Hormone Replacement Therapy

Hormone replacement therapy (HRT) is used in perimenopausal and postmenopausal women to alleviate symptoms associated with menopause. These symptoms are associated with a declined in the level of oestrogen. Exogenous oestrogen is given to alleviate the symptoms.

Progesterone needs to be given (in addition to oestrogen) to women that have a uterus. The primary purpose of adding progesterone is to prevent endometrial hyperplasia and endometrial cancer secondary to “unopposed” oestrogen.

Not all menopausal women require hormone replacement therapy. Women have often tried non-hormonal methods of controlling their symptoms before seeking help from their GP. HRT can offer very effective relief from symptoms, and in the majority of women the benefits will outweigh the risks.

TOM TIP: Hormone replacement therapy is a massive topic. If you remember one thing about HRT for your exams, remember the basics of choosing the HRT regime. Women with a uterus require endometrial protection with progesterone, whereas women without a uterus can have oestrogen-only HRT. Women that still have periods should go on cyclical HRT, with cyclical progesterone and regular breakthrough bleeds. Postmenopausal women with a uterus and more than 12 months without periods should go on continuous combined HRT.

 

Non-Hormonal Treatments for Menopausal Symptoms

Non-hormonal treatments may be tried initially, or used when there are contraindications to HRT. Options include:

• Lifestyle changes such as improving the diet, exercise, weight loss, smoking cessation, reducing alcohol, reducing caffeine and reducing stress
• Cognitive behavioural therapy (CBT)
• Clonidine, which is an agonist of alpha-adrenergic and imidazoline receptors
• SSRI antidepressants (e.g. fluoxetine)
• Venlafaxine, which is a selective serotonin-norepinephrine reuptake inhibitor (SNRI)
• Gabapentin

 

Clonidine

Clonidine act as an agonist of alpha-2 adrenergic receptors and imidazoline receptors in the brain. It lowers blood pressure and reduces the heart rate, and is also used as an antihypertensive medication. It can be helpful for vasomotor symptoms and hot flushes, particularly where there are contraindications to using HRT. 

Common side effects of clonidine are dry mouth, headaches, dizziness and fatigue. Sudden withdrawal can result in rapid increases in blood pressure and agitation.

 

Alternative Remedies

Patients might try alternative remedies, although they are not generally recommended as the safety and efficacy is unclear. They can have significant side effects and interact with other medications. These alternative remedies are intended to manage the vasomotor symptoms, such as hot flushes:

• Black cohosh, which may be a cause of liver damage
• Dong quai, which may cause bleeding disorders
• Red clover, which may have oestrogenic effects that would be concerning with oestrogen sensitive cancers
• Evening primrose oil, which has significant drug interactions and is linked with clotting disorders and seizures
• Ginseng may be used for mood and sleep benefits

 

Indications for HRT

The indication for HRT are:

• Replacing hormones in premature ovarian insufficiency, even without symptoms
• Reducing vasomotor symptoms such as hot flushes and night sweats
• Improving symptoms such as low mood, decreased libido, poor sleep and joint pain
• Reducing risk of osteoporosis in women under 60 years

 

Benefits of HRT

In women under 60 years, the benefits of HRT generally outweigh the risks. 

The key benefits to inform women of include:

• Improved vasomotor and other symptoms of menopause (including mood, urogenital and joint symptoms)
• Improved quality of life
• Reduced the risk of osteoporosis and fractures

 

Risks of HRT

Women may be concerned about the risks of HRT. It is crucial to put these into perspective. In women under 60 years, the benefits generally outweigh the risks. Specific treatment regimes significantly reduce the risks associated with HRT.

The risks of HRT are more significant in older women and increase with a longer duration of treatment. The principal risks of HRT are:

• Increased risk of breast cancer (particularly combined HRT – oestrogen-only HRT has a lower risk)
• Increased risk of endometrial cancer
• Increased risk of venous thromboembolism (2 – 3 times the background risk)
• Increased risk of stroke and coronary artery disease with long term use in older women 
• The evidence is inconclusive about ovarian cancer, and if there is an increase in risk, it is minimal

 

These risks do not apply to all women:

• The risks are not increased in women under 50 years compared with other women their age
• There is no risk of endometrial cancer in women without a uterus
• There is no increased risk of coronary artery disease with oestrogen-only HRT (the risk may even be lower with HRT)

 

Ways to reduce the risks:

• The risk of endometrial cancer is greatly reduced by adding progesterone in women with a uterus
• The risk of VTE is reduced by using patches rather than pills

 

Contraindications to HRT

There are some essential contraindications to consider in patients wanting to start HRT:

• Undiagnosed abnormal bleeding
• Endometrial hyperplasia or cancer
• Breast cancer
• Uncontrolled hypertension
• Venous thromboembolism
• Liver disease
• Active angina or myocardial infarction
• Pregnancy

 

Assessment Before HRT

Before initiating HRT, there are a few things to check and consider:

• Take a full history to ensure there are no contraindications
• Take a family history to assess the risk of oestrogen dependent cancers (e.g. breast cancer) and VTE
• Check the body mass index (BMI) and blood pressure
• Ensure cervical and breast screening is up to date
• Encourage lifestyle changes that are likely to improve symptoms and reduce risks

 

Choosing the HRT Formulation

There are three steps to consider when choosing the HRT formulation:

Step 1: Do they have local or systemic symptoms?

• Local symptoms: use topical treatments such as topical oestrogen cream or tablets
• Systemic symptoms: use systemic treatment – go to step 2

 

Step 2: Does the woman have a uterus?

• No uterus: use continuous oestrogen-only HRT
• Has uterus: add progesterone (combined HRT) – go to step 3

 

Step 3: Have they had a period in the past 12 months?

• Perimenopausal: give cyclical combined HRT
• Postmenopausal (more than 12 months since last period): give continuous combined HRT

 

Options for Oestrogen Delivery

Oestrogen is the critical component of HRT for reducing the symptoms of menopause. There are two options for delivering systemic oestrogen:

• Oral (tablets)
• Transdermal (patches or gels)

 

Patches are more suitable for women with poor control on oral treatment, higher risk of venous thromboembolism, cardiovascular disease and headaches. 

 

Options for Progesterone Delivery

Progesterone is added to HRT to reduce the risk of endometrial hyperplasia and endometrial cancer. Progesterone is only required in women that have a uterus. Women without a uterus do not need progesterone, and can have oestrogen-only HRT. 

Cyclical progesterone, given for 10 – 14 days per month, is used for women that have had a period within the past 12 months. Cycling the progesterone allows patients to have a monthly breakthrough bleed during the oestrogen-only part of the cycle, similar to a period. 

Continuous progesterone is used when the woman has not had a period in the past: 

• 24 months if under 50 years 
• 12 months if over 50 years

 

Using continuous combined HRT before postmenopause can lead to irregular breakthrough bleeding and investigation for other underlying causes of bleeding.

You can switch from cyclical to continuous HRT after at least 12 months of treatment in women over 50, and 24 months in women under 50. Switch from cyclical to continuous HRT during the withdrawal bleed. Continuous HRT has better endometrial protection than cyclical HRT.

 

There are three options for delivering progesterone for endometrial protection:

• Oral (tablets)
• Transdermal (patches)
• Intrauterine system (e.g. Mirena coil)

 

Cyclical combined HRT options include sequential tablets or patches containing continuous oestrogen with progesterone added for specific periods during the cycle.

The Mirena coil is licensed for four years for endometrial protection, after which time it needs replacing. The Mirena coil has the added benefits of contraception and treating heavy menstrual periods. It can cause irregular bleeding and spotting in the first few months after insertion. This usually settles with time and many women become amenorrhoeic.

 

Types of Progesterone

The terms around progesterone can be confusing. There are some key definitions to remember:

• Progestogens refer to any chemicals that target and stimulate progesterone receptors
• Progesterone is the hormone produced naturally in the body
• Progestins are synthetic progestogens

 

There are two significant progestogen classes used in HRT. If the woman experiences side effects, consider switching the progestogen class. They can be described as C19 and C21 progestogens, referring to the chemical structure and number of carbon atoms in the molecule. 

C19 progestogens are derived from testosterone, and are more “male” in their effects. Examples are norethisterone,  levonorgestrel and desogestrel. These may be helpful for women with reduced libido. 

C21 progestogens are derived from progesterone, and are more “female” in their effects. Examples are progesterone,  dydrogesterone and medroxyprogesterone. These may be helpful for women with side effects such as depressed mood or acne.

 

Example Regimes

In a women with no uterus:

• Oestrogen-only pills, for example, Elleste Solo or Premarin
• Oestrogen-only patches, for example, Evorel or Estradot

 

In a perimenopausal woman with periods:

• Cyclical combined tablets, for example, Elleste-Duet, Clinorette or Femoston
• Cyclical combined patches, for example, Evorel Sequi or FemSeven Sequi
• Mirena coil plus oestrogen-only pills, for example, Elleste Solo or Premarin
• Mirena coil plus oestrogen-only patches, for example, Evorel or Estradot

 

In a postmenopausal woman with a uterus:

• Continuous combined tablets, for example, Elleste-Duet Conti, Kliofem or Femoston Conti
• Continuous combined patches, for example, Evorel-Conti or FemSeven Conti 
• Mirena coil plus oestrogen-only pills, for example, Elleste Solo or Premarin
• Mirena coil plus oestrogen-only patches, for example, Evorel or Estradot

 

TOM TIP: The key to HRT is to remember the principles, so that you can counsel women and look up the specific regimes when required. The best way of delivering oestrogen is with patches, due to the reduced risk of venous-thromboembolism. The best way of providing progesterone is with an intrauterine device, for example, the Mirena coil. The coil has the added benefits of contraception and treating heavy menstrual periods. Additionally, women will not experience progestogenic side effects.

 

Tibolone

Tibolone is a synthetic steroid that stimulates oestrogen and progesterone receptors. It also weakly stimulates androgen receptors. The effects on androgen receptors mean tibolone can be helpful for patients with reduced libido. 

Tibolone is used as a form of continuous combined HRT. Women need to be more than 12 months without a period (24 months if under 50 years). They would be expected not to have breakthrough bleeding. Tibolone can cause irregular bleeding, resulting in further investigations to exclude other causes.  

 

Testosterone

Testosterone is a male sex hormone (androgen). It is naturally present in low levels in women. Menopause can be associated with reduced testosterone, resulting in low energy and reduced libido (sex drive). Treatment with testosterone is usually initiated and monitored by a specialist. It is given by transdermal application, applied as a gel or a cream to the skin.

 

Additional Management Points

• Follow up three months after initiating HRT to review symptom and side effects
• Side effects often settle with time, so it is worth persisting for at least three months with each regime
• It takes 3 – 6 months of treatment to gain the full effects
• Problematic or irregular bleeding is an indication for referral to a specialist
• Ensure the woman has appropriate contraception
• Stop oestrogen-containing contraceptives or HRT 4 weeks before major surgery (NICE guidelines 2018 – NG89)
• Consider other causes of symptoms where they persist despite HRT (e.g. thyroid, liver disease and diabetes)

 

Contraception with HRT

Hormone replacement therapy does not act as contraception. It is important to ensure perimenopausal women have adequate contraception. Common options are:

• Mirena coil
• Progesterone only pill, given in addition to HRT

 

Side effects

The oestrogen and progesterone components of HRT cause different side effects. 

 

Oestrogenic side effects:

• Nausea and bloating
• Breast swelling
• Breast tenderness
• Headaches
• Leg cramps

 

Progestogenic side effects: 

• Mood swings
• Bloating
• Fluid retention
• Weight gain
• Acne and greasy skin

 

Where patients experience side effects, it is worth changing the type of HRT or the route of administration (switch between patches and pills).

Patients with progestogenic side effects may do better switching to an HRT with a different form of progesterone. For example, patients with acne and mood swings may do better with a dydrogesterone progesterone (e.g. Femoston). In contrast, patients with reduced libido may do better with a norethisterone progesterone (e.g. Elleste-Duet). Progestogenic side effects can be avoided altogether by using a Mirena coil for endometrial protection. 

Unscheduled bleeding can occur in the first 3 – 6 months of HRT (in women with a uterus). If unscheduled bleeding continues, consider referral for investigations, particularly regarding endometrial cancer.

 

Stopping HRT

There is no specific regime for stopping HRT. It can be reduced gradually or stopped abruptly, depending on the preference of the woman. This choice does not affect long term symptoms. Gradually reducing the HRT may be preferable to reduce the risk of symptoms recurring suddenly.

 

Last updated June 2020