abortion, conception and pregnancy, and become entangled in the sometimes vague legislative language used to describe events in the reproductive process (Banwell and Paxman 1992; Cook 1989; Swazey 1992). Roussel-Uclaf, the developer of mifepristone, assigned the rights for production and distribution of RU 486 in the United States to the Population Council, citing a ''hostile political climate in the United States" (Roussel-Uclaf press release, cited in US Department of State 1993; Tanouye 1994) and is said to have closed its research laboratories in this area. In such a climate, it seems unlikely that any large pharmaceutical company would work in this product category, even were the financial gain to be large (Swazey 1992). Two European companies (Organon and Schering AG) have also developed effective antiprogestins, but have decided not to bring them to market.

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--> Methods for Males Other than modifications of the male condom, work on alternative contraceptive methods for men has been limited largely to techniques to permit reversal of sterilization, primarily different methods for occluding the vas deferens and use of no-scalpel vasectomy. A mechanical intervention that is nearing completion in India involves injecting into the vas deferens a non-toxic polymer (styrene maleic anhydride) that blocks the passage of sperm. Unlike a vasectomy, this method is intended to be reversible. Another substance, dimethyl sulphoxide (DMSO), can be injected to dissolve the first. While early animal toxicity studies suggested that DMSO might be carcinogenic, later studies proved those fears unfounded. The product is now being tested in clinical trials with humans. The other area of work has centered on administration of hormones to inhibit spermatogenesis, the process of sperm production that is regulated by luteinizing hormone (LH) and follicle stimulating hormone (FSH). One hormonal method for men being investigated by the Population Council is a system of two implants which could provide a convenient one-year contraceptive method for men. One implant delivers an agonist of luteinizing hormone releasing hormone (LHRH) that suppresses sperm production; the other implant, required to compensate for resulting diminution of testosterone, the androgen that governs sexual function, supplies a synthetic androgen (MENT) (Waites 1992). This system is in phase I clinical trials in two countries, and entering human trials under the Population Council (WHO 1995a). Antifertility vaccines that neutralize hormones required for sperm production or sperm maturation are also in the early stages of development, again under the aegis of the Population Council and the National Institute of Immunology (New Delhi). Phase I clinical trials were expanded in 1993 and, as of June 1995, 12 men had been immunized. The vaccine would be combined with the MENT implant to provide androgen replacement needed for normal sex drive and behavior. In addition to the challenge of affecting spermatogenesis without impact on sexual function, there is the challenge of achieving infertility in all subjects. International multicenter studies by the WHO and CONRAD/USAID have been struggling with this dilemma and have produced considerable understanding but no product yet. Another challenge has been finding a delivery mechanism that can provide more than a week's worth of protection and there have been international collaborative efforts over the past 15 years to develop longer-acting steroid formulations. This research has focused on methods of administering testosterone, either as testosterone enanthate (TE) or testosterone buciclate, alone or in combination with a progestin such as DMPA or levonorgestrel, or anti-androgenic steroids (e.g., cyproterone acetate, CPA) to interfere with spermatogenesis (Contraceptive Technology Update, August 1995). The problem with any method that is based on suppression of spermatogen-

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--> esis is the two- to three-month delay between method initiation and infertility, requiring use of another contraceptive method during the initial months of use (PATH 1995). Researchers are evaluating and planning evaluations of the efficacy and acceptability of testosterone enanthate, levonorgestrel butanoate/testosterone buciclate (WHO/NICHD), 7-alpha-19-methyl-nortestosterone (MENT) (Population Council), levonorgestrel/testosterone enanthate, and desogestrel/ testosterone enanthate (University of Washington/CONRAD). Work on the latter combination is particularly promising, since it exhibits faster suppression of spermatogenesis than any testosterone formulation alone. The level of suppression approaches complete azoospermia. When the drug is discontinued, sperm counts rapidly return to normal. Some analysts predict that such a product could be available by the year 2005 (Alexander 1995). Because of the challenges of duration, lag times in return to fertility, and hormonal balance that have been the focus in work on male methods to date, there is something of a shift in research emphasis toward an emphasis on how to interfere with sperm maturation rather than sperm production (spermatogenesis), since that would avoid disruption of the hormonal balance needed for sexual function. Eventually, new knowledge on the basic biology of reproduction should allow researchers to interfere with spermatogenesis closer to the end of the process, that is, in the testes or epididymis rather than the brain or pituitary, thereby avoiding the wide range of systemic effects. The products of such research are unlikely to be available in the next decade and are, therefore, discussed in further detail in the following chapter. A final avenue of research focuses on plant compounds that interfere with male fertility. The best known—and most controversial—of these compounds, gossypol, is derived from cottonseed oil. Studied now for over two decades, gossypol is known to effectively suppress sperm production, but has also caused hypokalemia and irreversible infertility in a significant number of subjects. Tripterygium wilfordii, a vine that grows in southern China, has also shown promise as a possible reversible male contraceptive. Researchers have thus far identified six components of the plant with antifertility activity. While toxicology studies have not been completed, these plant compounds show particular promise because they seem to work by interfering in sperm maturation in the epididymis, thus offering a potential contraceptive without side effects involving male sex hormones. Concluding Comment At the outset of this chapter, we stated that there was reasonable probability that a number of improvements in existing contraceptive technologies could become available in the next decade. We also used the term "all things being equal." The case of RU 486, the tensions around the approvals of the Avanti and Reality condoms, and the still-pending fate of Norplant liability, make it clear

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--> that all things are not, in fact, equal. At the same time, the history of the oral contraceptive and the IUD, troubled in a variety of ways, suggests that the needs of individuals worldwide to plan their families somehow, sooner or later, wins out. References Alexander NJ. Future contraceptives: Vaccines for men and women will eventually join new implants, better spermicides and stronger, thinner condoms. Scientific American 273(3):136-141, 1995. American College of Obstetricians and Gynecologists (ACOG). Poll shows women still skeptical of contraceptive safety: ACOG News Release. Washington, DC: American College of Obstetricians and Gynecologists. 1994. ACOG. Attitudes Toward Contraception. Princeton, NJ: The Gallup Organization. 1985. American Health Consultants. AIDS Alert: Special Series on Avanti Condom 10(1):1-16, 1995; 10(2):17-32, 1995; 10(5)71-72, 1995. Baird DR. Potential contraceptive effects of antigestogens. IN Clinical Applications of Mifepristone (RU 486) and Other Antiprogestins: Assessing the Science and Recommending a Research Agenda. MS Donaldson, L Dorflinger, SS Brown, LZ Benet, eds. Washington, DC:National Academy Press. 1993. Baird DT, M Rodger, IT Cameron, et al. Prostaglandins and antiestrogens for the interruption of early pregnancy. Journal of Reproduction and Fertility 36:173-179, 1988. Banwell SS, JM Paxman. The search for meaning: RU 486 and the law of abortion. American Journal of Public Health 82(10):1399-1406, October 1992. Bardin CW. Mechanism of action of IUDs. Paper presented at: "IUDs-A State-of-the-Art Conference," National Institutes of Health, Bethesda, MD, 15-16 February 1996. Baulieu EE. RU 486-A decade on today and tomorrow. IN Clinical Applications of Mifepristone (RU 486) and Other Antiprogestins: Assessing the Science and Recommending a Research Agenda. MS Donaldson, L Dorflinger, SS Brown, LZ Benet, eds. Washington, DC:National Academy Press. 1993. Camp S. Emergency contraception in seven European countries. Reproductive Health Technologies Project 7:12, 1994. Contraceptive Technology Update (untitled), August 1995. Contraceptive Technology Update. Special Report: Studies Found Plastic Condom Unsafe, yet FDA Cleared It for Market, June 1995. Cook RJ. Antiprogestin drugs: Medical and legal issues. Family Planning Perspectives 21(6):267-272, 1989. Coutinho E. One year contraception with a single subdermal implant containing nomegestrol acetate (Uniplant). Contraception 47:97-105, 1993. Croxatto HB, AM Salvatierra, HD Croxatto, et al. Effects of continuous treatment with low dose mifepristone throughout one menstrual cycle. Human Reproduction 8:201-207, 1993. Darney PD. Hormonal implants: Contraception for a new century. American Journal of Obstetrics and Gynecology 170:1536-1543, 1994. Executive Briefing. Melatonin-A New Approach to Contraception. October 1995. Farley TMM, MS Rosenberg, PJ Rowe, et al. Intrauterine devices and pelvic inflammatory disease: An international perspective. Lancet 339(8796):785-788, 1992. Grossman RA, BD Grossman. How frequently is emergency contraception prescribed? Family Planning Perspectives 26(6):270-271, 1994. Hatcher RA, J Trussell, F Stewart, et al. Emergency Contraception: The Nation's Best Kept Secret. Decatur, GA: Bridging the Gap Communications. 1995.

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--> Hatcher RA, J Trussell, F Stewart, et al. Contraceptive Technology, 16th Revised Edition. New York: Irvington Publishers. 1994. Hughes S. Emergency contraception—A hard pill to swallow? Scrip Magazine, October 1995. Institute of Medicine (IOM). Summary of Proceedings: Workshop on Contraceptive Research and Development and the Frontiers of Contemporary Science, 9-10 December 1994. Washington, DC: Division of Health Sciences Policy. Unpublished document. 1995. IOM. Clinical Applications of Mifepristone (RU 486) and Other Antiprogestins: Assessing the Science and Recommending a Research Agenda. MS Donaldson, L Dorflinger, SS Brown, LZ Benet, eds. Washington, DC: National Academy Press. 1993. Kaiser/Harris. Survey on Obstetricians/Gynecologists' Attitudes and Practices Related to Contraception and Family Planning, I February-21 March 1995. Menlo Park, CA: The Kaiser Family Foundation. 1995. Labbok M, A Pérez, V Valdés, et al. The Lactational Amenorrhea Method: A new postpartum introductory family planning method with program and policy implications. Advances in Contraception 10:93-109, 1994. Labbok M, V Jennings. Advances in fertility regulation through ovulation prediction during lactation and during menstrual cycles. IN Contraceptive Research and Development 1994: The Road from Mexico City to Cairo and Beyond. PFA Van Look, G Pérez-Palacios, eds. Delhi:Oxford University Press. 1994. [The] Lancet. Editorial: After the morning after and the morning after that. Lancet 345(8962):1381-1382, 1995. Landgren B-M, A-R Aedo, E Johannisson, et al. Studies on a vaginal ring releasing levonorgestrel when used alone or in combination with transdermal systems releasing estradiol. Contraception 50:87-100, 1994. Larsen B. Vaginal flora in health and disease. Clinical Obstetrics and Gynecology 36:107-121, 1993. Mauck CK, M Cordero, HL Gabelnick, JM Spieler, R Rivera, eds. Barrier Contraceptives: Current Status and Future Prospects. New York: Wiley-Liss. 1994. McCann MF, LS Potter. Progestin-only oral contraception: A comprehensive review. Contraception 50(6):S13-S21, 1994. Mishell DR Jr. Vaginal contraceptive rings. Annals of Medicine 25:191-197, 1993. Pérez A, M Labbok, J Queenan. A clinical study of the lactational amenorrhea method for family planning. Lancet 339:968-970, 1992. Program for Appropriate Technology in Health (PATH). Contraceptive research and development: Progress toward a woman-centered agenda. OutLook 13(2), 1995. PATH. Contraceptive technologies in development: Many leads, progress slow. OutLook 11(2):18, June 1993. PATH. Selected Contraceptive Technologies in Development. Seattle, WA. March 1993. Psychoyos A, G Creatsas, E Hassan, et al. Spermicidal and antiviral properties of cholic acid: Contraceptive efficacy of a new vaginal sponge (Protectaid) containing sodium cholate. Human Reproduction 8(6):866-869, 1994. Queenan JT, M Labbok. Periodic abstinence: The "natural family planning" methods. IN The Best of Dialogues in Contraception. D Mitchell, ed. Los Angeles: Health Learning Systems. 1992. Russell C. From frogs and sharks, a better vaginal foam? Washington Post, Health section, p. 7, 20 February. 1996a. Russell C. The pill is popular but not well understood: New survey shows many women overestimate the risks, underestimate the benefits. Washington Post, Health section, p. 9, 6 February. 1996b. Singh M, BB Saxena, R Craver et al. Contraceptive efficacy of norethindrone encapsulated in injectable biodegradable poly-dl-lactide-coglycolide microspheres: Phase II clinical study. Fertility and Sterility 52:973-980, 1989.

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--> Singh M, BB Saxena, R Landesman, et al. Contraceptive efficacy of bioabsorbable pellets of norethindrone (NET) as subcutaneous implants: Phase II clinical study. Advances in Contraception 1:131-149, 1985. Stein Z. Barriers Women Can Use in Preventing STDs/HIV: Summary and Recommendations from the November 1995 Meeting of the American Public Health Association, San Diego, California (memorandum). New York: Columbia University. November 1995. Stewart F. Vaginal barrier contraceptives and infection risk. IN Barrier Contraceptives: Current Status and Future Prospects, CK Mauck, M Cordero, H Gabelnick, et al., eds. New York: Wiley-Liss. 1994. Swazey JP, ed. Conference on the Development and Use of Antiprogestin Drugs: Social, Political, Economic, and Legal Issues, 6-7 February 1992, Palm Beach, Florida. Boston, MA: Medicine in the Public Interest. 1992. Tanouye E. Technology and health: U.S. companies targeted in protest of abortion pill. Wall Street Journal, 8 July 1994. Trussell J, C Ellertson. Efficacy of emergency contraception. Fertility Control Reviews 4(2):8-1 1, 1995. U.S. Department of State. French abortion pill to be marketed in the U.S. by an American company. Incoming Telegram (unclassified) from U.S. Embassy Paris, 29 April 1993. Van Look PFA, G Pérez-Palacios, eds. Contraceptive Research and Development 1984 to 1994: The Road from Mexico City to Cairo and Beyond. Delhi: Oxford University Press. 1994. Van Look PFA, H von Hertzen. postovulatory methods of fertility regulation: The emergence of antiprogestogens. IN Institute of Medicine. Clinical Applications of Mifepristone (RU 486) and Other Antiprogestins. Washington, DC: National Academy Press. 1993. Waites G. Methods for the regulation of male fertility. Annual Technical Report of the Task Force on Methods for the Regulation of Male Fertility. Geneva: World Health Organization. 1992. White K. Contraceptive makers chilled by court challenges. Journal of Women's Health 4(3), 1995. World Health Organization (WHO). The Role of the Programme in Technology Development and Assessment: A Discussion Paper. Geneva: UNDP/UNFPA/WHO/World Bank/WHO Special Programme of Research, Development and Research Training in Human Reproduction. 1995a. WHO. International Consultation for Policy-Makers on Women and AIDS in Preparation for the Beijing Conference, 6-8 February 1995. Geneva: Global Programme on AIDS. 1995b. WHO. Challenges in Reproductive Health Research: Biennial Report 1992-1993 . Geneva: Special Programme of Research, Development and Research Training in Human Reproduction. 1994a. WHO (Special Programme of Research, Development and Research Training in Human Reproduction, IUD Research Group. A randomized multicentre trial of the Multiload 375 and TCu380A IUDs in parous women: Three-year results. Contraception 49:543-549, 1994b. WHO. Annual Technical Report 1992. Geneva: Special Programme of Research, Development and Research Training in Human Reproduction. Geneva: World Health Organization. 1993. Notes 1.   A minipill is an oral contraceptive containing no estrogen and generally less than 1 mg of a progestational agent per pill (Hatcher et al. 1994). 2.   The U.S. Food and Drug Administration (FDA) recently approved labeling changes extending the use of the Copper T380A from 8 to 10 years and made two additional labeling revisions. First, the FDA added data from studies by the WHO, Population Council, and the manufacturer indicating that the risk of PID is highest 20 days post-insertion, then declines, and remains low and constant thereafter (Farley et al. 1992). Second, a history of ectopic pregnancy is no longer a contraindication. 3.   This refutes the usually held perception that the major mechanism of action of IUDs in

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-->     humans is to disrupt implantation of a fertilized ova. Thus, it would seem to be no longer tenable to propose that the major action of IUDs is to induce abortion (Bardin 1996). 4.   Oral contraceptives are packaged specifically for emergency contraception use in Bulgaria, Finland, Germany, Hungary, Jamaica, Malaysia, the Netherlands, Nigeria, Pakistan, Poland, Singapore, states of the former Soviet Union, Sweden, Switzerland, the United Kingdom, Uruguay, and Zimbabwe (Camp 1994). They have been marketed for emergency contraception in England since 1984. 5.   The gels are currently covered by a patent application assigned to ReProtect, LC. 6.   Antiprogestins that have reached in vivo testing include onapristone, lilipristone, and ZK 98 734 (Schering AG); ORG 31710 and 31806 (Organon); and HRP 2000 (Research Triangle Institute)(Institute of Medicine 1993).