Clinical Review: The menopause

The menopause is a natural process in a woman's reproductive life, characterised by follicular depletion and a fall in the levels of estrogen and progesterone.

Increased risk of fragility fracture (SPL)
Increased risk of fragility fracture (SPL)

Section 1: Epidemiology and aetiology

Women can expect to spend up to 40% of their lives after reaching the menopause. Transition through it may give rise to a wide range of physical and physiological symptoms.

Up to 70% of women report experiencing symptoms, but many do not seek advice or treatment.1,2

These symptoms commonly affect quality of life, but the menopause is also an important factor in the development of osteoporosis and cardiovascular disease.

Physiology
The human ovary contains the maximum number of follicles before birth. Numbers begin to decline from birth, with more rapid decline after the age of 40 years.

During reproductive life, FSH stimulates production of inhibin B, a glycoprotein released from granulosa cells of the ovary and estradiol. Inhibin B suppresses FSH production in a negative feedback loop.

After the age of about 45, depleted numbers of primordial follicles result in reduced inhibin production, leading to a loss of the negative feedback and hence rising FSH levels.

Levels of estradiol fluctuate during the menopausal transition. Most postmenopausal estrogen is estrone, produced from peripheral conversion of androgens.1,2

The menopause may also be iatrogenic, where the ovaries are surgically removed or damaged by chemotherapy and/or radiotherapy.

Treatment with gonadotropin-releasing hormone analogues may give rise to a temporary menopausal status, with associated symptoms.

Commonly used menopause terminology is listed in box 1.

Premature menopause
Premature menopause or ovarian failure affects about 1% of women and is defined as cessation of ovarian function before the age of 40.2 

This has major physical and psychological implications. Women present with menstrual disturbance, typically amenorrhoea, and menopausal symptoms.

Diagnosis can be confirmed with an FSH level of >20IU/L on two occasions.1-3 Other investigations usually include karyotype, ovarian autoantibody screen, screening for autoimmune disease and possible infection, such as mumps, and baseline bone mineral density (BMD).

These women sometimes require multidisciplinary management in secondary care. HRT is recommended for symptom control and the prevention of osteoporosis and cardiovascular disease (CVD). Younger women taking HRT are not exposed to the same risks associated with treatment until they reach the usual age of menopause.4

Premature menopause may also result from surgical removal of the ovaries or chemotherapy/radiotherapy and with the exception of women with breast or gynaecological cancers, should be managed in the same way.

For many of these women, the main concern is loss of natural fertility. For most of those wishing to conceive, assisted reproduction with oocyte donation is recommended.

Section 2: Making the diagnosis

Menopausal symptoms are present to different degrees in individual patients. Fluctuating levels of sex hormones can also result in symptoms occurring intermittently.

Some women have symptoms while still menstruating monthly; most notice menstrual irregularity. Symptoms are categorised as physical, sexual and psychological (see box 2). In 20% of women, symptoms affect quality of life.

A symptom rating questionnaire, such as the Greene Climacteric Scale or the Menopause Rating Scale, is a useful way to assess the degree of estrogen deficiency and response to treatment.5

Associated diseases
Estrogen plays an important part in calcium metabolism and inhibits bone reabsorption. Peak bone mass is reached at 25 to 30 years of age.

Reduced estrogen levels in the climacteric period result in increased bone turnover and a loss in BMD, increasing the risk of fragility fractures, with potentially huge impact on quality of life and independent functioning.6 

NICE guidelines state that all younger women with untreated premature menopause and women aged 50-64 years with a risk factor (family history, steroid use, smoker) need assessment using FRAX or QFracture to determine if their BMD should be measured with a DXA scan.6,7

The menopause is an independent risk factor for CVD, including peripheral vascular disease, heart disease and stroke.8 The Framingham Heart Study has shown that the incidence of CVD is higher in postmenopausal women when compared to premenopausal women of equivalent age.9

At the menopause, there is redistribution of body fat to the abdomen and an increased risk of impaired glucose tolerance.

The menopause can cause abnormal lipid metabolism with increased LDL and reduced HDL, leading to increased total cholesterol, atherosclerosis and hypertension.

In addition, studies have shown that falling estrogen levels play a part in the pathogenesis of vascular plaque formation.8

Investigations
No investigations are required as routine, although FSH levels may be measured. A diagnosis of the menopause or climacteric transition can be made from a detailed history and clinical assessment of the woman’s symptoms and menstrual pattern.

In younger women presenting with menstrual irregularities and menopausal symptoms, blood tests can be a useful adjunct.

A diagnosis of premature ovarian failure can be made from two FSH levels of >20IU/L. FSH >30IU/L is indicative of postmenopausal status. FSH should ideally be measured on days two to five of the menstrual cycle.1-3

TFTs may be useful in formulating a differential diagnosis and a thrombophilia screen should be considered in women with a personal or family history of thromboembolism.

Physical assessment should also include BP, BMI, blood glucose and lipid profile.

Women should be encouraged to be up to date with their cervical screening and mammograms.

Endometrial assessment may be required if there is a history of sudden change in menstrual pattern or a history of intermenstrual bleeding.

Section 3: Managing the condition

Studies have shown that aerobic exercise can improve vasomotor symptoms, insomnia and psychological health in women in the climacteric transition. It also has a positive impact on osteoporosis and cardiovascular health.

Promotion of a well-balanced diet is important, including 700mg calcium per day. Consider advice about weight loss for those with an increased BMI, as obesity has been linked to worsening of vasomotor symptoms, as well as breast cancer, endometrial cancer and CVD.

HRT aims to supplement diminished circulating levels of estrogen and progesterone. It is the most effective available treatment for vasomotor symptoms and reduces their severity by 87%.3

Bone protection, sexual, urogenital and psychological symptoms are not indications for HRT, although outcomes may be improved by taking it. Box 2 summarises its benefits.

HRT side-effects and risks
The most common side-effect and reason for stopping HRT is irregular bleeding. Women should be warned about this and advised to persist with it for at least three months before considering changing or stopping.

Bleeding on HRT may prompt the need for endometrial assessment, particularly if it is heavy or occurs after a period of amenorrhoea. It can be managed by altering the progesterone element. 

Women may also experience side-effects related to the individual estrogen and progesterone components of HRT (see box 3). These can be improved by altering the dose, type and route of administration.

About 12 years ago, the Women’s Health Initiative (WHI), involving more than 27,000 women, and the Million Women Study (MWS) published data raising concerns about the risk of HRT, particularly in regard to CVD and breast cancer.10,11 Endometrial cancer, ovarian cancer, gall bladder disease and venous thromboembolism (VTE) are also documented risks. Consequently, many women stopped taking HRT.

Recent studies have shown more favourable data and usage is increasing again. Fresh analysis of the WHI data has indicated that in younger and slimmer women, who start HRT closer to the menopause, the risk/benefit ratio is favourable. Contraindications to HRT are listed in box 3.

Box 3: HRT side-effects and contraindications

Breast cancer

The WHI study showed no increase in breast cancer within the first five to seven years of HRT use.10

Combined HRT has been shown to increase breast cancer, but the absolute risk is small, at less than 1.0 per 1,000 women per year or three to four per 1,000 women over five years.12

This is lower than the risks associated with drinking 14-21 units of alcohol per week and the respective risks for obesity, nulliparity, early menarche and late menopause.

Most women in the WHI trial were overweight and older (average age 63 years), so it is difficult to apply these data to younger women, on whom there are no current RCTs.

Combined HRT has also been shown to increase breast density, leading to an increased risk of having an abnormal mammogram.

Breast cancer risk is only increased in women taking HRT for more than five years after the age of 50, so younger women taking HRT in premature or early menopause are at no increased risk. Risks return to baseline five years after stopping HRT. Estrogen-only HRT has not been shown to increase risk of breast cancer.

In breast cancer survivors, oral HRT and tibolone are not recommended. Topical vaginal estrogens may be an option, although there are limited studies to support this.

Cardiovascular disease
The evidence concerning HRT and CVD has been a cause of confusion for patients and prescribers.

Early studies showed a decrease in cardiovascular events in women taking HRT. However, the Heart and Estrogen/Progestin Replacement study (HERS) and the WHI produced data that raised concerns over cardiovascular risks in women taking HRT.

HERS included 2,763 women with existing CVD taking combined HRT. Both WHI and HERS suggested that HRT had no cardioprotective benefits and could lead to increased risk of MI and stroke.

Confusing the issue further, in 2007, WHI data were re-analysed and showed no increase in CVD for younger women (aged 50-59 years) taking estrogen-only HRT, demonstrating that there was in fact a significant (<0.05) decrease in all-cause mortality.10

In conclusion, the age of the patient, timing in relation to onset of the menopause and type of HRT are important to consider in assessing cardiovascular risk.13,14

For women taking combined HRT, risks are only present in older women, taking HRT ≥20 years post-menopause and in the first year of use. In women with existing CVD, HRT should be avoided. It is recommended that women with premature menopause should receive HRT, to reduce the risk of CVD and osteoporosis.

Stroke
Overall, studies have shown HRT increases the risk of stroke. The risk of stroke increases with age, so the effect of HRT on stroke risk is most significant after the age of 60 years.

The risk of stroke is lower with transdermal preparations and appears to be dose dependent, so using the lowest possible dose for the shortest possible time is advised.

Tibolone, a synthetic steroid hormone that works on estrogen receptors, should be avoided in women at risk of stroke.10,11

Venous thromboembolism
Oral HRT increases the risk of VTE and pulmonary embolism. It is further increased with age, smoking, previous or familial history of VTE and immobility. Combined HRT carries greater risk than estrogen-only.

Recent studies have shown VTE risk is not increased with transdermal preparations because this avoids first-pass metabolism of the liver and is therefore an option in higher-risk patients. The WHI showed VTE risk in combined preparations conferred an additional 11 cases per 10,000 women-years, and four cases for estrogen-only HRT. Similarly to CVD risk, the risk is greatest in the first year of use.

Endometrial cancer
Estrogen-only HRT is associated with endometrial hyperplasia and endometrial cancer. This risk increases with duration and is dose-related.

The risk is reduced by supplementing with sequential progesterone from day 10-14 of the cycle. Risk continues several years after stopping.

After treatment for endometrial cancer, HRT should be avoided. The risk of endometrial hyperplasia and endometrial cancer is further increases in obese women.10,11

Ovarian cancer
The link between HRT and ovarian cancer has caused confusion in recent years. The WHI showed no increased risk of ovarian cancer with HRT use. However, the MWS showed an increased risk of one case per 2,500 women over five years, so the risk is small.10,11

Gall bladder disease
HRT is associated with an increased risk of cholecystitis, which is reduced by transdermal routes.

Choice of HRT
The estrogen component of HRT is in the form of estradiol, estradiol-17 beta, estronone or conjugated equine estrogen. These are considered natural estrogens as they mimic those produced by the body.

Estrogen can be given in oral, vaginal or transdermal forms. Local estrogens can be used for sexual and urogenital symptoms.3

The progesterone component is available in two subgroups. Progesterone-similar modulations include dydrogesterone and drospirenone medroxyprogesterone acetate. Testosterone-similar modulations include norethisterone, norgestrel and levonorgestrel.1-3

The progesterone can be oral, transdermal or via a levonorgestrel-releasing intrauterine system (LGR-IUS). The LGR-IUS is useful in women requiring contraception.

Tibolone is a synthetic sex steroid that has estrogenic, androgenic and progestogenic properties and can be used as HRT, although studies have shown it to be less effective in treating menopausal symptoms.

Transdermal routes are the preferred method in liver disease, diabetes, history of gall stones, history of thrombosis and in women taking enzyme-inducing drugs.

Estrogen-only HRT is only appropriate in women who have had a hysterectomy and those with a uterus must have a combined preparation with progesterone, to prevent endometrial proliferation and risk of endometrial cancer.

In combined HRT there are two regimens, sequential (cyclical) or continuous (daily) HRT.

In sequential HRT, progesterone is normally given for 10-14 days per month and most women will have a monthly withdrawal bleed. This is most suitable for women whose last period was less than a year ago.

Continuous HRT is used in women whose last period was more than one year ago. Erratic bleeding may be expected in the first six months, but most women will not bleed on this regimen. If it continues after six months, investigation is warranted.

Testosterone
Testosterone levels may fall following the menopause. Supplementing with testosterone has been shown to improve aspects of sexual function. It can be administered via a patch or an implant, but is often only commenced in secondary care.

Monitoring HRT

Guidelines recommend HRT for the treatment of premature (less than 40 years) and early (less than 45 years) menopause until the age of 51, although this is not absolute and continuing HRT should be based on risks and benefits.3

When commenced after the age of 51, most guidelines suggest discontinuing after five years.1,2 Commencing HRT after the age of 60 is not recommended and is associated with increased risk of CVD.

When commencing HRT, it is important to discuss the risks and benefits. Use the lowest possible dose for the shortest possible duration, to minimise risks. Titrate up slowly if symptoms have not improved after four to six weeks.

Perimenopausal women may need contraception, as women are deemed fertile until two years after their last period.

This can be provided by a hormone-releasing IUD as the progesterone component of combined HRT, or if they are aged  less than 50 years and there are no contraindications, a low-dose combined oral contraceptive pill.

Review patients once a year to check symptom control and side-effects, and measure weight and BP.

Stopping HRT

There are no strict rules about when to stop HRT. The British Menopause Society guidelines recommend that there are no arbitrary limites to the duration of HRT - it can be taken for as long as women feel that the benefits outweigh the risks to them. 2 The decision should, however, be patient-centred, with knowledge of potential risks and benefits.

Many women stopping HRT have recurring symptoms, but these may disappear after two to three months. There is insufficient evidence to suggest that tapering down the dose is beneficial in reducing recurrence. Risk factors and preventive measures for osteoporosis should be reviewed at this time.

Box 4: Alternatives to HRT

Vaginal lubricants and moisturisers
Topical products can improve vaginal dryness and sexual function. Supporting evidence is limited.

Clonidine
Clonidine, an alpha-2 agonist, is normally used in managing hypertension. Evidence about its efficacy is contradictory and inconclusive. A recent systematic review showed marginal improvement compared to placebo, although it was not as effective as estrogen.

SSRIs/SNRIs*
There is substantial supporting evidence regarding use of SSRIs and SNRIs for menopausal symptoms. In particular, venlafaxine at a dose of 37.5mg twice daily has been shown to be effective.

However, the side-effects of nausea and sexual dysfunction often make this difficult to tolerate.

Gabapentin
The gamma amino butyric acid analogue and antiepileptic gabapentin has been used in the treatment of vasomotor symptoms.

One study has shown a 45% reduction in hot flush frequency and 54% reduction in symptom severity scoring. Its use is off licence and women should be informed of the side-effects of drowsiness and dizziness.

Progesterone creams
Progesterone transdermal creams are used in the treatment of vasomotor symptoms and skeletal protection, but evidence supporting this use is unconvincing and it is important to note these creams offer no endometrial protection as part of combined HRT.

Phytoestrogens
Phytoestrogens, natural compounds that occur in plants, are structurally similar to estradiol. The two most common groups are isoflavones and ligans, found in soy beans, chick peas and green legumes.

Japanese women, who have a diet high in phytoestrogens, are reported to have fewer menopausal symptoms.

Supporting evidence is conflicting and inconclusive, and a systematic review of 30 randomised trials has concluded there is no evidence to support using phytoestrogens in treating menopausal symptoms.

In addition, there are concerns about the effects of phytoestrogen use on estrogen-receptive tissues, such as the breast and endometrium.

Black cohosh
Black cohosh has been widely used for many years to treat menopausal symptoms. However, the evidence is conflicting and concerns have been raised about patient safety, given limited knowledge of its pharmacology and risk of liver toxicity.

Evening primrose oil
Not shown to be effective in treating menopausal symptoms.

Ginseng
Evidence has not shown ginseng to be superior to placebo in the treatment of menopausal symptoms. Case reports have shown it can be associated with breast pain and abnormal vaginal bleeding, and its use is not recommended.

Chinese medicine
The herb dong quai is a traditional Chinese medicine often used to relieve symptoms of the menopause. Studies have shown it to be an effective treatment and it carries the risk of interaction with several other drugs.

St Johns wort
St Johns wort has been found to improve mild and moderate depression and quality of life symptoms in perimenopausal women.

However, it is an enzyme inducer and interacts with many other drugs, and its concomitant use with HRT is not recommended.

Agnus castus
Agnus castus has been used in the treatment of menopausal symptoms, but there is limited supporting evidence and more research is needed.

Other complementary therapies
Acupuncture, reflexology and magnetism are marketed as treatments for menopausal symptoms.

Although they may improve sense of wellbeing, reduce stress and promote relaxation, there is no current evidence supporting their use.

*Speroff L, Gass M, Constantine G et al. Obstet Gynecol 2008; 111: 77-87

Source: RCOG. Alternatives to HRT for the management of symptoms of the menopause. www.rcog.org.uk/files/rcog-corp/uploaded-files/SIP_No_6.pdf. London, RCOG, September 2010

Section 4: Referral

Referral should be made on a case-by-case basis to a specialist menopause clinic or a gynaecologist with a specialist interest.

The following usually require secondary care management:

  • Failure of standard HRT (try changing dose, preparation, route of administration first)
  • Premature menopause/ovarian failure
  • Women with a history of breast, ovarian or endometrial cancer
  • Women with contraindications to HRT
  • Women with persistent vaginal bleeding on HRT (try changing progesterone element, preparation, duration, route)

Women with vaginal bleeding on HRT may require endometrial assessment and referral for this should be on an urgent basis.

Section 5: Case study

A 35–year-old nulliparous teacher presented with a vague history of fatigue, loss of libido and dry skin.

She was initially investigated for suspected hypothyroidism, but TFTs were reported as normal.

She returned four months later with the same symptoms, now associated with amenorrhoea for the preceding three months, and debilitating hot flushes. A home pregnancy test was negative.

Initial investigations demonstrated an FSH of 22IU/L, which was similarly raised on a repeat sample.

She also underwent a pelvic ultrasound scan, which showed small ovaries with no obvious follicular activity and a thin endometrium.

The patient was referred to the menopause clinic with suspected premature ovarian failure.

The diagnosis was confirmed and she started on the combined oral contraceptive pill as HRT, from which she gained symptom relief. She had a baseline DXA scan to assess BMD, which was normal.

The patient also saw a counsellor to help her cope with the implications of the diagnosis.

The woman and her husband explored the possibility of egg donation assisted conception, but instead opted for adoption. 

At the age of 40 years, the woman switched to sequential cyclical HRT in an oral preparation, which she tolerated well for several years. However, she was seen again at 47 with erratic vaginal bleeding, which was heavy and prolonged. She was referred under the two-week wait pathway.

Pelvic ultrasound demonstrated an endometrial thickness of 8mm and she went on to have a hysteroscopy. A benign endocervical polyp was identified and removed. The biopsy was normal.

At the same time, a hormone-releasing IUD was fitted and she subsequently became amenorrhoeic. For estrogen replacement, she opted for a transdermal patch.

This combination was effective until she reached the age of 55, when treatment was discontinued.

Section 6  Evidence base

Clinical trials

  • Writing Group for the WHI Investigators. Risks and benefits of estrogen plus progestin in healthy post-menopausal women: principal results of the Women’s Health Initiative randomized controlled trial. JAMA 2002; 288(3): 321-33.
  • The Women’s Health Initiative Steering Committee. Effects of conjugated equine estrogen in postmenopausal women with hysterectomy. The Women’s Health Initiative Randomized Controlled Trial. JAMA 2004; 291: 1701-12.
  •  The WHI was an RCT involving 27,000 women, aged 50-79 years. HRT was shown to increase the risk of CVD, breast cancer, ovarian cancer, endometrial cancer and VTE. Data re-analysis in 2007 showed there was no increase in CVD for younger women aged 50-59 and a 30% decrease in all-cause mortality.
  • Lind Schierbeck L, Rejnmark L, Landbo Tofteng C et al. Effect of hormone replacement therapy on cardiovascular events in recently postmenopausal women: randomised trial. BMJ 2012; 345: e6409.

This small RCT assessed 1,006 patients who were treated with HRT consisting of a triphasic estradiol and norethisterone acetate.

Primary composite endpoints of death and admission to hospital with MI or heart failure were measured.

The study concluded there was a statistically significant improvement in cardiovascular composite endpoints in patients who were being treated with HRT.

Guidelines

  •  NICE. Clinical Knowledge Summaries. Menopause. http://cks.nice.org.uk/menopause. London, NICE, June 2013.

Further reading

  • Currie H. Menopause: Answers at your fingertips. London, Class Publishing, 2006.

* Dr Cantlay is a GP ST1, Riverside VTS, Charing Cross Hospital, London, and Dr Mitchell-Jones an ST5 obstetrics and gynaecology, Chelsea and Westminster Hospital, London.

Online resources

Reflect on this article and add notes to your CPD organiser on MIMS Learning

References

1. Menopause Matters 

2. The British Menopause Society (www.thebms.org.uk)

3. Roberts H. Managing the menopause. BMJ 2007; 334: 736.

4. Gelbaya TA, Vitthala S, Nardo LG et al. Hormone therapy in women with premature ovarian failure (Protocol). Cochrane Database Syst Rev 2010, Issue 1. Art No: CD008209. DOI: 10.1002/14651858.CD008209

5. Greene JG, Cooke DJ. Life stress and symptoms at the climacteric. Br J Psychiat 1980; 136: 486-91.

6. NICE. Osteoporosis overview and fragility fracture risk assessment. London, NICE, January 2014. http://pathways.nice.org.uk/pathways/osteoporosis

7. Middleton ET, Steel SA. The effects of short term hormone replacement therapy on long-term bone mineral density. Climacteric 2007; 10(3): 257-63.

8. Rosano G, Vitale C, Marazzi G et al. Menopause and cardiovascular disease: the evidence. Climacteric 2007; 10(s1): 19-24.

9. Gordon T, Kannel WB, Hjortland MC et al. Menopause and coronary heart disease. The Framingham Study. Ann Intern Med 1978; 89(2): 157-61.

10. Writing Group for the WHI Investigators. Risks and benefits of estrogen plus progestin in healthy post-menopausal women: principal results of the Women’s Health Initiative randomized controlled trial. JAMA 2002; 288(3): 321-33.

11. Beral V, Banks E, Reeves G. Million Women Study. Effects of estrogen-only treatment in postmenopausal women. JAMA 2004; 292(6): 684.

12. Chlebowski RT, Hendrix SL, Langer RD et al. Influence of estrogen plus progestin on breast cancer and mammography in healthy postmenopausal women: the Women’s Health Initiative Randomized Trial. JAMA 2003; 289: 3243-53.

13. Harman SM, Vittinghoff E, Brinton EA et al. Timing and duration of menopausal hormone treatment may affect cardiovascular outcomes. Am J Med 2011; 142: 199-205.

14. Stampfer MJ, Colditz GA, Willett WC et al. Postmenopausal estrogen therapy and cardiovascular disease. Ten-year follow-up from the Nurses’ Health Study. N Engl J Med 1991; 325(11): 756-62.

15. Mosekilde L, Beck-Nielsen H, Sorensen OH et al. Hormonal replacement therapy reduces forearm fracture incidence in recent postmenopausal women – results of the Danish Osteoporosis Prevention Study. Maturitas 2000; 36(3): 181-93.

16. Chlebowski RT, Wactawski-Wende J, Ritenbaugh C et al. Estrogen plus progestin and colorectal cancer in postmenopausal women. N Engl J Med 2004; 350(10): 991-1004.

CPD IMPACT: EARN MORE CREDITS

These further action points may allow you to earn more credits by increasing the time spent and the impact achieved.

  • Refamiliarise yourself with menopause terminology.
  • Carry out a search of patients in your practice who are receiving HRT and check if there were any new cases of breast cancer or CVD in this group.
  • Review the latest clinical trials on the effectiveness of HRT and alternative therapies, and write a guide for patients about treatment options.

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