Hormone replacement therapy: update and practical prescribing

Peri-menopause and menopause are not a disease or disorder but a natural change that occurs at midlife, and a normal part of the aging process (Banks, 2019). The average age of menopause in the UK is 51, although symptoms usually start prior to this, around the age of 47-48 (Bagness and Holloway, 2015). This time is called the perimenopause. This is defined as the time when a woman has irregular cycles of ovulation and menstruation leading up to menopause and continuing until 12 months after her final period (National Institute for Health and Care Excellence (NICE), 2015). Menopause is defined as a biological stage in a woman's life that occurs when she stops menstruating and reaches the end of her natural reproductive life (NICE, 2015). Usually, it is defined as having occurred when a woman has not had a period for 12 consecutive months (for women reaching menopause naturally). The changes associated with menopause occur when the ovaries stop maturing eggs and secreting oestrogen and progesterone (NICE, 2015). These definitions are medical in nature and it is important to remember that ‘menopause is a major clinical event that is universally experienced by women, but affects each individual woman uniquely’ (Andany et al, 2016).

Menopause symptoms

Symptoms are experienced by around 70-80% of women during the perimenopause and menopause (O'Neill and Eden, 2012). The symptoms are varied and include vasomotor symptoms, such as flushing and night sweats, palpitations, feeling faint, and nausea (Noble, 2018). There are numerous psychological symptoms such as nervousness, reduced interest in socialising, anxiety or panic attacks, mood changes (irritability, anger, rage, agitation), depression, poor self-esteem and sleep disturbances. There may be changes in sexual function, such as loss of libido or difficulties with arousal, or genitourinary symptoms, such as vaginal dryness, itching, urinary frequency, and incontinence (Jaffe, 2013). Women also experience cognitive changes such as changes to memory and concentration, joint aches and pain, and general skin itching (Hillard et al, 2017; Noble and Holloway, 2019).

The importance of lifestyle measures cannot be underestimated. Diet, exercise, stopping smoking, and reducing caffeine can all contribute to an improvement of menopausal symptoms (Holloway, 2017), however further discussion of this is outside the scope of this article.

There are many different alternative treatments (herbal, aromatherapy) and non-hormonal prescribable treatments but the NICE guidelines (2015) state hormone replacement therapy (HRT) is the first-line treatment for menopause symptoms.

What is HRT?

Oestrogen

The oestrogen used in HRT is considered natural, as it is molecularly identical to naturally-occurring human oestrogen (Hillard et al, 2017). It is the lack of oestrogen in the body at the time of menopause that causes symptoms. By replacing the oestrogen, the symptoms are relieved. There are several available routes of administration of oestrogen: oral, transdermal as a patch or a gel, or a subcutaneous implant. Implants are usually fitted in a specialised menopause service, as they are not licensed in the UK.

Progestogen

Using oestrogen without progestogen in women with a uterus is associated with an increased risk of endometrial hyperplasia and, therefore, a potential endometrial cancer (Stute et al, 2018). If a woman has not had a hysterectomy, she needs to take progestogen with the oestrogen. Depending on when the womens' last period was, the progestogen is taken either sequentially or continuously. The progestogens used in HRT are mainly synthetic. They are available in tablet form, a patch, or the Mirena® intrauterine system. The Mirena is the only licensed intrauterine system for use as HRT – it can be used for 5 years, although this is outside of the product licence (FSRH, 2017).

Testosterone

Testosterone generally declines from a woman's mid-thirties onwards. The greatest decline is seen in women who have had their ovaries removed. Symptoms experienced following removal of the ovaries include loss of libido, lack of energy and low mood. These symptoms may respond to testosterone replacement in conjunction with HRT.

In 2019, a global consensus on testosterone use was published (Davis et al, 2019), which concluded that testosterone therapy for women is indicated for the treatment of hypoactive sexual desire disorder/dysfunction (HSDD) and this should be diagnosed prior to starting testosterone. This would include women who have low libido at menopause. They also concluded that no severe adverse events are likely during physiological testosterone use, when used in women without cardiometabolic risk factors. Transdermal testosterone is the preferable route as it has a neutral lipid profile. The only route currently available in the UK is a transdermal gel (JFC, 2017), and subcutaneous implants. The effects of testosterone on cognitive and musculoskeletal health requires further research (Islam et al, 2019).

There are no licensed testosterone preparations for women in the UK at present (Panay, 2019). The British Menopause Society states that the data from female preparations of testosterone can be extrapolated to products licensed in men (mainly gels) to be prescribed off-label in female doses (Panay, 2019). The most commonly used in the United Kingdom are Testogel and Tostran. The following information is taken directly from the British Menopause Society's Tool for Clinicians: Testosterone replacement in menopause (2019)

• Testogel (Besins Healthcare UK) (1% testosterone gel in 5.0 g sachets containing 50 mg testosterone): Starting dose 1/10 of a sachet/day = 5 mg/day ie each sachet should last 10 days
• Tostran (Kyowa Kirin Ltd) (2% testosterone gel in a canister containing 60 g ) : Starting dose 1 metered pump of 0.5 g = 10 mg on alternate days – each canister should last 240 days
• AndroFeme (Lawley Pharma) (1% testosterone cream in 50 ml tubes with screw cap): Starting dose 0.5 ml/day = 5 mg/day ie each tube should last 100 days
• Testosterone Implants (Smartway Pharma) (100 mg implanted pellets) Unlicensed – imported from USA.
• AndroFeme is not currently available via the NHS. Testosterone implants, which are designed for female use, are only available on the NHS through agreement with the local formulary committee (Panay, 2019). NICE (2015) states that clinicians should consider testosterone supplementation for menopausal women with low sexual desire if HRT alone is not effective.

Indications for HRT

Women with vasomotor symptoms (flushes and sweats) should be offered HRT after discussing the long-term benefits and risks. HRT should be considered to improve low mood that has arisen as a result of menopause (NICE, 2015).

Contraindications and cautions

There are several contraindications to HRT and these are: breast cancer, unexplained vaginal bleeding, active liver disease, and uncontrolled hypertension (Abernethy, 2015; Roberts and Hickey, 2016). HRT can be used with caution in the following conditions: migraine (should be given transdermally), epilepsy, fibroids, and endometriosis (Abernethy, 2015).

Is route of oestrogen important?

There is observational evidence that transdermal oestrogen (patch, gel or spray), is associated with a lower risk of deep vein thrombosis and stroke than oral oestrogen (Roberts and Hickey, 2016). Transdermal oestrogen is preferable for women with a higher thrombolic risk, such as those with a body mass index (BMI) over 30, hypertension, or migraines (Loder, 2009; NHS, 2019). Transdermal oestrogen is also the preferred route for women living with HIV, as it is a prothrombotic condition (Bibas et al, 2011; Rasmussen et al, 2011).

Is the type of progestogen important?

The majority of progestogens used in HRT are synthetic and derived from different sources. Progestogens that are C19 testosterone derivatives, such as norethisterone and levonorgestrel, have better cycle control, are androgenic so may be helpful for libido, but have an unfavourable effect on lipids (Shaw, 2017). Medroxyprogesterone is a C21 derivative, taken orally, androgenic, and has a favourable effect on lipids.

Dydrogesterone is a C21 progestogen, which is non-androgenic but has a preferable risk profile in relation to breast cancer and cardiac health (Fournier et al, 2008; Jiang and Tian, 2017). Micronised progesterone is natural, and has fewer progestogenic side effects, no impact on lipids, and a smaller risk of breast cancer when compared to other progestogens (Stute et al, 2018). It is, however, less helpful for cycle/bleeding control (Shaw, 2017). Table 1 illustrates the available progestogens and their brand names.

Breast cancer and HRT

Breast cancer is a complex disease, therefore the link between HRT and breast cancer is also complex. Evidence suggests that taking combined HRT (oestrogen and progestogen) for longer than 5 years is associated with an increased risk (Abernethy, 2015). The Lancet published a meta-analysis in August 2019 of the type and timing of HRT and breast cancer risk. This was widely discussed in mainstream media. Generally, the findings echoed the NICE (2015) guidelines on menopause diagnosis and management, that HRT does slightly increase the risk of breast cancer (Royal College of Obstetricians and Gynaecologists and the British Menopause Society, 2019). Following the publication of the study in the Lancet, the Medicines and Healthcare products Regulatory Agency (MHRA) released a statement of guidance when prescribing HRT. This included:

• HRT should be used at the lowest dose for the shortest amount of time
• Women who use HRT for longer than 1 year have a higher risk of breast cancer than women who have never used it
• The increased risk of breast cancer is seen with all types of HRT except topical vaginal oestrogen.

There is an infographic chart that can be used to explain breast cancer risk to women, available on the British Menopause Society website (2015). This is currently being updated, please check the BMS website for the most up to date version.

It is important to note that obesity and alcohol use are bigger risk factors for breast cancer than HRT and women should be counselled on these factors too (Royal College of Obstetricians and Gynaecologists [RCOG] and British Menopause Society [BMS], 2019).

Stroke

Oral oestrogen is associated with an increased risk in stroke. However, the baseline risk of stroke in women under 60 is low, so the increased risk is not significant (Shaw, 2017). If there are other risk factors such as hypertension, obesity or a family history of stroke, then the transdermal route would be preferable.

Venous thromboembolism

The risk of venous thromboembolism (VTE) increases when using oral oestrogen compared to transdermal oestrogen. This is because when oestrogen is taken orally it is absorbed from the gastrointestinal tract and undergoes first pass metabolism. The first pass metabolism of oestradiol leads to an increased production of blood coagulation factors and alteration of the clotting cascade (Hamoda, 2016). A higher dose of oestrogen is taken orally than transdermally as metabolic changes occur before reaching the general circulation (Voican et al, 2012; Janssen-Cilag, 2017).

Ovarian cancer

There may be an association between ovarian cancer and HRT, but there is insufficient evidence to claim HRT causes ovarian cancer. After 5 years of using HRT there is a 0.1% increase in the risk of ovarian cancer (Shaw, 2017).

How to prescribe HRT

If a woman is still having periods and has had a period within the last 12 months, then a sequential HRT preparation is the most appropriate. A sequential regimen mimics the normal menstrual cycle: the oestrogen is taken daily and the progestogen (depending on which is type is used) is taken for 12-14 days out of 28 days. If the periods are fairly regular then HRT should be started at the beginning of a cycle, which should minimise irregular bleeding. If the woman has not had a period for several months then HRT can be started at any time (Hillard et al, 2016). If the woman is post-menopausal then HRT can be started straight away with a ‘no-bleed’ regime. This regimen is continuous and the oestrogen and progestogen are both taken every day. The Mirena® intrauterine system can be used for the progestogen component in peri-menopausal and post-menopausal women.

If a woman is using a sequential regime, she can change to continuous HRT at the age of 54. This is because 80% of women would be considered post-menopausal by this time, so this is considered an appropriate time to switch (Hillard et al, 2017). This is more convenient for women, as they will have HRT with no bleeding and the risk of endometrial cancer will be eradicated, as a continuous combined regime provides optimal endometrial protection (O'Neill and Eden, 2012).

Figure 1. How to prescribe hormone replacement therapy (HRT)

Side-effects of systemic HRT

Unscheduled vaginal bleeding is a common side effect of HRT within the first 3-6 months of treatment, but should be reported at the 3-month review appointment, or promptly if it occurs after the first 3 months. Other side effects and the likely hormone responsible are listed in Table 2.

How to monitor following a prescription of HRT

Treatment for short-term menopausal symptoms should be reviewed initially at 3 months, to assess efficacy and tolerability. Reviews can be held annually thereafter, unless there are clinical indications for an earlier review, such as treatment ineffectiveness, side effects or adverse events (NICE, 2015).

When to stop HRT

The decision to stop HRT should be made on an individual basis and guidelines state that, as long as there are no contraindications, it can be used for as long as the woman feels the benefits outweigh the risks (Roberts and Hickey, 2016).

Gradually reducing HRT may limit recurrence of symptoms in the short term, but gradually reducing or immediately stopping HRT makes no difference to symptoms in the longer term (NICE, 2015).

Current shortage of HRT products

There are currently supply issues affecting the supply of some HRTs in the UK at present. Angelique, an oral HRT, was discontinued in early 2019 (BMS, 2019a) and Duavive has been recently been discontinued (BMS, 2019c). The shortages are due to issues such as manufacturing shortages (BMS, 2019b), while others are related to supply issues.

The British Menopause Society website is updated on a monthly basis, which you can check for the most accurate and up to date information on HRT availability.

Conclusion

Menopause is a normal transition in life that will be experienced by all women. The symptoms vary and can affect women in different ways and some women may not get any symptoms at all. HRT is the first line treatment for menopausal symptoms and, when used under the age of 60, the benefits outweigh the risks. There is NICE guidance to support the use of HRT for the management of menopause symptoms. Despite there being shortages of certain HRTs at present, there are still lots of formulations and combinations available for it to continue to be used for treating symptoms associated with the menopause.

KEY POINTS:

• The transdermal route of oestrogen is widely available and has a better safety profile than oral oestrogen in terms of VTE and CVA risk so is preferable when other risk factors are present such as hypertension, smoking and obesity
• Progestogens are derived from different sources and each has a different side-effect and risk profile
• Testosterone is may be beneficial for women with low libido and should be considered for women if HRT alone is not effective
• An up to date list of available preparations of HRT is available on the British Menopause Society's Website

CPD reflective practice:

• What type of HRT would you prescribe to a woman whose last period was 6 months ago?
• Reflect upon the last patient you saw for menopause symptoms. What treatments did you offer? Did you discuss the risks, benefits and side-effects of each treatment?
• Reflect upon the last time you prescribed HRT: what route and which progestogen did you prescribe? What was your rational for these choices?