Hormone replacement therapy

Hormone replacement therapy aims to replace oestrogen in the postmenopausal woman and so reverse the adverse effects of oestrogen lack.

• this is particularly important since the key indication for the use of HRT is to relieve troublesome vasomotor symptoms associated with menopause and to improve quality of life (1)
• the aims, therefore, are quite different to those of contraception for which high-dose artificial steroids are used in order to suppress ovulation. HRT uses more "natural" steroids and in lower doses.

The appropriate type of HRT depends on the following factors:

• whether or not she has had a hysterectomy
  • in women who still have their uterus, a progestogen must be included to avert the consequences of prolonged exposure to unopposed oestrogen
  • women who have had a hysterectomy are offered oestrogen-only therapy (1).
• the menopausal status
  • perimenopausal women should be offered sequential therapy using daily oestrogen and cyclical progestogen while postmenopausal women can be offered continuous combined therapy using daily oestrogen and daily progestogen
• preference for type of treatment: oral or non-oral
• past medical history
• current medication (1)

Tibolone which is used as a postmenopausal therapeutic alternative to HRT, is an oral synthetic steroid preparation with oestrogenic, androgenic, and progestogenic actions (2).

A study has shown that an increased risk of breast cancer with HRT is similar whether HRT is taken orally (swallowed) or delivered via patches or gels or implants (3,4)

In the UK about 1 in 16 women who never use HRT are diagnosed with breast cancer between the ages of 50 and 69 years.

This is equal to 63 cases of breast cancer per 1000 women. Over the same period (ages 50-69 years), with 5 years of HRT use, the study estimated:

• about 5 extra cases of breast cancer per 1000 women using estrogen-only HRT
• about 14 extra cases of breast cancer per 1000 women using estrogen combined with progestogen for part of each month (sequential HRT)
• about 20 extra cases of breast cancer per 1000 women using estrogen combined with daily progestogen HRT (continuous HRT) These risks are for 5 years of HRT use.

The numbers of extra cases of breast cancer above would approximately double if HRT was used for 10 years instead of 5.

There was no increased risk of breast cancer associated with use of vaginal oestrogen preparations (2)

MHRA has stated (4):

• All forms of systemic HRT are associated with a significant excess incidence of breast cancer, irrespective of the type of estrogen or progestogen or route of delivery (oral or transdermal)
• There is little or no increase in risk with current or previous use of HRT for less than 1 year; however, there is an increased risk with HRT use for longer than 1 year
• Risk of breast cancer increases further with longer duration of HRT use
• Risk of breast cancer is lower after stopping HRT than it is during current use, but remains increased in ex-HRT users for more than 10 years compared with women who have never used HRT
• Risk of breast cancer is higher for combined estrogen-progestogen HRT than estrogen-only HRT
• For women who use HRT for similar durations, the total number of HRT-related breast cancers by age 69 years is similar whether HRT is started in her 40s or in her 50s
• The study found no evidence of an effect on breast cancer risk with use of low doses of estrogen applied directly via the vagina to treat local symptoms

Note though that the British Menopause Society (BMS), International Menopause Society (IMS), European Menopause and Andropause Society (EMAS), Royal College of Obstetricians and Gynaecologists (RCOG) and Australasian Menopause Society (AMS) have issued clarification of the evidence on the risk of breast cancer with menopausal hormone therapy (MHT) in response to the recommendations of the European Medicines Agency (EMA) - the central European drug regulatory body - Pharmacovigilance Risk Assessment Committee on 11-14 May 2020 that followed on from a meta-analysis by the Collaborative Group on Hormonal Factors in Breast Cancer (CGHFBC) published in the Lancet on 30 August 2019 (5)

• Interpretation of the evidence on the risk of breast cancer with menopausal hormone therapy (MHT) (5)
  • the findings from the CGHFBC meta-analysis are in keeping with the NICE guidance 2015 analysis of the observational data on the risk of breast cancer and MHT
  • the findings from the CGHFBC meta-analysis should be explained to women when discussing the benefits and risks of MHT. However, discussions on the risk of breast cancer with MHT should also include the findings from the WHI placebo-controlled randomized trials and the large E3N observational studies, which reported on the risk of breast cancer risk in users of micronized progesterone and dydrogesterone compared with other progestogens. Neither of the latter two studies was included in the CGHFBC meta-analysis
  • the recently published WHI data showed a significant decrease in the risk of diagnosis of breast cancer with estrogen-only MHT and a significant reduction in breast cancer mortality compared with placebo
    • women who took combined estrogen and progestogen MHT had an increased risk of breast cancer compared to placebo, in keeping with NICE guidance conclusions, but showed no significant difference in breast cancer mortality compared with placebo
  • the E3N observational studies suggested a lower breast cancer risk in users of micronized progesterone and dydrogesterone compared to users of other progestogens
  • the joint statement highlights that
    • " Recommendations on the risk of breast cancer with MHT should take into consideration the findings from the WHI randomized trials and the observational data on micronized progesterone and dydrogesterone from the E3N study as well as those from the CGHFBC meta-analysis"
  • the joint statement concluded (5): "We believe that the findings from the CGHFBC meta-analysis should be explained to women when discussing the benefits and risks of MHT. However, discussions on the risk of breast cancer with MHT should also include the findings from the WHI placebo-controlled randomized trials and the large E3N observational studies, which reported on the risk of breast cancer risk in users of micronized progesterone and dydrogesterone compared with other progestogens. Neither of the latter two studies was included in the CGHFBC meta-analysis."

With respect to urogenital atrophy, NICE states (6):

• offer vaginal oestrogen to women with urogenital atrophy (including those on systemic HRT) and continue treatment for as long as needed to relieve symptoms
  • consider vaginal oestrogen for women with urogenital atrophy in whom systemic HRT is contraindicated, after seeking advice from a healthcare professional with expertise in menopause
  • if vaginal oestrogen does not relieve symptoms of urogenital atrophy, consider increasing the dose after seeking advice from a healthcare professional with expertise in menopause

Consider testosterone supplementation for menopausal women with low sexual desire if HRT alone is not effective (5).

Reference:

1. Currie H, Cochrane R. Current options in the treatment of menopausal symptoms. Prescriber 2010;21(13)
2. Hickey M, Elliott J, Davison SL.Hormone replacement therapy. BMJ. 2012;344:e763
3. 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. The Lancet. Published August 29, 2019.
4. MHRA (August 2019). Hormone replacement therapy and risk of breast cancer
5. BMS, IMS, EMAS, RCOG and AMS Joint Statement on menopausal hormone therapy (MHT) and breast cancer risk in response to EMA Pharmacovigilance Risk Assessment Committee recommendations in May 2020
6. NICE (November 2015). Menopause: diagnosis and management