Send Orders of Reprints at [email protected] 276 Current Women’s Health Reviews, 2012, 8, 276-288 An Update on Developments in Female Hormonal Contraception Deborah A. Garside1, Ayman Gebril2, Natalie Nimmo2, Manal Alsaadi2, Alexander B. Mullen2 and Valerie A. Ferro2,* 1Imperial College London, Faculty of Medicine, London, SW7 2AZ, UK; 2University of Strathclyde, Strathclyde Insititute of Pharmacy and Biomedical Sciences, 161 Cathedral Street, Glasgow, G4 0RE, UK Abstract: The human population continues to grow in some parts of the world, which has severe impact on resources, health and the environment. Individually, contraception enables women to choose their optimal family size and birth spacing, while in resource-poor countries it can help lift families out of poverty. While the oral contraceptive pill revolutionised female contraceptive options, there was a price to pay in terms of increased health risks. Today, improved formulations have been developed, together with non-oral hormonal technologies. This review will examine the history of female contraceptive research and provide an update on the status and future direction of new products. Keywords: Combined formulations, contraception, devices, hormones, implants, oestrogen, oral, progestogen. HUMAN POPULATION GROWTH various types of contraception is available to most women in the developed world, this is not generally the case for those The statistics on human population growth present a in developing countries. There is therefore a significant confusing picture, making it necessary to ask whether there unmet need for contraception that meets the particular health is a continuing need for contraceptive research. The and cultural needs of women in these countries. For population growth rate over 5 years (2005-2010) is shown in example, Fig. (2a and 2b) show the percentage number of Fig. (1). In 2011, the global population reached 7 billion women using some method of contraception and areas of the people and is expected to expand to 10.1 billion by the end world where there is still an unmet need for family planning, of this century [1]. However, individual regions show vast respectively. Clearly safe, and effective population control is differences in terms of birth, death and population growth rates. The latter can be divided into four categories - less still needed to address regio-specific patterns, but it is critical than 0% (in decline), less than 1% (low), 1-2% (moderate) that whatever methods are available, that they are readily and greater or equal to 2% (rapid) growth per anuum. These accessible and not subject to economic constraints. Methods have significant impacts which are summarised in Table 1, being developed should also take into account efficacy, side- and it is clear that there are many challenges, albeit different effects, ease of use, including the need for the user to ones, still being faced at both ends of the growth spectrum. remember repeat administrations, cultural factors and Furthermore, overall, the world’s total fertility rate has fallen convenience of application [4]. These therefore provide significantly from the 1950s to the present day, from 5 to 2.6 drivers for innovations in the modern contraceptive field. children per woman – this is attributed to widespread use of contraceptives [2]. However, in the poorest countries CONTRACEPTION THROUGH THE AGES maternal mortality continues to be high. The numbers of Limiting the number of pregnancies is not a modern deaths were 2.91 million in 1990-1995, and only fell to 2.76 phenomenon. Behavioural methods (abstinence, coitus million in the following 5 years. inerruptus, avoidance during certain times of a cycle, breast- Stover and Ross [3] have described in detail how feeding) have played a major role, along with barrier effective family planning can reduce the number of these methods, chemical intervention (including use of natural deaths by: reducing the number of births; averting high-risk products since ancient times and contemporary spermicidal births and preventing the number of abortions, with methods), intrauterine devices (IUD) and sterilisation [5-8]. associated health risks. Importantly, therefore, access to However, by far the most influential contraception method in suitable, effective and affordable contraception is a key issue modern times has been hormonal control, brought about by for global women’s health. The ability for women not to be the advent of the oral contraceptive pill. able to choose when they are pregnant and how many children they have, can have a profound effect on their HISTORY OF THE ORAL CONTRACEPTIVE PILL health, education and socio-economic status. While access to Since its inception, the oral contraceptive (OC) pill has, and continues to evoke controversy on various levels (cultural, economic, ethical, medical, moral, political, *Address correspondence to this author at the University of Strathclyde, religious and social). The historic context leading to the Strathclyde Insititute of Pharmacy and Biomedical Sciences, 161 Cathedral Street, Glasgow, G4 0RE, UK; Tel: +44 141 548 3724; Fax: +44 141 552 2562; launch of the “Pill” in terms of scientific and personal trials E-mail: [email protected] faced by individuals and the approaches taken by the 1875-6581 $58.00+.00 © 2012 Bentham Science Publishers Female Hormonal Contraception Current Women’s Health Reviews, 2012, Vol. 8, No. 4 277 Fig. (1). Population growth rate by country (Data from [1]). Table 1. Population Growth Category and Impacts (Summarised from [105]) % Population Growth Regions Impacts Rate Per Annum Less than 0 Japan, Germany, Russia, eastern Europe • Widespread use of contraception (sub-replacement • Greatest ageing population impact fertility, low mortality) • Encourages economic migration 0-1 USA, Canada, much of Europe, • Widespread use of contraception (low fertility, low China, Brazil • Ageing population dependent on public resources for support mortality) • Major effect on global environment stresses 1-2 India, Indonesia, north Africa, • Widespread use of contraception (declining fertility, low western Latin America • Less time spent in childrearing, so more women in employment mortality) • High labour force, fewer young or old dependents – economic benefits • Reduced stress on public services and infrastructure Greater or equal to 2 Sub-Saharan Africa, • Poor use of contraception (relatively high fertility Pakistan, Afghanistan, • Childbearing at very young and advanced ages, with short birth intervals and moderate to low Arabian peninsula • Pressure on public services and infrastructure mortality) • Stress on environment • Reduced economic growth and inadequate healthcare systems • Increased maternal and child mortality pharmaceutical companies, is far more interesting than the menstrual disorders, however, it was only in 1961 that subsequent lack of innovation in the field [reviewed by [9- approval was given for a contraceptive (75µg mestranol/5mg 12]. Nevertheless, the Pill has survived for over half a norethynodrel) to be used by married women in the US. The century and is likely to be hailed as one of the twentieth “Pill” revolutionised society, although it took another decade century’s greatest “life-changing” scientific drugs. Since the before unmarried women were allowed access to OCs [10]. 1920s, there were a number of key players and milestones 1 While the early OCs were based on oestrogens or (summarised in Textbox 1) that influenced the launch of progestogens, for safety reasons and improved cycle control, Searle’s Enovid™ (which contained the actives 150µg mestranol/9.85mg norethynodrel). It was approved by the Food and Drug Administration (FDA) in 1957 to treat 1oestrogen and estrogen are used interchangeably 278 Current Women’s Health Reviews, 2012, Vol. 8, No. 4 Garside et al. Fig. (2). (a). Percentage of women using some method of contraception among those aged 15-49 who are married or in a union (Data from [1]). (b). Percentage of women with an unmet need for family planning among those aged 15-49 who are married or in a union (Data from [1]). Text Box 1. Timeline of Discoveries Leading to the First Contraceptive Pill 1921: Ludwig Haberlandt coined the term hormonal sterilisation and demonstrated in rabbits and guinea pigs that ovulation could be temporarily suppressed by transplanting ovaries from pregnant animals into recipients [125]. For human studies, since surgery was not an option, the company Gideon Richter produced the preparation Infecundin that enabled Haberlandt to investigate the use of parenterally or orally administered ovary extracts, to induce sterility [9, 126]. 1929: Adolf Butenandt isolated estrone, a female sex hormone, and in the early 1930s he and other researchers isolated progesterone from pig ovaries [127]. 1936: AW Makepeace demonstrated the anti-ovulatory effect of progesterone [128], however, extraction from animal ovaries made it expensive for a commercial product. 1941: Russell Marker developed a more cost effective chemical synthesis method by extracting diosgenin from Mexican wild yam (Dioscorea) roots [129] and founded the company Syntex. 1951: Carl Djerassi working at Syntex produced the first progestin (or progestogen) in the form of the steroid norethistrone, which was orally active and an advancement of any other progestational hormone [130]. A year later, Frank Colton at Searle Company developed a close isomer of norethistrone, norethynodrel [10]. 1951: Margaret Sanger (founder of the Planned Parenthood Federation