Unscheduled bleeding whilst on HRT

NICE notes with respect to clinical features suggestive of endometrial cancer (1)

Symptoms suggestive of endometrial cancer

• refer women using a suspected cancer pathway referral (for an appointment within 2 weeks) for endometrial cancer if they are aged 55 and over with post-menopausal bleeding (unexplained vaginal bleeding more than 12 months after menstruation has stopped because of the menopause)
  
  
• consider a suspected cancer pathway referral (for an appointment within 2 weeks) for endometrial cancer in women aged under 55 with post-menopausal bleeding

A direct access ultrasound scan to assess for endometrial cancer should be considered in women aged 55 and over with:

• unexplained symptoms of vaginal discharge who:
  • are presenting with these symptoms for the first time or
  • have thrombocytosis
  • or report haematuria,
• or visible haematuria and:
  • low haemoglobin levels or
  • thrombocytosis
  • or high blood glucose levels

In the full guideline (1) the CDG states "Based on their clinical experience they considered that whilst ultrasound is an investigation commonly used to diagnose endometrial cancer in secondary care, it could have value as an investigation in primary care to determine if a suspected cancer pathway referral was needed."

NICE does not consider PMB in the context of HRT. This scenario has been addressed by a joint guideline (2):

Assessment of women presenting with unscheduled bleeding on HRT

• when women present with unscheduled bleeding on HRT, clinical assessment should start with a comprehensive review detailing bleeding patterns, HRT preparations and individual risk factors for cancer
• an examination (abdominal, pelvic) should be offered and, where relevant, initial investigations such as cervical screening, lower genital tract swabs and body-mass index (BMI).

Endometrial cancer risk factors in women taking HRT

• risk factors for endometrial hyperplasia and cancer, independent of HRT, should be identified
  • major risk factors are
    • BMI ≥ 40
    • hereditary conditions such as Lynch or Cowden syndrome
  • minor risk factors
    • BMI 30-39,
    • diabetes
    • polycystic ovarian syndrome (PCOS)
  • optimisation of modifiable factors can, in themselves, reduce episodes of unscheduled bleeding on HRT and endometrial cancer risk.
• a monthly progestogen dose, in proportion to the estrogen dose, is recommended in women with a uterus.
• in women using sequential HRT (sHRT) offer monthly dose of progestogen
  • offer a minimum of 10 days norethisterone (NET) or medroxyprogesterone acetate (MPA),
  • or 12 days of micronised progesterone
• women taking a sequential preparation (sHRT) over the age of 45 should be offered, after five years of use or by age 54 (whichever comes first), a change to continuous combined (ccHRT)

When to investigate unscheduled bleeding on HRT

• in the absence of risk factors for endometrial cancer, offer adjustments in the progestogen or HRT preparation, for 6 months in total, if unscheduled bleeding
  • a) occurs within six months of starting HRT or
  • b) is persisting three months after a change in HRT dose or preparation
• if unscheduled bleeding continues in low-risk women, after six months of adjustments, discuss the options of an urgent ultrasound (within six weeks) versus weaning off HRT and consideration of non-hormonal alternatives (to avoid invasive investigations)
• for those women who elect to stop HRT, if the bleeding has settled at a 4-week follow-up, and continued cessation of HRT is acceptable, no further investigations are required
  • if the bleeding has settled at a 4-week follow-up and there is a preference to restart HRT, offer adjustments in HRT for six months and then an urgent ultrasound if bleeding is heavy/persistent during the 6 months or, is continuing after this interval
• offer an urgent TVS (within 6 weeks) if the first presentation with bleeding occurs more than six months after initiating, or three months after changing, the HRT preparation
• offer an urgent TVS (within 6 weeks), irrespective of interval since starting, or changing, HRT preparations if
  • a) bleeding is prolonged / heavy or,
  • b) there are 2 minor risk factors for endometrial cancer
• offer an urgent suspicion of cancer pathway (USCP) referral to women with one major or three minor risk factors for endometrial cancer – irrespective of bleeding type or interval since starting or changing HRT preparations
  • adjustments to the progestogen, or stopping HRT, should be offered whilst awaiting assessment

How should unscheduled bleeding on HRT be investigated

• women with unscheduled bleeding, in the presence of a uniform endometrium which is fully visualised, and measures ≤ 4 mm with ccHRT or ≤ 7 mm with sHRT, can be reassured that the risk of endometrial cancer is low
  • offer HRT adjustments for 6 months and then offer endometrial assessment, on an urgent pathway, if bleeding increases during the 6 months or, is continuing after this interval
• women with a thickened endometrium on TVS (> 4 mm for ccHRT or > 7 mm for sHRT) should be offered referral to the urgent suspicion of cancer pathway (USCP) for endometrial assessment (biopsy and / or hysteroscopy)
• in the presence of a normal endometrial biopsy, discuss adjustments in the progestogen and provide reassurance for three months
  • if hysteroscopy and biopsy are normal, reassurance can be provided for six months
    • if unscheduled bleeding continues
      • adjustments to the progestogen, and management strategies to reduce cancer risk factors such as diabetes and BMI (if > 30) should be offered to reduce the likelihood of recurrent episodes
    • reassessment (TVS within 6 weeks) should be offered before six months if the nature of the bleeding changes e.g. heavier or more persistent
      • if bleeding is ongoing, despite adjustments in the progestogen, hysteroscopic assessment should be offered on an urgent pathway
      • reassessment before three months should be offered if the nature of the bleeding changes e.g. heavier or more persistent

Adjusting HRT to reduce unscheduled bleeding episodes

• assess adherence and understanding of how to use the prescribed preparation including dose and duration of progestogen – for example, would a combined patch or pill reduce administration errors when compared to a separate estrogen and progestogen component.
• offer all women a 52 mg LNG-IUD; this preparation reduces episodes of unscheduled bleeding when compared to all other preparations
• oral preparations provide higher rates of amenorrhoea when compared to transdermal preparations and could be offered, if there are no risk factors for thrombosis, as a) a first-line therapy or b) to women who have recurrent unscheduled bleeding with transdermal preparations.
• offer vaginal estrogens if there are atrophic findings on examination

Reference:

1. NICE (June 2015). Suspected cancer: recognition and referral.
2. BMS (British Menopause Society) Joint Guideline (April 2024). Management of unscheduled bleeding on hormone replacement therapy (HRT)