Menopause and HRT (Guidelines)

Diagnosis of perimenopause or menopause should be based on the woman’s symptoms and age. Healthy women over 45 years with menopausal symptoms, may be diagnosed without laboratory tests (FSH) if:

• new onset vasomotor symptoms and changes in their menstrual cycle (perimenopause)
• they have not had any periods for at least 12 months and are not on hormonal contraception (postmenopause)
• menopausal symptoms in those without a uterus

FSH level over 30 units/L is diagnostic of ovarian decline. Fluctuations of FSH in perimenopause limit its value. FSH should not be done if taking combined oestrogen and progestogen contraception (CHC) or if on HRT. If FSH needs to be checked, stop CHC or HRT for at least 6 weeks.

Diagnosis of Premature Ovarian Insufficiency (POI) should be based on a combination of oligomenorrhoea / amenorrhoea of more than 4 months’ duration associated with elevated gonadotropins (FSH >40 unit/L) on at least two occasions measured 4 to 6 weeks apart in women under the age of 40. (Premature ovarian insufficiency - British Menopause Society (thebms.org.uk)

BMS Management Recommendations

There should be a holistic and individualised approach in assessing menopausal women, with particular reference to lifestyle advice, diet modification as well as discussion of the role of HRT.

The decision whether to take HRT, the dose of HRT used and the duration of its use should be made on an individualised basis after discussing the benefits and risks with each patient. This should be considered in the context of the overall benefits obtained from using HRT, including symptom control and improving quality of life, as well as considering the bone and cardiovascular benefits associated with HRT use. Women with POI and early menopause should be encouraged to use HRT at least until the average age of the menopause (51 years).

HRT prescribed before the age of 60 has a favourable benefit/ risk profile. Arbitrary limits should not be placed on the duration of usage of HRT; if symptoms persist, the benefits of hormone therapy usually outweigh the risks.

HRT may be appropriate for prevention of osteoporosis related fractures in women below the age of 60 years or within 10 years of menopause in symptomatic women or for the prevention of osteoporosis in women who are at higher risk.

HRT is 1st line treatment for menopause related mood disorders. There is no clear evidence that SSRIs or SNRIs ease low mood in menopausal women who have not been diagnosed with depression.

*52mg LNG-IUD

Mirena is licensed for the endometrial protection for use with oestrogen only HRT for 4 years. FSRH (2023) states that any 52mg LNG-IUD (Mirena, Levosert, Benelexa) may be used for 5 years for this indication.

Contraception

This may be stopped at age 55 years as spontaneous conception after this age is exceptionally rare even in women experiencing menstrual bleeding. If not on hormonal contraception, contraception may be stopped after 2 years of amenorrhoea if age 40 to 50, or after 1 year of amenorrhoea if age over 50 years. FSRH Clinical Guideline: Contraception for Women Aged over 40 Years (August 2017, amended July 2023) - Faculty of Sexual and Reproductive Healthcare.

POI

Women with Premature Ovarian Insufficiency (POI) can have intermittent ovarian activity and have a chance of natural conception estimated to be in the region of 5 to 10%. If pregnancy is not desired, contraception should be advised.

Oral or transdermal? 

Oral HRT is convenient and suitable for majority of healthy women who are below the age of 60 years. If there are any VTE, stroke or CVD risk factors, or woman wishes to continue HRT beyond age 60, transdermal HRT is the preferable option.

Contraindications

Seek menopause specialist advice

• Current, past, or suspected breast cancer or oestrogen sensitive cancer
• Undiagnosed abnormal vaginal bleeding
• Untreated endometrial hyperplasia
• Untreated hypertension
• Active liver disease with abnormal liver function tests

Caution 

Seek menopause specialist advice

• Active or recent arterial thromboembolic disease (for example angina or myocardial infarction): refer to specialist service
• History of stroke: refer to specialist service
• Current or past history of venous thromboembolism (deep vein thrombosis or pulmonary embolism): seek advice or refer to specialist service
• Migraines (transdermal preparation starting at low dose is advised with dose gradually increased to control symptoms).
  Sequential progestogen may worsen migraines.
  52mg LNG-IUD for endometrial protection with transdermal oestrogen may be a better option.

Duration of treatment 

No arbitrary limits should be placed on the dose or duration of usage of HRT as decisions should be made on an individualised basis after discussing the benefits and risks with each patient. In addition to the potential increased risks of breast cancer, they should also be considered in the context of the overall benefits obtained from using HRT, including symptom management and improved quality of life, as well as the cardiovascular and bone protective effects associated with HRT.

Venous thromboembolism (VTE)

• The risk of VTE is increased by oral HRT, particularly in the first year of use. Background risk is 1.7 per 1000 women aged over 50.
• The risk associated with standard transdermal HRT is no greater than baseline population risk.
• Consider transdermal HRT if woman has VTE risk factors including BMI greater than 30.
• If high risk of VTE, including family history, consider advice from, or referring to, specialist service.

Cardiovascular disease (CVD)

• HRT initiated before the age of 60 or within 10 years of the menopause is likely to be associated with a reduction in coronary heart disease and cardiovascular mortality.
• The risk of coronary heart disease and stroke for women around menopause varies according to their own risk factors.
• The presence of CVD risk factors is not a contraindication to HRT if they are optimally managed.
• The risk of stroke is age related and overall the risk is low in women under the age of 60.
  Oral estradiol is likely to be associated with a small increase in the risk of stroke. This effect is likely to be dose and duration related and the lowest effective dose should therefore be prescribed. 
  Low or standard dose transdermal estradiol is unlikely to increase the risk of stroke above the woman’s own baseline risk. Consideration should therefore be given to administering estradiol transdermally in women with risk factors or those over the age of 60.

Breast cancer 

Lifestyle risk factors to discuss with patients: click here

• Vaginal oestrogen is not associated with an increase risk.
• Oestrogen-only HRT is associated with little or no increased risk of breast cancer.
• In women over the age of 50, combined HRT can be associated with an increased risk of breast cancer after 5 years use, but this is less than other lifestyle risk factors for breast cancer (eg obesity, alcohol intake). Any increase in risk reduces after stopping.
• Mortality is not increased.

Ovarian Cancer 

• HRT use may be associated with a small increased risk of ovarian cancer with both oestrogen only and combined HRT but the risk falls after cessation of HRT.

Diabetes 

• HRT has been shown to decrease incidence of risk of developing type 2 diabetes as well as improving glycaemic control.
• Consider HRT for the same indications as a non diabetic woman.
• Seek specialist advice if co-morbidities

Cervical cancer 

• There is no association between cervical cancer & HRT

Endometrial cancer 

• Continuous combined HRT does not increase risk. Sequential combined HRT may slightly increase the risk of endometrial cancer, and that risk may be greater with: longer duration of use; fewer days of progestogen per cycle: increased dosage of oestrogen
• In women with a uterus, use of unopposed oestrogen is associated with an increase risk of endometrial hyperplasia and endometrial cancer.

Risk is increased with:

• BMI ≥ 40
• Genetic predisposition to endometrial cancer (Lynch / Cowden Syndrome)
• Oestrogen-only HRT for >6 months in women with a uterus (including expired 52mg LNG-IUD)
• Tricycling HRT (quarterly progestogen course) for more than 6 months
• Prolonged sequential HRT regimes use for more than 5 years in women aged >50
• Reduced length of progestogen per month as part of a sequential regime. NET/MPA for <10 days or MP for <12 days for more than 6 months
• Oestrogen dose where the progestogen is not in proportion for > 12 months

Colorectal cancer

• Data suggests a reduced risk of colorectal cancer with use of combined HRT.

Check compliance 

• Are patches sticking or being changed at correct interval?
• Is gel applied correctly and allowed to dry for 5 minutes?
• Are pills or patches taken in the appropriate order for sequential regime?
• Any drug interactions or mal-absorption issues?

Consider if symptoms are due to other causes

• Symptoms may be worse with obesity, smoking, alcohol intake, stress, thyroid issues or nutritional deficiency (Eg low iron).
• Consider if symptoms are due to excessive oestrogen dose or progestogenic side effects.

If symptoms are due to oestrogen insufficiency 

• Consider changing delivery route: transdermal may give better symptom control.
• Increase dose of HRT (to no more than the licensed maximum dose of oestrogen), ensuring that the dose of progestogen is appropriate for the dose of oestrogen.

Routine testing of serum oestrogen levels

is unnecessary and is associated with additional costs both to NHS and patients in private clinics. Serum estradiol levels is influenced by many factors, including the timing of the dose, the type of assay and cannot be assumed to be indicative of levels over a 24-hour period. There is no recommended systemic level of oestrogen in association with the use of HRT and the response to treatment should be based on symptom control.

Unopposed Oestrogen (eg, none or inadequate progestogen for the dose of oestrogen in women who have a uterus) increases the risk of endometrial hyperplasia, which can increase the risk of endometrial cancer. ‘The dose of the progestogen should be proportionate to the dose of oestrogen. Women who require high dose oestrogen intake should consider having their progestogen dose increased to ensure adequate endometrial protection.’ (BMS 2022 Recommendation, see: click Progestogens and endometrial protection)

Prescribing combined preparations or using a 52mg LNG-IUD (rather than separate oestrogen & oral progestogen) will minimise the risk of poor compliance of progestogens or overuse of oestrogen

Licenced oestrogen dose for specific preparations

*Off-license use
**Off-license and rarely required to achieve symptom control

Progestogen dose per licensed oestrogen dose in the baseline population

If unscheduled bleeding occurs with low to moderate dose oestrogen, and other preparations which manage bleeding are not acceptable, offer micronised progesterone (MP) at dosage used for high dose oestrogen.

*1mg NOR provides endometrial protection for low and standard dose oestrogen but the lowest dose stand-alone preparation in the UK is 5mg.
**There is no evidence in relation to optimal MPA dose with high dose oestrogen; until evidence is available to guide practice, the advised dose is based on studies reporting 100mg providing protection with up to moderate dose oestrogen

May occur in the 1st 3 to 6 months of starting HRT or on changing preparations. The risk of endometrial cancer in women on HRT is extremely low (<1%) with postmenopausal women on continuous progestogens having a lower risk of endometrial cancer than in postmenopausal women not taking HRT.

Consider causes of unscheduled bleeding on HRT:

Compliance, drug interactions, GI or other absorption problems, STI and (rarely) pregnancy, pelvic pathology (patient needs to be examined).

Perimenopausal women have higher rates of unscheduled bleeding and proliferation on biopsy, than postmenopausal women.

An oral preparation (in women who have no risk factors for thrombosis), could be offered as a first-line therapy, or to those in whom their initial preference was for transdermal but have unscheduled bleeding episodes despite adjustments.

HRT combinations containing androgenic progestogens (NET or MPA) have a better bleeding profile than those with non-androgenic progestogens (dydrogresterone, MP).

Consider 52mg LNG-IUD, which will provide bleeding control & reduce risk of endometrial hyperplasia

For when to refer to Gynaecology for Unscheduled Bleeding on HRT

• TAM guideline: Unscheduled bleeding on HRT
• See: BMS guidance 

For postmenopausal bleeding, refer to Gynaecology PMB Clinic (via SCI Gateway) as per: Post-menopausal bleeding and endometrial cancer (Guidelines) | Right Decisions (scot.nhs.uk)

Hormone replacement therapy (HRT) is established as the most effective treatment for menopausal vasomotor symptoms and is thus recommended as the first-line choice for women requiring pharmacological management. However, alternatives may need to be considered for women with contraindications or do not wish to take HRT. NICE advise that women with or at high risk of breast cancer should be offered information on all available treatment options.

Lifestyle measures 

• Evidence suggests that regular sustained aerobic exercise such as swimming or running improve several common menopause-related symptoms (infrequent, high-impact exercise should be avoided as it can make symptoms worse)
• Avoidance or reduction of alcohol and caffeine intake may help to reduce the severity and frequency of vasomotor symptoms

Cognitive behavioural therapy (CBT) 

https://www.womens-health-concern.org/help-and-advice/factsheets/cognitive-behaviour-therapy-cbt-menopausal-symptoms/

• Recommended treatment option for anxiety experienced during the peri and post-menopause and can improve hot flush perception and reduce stress and sleep problems.

Non hormonal prescribed treatments

NICE Guidelines (2015): recommend that women should not routinely be offered antidepressants as first-line treatment for vasomotor symptoms alone. SSRIs should not be offered for vasomotor symptoms unless HRT cannot be given.

British Menopause Soc: https://thebms.org.uk/wp-content/uploads/2020/07/02-BMS-TfC-Prescribable-alternatives-to-HRT-July2020-01B.pdf

• Selective Serotonin Re-uptake Inhibitors (SSRI) [fluoxetine, paroxetine, citalopram, sertraline] and the Serotonin Noradrenaline Re-uptake Inhibitor/Selective Serotonin Re-uptake Inhibitors (SSRI-SNRI) [venlafaxine]: can have associated significant side effects, such as dry mouth, nausea, constipation and appetite problems, and reduction in libido.
• Those women taking tamoxifen should not take fluoxetine or paroxetine, as it makes the tamoxifen ineffective.
• Venlafaxine is the preferred treatment for breast cancer survivors taking tamoxifen and at 75mg there can be reduction in hot flushes with improvement in fatigue, mental health and sleep disturbance.
• Clonidine: the only non-hormonal drug licensed for use for hot flushes in the UK. NICE Menopause Guidelines recommend women should not routinely be offered clonidine as first-line treatment for vasomotor symptoms alone. Although evidence indicates efficacy in reducing hot flushes, the side effects of clonidine (e.g. hypotension, sedation, dry mouth, dizziness) limit its clinical use
• Gamma aminobutyric acid (gabapentin): can improve flushes and sweats. Improves sleep, but others find it very sedating in the day as well (unlicensed)

Herbal treatments

• There is limited evidence that herbal remedies may relieve vasomotor symptoms. Explain to women who wish to try complementary therapies that the quality, purity and constituents of products may be unknown. Also, they may have significant drug interactions and unknown risks regarding safety.
• St John’s Wort: Although there is some evidence that St John's wort may be of benefit in the relief of vasomotor symptoms in women with a history of, or at high risk of, breast cancer, there is uncertainty about:
  • appropriate doses
  • persistence of effect
  • variation in the nature and potency of preparations
  • serious interactions with other drugs (including tamoxifen (makes it less effective), anticoagulants and anticonvulsants).

Isoflavones and soya products 

• There are very many studies looking at the effectiveness of these food substances, but the results are variable and generally show little value. They are not recommended in patients with breast cancer.

Acupuncture

• Studies show a very high placebo effect

Clinical advice may be sought from the Menopause Clinic (at Highland Sexual Health) via Clinical Dialogue.

Refer via SCI Gateway to Menopause Clinic, Highland Sexual Health:

• Complex medical history
• Safety concerns of HRT
• Uncertainty about most suitable treatment option
• Ongoing symptoms despite treatment
• Persistent troublesome adverse effects
• History of hormone dependent cancer and patients with BRCA gene
• Confirmed diagnosis of Premature Ovarian Insufficiency requiring optimisation of management.
• Patient Request