Part 1

Hello and welcome to our case study on HRT.

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Introduction

Ruth is a 49 year old woman who asks for advice about the menopause and HRT. She is
otherwise fit and healthy and has an unremarkable medical history.

Over the last few months Ruth has noticed that her menstrual cycle has become irregular, and
she seems to be bleeding slightly more heavily. However, she has been prompted to come and
see you because she is experiencing hot flushes. These affect her face and head and
sometimes her chest. Although they are short-lived (a few minutes) they are distressing and
embarrassing. In addition, Ruth sometimes experiences night sweats, which disturbs her
sleep. She complains of vaginal dryness and irritation, and this has affected her enjoyment of
sexual intercourse.

Ruth also feels more anxious and irritable, and has some difficulty concentrating. She
wonders if these symptoms might be caused by 'the change' (her words), although she
concedes that they may be more to do with stresses at work.

1
Think about the following questions:

 Are Ruth's symptoms typical of those associated with the menopause?

 What proportion of women experience menopausal symptoms?

 How long might the symptoms last?

Ruth's symptoms - hot flushes and sweats (vasomotor symptoms), sleep disturbances,
urinary and vaginal symptoms - are indeed typical of those experienced by many women
around the menopause. Defined more strictly, the menopause is the point in time when
menstruation ceases permanently. It occurs with the final menstrual period, and can
therefore be diagnosed with certainty only after 12 months' spontaneous amenorrhoea.

The mean age of the menopause in industrialised societies such as UK is 52 years. The time
period from when the ovaries start to fail (and symptoms such as irregular periods or hot
 flushes may begin) until 12 months after the final menstrual period is known as the
perimenopause.

Eighty per cent of women experience menopausal symptoms and 45% find them distressing.

Although usually self-limiting (2-5 years), some women experience symptoms for many
years.

References

National Prescribing Centre: Hormone Replacement therapy - an update. MeReC Bulletin

2005; 15: 13-16

CKS (2007) Menopause (Topic Review). Clinical Knowledge Summaries Service. Available
at http://www.cks.library.nhs.uk/menopause. Last revised January 2008, accessed March
2008

2
What are the longer term health implications of the menopause?

The long-term consequences of the menopause remain clinically silent

for many years. Osteoporosis, urogenital atrophy, cardiovascular disease,
and stroke all increase after the menopause. They are all associated with,
but not necessarily caused by, the menopausal drop in oestrogen levels. It
is unclear whether dementia is associated directly with a fall in oestrogen
levels.

Women with premature menopause (i.e. before the age of 40-45 years)
are at increased risk of developing osteoporosis and cardiovascular
disease, but are at lower risk of breast cancer. Women show an increase
in bodyweight with age, and this tends to begin at or near menopause.
Body fat redistribution to the abdomen also occurs with age
(independently of weight gain). This centralized abdominal fat
distribution is recognised as an independent risk factor for cardiovascular
disease in women.

References

CKS (2007) Menopause (Topic Review). Clinical Knowledge Summaries

Service. Available at http://www.cks.library.nhs.uk/menopause. Last
revised January 2008, accessed March 2008
3
What are the treatment options for Ruth?

For many women, menopausal symptoms are mild and of short duration,
and may not require management beyond lifestyle adjustments,
information, and reassurance. Exercise, lighter clothing, sleeping in a
cooler room, and reducing stress, together with avoiding triggers such as
spicy foods, caffeine, smoking, or alcohol may help hot flushes and
sweats. Vaginal lubricants and vaginal moisturisers (available for
purchase over the counter) can help ease vaginal dryness.

These may be sufficient for many women, but systemic HRT is generally
more effective at relieving symptoms: [2] it is a question of weighing up
the risks and benefits for the individual woman. Local low-dose vaginal
oestrogen is generally preferred for urogenital atrophy: it is as effective
as systemic HRT (oral, patches, or implant), but systemic absorption is
low. Other potential treatments for menopausal symptoms include
clonidine, various antidepressants and testosterone (only clonidine is
licensed for this indication). There is little evidence from placebo-
controlled RCTs on the effectiveness and safety of these treatments.

Tibolone is an option for some women: it has been shown to be effective

in the treatment of menopausal symptoms, but like HRT, is associated
with an increased risk of breast cancer and venous thromboembolism
(VTE). Women experiencing a natural menopause should not commence
treatment with tibolone until at least 12 months after their last natural
bleed [3], so this is not an option for Ruth just now. Women experiencing
a surgical menopause may commence treatment with tibolone
immediately.

References

National Prescribing Centre: Hormone Replacement therapy - an update.

MeReC Bulletin 2005; 15: 13-16

CKS (2007) Menopause (Topic Review). Clinical Knowledge Summaries

Service. Available at http://www.cks.library.nhs.uk/menopause. Last
revised January 2008, accessed March 2008

Organon Laboratories Ltd: Summary of Product Characteristics for

Livial. Last updated May 2006. Accessed from
http://emc.medicines.org.uk/emc/assets/c/html/displayDocPrinterFriendly
.asp?documentid=8552 March 2008
Part 2
Ruth asks you about the risks and benefits of hormone replacement therapy (HRT). She has
read in her newspaper and several magazines that they can cause breast cancer but may help
reduce heart disease and osteoporosis. She tells you that she dreads getting breast cancer and
asks you if a 'natural product' would be safer?

1
How would you answer Ruth about 'natural' remedies for menopausal symptoms?

Many herbal preparations including red clover, black cohosh, ginseng, isoflavones,
phytoestrogens, etc. have been used to alleviate menopausal symptoms. Many contain
estrogenic principles, just like HRT. There is little good quality evidence to support their use
and high quality trials are needed to ascertain the long-term risks and benefits of these
therapies.

References

National Prescribing Centre: Hormone Replacement therapy - an update. MeReC Bulletin

2005; 15: 13-16

CKS (2007) Menopause (Topic Review). Clinical Knowledge Summaries Service. Available
at http://www.cks.library.nhs.uk/menopause. Last revised January 2008, accessed March
2008

2
How would you summarise the risks and benefits of HRT in a way that makes
sense to Ruth?

a) First the benefits:

The best way of doing this may be to use a patient decision aid which can
be used to explain the pros and cons of HRT. You may wish to use the
patient decision aid on this floor of NPCi
(http://www.npci.org.uk/therapeutics/therap/hrt/patient_decision_aids/pat
 ient_decision_aid1.php).

The best data we have around this comes from systematic reviews and various randomised
controlled trials (RCTs). These provide evidence that, compared with placebo, HRT can give
benefits in terms of:

 Local symptoms
 Fracture risk
 Colorectal cancer.

Local symptoms - HRT may be effective for the treatment of vasomotor symptoms, some
urogenital symptoms and possibly quality of life in the short term. However, in one large
RCT, HRT did not show any clinically meaningful benefit on quality of life compared to
placebo after three years. In 2002, the Committee on Safety of Medicines (CSM) advised
that, for 'short-term' treatment of menopausal symptoms, the balance of risks and benefits of
HRT is generally favourable.

Fracture risk - Bone mineral density starts to decrease after the menopause. Along with the
risk of falls, lower bone strength and poorer bone quality are risk factors for low-trauma
fractures. A large RCT (Women's Health Initiative, WHI) confirmed that both combined and
oestrogen-alone HRT has a modest but significant benefit in the prevention of total fractures
but other data suggest this benefit is lost within a year of stopping HRT. In the WHI trial,
hip fracture rates were reduced by about a third. Although this sounds impressive, Ruth
should note that in the UK, hip fractures are relatively uncommon in the perimenopausal
women who are likely to be taking HRT, therefore, the absolute benefit on fracture risk is
small. In December 2003, a review by the European Medicines Agency (EMEA) concluded
that the balance of risks and benefits of HRT as first-line therapy for the prevention of
osteoporosis was unfavourable.

Colorectal cancer - combined HRT decreased the risk of colorectal cancer in WHI, but
tumours were diagnosed at a more advanced stage and had more positive lymph nodes than
in the placebo group.

Reference

National Prescribing Centre: Hormone Replacement therapy - an update. MeReC Bulletin

2005; 15: 13-16

3
b) Secondly, the harms:
Again, the best way of doing this may be to use a patient decision aid which can be used to
explain the pros and cons of HRT. You may wish to use the patient decision aid on this floor
of NPCi
(http://www.npci.org.uk/therapeutics/therap/hrt/patient_decision_aids/patient_decision_aid1
.php).

Data from observational studies, and randomised controlled trials (RCTs) that used
surrogate endpoints, suggested protective effects of HRT on chronic diseases such as
coronary heart disease (CHD) and dementia. There was also evidence of harm associated
with HRT such as increased risk of breast and endometrial cancer, and venous
thromboembolism. New evidence using patient-oriented clinical outcomes casts doubt on
some of these suggested benefits, whilst confirming other risks.

Overall, there is evidence that, compared with placebo, HRT can produce harms in terms of:

 Breast cancer
 Ovarian and endometrial cancer (in oestrogen-only HRT users)
 Cardiovascular disease
 Dementia
 Venous thromboembolism (VTE)

The use of HRT, especially long term, is now thought to be associated with an increased risk
of breast cancer, endometrial cancer (in oestrogen-only HRT users), cardiovascular disease,
dementia and venous thromboembolism (VTE). It is important to remember that the
absolute increase in risk for a particular woman depends on her baseline risk. For example,
in a large RCT of older HRT users, HRT was associated with approximately a 76% increase
in risk of probable dementia. However, in absolute terms this observed increased risk was an
extra 14 cases per 10,000 women per year (41 cases per 10,000 women per year compared
to 23 cases per 10,000 women per year).

Breast cancer - HRT is associated with an increased risk of breast cancer, which subsides
within five years of stopping. In the combined HRT arm of WHI, the invasive breast cancers
diagnosed in the HRT group were larger and more advanced than in the placebo group,
casting doubt on previous data showing that breast tumours found in HRT users have a
better prognosis. The increased breast cancer risk was apparent within 1-4 years of starting
HRT.

Ovarian and endometrial cancer - There is evidence of an increased risk of ovarian cancer
with oestrogen-only HRT, that becomes more pronounced with longer duration of therapy.
In women with an intact uterus, use of oestrogen-only HRT increases the risk of endometrial
cancer, the risk increasing with duration of use. The CSM has in the past advised that adding
a progestogen to oestrogen-alone therapy for at least 12 days per month greatly reduces this
risk. More recently, the Medicines and Healthcare products Regulatory Agency has stated
that addition of progestogen cyclically for at least 10 days per 28-day cycle (so-called
"opposed oestrogen") greatly reduces the risk, and addition of progestogen every day
eliminates the risk.
 Cardiovascular disease - The WHI study showed no evidence of cardiac protection with
HRT: an increased risk of coronary heart disease (CHD) events of about 29% was seen in
the combined HRT arm compared with placebo. Compared with placebo, the incidence of
stroke also increased (by about 31% in the combined HRT group and by about 39% in the
oestrogen-only group.

Venous thromboembolism (VTE) - in WHI the risk of VTE was more than doubled with
combined HRT compared to placebo. In women taking oestrogen-only HRT the increased
risk of VTE was not statistically significant, although a 47% increased rate of deep vein
thrombosis was seen.

Reference

National Prescribing Centre: Hormone Replacement therapy - an update. MeReC Bulletin

2005; 15: 13-16

MHRA & CHM. Drug Safety Update 2007; 1(2): 2-6

4
If Ruth decides to use HRT, what kind of preparations might be suitable for her -
continuous or cyclical HRT?

Combined HRT is available as cyclical or continuous regimens. In

perimenopausal women (i.e. those who are less than 12 month after their
last menstrual period) monthly or 3-monthly cyclical regimens may be
used: A 3-monthly regimen may be more suitable for women with
infrequent periods or who are intolerant of progestogens. A monthly
regimen produces monthly bleeding and a 3-monthly regimen produces a
bleed every three months. They produce a predictable withdrawal bleed,
whereas continuous regimens often cause unpredictable bleeding in this
group. Cyclical regimens may also be taken by postmenopausal women
(i.e. those at least 12 months after their last menstrual period), and will
also produce a predictable withdrawal bleed in these women. Continuous
combined regimens are also suitable for postmenopausal women. They
induce endometrial atrophy and so do not produce a withdrawal bleed,
although irregular bleeding or spotting can occur in the first 4-6 months
of treatment.

Reference

CKS (2007) Menopause (Topic Review). Clinical Knowledge Summaries

Service. Available at http://www.cks.library.nhs.uk/menopause. Last
 revised January 2008, accessed March 2008

5
If Ruth decides to use HRT, when should she be next reviewed?

Adverse effects account for almost 35% of HRT discontinuations. Ruth

should be followed up 3 months after her first prescription to allow
adequate time for adverse effects to settle. Once stabilised, subsequent
follow-up should usually occur annually. All women should be reviewed
at least annually, as the risks and benefits of HRT for each individual
woman will alter with time, and need to be discussed on an annual basis.

Reference

CKS (2007) Menopause (Topic Review). Clinical Knowledge Summaries

Service. Available at http://www.cks.library.nhs.uk/menopause. Last
revised January 2008, accessed March 2008

6
If Ruth decides to use HRT, how long should she plan to take it for?

HRT can be withdrawn once the woman is no longer bothered by

symptoms. In practice, if a woman is symptom-free on HRT, a trial
withdrawal can be undertaken after 1-2 years of therapy. Women should
be advised that symptoms sometimes recur once HRT is stopped.

Many women do not notice any symptoms even with abrupt cessation of
HRT, but others may experience a recurrence of hot flushes and sweats.
In older women, sleep disorders, rather than hot flushes may be the major
manifestation of renewed menopausal symptoms. Some experts suggest
that HRT should be gradually reduced rather than stopped abruptly.

If symptoms are severe after HRT is stopped, or persist for several

months after stopping, the woman may wish to restart HRT after
reassessment and counselling. Often a lower dose of HRT can be used if
 HRT is restarted.

The Committee on Safety of Medicines (CSM) advised that, for 'short-term' treatment of
menopausal symptoms, the balance of risks and benefits of HRT is generally favourable.
Women who choose to take HRT for more than 5 years should be counselled about the long-
term risks.

References

National Prescribing Centre: Hormone Replacement therapy - an update. MeReC Bulletin

2005; 15: 13-16

CKS (2007) Menopause (Topic Review). Clinical Knowledge Summaries Service. Available
at http://www.cks.library.nhs.uk/menopause. Last revised January 2008, accessed March
2008
http://www.npc.nhs.uk/therapeutics/other/hormone/case.php