Clinical review

Contraception

David T Baird, clinical research professor ^a,  Anna F Glasier, director of family planning and well woman services ^b. 

^a Centre for Reproductive Biology, University of Edinburgh, Edinburgh EH3 9EW, ^b Edinburgh Primary Care NHS Trust, Edinburgh EH4 1NL

Correspondence to: D T Baird dtbaird{at}ed.ac.uk

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

Top Social influences Hormonal contraception for... Hormonal contraception for men Beyond 2010 Conclusions References

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 benefitsmethods 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

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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 methodsnew delivery systems (implants and hormone releasing intrauterine devices), better progestogens, and lower doses of oestrogen.

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 eventsincluding ovulation, fertilisation, and implantationdepend 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.

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

Top Social influences Hormonal contraception for... Hormonal contraception for men Beyond 2010 Conclusions References

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 7-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

Top Social influences Hormonal contraception for... Hormonal contraception for men Beyond 2010 Conclusions References

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

View larger version (39K): [in this window] [in a new window]   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.

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.

Preventing implantation
Progesterone induces the transcription of various endometrial gene products involved in implantationfor example, leukaemic inhibitory factor, calcitonin, vitronectin, _v3 integrin, and ₄₁ integrin. ^{15 16} Specific antagonists of these products would be promising as new contraceptives because they should only act at the uterus.

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

	Conclusions

Top Social influences Hormonal contraception for... Hormonal contraception for men Beyond 2010 Conclusions References

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 interest: 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.

	References

Top Social influences Hormonal contraception for... Hormonal contraception for men Beyond 2010 Conclusions References

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