Hormone replacement therapy (HRT) is a treatment used to replace the female hormones that a woman’s body is no longer producing because of the menopause. It is sometimes called oestrogen replacement therapy or ERT, as it refers to a woman taking supplements of hormones such as oestrogen alone or oestrogen with another hormone called progesterone (progestin in its synthetic form). HRT replaces hormones that a woman’s body should be making or used to make. HRT comes in different forms too. You can get pills, patches, or gels. You need a prescription from your doctor to get it. The brand names include Climesse, Elleste Solo, Estraderm, and Premique.Generally, HRT is prescribed for two groups of women:

• Women going through menopause and who had already gone through it (called post – menopausal)—The natural levels of these hormones drop during menopause. This drop can lead to symptoms such as hot flashes, night sweats, vaginal dryness, and sleep disturbances. HRT may be used to help lessen some of these symptoms.
• Women with certain health conditions—In some cases, women’s bodies don’t make normal levels of the hormones because of a medical problems, such as premature ovarian failure. For these women, HRT replaces the hormones that their bodies should be making.

Oestrogen plays  an important  role in the release of eggs from the ovaries. It regulates a woman’s periods and helps her to conceive. Oestrogen also helps to regulate many other body functions, including bone density, the temperature of your skin and keeping the vagina moist. It is the reduction of oestrogen that causes most of the symptoms associated with the menopause. The main function of progesterone is to prepare the womb for a possible pregnancy. It also helps to protect the lining of the womb (endometrium). A falling level of progesterone does not have the same wide-ranging effects on the body as falling levels of oestrogen. However, falling levels increase the risk of developing cancer of the linning of the womb (endometrial cancer). Therefore, progesterone is usually used in combination with oestrogen in HRT (although women who have had a hysterectomy do not need progesterone and can take oestrogen-only HRT).

Benefits and risks

The main and most obvious  benefit of HRT is that it has proved  very successful in controlling the symptoms of the menopause. Taking HRT can make a huge difference to a woman’s quality of life and wellbeing. HRT can also reduce a woman’s risk of developing osteoporosis (brittle bones) and cancer of the colon and rectum. However, the long-term use of HRT to prevent osteoporosis is not usually recommended. This is because HRT slightly increases the risk of developing breast cancer, endometrial cancer, ovarian cancer and stroke, and there are other medicines available for osteoporosis that dos not carry the same level of associated risk. Most experts agree that if HRT is used on a short-term basis (no more than five years) then the benefits of it outweigh any associated risk. The risks of HRT differ depending on the health status of the woman and the type of HRT.

Women whose bodies have stopped making oestrogen or don’t make enough oestrogen often take HRT to reduce symptoms and maintain overall health. For instance, low oestrogen levels in women with premature ovarian failure put these women at risk for osteoporosis and heart disease. HRT helps maintain bone health and reduce the risk of heart disease. In these cases, HRT is actually replacing hormones  that  the women’s  bodies  should be making—hormones that they need for their overall health.   HRT taken by  women with certain health conditions  is  different  than that taken my post-menopausal women. The risks associated with post-menopausal HRT do not apply to pre-menopausal women taking HRT.

 

HRT may not be suitable if there is:

• history of breast, ovarian or endometrial cancer
• history of blood clots
• history of heart disease or stroke
• untreated high blood pressure ( treatment is given first before starting HRT)
• have liver disease

HRT and Breast Cancer risk

Many studies have looked at the association between hormone therapy and breast cancer. The best evidence for the benefits and risks of hormone replacement therapy come from the US Women’s Health Initiative (WHI), a large study involving more than 16,000 healthy women. The results published in July 2002 showed that the risks of combined HRT of oestrogen plus progestogen outweigh the benefits. These risks include an increase in breast cancer, heart disease, stroke and blood clots. Not only does combined HRT increase the risk of developing breast cancer, but it also increases the chances that the cancer will be discovered at a more advanced stage. This is due to its influence in reducing the effectiveness of mammography.

If a woman no longer has a uterus, oestrogen alone may be given for symptoms of menopause. This probably does not increase the risk of developing breast cancer much, if at all. In March 2004 it was concluded from the WHI study that those taking only oestrogen had no increased risk of breast cancer or heart disease, however oestrogen does appear to increase one’s risk of stroke.

 

Here is what the study further showed.

• About 20 in 1,000 women taking HRT got breast cancer. This compared with 15 in 1,000 taking the dummy treatment.
• About 19 in 1,000 women taking HRT had heart attacks. This compared with 15 in 1,000 taking the dummy treatment.
• About 15 in 1,000 women taking HRT had strokes. This compared with 11 in 1,000 women taking the dummy treatment.
• About 8 in 1,000 women taking HRT got blood clots in their lungs. This compared with 4 in 1,000 women taking the dummy treatment.

HRT can have other side effects that are less serious. But they can be annoying. Some of the more common ones are:

• Unexpected spotting and bleeding from your vagina – monthly sequential preparations should produce regular, predictable and acceptable bleeds starting towards the end, or soon after, the progestogen phase. Breakthrough bleeding is common in the first 3-6 months of continuous combined and long-cycle HRT regimens
• Headaches
• Soreness and swelling of your breasts
• Changes in your mood.

HRT and Osteoporosis (Bone Loss)

Hormone replacement therapy (HRT) protects the bonesafter menopause and reduces the chances of fracture. But there is a small risk of serious side effects from HRT. These include breast cancer, heart attack, stroke, and blood clots. For this reason, doctors don’t usually recommend HRT as the first choice for treating osteoporosis. Also, HRT may not work as well as a drug called alendronate. That drug belongs to a group called bisphosphonates.HRT works best for preventing osteoporosis if you start taking it early in the menopause and keep taking it for up to five years. In a big review of studies, women taking HRT for at least a year got fewer broken bones in their spine than women taking a dummy treatment (called a placebo), calcium alone, calcium plus vitamin D, or no treatment. Their chances of breaking a bone in their spine were about one-third lower.In another, smaller study, women taking HRT for at least a year got fewer broken bones in parts of their body other than their spine. But this happened mostly in women under 60.

HRT Preparations

There are more than 60 different preparations  of HRT, in various  formulations, as below.

• a cream or gel, which can be applied to the skin or directly into the vagina if you are experiencing vaginal dryness
• tablets, which can be taken by mouth or placed directly into your vagina to treat dryness
• a patch that you stick on your skin
• an implant – your doctor inserts small pellets of oestrogen under the skin of your abdomen (tummy), buttock or thigh under a local anaesthetic (the skin is numbed)

However,there  are three main types are discussed below :

Oestrogen-only HRT

This type of HRT is usually recommended for women who have had their womb and ovaries removed by hysterectomy. As there is no longer a uterus, there is no need to take progestogen because there is no risk of endometrial cancer (cancer of the womb lining).

Cyclical HRT

Cyclical HRT (also known as sequential HRT) is recommended for women who are experiencing menopausal symptoms but still have their periods.There are two types of cyclical HRT:

• monthly HRT – where you take oestrogen every day and also take progestogen at the end of your menstrual cycle for 14 days
• three-monthly HRT – where you take oestrogen every day and also take progestogen for 14 days every 13 weeks

Monthly HRT is normally recommended for women who are having regular periods. You will continue to have monthly periods until your menopause causes them to stop. Three-monthly HRT is normally recommended for women who are having irregular periods. You should experience your period every three months.It is useful to maintain regular periods so you know when your periods naturally stop, and when you are likely to progress to the last stage of the menopause.

Continuous combined HRT

Continuous combined HRT is usually recommended for women who are post-menopausal. A woman is normally defined as being post-menopausal if she has not had a period for a year. As the name suggests, continuous HRT involves taking oestrogen and progestogen every day, without a break.

When and How to Stop HRT

Most women should be able to stop taking HRT once their menopausal symptoms have finished . Menopausal symptoms (hot flushes and sweats) last on average between 2-5 years but there is considerable individual difference and they may last decades in some women. A trial of withdrawal of HRT should be considered in:

• Those women symptom-free on HRT after 1-2 years.
• Women who have been on HRT for longer than 5 years.
• Women on HRT for premature menopause after the age of 50.

There is scanty evidence to advice on whether to stop HRT abruptly or stop gradually. Many women do not notice symptoms with an abrupt cessation, whilst others revert swiftly to their original problems with hot flushes, sweats and sleep disturbance. Some experts suggest gradual reduction of HRT dose

• Oestrogen-only tablets – decrease from 2 mg to 1 mg daily for 1-2 months and then take on alternate days for a further 1-2 months.
• Oestrogen-only patches – gradually reduce patch strength to 25 micrograms daily by reducing a patch strength every month. Half a 25 microgram patch can then be used for a further 1-2 months.
• Cyclical combined tablets – step down to pack containing 1 mg estradiol daily for 1-2 months, then cut the tablet in half for 1-2 months and throw away the unused half. This ensures that the women still gets progestogen.
• Cyclical combined patches – gradually reduce the patch strength as for oestrogen-only patches but ensure use of oestrogen-only patches for just 2 weeks of cycle and combined patches for the next 2 weeks.
• Continuous combined tablets or patches – reduce dose gradually to the lowest strength of tablets or patches and then use half a tablet daily or half a patch for a further 1-2 months.

Vasomotor symptoms frequently recur on stopping HRT and, where severe, restarting treatment may be the most appropriate course of action. Once your HRT has finished, you may need additional treatment for vaginal dryness and to prevent osteoporosis. Creams and lubricants are available for vaginal dryness, and there are medicines called bisphosphonates that have proved to be successful in the treatment of osteoporosis.

Alternatives to HRT

If you are unable or unwilling to take hormone replacement therapy (HRT), some alternative approaches and treatments may help to control symptoms of the menopause. These are:.

Tibolone

Tibolone is a synthetic hormone that can be used as an alternative to HRT. It contains a combination of oestrogen and progestogen, so you only need to take one tablet. It is a selective oestrogen receptor modulator (SERM) which has oestrogenic, progestogenic and androgenic properties.

It can be used in women with an intact uterus who have had no bleeding for more than one year, without the need for cyclical progesterone. Randomised controlled trials suggest it may be helpful in improving sexual function and vasomotor symptoms. It may also reduce the risk of spinal fractures.

Tibolone has the same associated health risks as continuous combined HRT. If you are unable to take HRT for medical reasons – for example, you have a history of breast cancer or heart disease – it is likely you will not be able to take tibolone. There may be a small increased risk of stroke, endometrial and breast cancer (including breast cancer recurrence) with tibolone. The risk profile is similar to combined HRT in younger women. However, in women over the age of 60 years, the increased stroke risk means that the risks outweigh the benefits.

Antidepressants

The following antidepressants have proved effective  in treating hot flushes in some women:

• Selective serotonin reuptake inhibitors (SSRIs) – paroxetine, fluoxetine or citalopram.
• Serotonin-noradrenaline reuptake inhibitors (SNRIs) – venlafaxine.

Side effects of these antidepressants include: Nausea, blurred vision, diarrhoea or constipation, dizziness, dry mouth, loss of appetite, sweating, feeling agitated, insomnia (not being able to sleep).

SSRIs have also been associated with a loss of libido (sex drive).

Clonidine

Clonidine is a medicine originally designed to treat high blood pressure, but studies have shown that it may reduce hot flushes in some women. Side effects of clonidine include: low blood pressure , dizziness, drowsiness, dry mouth, fluid retention. Using clonidine is not recommended if you have depression or insomn ia, as it could make these conditions worse.

Alternative medicines

Claims have been made for a number of herbal supplements for the treatment of the menopause. These include: soya beans, ginseng, ginkgo biloba, black cohosh, red clover and kava . There is no clear evidence that any of these are effective. Little is known about their long -term effects. Kava and red clover have been linked to liver disease. Avoid taking black cohosh, ginseng and red clover if you have a history of breast, ovarian or endometrial cancer, as there is some evidence they could trigger a relapse of the condition.

HRT and Ovarian cancer

Cancer Research UK summarises the ovarian cancer risk associated with HRT as follows: that research has shown that taking HRT slightly increases the risk of developing ovarian cancer and that the longer HRT is taken, the more the risk increases. However: when the HRT is stopped, the risk goes back down to normal over a few years

HRT and Endometrial cancer

If you take your progestogen as directed, there is no increased risk of developing endometrial cancer. It is very important to take your progestogen as directed because only taking oestrogen will raise your risk of developing endometrial cancer significantly.

Stroke and heart attacks

The Stroke Association recently produced a factsheet that summarises the stroke and heart attack risks of HRT. It concluded that “HRT carries a small risk of stroke and heart attacks because it increases the risk of abnormal blood clotting and raised blood pressure”.

Management of HRT side-effects

Side-effects account for 35% of HRT continuously or randomly through a progestogen phase). discontinuations.  These may  be oestrogen-related (occurring cycle)  or  progestogen-related  (occurring  cyclically  during

Side effects of oestrogen

Side effects associated with oestrogen include: fluid retention, bloating,, breast tenderness or swelling, nausea, leg cramps, headaches and indigestion. In some cases, making small lifestyle changes can help to relieve side effects. For example:

• taking your oestrogen dose with food may help to reduce nausea and indigestion
• eating a low-fat, high-carbohydrate diet may reduce breast tenderness
• regular exercise and stretching can help to reduce leg cramps

Side effects of progestogen

Side effects associated with progestogen include: fluid retention, breast tenderness, headaches, mood swings, depression, acne and backache

Managing Oestrogen-related side effects

These are usually transient and resolve spontaneously with increasing duration of use. E ffort should be made to persist with a particular treatment for at least 12 weeks. Side-effects are more likely to occur or be problematic where there has been a longer interval since ovarian failure. Oestrogen – related side-effects include:

• Breast tenderness or enlargement – try a low fat, high carbohydrate diet. Evening primrose oil is no longer recommended.
• Leg cramps – try exercise and calf stretching.

• Nausea and dyspepsia – adjust time of dose, and administer with food.
• Headaches – try oestrogen patches, as this may produce more stable oestrogen levels.

 

For side-effects persisting beyond 12 weeks:

• Reduce the oestrogen dose (though this may limit original menopausal symptom control).
• Change the oestrogen type, i.e. between oestradiol and conjugated oestrogens.
• Change the route of delivery.

Managing Progestogen-related side-effects

These may be more problematic and are usually connected to the type, duration and dose of progestogen. They include: Fluid retention, Headaches or migraine, Breast tenderness, Mood swings and depression, Acne, Lower abdominal and back pain

Again encourage perseverance, as symptoms may improve over 3 months. If there is no improvement, strategies include:

• Change of progestogen type.
• Reduce dose (but not below recommended ceiling required for endometrial protection).
• Change route away from oral therapy.
• Reduce duration of therapy – change from a 14-day progestogen to a 12-day monthly sequential replacement regime.
• Reduce frequency, using long-cycle HRT – this is progestogen for 14 days every 3 months (only suitable for women without natural regular cycles).
• Use of continuous combined therapy or tibolone often reduces progestogen-related side-effects with established use (only suitable for postmenopausal women).

Bleeding

Monthly sequential preparations should produce regular, predictable and acceptable bleeds starting towards the end, or soon after, the progestogen phase. This pattern may be altered by:

• Not taking the HRT reguarly as instructed
• Drug interaction
• Gastrointestinal upset

Breakthrough bleeding is common in the first 3-6 months of continuous combined and long-cycle HRT regimens. Where pelvic pathology is excluded, strategies for tackling bleeding problems include:

• Heavy or prolonged bleeding – increase dose, duration or type of progestogen. Consider the use of the Mirena – levonorgestrel-releasing intrauterine system (IUS) – combined with oral or transdermal oestrogen.
• Bleeding early in progestogen phase – increase dose or change type of progestogen.
• Painful bleeding – change type of progestogen.
• Irregular bleeding – change regimen or increase progestogen.
• No bleeding – occurs in 5% of women and is due to an atrophic endometrium. Need to exclude pregnancy in perimenopausal women and to ensure compliance with the progestogen element of the HRT regimen.

 

Switching from cyclical HRT to continuous combined HRT

Cyclical HRT can be changed to continuous combined HRT when the woman is considered to be postmenopausal. This is generally:

• Women older than 54 (about 80% of women are postmenopausal by this age).
• Women who experienced 6 months of amenorrhoea or had increased follicle-stimulating hormone levels in their mid-40s. Such women are likely to be postmenopausal after taking several years of cyclical HRT.

 

Investigations before starting HRT

Investigations  are not usually necessary before starting HRT unless:

• There is sudden change in menstrual pattern, intermenstrual bleeding, postcoital bleeding, or postmenopausal bleeding – refer for endometrial assessment.
• There is a personal or family history of VTE – a thrombophilia screen may be helpful.
• There is a high risk of breast cancer – consider mammography or MRI scan; refer to NICE guidance on familial breast cancer
• The woman has arterial disease or risk factors for arterial disease – check lipid profile.

 

Prescribing HRT

Delivery routes include: Continuous or cyclical oral therapy, Patches, Creams or gels, Nasal sprays, Local devices such as the progesterone-releasing Mirena® coil, The oestrogen-releasing vaginal ring, and Subcutaneous implants. The choice of delivery route depends partly on patient preference but there may also be other advantages to certain delivery routes:

• Transdermal patches may be preferred to oral administration in some situations: o If there is poor control of symptoms with oral treatment.

1. If there are side-effects such as nausea.
2. There may be a lower risk of VTE with patches.
3. If the woman is taking a liver enzyme-inducing drug.
4. If the woman has a bowel disorder which may affect oral absorption.
5. Steadier hormone levels with patches may be beneficial if there is a history of migraine.
6. Most HRT tablets contain lactose, so patches are preferred  in lactose sensitivity.

 

• Low-dose vaginal oestrogen (tablet, cream, pessary, or vaginal ring) may be preferred if symptoms are primarily urogenital.
• Estradiol implants are sometimes used after hysterectomy if symptoms cannot be controlled using other delivery routes.
• Levonorgestrel -releasing intrauterine system (Mirena®) plus oestrogen component may be used if:

1. Progestogen side-effects are experienced with other progestogen preparations and delivery routes.
2. Contraception is still needed.
3. There is persistent heavy bleeding on cyclical combined HRT and normal investigations.

In discussing risk, its good to remember that 5 in 1,000 non HRT-using women aged 50-59 years will have a VTE over five years, increasing to 8 in 1,000 in the 60-69 year age bracket.In women using oestrogen-only HRT, 7 per 1,000 of the 50-59 year-olds (i.e. an extra two cases) and 10 per 1,000 in the 60-69 year olds (again an extra two cases) will experience a VTE in a five-year period. In women using combined HRT, 12 women aged 50-59 years (i.e. an extra seven cases) and 18 women aged 60-69 years (an extra ten cases) will experience a VTE in five years.