6.4.1 Female sex hormones and their modulators

Further guidance supporting the prescribing of HRT preparations and the clinical management of menopause: Guidance on the management of menopause.

6.4.1.1 Oestrogens and HRT

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 in section 7.2.1 Preparations for vaginal and vulval changes.

Conjugated oestrogens (equine)

Premarin®
  • Tablets conjugated oestrogens (300 micrograms, 625 micrograms, 1.25mg) (£2.02, £1.34, £1.19)

Dose and indication

  • 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

Estradiol

Elleste solo®
  • Tablets estradiol (1mg, 2mg) (£1.69)

Dose and indication

  • 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.
Evorel®
  • Patches estradiol (25micrograms, 50 micrograms, 75 micrograms, 100 micrograms) (£4.12 = 75 micrograms)

Indications

  • Menopausal symptoms and 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
  • 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

Ethinylestradiol

Ethinylestradiol
  • Tablets 2 micrograms, 10 micrograms, 50 micrograms, 1mg (£200.00 = 1mg x 28)

Oestrogen with progestogen

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®
  • Low dose tablets conjugated oestrogen (300 micrograms and medroxyprogesterone acetate 1.5mg) (£2.17)

Indications

  • Menopausal symptoms

Dose

  • 1 tablet daily, continuously

Notes

  1. Premique® contains medroxyprogesterone and is less androgenic.
  2. Animal source of oestrogen.

Estradiol with norethisterone

Kliofem®
  • Tablets estradiol (2mg) and norethisterone acetate (1mg) (£3.81)

Indications

  • Menopausal symptoms and 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
Kliovance®
  • Tablets estradiol valerate (1mg) and norethisterone (500microgram) (£4.40)

Indications

  • Menopausal symptoms and 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. Kliovance® has a lower norethisterone content.
Evorel® Conti
  • Patches estradiol (50 micrograms) and noresthisterone (170 micrograms) (£13.00)

Indications

  • Menopausal symptoms and osteoporosis prophylaxis

Dose

  • 1 patch to be applied twice weekly continuously

Estradiol with dydrogesterone

Femoston Conti®
  • Tablets estradiol valerate (0.5mg) and dydrogesterone (2.5mg) (£8.14)
  • Tablets estradiol valerate (1mg) and dydrogesterone (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. Femoston Conti® is less androgenic.
  2. 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®
  • Tablets estradiol (1mg, 2mg) with norethisterone acetate (1mg) (£3.07)

Indications

  • Menopausal symptoms
  • Menopausal symptoms and 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 norersthisterone) daily for 12 days; subsequent courses are repeated without interval

Notes

  1. There are two prescription charges for Elleste Duet®
Evorel® Sequi
  • Patches estradiol (50 micrograms) and norethisterone acetate (170 micrograms) (£11.09)

Indications

  • Menopausal symptoms and osteoporosis prophylaxis

Dose

  • One Evorel® 50 patch to be applied twice weekly for 2 weeks, starting within 5 days of onset of menstruation (or at any time if cycles have ceased or are infrequent), followed by one Evorel® Conti patch twice weekly for 2 weeks; subsequent courses are repeated without interval

Notes

  1. There are two prescription charges for Evorel Sequi®

Estradiol with dydrogesterone

Femoston®
  • Tablets estradiol (1mg, 2mg) with dydrogesterone (10mg) (£5.39)

Indications

  • Menopausal symptoms and 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. Femoston® is included as a less androgenic alternative allowing dose titration.
  2. Femoston® products are included for patients experiencing progestogenic side effects with the first line agents.
  3. There are two prescription charges for Femoston®

Selective oestrogen receptor modulators

Raloxifene
  • Tablets 60mg (£3.62)

Indications

  • Treatment and secondary prevention of postmenopausal osteoporosis

Dose

  • 60mg once daily

Notes

  1. Raloxifene® does not reduce menopausal vasomotor symptoms.
  2. Women taking raloxifene are at increased risk of thromboembolism.
  3. Do not offer raloxidene to women who were at high risk of breast cancer but have had a bilateral mastectomy. NICE CG164 (June 2013)
  4. NICE TA160: Raloxifene is not recommended as a treatment option for the primary prevention of osteoporotic fragility fractures in postmenopausal women (February 2018)
  5. NICE TA161: Raloxifene is recommended as an alternative treatment option for the secondary prevention of osteoporotic fragility fractures in postmenopausal women (February 2018)

Noretynodrel derivatives

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.

6.4.1.2 Progestogens and progesterone receptor modulators

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.

Progestogens have been used for the prevention of miscarriage in women with a history of recurrent miscarriage but there is no evidence of benefit and they are not recommended for this purpose.

Medroxyprogesterone acetate

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, menorrhagia, 5mg 3 times daily for 10 days to arrest bleeding; to prevent bleeding 5mg twice daily from day 19 to 26
  • Dysmenorrhoea, 5mg 3 times daily from day 5 to 24 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
Progesterone
  • Vaginal gel 90mg (8%) / application (£30.83 = 15)
  • Pessaries 200mg, 400mg (£8.95, £12.96 = 15 pessaries)
  • Injection 50mg in1ml, 100mg in 2ml (£4.50 per ampoule)

Notes

  1. Progesterones have been used for the prevention of spontaneous abortion in women with a history of recurrent miscarriage (habitual abortion) but there is no evidence of benefit and they are not recommended for this purpose.
Hydroxyprogesterone caproate
  • Injection 250mg/ml (unlicensed preparation)

Progesterone receptor modulators

Ulipristal acetate
  • Tablets 5mg (£114.13)

Indications

  • Pre-operative treatment of moderate to severe symptoms of uterine fibroids
  • Intermittent treatment of moderate to severe symptoms of uterine fibroids (up to four courses), in line with NICE CG44 (see commissioning policy for more information, please also see notes below).

Dose

  • 5mg daily for up to 3 months (maximum) starting during the first week of cycle
  • Re-treatment courses should start at the earliest during the first week of the second menstruation following the previous treatment course completion. Treatment courses should each not exceed 3 months.

Notes

  1. MHRA New Temporary Safety Measures (March 2018): Esmya (ulipristal acetate) for uterine fibroids: monitor liver function in current and recent users; do not initiate treatment in new users or those between treatment courses
    1. Do not initiate new treatment courses of ulipristal acetate, including in women who have completed one or more treatment courses previously
    2. Perform liver function tests at least once a month in all women currently taking ulipristal acetate. Liver function tests should be repeated in all women 2 to 4 weeks after stopping treatment.
    3. Check transaminase levels immediately in current or recent users of ulipristal acetate who present with signs or symptoms suggestive of liver injury (such as nausea, vomiting, malaise, right hypochondrial pain, anorexia, asthenia, jaundice). If transaminase levels are more than 2 times the upper limit of normal, stop treatment, closely monitor and refer for specialist hepatology evaluation as clinically indicated.
    4. Advise women using ulipristal acetate about the signs and symptoms of liver injury and tell them to seek immediate medical attention if they occur.
  2. In the case of repeated intermittent treatment, each 12 week course should be initiated by the consultant, who should prescribe the first 28 days' supply. GPs may then be asked to prescribe the remaining 56 days' supply
  3. Periodic monitoring of the endometrium with annual ultrasound (performed after resumption of menstruation during off-treatment period) is recommended with repeated intermittent treatment with UPA 5mg (Esmya SPC). Specialists will be responsible for requesting transvaginal ultrasound if clinically indicated, and acting on the results
  4. Repeated intermittent treatment has been studied up to 4 intermittent courses; the efficacy, safety and cost-effectiveness of more than 4 courses are uncertain
  5. If symptoms return after 4 intermittent courses, the patient should be referred back to a specialist for further consideration of treatment options.

 

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