The aim of this article is to cover the causes of post-menopausal bleeding and irregular bleeding for women taking hormone replacement therapy (HRT) and how to manage it. Bleeding while on HRT is common and if once investigated no cause has been found, then the HRT prescribed may need to be changed.
Bleeding while taking HRT is a common problem and in the Women's Health Initiative trial 40% women were unblinded due to vaginal bleeding (Rossouw et al, 2002). It is estimated that 38% of women using sequential HRT and 41% of women on continuous combined HRT (CCT) attend clinics with bleeding (Hickey et al, 2009). Problems with bleeding do lead to the discontinuation of therapy and expensive and invasive tests to exclude cancer and pathology, and this may affect the acceptability of treatment for women.
The majority of women with post-menopausal bleeding on and off HRT will have either no cause or a benign cause, but about 10% of women will have endometrial cancer (Scottish Intercollegiate Guidelines Network [SIGN], 2002). Endometrial cancer accounts for 1 in 18 of all female cancers and is increasing due to multiple factors (Bray et al, 2005), the most prominent being obesity.
For women on HRT the figures are slightly different: there is an increase in endometrial cancer if unopposed oestrogen is used, but for women on continuous combined HRT the risks are lower than non-users of HRT and the risks are the same for sequential users and non-users (Brinton et al, 2005).
Post-menopausal bleeding and bleeding on HRT
Post-menopausal bleeding is defined as unscheduled vaginal bleeding that occurs a year after the last natural menstrual period (SIGN, 2002), or any breakthrough bleeding on cyclical HRT, or breakthrough bleeding after 6 months on continuous combined therapy when there has been established amenorrhoea. It does not apply to scheduled bleeding on sequential HRT. This therapy has 12 to 14 days of progestogen in a 28-day cycle and the bleeding comes at the end of this.
This definition is an important starting point as it states bleeding after 6 months on HRT – this highlights that when women start on, or change, HRT treatments there can be a period of adjustment when bleeding may occur and women need to be warned and counselled about this. It is common, happening in about 80% of women starting therapy (Gajjar Dave et al, 2019).
Through there is rarely a cancerous cause for the bleeding on HRT, as the risk of endometrial cancer is less on continuous combined therapy, the abnormal bleeding, its impact on quality of life and the worry that there may be a cancer, can be one of the reasons for discontinuation of treatment.
The bleeding on HRT that requires investigation is:
- Break-through bleeding on sequential HRT
- A change in pattern of withdrawal bleeds
- Bleeding that occurs on continuous combined HRT after the first 6 months of initiating therapy.
When taking HRT the risk of endometrial cancer is less on the continuous combined therapy HRT than on no therapy or sequential therapy.
There is an estimated 10% of women on continuous combined therapy who continue to bleed despite normal investigations (Gajjar Dave et al, 2019), which can rise to up to 20% in women on a transdermal routine. For sequential regimes, irregular bleeding can happen in an estimated 40% of women – this may be bleeding before the end of the progestogen part.
The management of post-menopausal bleeding (and some of the bleeding on HRT) comes as a suspected cancer and this was covered in the NHS Cancer Plan (2000). This gave guidance for the referral and treatment times for a suspected cancer and the organisation of systems.
Assessment
When women bleed on HRT it is important to take a comprehensive history and work out those who need adjustments in HRT and those who need further investigations and referral.
When assessing bleeding in women on HRT it is essential to know what is normal:
- With sequential HRT there should be a bleed after the progestogen part of the medication. It should be like a period and lasts 3–7 days. About 85% of women will have a regular bleed, but if they do not it is not a cause for concern
- Continuous combined therapy – there should be no bleeding.
Prior to referral women should have a history and examination, noting the following:
- Use of HRT, including type, duration of use and compliance, and any changes in treatment, previous treatment, missed medication, use of unregulated bioidentical HRT (such as transdermal progestogen cream)
- Last menstrual period off HRT and on HRT
- Last cervical smear, with results and any abnormalities in the past
- Amount and type of bleeding, number of episodes
- Assessment of risk factors for endometrial cancer, which include use of unopposed oestrogen, obesity, nulliparous, late menopause, diabetes, previous hyperplasia, tamoxifen use and history of polycystic ovaries
- Speculum examination with cervical screening and swabs, if indicated.
Dependent on the history, some women will need referral under the 2-week wait system and others may need referral for a transvaginal scan and then review.
Investigations
- Ultrasound: management will depend on the endometrial thickness and outline of the endometrium. A general cut-off of 4–5 mm is seen as normal for post-menopausal women. When women are on HRT there will be some variation in the endometrial thickness. Some hospitals have a 4 mm cut off value for endometrial thickness in women who are postmenopausal or on continuous HRT. However, in women on sequential HRT in the peri menopause, there is no standard measure of endometrial thickness. If possible women should have an ultrasound performed just after a bleed
- Bimanual examination
- Hysteroscopy and biopsy, if indicated from ultrasound. If the endometrium is 4-5 mm or more, or the endometrium is irregular in its outline or shows endometrial pathology (this is dependent on individual units) or in cases of multiple episodes of bleeding.
There can be many causes of bleeding and once investigated with hysteroscopy and biopsy, there may be no cause found, but negative histology is reassuring and patients can then be managed by changing medication.
Causes
The reasons why women bleed are varied and can be broken into those related to hormones and those that are independent factors. Those not related to hormones are normally pathology, which includes some cancers as outlined in Table 1.
Table 1. Causes of bleeding not related to HRT
| Causes | Treatment |
|---|---|
| Vaginal/vuvla | |
| Vulvar intraepithelial neoplasia (VIN) | VIN is a precancerous skin condition on the vulva. Refer to gynaecology |
| Vaginal/vulva cancer | Referral to gynaecological oncology |
| Atrophic vaginitis | Thinning, drying and inflammation of the vaginal walls. Local or systemic oestrogens or vaginal moisturizers should be prescribed |
| Ovarian | |
| Tumours | Ultrasound and tumour markers. Further imaging and referral to gynaecological oncology |
| Cervical pathology | |
| Cervical polyps | Cervical polyps are very common and found within the cervical canal. They can cause bleeding which is intermittent or postcoital. They are normally benign with a prevalence of malignancy of 0.1% (Berzolla et al, 2007). It is estimated that approximately 30% of post-menopausal women will have a co-existing endometrial polyp, which would suggest that post-menopausal women with a cervical polyp and no bleeding will need an ultrasound. These can easily be removed by avulsion in an outpatients setting |
| Cervical intraepithelial neoplasia (CIN) | Premalignant condition of the uterine cervix. Colposcopy required |
| Cervical cancer | Referral to gynaecological oncology |
| Ectopy | When the soft glandular cells that line the inside of the cervical canal spread to the outer surface of the cervix. Reassurance or cautery |
| Endometrial pathology | |
| Hyperplasia: simple and atypical | Simple—consider progestogens or IUS. If atypical referral. Total abdominal hysterectomy with bilateral salpingo-oophorectomy |
| Atrophic endometrium | Reassurance |
| Cancer | Referral to gynaecological oncology |
| Fibroids | Fibroids are common and occur in an estimated 20% of women. The aetiology is unknown but they are oestrogen-dependant and regress after the menopause. Fibroids differ from polyps and are derived from smooth muscle, with fibrous tissue elements, they are well defined tumours with a capsule and are more common in women who are overweight and African-Caribbean. If causing bleeding they can be resected or morcellated in outpatients or under a general anaesthetic dependant on the size of fibroid and tolerance of the woman |
| Endometrial polyps | Endometrial polyps have an estimated prevalence of 10–40% in post-menopausal women with abnormal bleeding and up to 12% are found in asymptomatic women. There is an estimated malignancy rate of up to 8% (Costa-Paiva et al, 2011) which increases with age. Bleeding polyps can be found singularly or there may be multiple polyps. Polyps can be resected via a hysteroscope in either outpatients, ambulatory or under a general anaesthetic dependent on the size and location and the tolerance of the woman |
Hormone-related
Table 2 shows some causes of hormone-related bleeding.
Table 2. Hormone-related bleeding
| Causes | Treatment |
|---|---|
| Hormonal such as HRT, endogenous cycles | Check if post-menopausal, consider follicle stimulating hormone (FSH)/luteinising hormone (LH). Check compliance with HRT medication |
| Wrong HRT, continuous combined therapy in non-post menopause women | Change HRT |
| Idiosyncratic | This can be reduced by changing the type of oestrogen, progestogen or the route of administration |
| Poor compliance/poor absorption (eg gastrointestinal issues, Crohn's disease | Change route of administration, consider intrauterine system (IUS) |
| Drug interactions | Eg anti-epileptic medications: change route to transdermal |
Wrong HRT
HRT needs to be prescribed to the correct woman at the correct time and with the correct preparation. Examples of bleeding due to the wrong HRT may be:
- A peri-menopausal woman who is on a continuous combined HRT designed for women who are post-menopausal
- Women with known absorption issues on oral therapy
- Women who do not like the progestogenic side effects and may miss out those tablets towards the end of the cycle
- Prescribing errors where women are on oestrogen only with a uterus
- Transcribing errors where women are on a continuous HRT and are given a sequential HRT leading to bleeds.
No progesterone
With many different preparations and brands of HRT it can be confusing and occasionally prescribing errors may occur. These can be giving an oestrogen-only preparation instead of a combined one, or an assumption that the transdermal gels do not need a progesterone. When oestrogen is given unopposed there is a build-up of the endometrium that then becomes unstable and is shed. It can also give rise to hyperplasia – this needs to be managed and investigated (Table 1).
Atrophy: vaginal and endometrial
After the menopause there can be problems in the vagina due to loss of oestrogen. These are bleeding, dryness, irritation, and pain and bleeding with intercourse, and they get worse over time. With the lack of oestrogen there is a decrease of blood flow and the vagina and the tissues become thinner, dryer and less elastic. The underlying tissues are vulnerable to infection from an increase in pH and irritation, and trauma from any activity such as sexual intercourse (Hillard et al, 2017). There is a less acidic environment and decrease in lactobacilli, which can lead to more infections. When women complain of these problems it is important to examine them using a small speculum and to take any swabs needed to rule out underlying infections. The main form of treatment for this is vaginal low-dose oestrogens in the form of tablets, pessary or cream (Hillard et al, 2017) and this can be needed even when a women is on systemic HRT. Other treatments are vaginal moisturizers which release water and produce a moist film over the vaginal surface. These are not used in relation to intercourse and can last up to 4 days. Vaginal lubricants can be used when having sexual intercourse.
Premature ovarian insufficiency
In premature ovarian insufficiency (POI) – the terminology has changed from failure to insufficiency – it is now thought that there can be some spontaneous ovarian activity in women with POI, leading to risk – all be it small – of pregnancy and bleeding. Women who have not had a bleed for a long time may describe a sudden period-like bleed, accompanied by pre-menstrual symptoms: in most cases this a menstrual cycle.
Management of bleeding problems with HRT
In the absence of any pathology and the management listed above, there are several changes to therapy that can be employed to stop the bleeding.
If the bleeding is persistent and there is no pathology, then the following may be useful:
- Intrauterine system (IUS) Mirena can be used as the progestogen component of the HRT alongside oral or transdermal oestrogen with a license of 4 years for this indication
- Wash out period. By stopping the HRT for 4–6 weeks and then re-starting the bleeding may be in a more regular pattern
- Synchronize HRT with cycle so progesterone occurs in luteal phase
- Higher or different progesterone
- If spotting prior to the bleeding this may indicate the need for an increased amount of oestrogen
- Absorption/compliance – change route.
Specific issues
Sequential therapy
- Heavy or prolonged bleeding: increase or change the type of progestogen or decrease the amount of oestrogen (prolonged bleeding may be more common on transdermal preparations)
- Early bleeding: increase or change the type of progestogen
- Spotting leading to withdrawal bleed: increase the dose of oestrogen
- Irregular bleeding: change regime or increase progestogen
- Painful bleeding: change type of progestogen
- In all of the above consider the use of the IUS.
Continuous therapy
- Change type of progesterone
- Decrease oestrogen
- IUS
- Consider sequential therapy for 12 months then change back to continuous.
Bleeding can occur due to HRT if there is too much oestrogen or too little progestogen. Other causes of bleeding can be:
- Poor absorption: due to bowel disorders such as Crohn's disease, lactose intolerance, patches falling off
- Compliance: missing out on the progestogen component of the HRT due to progestogenic side effects or missing tablets
- Drug interactions, eg St John's wort
- Underlying cycle.
If all else fails (including an IUS), women may opt for an endometrial ablation to solve the bleeding issue but need to use a continuous combined therapy after as there may still be some residual endometrium left and this needs to be protected. They could also consider stopping HRT and monitoring symptoms and then restarting if needed after a period without any treatment.
Conclusion
Although the benefits of HRT to women can be marked, bleeding on HRT can be a big issue and can have a negative impact on women and their quality of life. There can be many different causes of bleeding on HRT and each one needs to be assessed for pathology and the exact problem and then treatment tailored to the individual to overcome the bleeding issues. There are many HRT options available to the health professional to provide this individualised approach.
KEY POINTS:
- Bleeding in women on hormone replacement therapy (HRT) is common and there can be many causes and solutions
- Only a small percentage of these will have serious pathology such as a cancer but it is important in investigate those women with persistent symptoms to exclude this
- When women start on, or change, HRT treatments there can be a period of adjustment when bleeding may occur and women need to be warned and counselled about this
- In the absence of any pathology and the management listed above, there are several changes to therapy that can be employed to stop the bleeding
CPD reflective practice:
- What is the definition of post-menopausal bleeding?
- Which types of bleeding on HRT require further investigations?
- How will this article affect your clinical practice?