3. Menopause Hormone Therapy (MHT/HRT): Principles and Prescribing
Pedagogy: This lesson uses classification and formulation matching — building a mental framework of oestrogen types, progestogen options, and routes that enables confident prescribing.
Learning Objectives
- Classify the types of oestrogen available for MHT: oestradiol, conjugated equine oestrogens, oestetrol
- Describe progestogen options: micronised progesterone, dydrogesterone, norethisterone, LNG-IUS
- Distinguish sequential from continuous combined regimens and state when each is appropriate
- Differentiate body-identical, synthetic, and compounded preparations
Key Facts
Oestrogen Options
| Type | Route | Examples | Key Point |
|---|---|---|---|
| 17-beta oestradiol | Oral, transdermal (patch/gel/spray) | Oestrogel, Sandrena, Evorel, Estradot | Body-identical; preferred by most guidelines |
| Conjugated equine oestrogens | Oral | Premarin | Used in WHI; less commonly prescribed in UK now |
| Oestetrol (E4) | Oral (investigational for MHT) | Approved as OCP component | Native fetal oestrogen; selective tissue activity; liver-friendly |
Progestogen Options
| Type | Route | Breast/VTE Profile | Key Point |
|---|---|---|---|
| Micronised progesterone (Utrogestan) | Oral | Lower risk vs synthetic | Body-identical; 200mg sequential / 100mg continuous |
| Dydrogesterone | Oral | Lower risk vs synthetic | Isomer of progesterone; well-tolerated |
| Norethisterone (NET) | Oral, transdermal (in combined patches) | Higher VTE/breast risk | Used in Evorel series; effective but synthetic |
| 52mg LNG-IUS (Mirena) | Intrauterine | Favourable | IMS 2025: most effective endometrial protection; provides contraception |
Sequential vs Continuous Combined
Sequential (cyclical): Oestrogen daily + progestogen for 12-14 days/month. Produces withdrawal bleed. For perimenopausal women. Continuous combined (bleed-free): Oestrogen + progestogen daily. For postmenopausal women (>12 months since LMP or age >=54). Switch from sequential to continuous after 5 years or by age 54 (BMS 2026).
Compounded Bioidentical HRT
Compounded preparations lack evidence for adequate potency, purity, and endometrial protection. Transdermal progesterone creams/gels have variable absorption and do NOT provide sufficient endometrial protection. The BMS and ESE do not recommend compounded products (1,2).
Clinical Pearl Micronised progesterone and dydrogesterone carry lower breast cancer and VTE risk than synthetic progestogens. This matters when counselling patients about the 'type' of HRT — not all progestogens are equal.
Clinical Pearl The 52mg LNG-IUS (Mirena) is the IMS 2025's 'most effective option' for endometrial protection within HRT. Lower-dose LNG-IUDs (13.5mg, 19.5mg) do NOT provide endometrial protection and require supplementary progestogen.
Case-Based Examples
Case 1: Perimenopausal woman requesting HRT
Presentation: A 48-year-old with irregular periods and moderate VMS (6/day). BMI 24, no VTE history, no contraindications. She asks about HRT options.
Question: What regimen would you initiate?
Model Answer: Perimenopausal: sequential regimen. Transdermal oestradiol gel (start at 1 pump/day = low dose) + micronised progesterone 200mg for 12-14 days/month at end of cycle (oral, taken at bedtime — has sedative effect, may help sleep). Review at 3 months: titrate oestrogen up if symptoms persist. Discuss: this will produce a monthly withdrawal bleed; once she is clearly postmenopausal (12 months amenorrhoea or age 54), switch to continuous combined.
Case 2: 55-year-old on sequential HRT for 6 years requesting review
Presentation: A 55-year-old has been on Evorel Sequi patches for 6 years. She is happy with symptom control but asks about 'going bleed-free.'
Question: Advise on switching to continuous combined HRT and progestogen choice.
Model Answer: She is 55 (>54) and has been on sequential HRT for >5 years — meets both BMS criteria for switching. Options: (a) Evorel Conti patches (combined transdermal); (b) Continue transdermal oestradiol + switch to continuous micronised progesterone 100mg daily (lower breast risk than continuing NET in the patch); (c) Transdermal oestradiol + 52mg LNG-IUS (most effective endometrial protection, eliminates need for oral progestogen). Counsel: light spotting may occur for 3-6 months during transition. If bleeding persists beyond 6 months, investigate per BMS/RCOG 2024.
Self-Assessment Questions
PLAB/MLA Sequential vs continuous combined HRT
A 46-year-old perimenopausal woman is starting HRT. Which regimen is most appropriate?
A. Continuous combined HRT
B. Oestrogen-only HRT
C. Sequential (cyclical) HRT
D. Tibolone
Answer: C. Perimenopausal women should be started on sequential HRT (oestrogen daily + progestogen for 12-14 days/month). Continuous combined is for postmenopausal women only.
MRCGP Progestogen choice to minimise breast cancer risk
A 51-year-old starting HRT is very concerned about breast cancer risk. Which progestogen has the most favourable risk profile?
A. Medroxyprogesterone acetate
B. Norethisterone
C. Micronised progesterone or dydrogesterone
D. Desogestrel
Answer: C. Micronised progesterone and dydrogesterone are associated with lower breast cancer and VTE risk compared with synthetic progestogens (MPA, NET). ESE 2025 supports this distinction.
Professor Evidence for progestogen-type breast cancer risk differences
NICE NG23 (2024) states there is 'insufficient evidence' to establish whether breast cancer risk differs between micronised progesterone and other progestogens. Critically appraise this position against the ESE and IMS recommendations.
A. All guidelines agree there is no difference between progestogens
B. NICE's position reflects the absence of head-to-head RCTs, whilst ESE/IMS cite observational data suggesting lower risk with micronised progesterone — a tension between evidence hierarchy and clinical pragmatism
C. RCT data clearly prove micronised progesterone is safer
D. Observational data are irrelevant to clinical practice
Answer: B. NICE applies a strict RCT-evidence hierarchy and found no direct comparative RCTs for progestogen types and breast cancer. The ESE and IMS cite large observational studies (E3N cohort, Finnish registry) showing lower breast cancer incidence with micronised progesterone vs synthetic progestogens. This represents a genuine tension: should clinicians await RCT evidence that may never come, or act on consistent observational signals? The BMS 2026 takes a pragmatic position, recommending micronised progesterone as first-line. A key research recommendation from NICE 2024 is specifically to study whether progestogen type affects breast cancer risk.
Take-Away Messages
- Oestrogen: 17-beta oestradiol (body-identical) via transdermal route is preferred by most guidelines
- Progestogen: micronised progesterone and dydrogesterone have lower breast/VTE risk than synthetic progestogens
- Sequential HRT for perimenopause; continuous combined for postmenopause (switch after 5 years or by age 54)
- 52mg LNG-IUS is the most effective endometrial protection option (IMS 2025)
- Compounded bioidentical products are NOT recommended — transdermal progesterone creams do NOT protect the endometrium