Clinical Review Science, medicine, and the future

Contraception

BMJ 1999; 319 doi: https://doi.org/10.1136/bmj.319.7215.969 (Published 09 October 1999) Cite this as: BMJ 1999;319:969
  1. David T Baird, clinical research professor (dtbaird{at}ed.ac.uk)a,
  2. Anna F Glasier, director of family planning and well woman servicesb
  1. a Centre for Reproductive Biology, University of Edinburgh, Edinburgh EH3 9EW
  2. b Edinburgh Primary Care NHS Trust, Edinburgh EH4 1NL
  1. Correspondence to: D T Baird

    The prevalence of contraceptive use is increasing worldwide, and in many countries over 75% of couples use effective methods.1 However, existing methods of contraception are not perfect, and their acceptability is limited by side effects and inconvenience. Even in developed countries where contraception is freely available, many unplanned pregnancies occur. There is thus a real need for new methods of contraception to be developed that are more effective, easier to use, and safer than existing methods. This article discusses current research into new forms of contraception and predicts what methods are likely to be used in the future.

    Social influences

    Demographic forces, prevalence of disease, and social and cultural factors influence not only the use of contraceptives but also the development of new methods. The age of onset of sexual activity is falling, while childbearing is being delayed or, in many developed countries, forgone altogether. There is pressure from the public for the use of more “natural products,” which are perceived to be safer, but at the same time demand that contraceptives have almost perfect efficacy.

    Those concerned with the development of new drugs and devices take efficacy as read and are now seeking positive health benefits—methods that prevent not only pregnancy but also sexually transmitted disease and, in the long term, common diseases such as breast cancer. Heterosexual intercourse is now the main route of transmission of HIV. While barrier methods such as condoms reduce the risk of transmission, there is a pressing need for additional and complementary methods of protection in the form of topical virucidal agents, which ideally would also be spermicidal.

    Hormonal contraception for women

    Methods involving steroid hormones have dominated new developments in contraception, and in the past 40 years more than 200 million women worldwide have taken “the pill.”2 Recent data confirm its excellent safety profile, and in many respects the pill will be hard to beat. In the past 15 years new developments in contraception have come mainly from tinkering with hormonal methods—new delivery systems (implants and hormone releasing intrauterine devices), better progestogens, and lower doses of oestrogen.

    Predicted developments

    Within five years
    • New delivery systems of conventional contraceptives, such as vaginal rings, transdermal patches, and gels

    • Contraceptives that also protect against sexually transmitted disease

    Short term (<10 years)
    • “Once a month” pill that inhibits implantation

    • Antiprogestogens used for oestrogen-free, daily pill for women

    • Orally active, non-peptide antagonists of gonadotrophin releasing hormone for men and women

    Long term (>10 years)
    • Antagonists of follicle stimulating hormone receptor

    • Arrest of spermatogenesis or sperm maturation

    • Arrest of final maturation of oocyte, such as with phosphodiesterase inhibitors

    • Inhibitors of follicle rupture

    New delivery systems and selective receptor modulators

    The early 21st century will probably witness the licensing of contraceptive vaginal rings, transdermal patches, and gels. In the longer term it seems likely that selective modulators of hormone receptors will replace currently available oestrogens and progestins in order to avoid their risks, particularly venous thrombosis, while also reducing the incidence of common diseases such as breast cancer Study of the molecular structure of hormone receptors has revealed that each ligand induces an almost unique conformational change and, hence, has slightly different biological effects.3 It is therefore likely that organ specific drugs, which produce the desired effect only on critical reproductive processes, will become available.

    Antiprogestins

    The most exciting development in the past 20 years has been the discovery of compounds that antagonise the action of progesterone. Progesterone is necessary for the establishment and maintenance of pregnancy. Key events—including ovulation, fertilisation, and implantation—depend on the secretion of progesterone by the ovary at the appropriate time. It is nearly 20 years since the discovery of the first antagonist of progesterone (mifepristone), which was shown to interrupt pregnancy The political controversy surrounding the “abortion pill” has impeded research into other potential uses of these compounds, including contraception.

    Some years ago we showed that a single dose of 600 mg mifepristone was highly effective as an emergency contraceptive after unprotected intercourse.4 The compound both inhibits ovulation and prevents implantation, properties which suggest that it could be used as a regular form of contraception. A daily dose of 2-5 mg (less than a hundredth of the dose required to induce abortion) inhibits ovulation and prevents the formation of a secretory endometrium.5 Oestrogen secretion by the ovary is maintained at the level of that found in the follicular phase of the menstrual cycle Preliminary data suggest that most women are amenorrhoeic while taking the antiprogestin, which could be a considerable advantage compared with other forms of oestrogen-free contraceptives such as gestogen only pills.

    Antigestogens might also be used for “once a month” pills. If they are given in the early luteal phase of the cycle the formation of a secretory endometrium is retarded without affecting the regular pattern of menstruation. In a pilot study of 21 women in Sweden who used this method as their sole means of contraception there was only one pregnancy in 153 menstrual cycles.6 A major practical problem with this approach is the difficulty in detecting ovulation so that the pill can be taken at the correct time of the cycle. A once a month pill that prevented ovulation or implantation would be welcomed by many women from various countries and cultures.7 In contrast, only a minority of women would be prepared to use a pill taken around the time of expected menses, when implantation of the embryo would already have occurred. In any case, current evidence suggests that mifepristone alone or in combination with misoprostol would result in too high an incidence of pregnancy to be useful as a regular method of inducing early menses.8

    Contragestion

    It has also been proposed that mifepristone could be taken only if the menses was overdue (“contragestion”). An inducer of a missed menses acts by disrupting an implanted embryo and induces a very early abortion. A pilot study supported by the World Health Organisation reported very few ongoing pregnancies in women given a combination of 600 mg mifepristone and 1 mg gemeprost within 10 days of their expected menses.9 Although this study showed “proof of concept,” there are legal, political, and ethical issues that make it unlikely that this approach would receive widespread acceptance. Moreover, in the above study there was considerable variation in the timing of the onset of the next menses, which would make it difficult for women to decide whether to take the pill again in subsequent cycles. However, for those women who find it ethically acceptable, a pill that induced missed menses might be more attractive than a monthly pill to induce early menses, perhaps because it would be required only two or three times a year.

    Hormonal contraception for men

    Evidence from different countries and cultures shows a growing demand for more effective and convenient methods of contraception for men.10 A recent survey in Scotland, South Africa, Hong Kong, and China found that most men would consider using a “male pill.” Although it has been known for nearly 50 years that azoospermia can be induced by the administration of large doses of testosterone, progress in the development of hormonal male contraception has been slow for several reasons. The supraphysiological dose of androgen required to induce azoospermia causes side effects, including prostate hypertrophy and unfavourable changes in plasma lipids, precluding wide scale use in otherwise healthy men.11

    Current research therefore focuses on lower physiological doses of androgen in combination with gestogens (such as desogestrel and cyproterone acetate) or gonadotrophin releasing hormone antagonists.12 Orally active non-peptide antagonists of gonadotrophin releasing hormone or a depot preparation could provide a practical method of suppressing gonadotrophins in combination with androgen replacement. However, there are presently no convenient, safe preparations of androgen for replacement therapy, although this is the subject of research by several pharmaceutical companies Encouraging progress is being made in the development of new androgens (such as 7α-methyl nortestosterone (MENT)) that have potential health benefits and in new methods of long term delivery of steroids in implants (such as Implanon).13 Development of a safe, acceptable treatment that is as effective as the combined oral contraceptive pill for women (Pearl index <1 per 100 women years) is at least five years away.

    Beyond 2010

    In the long term there are several potential approaches for contraception in men and women (see figure).14

    Figure1

    Potential targets for contraception in men and women

    Meiotic arrest

    In both sexes the formation of gametes (spermatogenesis and oogenesis) involves the process of meiosis, whereby the number of chromosomes in a diploid nucleus is halved to the haploid state by cell division. Meiosis occurs only in germ cells, and, hence, substances that interfere with meiotic division should be specific for the gonad. Specific genes are expressed at different stages of spermatogenesis, and antagonism of their products (such as activin) could lead to sterility.

    In the female, meiosis is almost completed during fetal development, but the final stages of meiotic division are delayed into adulthood, until just before ovulation. If we knew the mechanism by which meiosis was arrested in the oocyte it might be possible to activate a similar mechanism to inhibit spermatogenesis in men. Arrest of meiosis in the oocyte involves at least one protein specific to germ cells (c-mos), which is also transcribed in the male during meiosis. A high concentration of cyclic AMP is apparently important in preventing final maturation of the oocyte, and specific inhibition of phosphodiesterase 3 (the enzyme that catalyses the breakdown of cyclic AMP) is contraceptive in rats, preventing the oocyte from acquiring developmental competence.

    Blockage of follicle stimulating hormone

    Blocking the follicle stimulating hormone receptor or inhibiting secretion of follicle stimulating hormone with analogues of inhibin will interfere with spermatogenesis, although whether sperm production can be maintained by testosterone alone in men, as it can in rodents, is not known. A minimum concentration of testosterone within the testis is probably required for spermatogenesis, so that inhibitors of androgen synthesis or action will be contraceptive. The key to successful use of these approaches is again specificity. It may be possible to use the follicle stimulating hormone receptor as a target to deliver another agent specifically to the testis.

    Mutations of the follicle stimulating hormone receptor have been described in women who present with primary amenorrhoea due to lack of follicle development Inhibitors of follicle stimulating hormone synthesis or action could prevent fertility but would require oestrogen replacement to prevent the consequences of hypo-oestrogenism. Arresting final maturation of the oocyte before ovulation or follicle rupture would be an attractive method of contraception that did not disrupt the endocrine events controlling the ovarian cycle.

    Preventing implantation

    Progesterone induces the transcription of various endometrial gene products involved in implantation—for example, leukaemic inhibitory factor, calcitonin, vitronectin, αvβ3 integrin, and α4β1 integrin. 15 16 Specific antagonists of these products would be promising as new contraceptives because they should only act at the uterus.

    The formation of new blood vessels (angiogenesis) is usually restricted in adults to repair of injury, but in the ovary and uterus there is extensive angiogenesis each month during the formation of the follicle, corpus luteum, and endometrium. A potent antagonist of vascular endothelial growth factor prevented pregnancy in mice without producing major systemic side effects in the long term.

    Immunisation

    Other likely targets for new contraceptives are proteins involved in fertilisation. 17 18 The sperm attaches to the egg through the interaction of specific antigens on the sperm surface with the zona pellucida proteins of the egg (such as ZP3). Immunisation of female monkeys with zona pellucida proteins prevents pregnancy, but unfortunately produces a form of autoimmune oophoritis with loss of oocytes and premature menopause Unforeseen consequences resulting from autoimmunity are a potential hazard of antifertility vaccines. Immunisation of women against sperm antigens should avoid such problems, but research is still at the initial stages.19

    Another possibility is disrupting the synthesis or delivery of proteins such as fertilin that are important for the function of sperm membrane, thus leading to incompetent spermatozoa. Interfering with the final maturation of the spermatozoa has the attraction that it would result in sperm that were incompetent to fertilise an egg without running the risk of producing genetically mutated germ cells. However, concerns have been raised about the potential misuse of contraceptive vaccines, particularly if they are not fully reversible.

    Because of these political concerns and doubt about long term consequences of immunisation, there is little commercial enthusiasm for further development of this approach in spite of the scientific potential.

    Conclusions

    Compared with many drugs, the product development of a new contraceptive is expensive and relatively high risk. It is unlikely that the pattern of contraceptive use will change radically in the next 10 years No one method will be suitable for everyone, and individuals' preferences will probably change through their reproductive life. In the next five years more sophisticated systems for the delivery of steroid hormones, through or under the skin and into the uterus, will extend the range of options available. In five to 10 years new steroid antagonists such as antiprogestins will replace some current contraceptive methods, such as gestogen only pills, and probably lead to new approaches like a “once a month” pill. By 10-15 years, the dream of an effective safe male pill will probably become a reality, shifting the burden of responsibility for contraception more equally between men and women. Only then will women have truly achieved “the fifth freedom”—freedom from the burden of excessive fertility.20

    Acknowledgments

    We thank the Medical Research Council and Department of International Development (DFID) for support for the Contraceptive Development Network.

    Footnotes

    • Competing interests Both authors have, on occasion, received reimbursement for attending meetings, research funding, employing staff, and consulting from several pharmaceutical companies engaged in contraceptive research, including Organon, Schering, Ayerst, Ortho-McNeill, Exelgyn, Leiras, Wyeth, Janssen-Cilag.

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