In the second of a two-part series on HRT, Dr Toni Hazell addresses prescribing issues, outlining the factors to consider when initiating treatment

Image of Dr Toni Hazell

Dr Toni Hazell

Read this article to learn more about:

  • when to start hormone-replacement therapy (HRT), and whether to initiate a continuous or a sequential preparation
  • how to manage women who still need contraception while taking HRT
  • treatment options available for women in whom HRT is contraindicated, or who do not want to take a hormonal treatment.

Read this article online at: GinP.co.uk/456952.article

Reflect on your learning after reading this article with our reflective template at: GinP.co.uk/454221.article

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Diagnosis of the menopause was covered in the first article in this series,1 and focused mainly on the vasomotor symptoms mentioned in NICE Guideline 23, Menopause: diagnosis and management.2 However, it is important to remember that not every woman presents with drenching night sweats and hot flushes. Women can present with symptoms that are not typically associated with the menopause (Box 1);3 they may be diagnosed with other conditions, such as depression, when their symptoms are in fact due to the menopause.

Box 1: Symptoms associated with menopause3

  • Hot flushes or night sweats (vasomotor symptoms)
  • Cognitive impairment—poor concentration, memory, and ability to multitask
  • Mood disorders—anxiety, mood swings, irritability
  • Disturbed sleep—this may be due to night sweats or to a mood disorder
  • Urogenital symptoms—vulvovaginal irritation, burning, itching, and recurrent urinary tract infections
  • Altered sexual function—reduced libido and dyspareunia, often related to dryness and pain on intercourse
  • Joint and muscle pain
  • Headache
  • Fatigue.

Diagnosis of menopausal symptoms

As discussed in the previous article last month, a woman aged 45 years or older with appropriate symptoms does not need a laboratory test to confirm a diagnosis of menopause.1,2 Follicle-stimulating hormone (FSH) levels are variable during the perimenopause, and it is possible to be misled by normal levels of FSH in a woman who is perimenopausal.4 It is reasonable to treat based on symptoms, and review after 3 months.5 Improvement of symptoms would support a diagnosis of perimenopause. If an initial period of treatment with HRT has not made a difference, then this should raise suspicion for an alternative diagnosis.

Patient considerations

The flowchart shown in Figure 1 outlines the basics of prescribing HRT,4  and will be discussed in more detail in the following sections.

Figure 1- Flowchart for hormone replacement therapy prescribing_PNG

Figure 1: Flowchart for HRT prescribing4

HRT=hormone replacement therapy; sx.=symptoms; LMP=last menstrual period; E.=oestrogen; P.=progestogen; IUS=intrauterine system; COC=combined oral contraception

© Primary Care Women’s Health Forum. Menopause—guidance on management and prescribing HRT for GPs. London: PCWHF, 2020. Available at: pcwhf.co.uk/wp-content/uploads/2021/12/Prescribing-HRT.pdf  Reproduced with permission.

Women without a uterus

For women with systemic symptoms of the menopause, the first thing to consider is whether they have had a hysterectomy. If so, then prescribing is straightforward—in this situation, women only need oestrogen,2 because no progestogen is required to protect the endometrium.5 However, be aware that women who have had a subtotal hysterectomy,6 or a hysterectomy to treat endometriosis,7 may still need combined HRT (oestrogen and progestogen)—if in doubt, check with their gynaecologist. Women without a uterus can be started on an oral or transdermal preparation of oestrogen, to be taken continuously.4 By definition, these women do not need contraception, which removes an element of complexity from prescribing. Examples of HRT preparations are provided in Table 1.

Women with a uterus

Women with an intact uterus will need combined HRT.2 Progesterone is required to guard against the risks of endometrial hyperplasia and malignancy.5 There are two factors to consider—the date of their last menstrual period, and whether contraception is required. If the last period was less than 1 year ago, then a sequential HRT preparation should be used (to avoid irregular bleeding).4 In contrast, if the woman had her last period more than 1 year ago, she can use continuous combined HRT, as set out in Table 1.4

Table 1: HRT preparations4
HRTTablets[A]Second line[A] Transdermal[A]

SEQUENTIAL PREPARATIONS

For patients with:

  • intact uterus
  • perimenopausal—under 1 year or amenorrhoea

Oestradiol 1 mg + norethisterone sequential

Oestradiol 2 mg + norethisterone sequential

Oestradiol + dydrogesterone 1/10 mg sequential

Oestradiol + dydrogesterone 2/10 mg sequential (nonandrogenic)

Oestradiol 50 mcg + levonorgestrel 10 mcg sequential patch

Oestradiol 50 mcg + norethisterone 170 mcg sequential patch

CONTINUOUS COMBINED

Bleed-free HRT; use if:

  • Over 1 year since last period
  • >54 years
  • >3 years on sequential HRT

Oestradiol 2 mg + norethisterone 1 mg continuous

Oestradiol 0.5 mg + dydrogesterone 2.5 mg continuous

Oestradiol 1 mg + dydrogesterone 5 mg continuous

Tibolone 2.5 mg

Can be useful if:

  • bloating on oestrogen
  • poor libido
  • endometriosis

Oestradiol 50 mcg + levonorgestrel 7 mcg continuous patch

Oestradiol 50 mcg + norethisterone 170 mcg continuous patch

UNOPPOSED OESTROGEN

Post hysterectomy

Oestradiol 1 mg tablets

Oestradiol 2 mg tablets

 

Oestradiol patch

25 mcg, 37.5 mcg, 50 mcg, 75 mcg, 100 mcg

Oestradiol 0.06% gel

 

Oestradiol 500 mcg or 1 mg gel sachets

TOPICAL VAGINAL OESTROGEN

   

Oestradiol 10 mcg vaginal pessaries

Oestriol 0.1% cream

Oestradiol vaginal ring

PROGESTOGEN ADJUNCT TO TOPICAL OESTROGEN IF NO HYSTERECTOMY

Medroxyprogesterone 10 mg day 14–28 or 2.5–5 mg daily[B]

Micronised progesterone 200 mg day 14–28 or 100 mg daily[B]

Levonorgestrel intrauterine system 52 mg

Replace after 5 years as per FSRH guidance

 

[A] Use the lowest dose to control symptoms

[B] Day 14–28 (sequential—i.e. still giving periods), daily for continuous combined (bleed-free)

HRT=hormone-replacement therapy; FSRH=Faculty of Sexual & Reproductive Healthcare

© Primary Care Women’s Health Forum. Menopause—guidance on management and prescribing HRT for GPs. London: PCWHF, 2020. Available at: pcwhf.co.uk/wp-content/uploads/2021/12/Prescribing-HRT.pdf Reproduced with permission.

HRT preparations

It is easy to become overwhelmed by the sheer variety of HRT products available and, ideally, a prescriber would become familiar with a few products and use them regularly. However, various shortages of different preparations of HRT mean that you may need to prescribe a wider range of products if women are unable to get hold of their usual HRT.

Oestrogen and progesterone combined in one therapy

A key decision is whether to prescribe oestrogen and progesterone separately or combined into one therapy. Single products containing both oestrogen and a progestogen (such as a combined pill or patch) are available in both sequential and continuous forms. The advantage of this preparation is that it is impossible for the woman to inadvertently continue with the oestrogen while forgetting to take the progestogen. 

Oestrogen and progesterone taken separately

Alternatively, oestrogen can be administered as a patch, gel, or tablet, with progestogen supplied by the Mirena® intrauterine system (IUS),8 or by an oral progestogen such as micronised progesterone.4 Using the Mirena has the advantage of also providing contraception, but it must be changed every 5 years if it is being used as the progestogenic component of HRT.9 Please note that the Faculty of Sexual & Reproductive Healthcare (FSRH) guidance supports extended use of the Mirena IUS for contraception until the age of 55 years if inserted at age 45 years or over, provided that it is not being used as the progestogen component of HRT for endometrial protection.9

If you are prescribing oestrogen plus an oral progestogen, then you should impress upon the woman the importance of taking both, and document this in the notes. Prescribing unopposed oestrogen to a woman with a uterus is medicolegally indefensible,10,11 so make sure that you have systems in place to avoid this. For women who still need contraception, the progesterone-only pill or implant can be used alongside combined HRT,9 which is not in itself a contraceptive.

Body-identical HRT versus custom-compounded bioidentical HRT

A bioidentical hormone is a plant-derived medication that has been structurally modified to mimic natural hormones found in the human body.5 The HRT that we prescribe can therefore be described as bioidentical. The British Menopause Society (BMS) has suggested the term ‘body identical’ to describe prescribed HRT, and it is also known as regulated bioidentical HRT (rBHRT).12

As with everything else we prescribe, rBHRT has an evidence base, and its production is regulated. This means that we can be confident that different batches of the same rBHRT preparation will contain the same amount of the same hormone.12  

Custom-compounded bioidentical HRT

In the past year, many celebrities have gone public with their use of HRT, some of whom have promoted custom-compounded bioidentical HRT (cBHRT), which patients then request from their GP.

However, this type of formulation may contain a variety of different hormones, manufactured by specialist pharmacies based physically in the UK or abroad, and often selling online.12 These preparations are not regulated by the Medicines and Healthcare products Regulatory Agency (MHRA), do not have a strong evidence base, and the amount of hormone present, or the potency, may not be consistent in each dose. The BMS warns that cBHRT is often prescribed by healthcare professionals who do not possess recognised training in treating the menopause, and that blood and saliva tests offered privately to monitor the precise components of cBHRT have no evidence base.12 cBHRT is not available on the NHS, and NICE and the BMS do not recommend its use.5,12

Alternative options

The use of HRT has been dogged by controversy over the years, with large studies about the risks of breast cancer hitting the headlines—this is discussed in more detail in the first article of this series.1 You are likely to see some women who are troubled by menopausal symptoms, but who will not consider HRT or for whom HRT is contraindicated (this includes women with a history of breast cancer). It is important that we can advise these women on the available nonhormonal options, both prescribed and over the counter.

All women should be advised on lifestyle measures such as weight loss (if appropriate), regular exercise, wearing lighter clothing, sleeping in a cooler room, reducing stress, and avoiding triggers such as caffeine, smoking, alcohol, or spicy foods.5 Some women may also find that cognitive behavioural therapy is useful.5

If lifestyle measures are not enough and the woman cannot, or will not, try HRT, there are other prescribed options. Vasomotor symptoms can be treated with the following drugs,5 of which only clonidine has a licence for this indication:

  • selective serotonin reuptake inhibitors (for example, fluoxetine, citalopram, or paroxetine)
  • serotonin and noradrenaline reuptake inhibitors (for example, venlafaxine)
  • alpha-2 adrenergic receptor agonists (for example, clonidine)
  • gabapentinoid drugs (for example, gabapentin). 

Treatment of vaginal symptoms

For those with vaginal symptoms, moisturisers or vaginal lubricants may be helpful.5 Vaginal oestrogen to treat local symptoms of vulvovaginal atrophy can be used alone, or in combination with systemic HRT—this is sometimes needed when systemic HRT has improved systemic symptoms but genital symptoms remain.

If the reason for not using HRT is a past history of breast cancer, then it is worth checking with the woman’s oncologist; they may be happy for her to use vaginal oestrogen, which comes with significantly lower absorption than systemic oestrogen.5  

Herbal remedies

It is more difficult to help and advise women who do not want any prescribed treatments, but would like advice on herbal remedies. We must always be aware that, as with cBHRT, herbal remedies are not all regulated by the MHRA, and so there is no guarantee that each dose contains the same amount of the active ingredient, or indeed any at all. It is medicolegally safer to signpost the patient to reliable information and let them make their own decisions rather than recommending any specific herbal preparations. The Royal College of Obstetricians and Gynaecologists’ patient-facing site13 signposts a leaflet on complementary therapies for menopausal symptoms written by Women’s Health Concern (bit.ly/3rKJB6m),14 which patients may find useful. It covers some basic principles of the use of herbal medicines, such as to look for the Traditional Herbal Registration logo,15 which indicates MHRA registration. This resource also gives information on various herbal remedies and other complementary therapies (for example, acupuncture).14

Other sources of information include the Rock my menopause campaign by the Primary Care Women’s Health Forum,16 and information on the Patient website.17

Testosterone therapy

Many women will find that their symptoms are well controlled by the first preparation of HRT that they are given, and will remain on it for many years. Unfortunately, this is not always the case and, if increasing the dose within the licensed limits does not help and alternative causes for symptoms have been considered and excluded, then some women may benefit from the added use of testosterone,5 particularly for low libido. Testosterone deficiency may also contribute to more general symptoms such as tiredness, low mood, headaches, and reduced cognition.18

There are no UK-licensed testosterone preparations for menopausal women, and so any prescribing is, by definition, off-licence.18 Tibolone is licensed and has mixed androgenic, progestogenic, and oestrogenic effects, so can be used alone for HRT in women who are at least 1 year past their final period.4,19 Tibolone is recommended for women with reduced libido.19 However, the licence only permits short-term use, and any woman wanting to remain on tibolone must do so off licence.20

As always, it is important that we stay within the limits of our competence, and many GPs will feel that the point at which a woman is requesting testosterone, or where standard HRT has not helped, is when referral to a specialist is needed. Indeed, the NICE Clinical Knowledge Summary on menopause advises referral at this point,5 although the actual NICE guideline is not so prescriptive, saying only that clinicians should ‘consider testosterone supplementation for menopausal women with low sexual desire if HRT alone is not effective’.2

In the real world, however, many GPs are operating with little or no access to secondary care menopause services, or with long waits for such services when they do exist. An article such as this is too brief to be the sole basis on which to start prescribing testosterone—those who are interested in gaining confidence in this area may wish to read the BMS information on the subject,18 and to undertake extra training on HRT, which is offered by a variety of organisations.21,22

Summary

Women going through the menopause may present with a variety of symptoms, not just hot flushes and night sweats. It is important to consider the menopause as a cause of, or contributor to, new symptoms that arise in a woman’s 40s or 50s and not to be afraid to treat on the basis of clinical symptoms rather than insisting on a confirmatory blood test.

Key points

  • Women without a uterus should be offered oestrogen-only HRT
  • As progesterone is required for endometrial protection, women with an intact uterus will need combined HRT—consider the date of their last period, and whether contraception is required
  • HRT preparations are available as rBHRT and cBHRT—rBHRT is prescribed, and has an evidence base for its use
  • Advise women that cBHRT preparations have not been regulated by the MHRA, and therefore the amount of hormone present, or the potency, may not be consistent in each dose
  • Consider nonhormonal options and lifestyle measures, such as weight loss (if appropriate) and CBT
  • Seek specialist advice when standard HRT has not helped, or if a woman is requesting testosterone therapy.

HRT=hormone-replacement therapy; rBHRT=regulated bioidentical HRT; cBHRT=custom-compounded bioidentical HRT; MHRA=Medicines and Healthcare products Regulatory Agency; CBT=cognitive behavioural therapy

Dr Toni Hazell

Portfolio GP, Tottenham, London

Conflicts of interest

Dr Hazell is on the Executive Committee of the Primary Care Women’s Health Forum, a role that includes paid and unpaid work, and she also does paid work for the Patient website

The first article in this two-part series was published in April 2022, and focused on the risks and benefits of HRT

Note: At the time of publication (May 2022), some of the drugs discussed in this article did not have UK marketing authorisation for the indications discussed. Prescribers should refer to the individual summaries of product characteristics for further information and recommendations regarding the use of pharmacological therapies. For off-licence use of medicines, the prescriber should follow relevant professional guidance, taking full responsibility for the decision. Informed consent should be obtained and documented. See the General Medical Council’s Good practice in prescribing and managing medicines and devices for further information.

References

  1. Hazell T. Hormone replacement therapy: what are the risks and benefits? www.guidelinesinpractice.co.uk/womens-health/hormone-replacement-therapy-what-are-the-risks-and-benefits/456887.article  (accessed 9 May 2022).
  2. NICE. Menopause: diagnosis and management. NICE Guideline 23. NICE, 2015 (last updated 2019). Available at: www.nice.org.uk/ng23
  3. NICE. When should I suspect a diagnosis of menopause or perimenopause? NICE Clinical Knowledge Summary. Available at: cks.nice.org.uk/topics/menopause/diagnosis/diagnosis-of-menopause-perimenopause/
  4. Primary Care Women’s Health Forum. Menopause—guidance on management and prescribing HRT for GPs. London: PCWHF, 2020. Available at: pcwhf.co.uk/wp-content/uploads/2021/12/Prescribing-HRT.pdf
  5. NICE. Managing women with menopause, perimenopause, or premature ovarian insufficiency. NICE Clinical Knowledge Summary. Available at: cks.nice.org.uk/topics/menopause/management/management-of-menopause-perimenopause-or-premature-ovarian-insufficiency/ (accessed 9 May 2022).
  6. Brockie J. The menopause and subtotal hysterectomy—information for patients. Oxford University Hospitals NHS Trust, 2011. Available at: www.cotswoldgynaecology.com/leaflets/Menopause%20and%20Subtotal%20Hysterectomy.pdf
  7. NHS.uk website. Treatment—endometriosis. www.nhs.uk/conditions/endometriosis/treatment/ (accessed 9 May 2022).
  8. Bayer plc. Mirena 20 micrograms/24 hours intrauterine delivery system—summary of product characteristics. www.medicines.org.uk/emc/product/1132 (accessed 9 May 2022).
  9. The Faculty of Sexual & Reproductive Healthcare. Contraception for women aged over 40 years. London: FSRH, 2017 (updated 2019). Available at: www.fsrh.org/standards-and-guidance/fsrh-guidelines-and-statements/contraception-for-specific-populations/aged-over-40/
  10. Medical & Dental Indemnity Protection UK website. HRT error. www.mddus.com/resources/resource-library/case-of-the-month/2020/may/hrt-error (accessed 9 May 2022).
  11. MDU Journal website. Case study—medication list error. mdujournal.themdu.com/issue-archive/issue-4/case-study—medication-list-error (accessed 9 May 2022).
  12. British Menopause Society website. Bioidentical HRT. thebms.org.uk/publications/consensus-statements/bioidentical-hrt/ (accessed 9 May 2022).
  13. Royal College of Obstetricians and Gynaecologists website. HRT and alternatives. www.rcog.org.uk/for-the-public/menopause-and-later-life/hrt-and-alternatives/ (accessed 9 May 2022).
  14. Women’s Health Concern website. Complementary/alternative therapies for menopausal women. www.womens-health-concern.org/help-and-advice/factsheets/complementaryalternative-therapies-menopausal-women/ (accessed 9 May 2022).
  15. HM Government. The Traditional Herbal Registration (THR) Certification Mark: guidance for business. London; HM Government, 2021. Available at: assets.publishing.service.gov.uk/government/uploads/system/uploads/attachment_data/file/949156/The_Traditional_Herbal_Registration__THR__Certification_Mark_Guidance_for_Business.pdf
  16. Rock My Menopause website. Rock my menopause. rockmymenopause.com/get-informed/treatment/#Natural-menopause-relief (accessed 9 May 2022).
  17. Patient website. Alternatives to HRT. patient.info/womens-health/menopause/alternatives-to-hrt (accessed 9 May 2022).
  18. British Menopause Society website. Testosterone replacement in menopause. thebms.org.uk/publications/tools-for-clinicians/testosterone-replacement-in-menopause/ (accessed 9 May 2022).
  19. NHS website. Alternatives: hormone replacement therapy (HRT). www.nhs.uk/conditions/hormone-replacement-therapy-hrt/alternatives/ (accessed 9 May 2022).
  20. British National Formulary. Tibolone. bnf.nice.org.uk/drug/tibolone.html (accessed 9 May 2022).
  21. British Menopause Society website. Education. thebms.org.uk/education/overview/ (accessed 9 May 2022).
  22. Fourteen Fish website. Confidence in the menopause. www.fourteenfish.com/menopause/subscribe (accessed 9 May 2022).

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