Why are some patients prescribed higher doses of oestrogen than others?
Newson Health Menopause and Wellbeing Centre was founded in 2018 to help women receive treatment for their menopausal and perimenopausal symptoms. Many women come to our clinic because they have been refused help on the NHS and/or because the type of HRT they are receiving is insufficient to alleviate their symptoms.
At Newson Health, our patients are central to all treatment decisions. We usually start our patients with the minimal effective doses of hormones, then assess scope for any changes based on clinical response and patients’ views.
We follow NICE menopause guidelines, adhere to the General Medical Council’s decision making and consent guidelines, and NICE shared decision-making guidelines [1-3].
Here we share our background to this approach.
Background on HRT prescribing and doses
The decision as to whether to prescribe HRT, the dose of HRT given, and the duration of its use should be made on an individualised basis after discussing the benefits and risks with each patient.
The optimum dose and duration of HRT treatment is decided according to the severity of a woman’s symptoms as well as her response to treatment. Every woman is different so a “one size fits all” approach to HRT is not the best for women.
There are many benefits of taking HRT as it usually improves symptoms and can also improve future health by reducing future risk of heart disease, osteoporosis, type 2 diabetes, clinical depression and dementia. Many women choose to take HRT for ever and there is no maximum time for taking HRT.
The dose of hormones – oestrogen, progesterone and testosterone – can vary between women and often women find that their doses change with time. So for example a woman may start on a low dose during the perimenopause and then increase as her own hormones decline with time.
Some women need higher doses of oestrogen than other women to achieve the same benefits, especially as oestrogen can often be absorbed differently through the skin.
Is there a maximum dose of hormones?
There is no current maximum licensed dose of oestrogen in the British National Formulary (BNF), a medical and pharmaceutical publication that contains information and advice on prescribing and pharmacology. The BNF states that doses of oestradiol should be adjusted according to response.
In addition, a consensus statement by the British Menopause Society states that HRT dosage, regimen and duration should be individualised, with annual evaluation of advantages and disadvantages .
However, the manufacturers in the UK have set a recommended maximum dose for each HRT medication. This does not mean that higher doses are not safe though.
Newson Health’s position on evidence-based medicine
Evidence based medicine is based not only on clinical trial data, but also a clinician’s experience and expertise individualised to a patient’s values and preferences.
Newson Health clinicians use both individual clinical expertise and the best available external evidence, and neither alone is enough. Absence of evidence does not mean proof of harm.
Off-label is not the same as unlicensed
Many medicines, including HRT, are prescribed ‘off-label’ – meaning it is used in a different way described in the license, for example using a medicine at a higher dose than stated in the license.
Note: this is not the same as ‘unlicensed’, which is a medicine that has no license, either in the UK or elsewhere.
Newson Health clinicians refer to Medicines and Healthcare products Regulatory Agency (MHRA) guidance on off-label or unlicensed use of medicines and best practice for patient communication .
Maximum doses explained
Manufacturers usually state a recommended maximum dose for a medication. However, this does not mean prescribing over that level is dangerous nor that clinicians cannot or should not do so – higher doses may be essential for an individual patient’s needs.
In the case of HRT, it is well documented there is a wide variation in the efficiency of transdermal drug (oestrogen as a patch, gel or spray) delivery across individuals. Absorption can be affected by both modifiable and non-modifiable factors such as gender, age, ethnicity hydration, temperature, metabolism, and site of application [6-9]. One study suggests that women taking a blood sample from the arm where oestrogen gel is applied may lead to falsely elevated oestradiol readings .
Newson Health audit data has shown that there is usually no correlation between dose of oestrogen prescribed and blood levels of oestrogen in the body.
Furthermore, recent evaluation of Newson Health clinic data has shown that women often require variable blood concentrations of oestradiol for adequate perimenopausal and menopausal symptom control.
It follows that two patients on the same dosage of oestradiol may therefore absorb quite different amounts, meaning that the patient who absorbs less will often need to be prescribed more simply to ensure her serum levels are equivalent to a patient who has better absorption. Making sweeping statements about ‘high’ or ‘low’ doses therefore has little to no meaning, because patients will often benefit from different doses of oestradiol in the HRT they are prescribed.
In practical terms, this means that the dose of oestradiol must be individualised to each woman, an approach supported by the BNF, which states that doses of oestradiol should be ‘adjusted according to response.’
There is no robust evidence that higher doses of oestrogen are associated with a greater risk to a patient as there have been no randomised controlled trials undertaken in this area.
And it should be noted, for example, that there are no maximum daily does limitations for Oestrogel in several European Union countries, including France and Belgium.
How often does Newson Health prescribe above the manufacturer’s maximum dose?
About a third of women who come to Newson Health are already taking HRT but they are still experiencing symptoms so their dose and/or type of HRT needs altering.
Many women come to Newson Health because they have either been refused help on the NHS and/or because the prescription they are receiving is insufficient to alleviate their symptoms.
A minority of Newson Health’s follow up patients are receiving a dose of oestradiol higher than the maximum stated dose on the Summaries of Product Characteristics (SPCs), a description of a medicinal product’s properties and the conditions attached to its use.
However these women will have already been prescribed lower doses, with inadequate results in terms of either symptom control, blood levels, or both.
The aims of our prescribing pathway
- to standardise the treatment of women receiving higher doses of oestradiol
- maintain patients’ wellbeing and safety
- support individualised care
- adhere to the MHRA guidance about prescribing off-label
- uphold the integrity of Newson Health and its clinicians
Note about progesterone dose
The Newson Health treatment pathways for women who bleed while taking HRT state that dose of progesterone should be increased, regardless of the dose of HRT in addition to these women having appropriate investigations when clinically indicated. There is no good quality evidence from studies demonstrating that a higher dose of progesterone should routinely be given for women who are prescribed higher doses of oestrogen and do not have any bleeding. Prescribing in this way is off-label.
- 2. https://www.gmc-uk.org/ethical-guidance/ethical-guidance-for-doctors/decision-making-and-consent
- 3. https://www.nice.org.uk/about/what-we-do/our-programmes/nice-guidance/nice-guidelines/shared-decision-making
- British Menopause Society (2020), ‘BMS & WHC’s 2020 recommendations on hormone replacement therapy in menopausal women’
- Tinhofer I.E., Zaussinger M., Geyer S.H., Meng S., Kamolz L.P., Tzou C.H., Weninger W.J. (2018), ‘The dermal arteries in the cutaneous angiosome of the descending genicular artery’, J Anat, 232(6) pp.979-86. doi: 10.1111/joa.12792.
- Singh I., Morris A.P. (2011), ‘Performance of transdermal therapeutic systems: effects of biological factors’, Int J Pharm Investig, 1(1):4-9. doi: 10.4103/2230-973X.76721.
- Liu, P., Higuchi, W.I., Ghanem, A.H., Good, W.R. (1994), ‘Transport of beta-estradiol in freshly excised human skin in vitro: diffusion and metabolism in each skin layer’, Pharmaceutical Research, 11(12), pp.1777–84. doi.org/10.1023/a:1018975602818
9. Leopold C.S, Maibach H.I, (1996), Effect of lipophilic vehicles on in vivo skin penetration of methyl nicotinate in different races, International Journal of Pharmaceutics, 139, 1–2, pp.161-67, doi.org/10.1016/0378-5173(96)04562-0.
- Vihtamäki, T., Luukkaala, T.,Tuimala, R. (2004), ‘Skin contamination by oestradiol gel–a remarkable source of error in plasma oestradiol measurements during percutaneous hormone replacement therapy’, Maturitas, 48(4), pp. 347–53. https://doi.org/10.1016/S0378-5122(03)00043-4