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.

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).

Chemical Barriers

Barrier methods of contraception fall into two, sometimes overlapping, categories: (1) physical barriers (male and female condoms, and diaphragms and cervical caps for women), which differentially prevent the passage of sperm and other constituents of semen to the partner's genital tract; and (2) chemical barriers, a more varied class of products and delivery systems. Chemical barrier methods contain a spermicide, which kills or immobilizes sperm (and other cells). The delivery vehicle can be a cream, gel, foam, film, or other formulation. A combined barrier approach involves using a physical barrier with a spermicide; the diaphragm and cervical cap are examples of this combination. The spermicidal agent in most products sold in the United States is nonoxynol-9, a nonionic detergent or surfactant.

There is renewed public interest in barrier methods, since they constitute the only category of contraceptives now available that can reduce the risk of transmission of sexually transmitted diseases (STDs). However, because they are coitally dependent, their effectiveness depends upon consistent and correct use. And, since cultural and motivational factors influence that use, their efficacy varies widely. Prevalence of use of most barrier methods has been increasing in recent years; still, they are used by less than half of all sexually active couples engaging in behaviors that put them at risk of transmitting or acquiring an STD.

Mechanical Barriers

The principal barrier method currently in use is the male condom, whose utilization has increased steadily since the late 1980s in response to growing consumer concern about sexually transmitted infection. That same concern has provoked interest in developing new condoms for males that are impermeable to virus and thinner but stronger, and to place control of self-protection in women's hands by developing a female condom, called Reality in the United States and Femidom elsewhere. The concern has also generated a tension in approval processes at the U.S. Food and Drug Administration (FDA) which must weigh the urgency of the public health and individual need for protection from sexually transmitted disease, on the one hand, and the need to assure that new products are safe as barriers against conception and infection, on the other. In addition, the ethical and physiologic challenges of product testing are large and complex. Studies of spermicides and drugs to protect against HIV infection are particularly difficult, since failure could result in either unwanted pregnancy, the transmission of a potentially life-threatening sexually transmitted disease, or both (Russell 1996b).

Some of these problems have already affected the availability on the market of both Reality and Avanti, a new male condom. Avanti is the first condom available for use by individuals allergic to latex (the material used for the overwhelming majority of currently available male condoms) and the first male polyurethane condom to be approved by the FDA. Avanti went onto the U.S. market in a limited number of western states in the fall of 1994, approved by the FDA before the agency began requiring manufacturers of medical devices to perform extensive clinical testing prior to marketing. Although it is actually made of a synthetic material that is similar to the material used for Reality, the FDA determined that Avanti was ''substantially equivalent" to the latex condom instead. The effect of this ruling was to exempt Avanti from the more rigorous clinical testing that had been required for Reality. However, the thinness of the material used for the first Avanti to go on the market produced breakage rates judged to be unacceptable. A thicker material is now being tested in clinical trials under the aegis of the National Institute of Child Health and Human Development (NICHD) (American Health Consultants 1995; Contraceptive Technology Update June 1995).

Other plastic condoms for males that are not polyurethane have also been developed. Carter-Wallace is bringing one to market and Smart Practice has developed the Tactylon condom. Core issues for any male condom are not only concerns about breakage, but concerns about the viral permeability of any material of which they are made.

The female condom has been on the market too short a time to assess its acceptability. Recent focus group research shows a positive response at about the 50-60 percent level; it is quite novel and will require familiarity with its use, on the part of men and women. Cost will continue to be an issue for many women, especially since reuse is not advised. While Reality is not without its limitations, it provides women with much more autonomy than other available methods, although it still requires some discussion with the male partner (WHO 1995b). A washable, reusable female condom would seem to be a useful area of improvement.

The Lactational Amenorrhea Method (LAM)

LAM, the newest method in this category, is an effective postpartum introductory family planning method based on breastfeeding's effect on a woman's fertility. LAM's efficacy depends on three parameters: a woman's menstrual period has not returned postpartum; she breastfeeds frequently, day and night; she gives her baby no other food or liquid regularly; and her baby is less than six months old. A change in any of these requires initiation of another method. LAM has shown up to 99.6 percent efficacy in clinical trtials (Pérez et al. 1992); other clinical studies have found only 1 to 2 pregnancies per 100 women in the first six months after delivery, by life table analysis (Labbok et al. 1994).

LAM's mechanism of action is based on the hypothalamic-pituitary-ovarian axis and its response to the suckling stimulus. Suckling sends neural signals to the hypothalamus. This mediates the level and rhythm of gonadotropin releasing hormone (GnRH) secretion. Early postpartum breastfeeding also affects pituitary responsiveness to GnRH. Since GnRH influences pituitary release of follicle stimulating hormone (FSH) and luteinizing hormone (LH), the hormones responsible for stimulating follicle development and ovulation in the ovary, frequent breastfeeding suppresses adequate ovulation and follicle development. In this manner, the woman's body is kept from producing eggs and becoming fertile in the early months after childbirth.

Periodic Abstinence Methods (PAM): Calendar Rhythm, Cervical Mucus/ Ovulation, and Symptothermal Methods

These methods provide instruction about the timing of ovulation during the ovulatory cycle and the days of potential fertilization of the ovum, and require abstinence at those times (Queenan and Labbok 1992). In recent decades several techniques have been developed, often referred to as "natural family planning (NFP) methods"; they have been comprehensively defined by the WHO as "methods for planning or preventing pregnancies by observation of naturally occurring signs and symptoms of the fertile and infertile phases of the menstrual cycle" and the practice of abstinence at those times.

Calendar Rhythm Although, worldwide, calendar rhythm remains the best known and most commonly used periodic abstinence method, new methods have been developed which allow abstinence decisions to be made in closer relationship to the actual physiology of the cycle in question. The two most widely taught methods are (1) ovulation (or cervical mucus) method, based on observations of changes in cervical mucus; and (2) the symptothermal method, which uses primarily basal body temperature changes in addition to calendar or observations of changes in cervical mucus. An estimated 2-5 percent of married American women exposed to the risk of pregnancy currently rely on these methods. Theoretically, these methods should provide reasonable efficacy; however, published figures on efficacy vary widely. Calendar rhythm generally is not prescribed today but may serve as an effective adjunct to newer methods.

Cervical Mucus , or Ovulation Method This method relies on the sensation and/ or observation of mucus, observed vaginally or at the vulva, to identify its characteristics over time. The scientific basis for these signs and symptoms is clear: The changes in the mucus reflect normal physiological reaction to the dynamic estrogen and progesterone levels of the menstrual cycle which can be used to approximate the time of ovulation. Use of this method generally includes maintenance of a daily record, often in a monthly format, to aid in assessment of the phase of the cycle; charts have been developed using colored tabs or symbols to indicate different signs and symptoms.

The Symptothermal Method The symptothermal method provides a multiple index approach and is based on the use of at least two indicators to identify the fertile period: the basal body temperature (BBT) shift, and either cervical mucus or calendar rhythm. The relationship between temperature and ovulation was identified as early as the 1920s: BBT, reflected in the temperature registered orally, rectally, or vaginally before rising in the morning, will rise slightly (about 0.2°-0.4°C, or about 0.4°-0.8°F) in concert with the increasing progesterone levels of the early luteal phase of the menstrual cycle. Generally, the shift is said to occur when the BBT reading is more than 0.05°C (0.1°F) higher than the highest of the previous six postmenstrual readings, although there are other acceptable approaches; a slight drop in temperature (about 0.1 F) may be noted around the time of ovulation. Interpretation of BBT charts may demand considerable education.

Fertility Awareness Methods "Fertility awareness" is a term used when signs and symptoms are taught as part of general reproductive health and family planning or family life education. The term "fertility awareness method," on the other hand, generally applies when either periodic abstinence or a barrier method is used only for pregnancy avoidance during the fertile phase, as that is identified using any of the three periodic abstinence methods listed above. Thus, periodic abstinence may be a part of practicing a fertility awareness method or of natural family planning, but the philosophies behind the two approaches are different.

Emergency Contraception

Interest in methods for emergency contraception is gaining momentum in the United States, although they have been available in Europe and the United Kingdom for over a decade. These methods are used after an act of unprotected intercourse, either because of method failure or failure to use a method. Emergency contraceptive approaches include the use of standard combination oral contraceptives (COCs) containing estrogen and progestin in a postcoital regimen to prevent pregnancy, a regimen of progestin-only minipills, or insertion of a copper-T intrauterine device. Mifepristone (RU 486) has been used as an emergency contraceptive in research trials but is not yet available for that purpose in any country.

When standard COCs are used for emergency contraception, they are called ECPs (emergency contraceptive pills). Though commonly known as the "morning after" pill, ECPs may actually be taken immediately after unprotected intercourse and up to 72 hours beyond; dosage and timing of administration vary according to formulation. Minipills are contraceptive pills that contain only progestin (and not estrogen). Their side effects (nausea and vomiting) are far less common than with COCs, but the window of use is narrower: The time limit for postcoital administration is 48 hours. The copper-T IUD can be inserted up to seven days after unprotected intercourse, is significantly more effective than either ECPs or minipills, and can be left in place to provide continuous effective contraception for up to 10 years. However, like any IUD, it requires skilled insertion using antiseptic practice and is not ideal for women at risk of sexually transmitted diseases (Hatcher et al. 1995).

In Europe, the main hormonal method used is the "Yuzpe Regimen," the sequential administration of higher-than-usual doses of estrogen and progestogen, marketed by Schering AG under the brand name PC4 and licensed in the United Kingdom and some European countries. The Hungarian company, Gedeon Richter, markets the progestogen-only product "Postinor" as a postcoital contraceptive in eastern Europe and some countries of the Far East (Hughes 1995).⁴

Each of the three methods that are available in the United States requires a prescription and all are currently marketed as regular methods of ongoing contraception; none is marketed as an emergency contraceptive, primarily because no pharmaceutical company has applied to the FDA to market emergency contraceptives (Kaiser/Harris 1995). Without FDA approval, manufacturers cannot market or advertise these products for postcoital use, so the normal educational function of drug promotion is absent (Hatcher et al. 1995). As a consequence, most women and many clinicians do not know about emergency contraception, even though a clinician may legally prescribe an approved drug for an unlabeled purpose ("off-label use") and even though considerable research demonstrates that emergency contraceptives are safe and effective (Grossman and Grossman 1994; Trussell and Ellertson 1995).

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 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 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 research and development activities with respect to products in this combined category.

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 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.