Combined Hormone Contraception and HRT (Benefits and Risks)

Naturally occurring oestrogens (mainly oestradiol in women of reproductive age and oestrone in the post-menopausal) have widespread effects on women's bodies. Their influences include:

• Fetal development of vagina, uterus and fallopian tubes
• The pubertal growth spurt
• The development of female secondary sexual characteristics (e.g. breast development, distribution of body fat)
• Cyclical ovulation
• Endometrial proliferation
• Lipid metabolism
• Bone reabsorption

Synthetically derived oestrogens have been widely used in both combined oral contraceptives (COCs) and hormone replacement therapy (HRT). These are known as xenooestrogens.

With COCs, 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 FSH and LH production and preventing ovulation. COCs have a Pearl Index of 0.3 (i.e. 3 pregnancies per 1000 women years of 'perfect' use).¹

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 so avoiding the mortality and morbidity associated with pregnancy, childbirth and termination. Worldwide, more than half a million women die from pregnancy-related complications and, even in the UK, the 2000–2002 Confidential Enquiry into Maternal and Child Health found a total of 261 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 COCs have reverberated far beyond the directly pharmacological.

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 symptoms³) and improves quality of life and sexual function in symptomatic, post-menopausal women. It also helps to prevent osteoporosis, though this beneficial effect is lost soon after stopping treatment.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.

History

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 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.⁶

Similarly, the pendulum is beginning to swing back towards recognition of the valid therapeutic uses of HRT following the scare post Women's Health Initiative (WHI) and Million Women Study (MWS). These were both large scale studies indicating increased risks associated with HRT compared to 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 consensus statement (2006) stressed that potential benefits could outweigh harms given appropriate dose, route and combination.⁷ WHI, on which many of our prescribing decisions are based, recruited post-menopausal women who were an average 63 years old (i.e. 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.⁴

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 COCs and HRT. When young women use COCs, 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 for those women with other risk factors. Assess all women carefully for pre-existing risk factors before prescribing COCs or HRT.

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 very 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.

Even weighing up the cancer-related risk/benefit equation of COCs is fraught. There is a protective effect of COC use against ovarian cancer (preventing 4 ovarian cancers and 2 deaths from ovarian cancer with 10,000 women years of use).⁸ The RCGP's Oral Contraception Study⁹ also showed a small decreased risk of colon cancer and endometrial cancer. Overall, the study suggested a 12% reduction in all cancer in COC past users, although a rise was found in the much smaller group of women who used them for over 8 years. Controversially, the study did not find the small increase in breast cancer found in most other studies of this subject. Methodological issues with the study have been highlighted and the overriding balance of risk and benefit for cancer and COCs remains elusive.¹⁰

Non-life-threatening adverse effects

Include:

• Breakthrough bleeding
• Breast tenderness
• Acne
• Mood changes

Venous thromboembolism

• The relative risk of venous thromboembolism with COC 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.
• Risk increases with doses of ethinyloestradiol greater than 50μg (modern pills range from 20μg low strength to 30-40μg standard strength).
• The risk of venous thrombosis is increased with obesity and is greatest in the first year of COC use. Approximate risks:^1,12
  • Healthy non-pregnant women - about 5-10 cases per 100,000 per year.
  • Second-generation pill users - about 15 per 100,000 per year.
  • Third-generation pill users - 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 second-generation pills.¹³
  • Evra, a combined hormonal contraceptive patch releasing norelgestromin, appears to have a risk slightly higher than standard second-generation pills (although this did not reach statistical significance).
  • Dianette (cyproterone acetate with ethinyloestradiol) 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 pelvic surgery or procedures that may require extensive immobilisation, COCs should be stopped 2-4 weeks before the procedure, and should not be resumed until 2 weeks after complete mobility.¹

Myocardial infarction

• For COC 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 COCs.
• There is a very small increase in risk of MI even in healthy non-smokers under 35.
• COC users with hypertension have a three-fold increased risk of MI compared with COC users without hypertension.

Stroke

• Very small increase in the absolute risk of ischaemic stroke with COC use.
• Whilst the use of COC is an independent risk factor for ischaemic stroke, 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 COC use is likely to be small. Most studies have suggested a marginally increased risk without strong associations to factors such age started, duration of use or time since first or last use.
• It is limited to current and recent use - ten years post-cessation, the incidence of breast cancer is the same as in women who have never used COCs.¹
• For those with a positive family history of breast cancer, risk associated with COC use is the same as for the general population.¹
• Carrying the BRACA1 mutation may slightly increase your risk of COC associated breast cancer, though the evidence for this is limited.¹

Cervical cancer

The association of cervical cancer with COC 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 less than 5 years does not increase the risk of cervical cancer.
• The risk of cervical cancer does increase with more than 5 years of COC use. This is estimated as:¹⁴
  • An additional 20 cases per 100,000 women at age 50 years following 5 years' consecutive use from 20 years
  • An additional 70 cases per 100,000 women at age 50 after 10 years' consecutive use from 20 years old.
• 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 COC use increases the risk, the absolute risk is very small.

Non life threatening adverse effects

Include:

• Breast enlargement and tenderness
• Erratic vaginal bleeding (must be investigated if persists beyond initial period of treatment)
• Weight changes
• Premenstrual-like syndrome and mood changes
• Fluid retention
• Glucose intolerance

Venous thromboembolism^4,15

• HRT (combined or oestrogen-alone) increases the risk of a DVT or PE 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 1000 non HRT-using women aged 50-59 years will have a VTE over five years, increasing to 8 in 1000 in the 60-69 year age bracket.
  • In women using oestrogen only HRT, 7 per 1000 of the 50-59 year olds (i.e. an extra 2 cases) and 10 per 1000 in the 60-69 year olds (again an extra 2 cases) will experience a VTE in a five year period.
  • In women using combined HRT, 13 women aged 50-59 years (i.e. an extra 7 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.¹⁶ 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 disease⁴

• There is no evidence of cardioprotection from HRT as originally thought.
• There is an increased risk of CHD in women starting combined HRT more than 10 years after menopause.¹⁷ There is less 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 7 years.
• Assess all women's risk of CHD prior to starting HRT.

Stroke

Risk of stroke is increased in those taking HRT:⁴

• There is a small increase in overall rate of stroke in women taking combined and oestrogen-only HRT from 4 to 5 strokes per 1000 women aged 50-59, taking HRT over 5 years.
• In older women, the baseline risk has increased and so older women have a higher absolute risk: 5 years' HRT use increases the risk of stroke from 9 to 12 per 1000 women aged 60-69.

Dementia

HRT does not appear to protect against cognitive decline. The WHI Memory Study trials suggest that HRT (pooled combined and oestrogen-only) increases the risk of dementia from 12 to 20 cases per 1000 women using HRT over 5 years.¹⁸

Breast Cancer⁴

• 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 e.g. alcohol intake, obesity and lack of exercise.
• Combined HRT is associated with a higher risk than oestrogen-alone. MWS¹⁹ suggested a small increase in risk of breast cancer with oestrogen-only HRT compared to combined HRT. This was not found in WHI²⁰ with unopposed oestrogen up to 7 years' use.
• MWS¹⁹ found an early increase in incidence of breast cancer, within 1-2 years of starting treatment. Some have criticised the study suggesting that the apparent increase in the first year was actually due to observational bias.²¹
• The increased risk is proportional to the duration of HRT but not the age at which treatment is started, but the baseline risk of breast cancer increases with age:
  • Using combined HRT for 5 years, in women aged 50-59, there are 6 additional cases of breast cancer per 1000 women on a baseline incidence of about 10 per 1000 women. For oestrogen-only HRT, there are about 2 extra cases per 1000 women.
  • Using combined HRT for 5 years in women aged 60-69, there are 9 extra cases per 1000 women on a baseline incidence of 15 per 1000 women. For oestrogen-only HRT, there are 3 extra cases.
  • If duration of use increases to 10 years, in women aged 50-59, there are 24 additional cases of breast cancer per 1000 women on a baseline incidence of 20 per 1000 women. For oestrogen-only HRT, there are 6 extra cases.
  • For women aged 60-69 with 10 years use, combined HRT increases cases of breast cancer by 36 per 1000 on a baseline of 30 per 1000 women and oestrogen-only by 9 cases.
• The excess risk subsides within 5 years of stopping.
• The invasive breast tumours diagnosed in the combined HRT group of WHI²² were larger and more advanced than the placebo group. Previously it had been thought that breast tumours found in HRT users had a better prognosis.
• HRT, especially certain regimes (e.g. conjugated equine oestrogens +/- medroxyprogesterone), can increase mammographic density and may increase the likelihood of having an abnormal mammogram that needs further investigation.

Endometrial cancer⁴

• 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 cancer⁴

• 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 1000 women) and two extra cases in women aged 60-69 (baseline 6 per 1000 women).²³