Background

Combined hormone contraception

With the combined oral contraceptive pill (COCP), the oestrogen component is combined with a progestogen (a synthetic progesterone) - these are designated by their generation of development:

• 2nd generation - containing norethisterone or levonorgestrel
• 3rd generation - containing desogestrel and gestodene

Oestrogens provide effective contraception primarily by inhibiting follicle-stimulating hormone and luteinising hormone production and preventing ovulation. The COCP has a Pearl Index of 0.3 (ie 3 pregnancies per 1,000 women-years of 'perfect' use).

An estimated 300 million women worldwide have used 'the Pill'. Its availability, particularly in the developed world, has made a significant and dramatic effect on women's lives: preventing pregnancy, and so avoiding the mortality and morbidity associated with pregnancy, childbirth and termination. Worldwide, 1,500 women die every day from pregnancy- or childbirth-related complications.^[1] Even in the UK, the 2003-2005 Confidential Enquiry into Maternal and Child Health found a total of 295 pregnancy-related deaths.^[2] Its beneficial effects on cycle control and menorrhagia improve quality of life for countless women. The social and economic consequences of the COCP have reverberated far beyond the directly pharmacological.

HRT

Hormone replacement therapy (HRT) is the replacement of physiological doses of oestrogen (plus progestogens for endometrial protection in those with a uterus) to treat ovarian insufficiency and failure during the climacteric and following the menopause. HRT is undoubtedly an effective treatment of menopausal symptoms (in particular, vasomotor^[3] but also urogenital symptoms^[4]) and improves quality of life and sexual function in symptomatic, postmenopausal women. It also helps to prevent osteoporosis, although this beneficial effect is lost soon after stopping treatment.^[5] HRT also reduces the risk of colorectal cancer (but its use is not currently recommended just for this purpose).^[4]

Some question the creeping medicalisation which advocates treatment (with attendant risks) for a normal physiological stage of life; others the politics of denying women effective treatment for a hormone deficiency state.

COCP and HRT in the news

The relatively short history of hormonal contraception and HRT has regularly been punctuated by 'scares' and controversies, often initiated by epidemiological studies suggesting increased risk of harm, inducing near panic in the media and patients, as well as in prescribers and the regulatory authorities.

Think back to the most recent 'Pill scare' of 1995, triggered by findings suggesting a doubling of risk of venous thromboembolism (VTE) with 3rd generation pills. Debate raged as to the scientific truth of the observation, prescribing practice altered, many women became pregnant through stopping their pills but the overall public health significance of the effect was probably minimal.^[7]

Similarly, the pendulum is beginning to swing back towards recognition of the valid therapeutic uses of HRT, following the scare post the Women's Health Initiative (WHI) study and Million Women Study (MWS). These were both large-scale studies indicating increased risks associated with HRT compared with those previously anticipated (see below). Large numbers of women are thought to have stopped HRT as a consequence and GPs appear much more cautious in their prescribing of HRT.

The British Menopause Society (BMS) consensus statement (2006) stressed that potential benefits could outweigh harms, given appropriate dose, route and combination.^[8] WHI, on which many of our prescribing decisions are based, recruited postmenopausal women who were an average 63 years old (ie older than average UK HRT users) and who were not strongly symptomatic, and thus may not necessarily be relevant to our younger postmenopausal patients in practice. Evidence for risks of HRT in women following premature menopause is limited: their baseline risk of adverse events is lower due to age, so the balance of benefits and risks may be more favourable.^[5]

Thinking about risk

Undeniably, awareness has grown of the increased risk of certain cancers and vascular disease (both venous and arterial) associated with the use of the COCP and HRT. When young women use the COCP, consideration must be of a vast pool of healthy individuals using a drug, frequently long-term, so even very small risks may be unacceptable at an individual or population level, compared to those tolerated when prescribing in established disease.

Risks should be carefully considered and explained in the context of the need, benefit and alternatives. This applies particularly to those women with other risk factors. Assess all women carefully for pre-existing risk factors that may increase individual risk before prescribing the COCP or HRT (see below).

Relative risks are misleading and their isolated use has fuelled scares - always present women with information about disease frequency and absolute risk. Risk-benefit equations will change over time so regular return to the subject is necessary.

Enabling women to come to an overall decision as to risk/benefit ratio is difficult and time-consuming, as it involves the explanation of background quantification of risks and potential benefits and these must be weighted according to individual priorities and pre-existing risk factors.

Risk factor assessment

When discussing either starting the COCP or HRT with a patient, enquire about any risk factors that they may have that could possibly increase their individual risk when using the medication.

A full discussion of risk factors and contra-indications to the COCP can be found in the related articles Pill Questions - What to Ask When Starting the OCP and Combined Oral Contraceptive (First Prescription).

Further discussion of risk factors and contra-indications to HRT can be found in the related article on Hormone Replacement Therapy.

Combined hormone contraception^[9]

Benefits^[10]

• A reliable and reversible form of contraception.
• There is reduced dysmenorrhoea and menorrhagia.
• There is reduced incidence of premenstrual tension.
• Use produces fewer symptomatic fibroids and functional ovarian cysts.
• There is less benign breast disease with COCP use.
• There is a reduced risk of ovarian cancer. Four ovarian cancers and two deaths from ovarian cancer are prevented with 10,000 women years of use.^[11]
• The Royal College of General Practitioners' (RCPG) Oral Contraception Study showed a small decreased risk of colon cancer and endometrial cancer.^[12]
• There is reduced risk of pelvic inflammatory disease.

Overall, the RCGP's Oral Contraception Study suggested a 12% reduction in all cancer in COCP past users, although a rise was found in the much smaller group of women who used them for over eight years.^[12] Methodological issues with the study have been highlighted and the overriding balance of risk and benefit for cancer and the COCP remains elusive.^[13]

Risks

• VTE^[10][14]
  • The relative risk of VTE with COCP use can increase up to five-fold compared with non-users but the absolute risk is still low, and considerably lower than the risk in pregnancy. The risk seems to be highest during the first year of use. The risk also increases with age and in the presence of other risk factors for VTE.
  • Risk increases with doses of ethinylestradiol greater than 50 μg (modern pills range from 20 μg low strength to 30-40 μg standard strength).
  • The risk of venous thrombosis is increased with obesity and is greatest in the first year of COCP use. Approximate risks:
    • Healthy non-pregnant women - about 5-10 cases per 100,000 per year.
    • 2nd generation pill users (eg levonorgestrel) - about 15 per 100,000 per year.
    • 3rd generation pill users (eg desogestrel and gestodene) - about 25 per 100,000 per year.
    • Pregnancy - estimated to be about 60 per 100,000 pregnancies.
    • Yasmin®, a newer pill using drospirenone as its progestogen, has a risk profile for VTE similar to standard 2nd generation pills.^[15]
    • Evra®, a combined hormonal contraceptive patch releasing norelgestromin, appears to have a risk slightly higher than standard 2nd generation pills (although this did not reach statistical significance).
    • Dianette® (cyproterone acetate with ethinylestradiol) is not licensed for contraceptive use alone as it has a risk of VTE higher than conventional low or standard dose pills, but is used to treat acne and hirsutism.
  • To minimise the risk of venous thrombosis before any major surgery, surgery to the legs, or surgery with prolonged immobilisation of a lower limb, the COCP should be stopped four weeks before the procedure. It should not be resumed until two weeks after complete mobility (start on day one of the first period after this time).
• Myocardial infarction (MI)
  • For COCP users who are heavy smokers (more than 15 cigarettes per day) the relative risk of MI may be up to 10 times that of smokers who do not use the COCP.
  • There is a very small increase in risk of MI even in healthy non-smokers who take the COCP.^[9]
  • COCP users with hypertension have a three-fold increased risk of MI compared with COCP users without hypertension.
• Stroke
  • There is a very small increase in the absolute risk of ischaemic stroke with COCP use.
  • Whilst the use of COCP is an independent risk factor for ischaemic stroke, the risk is doubled in patients who are also hypertensive and trebled in those who smoke.
  • The presence of Factor V Leiden mutation or homocystinuria significantly increases the risk of ischaemic stroke.
• Breast cancer
  • Any increased risk of breast cancer with COCP use is likely to be small. Most studies have suggested a marginally increased risk without strong associations to factors such as age started, duration of use, or time since first or last use.
  • In COCP users, the cancers are more likely to be localised to the breast.^[10]
  • The most important factor for diagnosing breast cancer appears to be the age at which the COCP is stopped rather than the duration of use.^[10] Any increased risk also reduces after stopping so that 10 years post-cessation, the incidence of breast cancer is the same as in women who have never used the COCP.^[10]
  • For those with a positive family history of breast cancer, the risk associated with COCP use is the same as for the general population. However, carrying the BRACA1 mutation may slightly increase your risk of COCP-associated breast cancer, although the evidence for this is limited.
• Cervical cancer
  • The association of cervical cancer with COCP use may be due to confounding factors (the influence of smoking, age at first intercourse, number of sexual partners) or may reflect a role in the malignant transformation of cervical cells.
  • The use of oral contraceptives for fewer than five years does not seem to increase the risk of cervical cancer.
  • The risk of cervical cancer does increase with more than five years of COCP use:^[14][16]
    • Women who use the COCP for five years from age 20 have an increased cumulative incidence of cervical cancer at age 50 years from 38 cases per 10,000 (in never users) to 40 cases per 10,000.
    • Women who use the COCP for 10 years from aged 20 years have an increased cumulative incidence of cervical cancer at age 50 years from 38 cases per 10,000 (in never users) to 45 cases per 10,000.
  • The risk returns to the level of never-users after 10 years of stopping.
• Liver cancer
  • Primary liver cancer is rare in developed countries and, although COCP use increases the risk, the absolute risk is very small.

Hormone replacement therapy

Benefits

HRT can help:^[4]

• Vasomotor symptoms (including sleep or mood disturbance caused by these symptoms).
• Urogenital symptoms.
• Prevent osteoporosis (although HRT should not be used as a first-line treatment, except in women who have premature menopause, because the risks outweigh the benefits).
• Reduce the risk of colorectal cancer (but HRT should not be used just for this purpose).
• When used in those with premature menopause, for prevention and treatment of cardiovascular disease and osteoporosis until 50 years (taken as the age of natural menopause).

Risks

• VTE^[5][10][17]
  • HRT (combined or oestrogen-alone) increases the risk of a DVT or pulmonary embolism, especially in the first year of treatment. The risk is more pronounced in women with pre-existing risk factors for VTE.
  • The baseline risk of VTE increases with age, and use of HRT further adds to this risk.
  • Approximate risks:
    • 5 in 1,000 non HRT-using women aged 50-59 years will have a VTE over five years, increasing to 8 in 1,000 in the 60-69 year age bracket.
    • In women using oestrogen-only HRT, 7 per 1,000 of the 50-59 year olds (ie an extra two cases) and 10 per 1,000 in the 60-69 year olds (again an extra two cases) will experience a VTE in a five-year period.
    • In women using combined HRT, 12 women aged 50-59 years (ie an extra seven cases) and 18 women aged 60-69 years (an extra 10 cases) will experience a VTE in five years.
  • A recent meta-analysis suggests that transdermal oestrogens may be a safer option - as regards risk of VTE - than oral oestrogens for HRT.^[18] This requires clarification but may offer a means of improving risk-benefit ratios in women with pre-existing risk factors for VTE who nonetheless require HRT.
• Coronary heart disease (CHD)^[5]
  • There is not the same evidence of cardioprotection from HRT as was originally thought.
  • There is an increased risk of CHD in women starting combined HRT more than 10 years after menopause.^[19] There are fewer data assessing the risk of younger, newly menopausal women, whose overall risk (baseline and that attributable to HRT) is likely to be low.
  • No increased risk of heart disease was found in the oestrogen-only arm of WHI after seven years.
  • Assess all women's risk of CHD prior to starting HRT.
• Stroke
  • Risk of stroke is increased in those taking HRT (both combined and oestrogen-only):^[5]
    • There is a small increase in overall rate of stroke in women taking either combined or oestrogen-only HRT from 4 (in non-users) up to 5 strokes per 1,000 women aged 50-59, taking HRT for five years.
    • In older women, the stroke risk in non-users is higher. So, older women taking either combined or oestrogen-only HRT have a higher absolute risk: five years' HRT use increases the risk of stroke from 9 up to 12 per 1,000 women aged 60-69.
• Dementia
  • If HRT is started after the age of 65, it is not thought to protect against dementia.
  • Also, combined HRT may increase the risk of dementia in women over the age of 75 years. The WHI Memory Study trials suggest that HRT (pooled combined and oestrogen-only) increases the risk of dementia from 12 to 20 cases per 1,000 women using HRT for five years.^[20]
• Breast cancer^[5]
  • HRT used for several years increases the risk of breast cancer but the additional breast cancer risk due to HRT for an individual is relatively small and multiple other risk factors also contribute, eg alcohol intake, obesity and lack of exercise.
  • Combined HRT is associated with a higher risk than oestrogen-alone. The Million Women study suggested a small increase in risk of breast cancer with oestrogen-only HRT compared to combined HRT.^[21] This increase in breast cancer with unopposed oestrogen was not found in the WHI study when oestrogen-only HRT was used for up to seven years.^[22]
  • The increased breast cancer risk is proportional to the duration of HRT but not the age at which treatment is started (but the baseline risk of breast cancer also increases with age):
    • Using combined HRT for five years, in women aged 50-59, there are six additional cases of breast cancer per 1,000 women on a baseline incidence of about 10 per 1,000 women. For oestrogen-only HRT, there are about two extra cases per 1,000 women.
    • Using combined HRT for five years in women aged 60-69, there are nine extra cases per 1,000 women on a baseline incidence of 15 per 1,000 women. For oestrogen-only HRT, there are three extra cases.
    • If duration of use increases to 10 years, in women aged 50-59 taking combined HRT, there are 24 additional cases of breast cancer per 1,000 women on a baseline incidence of 20 per 1,000 women. For oestrogen-only HRT, there are six extra cases.
    • For women aged 60-69 with 10 years' use, combined HRT increases cases of breast cancer by 36 per 1,000 on a baseline of 30 per 1,000 women and oestrogen-only by nine cases.
  • The excess breast cancer risk subsides within five years of stopping.
  • The invasive breast cancers diagnosed in the combined HRT group of WHI were larger and more advanced than the placebo group.^[23] Previously it had been thought that breast tumours found in HRT users had a better prognosis.
  • HRT, especially certain regimes (eg conjugated equine oestrogens +/- medroxyprogesterone), can increase mammographic density and may increase the likelihood of having an abnormal mammogram that needs further investigation.
• Endometrial cancer^[5]
  • Oestrogen-only HRT substantially increases the risk of endometrial cancer in women with a uterus.
  • The use of cyclical progestogen for at least 10 days per 28-day cycle eliminates the risk.
• Ovarian cancer^[5][24]
  • There is a small increased risk of ovarian cancer developing in current, or recent, users of HRT, which increases with duration of use, and is seen whichever preparation, constituents or mode of administration is used.
  • It amounts to one extra ovarian cancer in women aged 50-59 using HRT for 10 years (baseline 4 per 1,000 women) and two extra cases in women aged 60-69 (baseline 6 per 1,000 women).