The Risks of Combined Hormone Contraception and HRT

Oestrogens in both combined oral contraceptives and hormone replacement have been shown to potentially increase the risk of certain cancers and both venous and arterial vascular disease. Therefore the risks should be carefully considered in the context of the need, benefit and alternatives to prescribing COCs and HRT. This applies particularly for those women with other risk factors:

• Risk factors for venous thromboembolism include:
  • Family history of venous thromboembolism in first-degree relative aged under 45 years or if known prothrombotic coagulation abnormality e.g. factor V Leiden or antiphospholipid antibodies (including lupus anticoagulant).
  • Obesity
  • Long-term immobilisation e.g. in a wheelchair
• Risk factors for arterial disease include:
  • Family history of arterial disease in first degree relative aged under 45 years
  • Dyslipidaemia
  • Diabetes mellitus
  • Hypertension
  • Smoking
  • Obesity
• Family history of breast cancer in first degree relative

The combined oral contraceptive or hormone replacement therapy should be stopped immediately if:

• Sudden severe chest pain
• Sudden breathlessness or cough with blood-stained sputum
• Unexplained severe pain in calf of one leg
• Severe stomach pain
• Serious neurological symptoms, e.g. severe, prolonged headache, sudden disturbance of vision or hearing, dysphasia, collapse, first unexplained epileptic seizure, motor disturbances or sudden numbness affecting one part of body
• Hepatitis, jaundice or liver enlargement
• Systolic blood pressure above 160 mmHg; diastolic blood pressure above 100 mmHg
• Prolonged immobility after surgery or trauma
• Diagnosis of any contraindication to therapy

• Non-life-threatening adverse effects:
  • Breakthrough bleeding
  • Breast tenderness
  • Acne
  • Mood changes
• Venous thromboembolism:
  • Relative risk of venous thromboembolism with COC use can increase up to five-fold compared with non-users.
  • The absolute risk is still low, and considerably lower than the risk in pregnancy.
  • The risk of venous thrombosis is increased with obesity and is greatest in the first year of COC use. Approximate risks:¹
    • 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 per year
  • To minimize 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. Healthy non-smokers have no increased risk of myocardial infarction with COC use.¹
  • 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.
• Breast cancer:
  • Any increased risk of breast cancer with COC use is likely to be small.
  • After 10 years since last use, the incidence of breast cancer is the same as in women who have never used COCs.¹
• Cervical cancer:
  • 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.¹
• Liver cancer:
  • Primary liver cancer is rare in developed countries and, although COC use increases the risk, the absolute risk is very small.

• Breast cancer:
  • There is a small increased risk of breast cancer.
  • The risk of breast cancer with HRT increases within 1-2 years of starting treatment; the risk then increases with increasing duration of use.
  • The risk of breast cancer begins to decline when HRT is stopped and reaches the same level as in women who have never taken HRT by 5 years after stopping HRT.
  • The oestrogen-only arm of the Women's Health Initiative reported no increase in the risk of breast cancer over 7 years of use but there are insufficient data to properly compare the relative risks of oestrogen only compared to combined HRT.²
  • For women aged 50-64 years, the baseline risk of breast cancer is about 14 cases per 1000 women over a 5 year period and this is increased to 20 women per 1000 for women for those taking HRT for the same 5 year period.³
• Endometrial cancer:
  • Unopposed oestrogen therapy increases the risk of endometrial cancer.
    Addition of progestogen reduces the risk of endometrial cancer: for those women with a uterus, a progestogen should be added to oestrogen therapy for at least 12 days per month.
• Ovarian cancer
  • Women who use HRT are at an increased risk of both incidental and fatal ovarian cancer.⁴
  • Over 5 years, one extra ovarian cancer is estimated to have occurred in about 2500 HRT users and one extra death from the malignancy in about 3300 users.⁴
• Venous thromboembolism:
  • There is an increased risk of venous thromboembolism, especially in the first year of use.
  • The risk should be assessed in the context of other risk factors, including past history of thromboembolism, obesity and increasing age.³

    CSM estimate of increased risk of VTE with use of HRT5
    Age Group	Number of cases per 1000 non- HRT users over 5 years	Extra cases per 1000 oestrogen-only HRT users (over same 5 year period)	Extra cases per 1000 combined HRT users (over the same 5 year period)
    50-59	10	1	4
    60-69	20	4	9

• Cardiovascular disease:
  • Following recent studies such as the Women's Health Initiative and the Heart and Estrogen/progestin Replacement Study (HERS), it is possible that certain types of HRT may confer an increased risk of cardiovascular events, particularly in the first year of treatment.²
  • Long term benefit of HRT in reducing the risk of cardiovascular disease in terms of primary prevention or secondary prevention has not been shown in the HERS study.⁶

    CSM estimate of increased risk of Stroke with use of HRT7
    Age Group	No. of cases per 1000 non-HRT users over 5 years	Extra cases per 1000 oestrogen-only HRT users (over same 5 year period)	Extra cases per 1000 combined HRT users (over same 5 year period)
    50-59 years	8	2 (+/- 2)	1 (+/- 1)
    60-69 years	15	6 (+/- 4)	4 (+/- 3)

• Women who have recently discontinued HRT are at risk of rapid bone loss.⁸

• Because of the lack of the first-pass effect on the liver, the non-oral route of administration may be preferable in women with hypertriglyceridaemia, liver disease, migraine headaches and increased risk of venous thrombosis.¹
• The non-oral route may also be appropriate for women who also take liver-enzyme inducing drugs, e.g. anticonvulsants, those with reduced gastrointestinal absorption and those with a history of gallstones.