Hormone replacement therapy and the menopause*

What are the common symptoms and complications of the menopause?

Oestrogens are responsible for producing feminine features, whereas androgens, although present in all women, promote masculine features such as facial hair. The symptoms of menopause result from the reduced level of oestrogens and the increased level of androgens and include:

• Hot flushes which affect 70% of women going through the menopause and can occur for two to five years
• Vaginal dryness which can lead to uncomfortable or painful sex
• Night sweats
• Insomnia
• Drier facial skin and hair
• Facial and body hair growth
• Poor memory and concentration
• Reduced libido
• Urinary problems

The reduced levels of oestrogens can also cause long-term effects on the body including:

• Osteoporosis which is a weakening of the bones because the bones lose minerals, mass and density
• Increased development of fatty cholesterol deposits in blood vessels (atheroma) which is a cause of heart attacks and strokes
• Prolapse of the womb where the womb drops down into the vagina
• Psychological illnesses (eg depression and anxiety) resulting from the unpleasant symptoms due to fluctuating hormone levels and difficulty adjusting emotionally to the change in fertility.

Osteoporosis

Osteoporosis, a reduction in bone mass and density leading to increased risk of fracture, back pain, weight loss, and curvature of the spine, results in about 60,000 hip fractures a year in the UK, 90% of which are in people over 50 and 80% of which are in women. There are also some 50,000 wrist and 40,000 clinically diagnosed fractures a year from osteoporosis.

Identifying Patients at Risk of Fractures Due to Osteoporosis

Those who are at increased risk of osteoporosis and therefore of fracture are those with:

• Early surgical or natural menopause (before age 45 years)
• Pre-menopausal amenorrhoea > 6 months not due to pregnancy
• Hysterectomy, with at least one ovary conserved, before age 45 (this may affect ovarian function)
• Predisposing factores – liver disease, alcoholism, malabsorption, thyroid disease, RA, hypogonadism in men
• Current or planned long-term oral corticosteroid use (>7.5 mg Prednisolone per day for 3 months or more) Family history of osteoporosis (especially maternal hip fracture)

Post-menopausal women and men with one or more fragility fractures need assessment to rule out secondary osteoporosis (see below) and must then be offered the option of treatment to prevent further bone loss and fractures. This is an important opportunity to target therapy to those at highest risk of future fractures but is often ignored.

Bone Density Measurement

DEXA results are reported as T scores (comparison with the young adult mean) and Z scores (comparison with reference values of the same age). The T score relates to absolute fracture risk whereas the Z score related to the individual’s relative risk for their age. The table below shows a simple classification of DEXA results and guidance for management:

T score (WHO standard reference)	Fracture Risk	Action
Normal T > -1.0	Low	Lifestyle advice
Low bone mass (osteopenia) T –1.0 to –2.5	Above average	Lifestyle advice. HRT especially in women aged 50 – 60 years. Calcium and vitamin D supplementation.
Osteoporosis T< -2.5 Treat	High	Lifestyle advice Calcium and vitamin D supplementation
Established osteoporosis T < -2.5 plus one or more fractures	Very high	Lifestyle advice. Pain control. Exclude secondary causes. Treat (see below). Calcium and vitamin D supplementation. Consider referral.

Exclude Causes of Secondary Osteoporosis and Other Conditions

Before initiating therapy it is important to:

• Confirm the diagnosis with DXA if appropriate
• Identify causes of secondary osteoporosis, eg hyperparathyroidism, alcohol abuse, hyperthyroidism or hypothyroidism.
• Exclude other diseases which may mimic osteoporosis, eg osteomalacia or malignancy.

This can be achieved by carrying out the following investigations:

X-ray of thoracic or lumbar spine if needed to confirm vertebral deformity.	Exclude obvious bony secondaries; proceed to bone scintography if doubt.
Urea and electrolytes	Exclude renal osteodystrophy
Liver function tests	Elevated in alcohol abuse
ESR	If elevated plasma electrophoresis to exclude myeloma
Calcium, phosphate and alkaline phosphatase	Abnormal in osteomalacia and bony secondaries
Thyroid function tests	Exclude hyperthyroidism and hypothyroidism

Osteoporosis prevention and treatment

Lifestyle Measures

Target all those with a risk of developing osteoporosis

• Stop smoking
• Avoid excessive alcohol intake
• Regular weight-bearing exercise. Avoid immobility
• Avoid excessive dieting and exercise resulting in amenorrhoea
• Maintain adequate reference nutrient intake of calcium and vitamin D

Calcium	Males 11 – 18 yrs 1,000 mg daily
	Females 11 – 18 yrs 800 mg daily
	Adults 19+ yrs 700 mg daily
Vitamin D	400 iu daily

  One pint of semi-skimmed mild or four ounces of cheddar cheese contain 700 – 800 mgs of calcium. If these levels cannot be achieved with diet alone consider supplements.

Drug therapy options for prevention

• HRT
• Tibolone
• Calcium and vitamin D
• Bisphosphonates

Further therapies such as raloxifene (a selective oestrogen receptor modulator) are under evaluation and if appropriate further guidance will be issued.

Drug therapy options for treatment

• HRT
• Tibolone
• Bisphosphonates
• Calcitriol
• Calcium and vitamin D
• Calcitonin

Referral for specialist opinion

The principal reasons for referral are for patients fulfilling criteric for DXA measurement where open access to this investigation is not available and when assistance is required in confirming the diagnosis or initiating management.

Other reasons for referral include:

• All young males and those with severe osteoporosis
• Patients who may have malignancy, renal osteodystrophy, osteomalacia or hyperparathyroidism
• Patients with rapidly progressive or severe disease

Osteoporosis Support Groups

These organisations can provide further information on all aspects of coping with the disease for both health care professionals and patients.

• The National Osteoporosis Society Helpline number is 01761 471 771
• Osteoporosis 2000 (Sheffield) can be contacted on 0114 272 2000
• Osteoporosis Dorset can be contacted on 01202 443064 or athttp://dialspace.dial.pipex.com/osteo.dorset/

Treatment for the menopause

Self Care Action Plan

All women will go through the menopause but a self-care action plan can help prevent the complications of the menopause. This involves:

• Daily exercise such as walking. This will help maintain general fitness and reduce the risk of developing heart disease and will strengthen the muscles and help build up and strengthen the bones to reduce the effects of osteoporosis.
• Daily pelvic floor exercises which involve pulling up the muscles around the vagina and anus. These exercises will help prevent a prolapse of the womb and may also prevent some of the urinary problems be strengthening the muscles involved in controlling urine flow.
• Becoming aware of the normal monthly changes in the breasts (women have a very slightly increased risk of breast cancer for every year after the menopause and this risk is a little higher in those who use HRT).
• A healthy well-balanced low-fat diet containing plenty of calcium containing foods (eg mild products, fish containing bones such as tinned sardines and salmon and dark green leafy vegetables). A good supply of calcium and vitamin D will help to minimise the effects of osteoporosis. Saturated fats such as those in meat fat and butter should be avoided; mono-unsaturated fats such as those in olive oil and omega fats found in oily fish such as mackerel and sardines should be eaten instead. A low-fat diet containing mono-unsaturated and omega fats instead of saturated fat helps prevent heart disease.
• Drinking one or two glasses of wine or other alcohol. Alcohol, particularly red wine and some beers, contains substances that can reduce the risk of heart disease and cancer. However, alcohol must always be drunk in moderation. It may also worsen certain conditions such as palpitations and should then be avoided.
• Getting out into the sun from time to time. This will boost the body’s vitamin D supply as exposure to the sun stimulates the production of vitamin D in the skin. It also appears to have an effect on chemicals in the brain resulting in a feeling of well-being.
• Counselling can be useful for those who are finding it difficult to adjust to the end of their fertility and childbearing ability and may help alleviate any resulting depression or anxiety.

Hormone Replacement Therapy

Rational for Use

• To treat menopausal vasomotor symptoms
• To treat menopausal uro-genital symptoms
• To prevent and treat osteoporosis. The risk of osteoporotic fractures is decreased by ove4 50% with HRT but these benefits may be lost on discontinuation.

Additional benefits may be:

• To prevent the development of coronary artery disease
• A possible reduction in the incidence of Alzheimer’s disease
• There may also be a positive effect on prevention of mood swings and depression at the time of the menopause Recent evidence suggests there may be a benefit on decreasing the incidence of large bowel cancer

Choosing a regimen

HRT compliance can be a problem because of side-effects and fear of an increased risk of cancer. Therefore treatment options and the long term benefits of HRT need to be fully discussed with patients. First line therapy is normally oral owing to lower cost and patient preference.

For those women who have had a hysterectomy, the addition of a progestogen is not needed when taking HRT. Therefore unopposed oestrogen can be given.

Women who have a uterus have had an endometrial ablation or who have had a sub-total hysterectomy still need cyclical or continuous progestogen with continuous oestrogen to prevent endometrial hyperplasia with its associated risk of endometrial cancer. Care must be taken to explain the necessity of progestogen to women especially if using preparations where there are separate tablets.

The following dosages are approximately equipotent and provide protection against osteoporosis when given as unopposed oestrogen replacement.

• 0.625 mg conjugated equine oestrogens
• 2 mg estradiol valerate
• 2 mg 17B estradiol
• 50 mcg estradiol transdermal patch
• 50 mg estradiol implant

However, when using a continuous combined HRT only 1 mg estradiol is required to provide osteoporosis protection.

Sequential HRT preparations

Over 28 days continuous oestrogen is given with 10 – 12 days of progestogen

Minimum daily progestogen doses for a sequential regimen to prevent endometrial hyperplasia are:

• 10 mg medroxyprogesterone acetate
• 0.7 mg norethisterone
• 10 mg dydrogesterone
• 75 mcg levonorgestrel
• 150 mcg norgestrel
• 45 mg progesterone vaginal gel (alternate days)
• 1 mg cyproterone acetate

Bleeding should occur at a regular time each month. However, the onset may vary between preparations. Absence of bleeding occurs in approximately 5 – 10% of women and requires no further investigation providing symptoms are controlled and there is no irregular bleeding.

Long cycle HRT

The only licensed preparation is Tridestra using 20 mg medroxyprogesterone acetate for 14 days each 3 month cycle. It produces four withdrawal bleeds per year and may cause initial irregular bleeding but this tends to settle.

Endometrial hyperplasia has been reported when lower doses of progestogens are used for 10 days, every 84 days.

Continuous combined HRT (CCHRT)

Continuous oestrogen is given with a continuous progestogen to induce endometrial atrophy.

• CCHRT should only be given to those women who have not had a natural period for 12 months
• 80% of women at the age of 54 are one-year post menopause.
• Older women are more likely to accept and continue to take HRT when it does not cause withdrawal bleeding or other nuisance side effects.
• Low dose CCHRT may have a better bleeding profile than 2 mg oestrogen preparations and appears to be bone-sparing.
• When a woman is switched from sequential HRT to CCHRT this should take place at the end of a withdrawal bleed when the endometrium is at its thinnest.
• Most women experience some light bleeding/spotting during the first few months of treatment. After six months more than 75% of women become amenorrhoeic.

Side effects with HRT

Women tend to gain weight at the menopause with the redistribution of body fat causing an increase in abdominal fat. There is no evidence that HRT causes additional weight gain.

• Oestrogenic side effects – normally transient and will usually subside after 3/12. If they persist, consider lowering the oestrogen dose and increase gradually over 3-6 months or consider changing the route of administration, ie using a patch or transdermal gel.
  • Fluid retention
  • Nausea
  • Headaches
  • Breast tenderness
  • Leg cramps
• Progestogenic side effects – normally transient and will usually subside after 3/12. If progestogenic side effects persist, consider change of progestogen, consider a long cycle HRT regimen or a transdermal/vaginal progestogen. Mirena IUS may also be an alternative choice (on a names patient basis as it is no licensed for this purpose in the United Kingdom).
  • PMS symptoms
  • Bloating
  • Depression

Absolute contra-indications

There is no absolute contra-indicationg to the prescribing of HRT in post-menopausal women. Extra caution may need to be exercised in the following situations:

• Active breast cancer / undiagnosed breast lump
• Active thrombo-embolic disease (phlebitis does not constitute thrombo-embolic disease)
• Undiagnosed vaginal bleeding
• Untreated/uncontrolled hypertension
• Coronary artery disease

Breast Cancer

Every women is at risk of developing breast cancer and that risk becomes greater with age. For women not on HRT aged 50, 45 in 1,000 will be diagnosed with breast cancer by the age of 70. For women who start using HRT at 50 an extra 2 in 1,000 breast cancer cases will be diagnosed after 5 years on HRT and an extra 6 in 1,000 after 10 years on HRT. The risk still remains small but it is up to each individual woman to decide if the benefits of HRT are greater on balance for her than the risk of breast cancer. What all women over the age of 50 should certainly do is have regular breast screening whether or not they are taking HRT.

Deep Vein Thrombosis

As with breast cancer, all women have a very small risk of developing blood clots in the leg or deep vein thrombosis, whether or not they take HRT. The risk for women not on HRT is 1 per 10,000 women. For women on HRT, there are an additional 2 cases per 10,000. All women can try to reduce their risk even further by not becoming overweight, not smoking and taking regular exercise.

Alternative therapies for controlling menopausal symptoms

• Tibolone may decrease hot flushes and improve vaginal atrophy and libido.
• Norethisterone 5-15 mg and Megestrol 40 mg may reduce vasomotor symptoms.
• Clonidine decreases hot flushes in women on Tamoxifen but the results of studies in post-menopausal women are inconsistent.
• Dietary phytoestrogens may reduce hot flushes but there is no effective quality control of content in different foods.
• Alternative therapies are available, eg homeopathy, acupuncture, herbal remedies, aromatherapy, dietary supplements, relaxation, exercise, stress reductin, counselling, lifestyle advice (ungraded as there is no evidence available).

There is currently no convincing evidence that oil of evening primrose decreases menopausal symptoms and limited information suggesting natural progesterone cream may be of benefit.

Some practical points

Diagnosing the menopause

• The menopause if often a diagnosis made retrospectively
• Contraception is still needed during the peri-menopausal years
• There is little place for the routine measuring of FSH, LH or oestradiol as women may suffer with vasomotor symptoms but have normal FSH, LH and oestradiol levels.
• If FSH, LH and oestradiol levels are measured then blood should be taken within the first 5-7 days of the menstrual cycle.
• FSH may be of some use in women: – Under 45 years with atypical symptoms – To help diagnose the menopause in those women taking COC or HRT – Who have had a hysterectomy with conservation of the ovaries.
• Oestradiol levels may be useful:
  • To assess the level of oestradiol absorption in patients using non-oral therapy in respect to adequate bone preservation or poor vasomotor symptom control.
  • In the management of patients with oestradiol implants (preventing tachyphylaxis).

Menopause and contraception

• Menopausal women over the age of 50 should use a contraceptive method for one year following their last menstrual period.
• Women under 50 should use a contraceptive method for 2 years following their last menstrual period as break through ovulation can occur.

Women using the combined oral contraceptive PILL (COC)

• May develop vasomotor symptoms in the pill free interval
• May have a rise in FSH during the pill free interval in 30% of menopausal women
• Diagnosis of the menopause may be possible by checking the FSH on day 7 of the pill free interval.
  • if the FSH is 30 U/L or more it should be repeated in 3 months – if the FSH is again raised above 30 U/L it is likely that the woman is menopausal
  • contraception should be continued for the next 2 years (the COC should only be used in women under 50 years old).
• Alternatively, a 50 year old woman could change to using a different contraceptive method such as a POP. If no bleeding occurs in the first two months an FSH level can be measured. If the FSH level is 30 U/L or more the above procedure is followed.

Contraception in women using HRT

• A number of women start HRT before the cessation of menstruation
• HRT is not a contraceptive
• The menopause is suggested if an FSH level taken within 7 days of the start of a withdrawal bleed is >30 U/L on two separate occasions, 1 – 3 months apart.
• In women under 50, contraception should be continued for two years.
• In women over 50, contraception should be continued for one year.

Duration of therapy

A number of women may wish to continue HRT long term (more than 10 years) particularly if they have risk factors for osteoporosis. This decision should be based upon clear, unbiased information leading to an informed choice once the short and long term benefits have been weighed against any risks.

Women who are at least one year past their menopause may benefit from taking a continuous combined HRT preparation:

• CCHRT ensures vasomotor symptom control and helps prevent post-menopausal osteoporosis.
• CCHRT provides period free therapy and may aid compliance.
• Enhanced endometrial protection is afforded.
• Low dose CCHRT may be better tolerated with reduced nuisance side effects.
• There is only one prescription charge for CCHRT.

Myths and misconceptions

HRT is not natural:

Not true. The oestrogens used in HRT are natural and some are identical to the ones that your own body produced before the menopause. These are different to the hormones that are used in the contraceptive pill which are not natural and which can cause different sorts of problems.

HRT is the elixir of youth:

Not true. HRT cannot make you young again or slow down the normal ageing process. What it can do is to help prevent the problems that are caused by the loss of oestrogen after the menopause. Many of these are ones that we associated with age, such as tiredness, poor concentration and memory, loss of bladder tone and changes in the quality of hair and skin. HRT can help to prevent the health problems that these changes can cause.

HRT is not suitable for women …

… who had problems on the contraceptive pill

Not true. The hormones used in HRT are natural and are different from those in the pill which are synthetic. If you had problems on the pill it does not necessarily mean that you will have problems with HRT. However, it is important to discuss any problems that you had with your doctor or nurse.

… who smoke

Not true. Smoking does not mean you cannot try HRT, but you should attempt to stop to improve your health.

… who have high blood pressure

Not true. Your blood pressure should be treated by your doctor before you start HRT but this is not a reason for not taking HRT.

… who have fibroids

Not true. Fibroids are an overgrowth of the muscle of the womb. They are not malignant and do not cause cancer. They may cause heavy or painful periods or may cause no problems at all. Fibroids may grow larger when you replace oestrogen after the menopause. If you know that you have fibroids or your doctor thinks that you may have them you should be monitored regularly while you are on HRT.

… who have varicose veins

Not true. Having varicose veins (or phlebitis) does not mean that you cannot take HRT but you should discuss this with your doctor. If you have had a deep vein thrombosis (blood clot) this may put you at a slightly increased risk of having a clot with HRT but again, if you are monitored regularly, you may still be able to take it.

… who are overweight

Not true. This is not a reason for not taking HRT although if you are very overweight you may have a higher risk of some problems with HRT. You should discuss this with your doctor. Being overweight does increase your risk of other illness and so you should try to lose weight to benefit your overall health.

… who are still having periods

Not true. Some women start to get menopausal symptoms while they are still having fairly regular periods. These symptoms occur because your own oestrogen levels are falling but are still high enough to produce periods. HRT can be given to add to the oestrogen that your body is still producing to relieve symptoms.

… who are too young or too old

Not true. HRT can be given whatever age you are when you go through the menopause. It is particularly important for young women who have had an early menopause either naturally or as a result of surgery.

If you have had a hysterectomy with removal of your ovaries, you should start taking HRT immediately. If your ovaries were not removed they may stop working earlier than they would have done if you had not had a hysterectomy.

… who are diabetic

Not true. Having diabetes does not mean that you cannot have HRT. Diabetic patients have a higher risk of having raised cholesterol. HRT might be especially useful for such patients as, by lowering cholesterol, it can reduce the risk of arterial disease.

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