Guideline

Pharmacologic approaches to prevention and treatment

Menopausal Hormonal Therapy

Last revised: 01 Mar 2024

Menopausal Hormonal Therapy

Recommendation 29

Grade

Consider oestrogen replacement therapy to reduce the risk of fragility fractures in postmenopausal women within 10 years of menopause. The increased risk of adverse events associated with treatment should be carefully weighed against benefits.

A

Recommendation 30

Grade

Selective oestrogen receptor modulators (SERMs) should be considered as a treatment option for postmenopausal women with osteoporosis where vertebral fractures are the major osteoporosis risk (based on low spine BMD and/or an existing vertebral fracture) and where other agents are poorly tolerated. SERMs may be particularly useful in younger postmenopausal women at risk of vertebral fracture with a prior or family history of breast cancer.

A

Oestrogen acts to decrease bone resorption and promote bone formation. Oestrogen replacement therapy effectively prevents loss of BMD and reduces the risk of fractures when given at, or near, menopause. Oestrogen therapy is most appropriate in women with vasomotor symptoms of menopause who are at risk of osteoporosis.1–5 Menopausal hormonal therapy (MHT) has been shown to reduce fracture risk regardless of falls or baseline FRAX®.6 Postmenopausal women at high risk of fracture may be more appropriately prescribed bone-specific antiresorptive or osteoanabolic therapies. Where appropriate, concurrent MHT and bone-specific therapies can be considered.

The minimum effective dose of oestrogen therapy on bone loss has yet to be clearly established,5 but beneficial effects of oestrogen therapy can be achieved by oral or transdermal administration, including patches and gels. The choice of oestrogen will also depend on patient preference and tolerance of side effects, including local skin irritation to transdermal formulations or migraines with oral oestrogens. Breast tenderness, swelling, and vaginal spotting are frequent side effects of oestrogen therapy, and a lower-dose regimen should be commenced with close assessment of tolerance. Lower doses of oestrogen may also be effective in preventing postmenopausal bone loss. However, higher doses may be considered in patients who demonstrate ongoing bone loss with low-dose oestrogen replacement, with attention paid to calcium intake and vitamin D status, provided the risk associated with oestrogen replacement therapy is not increased (e.g., clotting, cardiovascular disease, or breast cancer). Women with a history of oophorectomy may require a higher-dose oestrogen regimen at an earlier time point.

Ideally, oestrogen therapy should be given continuously (i.e., without a break in therapy) and a transdermal approach is ideal to avoid a greater risk of thrombosis in women taking oral oestrogen preparations. Women at higher risk of thrombosis, such as those with previous venous thrombosis, Factor V Leiden mutations, or other coagulopathy, should not be prescribed oral oestrogens.

Adjuvant progestogens are necessary in women who still have a uterus to protect against endometrial cancer. Progestogens may be given cyclically for 10–14 days each month in perimenopausal women or as continuous therapy combined with oestrogen in postmenopausal women. The latter is more suitable for women more than two years postmenopause to avoid the initial irregular bleeding commonly seen with this regimen being unduly prolonged.

Tibolone is a form of MHT with oestrogenic, progestogenic, and androgenic effects and does not need to be given with a progestogen. It has similar efficacy to traditional MHT in reducing fracture risk and is used for the relief of vasomotor menopausal symptoms. Tibolone, at a dose of 1.25 mg daily, reduces the risk of fractures in postmenopausal women. However, its use in older postmenopausal women should be undertaken with caution due to a higher risk of stroke.3 Currently, tibolone is not subsidised by the PBS.

All postmenopausal women on MHT should have regular mammographic screening and frequent assessment of risks and benefits of continuing therapy beyond five years of postmenopause. Upon ceasing MHT, bone density is likely to decline because the effects of oestrogen on bone are reversible. A long-term treatment approach to treat osteoporosis may then be required following MHT.

Available on the PBS for treatment of postmenopausal osteoporosis, SERMs such as raloxifene have evidence for breast cancer prevention,7 so their use can be tailored to suit an individual’s unique risk factor profile and they may be particularly useful in the younger postmenopausal female with low spine BMD and a prior or family history of breast cancer.

Although there is excellent evidence for raloxifene in the reduction of vertebral fracture risk, there is minimal evidence for reduction in non-vertebral fractures.8 Therapy should be continuous; there is no need for concomitant progestogens and, following therapy, a long-term treatment approach to osteoporosis is required because the effects on bone density are reversible. Raloxifene has also been associated with an increase in hot flushes and thromboembolism.7,8

Treatment effect

The role of long-term MHT in the prevention and management of osteoporosis remains controversial, following results of the Women’s Health Initiative (WHI) study of combined oestrogen and progestin therapy4 and its study of oestrogen-alone therapy.2

Tibolone has a different side effect profile from traditional MHT. A Cochrane systematic review found no evidence for an increase in breast cancer in women with no history of breast cancer (OR 0.52; 95% CI: 0.21–1.25).9 However, tibolone does appear to increase breast cancer recurrence in those with treated breast cancer.9,10 There is no evidence for increased heart disease or thromboembolic events with tibolone, but in older women there was an increased risk of stroke.3

Raloxifene may increase hot flushes and is likely to aggravate vasomotor symptoms. Like traditional MHT, raloxifene is associated with increased thromboembolic events, but has not been associated with heart disease or overall risk of stroke.11 In one study of women at high heart disease risk, raloxifene increased fatal, but not overall, stroke risk.7

Evidence Statement

Treatment effect

In a clinical trial of 7705 women randomised to two doses of raloxifene or placebo followed for up to four years, there was a reduction in vertebral fractures (RR 0.64; 95% CI: 0.53–0.76) at the approved dose of 60 mg per day.8 There was no significant reduction in non-vertebral fractures (RR 0.93; 95% CI: 0.81–1.06). Similar results were found for another good-quality study of raloxifene in over 10,000 women at high risk of heart disease at baseline.7

There is good evidence that, compared with placebo, oestrogen is associated with a decreased risk of vertebral, non-vertebral, and hip fractures. This effect was observed in the analysis for all postmenopausal women (OR not reported), as well as for groups at higher risk of fractures (RR ~0.7).1 In two clinical trials conducted by the WHI, conjugated oestrogen in combination with progestin in postmenopausal women (n=16,608) or conjugated equine oestrogen (CEE) alone in women after hysterectomy (n=10,739) were shown to reduce the risk of osteoporotic fractures.2,4 Participants taking CEE 0.625 mg and medroxyprogesterone acetate 2.5 mg per day in a combined tablet (as opposed to oestrogen therapy) for an average of five years had significant reductions in total fractures (HR 0.76; 95% CI: 0.69–0.85; P=0.05) and hip fractures (HR 0.66; 95% CI: 0.45–0.98; P=0.05).4 Participants taking CEE 0.625 mg per day for an average of six years had significant reductions in the rates of all osteoporotic fractures (HR 0.70; 95% CI: 0.63–0.79; P=0.01) and hip fractures (HR 0.61; 95% CI: 0.41–0.91; P=0.01).3 An RCT of tibolone in 4500 women over three years found decreased risks of vertebral fracture (HR 0.55; 95% CI: 0.41–0.74) and non-vertebral fracture (HR 0.74; 95% CI: 0.58–0.93).3

Safety

Oestrogen alone or combined with progestagens

The WHI reported that in the oestrogen-alone group there was no increased risk of invasive breast cancer or cardiovascular disease, although the other outcomes were similar to the combined group.2 For the combined oestrogen/progesterone group, increased risk of invasive breast cancer has been reported in multiple analyses, although the initial report of increased coronary heart disease was no longer significant in subsequent analyses.2–5,9 Increased risks of thromboembolic events and stroke are reported for both groups. Subsequent to the initial publication, there have been multiple reanalyses of the data, including by age of initiation of MHT. The side effect profile is more favourable for those women starting MHT within 10 years of menopause (age 50–59 years) with low absolute risks of thromboembolic events and stroke.9

In a large meta-analysis12 and nested case-control study,13 the risk of breast cancer increased steadily with longer duration of MHT use and was greater in those on combined oestrogen/progesterone therapy compared with oestrogen alone, with the increased risk persisting for several years following cessation.12 Different progesterones are associated with differential breast cancer risk, with micronised progesterone having the lowest risk.14

Long-term follow-up (median follow-up >20 years) of the WHI study cohort found that CEE alone compared with placebo in women with hysterectomy was associated with lower breast cancer incidence (HR 0.78; 95% CI: 0.65–0.93) and lower breast cancer mortality (HR 0.60; 95% CI: 0.37–0.97).15 However, compared with placebo, CEE plus medroxyprogesterone acetate in women with a uterus was associated with higher breast cancer incidence (HR 1.28; 95% CI: 1.13–1.45), but no difference in breast cancer mortality (HR 1.35; 95% CI: 0.94–1.95).15

The most recent systematic review that looked at 27 RCTs and 47 observational studies between 2009 and 2019 reported an increased risk of thromboembolic events (for RCTs, summary estimate [SE] 1.70 [95% CI: 1.33–2.16]; for observational studies, SE 1.32 [95% CI: 1.13–1.54]).16 The authors noted that the study populations in the RCTs were older and had more underlying disease than those in the observational studies. In the same systematic review, an increased stroke risk was only seen in the RCTs (SE 1.14; 95% CI: 1.04–1.25) and a decreased risk of myocardial infarction was seen in observational studies (SE 0.79; 95% CI: 0.75–0.84).16 Multiple subgroup analyses were also performed to better understand the clinical effects of MHT. These analyses suggest that choice of MHT, underlying disease, and timing of initiation should be considered. In subgroup analyses of observational studies, a decreased risk of all-cause death was observed among oestrogen-only MHT (SE 0.85; 95% CI: 0.77–0.95) and early users after menopause (SE 0.68; 95% CI: 0.51–0.92).16 In addition, increased risk of stroke was seen in observational studies in women administered oral MHT (SE 1.24; 95% CI: 1.11–1.39), whereas a decreased risk of stroke was observed in women administered non-oral MHT (SE 0.86; 95% CI: 0.77–0.96). Overall, analyses favour earlier initiation (within 10 years of menopause) and non-oral MHT, and support safe use for at least five years in healthy women initiating treatment before the age of 60 years. The International Menopause Society supports tailoring MHT duration to the individual’s needs.17

Tibolone

An RCT of women aged >60 years reported a reduction in the risk of invasive breast cancer (absolute risk reduction [ARR] 1.9 per 1000 person-years; 95% CI: 0.5–3.4; P=0.02) and colon cancer (ARR 1.3 per 1000 person-years; 95% CI: 0.1–2.6; P=0.04) associated with tibolone therapy.3 However, the relative hazard for stroke was 2.19 (95% CI: 1.14–4.23) and the absolute risk increase was 2.3 per 1000 person-years (95% CI: 0.4–4.2), leading to early cessation of the trial. Absolute risk increased more in participants aged >70 years (absolute risk increase 3.1 per 1000 person-years). There was no increased risk of heart disease or venous thromboembolic events.3 In a subsequent study of women already treated for breast cancer, tibolone was found to decrease vasomotor symptoms and maintain BMD, but there was an increased risk of breast cancer recurrence (HR 1.40; 95% CI: 1.14–1.70).10 Similar to the earlier study, there was no increased risk of venous thromboembolic events or heart disease in this younger group.

Raloxifene

In the four-year follow-up of the pivotal raloxifene Multiple Outcomes of Raloxifene Evaluation (MORE) study,8,18 there was an increased risk of thromboembolic events, with an RR of 2.76 (95% CI: 1.30–5.86) for deep venous thrombosis and 2.76 (95% CI: 0.95–8.01) for pulmonary embolism. Unlike MHT, there was a reduced risk of breast cancer (RR 0.38; 95% CI: 0.24–0.58) and no increased risk of cardiovascular events.19 In a subsequent RCT of raloxifene in over 10,000 women with either established heart disease or risk factors for heart disease, there was a similar reduction in breast cancer (primarily estrogen receptor positive) and no increased risk of primary coronary events, overall risk of stroke or overall deaths.7 However, there was an increased risk of fatal strokes (HR 1.49; 95% CI: 1.00–2.24) and venous thromboembolism (HR 1.44; 95% CI: 1.06–1.95).7

  • GPs should discuss with patients the long-term risks and benefits of MHT, especially breast cancer and thromboembolic and cardiovascular effects. Side effects of traditional MHT are minimised, with absolute risk low, if given within 10 years of menopause.
  • The side effect profiles of traditional MHT, tibolone and raloxifene are different. MHT is ideal for postmenopausal women with vasomotor menopausal symptoms and who are at risk of osteoporosis, in the absence of contraindications.
  • Women taking MHT should have at least an annual consultation with their GP to review their risks and the ongoing need for MHT.
  • Individuals who require immobilisation for any period (eg hospitalisation or a long plane trip) should cease MHT or raloxifene for a week before and after.
  • Postmenopausal women taking MHT should maintain adequate calcium intake (from dietary sources or supplements) and be vitamin D replete.
  • Raloxifene should not be used in combination with oestrogen therapy.
  • The use of bone-specific antiresorptive or anabolic therapies is more appropriate than MHT in patients at high risk of fracture.
  • The risks of MHT must be weighed against the clear benefits of MHT in women with menopausal vasomotor symptoms and osteoporosis, in particular the beneficial effects on quality of life and fracture prevention.
  1. MacLean C, Newberry S, Maglione M, et al. Systematic review: Comparative effectiveness of treatments to prevent fractures in men and women with low bone density or osteoporosis. Ann Intern Med 2008;148(3):197–213.
  2. Anderson GL, Limacher M, Assaf AR, et al. Effects of conjugated equine estrogen in postmenopausal women with hysterectomy: The Women’s Health Initiative randomized controlled trial. JAMA 2004;291(14):1701–12.
  3. Cummings SR Sr, Ettinger B, Delmas PD, et al. The effects of tibolone in older postmenopausal women. N Engl J Med 2008;359(7):697–708.
  4. Rossouw JE, Anderson GL, Prentice RL, et al. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: Principal results from the Women’s Health Initiative randomized controlled trial. JAMA 2002;288(3):321–33.
  5. Wells G, Tugwell P, Shea B, et al. Meta-analyses of therapies for postmenopausal osteoporosis. V. Meta-analysis of the efficacy of hormone replacement therapy in treating and preventing osteoporosis in postmenopausal women. Endocr Rev 2002;23(4):529–39.
  6. Lorentzon M, Johansson H, Harvey NC, et al. Menopausal hormone therapy reduces the risk of fracture regardless of falls risk or baseline FRAX probability – results from the Women’s Health Initiative hormone therapy trials. Osteoporos Int 2022;33(11):2297–305.
  7. Barrett-Connor E, Mosca L, Collins P, et al. Effects of raloxifene on cardiovascular events and breast cancer in postmenopausal women. N Engl J Med 2006;355(2):125–37.
  8. Delmas PD, Ensrud KE, Adachi JD, et al. Efficacy of raloxifene on vertebral fracture risk reduction in postmenopausal women with osteoporosis: Four-year results from a randomized clinical trial. J Clin Endocrinol Metab 2002;87(8):3609–17.
  9. Formoso G, Perrone E, Maltoni S, et al. Short-term and long-term effects of tibolone in postmenopausal women. Cochrane Database Syst Rev 2016;10(10):CD008536.
  10. Kenemans P, Bundred NJ, Foidart JM, et al. Safety and efficacy of tibolone in breast-cancer patients with vasomotor symptoms: A double-blind, randomised, non-inferiority trial. Lancet Oncol 2009;10(2):135–46.
  11. Barrett-Connor E, Grady D, Sashegyi A, et al. Raloxifene and cardiovascular events in osteoporotic postmenopausal women: Four-year results from the MORE (Multiple Outcomes of Raloxifene Evaluation) randomized trial. JAMA 2002;287(7):847–57.
  12. Collaborative Group on Hormonal Factors in Breast Cancer. Type and timing of menopausal hormone therapy and breast cancer risk: Individual participant meta-analysis of the worldwide epidemiological evidence. Lancet 2019;394(10204):1159–68.
  13. Vinogradova Y, Coupland C, Hippisley-Cox J. Use of hormone replacement therapy and risk of breast cancer: Nested case-control studies using the QResearch and CPRD databases. BMJ 2020;371:m3873.
  14. Asi N, Mohammed K, Haydour Q, et al. Progesterone vs. synthetic progestins and the risk of breast cancer: A systematic review and meta-analysis. Syst Rev 2016;5(1):121.
  15. Chlebowski RT, Anderson GL, Aragaki AK, et al. Association of menopausal hormone therapy with breast cancer incidence and mortality during long-term follow-up of the Women’s Health Initiative randomized clinical trials. JAMA 2020;324(4):369–80.
  16. Kim JE, Chang JH, Jeong MJ, et al. A systematic review and meta-analysis of effects of menopausal hormone therapy on cardiovascular diseases. Sci Rep 2020;10(1):20631.
  17. Baber RJ, Panay N, Fenton A; IMS Writing Group. 2016 IMS recommendations on women’s midlife health and menopause hormone therapy. Climacteric 2016;19(2):109–50.
  18. Grady D, Ettinger B, Moscarelli E, et al. Safety and adverse effects associated with raloxifene: Multiple Outcomes of Raloxifene Evaluation. Obstet Gynecol 2004;104(4):837–44.
  19. Cauley JA, Norton L, Lippman ME, et al. Continued breast cancer risk reduction in postmenopausal women treated with raloxifene: 4-Year results from the MORE trial. Breast Cancer Res Treat 2001;65(2):125–34.
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