Diagnosis of the menopause: NICE guidance and quality standards

New NICE Quality Standards on Menopause were published in February 2017, ¹ based on NICE guidance on ‘Menopause: diagnosis and management’; ² this editorial summarizes the aspects of relevance to clinical biochemistry laboratories.

Women in the UK typically experience menopause at the age of 51, though there is wide variation. ³ ‘Menopause’ refers specifically to the last menstrual period, which can only be confirmed in retrospect, and the ‘perimenopause’ (also termed the menopausal transition or climacteric) refers to the time in which many women have irregular menstrual cycles before menopause through to a year after the last period. Most women (8 out of 10) experience vasomotor symptoms (hot flushes and night sweats) but symptoms may include mood changes, lack of concentration and memory loss, joint and muscle stiffness, headaches, vaginal dryness and loss of libido. Symptomatic women frequently consult their GPs for advice and treatment.

Menopause is usually a clinical diagnosis. This is emphasized by the first NICE Quality Statement: ‘Women over 45 years presenting with menopausal symptoms are diagnosed with perimenopause or menopause based on their symptoms alone, without confirmatory laboratory tests’. In developing the NICE guideline, a systematic review was carried out to assess the diagnostic accuracy of clinical indicators (age and menopausal symptoms), ultrasound parameters (ovarian volume, total antral follicle count) and biochemical tests (specifically follicle-stimulating hormone [FSH], anti-Muüllerian hormone [AMH], oestrogen, inhibin A, inhibin B). These indices were considered either individually or in combination. Twenty-one studies were identified as meeting the protocol, of which four looked at the diagnostic accuracy of biochemical measurements.^4–7 No single parameter, even hot flushes, was found to be useful in isolation, although algorithms combining menstrual history, surgical history, age, FSH and oestradiol concentrations did achieve correct classification of women with/without diagnosis of menopause. The reviewed evidence did not give the guideline development group confidence to recommend biochemical tests or ultrasound in diagnosis of menopause, as the results did not provide robust evidence for their routine use.

In conclusion, the NICE guideline recommends that diagnosis is made without laboratory tests in otherwise healthy women aged over 45 years with menopausal symptoms:

perimenopause based on vasomotor symptoms and irregular periods;

menopause in women who have not had a period for at least 12 months (who are not using hormonal contraception);

menopause based on symptoms in women who have undergone hysterectomy.

FSH was considered unreliable as a diagnostic test, because FSH concentrations fluctuate considerably over short time periods in the perimenopause. ⁸ Moreover, FSH concentrations are affected by hormonal treatment and by hormonal contraception, both of which are commonly prescribed; some hormonal contraceptives may also cause menstrual irregularity and amenorrhoea, making diagnosis of menopause difficult. FSH should not be measured in women using combined oestrogen and progestogen contraception (the combined Pill) or high-dose progestogen. NICE recommends that FSH measurement should be considered to diagnose menopause only in women aged 40–45 with menopausal symptoms, including a change in their menstrual cycle, and in women aged under 40 in whom menopause is suspected (see below). In women aged over 45, anti-Müllerian hormone, inhibin A and B, and oestradiol measurements should not be used.

Accurate diagnosis leads to improved management and outcomes; however, inappropriate diagnostic tests may be wasteful of resources. Health economic analysis is an essential aspect of the NICE process, and reducing unnecessary FSH tests has been highlighted as a key area for implementation. ² The UK National External Quality Assessment Service (UK NEQAS) and Lab Tests Online UK are involved in raising awareness of the new NICE guidance. At local level, laboratory staff and managers should consider auditing the number of FSH tests undertaken by age and clinical indication. Clinical biochemistry laboratories should encourage GPs to stop requesting FSH tests for women aged over 45 years by drawing attention to the fact that this test is unlikely to be informative and is not recommended (for example, by a prompt in electronic reporting systems). Educational interventions with referring clinicians were shown to reduce inappropriate FSH tests by over 50% in Dumfries and Galloway. ⁹ A local laboratory liaison group provides a good forum to promote changes in practice. A costing analysis (based on 2014 Oxfordshire data) indicates that savings of £16,500 could be made for a population of 100,000; ¹⁰ a costing template is available from the NICE website for organizations to estimate the local financial impact. ¹¹

Premature ovarian insufficiency (POI), previously termed premature menopause or premature/primary ovarian failure, is defined as loss of ovarian function before the age of 40. POI occurs in about 1% of women ¹² and is increasingly common among survivors of childhood and young adult cancers. It carries long-term health risks including osteoporosis and cardiovascular disease. Diagnosis is often delayed, even among women with typical symptomatology, ¹³ and the second NICE quality statement is ‘Women under 40 years presenting with menopausal symptoms have their levels of follicle-stimulating hormone measured’.

A systematic review was conducted during NICE guideline development to assess the diagnostic accuracy of clinical indicators (cycle irregularity and vasomotor symptoms), ultrasound features (antral follicle count and ovarian volume) and biochemical measurements (FSH, AMH, inhibin B, inhibin A and oestrogen). Only three published studies matched the review protocol.^14–16 FSH concentrations above 30 mIU/mL were found useful to identify women with POI (positive likelihood ratio: 38 (95% CI: 0.69 to 62), whereas no other single test or combination of tests was found to be useful in diagnosing POI.

The NICE guideline recommends that diagnosis of POI should be based on menopausal symptoms, including no or infrequent periods, and elevated FSH concentrations on two blood samples taken 4–6 weeks apart. POI should not be diagnosed on the basis of a single blood test, because of the well-recognized fluctuations in FSH in the perimenopause, as well as the cyclical variation of FSH in women who continue to menstruate (in these women, timing of FSH measurement is standardized by convention to day 2–5 of the cycle).

Anti-Mullerian hormone measurement is now widely used to assess ovarian reserve ¹⁷ and is validated in assisted reproductive treatment as a predictor of egg number. ¹⁸ However, the evidence for AMH testing in diagnosis of POI was limited: in studies of women who had undergone chemotherapy and women and adolescents with Turner syndrome, low AMH was found to be moderately useful for the diagnosis of POI (AMH <8 pmol/L, positive likelihood ratio: 2.99 [95% C.I: 0.34 to 26.39]), although this was interpreted with caution because of uncertainty in the results (i.e. wide confidence intervals), and the variation in AMH assays used in the studies. The guideline recommended that AMH should not be routinely used to diagnose POI.

It is hoped that the NICE guidance will clarify the diagnosis and management of menopause, provide information for women and for health professionals and help to standardize practice. By implementing the recommendations on biochemical diagnosis of menopause, which are addressed to clinicians and laboratory staff, there will be considerable cost-savings to the NHS. By highlighting the criteria for diagnosis of POI, young women should obtain earlier diagnosis and referral to specialist services, and thus improve their management and long-term health outcomes.