Dilemmas in HRT: Managing adverse effects

In the second of this three-part miniseries, Dr Toni Hazell discusses adverse effects of HRT and how to manage them

What are the commonest adverse effects from HRT?

Adverse effects from HRT can broadly be divided into three categories – oestrogenic affects, progestogenic effects and unscheduled bleeding; symptoms in the first two groups are listed in the table below. It is common for adverse effects to settle over the first 3–6 months of use, and it is worth advising women of this when HRT is started or changed, so that they are comfortable persisting if an adverse effect is not too severe. Some adverse effects can be caused by either hormone; a careful history of the combination of symptoms may give you an idea of which hormone is to blame (see box 1).

Box 1. Adverse effects of HRT

Oestrogenic:

Bloating
Nausea/dyspepsia

Progestogenic:

Mood swings
Pre-menstrual tension (PMT)-like symptoms
Acne/greasy skin

May be due to either hormone:

Fluid retention
Breast tenderness
Headaches

How do you manage unscheduled bleeding on HRT?

There are two issues to consider when a woman presents with unscheduled bleeding on HRT: whether it is indicative of serious pathology, particularly endometrial cancer; and how it can be managed. Over the last few years there has been a significant increase in suspected cancer pathway referrals for unscheduled bleeding on HRT, with no corresponding increase in the diagnosis of endometrial cancer in this cohort. This was probably due to the lack of any other pathway by which to get these women seen promptly and it prompted the British Menopause Society (BMS) to issue a comprehensive guideline on unscheduled bleeding in women taking HRT. Bleeding, which is usually light, generally only needs to be investigated if it persists for six months after HRT is started, or three months after a change in the dose or preparation of HRT; earlier investigation might be warranted if the bleeding is particularly heavy.

Assessment of a woman with unscheduled bleeding should start with a clear history, including adherence to the HRT as prescribed, risk factors for endometrial cancer and past medical history. Where the oestrogen and progestogen components of the HRT are not in the same preparation (eg, oestrogen gel with micronised progesterone or a levonorgestrel intrauterine device (LNG-IUD), rather than a combined preparation such as a combined patch), particular attention should be paid to whether the progesterone is being taken – is oral progesterone being requested at the correct frequency, and could a LNG-IUD have fallen out? Examination should include a speculum examination, swabs for infection, BMI and cervical screening test if this is due.

The focus of the history should be to gather information about the number of major and minor risk factors, as outlined in the BMS guideline and listed in box 2 below. If one major or three minor risk factors are present, an urgent suspected cancer pathway (USCP) referral should be made; if this or other investigations are declined then the woman should be weaned off HRT and non-hormonal alternatives explored.

Box 2. Risk factors for endometrial cancer

Major risk factors

BMI ≥40
Genetic predisposition (Lynch / Cowden syndrome)
Estrogen-only HRT for >6 months in women with a uterus
Tricycling HRT (quarterly progestogen) for >12 months
Prolonged sHRT regimen: use for more than 5 years when started in women aged ≥45 years
12 months or more of using norethisterone or medroxyprogesterone acetate for <10 days/month or micronised progesterone for <12 days/month, as part of a sequential regimen

Minor risk factors

BMI 30-39
Unopposed estrogen >3 months but <6 months
Tricycling HRT (quarterly progestogen) for >6 but <12 months
>6 months but <12 months of using norethisterone or medroxyprogesteorne acetate for <10 days/month or micronised progesterone for <12 days/month, as part of a sequential regimen
Where the progestogen dose is not in proportion to the estrogen dose for >12 months (including expired 52mg LNG-IUD)
Anovulatory cycles, such as in polycystic ovarian syndrome
Diabetes

For those who do not have one major or three minor risk factors, management should follow the flow chart and this might lead to a request for an urgent transvaginal ultrasound (within six weeks), or an attempt to optimise the HRT and see if the bleeding improves. A lengthy list of recommendations for reducing unscheduled bleeding by optimising HRT is given in table 6 the BMS guidance, and some highlights are listed in box 3 below.

Box 3. Ways to reduce unscheduled bleeding on HRT, when there are no concerns about pathology

Review the type of HRT:

Change to sequential HRT (sHRT), if continuous combined HRT (ccHRT) may have been started too close to the last natural period (should be at least 12 months), or a change to ccHRT has been done after too short a period on sHRT.
Ensure that the LNG-IUD is still present/in date if used and offer a change of LNG-IUD if the current one is at least four years old.
Add vaginal HRT if there are clinical signs of genitourinary syndrome of the menopause.
Change to an HRT where it is not possible to take the oestrogen component without the progestogen component (e.g. a combined patch or tablet).
If the woman has obesity, offer a LNG-IUD or an increase in dose of micronised progesterone, and encourage weight management.
For women in the perimenopause, consider changing to a combined hormonal contraceptive (if <50 and not contraindicated), changing the type of progestogen or adding another progestogen on top of the one already being used.

Change how the HRT is used:

If transdermal HRT is combined with an oral progesterone, advise that they be used at the same time of day.

For women with fibroids:

Offer a LNG-IUD if the largest fibroid is <3cm.
If micronised progesterone is used, increase the dose or change to a synthetic progestogen.
Reduce the dose of oestrogen if this can be done whilst still controlling menopausal symptoms.

How do you manage other adverse effects?

Some of the principles of managing unscheduled bleeding will apply to other adverse effects; these include checking adherence to both hormones and encouraging persistence if the adverse effects have only recently started.

The transdermal route of oestrogen administration gives more stable oestrogen levels and avoids first-pass metabolism in the liver. For women who are experiencing adverse effects when taking oral HRT, simply changing to a patch, spray or gel might be enough to give an improvement. Reducing the dose can also help, and it may then be possible to slowly titrate the dose up again, if the reduced dose does not completely control the menopausal symptoms for which the HRT is being used.

Breast tenderness can be due to either the oestrogen or the progestogen; it may be partly or wholly alleviated by a low-fat, high-carbohydrate diet, without making any significant changes to the HRT. If this doesn’t work, or the woman isn’t able to try it, and the breast tenderness does not improve with a reduction in dose of oestrogen (or change to the transdermal route), then it may be appropriate to consider changing the type of progestogen given. In general, the synthetic androgenic progestogens (norethisterone and levonorgestrel) are more likely to cause breast tenderness than a LNG-IUD, the less androgenic synthetic progestogens (medroxyprogesterone acetate [MPA] and dydrogesterone) or micronised progesterone, which is bioidentical. Reducing the dose of the progestogen, or the number of days per month that it is taken (from 14 to 10) can also be tried, but the dose should not go below that appropriate for the dose of oestrogen (see tables 2 and 3 in the BMS guidance on unscheduled bleeding with HRT).

Changing to a less androgenic progestogen or trying the other changes in the paragraph above may also alleviate mood swings, PMT-type symptoms and changes to the skin such as acne. Gastrointestinal symptoms such as nausea and bloating can be helped by taking oral HRT with food or changing to a transdermal preparation. Headaches can be due to either hormone; they are also a very common symptom in those not taking HRT and so a good history is important in order to establish whether it is in fact an adverse effect of the HRT, or was present before HRT was started. If it does seem to be an adverse effect then any of the methods already mentioned might help, and they should be tried sequentially rather than at the same time, so that if the headache improves, you know which change made the difference.