HRT Review


BHWC Pharmacist Protocol for annual HRT review


1. Check blood pressure & weight and record BMI

2. Have they attended mammography every 3 years if aged between 50 and 71

3. Ensure patient is on the correct HRT therapy:


Taking oestrogen on its own can increase the risk of developing womb (endometrial) cancer. Taking progestogen minimises this risk. So this only applies if their womb is intact.

UTERUS INTACT WITH BLEED – sequential combined (also called cyclical) - oestrogen every day and progestogen added to 14 days per cycle. This results in regular bleeds.

UTERUS INTACT WITHOUT BLEED – continuous combined – oestrogen and progesterone every day

NO UTERUS – oestrogen only

Eg. If patient has recently had UTI removed they may need oral progesterone added


4. Ensure compliance

5. Check effectiveness of therapy and presence of side effects


* Any red flags book in with Jenny / Jacquie / Jane

* Treatment is ineffective

* They have ongoing troublesome side effects

* There are 'red flag' symptoms such as unexplained bleeding — refer to duty doctor with potential urgent 2-week referral if a gynaecological cancer is suspected

Scheduled or unscheduled bleeding 

With continuous combined HRT regimens, up to 80% of women will experience breakthrough bleeding or spotting in the first month of treatment (Figure 3; MacLennan et al, 1993). After 6 months of therapy, 20-50% of women will continue to have such bleeding, depending on the type of continuous combined regimen used.

Distinguish between schedued bleeding, experienced on a cyclical basis with sequential HRT regimens following progestogen withdrawal, and unscheduled or breakthrough beeding:

Certain clinical factors may correlate with unscheduled bleeding and spotting and include:

  • Poor compliance
  • Intrauterine pathology, especially endometrial polyps.
  • Proximity of women to the menopause. Perimenopausal women appear more likely to experience breakthrough bleeding on continuous combined regimens than women who are fully menopausal. This is presumably because perimenopausal women still have erratic endogenous ovarian follicular activity
  • Higher endogenous oestrogen production in women with obesity. After the menopause, endogenous oestrone (and thus some oestradiol) is produced from a number of sources by peripheral conversion of androgens. This is well documented in adipose tissue, and women with more fat stores may experience a higher endogenous production of oestrogens, with consequent action on the endometrium. 

Within 12 months of the last menstrual period

Women who are within 12 months of the last natural menstrual period often do not achieve amenorrhoea with CCMHT, presumably because some residual endogenously oestrogen-stimulated endometrium is present. Unpredictable breakthrough bleeding is common in this situation and does not need investigation. To avoid this, it is recommended that cyclical MHT be used for the first 12 months at least following the LMP.


After 12 months since the LMP and within six months of the institution of CCMHT

In women who are more than 12 months post the LMP, breakthrough bleeding is often common within the first six months of the institution of CCMHT and does not necessarily need investigation unless the bleeding is unusually heavy.

After 12 months since the LMP and after six months of CCMHT

Bleeding should be investigated if it occurs after six months use of CCMHT or tibolone, or starts after amenorrhoea has been established on this regimen. Why does breakthrough bleeding occur in a regimen designed to achieve amenorrhoea? Amenorrhoea in this setting depends upon the balance between the oestrogenic effect and progestogenic effect of the MHT components on the endometrium. Inadequate progestogenic effect will result in endometrial proliferation and possibly hyperplasia and bleeding. It may, like unopposed oestrogen therapy, lead to endometrial cancer. However, more commonly in women taking pharmaceutical preparations of CCMHT, excessive progestogenic effect may produce bleeding from an atrophic endometrium.

Investigation of postmenopausal bleeding (PMB)

The primary goal in investigation is to exclude malignancy, and secondarily to elucidate a treatable non-malignant cause (2). In particular, patients with diabetes, obesity, history of PCOS, or a family history of endometrial cancer are at greater risk of malignancy (3). Patients taking non-conventional MHT, such as troches and transdermal progestogen are at risk of endometrial hyperplasia and cancer (4) (See AMS Information Sheet Bioidentical custom compounded hormone therapy).

A detailed history should be taken. When does the bleeding occur? Is it post-coital? What medications is the patient taking? Is the patient taking tamoxifen? Is the patient taking so-called “bioidentical” hormones? Has the patient missed MHT doses? When was the last Pap smear?

Physical examination should include inspection of the vulva, vagina and the cervix for visual evidence of lesions or bleeding, taking note of any signs of atrophy. Bleeding from the perineum, urethra and anus is also a possibility. A Pap smear should be done.

Endometrial ultrasound

Endometrial ultrasound is the first investigation of choice. This should be done by an experienced specialist gynaecological ultrasonographer and with transvaginal ultrasound (TVUS). In women taking cyclical MHT, it should be done immediately after the withdrawal bleed (5). The ultrasound should be able to identify any localised uterine lesion which may contribute to bleeding – endometrial polyp, submucosal fibroid, hyperplasia or cancer. The significance of PMB for the risk of malignancy differs with use of MHT and endometrial thickness on TVUS. What investigations are done next will depend very much upon the ultrasound findings, so the experience of the ultrasonographer is critical.

Medical management

When a localised or neoplastic lesion is found, the management is surgical. However, when the findings are benign and the patient is taking MHT some modification of the MHT dose or regimen is required. Although there is an abundance of literature about the incidence of bleeding on MHT and the histological findings, unfortunately, the literature is lacking in data from randomised clinical trials of therapeutic interventions. Therefore, the following recommendations are based on clinical practice advice from the literature and based on the patterns of histology seen in women with breakthrough bleeding (8-11). They are made here with the proviso that continued bleeding should prompt re-investigation, as above.

a) Cyclical MHT with unpredictable bleeding and negative histological screen for pathology

This may respond to a change in the progestin component of the MHT either by changing dose or progestin type or mode of delivery e.g. intrauterine progestin.

b) CCMHT with breakthrough bleeding, endometrium >4mm and negative histology

If less than 12 months post LMP, change to cyclical MHT or intrauterine progestin. If more than 12 months post LMP, change oestrogen/progestin balance by reducing oestrogen or changing progestin dose, type or delivery.

c) CCMHT with breakthrough bleeding, endometrium <4mm

This is the most difficult scenario to manage, especially in a patient who wants to have no withdrawal bleeding. The TVUS suggests adequate, if not excessive, progestogenic effect, especially if tissue sampling demonstrates an atrophic sample. Increasing the dose or changing the progestogen formulation does not always address the underlying problem. Continuous progestogen effect on the endometrium exposes superficial dilated blood vessels which predispose to bleeding (12). The same may occur with prolonged tibolone therapy. A change back to cyclical MHT, at least for a while, is recommended or an increase in the oestrogen dose may be effective.

Surgical management

Surgical management is appropriate for neoplastic and local lesions causing bleeding. However, women who have heavy or unmanageable breakthrough bleeding in the absence of pathology, may prefer to have a hysterectomy, after which they need take only oestrogen as MHT. The alternative is endometrial ablation. This may resolve the PMB but it should be noted that progestogen is still necessary since there will be residual endometrium left. Moreover, the above investigations – TVUS, hysteroscopy, endometrial sampling - will be difficult if there is subsequent PMB (13).


6. Discuss pros and cons of continuing HRT


* Stroke - Oral oestrogen (not transdermal) especially in patients over 60 years

* VTE - Oral oestrogen (not transdermal)

* Breast cancer – progestogen and risk reduces after stopping HRT

* Ovarian cancer – oestrogen and progestogen - HRT for 5 years from around age 50 years has a 1 in 1000 extra risk of ovarian cancer


* Bone protection

* Fragility fractures

* Osteoporosis

* Hypertension and CVD

7. Review whether HRT should be stopped

* For vasomotor symptoms, most women require 2–5 years of HRT, but some women may need longer. This judgement should be made on a case-by-case basis with regular attempts to discontinue treatment. Symptoms may recur for a short time after stopping HRT.

* Topical (vaginal) oestrogen may be required long term. Regular attempts (at least annually) to stop treatment are usually made. Symptoms may recur once treatment has stopped.

* Women with premature menopause usually take HRT up to the average age of the natural menopause (51 years), after which the need for HRT should be reassessed. Some women will still be symptomatic.

* Gradually reducing HRT may limit recurrence of symptoms in the short term.

8. Encourage breast awareness


* Look at and feel your breasts so you know what’s normal for you

* Remember to check all parts of your breasts, your armpits and up to your collarbone.

* Do this regularly to check for changes

* Do it as part of your usual routine

* Tell your doctor as soon as possible if you notice a change



Venous thromboembolism (VTE)

* The risk of VTE associated with HRT is greater for oral than transdermal preparations.

* The risk associated with transdermal HRT given at standard therapeutic doses is no greater than baseline risk.

Coronary heart disease (CHD) and stroke

* The baseline risk of CHD and stroke for women around menopausal age varies from one woman to another, depending on the presence of cardiovascular risk factors.

* HRT with oestrogen alone is associated with no, or reduced, risk of CHD; HRT with oestrogen and progestogen is associated with little or no increase in the risk of CHD.

* The baseline risk of stroke in women younger than 60 years is very low.

* Oral (but not transdermal) oestrogen is associated with a small increase in the risk of stroke

* HRT does not increase CVD risk when started in women younger than 60 years.

* HRT does not affect the risk of dying from CVD.

Breast cancer

* The baseline risk of breast cancer for women around menopausal age in the UK varies from one woman to another.

* HRT with oestrogen alone is associated with little or no increase in the risk of breast cancer.

* HRT with oestrogen and progestogen can be associated with an increase in the risk of breast cancer.

* Any increase in risk of breast cancer is related to treatment duration and reduces after stopping HRT.

* HRT does not affect the risk of dying from breast cancer.

Ovarian cancer

* Women aged 50 to 54 years who take 5 years of HRT, this results in about 1 extra case per 2,000 users. In women aged 50 to 54 who are not taking HRT, about 2 women in 2,000 will be diagnosed with ovarian cancer over a 5-year period.

* Among women last recorded as current users of HRT, the risk was increased even with less than 5 years of use Similar for oestrogen-only and oestrogen-progestogen HRT.

* Increased for the two most common types: serous and endometrioid.

* The risk declined the longer ago use had ceased, although about 10 years after stopping long-term HRT use there was still an excess of serous or endometrioid tumours.


Decreased risk of fragility fractures

* the baseline risk of fragility fracture for women around menopausal age in the UK is low and varies from one woman to another. The risk of fragility fracture is decreased while taking HRT and this benefit:

* Is maintained during treatment but decreases once treatment stops.

* May continue for longer in women who take HRT for longer.

Effect on muscle mass and strength

* limited evidence suggests that HRT may improve muscle mass and strength. Muscle mass and strength are maintained through, and are important for, activities of daily living.

Cardiovascular disease and osteoporosis.

* Starting hormonal treatment (either with HRT or a combined oral contraceptive) and continuing treatment until at least the age of natural menopause (unless contraindicated) reduces the risk of chronic diseases, including cardiovascular disease and osteoporosis.

* HRT may have a beneficial effect on blood pressure when compared with a combined oral contraceptive.

* Both HRT and combined oral contraceptives offer bone protection.

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