(See also Menopause – a management algorithm)

The term “hormone replacement therapy” (HRT) as discussed here refers to the use of exogenous oestrogen, either alone (ET) or in combination with a progestogen (EPT) where a woman has an intact uterus to prevent endometrial hyperplasia/ carcinoma. Observational studies, predominately conducted in symptomatic women close to the time of menopause, suggested that HRT reduced CVD and osteoporosis risk but increased the risk of venous thromboembolism and breast cancer (EPT).  However, the publication in 2002 of the Women’s Health Initiative (WHI) randomised controlled trial (RCT) of combined HRT caused alarm with data indicating significant adverse cardiovascular and breast cancer outcomes; many HRT users subsequently ceased HRT, often without medical consultation, and women were reluctant to commence, or doctors prescribe, HRT. The WHI trial involved women (majority without significant menopausal symptoms) who were on average 63 years of age at initiation of treatment, many with significant cardiovascular risk factors including elevated body mass index, hypertension and smoking (see Table: Summary of the WHI). More recent analyses of the WHI data and results from other studies provide clarification regarding the risk/benefit analysis of HRT use around the time of menopause. Information regarding the benefits/ risks of HRT has mainly been derived from studies involving the use of oral ET (mainly conjugated equine oestrogens (CEE)) or oral EPT (predominately CEE + medroxy-progesterone acetate (MPA)). How the findings of these studies relate to the use of other HRT preparations is unclear. HRT benefits and risks has recently been comprehensively reviewed by the US Endocrine Society (Santen et al., 2010) and the findings for women aged 50-59 or less than 10 years post-menopause are summarised in the figure:  Benefits and Risks of Hormone Replacement Therapy.  The current indications for use of HRT are relief of menopausal symptoms and management of premature menopause. Contraindications to HRT are shown in Table: Contraindications to HRT.

HRT is not contraceptive. The low dose oral contraceptive pill , oestrogen/ progestogen vaginal ring or ET plus MIRENA^® (levonorgestrel releasing intrauterine device) are therapeutic options particularly in perimenopausal women requiring contraception or in women with premature menopause. The usual contra-indications to contraceptive pill use apply.

Vaginal oestrogen is the preferred therapy for isolated urogenital symptoms. Use of vaginal oestrogens has been considered to be associated with minimal systemic absorption. However, elevated serum oestrogen levels above pre-treatment levels have been observed with different vaginal oestrogen preparations and their use in women taking aromatase inhibitors as part of breast cancer therapy is controversial. Vaginal oestrogen therapy and systemic HRT may be used concurrently where there is inadequate control of urogenital symptoms with systemic therapy alone. 

10.2.1 Use of HRT in early/ premature menopause

Evidence from observational studies indicates that the use of HRT in women with premature/ early menopause negates or minimizes the increased risk of osteoporosis, cardiovascular disease and cognitive decline/ dementia, in addition to improving menopausal symptoms and sexual dysfunction. However, there is a paucity of RCT data to guide clinical management and doubt regarding the applicability of studies conducted in older women (such as WHI) to these younger women. The current recommendation for management of premature/ early menopause is to initiate HRT early (unless contraindicated) and continue HRT until age 50 years. There is no consensus as to the most appropriate HRT preparation; however, higher oestrogen doses are often required to achieve symptomatic relief compared with older women.

10.2.2 Use of HRT in women with connective tissues disorders

The effect of oestrogen appears to vary according to the HRT preparation used (ET or EPT, mode of delivery), phase/ severity of the inflammatory process and receptors/ immune cells involved. Observational data is conflicting as to whether HRT use increases the risk of developing systemic lupus erythematosus (SLE); however, oral  EPT use increased the risk of mild-moderate (but not severe) flares in the SELENA- RCT (RR 1.34; CI 1.07-1.66). In addition, thrombosis risk increased 4 fold with oral HRT use compared to the placebo group. Thus transdermal oestrogen should be used preferentially. Data from the WHI study suggests that HRT use does not affect the risk of developing rheumatoid arthritis or disease activity with some benefit reported in smaller RCTs. HRT use in women with SLE/ rheumatoid arthritis was associated with increased bone density. Limited data exists regarding other connective tissue disorders and HRT use.

Table: Summary of the WHI 

Figure: Benefits and Risks of Hormone Replacement Therapy

Figure A shows the attributable excess risk or benefit in women commencing HRT ( either oestrogen alone-E or combined oestrogen/ progestogen- E+P) at the usual age (50-59 years) or less than 10 years after menopause.

Figure B presents the same data as Figure A in relation to the benefit of symptomatic improvement.

Reproduced from Santen et al., 2010 (used with permission)

Table: Contraindications to HRT

10.3 Tibolone

Content updated December 2010