As the world grows: contraception in the 21st century R. John Aitken, … , Christine K. Mauck, Michael J.K. Harper J Clin Invest. 2008;118(4):1330-1343. https://doi.org/10.1172/JCI33873. Review Series Contraceptives that are readily available and acceptable are required in many poorer countries to reduce population growth and in all countries to prevent maternal morbidity and mortality arising from unintended pregnancies. Most available methods use hormonal steroids or are variations of barrier methods. Reports from several fora over the last 12 years have emphasized the number of unwanted pregnancies and resultant abortions, which indicate an unmet need for safe, acceptable, and inexpensive contraceptive methods. This unmet need can be assuaged, in part, by development of new nonhormonal contraceptive methods. This Review addresses the contribution that the “omic” revolution can make to the identification of novel contraceptive targets, as well as the progress that has been made for different target molecules under development. Find the latest version: https://jci.me/33873/pdf Review series As the world grows: contraception in the 21st century R. John Aitken,1 Mark A. Baker,1 Gustavo F. Doncel,2 Martin M. Matzuk,3 Christine K. Mauck,2 and Michael J.K. Harper2 1Discipline of Biological Sciences and ARC Centre of Excellence in Biotechnology and Development, University of Newcastle, Callaghan, New South Wales, Australia. 2CONRAD, Eastern Virginia Medical School, Arlington, Virginia, USA. 3Departments of Pathology, Molecular and Cellular Biology, and Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA. Contraceptives that are readily available and acceptable are required in many poorer countries to reduce popula- tion growth and in all countries to prevent maternal morbidity and mortality arising from unintended pregnancies. Most available methods use hormonal steroids or are variations of barrier methods. Reports from several fora over the last 12 years have emphasized the number of unwanted pregnancies and resultant abortions, which indicate an unmet need for safe, acceptable, and inexpensive contraceptive methods. This unmet need can be assuaged, in part, by development of new nonhormonal contraceptive methods. This Review addresses the contribution that the “omic” revolution can make to the identification of novel contraceptive targets, as well as the progress that has been made for different target molecules under development. Retrospect been developments of new delivery methods for existing and novel More than 700,000 maternal deaths, most in the developing hormonal steroids, mostly acting by inhibition of ovulation. This has, world and related to causes associated with unintended pregnan- to a large extent, been conflated by the fact that the length of time cies, occurred between 1995 and 2000; more than 400,000 of these required to develop new methods has been substantially longer than deaths resulted from unsafe abortions (1). This indicates that exist- many investigators and other experts in the field estimated (10, 11). ing contraceptives are either not available or not adequate. The need Other problems hampering the development of new contraceptive for safe and effective contraceptives has also been highlighted in two methods include the fact that within the last two years, most large Institute of Medicine reports, published in 1996 and 2004 (2, 3). pharmaceutical companies involved in fertility regulation have with- The 1996 report concluded that there is a need for contraceptive drawn from the contraceptive research and development field. Thus, research and development; that contraceptive research and develop- the outlook for the development of new contraceptives is grim and ment need to be revitalized; and that there are scientific prospects will depend solely on the public sector, where funding is also more that could revitalize the field (2). The 2004 report was more focused constrained than in 1996. Realistically, development of a new con- and addressed only two issues — facilitating translational research traceptive agent from target validation to the pivotal clinical trials from contraceptive target identification to initial clinical studies can take up to 15–20 years and cost $100 million or more. These and developing strategies for research success (3). Specific recom- facts have been responsible for donor fatigue and some means has mendations in the 2004 report were to utilize new “omic” technolo- to be devised to reenergize the field (12). gies to assist in contraceptive target identification and validation; to Indeed, progress in the contraceptive development arena has improve the translational process with financial support and use of been so poor that a recent report by the United Kingdom All Party surrogate markers; to focus on druggable targets and tissue speci- Parliamentary Group on Population, Development and Reproduc- ficity; to seek to identify a priori rather than by serendipity other tive Health (13) has concluded that the UN Millennium Develop- health benefits that the drugs might have in addition to contra- ment Goals cannot be met given the levels of population growth ception (e.g., prevention of breast and prostate carcinoma); and to in the poorest countries. The Parliamentary Report also clearly recruit industry and a new generation of scientists to the cause. indicated that claims advanced to refute the need for more con- There have been some advances in contraceptive development in traceptive development — that birth rates are falling and good the years since the first contraceptive revolution provided by the oral contraceptive methods are available now (14) — are not correct contraceptive (OC) pill regimen (4–6), e.g., the development of Copper for many poor countries. In their 2004 article, Collumbien et al. T380A and levonorgestrel-releasing (LNG-releasing) intrauterine (15) concluded that globally, maternal conditions stemming from devices (IUDs) (7–9). However, most of the advances have, in fact, unwanted births resulted in a loss of 98,000 lives and 4.5 million disability-adjusted life years. However, regional differences were Nonstandard abbreviations used: Eppin, epididymal protease inhibitor; FSH, fol- large, with the effects being especially high in eastern and southern licle-stimulating hormone; GAPDHS, GAPDH, spermatogenic; hCG, human chori- Africa. Non-use of available contraceptives is responsible for 90% onic gonadotropin; IUD, intrauterine device; LH, luteinizing hormone; LIF, leukemia of these unwanted births. A recent report from the Guttmacher inhibitory factor; LIFR, LIF receptor; LNG, levonorgestrel; OC, oral contraceptive; OR, odorant receptor; PC6, proprotein convertase 6; PEGylated, conjugated to polyethyl- Institute concluded that unmet contraceptive need ranges from ene glycol; PRM, progesterone receptor modulator; RARα, retinoic acid receptor-α; 10%–12% in developing countries and that health effects and TEX14, testis-expressed gene 14. inconvenience are the main reasons for this non-use (16). For Conflict of interest: M.J.K. Harper has stock holdings in GlaxoSmithKline and many women, existing contraceptives are therefore not accept- Procter & Gamble. M.J.K. Harper, G.F. Doncel, and C.K. Mauck work for CONRAD, which has received support from the Bill and Melinda Gates Foundation. The remain- able or not available and thus in many cases are not used. Further, ing authors have declared that no conflict of interest exists. the importance of developing a diverse range of contraceptives Citation for this article: J. Clin. Invest. 118:1330–1343 (2008). doi:10.1172/JCI33873. acceptable to individual preferences is highlighted by the observa- 1330 The Journal of Clinical Investigation http://www.jci.org Volume 118 Number 4 April 2008 review series tion that women in the United States who are neutral about or emergency contraception. When taken within 72 hours of unpro- dissatisfied with their contraceptive method are more than three tected sex, they reduce the chance of pregnancy by 75%–89%. The times more likely than women satisfied with their contraceptive main mechanism of action of such OCs is interference with ovula- method to have a gap of at least one month in a 12-month period tion, either by preventing or delaying luteal function (22). Steroi- during which they use no contraception despite being sexually dal antiprogestins are also effective (Table 1) (23). active (17). There is very unlikely ever to be a contraceptive “silver Although efforts in the United States and other countries have bullet” that will suit all men or all women, irrespective of whether centered on making emergency contraception more readily avail- they are healthy and at what stage of their reproductive life cycle able, some new products are also being studied as alternatives to they are. This reinforces the need to develop various new (prefer- traditional steroidal methods in the hope that they have fewer side ably nonhormonal) methods that are easy to use, safe, inexpensive, effects or are active for a longer period of time after unprotected and sufficiently diverse in their methodology to be acceptable to intercourse (Table 1). For example, meloxicam is a COX-2 inhibitor individuals of different cultures and with different medical needs. that prevents follicular rupture and is being studied as an alterna- Contraceptives that also provide protection against sexually trans- tive emergency contraceptive that might expand the window dur- mitted infections,