Hormone therapy Learning objectives: Assess options to address quality of life and health concerns of menopausal women Outline indications for hormone therapy Counsel women on the risks and benefits of hormone therapy Direct patients to evidence-based information resources Introduction Understanding the risks and benefits of post-menopausal hormone therapy (HT) is a complex area with significant shifts in the evidence over the last twenty years. Since the 1960s oestrogen has been prescribed as an effective treatment for vasomotor symptoms associated with menopause. It is interesting to reflect on the early marketing of the then-called hormone replacement therapy where it was viewed as a revolutionary breakthrough for women. In 1966 New York gynaecologist Robert Wilson stated in his book Feminine Forever that "menopause is a hormone deficiency disease, curable and totally preventable, and that every woman, no matter what her age, can safely lead a fully-sexed life for her entire life." 1 He described oestrogen therapy as the fountain of youth that would prevent women from experiencing the "tragedy" of menopause, which would leave them dried up, sexless, and depressed. The use of oestrogen declined in the mid-1970s when endometrial cancer was linked to unopposed oestrogen use. During the 1980s use increased again when it was shown that the addition of progestogens was protective. During the 1990s, HT was being used to reduce heart disease, in addition to treating menopausal symptoms. The Women's Health Initiative (WHI) Study first published in 2002 has had a major impact on the understanding of the actual benefits and risks of menopausal hormone therapy. 2 Menopause Menopause occurs when the ageing ovaries become less responsive to follicle-stimulating hormone (FSH) and luteinising hormone (LH), resulting in fewer ovulations and decreasing amounts of circulating progesterone and oestrogen. Women are considered to be perimenopausal when menstrual regularity discontinues, typically around 51 years of age. Women with early or surgical menopause may have worse or persistent symptoms. Up to 80% of perimenopausal and early postmenopausal women will experience some menopause symptoms, hot flushes being the most common. Whilst oestrogen remains the most effective treatment,
concerns around the adverse effects of hormone replacement therapy have lead to increased interest in other therapies for improving menopausal symptoms. Menopausal symptoms include hot flushes, night sweats, vaginal dryness, impaired sexual function and sleep disorders. Other common symptoms associated with menopause include difficulty concentrating, fatigue, irritability, headaches and musculoskeletal discomfort. The average duration of these symptoms is 5.5 years, although symptom duration can range anywhere from five months to 10 years, with the severity varying from mild to severe. When menstruation ceases for more than one year, women are considered to be post-menopausal. After menopause, symptoms will decline in most women. However symptoms may continue in around 2% of women into their 70s. 3 Hormone therapy Oestrogen is considered the most effective known hormone therapy. However it is neither appropriate nor desirable for every symptomatic woman. Other hormonal treatments include progestins, raloxifene (a selective oestrogen receptor modulator or SERM) and tibolone. Indications The principle indication for hormone therapy is the treatment of vasomotor symptoms (hot flushes and night sweats) associated with menopause. Vasomotor symptoms affect up to 80% of women and typically begin in perimenopause. Current evidence suggests that the benefits generally outweigh the risks for healthy women with bothersome symptoms who decide to take HT at the time of menopause. In the late 1980s around 40 retrospective observational studies suggested that HT reduced the risk of heart attack by 50%. This led to the conventional wisdom that all women should use HT for heart protection, unless there was a reason not to do so. Women with cardiovascular disease risk factors, especially previous myocardial infarction, stroke, hypertension or diabetes, we encouraged to use HT even in the absence of vasomotor symptoms. Then came two randomised controlled trials designed to evaluate cardioprotection by hormone therapy: HERS, 4 a secondary prevention trial; and WHI, a primary prevention trial. Current data does not support a role for HT in the primary or secondary prevention of heart disease. Benefits Oestrogen is the most effective treatment for hot flushes. Oestrogen also improves bone mineral density and vaginal dryness, and possibly mood and sleep disturbances. Vasomotor symptoms
Oestrogen with or without a progestogen significantly lowers the frequency and severity of hot flushes. About 80% of women will experience relief from symptoms with hormone therapy. 5 Treatment with oestrogen reduces the number of hot flushes by about 18 per week, compared with placebo. 6 Tibolone also alleviates post-menopausal vasomotor symptoms. It should also be noted that the placebo effect in studies of hot flush treatments is as high as 50%. 6,7 Cardiovascular Oral oestrogen initiated around the time of menopause may provide cardioprotection by reducing the progression of atherosclerotic plaques. Administration of oestrogen many years after menopause may disrupt established plaques, leading to adverse cardiovascular outcomes. 8 In WHI study the increase in cardiovascular events only reached statistical significance in the 70 to 79 year old group on combined HT. Urogenital system Vaginal dryness and associated symptoms such as pruritus, bleeding, dysuria, urinary urgency and recurrent urinary tract infections affect up to 75% of postmenopausal women. Urogenital atrophy is generally progressive in the absence of treatment. Very low doses of vaginal oestradiol relieve symptoms and normalise vaginal atrophy associated with menopause. A Cochrane review concluded that vaginal oestrogen preparations including creams, rings, and tablets were equally effective in treating the symptoms of vaginal atrophy. 9 Low doses of oestrogen cream are effective when used one to three times a week. Tibolone improves urogenital atrophy. Vaginal oestrogen may reduce the symptoms of overactive bladder, such as urgency and frequency. It can also reduce the likelihood of recurrent urinary tract infections in postmenopausal women. Oral HT was reported to increase stress and urge incontinence in the WHI trial. 10 Bone Hormone therapy is effective at both preventing and treating osteoporosis. Oestrogen with or without progestogen prevents early postmenopausal bone loss and augments bone mass in late menopause as effectively as bisphosphonates. In addition, oestrogen alone or in combination with a progestogen can prevent hip and vertebral factures. In the WHI study there was a 33% reduction in hip fractures after an average follow-up of 5.6 years. 11 Unfortunately this benefit does not persist after HT discontinuation. Tibolone is considered second line therapy for prevention of BMD loss in postmenopausal women at high risk of osteoporotic fractures. It significantly reduces vertebral and non-vertebral fractures in women over the age of 60 years with osteoporosis. Raloxifene improves BMD and reduces vertebral but not hip fractures. Breast cancer Raloxifene and tibolone decreases breast cancer risk. Colon cancer Combined HT decreases colon cancer risk. Tibolone is associated with a reduction of colon cancer.
Joint pain Oestrogen exerts a protective effect on osteoarthritis. The Women s International Study of long Duration Oestrogen after Menopause (WISDOM) showed a significant reduction in joint pain in the HT groups compared with placebo. 12 Quality of life Overall quality of life was also improved in the WISDOM study with combined HT started many years after menopause. 12 Health-related quality of life is improved through decreased symptoms, sleep enhancement and possibly mood enhancement. Risks Hormone therapy is associated with an increased incidence of venous thromboembolic events, pulmonary embolus, stroke, breast cancer and gallbladder disease. The Million Women Study showed an association with an increased risk of heart disease, thromboembolic disease and stroke, and breast cancer. 13 Event Increased risk per 10,000 women per year using HT Oestrogen only Oestrogen and progestogen Stroke 12 extra 8 extra VTE 8 extra 18 extra Coronary Heart Disease No increase 6 extra CHD events Breast Cancer No increase 8 extra Endometrial Cancer n/a No increased risk Colorectal Cancer 1 extra 7 less Hip fractures 7 less 5 less Total fractures 53 less 47 less Cardiovascular Retrospective epidemiological studies reported a 50% decrease in heart disease in women who use HT. 14 this observed reduction in CHD was thought secondary to beneficial effects of HT on lipids and direct actions on blood vessels. However most studies included women in their 50s and were at lower risk of heart disease than nonusers. Despite the limitations of the WHI, it remains clear that hormone therapy initiated at or after the median age of women in this study (63 years) increases the risk of detrimental vascular outcomes. 15 The WHI trial of oestrogen and progestogen therapy demonstrated an increased risk of CHD in postmenopausal women. The hazard ratio for increased CHD was 1.3 and 1.4 for stroke. The absolute risk per 10,000 woman-years attributable to HT was small, with seven more CHD events and eight strokes. In the WHI trial of unopposed oestrogen a small increased risk of stroke and VTE was observed, but no increased risk of CHD. Reanalysis of data from the WHI has confirmed that the increased risk of CHD occurs principally in older women and in women taking HT for more than 5 years. No increased risk of CHD was seen in women between the ages of 50 and 59 or in those within 10 years of menopause. 16
The risk of stroke is increased with HT, although the absolute excess risk of stroke in younger women is minimal. Analysis of WHI data has shown that oestrogen therapy alone for an average of 7 years increases the risk of stroke in older women. 17 Tibolone does not increase the risk of CHD events. There is no increase in stroke with the use of raloxifene. Tibolone increases the risk of stroke in older women, but not younger women. Breast cancer The lifetime risk of invasive breast cancer is 12%. Risk factors for breast cancer age, early menarche, late menopause, family history, and prior breast disease. Pregnancy before the age of 30 years is associated with a reduced risk. Current data suggests the increased risk of breast cancer on combined HT is four per 10,000 women-years, i.e. two per 1,000 women after 5 years. 6 WHI reported an increased relative risk (RR) of breast cancer with long-term combined HT of 1.53 after a median of 8 years. 2 However, the risk of breast cancer does not increase with oral or transdermal application of oestrogen when used for less than 5 years. 18,19 Analysis has shown that there was no significant increase in breast cancer among those who initiated combined HT for the first time during the 7 years of WHI. 20 In fact, the use of oestrogen alone for less than 5 years may reduce the risk of breast cancer in women starting therapy many years after the onset of menopause. It is important to put this in perspective with other risk factors include lifestyle issues. The relative risk seen in WHI for breast cancer was 1.26. This is similar to a late menopause of 55 years or more (RR 1.22), three alcohol drinks per day (RR 1.4) or nulliparity (RR 1.67). Factor Estimated relative risk High fat diet 2.0 First pregnancy >30 years 1.48 BMI> 30 1.36 Non breast feeding 1.2 Alcohol use > 5g/ day 1.16 Delayed menopause 1.14 Hormone therapy overall 1.24 Current user for 5 years 2.0 In general consensus is that HT should not be prescribed to women with a history of breast cancer and should only be used by women at high risk after a careful assessment of risks and benefits. Tibolone increases the risk of breast cancer recurrence. Endometrial cancer No difference in the risk of endometrial cancer was seen with combined oestrogen and progestogen therapy compared with placebo in WHI. 21 Ovarian cancer
No significant difference in the risk of ovarian cancer was seen with combined oestrogen and progestogen therapy compared with placebo in WHI. 21 Colorectal cancer The WHI identified a reduced risk of colorectal cancer in women on combined HT, but no beneficial affect was seen in women who had undergone hysterectomy on oestrogen alone. VTE HT increases the risk of venous thromboembolic events (VTE) approximately 2-fold. Raloxifene also increases the incidence of VTE. Dose and duration The lowest effective dose of hormone therapy should be used to minimise adverse effects for the shortest duration to minimise symptoms. For younger women aged less than 60 years in the early postmenopausal period, oestrogen therapy may be cardioprotective. 22 This window of therapeutic opportunity should be explained to patients when discussing the risk and benefits of HT. HT can be stopped abruptly or tapered. 23 Regardless some women will experience recurrence of vasomotor symptoms and will restart HT. Implications for practice Community and accredited pharmacists are often asked for advice on the use of hormone therapy. Best available evidence supports the use of hormone therapy for management of severe vasomotor symptoms. While oestrogen remains the most effective therapy for hot flushes, the risk/benefit needs to be considered, together with patient preferences. Recommendations should consider the patient's personal choice, symptom severity, existing risks, age and years since menopause. Pharmacists should discuss the potential benefits, adverse effects and the uncertainties of hormone therapy and advice patients on where to access further information. Patients and pharmacists should periodically assess the treatment outcomes. Further reading and patient information NPS News 64: Therapeutic choices for menopausal symptoms NPS Prescribing Practice Review 47: Managing menopausal symptoms The Jean Hailes Foundation for Women's Health Debbie Rigby September 2010
MCQs 1) Regarding the use of oestrogen therapy for the management of hot flushes, which of the following statements is incorrect? a) cardiovascular disease may be reduced when HT is initiated near menopause b) oestrogen therapy is the most effective therapy for menopausal symptoms c) breast cancer risk decreases after several years of combined HT d) no increase in breast cancer risk is seen with oestrogen-only HT 2) Which of the following statements regarding the absolute risks of HT is correct? a) Absolute risks of HT decrease with age b) Combined HT does not affect the absolute risk of breast cancer c) Oestrogen therapy alone does not affect the absolute risk of breast cancer d) Duration of therapy of HT has no affect on the absolute risk of breast cancer 3) The balance of risks and benefits for oestrogen-alone therapy is more favourable for women without a uterus. a) True b) False 4) Which of the following statements regarding the risk of breast cancer is incorrect? a) Long-term use of HT is associated with an increased risk of breast cancer b) Oestrogen-alone therapy increases the risk of breast cancer after 15 years of current use c) Combined oestrogen and progestin therapy increases the risk of breast cancer after 7 years of current use d) The risk of breast cancer is similar for HT and 3 standard drinks of alcohol per day 5) Regarding the WHI study, which of the following statements is correct? After 5 years of combined oestrogen and progestogen therapy there is: a) Reduction in fractures, no overall cardiovascular benefit, an increased risk of breast cancer and thromboembolism b) Reduction in fractures, decreased cardiovascular risk, an increased risk of breast cancer and thromboembolism c) Reduction in fractures, no overall cardiovascular benefit, an increased risk of breast cancer, decreased risk of thromboembolism d) Increased risk of hip fractures, no overall cardiovascular benefit, an increased risk of breast cancer and thromboembolism 6) In the WHI, a reduced risk of which type of cancer was observed in women on combined HT? a) Endometrial cancer b) Colorectal cancer c) Ovarian cancer d) All of the above
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