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Send Orders of Reprints at [email protected] 276 Current Women’s Health Reviews, 2012, 8, 276-288 An Update on Developments in Female

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 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, .

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 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 /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 , 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 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 , and in the early 1930s he and other researchers isolated 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 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 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 of America) approached Gregory Pincus and provided a grant to begin hormonal contraceptive research [131, 132]. John Rock, was also experimenting with administration of high doses of diethylstilboestrol (oestrogen) and progesterone to treat infertility in women [10]. Together they demonstrated that breakthrough bleeding could be controlled with a mixture of norehynodrel and a synthetic oestrogen (mestranol) [133]. 1955: Clinical trials were carried out in Puerto Rico in 1955 (as it was a criminal offence to dispense contraceptives in the US) [10]. 1957: Enovid® marketed to treat menstrual problems by Searle [10]. 1961: Enovid® marketed as a contraceptive [10]. Female Hormonal Contraception Current Women’s Health Reviews, 2012, Vol. 8, No. 4 279 new hormone combinations were developed and improved showing androgenic and GR-like effects. The main hormone analogues were synthesised to try and reduce new progestogens in current use are , triegestone clinical side-effects. In addition, reduction in hormone doses, and . Examples of new brands incorporating these use of new oestrogen and progestogen analogues, together are Natazia® (dienogest with estradiol2 valerate), Yasmin® with development of formulations for non-oral routes of (drospirenone) and Beyaz® (drospirenone with levomefolate). administration were investigated. These were all necessary due to a need for reducing the clinical side effects and health Progestogen only Pills risks associated with the early forms of contraceptive pill [8]. In addition, several new formulations are based on The concept of multiphasic oral contraceptives arose because progestogen-only pills (‘mini-pills’), which without an while oestrogen and progesterone doses were being lowered, oestrogen component decrease complications such as this caused greater incidences of intermenstrual bleeding and thrombophlebitis, cardiovascular disease (CVD) and led to the first triphasic oral contraceptive, Ortho-Novum pulmonary embolism [18]. The mechanism of action for 7/7/7 in 1984 [8]. Since then, different brands of OC have progestogen-only methods include prevention of ovulation, been developed including combined monophasic (contain the changes in cervical mucus, suppression of LH and FSH same amount of hormone in each active pill), biphasic peaks, inhibition of production and (alteration of progestogen-estrogen ratio in two phases), premature luteolysis (reduced corpus luteum function) [19]. triphasic (three variations of progestogen-estrogen ratio) or quadriphasic (produces four ratios of progestogen-estrogen) New Developments in Combinations and progesterone only preparations. A comprehensive review, detailing dosing regimens of different types of The number of combined OC (COC) on the market has contraceptives is provided by Read [13]. increased in recent years. New formulations contain dosages of oestrogen as low as 20µg. In addition, some combinations UPDATE ON RECENT OC DEVELOPMENTS avoid the standard 7 day placebo followed by 21 days of active pills and now provide a 26 day active and 2 day Since OCs were first introduced more than 50 years ago, placebo (or no pill) period. Interestingly, this approach there have been few innovations to the concept. Recently appears to result in a higher rate of pill use compared with though, several brands have been developed that claim to the standard regime [20]. In general, the efficacy, side effects have more non-contraceptive benefits than previous and cycle control of these new formulations are similar to formulations, as well as improved bleeding and side effect those with 35µg oestrogen and the low dose may provide the profiles. These are outlined below. potential for fewer oestrogen side effects. However, it is yet The major part of contraceptive efficacy in hormonal to be determined if the low dose has similar non- formulations is due to the progestogen compound, so this contraceptive benefits as the higher dose pills. has been the main focus of recent research. In addition, Further to changes of dose and regime for combination new developments that have notably taken place are in oral contraceptive pills, there are also new combinations the 19-nortestosterone derivatives (second generation being researched using novel steroids. Examples of new progestogens), lowering the amounts of oestrogens present combinations that are currently being investigated or recently or eliminating them completely (progesterone only pills) and marketed include: new hormone combinations.The purpose of the progestogens ensures prevention of ovulation, enables changes in the LoLoestrin Fe cervical mucus to inhibit penetration. Furthermore, they can be used at very low doses [14]. While they have the LoLoestrin Fe contains pills of 10µg of ethinyl potential to reduce many of the side-effects attributed to the /1 mg of norethindrone together with placebo pills combination formulations, they are not used extensively with 75 mg ferrous fumarate (non-contraceptive additive). mainly because they cause abnormal bleeding patterns [15, 16]. This was recently approved by the FDA and offers an even lower dose of oestrogen [21]. New Progestogens (Progestins) /Dienogest Newer progestogens have been designed that evoke the benefits of progesterone with improved progestational and Estradiol valerate/dienogest formulations show good anti-oestrogenic action on the endometrium as well as having efficacy, safety and tolerability profiles with potentially more potent anti-gonadotropic effects [14, 17]. While better control over menstrual cycles than (LNG) previous synthetic progestogens were structurally related to OCs. This formulation is considered suitable for older women testosterone (oestranes and gonanes) or progesterone of reproductive age who wish for shorter and/or lighter flow (pregnanes and 19-norpregnanes), various new progestogens menstrual cycles [22]. It is a multiphasic preparation and in have been synthesised that minimize the side-effects related some countries is indicated for menorrhagia. to androgenic, oestrogenic or receptor (GR) interactions to prevent side-effects. These new progestogens Acetate (NOMAC) are different in structure, metabolism and pharmacodynamic (NOMAC) is a highly selective and mechanism with respect to the earlier compounds and have a potent progestogen, similar in structure to 19-norprogesterone. higher contraceptive efficacy. They are similar to natural progesterone and hence, side effects such as adverse cardiovascular related events, are reduced compared with 2estradiol and oestradiol are used interchangeably 280 Current Women’s Health Reviews, 2012, Vol. 8, No. 4 Garside et al.

It has strong progesterone receptor agonist activity, with for women over the age of 17. In the UK little binding to receptors and GR. In animal Levonelle can be given to girls over the age of 13, provided models, it has shown to have moderate anti-androgenic and the Pharmacist is satisfied there are no child abuse issues. strong anti-estrogenic activity. In clinical studies, this Other selective progesterone receptor modulators hormone effectively suppressed gonadotropic activity and (SPRMs), are being further researched for use for EC. These ovulation in premenopausal women. NOMAC has been progesterone receptor ligands bind with progesterone combined with oestrogen as a monophasic oral contraceptive receptors and exert antagonistic, agonistic or mixed (Zoely®) and has shown safety and efficacy in clinical trials agonistic-antagonistic effects, depending on the cellular [23]. context of the target tissues [31]. To date, about a dozen In addition, ‘continuous pills’ that either decrease or SPRMs have been evaluated, the best known of which are eliminate the hormone free interval have also been , , , and developed, such as Seasonale, Seasonique and Lybrel. proellex [32]. Currently developed SPRMs are derivatives of Seasonal has a 91 day extended cycle with continous ethyl steroids with either mild or potent anti-progestogen activity. estradiol and Lybel is a continuos oral contraceptive. Lo- Their contraceptive activity is achieved through various seasonique, a low dose continuous pill, has 7 days of pills different mechanisms, for example by inhibiting ovulation or with only 10µg . Several studies have disrupting endometrial synchronisation. investigated the safety of these contraceptives and conclude that they are safe for long-term use [24-26]. Ulipristal acetate was shown to be as effective as LNG in preventing pregnancy in EC comparison trials, when given In summary, although there are now new OC as a single dose [33]. It has a wider ‘window of effect’ by formulations coming to the market, there have been few inhibition of the LH peak even if administered at the studies that have directly compared the different brands. advanced pre-ovulatory phase, a time when levonorgestrel is Evidence from some studies suggest that certain new no longer effective as an EC. It may, therefore, provide a formulations may offer advantages to patients in terms of new option for women who require EC for upto 5 days after efficacy, cycle control, treatment of heavy bleeding, and unprotected intercourse. Since ulipristal acetate appears to be other undesired menstrual symptoms. However, there is a better EC than LNG, it may therefore provide the impetus also evidence suggesting that certain formulations may be for further research into the use of new SPRMs as EC riskier in terms of side-effect profile than others. More candidates. Ulipristal acetate has recently been marketed in comprehensive studies are needed to compare the benefits several european countries, however, further studies are and disadvantages of the new formulations over the previous needed to explore the potential of other SPRMs to be cutting generation of OCs. edge emergency contraceptive drugs.

Emergency Contraception RECENT NON-ORAL HORMONAL CONTRACEPTIVES provides an alternative to Alternatives to oral formulations have been designed to traditional OC. Emergency contraception (EC) may be reduce daily compliance challenges and decrease side-effects defined as the treatment received by, or given to women while maintaining efficacy. Furthermore, in many cases for prevention of pregnancy within 72-120 hours after it has enabled compounds nearing patent expiry to be unprotected . Hormonal EC is covered by extended, through use via a different route of administration. two main methods: (1) A combined high-dose oestrogen/ Overall, the growing range of effective contraceptive options progesterone pill, taken twice at 12h intervals, generally have helped women in mid-high income countries a choice with a 72 hour time limit after unprotected intercourse (the of methods that suits them best [34-36]. A comparison of the ). In many countries this method has been effectiveness of key hormonal contraceptives is shown in replaced by a 1500µg dose of LNG (such as Levonelle) (2) Table 2. Mifepristone (or RU486), is a potent antiprogesterone used as an abortifacient [27, 28]; it is taken once at 10-600mg and Hormonal Injections and Implants has a 96h time limit. Mifepristone is used as for EC in many countries, including Europe, China, Thailand and Cuba, For over thiry years, slow release, low dose progestogen while it is generally available in more than 140 countries. formulations have been available [35-37]. The 3 month It is also available over-the-counter without a clinician’s intramuscular Depo-Provera, containing 150mg medro- prescription in about 50 countries. In a recent review, xyprogesterone acetate (DMPA) has been in use for the intermediate-dose mifepristone (25-50mg) was found to be last two dacades [38]. It has a far improved first year failure superior to LNG and Yuzpe regimens, while low dose rate (0.3%-3%) than OCs (8%) [39], but also has some (<25mg) may be more effective than LNG (0.75mg two disadvantages, such as amenorrhea and a delayed return to doses). In comparison, the non-hormonal copper IUD was fertility [40, 41]. The disadvantage of this method is that it the most effective EC method and has the advantage of relies on the user returning for a repeat injection [42]. One providing ongoing contraception if left in [29]. way round this could be to provide women with a self- administration subcutaneous method for emergency cover Moreover, progestogen-only EC products have been [43, 44], reducing the need for visits to hospitals or surgeries. available for a number of years in some countries which are more effective and associated with less nausea or vomiting Progestogen-only subdermal implants, such as Implanon than the Yuzpe regime [30]. The FDA has approved over the (now withdrawn from market due to administration issues), counter use of progestogen only EC for prevention of consisted of a single non-biodegradable rod, containing Female Hormonal Contraception Current Women’s Health Reviews, 2012, Vol. 8, No. 4 281

Table 2. Key Non-Oral Hormonal Contraceptives Currently in Use

Contraceptive Examples Dose Frequency (PI)* References

Perfect Use Typical Use

Hormonal Intra-Uterine Systems Levonorgestrel, LNG (Minerva, Mirena), Every 3-5 years 0.2 0.2 [106] Progesterone (Progestrasert)

Vaginal Rings Ethinyl estradiol/ Monthly 0.3 9 [43] (NuvaRing)

Intramuscular Injection Depot- acetate (DMPA) 3-monthly 0.2*** 8 [107, 108] or Depo-Provera

Subcutaneous Injection Depot-medroxyprogesterone acetate 3-monthly 0.2 6 [43] (DMPA-SC or Depo-Provera-SC)

Percutaneous Patches Ethinyl estradiol/ Weekly 0.3 9 [109] (EVRA)

Hormonal Implants LNG (Norplant), Etonogestrel (Nexplanon) Every 5 years 0.05 0.05 [43]

*PI = (number of pregnancies x 12)/(number of subjects x number of months in study) x 100, **includes use as emergency contraception ***according to National Institute for Health and Clinical Excellence

68mg etonogestrel in a synthetic membrane and was weeks, followed by a patch-free week. Another recent effective for contraception for 3 years. A number of similar development is a 17β estradiol/LNG combination, administered products exist that are marketed in different countries, once weekly [53]. including Nexplanon, which contains barium sulphate to facilitate the ability to localise the implant with imaging Hormone Releasing IUDs  technology and Jadelle which is approved for 5 years These have been under development for some years, continuous use [45]. The 5-year implants ensure increased including an annual progesterone-releasing Progestasert patient compliance, as the error in forgetting to use (Alza Corp, US) and a 5 year LNG system (Mirena, Berlex contraception is negated, and implants have the added Laboratories, US). This releases 20µg LNG per day and benefit of alleviating pain in users with endometriosis provides the same contraceptive efficacy and reduced risk of [46]. The procedure is seen as invasive and there are pelvic inflammatory disease as a conventional IUD. As with still side-effects associated with the implants, due to the NuvaRing, it also reduces menorrhagia and dysmenorrhea hormonal nature of the contraceptive, such as irregular [50] and is FDA approved to treat heavy menstrual bleeding bleeding [47]; however the reduced doses of LNG can limit as it significantly reduces this compared to COCs and the side-effects. NuvaRing. Care must be taken to ensure the user is not already pregnant on installation, due to the risk of issues Non-Oral Combined Contraceptives such as the introduction of infection and the possible risk of etopic pregnancies within pregnant users [54]. In Vaginal rings release a constant stream of hormones into comparison, the mode of action of the copper IUD, which is the , where they cross the epithelium into systemic a non-hormonal system is well documented [55] and so is circulation. Thus daily administration is not required, not discussed in this review. fluctuations of hormones are avoided and there is no first pass liver metabolism (enabling lower drug doses to be SIDE-EFFECTS AND HEALTH RISKS ASSOCIATED used). Development began in the 1960s, but products did not WITH OC appear on the market till much later [42, 48]. Combined hormonal vaginal rings, such as NuvaRing (Organon Inc, Problems with early OCs included headaches, gastric US), releases 15µg ethinyl estradiol/120µg etonogestrel per upsets, nausea, body weight, depression and effects on day from a 54mm diameter flexible ring, which is inserted . Other common effects included irregular cycles, into the vagina for three weeks, removed for one week, then water retention, breast tenderness and eye problems [56-59]. a new ring is inserted [49, 50]. The first year failure rate is In relation to the new generation of OC products approximately 0.5-2%. Newer products include combinations discussed in this article, there has been the following specific of ethinyl estradiol and nestorone [51]. safety investigations and advice: Transdermal patches effectively deliver hormones, Arterial Disease minimize fluctuations of hormones and avoid hepatic first- pass metabolism [52]. They deliver ethinyl estradiol (20µg) There is no strong evidence that specific progestogens and norelgestromin (150µg) through a 20cm2 patch. The in the newer OCs have differential effects on venous patch is applied after menses on a weekly basis for three thromboembolism (VTE) risk. Studies have shown that 282 Current Women’s Health Reviews, 2012, Vol. 8, No. 4 Garside et al. clotting factors may be differentially altered by certain factors, such as smoking, can help women minimise their progestogens. However, as there is not a proven surrogate arterial risks considerably. marker for VTE risk, it is difficult to estimate the clinically relevance of these findings [60, 61]. For example, pharmaco- Stroke and Myocardial Infarction epidemiological studies undertaken around 20 years ago, Several studies investigating the relationship between indicated that women taking OCs containing and COC use and CVD have been undertaken in younger women had a higher risk of VTE compared to those with low cardiovascular risk or have included changing COC taking OCs containing LNG and norethindrone [62, 63]. composition [74]. These differences in the prevalence of risk However, this was contradicted by later studies that factors (particularly smoking and hypertension), may account indicated a weak association between OCs and VTE. In for the inconsistent results found in studies of myocardial contrast, some studies interestingly indicated that higher infarction amongst COC users. The evidence, therefore, for doses of oestrogen were associated with a lower risk of VTE key differences in the risk of myocardial infarction between [64]. This later finding has questioned the hypothesis that OC formulations is contradictory. It is yet to be proven ‘new progestins’ increased the risk of deep venous whether current users of the recent generation of COCs have thrombosis (DVT). The majority of the risk in a COC is an increased risk of myocardial infarction, but further probably conferred by the oestrogen, but additional studies definitive studies need to be undertaken to confirm this. are required to establish the risk of VTE due to OCs and this remains a controversial issue. Additionally, current users of low oestrogen dose COCs would also appear to have a small increased risk of Recently however, a similar debate has been raised with ischaemic stroke, as it occurs mainly in women with other regard to drospirenone-containing OCs. There have been risk factors (notably smoking and hypertension). To date, several studies investigating the risk of VTE associated with there is insufficient information to confirm whether there are drospirone containing OCs in comparison to other significant differences in the risk of ischaemic stroke progestogens. A European study of women taking OCs, between new OCs. Most users appear to have a small found a comparable risk of DVT among all 3 categories of increase in the risk of haemorrhagic stroke, which is mainly progestogens [65]. This was a large prospective study where seen in women older than 35 years [75]. In summary, the the main objective was to assess safety across COC user information from studies examining the risk of haemorrhagic groups. These findings relating to drospirenone have been stroke in current COC users is not sufficient to form a confirmed in other studies that have shown an increased risk definite conclusion. This is particularly the case for those of VTE amongst women taking OCs [66]. However, these studies comparing other risk factors or the risk associated studies have flawed methodologies, such as the enrolled with particular COCs. women having different levels of risk when entering the study, and the consensus was that there is no additional risk Although the overall risk of thrombotic stroke and with drospirenone (DRSP) [67-69]. More recent meta- myocardial infarction associated with the use of OCs is low, analyses suggests that there is a greater risk compared with the risk was increased in those that included ethinyl other hormonal formulations [70]. oestradiol. However, this was only seen if the ethinyl oestradiol was increased by a factor of 0.9 to 1.7 with OCs Several studies have found increased risk of VTE among that included ethinyl oestradiol at a dose of 20µg. Also, the current users of low dose oestrogen COCs. This risk is risk increased by a factor of 1.3 to 2.3 with those that significantly raised among those women with inherited included ethinyl oestradiol at a dose of 30 to 40µg. There clotting factor defects [71]. In particular, some studies have were relatively small differences in risk in relation to shown relatively higher risks among women currently taking progestogen type. Again, it seems that ethinyl oestradiol may low oestrogen dose COCs that contain desogestrel or primarily be responsible for thrombotic side effects of the gestoden, compared to COCs containing LNG [72]. pill. However, these clinical differences are small and may be accounted for by differences in study bias. In the literature, Cancer COCs would appear to differ in relation to VTE risk, depending on the oestrogen concentration and progesterone In general it is believed that combining progestogens and type used. There is some evidence from research using oestrogens in OCs can increase the risk of [76, surrogate markers that the use of progesterone only and 77], although it is still a controversial subject since there combined pills which use drospirenone and ethinyl may be a promoter effect on women who already have oestradiol, rather than levenorgestrel, appear to have a higher cancer. To date, it has not been possible to discriminate risk of thrombosis [73]. Interestingly, the VTE risk for between the various progestogens used in the various clinical NuvaRing and the patch Evra, would appear to be as studies, mostly due to small patient numbers in the high as for the first generation COCs while the new subgroups [78, 79]. However, there is recent information that generation of COCs with estradiol valerate or estradiol have there may be differences regarding breast cancer risk, a lower degree of VTE incidence to date. Ethinyl oestradiol although there is no clinical data to confirm this. It may be has been stated to be primarily responsible for thrombotic that and the transdermal usage of synthetic side effects of the pill. progestogens may have fewer risks [79]. Effects on benign and malignant breast epithelial cells suggest that there may Generally, the consensus is that the risk of VTE is low in be differences in primary risk and risk in patients after breast COC users, although more studies are required to confirm cancer in these cases; however, this must be proven in this. However, the elimination of additional VTE risk additional clinical trials. It should also be noted that ovarian Female Hormonal Contraception Current Women’s Health Reviews, 2012, Vol. 8, No. 4 283 and uterine cancer risks are greatly diminished in users of including human immunodeficiency virus (HIV) are linked COCs [80]. to hormonal contraceptive use [88]. There is also continuing debate whether OC use, as opposed to other hormonal Bone Density contraceptives, are linked to increased chlamydial and gonococcal [89, 90]. There are some indications that other Most studies have shown a negative effect of COC on the bacterial and fungal infections maybe affected by the effect bone mineral density of adolescents [81]. Certainly, studies of hormonal contraceptives on the normal microbiota of the in adolescents taking OCs for 2 years indicate that this had vagina, but this is thought to be linked to age group [91]. no significant effect on bone density. However, there have been some studies for longer periods that have investigated Hyperkalemia whether long-term use has a significant on the There is little evidence that drosperinone and other attainment of peak bone mass [82-84]. Overall, various similar compounds with antimineralocorticoid effects have studies indicate different effects of COCs on pre, peri and the potential to induce hyperkalemia [92]. Interestingly, in post menopausal bone mineral density (BMD) and the spite of this, several manufacturers include this risk as a situation is not currently clear. For instance, Nomac, the contraindication on the OC safety labelling on packaging. synthetic progesterone derivative, nomegestral acetate, does not appear to have effects on BMD [85]. However, oestrogen NON-ORAL CONTRACEPTIVE SIDE-EFFECTS AND seems to mainly effect post menopausal women, with HEALTH RISKS indications of demineralisation even at low doses of oestrogen (20µg), though this may be reversible after In general, many of the hormone-caused risks of OCs are discontinuation [86]. There is limited information on the retained in non-oral hormonal contraceptive products. In effects of both the patch and ring applications, but these may addition, new risks and complications can be introduced. A also have an effect on BMD [87]. In conclusion, there is a summary of currently known side-effects and risks are need for more randomised controlled studies using shown in Table 3. alternative indicators of bone fracture to assess the effects of Contraceptive benefits, of hormonal OC supercede the COCs on fracture risk, as using BMD as the primary potential health risks. Therapeutic effects include endpoint may not be the most appropriate indicator. improvements to cycle regulation, bleeding anomalies, premenstrual syndrome, reduction in menstrual flow and Effects on Immunity to Infections frequency, severity of dysmenorrhoea and androgenisation. There is continuing controversy with respect to whether Protective effects include reduction in risk of pelvic increased acquisition of genital tract viral infections, inflammatory disease (PID), ovarian/endometrial/coleorectal

Table 3. Key Side-Effects and Health Risks of Non-Oral Hormonal Contraceptives

Type Active Commercial Established and Possible Bleeding Side-Effects References Component Example Health Risks Irregularities

Injections DMPA Depo-Provera Ovarian cysts, reduced bone Irregular spotting, Weight gain, delayed return [94] mineral density, risk of and with possible to fertility. stroke, myocardial amenorrhea infarction or venous thromboembolism.

Subcutaneous Etonorgestrel Implanon®, now Complications of insertion Infrequent, Weight change, mood [110, 111] implants replaced with and removal now eased by frequent or change, headaches, acne and Nexplanon® new product prolonged loss of libido. menstruation. Amenorrhea.

Transdermal Norelgestromin Ortho Evra Venous thromboembolism Breakthrough Breast tenderness, headache, [62, 112] patches Ethinyl estradiol bleeding/spotting nausea and vomiting, and dysmenorrhea dysmenorrhea, and abdominal pain

Vaginal Etonorgestrel NuvaRing Venous thromboembolism Frequent or Gallbladder disease, [62, 112] rings Ethinyl estradiol prolonged hypertension, spontaneous menstruation expulsion, and vaginal discharge.

Intrauterine LNG Mirena Pelvic infections, Menorrhagia and Headaches, acne, bloating [113] systems Ovarian cysts, uterine dysmenorrhoea and breast tenderness. Perforation, expulsion

284 Current Women’s Health Reviews, 2012, Vol. 8, No. 4 Garside et al. cancers and benign changes of the breast. Other benefits allocation of resources to maximise the impact of and include reduction in menstrual-related symptoms, anaemia, access to, safe and effective contraception. It has also been reduction in ectopic pregnancies and a possible increase in suggested that integration of contraceptive services with bone density [52]. The newer formulations also reduce the other services, such as immunisation, would increase access risk of cardiovascular events and can be used to treat and reduce overall healthcare costs [99]. endometriosis and leiomyoma [93]. However, difficulties in contraceptive access are not Specific non-contraceptive benefits of the mini-pill solely the reserve of developing countries. In the US for include brief or no menses, decreased menstrual cramps example, income inequality is associated with social and pain, reduction in PID and some cancers, and relief marginilisation and appreciably higher pregnancy rates in of endometriosis pain. These OCs are also considered teenagers on lower incomes [100]. Furthermore, medico- beneficial for women who are breastfeeding, those at greater legal and ethical provison of emergency hormonal contraception risk of thromboembolic events or who cannot take oestrogen. in the US creates additional barriers and restricts timely access to this resource by women who have had unprotected With respect to non-oral methods, first-pass metabolism intercourse. In contrast to other developed countries, some is avoided and so there is less toxicity to the liver. A states in the US make emergency hormonal contraception a summary and comparison of benefits of non-hormonal and hormonal contraceptives is shown in Table 4 [94]. prescription-only medicine as opposed to a pharmacy-only medicine, thereby limiting ease of access. In addition, many ACCESSIBILITY OF HORMONAL CONTRACEPTIVES pharmacies do not routinely stock emergency hormonal contraception (thereby introducing a delay in the provision Human population control initiatives implemented in the of the medicine) or are unwilling to supply on moral past 50 years have dramatically increased the access and use grounds, creating additional access issues [101]. This is of contraceptives and helped to reduce the mortality and particularly important given the 72 hour window for effective morbidity associated with unwanted pregnancy. However EC use. despite most governments having family planning policies, The predominance of private healthcare in the US and a the degree to which they are pursued varies considerably reliance on having appropriate insurance coverage, creates between countries and is exacerbated due to uncoordinated access issues to hormonal contraceptives for millions international support [95, 96]. As a consequence the use of contraception by those of lower economic status remains of American women. Only 28 US States have laws or regulations ensuring equity in private insurance coverage for below the norm, and this ‘contraceptive gap’ is wider in prescription contraceptives. This means that many American more affluent countries. This may be a consequence of a women are denied access to prescription contraception variety of socio-economic and cultural factors, as well as an through their health insurance plans. As such, contraceptives inability of governments and international aid to provide are often unaffordable, increasing the risk of unwanted contraceptive access in a way that is readily accesible to people on very low incomes [97]. In addition, a recent pregnancies. study by Elfstrom and Stephenson [98] has identified that In summary, although access to safe and effective within the African region community, level factors of contraception was deemed a fundamental human right in demographics, fertility and gender norms, inequalities and 1994 by the International Conference on Population and health knowledge, remain significantly associated with Development, there remains a considerable amount of work contraceptive use and impact on the empowerment of to be undertaken before realising the goal of universal access women to control their fertility. Therefore, a better to family planning services and effective contraceptives. The understanding of these local factors may allow better July 2012 family planning summit held in London by the UK

Table 4. Comparison of the Benefits of some Commonly Used Non-Hormonal* and Hormonal Contraceptives (Summarised from [94])

Type Examples Established and Possible Health Benefits

Barrier methods* and Reduced sexually transmitted infections (STIs); protection against transmission of HIV is 85%, femidoms chlamydia 40%, Trichomonas vaginalis 60% and gonorrhoea 49%.

Combined Contraceptive patches Established benefits: regulation of menstruation, and reduction in the following: iron-deficiency anaemia, hormonal (Evra), Contraceptive ovarian cysts, acne vulgaris, epithelial , and colorectal cancer. contraception rings (Nuvuring) Possible benefits: reduction in uterine fibroids, endometriosis, premenstrual syndrome and rheumatoid arthritis, and increase in bone mineral density.

Progesterone - only DMPA, Implanon, Established benefits: Amenorrhoea or hypomenorrhoea, endometrial protection. methods Mirena IUS, Possible benefits: reduction in dysmenorrhoea, in sickle cell crises, in epileptic seizures, and in Progesterone only pill endometriosis

Intrauterine Copper (Para-Gard) 5–10 years (depending on the type of device) of effective, reversible, non-hormonal, contraception, contraceptive device* unrelated to coitus.

Female Hormonal Contraception Current Women’s Health Reviews, 2012, Vol. 8, No. 4 285

Table 5. Action of Fourth Generation Progestogens (Summarised from [14])

Name Comments Key References

Drosperinone Anti-mineralocorticoid derived from spirolactone, which prevents water retention and can control blood [114-117] (DRSP) pressure. Rapidly absorbed orally, is 76% bioactive and found at peak levels in plasma with 1-2h. Can help in treatment of moderate acne.

Dienogest (DNG) 19-nortestosterone derivative. Highly potent anti-andogenic progestogen. Rapidly absorbed, with high oral [115, 118-120] bioavailability (90%), peak levels reached after 2h. Uses in hormone replacement treatment (HRT) and endometriosis.

Trimegestone 19-norprogesterone derivative. Strongly progestational, weak anti-androgenic and modest anti- [119] (TMG) mineralocorticoid activity. Does not produce low mood effects. Mainly used in hormone replacement therapy.

Nestorone 19-norprogesterone derivative. Non-androgenic, with potential use in male contraception. Inactive orally and [48, 121, 122] exhibits high contraceptive activity in non-oral products (rings, implants, transdermal patches).

Nomegestrol 19-norprogesterone derivative. Potent anti-gonadotrpic agen, with high progestational action, some anti- [123, 124] acetate (NOMAc) androgenic activity. Due to long elimination half-life, is useful when dosages are missed.

government, the Bill & Melinda Gates Foundation and the microbicides and or vaccination attractive future prospects. United Nations Population Fund addressed the current issue Several developments are reported to be due to enter clinical of global access to contraception. It agreed an initiative to trials and the main technology that is being used is the allow 120 million women in developing countries who vaginal ring that contains hormonal contraceptive and an currently have an unmet contraceptive need, access to anti-HIV drug [104]. suitable forms of contraception by 2020. If effective, this Finally, while this review has focussed on female may go a considerable way to addressing inequalities. hormonal contraceptive developments, in recent years, However, there is a recognition that for this initiative to be developments have begun to focus more on male successful, all key stakeholders must cooperate and act in contraceptives. Therefore, the next contraceptive innovations concert [102]. may not be female but male related: it will be interesting to see what impact such male contraceptive developments have FUTURE DEVELOPMENTS on female health. Despite the apparent success of controlling population AUTHOR CONTRIBUTIONS numbers in middle-high income countries, there is a still a need for further developments. In particular, providing All authors contributed to the writing of this paper and access to safe and highly effective contraceptives that offer state that there are no conflicts of interest. women ease of use and minimal side effects, especially in areas of low income and poor education. New hormones are CONFLICT OF INTEREST actively being researched and current OC developments The authors confirm that this article content has no include: (1) introduction of new progestogens, (2) replacement conflict of interest. of ethinyl estradiol (3) development of new delivery systems. Fourth generation progestogens continue to be ACKNOWLEDGEMENTS tested alone, in combination with other hormones or delivered by non-oral means (Table 5) [14]. While, natural None of the authors has any connections to pharma- oestrogen (estradiol) and its valerate ester is now being used ceutical companies developing female contraceptive products. in combination with acetate (Femilar®) and AG and MA are supported by the Libyan Government. NN dienogest (Qlaira®/Natazia®) [22]. is supported by an EPSRC Doctoral Training Centre studentship. The global contraceptive market, including OCs, continues to grow. In 2010, the contraceptives market was ABBREVIATIONS valued at $15.5 billion and has been predicted to grow to $19.2 billlion by 2017 [103]. It is most likely that devices OC = oral contraceptive (IUD, vaginal rings and transdermal products) will have a FDA = Food and Drug Administration more prominent role, as it is easier to carry out clinical trials with known drugs in a new delivery system, while the GR = development of generic off-patent hormonal drugs may CVD = cardiovascular disease encourage development of newer contraceptives. However, this is unlikely to be undertaken by the large pharmaceutical LH = luteinizing hormone companies, who are more likely to licence technologies FSH = follicle stimulating hormone once they are fully developed. The increase in sexually transmitted diseases also make dual purpose therapies with COC = combined oral contraceptive 286 Current Women’s Health Reviews, 2012, Vol. 8, No. 4 Garside et al.

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Received: September 18, 2012 Revised: November 27, 2012 Accepted: December 13, 2012