Hormonal contraceptive regimens in the perimenopause

Maturitas 63 (2009) 204–212

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Review

Hormonal contraceptive regimens in the perimenopause Sarah M.R. Hardman, Ailsa E. Gebbie ∗ NHS Lothian Family Planning and Well Woman Services, 18 Dean Terrace, Edinburgh, UK

a r t i c l e

i n f o

Article history: Received 1 May 2009 Accepted 1 May 2009 Keywords: Hormonal Contraceptive Regimens Perimenopause

a b s t r a c t Perimenopausal women have low fertility but still need contraception if they are sexually active. They often have co-existing menstrual problems and menopausal symptoms. No method of contraception is contraindicated by age alone. In addition to highly effective contraception, hormonal methods offer non-contraceptive benefits which can improve quality of life for perimenopausal women. Combined hormonal oral contraception has been available for many decades. The combined vaginal ring and transdermal patch are newer methods offering alternative delivery systems but similar risk profiles to oral preparations. New combinations containing naturally occurring estrogens in place of the synthetic hormone ethinylestradiol are now available and, in theory, could be safer. The progestogen-only methods have an excellent safety profile and have a range of delivery systems and dosages to suit all. Concerns regarding loss of bone mineral density with the injectable depot medroxyprogesterone acetate continue but to date there is no evidence that this translates into higher fracture risk. Effective use of any method of contraception is strongly dependent on good counselling and support from healthcare professionals. Risks should be explained in absolute terms for each individual woman, enabling her to make an informed choice on evidence-based medicine and not influenced by ill-informed media publicity. © 2009 Elsevier Ireland Ltd. All rights reserved.

Contents 1. 2.

3.

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Issues to consider in the perimenopause . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.1. Fertility . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.2. Menstrual dysfunction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.3. Vasomotor symptoms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.4. Age-related risks . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Combined hormonal contraceptive regimens . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1. Oral formulations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2. Non-oral combined hormonal contraception . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.3. Contraceptive use . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.4. Menstrual dysfunction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.5. Hormone replacement . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.6. Risks and benefits of COC . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.7. Risks . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.7.1. Venous thromboembolism (VTE) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.7.2. Myocardial infarction (MI) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.7.3. Stroke (CVA) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.7.4. Breast cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.7.5. Cervical cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.7.6. Risks with non-oral combined hormonal contraception . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.8. Benefits . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.8.1. Ovarian cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

∗ Corresponding author. Tel.: +44 1313430902. E-mail address: [email protected] (A.E. Gebbie). 0378-5122/$ – see front matter © 2009 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.maturitas.2009.05.001

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4.

5.

6.

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3.8.2. Endometrial cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.8.3. Bone mineral density (BMD) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.9. Combined preparations containing natural estrogens . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Progestogen-only methods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.1. Oral preparations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.2. Cyclical progestogens . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.3. Subdermal progestogens . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.4. Injectable progestogens . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.5. Intra-uterine system . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.6. Risks of progestogen only methods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.6.1. Cardiovascular disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.6.2. Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.6.3. Bone mineral density . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . HRT regimens . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.1. Sequential hormonal regimens . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.2. Continuous hormonal regimens . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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1. Introduction The years of fluctuating ovarian function leading up to the final cessation of menstruation are termed the perimenopause. This commonly lasts around 2–3 years, usually in a woman’s late forties or early fifties. During the perimenopause, menstrual bleeding typically becomes irregular, and menopausal symptoms may be experienced. Fertility is low but not zero. The confidence of women generally in using exogenous hormones has been greatly affected by media publicity surrounding studies suggesting risks associated with their use, dating back to the early 1980’s [1]. The ‘pill scare’ of 1995 lead to an instant change in contraceptive practice with significant discontinuations or switches to less effective methods resulting in a demonstrable increase in unintended pregnancies [2,3]. The findings of the Women’s Health Initiative (WHI) trial [4] and the Million Women Study (MWS) [5] on the risks of hormone replacement therapy (HRT) caused great controversy and confusion. Healthcare professionals are tasked with assessing a woman and advising how the benefits and risks of hormone preparations relate to each individual. This is often not an easy task and it is crucial to have unbiased, balanced information to hand. In the absence of any contraindicating medical factors, most perimenopausal women requesting contraception or with gynaecological or menopausal problems will benefit from use of hormonal regimens. This review article will look at the available options for this group of women and will reassess the evidence for the safety and efficacy of various contraceptive regimens. 2. Issues to consider in the perimenopause 2.1. Fertility Women do remain potentially fertile until the menopause although their fertility has gradually begun to decline by the time they reach their late thirties [6]. In the UK, the annual conception rate for women over 40 is about 12:1000 which compares with 110:1000 in women aged 20–25 years [7]. A recent Australian study reported that amongst middle aged women one third of pregnancies were unplanned [8]. The risk of fetal abnormality, miscarriage and other pregnancy complications rises significantly with increasing maternal age. Effective contraception, therefore, remains an important issue for women in the perimenopause. Usage of contraception in most countries varies strikingly according to age and hormonal regimens become much less popular with increasing years (Fig. 1). However, guidance from the World

Health Organisation Medical Eligibility Criteria (WHOMEC) advises that “No contraceptive method is contraindicated by age alone” [9]. Despite this, hormonal contraception is almost universally perceived mainly as a method for young women. 2.2. Menstrual dysfunction The perimenopause is a time when many women experience a change in menstrual bleeding pattern, which often involves unpredictable and heavier bleeding. Historically, many women in consequence had gynaecological surgery at this stage. It is estimated that around 60% of UK women with HMB underwent hysterectomy in the 1990s [10]. Hormones, particularly contraceptive regimens, can considerably improve heavy and irregular menstrual bleeding in women at this stage of their lives and provide effective alternative strategies to hysterectomy for heavy menstrual bleeding [11]. 2.3. Vasomotor symptoms Vasomotor symptoms (VMS) are experienced by up to 80% of women during the menopausal transition. Hot flushes, night sweats and palpitations may significantly affect daily life and interfere with sleep: quality of life for perimenopausal women may be poor as a result. Estrogen-containing hormonal regimens offer effective treatment for vasomotor symptoms and remain the treatment of choice if symptoms are severe [12]. No other therapeutic options for VMS have been shown to be as effective. Short randomised trials show that agents such as anti-depressants and gabapentin will improve VMS in some women [13,14] but they have their own risks and side effects and are often unacceptable to women. There is no convincing evidence of benefit with herbal and complementary treatments [15]. 2.4. Age-related risks Whilst recent randomised trials and large observational studies on hormone replacement preparations showed small increases in risk, it is crucial that any risks are put in perspective in absolute terms. Perimenopausal woman are generally at low risk of chronic disease, particularly arterial disease, although breast cancer rates do begin to rise significantly at this age (Table 1). The WHI findings are difficult to extrapolate to perimenopausal women as the study looked at mainly older, postmenopausal women. Subgroup analysis for younger age groups (aged 50–60 years) is limited although generally reassuring [16].

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Fig. 1. Current use of contraception by women using at least one method: by age, 2007–2008 (hormonal methods are highlighted). (See Ref. [104]).

3. Combined hormonal contraceptive regimens The combined oral contraceptive pill (COC) has been licensed in North America and Europe for around 50 years. Over the years, the dosages and formulations of both estrogen and progestogen in COC have changed, and equally effective, newer preparations contain much lower dosages and are safer as a result. COC has been extensively researched and the data on long-term use (largely based on higher dose pills) are very reassuring and suggest that use of COC may even produce a net public health gain [17,18]. 3.1. Oral formulations For most perimenopausal women, a monophasic pill containing 30 mcg or less of ethinylestradiol will be appropriate as first line choice. It is generally advised that the lowest dose of estrogen that gives adequate cycle control for each individual woman should be used, although there is no evidence of any greater safety of lower dose 20 mcg estrogen formulations over those containing 30 mcg [19]. For many women, 20 mcg pills have poorer cycle control resulting in higher rates of breakthrough bleeding (BTB) which can be an important issue for older women [20]. Even lower dose pills have been studied (15 mcg) but to obtain good efficacy it is necessary to shorten or abolish the pill free interval and the risk of breakthrough ovulation if pills are missed is high. Bi- and tri-phasic combined pills, which have two or three different dosages of hormone over the 21 days of pill-

taking were developed in the 1980s in an attempt to mimic more closely the natural menstrual cycle. There is insufficient evidence to demonstrate whether they reduce BTB and in practice they have no real advantage for a woman of any age [21]. A greater variety of pill regimens are now available (but not universally available in all countries) which move away from the traditional 21/7 pattern of pill-taking (Fig. 2). Two formulations have a 24/4 regimen; the shortened pill-free interval is in theory designed to improve efficacy and minimise bleed related problems. In addition, two 84/7 formulations are licensed in the USA and may suit individual women. Some preparations have very low dose estrogen instead of the pill free week in order to improve efficacy by maintaining suppression of the pituitary hormone, follicle stimulating hormone (FSH). Continuous use COC regimes are not currently licensed in Europe although one preparation is available in the USA. Evidence indicates that contraceptive efficacy is equivalent to that of a traditional 21/7 regimen, and that the incidence of menstrual-related symptoms such as pain or headache which may particularly trouble older women is reduced with continuous regimens. BTB does not appear to worsen significantly with extended regimes, and often settles with increased duration of use [22]. A more novel idea is to tailor the length of pill use to the individual woman by extended use of COC until BTB develops. She then stops the pill at that stage for 4 days. Once she has established how long she can take the pill without bleeding, the bleed-free duration for her should always be the

Table 1 Age-related disease incidences. Condition

Age range

Incidence

Reference group

Myocardial infarction Stroke Venous thromboembolism Breast cancer

35–49 years 45–55 years 40–44 years 45–49 years

13 per 100,000 24 per 100,000 5–17 per 100,000 90.7 per 100,000

UK women 1998 [105] UK women 2005 [106] World Health Organisation 1998 [32] Scottish women 2001–2005 [107]

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use of COC for menstrual control [28], perhaps because the method has been used to good effect for so many years. There has been little financial incentive for any pharmaceutical company to actually demonstrate its effectiveness in this respect. In healthy older women, these very significant menstrual benefits may well outweigh any small risks associated with COC use [29]. The combined vaginal ring appears to have a more favourable bleeding profile than COC when used either in a 21/7 pattern or continuously [30,31]. It has not been studied specifically in women with pre-existing menstrual dysfunction. 3.5. Hormone replacement

Fig. 2. Combined hormonal regimens.

same and she can control her individual situation with a tailored extended COC use [23]. A wider range of progestogens are now available in COC preparations although, again, this varies from country to country. Progestogens differ in their hormonal pattern and, in addition to their progestogenic and antiestrogenic action on the endometrium, can exert androgenic, antiandrogenic, glucocorticoid and/or antimineralocorticoid effects. There are no comprehensive trials directly comparing the modulating effects of the various progestogens, and clinical and epidemiological data do not allow a definite conclusion on the clinical relevance of differences between progestogens and how this might relate to use in the perimenopausal woman. 3.2. Non-oral combined hormonal contraception Non-oral routes of administration of combined hormonal contraception have become available relatively recently in the form of transdermal patches and the vaginal ring. The transdermal preparation comprises a 20 cm2 matrix patch, each applied weekly for 3 weeks followed by a 1 week break [24]. The flexible, silastic vaginal ring is inserted for 3 weeks with a subsequent 1 week break [25]. Although these methods have been much less extensively studied that COC, it is highly likely that they share most of the same benefits and risks. They have similar efficacy and non-oral routes may actually improve compliance [26]. They are acceptable choices for older women who have no contraindications to COC and prefer to avoid daily pill-taking. Perimenopausal women with particular medical disorders such as lactose intolerance, inflammatory bowel disease or liver disease may be specifically advised to choose a non-oral route. 3.3. Contraceptive use Combined oral contraception (COC) offers effective contraception (0.3% failure rate with perfect use) together with excellent cycle control for women of all ages. Evidence-based guidance in the UK from the Faculty of Sexual and Reproductive Healthcare (FSRH) recommends that for non-smoking women with no contraindicating medical health issues or family history, COC can be continued until age 50 [27]. 3.4. Menstrual dysfunction For perimenopausal women with typically irregular, anovulatory cycles, COC regulates the menstrual bleeding pattern, reducing both bleeding and pain. There is surprisingly little published data on

COC treats menopausal symptoms effectively in perimenopausal women, although some women experience some VMS in the pillfree week. If used up to the age of 50 years, COC may be a more acceptable treatment to women than HRT: women with premature menopause may perceive COC to be a treatment that other “normal” women use at their age. COC is also reliably contraceptive, whilst sequential HRT is not. The added benefit of prescribing COC to women in the UK instead of HRT is that it is free on prescription whereas women pay a charge for HRT. It must be remembered, and explained carefully to each woman, that COC contains a relatively higher dose of more potent synthetic hormones than HRT, which ‘theoretically’ could have more impact on cardiovascular risk. 3.6. Risks and benefits of COC The specific risks to be considered in the perimenopause are venous thromboembolism, myocardial infarction, stroke, cervical cancer and breast cancer. These need to be evaluated in the context of each woman’s individual risk profile and weighed against the potential benefits: effective contraception, predictable bleeding patterns with less heavy and less painful menstrual loss, reduction in vasomotor symptoms, maintenance of bone mineral density and protection against ovarian and endometrial cancer. 3.7. Risks 3.7.1. Venous thromboembolism (VTE) It is well established that the risk of VTE is increased by a factor of 3 to 6 fold in COC users. The absolute risk of VTE with COC use is small (15–30 per 100,000 woman years), but there is a modest age-related rise in risk of VTE amongst COC users. In women between the ages of 40–44 years, the risk of VTE is about 18 events per 100,000 (double that of women aged between 20 and 24 years) [32]. Additional risk factors for VTE include presence of an inherited thrombophilia (which contraindicates COC in all users), obesity and possibly smoking [33,34]. A meta-analysis in 2008 identified hypertension and diabetes as additional significant risk factors for VTE [35], whilst a recent study indicated reduced incidence of VTE in physically active women and those that drink moderate alcohol [34]. VTE risk is greatest in the first year of COC use, perhaps because of the early unmasking of thrombophilias [36]. If a perimenopausal woman wishes to continue COC until the age of 50 years, she should ideally be fit and slim, a non-smoker with normal blood pressure and have no significant medical history of note. The “pill scare” in 1995 arose from data suggesting that the risk of VTE was higher with 3rd generation than with 2nd generation progestogens [37]. Following intense debate and scrutiny of the scientific evidence, it is now agreed that all COC are prescribable in the first line and choice of pill is generally based on what suits each individual woman, particularly if she is a long term user or is taking COC for menstrual dysfunction. This principle applies to perimenopausal women and there is no perfect formulation of COC

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that will suit all. There is no evidence to support routine screening for inherited thrombophilias in women at any age prior to use of COC [38]. 3.7.2. Myocardial infarction (MI) In women of reproductive age, the incidence of MI is extremely low although increases exponentially from the age of 35 years. A meta-analysis of 23 studies estimated an odds ratio for MI in all current users of COC of 2.5 (95% confidence intervals 1.9–3.2) regardless of age [39]. To put this into perspective, because the background rate of MI is greater in older women, the annual risk of death from MI attributable to the COC is 22 per million users in the 40 to 44 year age group compared to 2 per million users aged 20 to 24 years [40]. The relative risk of MI is increased by smoking, hypertension, diabetes and hypercholesterolaemia. Therefore older women with any of these risk factors must consider alternative contraceptive methods. However, non-smoking COC users without specific risk factors in many studies do not appear to be at increased risk of MI [41]. Recent studies show no clinically significant metabolic changes with low-dose COC use in older women compared to users of non-hormonal contraceptive methods [42]. It seems unlikely that MI risk is reduced with pills containing 20 mcg rather than 30 mcg of oestrogen, but some studies suggest that 3rd generation progestogens may be associated with a slightly lower incidence of MI than 2nd generation progestogens [43]. There is not enough evidence to recommend selective prescribing of 3rd generation pills to older women [44]. 3.7.3. Stroke (CVA) As with MI, the incidence of CVA is very low amongst women of reproductive age, but increases with age. There is a small increased risk of ischaemic stroke in ever users of COC, both smokers and nonsmokers [45,46]. The increase may be twofold amongst current COC users, and is greater when women smoke, are hypertensive or suffer from migraine [47]. COC users over 35 are twice as likely to suffer a haemorrhagic stroke as non-users; the risk is further increased by smoking and hypertension [45]. 3.7.4. Breast cancer The incidence of breast cancer is low in young women but rises dramatically with age in the western world. Between the ages of 40 and 50, women in the USA have a 1:63 risk of developing breast cancer [48]. Fear of developing breast cancer and the extensive media publicity surrounding its possible association with hormone therapy has been a powerful motive for women to avoid taking COC in the later reproductive years. Women over 40 should be advised that any effect of COC on the risk of breast cancer is very small, but is in addition to the rapidly rising background risk. The most comprehensive evidence suggests that the relative risk of breast cancer in current and recent COC users is around 1.24 and reduces to normal 10 years after stopping COC [49]. Other studies have failed to show any increased risk [50]. From the available data, there is no evidence that duration of use, family history, age at first use or type of hormones impact the effect of COC on breast cancer. 3.7.5. Cervical cancer The risk of cervical cancer increases with duration of use of COC beyond 5 years [51]. The biological mechanism for this effect of COC on cervical cancer is not understood although it is assumed to be acting as a co-factor with human papilloma virus (HPV) infection in some way. Pooled data from eight case controlled studies, found the relative risk for 5–9 years of COC use was 2.82 (95% CI 1.46–5.42) compared with never-use, and this rose to 4.03 (2.09–8.02) for 10 years use or longer [52]. The risk reduces over 10 years after discontinuation of COC. The peak age for developing cervical cancer

is 30–35 years in western countries and declines steadily after this until a second peak in incidence in very old age. National screening programmes in many developed countries have lead to a significant decrease in cervical cancer incidence rates and, in particular, the incidence in women aged over 45 years has declined significantly since the mid 1970’s [53]. 3.7.6. Risks with non-oral combined hormonal contraception - Combined hormonal transdermal patches appear to have similar effects on vascular risk markers to oral preparations [54]. The evidence for VTE risk with the combined patch is conflicting: some studies show a similar profile to COC [36,55], but others suggest that the VTE risk may be greater with the transdermal route [56]. Women of all ages can be reassured that the absolute risk of a VTE with combined patches is still extremely small (and less than in pregnancy). - Combined hormonal vaginal rings (CVR). As the systemic ethinylestradiol exposure is about 50% of that of a 30 mcg combined pill, there may be fewer metabolic effects than with COC [57,58] In some respects therefore, the CVR would appear to offer the woman in her older reproductive years some favourable advantages. 3.8. Benefits 3.8.1. Ovarian cancer The risk of ovarian cancer is significantly reduced with COC use and the longer it is used, the lower the risk. The Collaborative Reanalysis of data from 45 epidemiology studies found that 5–9 years of use gave a relative risk of 0.64 (CI 0.59–0.69) which fell to 0.42 (CI 0.36–0.49) after 15 years or more of use [59]. The protective effect persisted for more than 30 years after COC use had ceased and the authors estimate that COC could potentially prevent 30,000 ovarian cancers per year worldwide in the next few decades. 3.8.2. Endometrial cancer A reduction in risk of endometrial cancer of around 40% is seen in ever users of COC. This marked effect persists for over 15 years after discontinuation [60]. 3.8.3. Bone mineral density (BMD) In women over 40, use of COC reduces bone demineralisation, and may in fact significantly increase BMD even at a 20 mcg dose [61,62] However, there is no evidence that COC reduces the risk of fracture prior to the menopause [63,64]. Post menopause, COC used after the age of 40 may reduce the incidence of hip fracture, although this has not been confirmed for low dose pills [65]. 3.9. Combined preparations containing natural estrogens It is thought that some of the adverse cardiovascular effects associated with COC are attributable to the potent effects on the liver of the synthetic hormone ethinylestradiol. Recent studies have looked at the possibility of using naturally occurring estrogens in contraceptive preparations as a safer substitute. Until recently most contraceptive combinations containing natural estrogens were limited in their use by very poor cycle control and lack of efficacy at standard dosages. 17␤-Estradiol was found to be associated with persistent BTB [66] but more favourable results have been obtained for both contraceptive efficacy and cycle control using the pro-drug of natural estradiol, estradiol valerate (EV) [67]. There is some evidence that the impact of 2 mg estradiol valerate has less effect on several haemostatic variables than that of 10 mcg ethinylestradiol [68]. A monophasic combination of EV in combination with the progestogen dienogest resulted in a poor bleeding pattern. Devel-

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opment of a four-phasic regimen of this combination with a 2 day placebo phase had reasonable cycle control and appeared to abolish ovulation, thus having contraceptive efficacy [67]. Active pills contain 1, 2 or 3 mg of EV. There were no VTE events in the clinical trials and the adverse event reporting was similar to those associated with COC preparations generally. The four-phasic regimen has recently been approved for use in Europe. Other progestogens are also being combined with natural estrogens in clinical trials. Animal studies are looking at use of estetrol, a human fetal estrogen steroid, which inhibits ovulation in rat models and might potentially have fewer adverse effects than conventional COC [69]. Further evaluation and follow-up data on all these preparations is required but for older women, this approach could potentially represent a safer contraceptive option for the future, bridging the gap between existing combined hormonal preparations and HRT. 4. Progestogen-only methods Progestogens have been widely used in clinical practice for decades for both gynaecological and contraceptive purposes. Although less well studied than combined oral contraception, progestogen-only methods of contraception can be ideal choices for perimenopausal women offering a wide choice of delivery regimens, dosages and potential non-contraceptive benefits. 4.1. Oral preparations Most traditional progestogen-only pills (POP) contain second generation progestogens (e.g. levonorgestrel or norethisterone and their derivatives). The contraceptive efficacy of the traditional POP in older women is excellent, although pills must still be taken within 3 h of the same time every day. Compliance may be easier with the newer desogestrel-containing pill (Cerazette® ), which reliably inhibits ovulation with a 12-h window of use, although it has no real advantages in terms of efficacy over older POP in older women [70,71]. Current breast cancer is the only absolute contraindication to use of POP in the UK [72]. With all POP, bleeding is often irregular and unpredictable (although not usually heavy or painful [73]. Irregular bleeding may require investigation in older women to exclude underlying pathology, and often leads to discontinuation if it is frequent or persistent. POP have no real role in the management of older women with menstrual dysfunction although occasionally Cerazette® can be helpful in dealing with cyclical menstrual symptoms such as pre-menstrual syndrome and menstrual migraine. 4.2. Cyclical progestogens Cyclical oral progestogens are not reliably contraceptive because of the lack of continuous progestogen administration. They have always been a popular choice (particularly by family physicians) for the management of heavy, irregular menstrual bleeding which is particularly common in the perimenopause. Varying regimens of norethisterone (e.g. 5 mg tds from days 5 to 25 of the menstrual cycle) are widely prescribed in many countries for this indication. A recent Cochrane systematic review concluded that cyclical progestogen significantly reduces bleeding in women with heavy menstrual bleeding, but is less effective than the intra-uterine system and is less acceptable to women [74]. 4.3. Subdermal progestogens The single rod subdermal etonogestrel implant, Implanon® offers women of all ages highly reliable (>99% effective) lasting contraception for 3 years [75]. As with POP, current breast cancer is the only absolute contraindication to its use.

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Although Implanon® renders 2 out of 10 women amenorrhoeic and reduces the overall monthly blood loss in almost all women, the irregular and unpredictable nature of the bleeding may make it a less acceptable option [76]. As with POP, menstrual irregularity in older women using Implanon® raises concerns regarding the possibility of underlying pathology. 4.4. Injectable progestogens Depot medroxyprogesterone acetate (DMPA) is a high dose progestogen method which has a potent suppressive effect on ovarian activity. It is administered by intra-muscular injection every 12 weeks and is highly effective. DMPA results in amenorrhoea in almost half of users at 3 months, 60% at 1 year and about 70% at 2 years [77]. Bleeding is generally lighter and less frequent amongst DMPA users than non-users but is usually irregular and does not particularly vary according to the age of the user. Many older women like the hormonal equilibrium and oligo-amenorrhoea offered by long-term DMPA and find it helpful in the management of pre-menstrual tension, menstrual migraine and menstrual dysfunction. 4.5. Intra-uterine system The intra-uterine system (IUS) is a recommendable choice for older women as it provides highly effective, long lasting contraception with control of heavy menstrual bleeding. It is steadily increasing in popularity in most Western European countries and North America. An IUS gives 5 years’ contraception, but if inserted over age 45 years, it may remain in situ and be used for contraception for 7 years. The IUS acts locally on the endometrium with a reduction in menstrual blood loss of up to 97% [78]. For the first 6–12 months after insertion, bleeding is irregular, although usually much lighter than previously. By 12 months, around 50% of women are amenorrhoeic [79], and the rate of amenorrhoea continues to increase with increasing duration of use [80]. Careful counselling is required to forewarn women of the likely initial bleeding disturbances. Both bleeding and quality of life in women with idiopathic menorrhagia have been shown to improve markedly with the IUS [81] satisfaction rates are high, and the rate of continuation at 12 months is up to 79% [82]. Studies have suggested that in management of perimenopausal heavy menstrual bleeding, the IUS is superior to DMPA and oral progestogens [83] although the bleeding pattern may be less regular with the IUS. Unfortunately it is not possible to predict bleeding outcomes by patient profiling [84]. When compared with endometrial ablation, it is uncertain whether the IUS is as effective at controlling blood loss, although patient satisfaction with outcomes is equally favourable [70]. IUS is cheaper than hysterectomy, but there is no difference in quality of life outcomes [85]. 4.6. Risks of progestogen only methods 4.6.1. Cardiovascular disease There is no known increase in the incidence of VTE, MI or stroke with the progestogen-only pill (POP) or the etonogestrel-containing subdermal implant, Implanon® [86,87]. These methods can therefore be used in women with a past history of cardiovascular disease or with risk factors. Similarly, DMPA has not been found to increase the risk of VTE, MI or CVA in normotensive women [88] although women with multiple cardiovascular risk factors may be better to consider lower dose progestogen-only methods as there is some evidence that some high dose progestogen can increase VTE risk [89].

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There are no known adverse metabolic effects with the IUS [90] which would impact of usage in any older woman, with or without cardiovascular risk factors. 4.6.2. Cancer There are very little data on breast cancer risk with POP but what exists suggests that it may be similar to that with COC [91,92]. Similarly, there are very few data on use of DMPA and breast cancer risk but the large collaborative re-analysis of the breast cancer data suggested a small increased risk in current and recent users, which is not related to duration of use and disappears within 10 years of discontinuing [49]. There is no evidence for any increase in the risk of breast cancer with IUS use [93]. Theoretically, any progestogen-only method which suppresses ovulation could reduce risk of ovarian and endometrial cancer although there is an absence of scientific evidence to support this hypothesis. 4.6.3. Bone mineral density Low dose progestogen-only methods do not adversely affect bone mineral density [94,95]. A major concern with regard to use of DMPA in older women is potential reduction in bone mineral density (BMD), increasing the risk of osteoporosis in later life. Across the age ranges of using DMPA, studies do appear to suggest a reduction in BMD, but whether this results in an increased fracture rate has not been demonstrated and the clinical significance is therefore uncertain [96,97]. Again, it is uncertain how rapidly BMD recovers after stopping DMPA [98,99] particularly in the later reproductive years. In one study, no correlation with fracture risk was found with duration of DMPA use, age at discontinuation or time between DMPA use and menopause [100]. Any residual effect of previous DMPA use on BMD post-menopause is likely to be small. Current guidance from most countries states that women should be advised that there is a small, probably reversible, reduction in BMD with DMPA, but that this should not contraindicate DMPA use of any duration, regardless of age [101]. DMPA should probably be avoided in older women with additional risk factors, e.g. smoking, low BMI, steroids, thyroid disease or family history of osteoporosis. 5. HRT regimens In the absence of acceptable, effective non-hormonal treatments, the benefits of HRT in terms of vasomotor symptom control will outweigh any risks for most perimenopausal women. The lowest dose that gives relief of symptoms should be used for the necessary duration of time for each individual perimenopausal woman. 5.1. Sequential hormonal regimens Perimenopausal women, who have residual ovarian function, should receive sequential combined HRT to avoid the erratic bleeding patterns associated with continuous regimens used close to menopause. Sequential HRT is not reliably contraceptive [102] and it is therefore important that an additional contraceptive method is used in the perimenopause if contraception is required. This can be achieved by adding continuous POP, or by use of an IUD or barrier method. 5.2. Continuous hormonal regimens The combination of an IUS with an estrogen of choice will provide a continuous combined regimen suitable for perimenopausal women who still require contraception. This offers a relatively low

progestogen dose which minimises side effects and has a potent local endometrial effect associated with oligo-amenorrhoea [103]. 6. Conclusion Hormonal contraceptive regimens are an important part of life for many perimenopausal women. In addition to highly effective contraception, they can be tailored and adapted to offer significant non-contraceptive benefits to help menstrual and menopausal problems. Every woman is an individual and will have her own risk profile as well as fears and concerns about use of hormones. A wellinformed healthcare professional can assist women to make safe and informed choices regarding the most appropriate hormonal therapy in the later reproductive years. References [1] Edouard L. Pill scare: communication conundrum. J Fam Plann Reprod Health Care 2009;35(2):121–2. [2] Committee on the Safety of Medicines. Combined oral contraception and venous thromboembolism. London: CSM; 1995. [3] Guillebaud J. Advising women on which pill to take. BMJ 1995;311:1111–2. [4] Rossouw JE, Anderson GL, Prentice RL, et al. Risks and benefits of estrogen plus progestin in healthy postmenopausal women; principal results from the WHI RCT. JAMA 2002;288(3):321–33. [5] Beral V, et al. Breast cancer and HRT in the Million Women Study. Lancet 2003;362(9382):419–27. [6] Dunson DB, Columbo B, Baird DD. Changes with age in the level and duration of fertility in the menstrual cycle. Hum Reprod 2002;17(5):1399–403. [7] UK Office for National Statistics. Conceptions: age of woman at conception; 1991 Onwards (England and Wales residents): Population Trends 134 http://www.statistics.gov.uk/STATBASE/ssdataset.asp?vlnk=9558&More=Y. [8] Weisberg E, Bateson D, Read C, Estoesta J, Lee C. Fertility control? Middle aged Australian women’s retrospective reports of their pregnancies. Aust N Z J Public Health 2008;32(4):390–2. [9] WHO e-reference http://www.who.int/reproductive-health/publications/ mec/mec.pdf. [10] NICE guideline; Heavy Menstrual Bleeding: cg44 www.nice.org.uk/ CG44niceguideline. [11] Lahteenmaki P, et al. Open randomised study of use of LNG-IUS as an alternative to hysterectomy. BMJ 1998;316(7138):1122–6. [12] MacLennan A, Lester S, Moore V. Oral estrogen replacement therapy versus placebo for hot flushes: a systematic review. Climacteric 2001;4(1):58– 74. [13] Archer DF, Seidman L, Constantine GD, Pickar JH, Olivier S. A double-blind, randomly assigned, placebo-controlled study of desvenlafaxine efficacy and safety for the treatment of vasomotor symptoms associated with menopause. Am J Obstet Gynecol 2008 [Epub ahead of print]. [14] Brown JN, Wright BR. Use of gabapentin in patients experiencing hot flashes. Pharmacotherapy 2009;29(1):74–81. [15] Low Doq T. Menopause: a review of botanical dietary supplements. Am J Med 2005;118(Suppl. 12B):98–108. [16] Grodstein F, Manson JE, Stampfer MJ. Hormone therapy and coronary heart disease: the role of time since menopause and age at hormone initiation. J Women Health 2006;15(1):35–44. [17] Beral V, Hermon C, Kay C, Hannaford P, Darby S, Reeves G. Mortality associated with OC use: 25 year follow up of 46000 women from RCGP oral contraception study. BMJ 1999;318(7176):96–100. [18] Hannaford PC, Selvaraj S, Elliiott AM, Angus A, Iversen L, Lee AJ. Cancer risk among users of oral contraceptives: cohort data from the Royal College of General Practitioners’ oral contracpetion study. BMJ 2007;335:651–4. [19] Gallo MF, et al. 20 mcg vs >20 mcg estrogen COC for contraception. Cochrane Database Syst Rev 2008;8(4):CD003989. [20] Akerlund M. Clinical experience of a COC with very low dose ethinyl estradiol. Acta Obstet Gynecol Scand Suppl 1997;164:63–5. [21] van Vliet HA. Triphasic vs monophasic oral contraceptives for contraception. Cochrane Database Syst Rev 2006;19(3):CD003553. [22] Edelman A, et al. Continuous vs cyclic use of COC: a systematic cochrane review of randomised controlled trials. Hum Reprod 2006;21(3):573–8. [23] Coffee AL, et al. Long-term assessment of symptomatology and satisfaction of an extended oral contraceptive regimen. Contraception 2007;75(6):444–9. [24] O’Connell K, Burkman RT. The transdermal contraceptive patch—an updated review of the literature. Clin Obstet Gynecol 2007;50:918–26. [25] Shimoni N, Westhoff C. review of the vaginal contraceptive ring. J Fam Plann Reprod Health Care 2008;34:247–50. [26] Lopez LM, et al. Skin patch and ring versus COC for contraception. Cochrane Database Syst Rev 2008;23(1):CD003552. [27] Faculty of Sexual and Reproductive Healthcare. Evidence based guidelines on contraception for women aged over 40; 2005. www.ffprhc.org.uk/ admin/uploads/contraceptionover40.pdf.

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