Menopause and Perimenopause

Definition/diagnostic criteria

• Menopause is diagnosed clinically after 12 months of amenorrhoea.
• Perimenopause is characterised by irregular cycles and menstruation before the onset of menopause.
• Post-menopause is the time after there has been no menstrual period for 12 months.
• Early menopause is the cessation of ovarian function between 40-45 years.
• Premature menopause is loss of ovarian function before 40 years.

Epidemiology Women are on average postmenopausal for more than a third of their lives. Menopausal symptoms are extremely common but are likely to be under-recognised and under-treated. A number of factors, including ethnicity, cultural, religious and sociological background, and nutrition, may impact the intensity, duration and incidence. Around 80-90% will have symptoms, with 25% describing them as severe. In the UK, the mean age of natural menopause is 51 years. Symptoms typically last 5-7 years, with some having symptoms for 10-15 years.

Diagnosis
Clinical features: The wide spectrum of symptoms include: a change to the menstrual pattern (the cycle interval may shorten or increase and blood loss typically increases); vasomotor symptoms (hot flushes, night sweats); cognitive impairment; mood disorders; urogenital symptoms (e.g., vulvovaginal irritation, dyspareunia, dysuria, urinary frequency and urgency, and recurrent lower urinary tract infections); reduced libido; sleep disturbance; joint and muscle pains; headaches (including worsening migraine); fatigue.

Investigations: Do not routinely use follicle-stimulating hormone (FSH) to diagnose perimenopause or menopause in women not using hormonal contraception aged over 45 years with typical menopausal symptoms. Diagnose the following without laboratory testing:

• Perimenopause in those with vasomotor symptoms and irregular periods
• Menopause in those with amenorrhoea for at least 12 months who are not using hormonal contraception
• Menopause based on symptoms in someone without a uterus.

Consider using FSH to diagnose menopause in women not using combined hormonal contraception/hormone replacement therapy/high-dose progestogen and aged:

• >45 years with atypical symptoms.
• 40–45 years with menopausal symptoms, including a change in menstrual cycle.
• <40 years with a suspected diagnosis of premature ovarian insufficiency.
• >50 years and using progestogen-only contraception, including the depo injection.

Treatment Treatment is multifaceted and will depend upon a woman’s comorbidities, family history, personal preferences, medications, symptoms and goals.

Lifestyle advice
Discuss, where relevant: regular exercise; weight loss; measures to help hot flushes (e.g., fans, lighter clothing); stress reduction; relaxation exercises; avoiding triggers, (spicy foods, caffeine, smoking and alcohol); sleep hygiene; national screening programme engagement (cervical, bowel and breast).

Contraception
A woman is potentially fertile for 2 years after her last menstrual period (LMP) if she is under 50 years of age and for 1 year if she is over 50. All women can stop contraception at 55 years. Hormone-replacement therapy (HRT) does not provide contraception. All progestogen-only methods of contraception are safe to use alongside cyclical HRT. Combined hormonal contraception can be used in eligible women under 50 years as an alternative to HRT for relief of menopausal symptoms and prevention of loss of bone mineral density.

Women should be advised to switch to a progestogen-only method of contraception at 50 years of age, if needed. Women over 50 years should be counselled regarding switching to alternative methods if using the depo injection. For those using the implant, progesterone-only pill or levonorgestrel intra-uterine system (IUS), if a woman >50 years with amenorrhoea wishes to stop before 55 years, check FSH. If FSH is >30 IU/L these contraception methods can be stopped after 1 more year of use. If FSH is in the premenopausal level, then the method should be continued and FSH rechecked 1 year later.

• Vasomotor symptoms: Offer HRT after discussing the risks and benefits. Do not routinely offer selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs) or clonidine as first-line treatment. Complementary therapies, e.g., isoflavones or black cohosh, may help, but their safety is uncertain. Avoid unregulated compounded bioidentical hormones.
• Psychological symptoms: Consider HRT or cognitive behavioural therapy (CBT). There is no clear evidence for SSRIs or SNRIs if not diagnosed with depression.
• Low libido: Consider seeking advice about testosterone supplementation if HRT alone is not effective.
• Urogenital symptoms: Offer vaginal oestrogen, moisturisers and/or lubricants.

HRT
Offer a choice of HRT based on age, symptoms and co-morbidities, aiming to prescribe the lowest dose for the shortest duration. HRT can be administered locally (vaginal) or systemically (oral or transdermal – e.g., patch, spray or gel).

Vaginal HRT: This can be used for as long as needed to relieve symptoms but regular attempts to stop treatment, such as annually, can be made. Options include creams (Gynest, Ovestin), vaginal tablets (Vagifem 10, Vagirux 10), vaginal ring (Estring), vaginal pessary (Imvaggis), and vaginal gel (Blissel). Symptoms often come back when treatment is stopped. Adverse effects are very rare. Unscheduled vaginal bleeding should be reported. There is no requirement for routine monitoring of endometrial thickness and no need for endometrial protection with progestogen. It can be used concurrently with systemic HRT. Vaginal moisturisers and lubricants can be used safely as well (e.g., Yes, Sylk, Regelle, Hyalofemme, Replens MD).

Systemic HRT: Oestrogen forms part of all systemic HRT regimens. Progesterone is needed if the uterus or any endometrial tissue is present to avoid endometrial hyperplasia, e.g., subtotal hysterectomy, endometriosis. Decide if the HRT regimen should be sequential or continuous, i.e., is the progesterone component going to be given intermittently cycling or continuously. This will depend upon if the patient is perimenopausal where the endometrium is more unstable (likely when the LMP is <12 months ago or there is regular bleeding ongoing) or post-menopausal where the endometrium is stable (more likely when the LMP is >12 months ago, the patient is aged >54, or is amenorrhoeic from contraception, e.g., progesterone only injection/implant/pill).

Continuous combined HRT: Can be used at any age, but it may cause erratic bleeding if given before a woman is post-menopausal (i.e., there is unstable endometrium present) and trigger the need for investigation, e.g., ultrasound for endometrial thickness review. If HRT was initiated in the perimenopause, consider switching from a sequential to continuous combined regimen after a minimum one year of sequential HRT use, or at least by the age of 54. This minimises the endometrial hyperplasia risk and also avoids monthly withdrawal bleeds. However, continuous combined HRT is associated with a slightly greater risk of breast cancer. Aim to do the switch when you might reasonably expect the periods to have ceased in relation to the woman’s age and cycle frequency prior to starting HRT, e.g., in a 51-year-old having a period every 3-4 months, you might give sequential HRT for a year then trial a switch to continuous combined HRT; in a 46-year-old with regular monthly periods and vasomotor symptoms, you may use sequential HRT for 4-5 years before considering switching. If unscheduled bleeding occurs, try switching back to sequential for another year.

Tibolone: a synthetic steroidal compound with oestrogenic, progestogenic and androgenic activity. It is licensed for the short-term treatment of oestrogen deficiency symptoms in postmenopausal women (>1 year post last period) and osteoporosis prophylaxis. This is a no bleed preparation taken as a daily tablet. However, tibolone is associated with increased risk of endometrial cancer, breast cancer and stroke in women older than 60 years of age. Indications for use may include patients with low libido or those with a history of endometriosis (if given oestrogen replacement therapy, they may experience stimulation of deposits).

Oestrogen: This can be prescribed transdermally via gels (e.g., Oestrogel, Sandrena), patches (e.g., Evorel, Estradot, Elleste) or spray (Lenzetto); or oral formulations that are oestrogen only (e.g., Elleste Solo, Premarin) or combined with progesterone sequentially (e.g., Elleste Duet, Femoston 1/10) or in continuous combined form (e.g., Elleste Duet Conti, Femoston Conti). The risk of VTE is greater for oral than transdermal preparations. If oral preparations are preferred, the safest in terms of clot and breast cancer risk contain dydrogesterone (Femoston range).

Transdermal preparations may be appropriate for issues with oral preparations: side-effects; absorption issues; a history or increased risk of venous thromboembolism (VTE); cardiovascular risk factors ( obesity, uncontrolled hypertension); concomitant hepatic enzyme-inducing drugs ( carbamazepine); migraine or gallbladder disease; and lactose sensitivity.

Progesterone: This should be included in the HRT regimen if the uterus or any endometrial tissue is present to avoid endometrial hyperplasia. It can be delivered orally (combined with oestrogen sequentially e.g. e.g. Elleste Duet, Femoston 1/10 or in continuous combined form e.g. Elleste Duet Conti, Femoston Conti); separate progesterone tablets (e.g. Utrogestan available as 200mg orally each evening for 2 out of 4 weeks in sequential HRT or 100mg each evening in continuous HRT); via a patch (sequentially, e.g., Evorel Sequi; continuous combined form, e.g.,Evorel Conti); or as a 52mcg levonorgestrel IUS (can be used for 5 years for endometrial protection).

Risks of HRT:
The risk of VTE is greater for oral than transdermal preparations.

The baseline risk of CHD and stroke for women around menopausal age varies from one woman to another, depending on the presence of cardiovascular risk factors. HRT with oestrogen alone is associated with no, or reduced, risk of CHD. Combined HRT with oestrogen and progestogen is associated with little or no increase in the risk of CHD. The baseline risk of stroke in women younger than 60 years is very low. Oral (not transdermal) oestrogen is associated with a small increase in the risk of stroke. HRT does not increase cardiovascular risk when started in women younger than 60 years and does not affect the risk of dying.

The baseline risk of breast cancer for women around menopausal age in the UK varies from one woman to another. HRT with oestrogen alone is associated with little or no increase in the risk of breast cancer. Combined HRT with oestrogen and progestogen is associated with an increased risk of breast cancer that is dependent on duration of treatment, which reduces after stopping HRT. HRT does not affect the risk of dying from breast cancer.

This risk of endometrial cancer increases if oestrogen-only HRT is given when the uterus/ endometrial deposits are present. This is reduced by adding progestogen. Continuous progesterone provides better long-term protection versus cyclical.

The likelihood of HRT affecting the risk of dementia is unknown.

Benefits of HRT:
The baseline risk of fragility fracture for women around menopausal age in the UK is low and varies between women. The risk is decreased while taking HRT, and this benefit is maintained during treatment but decreases once treatment stops; this benefit may continue for longer in women who take HRT for longer. There is limited evidence that HRT may improve muscle mass and strength.

HRT contraindications and cautions:
Do not prescribe HRT in those with: current, past, or suspected breast cancer; known or suspected oestrogen-dependent cancer; undiagnosed vaginal bleeding; untreated endometrial hyperplasia; current or past venous thromboembolism; active or recent arterial thromboembolic disease (e.g., angina or MI); active liver disease with abnormal liver function tests; pregnancy; thrombophilic disorders; porphyria cutanea tarda.

Prescribe HRT with caution in women with diabetes mellitus (increased risk of heart disease), factors predisposing to venous thromboembolism, history of endometrial hyperplasia, migraine, increased risk of breast cancer.

Managing co-morbidities and HRT:

• Breast cancer risk or disease: Stop HRT in those diagnosed with breast cancer. Do not offer HRT in those with a history of breast cancer. Refer for specialist advice if a woman wishes to consider the use of hormonal therapy, including vaginal oestrogen. Advise on lifestyle measures, non-hormonal, and non-drug treatment options. Women taking tamoxifen should not use fluoxetine or paroxetine, as they may inhibit the effect of tamoxifen. Do not recommend complementary therapies – e.g., isoflavones, red clover, black cohosh, St John’s wort – due to safety issues.
• VTE: Consider the use of transdermal rather than oral HRT for women at increased risk of VTE, including women with a BMI over 30kg/m². Before giving HRT, consider referring women at high risk of VTE (e.g., strong family history of VTE or a hereditary thrombophilia) to a haematologist for assessment.
• CVD: Manage any CV risk factors before considering the use of HRT. The presence of CV risk factors is not a contraindication to taking HRT as long as they are optimally managed. Consider transdermal HRT for women at increased risk.
• Diabetes: Consider HRT after taking other co-morbidities into account. HRT is not associated with an adverse effect on blood glucose control.
• Hypothyroidism: Check the thyroid-stimulating hormone (TSH) 6–12 weeks after starting or stopping oral HRT, to ensure that levels remain in the acceptable range.
• Migraine: Fluctuating oestrogen with vasomotor symptoms in menopause can increase the frequency of migraine. Migraine with aura does not contraindicate HRT but avoid oral oestrogen. Use the lowest effective dose of transdermal oestrogen. Where progestogen is required, continuous delivery is recommended, e.g., a levonorgestrel IUS. Consider non-HRT options for vasomotor symptoms, e.g., venlafaxine.
• Endometriosis: Those who have had a hysterectomy can usually take oestrogen-only HRT if the surgeon is confident that all tissue has been removed: check with the specialist if needed.

HRT adverse effects:
These may include: oestrogen-related adverse effects (e.g., fluid retention, bloating, breast tenderness, nausea, headaches, leg cramps); progestogen-related adverse effects (e.g., fluid retention, breast tenderness, headaches, mood swings, premenstrual syndrome-like symptoms, depression, acne vulgaris, lower abdominal pain); and vaginal bleeding problems.

Unscheduled vaginal bleeding is a common adverse effect of HRT within the first 3 months of treatment. Monthly cyclical regimens should produce regular withdrawal bleeding towards the end of the progestogen phase. Continuous combined HRT commonly produces irregular bleeding in the first 4–6 months of treatment. If bleeding persists beyond 6 months, becomes heavier, or occurs after a spell of amenorrhoea, endometrial pathology should be excluded.

Consider other causes like pregnancy, sexually transmitted infections, cervical pathology (check for symptoms like postcoital bleeding, consider cervical examination, and review cervical screening history), non-adherence with treatment, drug interactions or absorption issues.

HRT review:
Review after 3 months if HRT has been started or changed, then at least annually thereafter, unless there are clinical indications for an earlier review. Assess for adverse effects or persistent symptoms, and offer to adjust the HRT dose or preparation if appropriate. Options include oestrogen dose change, changing the dose or type of progestogen, and changing route of administration. Review the duration of HRT treatment and if started in the perimenopause, discuss changing to preparations better suited for postmenopausal women.

HRT should be continued for as long as benefits of symptom control and improved quality of life outweigh any risks: there is no arbitrary limit for duration of HRT use. When stopping it may be reduced gradually or stopped suddenly, depending on the woman’s preferences. Gradual reduction may limit recurrence of symptoms in the short-term, but makes no difference to symptoms in the longer term.

Non-hormonal options
For vasomotor symptoms, consider a trial of SSRIs (off-label) or SNRIs (off-label) for 2 weeks initially, e.g., fluoxetine (20mg daily), citalopram (20mg daily), paroxetine (10mg daily), or venlafaxine modified-release (37.5mg daily for 1 week then increased to 75mg once daily if needed), clonidine initially 50mcg twice daily for 2 weeks, then increased to 75mcg twice daily, if needed; gabapentin (off-label) titrated up to 300mg three times a day; or CBT.

• Mood disorders: Consider self-help resources and a trial of CBT.
• Urogenital symptoms: Consider a trial of vaginal moisturizers or lubricants.

Complementary therapies have some evidence (e.g., isoflavones, black cohosh) but safety is unknown.

Referral Consider referral for those with:

• Ongoing symptoms when lifestyle measures, hormonal, non-hormonal or drug-treatments are ineffective.
• Adverse treatment effects.
• Uncertainty about optimal management options, e.g., in those with comorbidities or contraindications.
• For advice about the use of testosterone (off-label) in those with persistent altered sexual function despite HRT treatment.
• Diagnostic uncertainty.
• Red flags symptoms, e.g., a sudden change in menstrual pattern, intermenstrual bleeding, postcoital bleeding, or postmenopausal bleeding warrant an urgent 2-week referral for suspected gynaecological cancer.

Prognosis Postmenopausal women are at increased risk of osteoporosis and fracture, CVD, stroke and genitourinary syndrome of menopause. Premature or early menopause may be associated with an increased risk of all-cause mortality, CVD, Type 2 diabetes, depression, osteoporosis and fracture.

Written by Dr Nazia Hussain,  a GP with a special interest in women’s health