6.4.1 Female sex hormones and their modulators

Further guidance supporting the prescribing of HRT preparations and the clinical management of menopause can be found here Guidance on the management of menopause

Oestrogen only

For women without a uterus, oestrogen-only HRT is appropriate, however, in endometriosis, endometrial foci may remain despite hysterectomy and the addition of a progestogen should be considered in these circumstances. For women with a uterus, oestrogen plus progestogen HRT is recommended. A progestogen should be added to reduce the risk of cystic hyperplasia of the endometrium and possible transformation to cancer.

Vaginal oestrogen preparations to be used in the relief of vaginal atrophy can be found here 7.2.1 Preparations for vaginal and vulval changes

Conjugated oestrogen, equine

Premarin®

(Conjugated equine oestrogens)

  • Tablets 300 micrograms, 625 micrograms, 1.25mg (£2.02, £1.34, £1.19)

Indications

  • Menopausal symptoms
  • Osteoporosis prophylaxis

Dose

  • Menopausal symptoms, 0.3–1.25mg daily continuously
  • Osteoporosis prophylaxis, 0.625-1.25mg daily continuously; with cyclical progestogen for 12-14 days of each cycle in women with a uterus

Notes

  1. Prescribe by brand (to aid identification where products contain multiple ingredients, or to prevent confusion where multiple brands contain similar ingredients)

Estradiol

Elleste solo®

(Estradiol)

  • Tablets 1mg, 2mg (£1.69)

Indications

  • Menopausal symptoms
  • Osteoporosis prophylaxis

Dose

  • Menopausal symptoms: 1 mg daily
  • Menopausal symptoms not controlled with lower strength or osteoporosis prophylaxis: 2 mg daily
  • Start treatment on day 1 of menstruation (or at any time if cycles have ceased or are infrequent), to be taken with cyclical progestogen for 12–14 days of each cycle in women with a uterus.

Notes

  1. Prescribe by brand (to aid identification where products contain multiple ingredients, or to prevent confusion where multiple brands contain similar ingredients)
Evorel®

(Estradiol)

  • Patches 25 micrograms, 50 micrograms, 75 micrograms, 100 micrograms per 24 hours (£4.12 = 75 micrograms)

Indications

  • Menopausal symptoms
  • Osteoporosis prophylaxis

Dose

  • 1 patch to be applied twice weekly continuously.
  • Start within 5 days of onset of menstruation (or at any time if cycles have ceased or are infrequent), to be used with cyclical progestogen for 12–14 days of each cycle in women with a uterus.

Notes

  1. Prescribe by brand (to aid identification where products contain multiple ingredients, or to prevent confusion where multiple brands contain similar ingredients)
  2. Therapy should be initiated with Evorel 50 patch; subsequently adjust according to response; dose may be reduced to Evorel 25 patch after first month if necessary for menopausal symptoms only

Oestrogen with progestogen

Continuous Combined Preparations

Continuous combined preparations are not suitable for use in the perimenopause or within 12 months of the last menstrual period; women who use such preparations may bleed irregularly in the early stages of treatment—if bleeding continues endometrial abnormality should be ruled out and consideration given to changing to cyclical HRT.

Conjugated oestrogens with medroxyprogesterone

Premique®

(Conjugated oestrogens with medroxyprogesterone)

  • Low dose modified release tablets (300 micrograms + 1.5mg) (£2.17)

Indications

  • Menopausal symptoms

Dose

  • 1 tablet daily, continuously

Notes

  1. Prescribe by brand (to aid identification where products contain multiple ingredients, or to prevent confusion where multiple brands contain similar ingredients)
  2. Premique contains medroxyprogesterone and is less androgenic.
  3. Animal source of oestrogen.

Estradiol with norethisterone

Kliofem®

(Estradiol with norethisterone)

  • Tablets (2mg + 1mg) (£3.81)

Indications

  • Menopausal symptoms
  • Osteoporosis prophylaxis

Dose

  • In women with a uterus whose last menstrual period occurred over 12 months previously, 1 tablet daily continuously; if changing from cyclical HRT begin treatment at the end of scheduled bleed.

Notes

  1. Prescribe by brand (to aid identification where products contain multiple ingredients, or to prevent confusion where multiple brands contain similar ingredients)
Kliovance®

(Estradiol with norethisterone)

  • Tablets (1mg + 500 microgram) (£4.40)

Indications

  • Menopausal symptoms
  • Osteoporosis prophylaxis

Dose

  • Women whose last menstrual period occurred over 12 months previously, 1 tablet daily continuously; start at end of scheduled bleed if changing from cyclical HRT

Notes

  1. Prescribe by brand (to aid identification where products contain multiple ingredients, or to prevent confusion where multiple brands contain similar ingredients)
  2. Kliovance has lower norethisterone content.
Evorel® Conti

(Estradiol with norethisterone)

  • Patches (50 micrograms/24 hours + 170 micrograms/24 hours) (£13.00)

Indications

  • Menopausal symptoms
  • Osteoporosis prophylaxis

Dose

  • 1 patch to be applied twice weekly continuously

Notes

  1. Prescribe by brand (to aid identification where products contain multiple ingredients, or to prevent confusion where multiple brands contain similar ingredients)

Estradiol with dydrogesterone

Femoston Conti®

(Estradiol with dydrogesterone)

  • Tablets (0.5mg + 2.5mg), (1mg + 5mg) (£8.14)

Indications

  • Menopausal symptoms
  • Osteoporosis prophylaxis (1mg/5mg strength only)

Dose

  • Women whose last menstrual period occurred over 12 months previously, 1 tablet daily continuously (if changing from cyclical HRT begin treatment the day after finishing oestrogen plus progestogen phase)

Notes

  1. Prescribe by brand (to aid identification where products contain multiple ingredients, or to prevent confusion where multiple brands contain similar ingredients)
  2. Femoston Conti is less androgenic
  3. Femoston products are included for patients experiencing progestogenic side effects with the first line agents.

Sequential Combined Preparations (Cyclical HRT)

Estradiol with norethisterone

Elleste Duet®

(Estradiol with norethisterone)

  • Tablets 1mg and (1mg + 1mg) (£3.07)
  • Tablets 2mg and (2mg + 1mg) (£3.07)

Indications

  • Menopausal symptoms
  • Osteoporosis prophylaxis, 2mg tablets only

Dose

  • 1 tablet (estradiol) daily for 16 days starting on day 1 of menstruation (or at any time if cycles have ceased or are infrequent), then 1 tablet (estradiol and norethisterone) daily for 12 days; subsequent courses are repeated without interval

Notes

  1. Prescribe by brand (to aid identification where products contain multiple ingredients, or to prevent confusion where multiple brands contain similar ingredients)
  2. There are two prescription charges for Elleste Duet

Estradiol with dydrogesterone

Femoston®

(Estradiol with dydrogesterone)

  • Tablets 1mg and (1mg + 10mg) (£5.39)
  • Tablets 2mg and (2mg + 10mg) (£5.39)

Indications

  • Menopausal symptoms
  • Osteoporosis prophylaxis

Dose

  • 1 tablet (estradiol) daily for 14 days, starting within 5 days of onset of menstruation (or any time if cycles have ceased or are infrequent) then 1 tablet (estradiol and dydrogesterone) daily for 14 days; subsequent courses repeated without interval

Notes

  1. Prescribe by brand (to aid identification where products contain multiple ingredients, or to prevent confusion where multiple brands contain similar ingredients)
  2. Femoston is included as a less androgenic alternative allowing dose titration.
  3. Femoston products are included for patients experiencing progestogenic side effects with the first line agents.
  4. There are two prescription charges for Femoston

Selective oestrogen receptor modulators

NICE CG164: Familial breast cancer: classification, care and managing breast cancer and related risks in people with a family history of breast cancer (July 2013, updated Nov 2019)

  • Unless the patient has a past history or may be at increased risk of thromboembolic disease:
    • Consider raloxifene for 5 years for postmenopausal women with a uterus at moderate or high risk of breast cancer who have severe osteoporosis or do not wish to take anastrozole or tamoxifen
Raloxifene
  • Tablets 60mg (£5.15 = 60mg once daily)

Indications and dose

  • Secondary prevention of osteoporotic fragility fractures in postmenopausal women
    • Adult: 60mg daily
  • Chemoprevention of moderate-to-high risk breast cancer in women (off-label) (refer to NICE CG164)
    • Adult: 60mg daily for 5 years

Notes

  1. Raloxifene does not reduce menopausal vasomotor symptoms
  2. Women taking raloxifene are at increased risk of thromboembolism
  3. NICE TA160: Raloxifene is not recommended as a treatment option for the primary prevention of osteoporotic fragility fractures in postmenopausal women (February 2018)
  4. NICE TA161: Raloxifene is recommended as an alternative treatment option for the secondary prevention of osteoporotic fragility fractures in postmenopausal women (February 2018)
    1. who are unable to comply with the special instructions for the administration of alendronate and risedronate, or have a contraindication to or are intolerant of alendronate and risedronate and
    2. who also have a combination of T-score, age and number of independent clinical risk factors for fracture as indicated in NICE TA161

Noretynodrel derivatives (Tibolone)

Tibolone is not suitable for use in the perimenopause or within 12 months of the last menstrual period; women who use such preparations may bleed irregularly in the early stages of treatment—if bleeding continues endometrial abnormality should be ruled out and consideration given to changing to cyclical HRT.

Tibolone
  • Tablets 2.5mg (£10.36)

Indications

  • Short-term treatment of symptoms of oestrogen deficiency (including women being treated with gonadotrophin releasing hormone analogues)
  • Osteoporosis prophylaxis in women at risk of fractures (second-line when other prophylaxis contra-indicated or not tolerated)

Dose

  • 2.5mg daily

Notes

  1. Tibolone is significantly more expensive than first line HRT preparations.
  2. Tibolone combines oestrogenic and progestogenic activity with weak androgenic activity; it is given continuously, without cyclical progestogen.
  3. The benefit-risk balance for tibolone, is described separately to conventional combined HRT. Refer to the September 2007 MHRA drug safety update, the BNF and the manufacturer's summary of product characteristics (SPC) for details.

Progestogens

Progestogens act mainly on tissues sensitised by oestrogens and are used for menstrual disorders including severe dysmenorrhoea and menorrhagia. Although oral progestogens have been used widely for menorrhagia they are relatively ineffective compared to tranexamic acid.

Miscarriage:
NICE guideline: Ectopic pregnancy and miscarriage [NG126, issued 2019, updated 2021] has been updated following an evaluation of progesterone for miscarriage:

  • Vaginal micronised progesterone is recommended for women with early pregnancy bleeding and a history of miscarriage (see entry below). There was no evidence of benefit for other preparations or doses of progesterone for this patient group.
  • The guidance does not support the use of vaginal micronised progesterone or other preparations or doses of progesterone for women with:
    • early pregnancy bleeding but no previous miscarriage, or
    • previous miscarriage but no early pregnancy bleeding in the current pregnancy

For further information, see NICE NG126 Rationale and Impact: Progestogens for preventing miscarriage.

Norethisterone
  • Tablets 5mg (£2.03 = 30 tablets)

Indications and dose

  • Endometriosis: 10–15mg daily for 4–6 months or longer, starting on day 5 of cycle (if spotting occurs increase dose to 20–25mg daily, reduced once bleeding has stopped)
  • Dysfunctional uterine bleeding or menorrhagia: 5mg 3 times daily for 10 days to arrest bleeding; 5mg twice daily from day 19 to 26 of cycle to prevent bleeding
  • Dysmenorrhoea: 5mg 3 times daily from day 5 to 24 of cycle, for 3–4 cycles
  • Postponement of menstruation: 5mg 3 times daily starting 3 days before expected onset (menstruation occurs 2–3 days after stopping)

Notes

  1. The norethisterone 5mg preparation is not licensed for HRT
Medroxyprogesterone acetate
  • Tablets 2.5mg, 5mg, 10mg, 100mg, 200mg, 400mg (£2.47 = 5mg x 10)

Indications and dose

  • Oral: 2.5–10mg daily for 5–10 days beginning on day 16 to 21 of cycle, repeated for 2 cycles in dysfunctional uterine bleeding and 3 cycles in secondary amenorrhoea
  • Oral: mild to moderate endometriosis, 10mg 3 times daily for 90 consecutive days, beginning on day 1 of cycle.
  • Doses used for the management of carcinoma are much higher – refer to specialist for guidance.
Utrogestan
(Micronised progesterone)
  • Vaginal capsule 200mg (£21.00 = 7 capsules with applicator)

Indication and dose:

  • Threatened miscarriage in women with a history of miscarriage (in line with NICE guideline NG126) (off-label):
    • Offer vaginal micronised progesterone 400mg twice daily to women with an intrauterine pregnancy confirmed by a scan, if they have vaginal bleeding and have previously had a miscarriage
    • If a fetal heartbeat is confirmed, continue progesterone until 16 completed weeks of pregnancy

Notes:

  1. First prescription (minimum 2 weeks supply) to be provided by the Early Pregnancy Unit. Prescribing may be continued in primary care until 16 completed weeks of pregnancy.
  2. Utrogestan vaginal 200mg capsules contain soya lecithin and may cause hypersensitivity reactions (urticarial and anaphylactic shock in hypersensitive patients). Patients with peanut or soya allergy should avoid using Utrogestan vaginal 200mg capsules. Specialists may prescribe an alternative vaginal progesterone for patients who should avoid using Utrogestan vaginal capsules.

Progesterone receptor modulators

Ulipristal acetate
  • Tablets 5mg

Indications

  • Up to 4 courses of intermittent treatment of moderate to severe symptoms of uterine fibroids in adult women who have not reached menopause when uterine fibroid embolisation and/or surgical treatment options are not suitable or have failed (see note 4)

Notes

  1. Please refer to section 7.3.5 Emergency Contraception for use of ulipristal acetate in emergency contraception
  2. Periodic monitoring of the endometrium including annual ultrasound is recommended
  3. The routine commissioning of ulipristal acetate 5mg tablets (Esmya®) is accepted in Devon for up to 4 courses of intermittent treatment of moderate to severe symptoms of uterine fibroids in adult women who have not reached menopause when uterine fibroid embolisation and/or surgical treatment options are not suitable or have failed (see Commissioning Policy for more details)
  4. MHRA Drug Safety Update (February 2021): Ulipristal acetate 5mg (Esmya): further restrictions due to risk of serious liver injury (see below):

Advice for healthcare professionals

  • Ulipristal acetate 5mg for uterine fibroids has been associated with cases of serious liver injury and liver failure (requiring transplantation in some cases); the licence was temporarily suspended in March 2020 to allow a further review of these risks
  • Although the temporary suspension has been lifted, the indication for ulipristal acetate 5mg has been further restricted – it should be used only for intermittent therapy of moderate to severe uterine fibroid symptoms before menopause and when surgical procedures (including uterine fibroid embolisation) are not suitable or failed
  • Ulipristal acetate 5mg should no longer be prescribed for controlling symptoms of uterine fibroids while waiting for surgical treatment
  • If ulipristal acetate 5mg is felt to be an appropriate therapy, talk about the risks and benefits with patients before prescribing so they can make an informed decision about treatment options; this conversation should include discussion of:
    • all available treatment options for moderate to severe symptoms of uterine fibroids, and the advantages and risks of these depending on personal situation
    • the potential risk of liver injury and liver failure with ulipristal acetate 5mg, which in rare cases has led to liver transplantation
    • signs and symptoms of liver injury and what to do if they occur
  • Continue to follow advice to monitor liver function according to the recommended schedule of liver function tests before, during, and after treatment courses. The prescriber is responsible for ensuring drug safety monitoring is undertaken

Reminder of liver function monitoring

  • Ulipristal acetate 5mg is contraindicated in patients with an underlying hepatic disorder.
  • Liver function tests must be performed before starting treatment with ulipristal acetate 5mg. Treatment must not be initiated if transaminases (alanine transaminase (ALT) or aspartate aminotransferase (AST)) exceed 2-times the upper limit of normal (ULN).
  • During treatment, liver function tests must be performed monthly during the first 2 treatment courses. For further treatment courses, liver function must be tested once before each new treatment course and when clinically indicated.
  • If a patient shows signs or symptoms compatible with liver injury (fatigue, asthenia, nausea, vomiting, right hypochondrial pain, anorexia, jaundice), treatment should be stopped, and the patient investigated immediately. Liver function tests should be performed urgently.
  • Stop treatment if transaminase levels (ALT or AST) are greater than 3-times the ULN and closely monitor patients. The need for specialist hepatology referral should be considered.
  • Liver function tests should also be performed 2–4 weeks after treatment has stopped

Advice to give to patients:

  • Infrequent but serious cases of liver damage (with some cases requiring a liver transplant) have been reported in association with ulipristal acetate 5mg for uterine fibroids
  • Ulipristal acetate 5mg can only be used for intermittent treatment of moderate to severe symptoms of uterine fibroids if:
    • you have not experienced menopause; and
    • an operation or embolisation procedure for uterine fibroids is not suitable for you or these procedures have not worked
  • Blood tests are needed before treatment is started, during treatment, and 2–4 weeks after treatment to check your liver is functioning normally
  • Stop taking your ulipristal acetate tablets and speak with your doctor immediately if you get any signs of liver damage such as yellowing of the skin or eyes, dark urine, or nausea or vomiting

 

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