Medicines Q&As
Q&A 383.3
How can hot flushes in men being treated for prostate cancer be
managed?
Prepared by UK Medicines Information (UKMi) pharmacists for NHS healthcare professionals
Before using this Q&A, read the disclaimer at www.ukmi.nhs.uk/activities/medicinesQAs/default.asp
Date prepared: November 2013, partial update February 2014
Background
Prostate cancer can be controlled by using hormonal manipulation methods, such as androgen
withdrawal (luteinising hormone-releasing hormone agonists, also known as androgen deprivation
therapy (ADT), such as goserelin and leuprolide) or androgen receptor blockade (anti-androgens,
such as cyproterone and bicalutamide).(1;2) The withdrawal of the sex hormones not only causes
disruption of the thermoregulatory centre in the hypothalamus but also causes noradrenaline
fluctuations, resulting in hot flushes (also called vasomotor symptoms or hot flashes).(3-5) The exact
mechanism of hot flushes is not fully understood.(6) The thermoregulatory centre in the
hypothalamus maintains the core body temperature within a normal thermoregulatory zone and it is
thought that a dysfunction of this centre as well as a downward shift and narrowing of the
thermoregulatory zone may be the cause.(6) In women, decreased endogenous oestrogen
concentrations causes these changes and it is thought that decreased testosterone in men has a
similar effect.(7)
The incidence of hot flushes in men undergoing ADT has been estimated at 55-85% and manifest as
a sensation of increased upper body temperature, skin reddening and sometimes profuse sweating,
followed by a cold, clammy feeling.(4;5) The intensity of the hot flush can be described as




Mild: generalised warmth or flushing lasting less than 3 minutes
Moderate: more warmth and/or flushing than a mild flush, lasting <5 minutes
Severe: hot or very hot, accompanied by anxiety or irritability, heavy perspiration, extreme
discomfort and may require a change of clothing, lasting <10 minutes
Very severe: very hot sensation lasting <30 minutes, drenching perspiration requiring a
change of clothing or bed and a bath/shower.(8)
Hot flushes are not necessarily self-limiting, can be incapacitating if they are severe and can last long
after therapy has been discontinued.(2;4) Hot flushes occurring at night can lead to frequent
awakening, which in the long-term can cause chronic fatigue, irritability and altered memory and
attention span.(9)
Unlike the use of oestrogen replacement therapy for treating hot flushes in postmenopausal women,
androgen replacement therapy cannot be used because the treatment aim of prostate cancer is to
deprive cancer cells of androgens.(10) NICE recommend that medroxyprogesterone (20 mg per day)
is offered initially for 10 weeks, to manage troublesome hot flushes caused by long term androgen
suppression and evaluate the effect at the end of the treatment period.(11) NICE advises to consider
cyproterone acetate (100mg twice daily for 3-4 weeks with the LNRH analogue) or megestrol acetate
(20mg twice a day for 4 weeks) to treat troublesome hot flushes if medroxyprogesterone is not
effective or tolerated.(11;12) Cyproterone acetate has progestogenic activity, exerting a negative
feedback on hypothalamic receptors and therefore reducing both gonadotrophin release and testicular
androgens.(12) It is licensed to treat hot flushes in patients undergoing LHRH analogue treatment or
orchiectomies.
Medroxyprogesterone and megestrol acetate both do not have a UK marketing authorisation for this
indication. The prescriber should therefore follow relevant prescribing guidance, taking full
responsibility for the recommendations. What evidence is there to support these, and other off-label
treatment for managing hot flushes in men with prostate cancer?
Available through NICE Evidence Search at www.evidence.nhs.uk
1
Medicines Q&As
Answer
NICE recommends that medroxyprogesterone, megestrol acetate or cyproterone are used to control
hot flushes caused by long-term androgen suppression (11) but other therapies have been used.
It has been postulated that neurotransmitters such as noradrenaline, serotonin and endorphins,
regulate the thermoregulatory centre in the hypothalamus, so agents which inhibit reuptake of these
neurotransmitters could have beneficial effects on hot flushes.(10) A number of different treatments
for hot flushes in men treated for prostate cancer have been studied. Hot flush diaries were used in
the studies to assess severity and frequency of the hot flushes and patient’s mood and quality of life.
Many of the studies are short, do not carry the strength of a longer, prospective, placebo-controlled
trial and may prevent firm conclusions being drawn. Only one randomised, controlled trial has been
carried out. The studies are summarised below with further details in table 1.
Clonidine
Small studies have evaluated the efficacy of transdermal or oral clonidine for reducing hot flushes,
with varied results.(13-15) The smaller studies showed a positive effect of clonidine on the frequency
and duration of hot flushes,(13;15) while the larger study did not.(14) Note that clonidine patches are
not licensed in the UK.
Gabapentin
Gabapentin 900mg/day has been shown to be significantly more effective in treating hot flushes than
300mg/day (16), but when treatment was continued after a phase 3 study, a 600mg/day dose was
favoured, possibly because of twice, rather than three times a day, dosing.(17) No significant
difference between the combined gabapentin groups and placebo was seen but a dose-response was
clear, with higher doses producing more positive results.
Medroxyprogesterone acetate (MPA) [recommended by NICE (11)]
Intramuscular injections of MPA have been successfully used to reduce the frequency and severity of
hot flushes.(18;19) A 400mg depot injection was used; the only IM injection in the UK is the 150mg
Depo-Provera, which is given every 12 weeks for contraception.(20) Medroxyprogesterone acetate
20mg orally has been used in one comparative randomised study.(21)
Megestrol acetate [recommended by NICE (11)]
Megestrol has been shown to be an effective treatment in reducing the frequency and severity of hot
flushes, in a short study (22) with a longer follow-up.(23) Note that only a 160mg megestrol tablet is
available in the UK (24) but doses used for treating hot flushes in the studies ranged from <20mg to
160mg/day.
Paroxetine
Two small, uncontrolled, open-label studies have evaluated the efficacy of paroxetine 10mg-37.5mg
in men receiving ADT and experiencing 7-14 hot flushes a week for at least 1 month.(10;25) The
studies showed that paroxetine reduced the frequency and severity of hot flushes over a 4-week
treatment period and also improved quality of life (QoL) measures.
Sertraline
Case reports of five men having ADT for prostate cancer and who were treated with sertraline for
anxiety or depression, showed that sertraline had a positive effect on the hot flushes that the men
were also experiencing.(26) Up to 10 hot flushes a day were occurring, some of which were
accompanied by drenching sweats, as well as several hot flushes during the night. When sertraline
doses were titrated up to 75-100mg/day the men noticed a considerable improvement in the hot
flushes, in frequency, intensity and duration.
Venlafaxine
Venlafaxine for treating hot flushes has been evaluated in two small open-label studies.(27;28) Men
having ADT for at least 6 weeks prior to study entry and experiencing at least 14 hot flushes a week
for at least one month were enrolled. After four weeks of venlafaxine 12.5mg bd treatment, an
Available through NICE Evidence Search at www.evidence.nhs.uk
2
Medicines Q&As
improvement in the number and severity of hot flushes was seen. See below for details of the
comparative randomised controlled trial.(21)
Venlafaxine, MPA and cyproterone acetate
A short randomised, double-blind study in 309 men having ADT, showed that cyproterone 100mg
daily and MPA 20mg/day were statistically significantly more effective than venlafaxine 75mg/day in
reducing the number and severity of hot flushes.(21) Significantly more patients considered treatment
with cyproterone and MPA to have good efficacy than those who considered venlafaxine to have good
efficacy. No significant difference in the number of adverse events between the three treatments was
seen.
Available through NICE Evidence Search at www.evidence.nhs.uk
3
Medicines Q&As
Table 1: Study reports
Limitations of many of these studies include short treatment durations and open-label designs.
Ref
Study design and treatment
Results
Comments


Open-label, pilot study.
Clonidine patches, 0.1mg/day, changed
weekly, in 7 men experiencing postorchiectomy hot flushes at night and
between <5 to >10 during the day,
lasting a median 3.5 minutes.

The minimum follow-up was 7 months. All patients experienced some relief from the transdermal
clonidine, with better results in those patients suffering with fewer hot flushes at baseline.
Symptoms resolved fully in two patients who experienced up to 5 flushes per day but only improved
in those experiencing >10. The main side effect was drowsiness.

A small, open-label, pilot study.
The very nature of an open-label
study can lead to bias and results
should be interpreted cautiously.


Open-label, pilot study.
Transdermal clonidine (0.1-0.6mg/day,
n=2) or oral clonidine (0.1-0.6mg/day,
n=2) in men receiving ADT and
experiencing hot flushes


Treatment was given for an average of 9 months (range 3-24).
All patients had a partial response to clonidine within 2 weeks, with a reduction in frequency of the
hot flushes, and, in the men treated with transdermal clonidine, a reduction in the duration, from 10
minutes to 1-2 minutes.

Small, open-label, pilot study, with
data presented per individual,
rather than as a group.

Double-blind, randomised, cross-over
trial.
Weekly transdermal clonidine
(equivalent to a daily oral dose of 0.1mg)
or placebo, given for 4 weeks, total trial
duration 9 weeks.
78 men who had undergone orchiectomy
(medical, 26% or surgical, 74%) and who
were suffering with at least seven hot
flushes a week for a month.
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
Fifty men completed the 9 weeks.
The median frequency of hot flushes during baseline was 8 per day, with a median severity of 1.7 (1
= mild, 4 = very severe). At the end of each treatment period, a minor trend for lower hot flush
frequency was seen with clonidine but no significant advantage over placebo was shown.
When asked which patch worked best to reduce the hot flushes, the majority of patients (47%) could
not tell which patch was better, 34% preferred clonidine and 19% preferred placebo.
Treatment with clonidine was associated with a higher incidence of dry mouth and redness under
the patch but most patients could not tell which treatment period was better in terms of adverse
events.

The negative result was not due
to insufficient sample size; the
study had at least 85% power to
detect a difference of 25% or
more in the value of the hot flush
frequency ratio or hot flush score
ratio between treatment arms.
Randomised, double-blind, placebocontrolled phase 3 study.
Gabapentin 300mg for 28 days (n=54),
gabapentin 300mg daily for 7 days then
300mg bd for 21 days (n=53),
gabapentin 300mg for 7 days, then
300mg bd for 7 days, then 300mg tds for
14 days (n=54), or placebo mirroring
each gabapentin dosing schedule
(n=53).
Men undergoing ADT who had at least


One of the better designed and
reported studies.
Although no significant difference
between the combined
gabapentin treatment and the
placebo treatment was seen, a
dose-response effect was clear,
with higher doses producing more
positive results.
(15)
(13)

(14)
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

(16)
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No significant differences were seen between the collective gabapentin groups and the placebo
group for the median changes from baseline in:
 Hot flush score (primary endpoint): -3.3 (gabapentin) vs. -2.8 (placebo), difference = -0.6, [95% CI
-2.3 to 1.0, p=0.48].
 Per treatment median changes were -2.4 (median -29.7% decrease from baseline, 300mg), 3.1 (-33.8%, 600mg) and -4.3 (-44.4%, 900mg, p=0.05 vs. 300mg).
 Mean hot flush scores fell by -4.1 (placebo), and by -3.2, -4.6 and -7.0 for gabapentin 300mg,
600mg and 900mg respectively.(17)
 Hot flush frequency: -2.1 (gabapentin) vs. -1.6 (placebo), difference = -0.6, [95% CI -1.6 to 0.3,
p=0.19].
 Per treatment median changes from baseline (median % decrease) were -1.8 (-22.8%,
Available through NICE Evidence Search at www.evidence.nhs.uk

4
Medicines Q&As
Ref
Study design and treatment



(17)


(18)
Results
14 hot flushes a week for at least 1
month.
Fifty patients per group would provide
80% power to detect a clinically
meaningful difference in the primary end
point between gabapentin and placebo.
8-week, open-label, uncontrolled,
continuation phase of the study above
(n=147) (13).
Patients treated with placebo were
started on gabapentin 300mg/day; all
could increase or decrease their dose by
300mg/day each week according to
control or toxicity, with a maximum dose
of 900mg/day.
Open-label, uncontrolled study.
Medroxyprogesterone acetate (MPA)
400mg by intramuscular (IM) injection in
55 men on ADT and experiencing hot
flushes.
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
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

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(19)
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
Retrospective review.
MPA 400mg or 150mg by IM injection in
48 men treated with LHRH agonists and
experiencing hot flushes.



Comments
gabapentin 300mg), -2.0 (-31.8%, 600mg) and -2.6 (-45.5%, 900mg, p=0.02 vs. placebo and
p=0.03 vs. 300mg).
Gabapentin had a significant positive effect on hot flush control (p=0.03 vs. placebo) and how they
affected quality of life (p=0.01 vs. placebo), mainly driven by significant differences between the
gabapentin 900mg/day group vs. placebo.
A higher incidence of appetite loss and constipation occurred in the placebo group.
Mean dose taken was 600mg/day (300mg bd).
By the end of the continuation phase, all patients had achieved similar reductions in hot flush
frequency and scores.
From the original baseline to week 12, mean hot flush scores fell by 44%, 46%, 48% and 49% in the
original placebo, 300mg, 600mg and 900mg groups. Corresponding reductions in hot flush
frequency were 49%, 57%, 51% and 51%.
No increase in adverse effects was seen.
Significant improvements in two QoL measures were seen in both the placebo and 300mg groups:
‘how distressing are your hot flushes’ and ‘how satisfied are you with your hot flush control’.
Patients in the original placebo group showed a significant improvement in the ‘how much did the
hot flushes affect your quality of life’ measure, in the continuation phase.
The men were followed for a mean of 17.2 months (range 6-36 months) and significant
improvements in symptoms were seen in 51 men (92.7%).
A single dose was administered to 27 men, 15 had 2 subsequent doses and 13 required 3 or more
additional doses. The response lasted 4-12 months in 35 men and in 15 men the response lasted a
year or longer.
Before MPA was used, the average number of hot flushes experienced was 4.73, and the severity
was 2.19 (1=mild, 3=severe).
After MPA treatment, the number had fallen to 1.50 and the severity was reduced to 0.075 (p<0.05
for both changes). No difference between the two doses was seen.
The majority of patients (81%) had significant improvements in the severity of their hot flushes and a
>50% reduction in the number and severity of hot flushes occurred in 76% and 78% of patients
respectively.
A median of 4 injections was given over a 43 month period, averaging 1 injection every 10 months.
Available through NICE Evidence Search at www.evidence.nhs.uk


An open-label continuation phase.
The majority of patients took
600mg/day, suggested that threetimes a day dosing may be
inconvenient.

The data from this study are
limited to an abstract
presentation.

The only IM injection in the UK is
the 150mg Depo-Provera, which
is given every 12 weeks for
contraception.(20)
5
Medicines Q&As
Ref
Study design and treatment
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
(22)


(23)




(25)

Cross-over study.
Megestrol 20mg bd or placebo for 4
weeks, then vice versa, followed by an
open-label 4-week treatment period of
megestrol 10-80mg/day.
Women (n=97) and men (n=66)
experiencing hot flushes following
treatment for breast cancer or ADT
(medical or surgical) for prostate cancer,
respectively.
Results
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
Long-term use following the above shortterm study.
Megestrol doses <20mg/day to
160mg/day.
59 patients (40 men).


Pilot study.
Paroxetine 12.5mg/day during week 1,
25mg/day during week 2, 37.5mg/day
during week 3 and the dose was either
maintained at 37.5mg/day or reduced to
12.5-25mg/day during week 4.
24 men with at least 14 bothersome hot
flushes/week following ADT.
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
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


(10)
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

Pilot study.
Paroxetine 10mg/day for 4 weeks.
10 men having at least 7 hot
flushes/week following ADT.


The median number of hot flushes per day at baseline was 8.4 (range 2 to 29.1) for the men, and
the median hot flush score was 17 for the men.
After 4 weeks of megestrol, the median number of hot flushes experienced by the men was 20% of
the baseline average vs. 81% of baseline average in the placebo group, p<0.001. The median hot
flush scores were 13% vs. 84% of the baseline averages, respectively, p<0.001.
A 50% reduction in hot flushes was reported by 79% of men treated with megestrol (26/33) vs. 12%
treated with placebo (4/33), p<0.001.
No clear answer to which treatment the patients preferred was seen. In the patients who received
placebo first, 87% said megestrol was better, but only 45% of those who received megestrol first
preferred it, probably because of the delayed effect after the start and the carryover effect after
stopping.
The most common dose was 20mg/day.
Breakthrough hot flushes were experienced by 17 men and 8 men reported infrequent and mild hot
flushes.
Episodes of chills were described by 22 of the men, even described as ‘cold flashes’, but these
were not as bothersome as the hot flushes.
At baseline, 14 patients reported 4-9 hot flushes a day, 3 reported 2-3 per day and 5 reported ≥10
per day.
18 patients completed the study.
The median daily hot flush frequency and hot flush score during the fourth treatment week
decreased from baseline by 50% (95% CI 34-92%) and 59% (95% CI 31-87%) respectively.
Median hot flush frequencies fell from 6.2 to 2.5/day.
Improvements were seen in various QoL measurements, including abnormal sweating, depression,
sleeping, anger and hot flush control.
The mean number of hot flushes experienced at baseline were 3.5 ± 2.6/day and were rated mainly
as ‘quite a bit’ or ‘extremely’ severe (mean 4.6 ± 3, 1 = not at all, 5 = intermediate, 10 = extremely
severe).
After 4 weeks of paroxetine treatment, the frequency of hot flushes was reduced to a mean of 2.0 ±
2.7/day (p=0.009) and the average rating for severity was also reduced to 2 ± 2.7 (p=0.0332).
Quality of life was improved, with an increase from the baseline score of 3.8 ± 2.3 to 6.9 ± 2.6
(p=0.0218, 1=worst possible life, 10=best possible life).
Available through NICE Evidence Search at www.evidence.nhs.uk
Comments


Cross-over analysis had to be
ignored because after stopping
megestrol, it took 2-3 weeks for
its effects to cease, giving a carryover effect.
This study does not address any
potential toxicity issues, e.g.
thromboembolism, which may be
a risk with higher doses, and the
effect of low doses megestrol on
the course of hormonally sensitive
cancers.

Note that only a megestrol 160mg
tablet is available in the UK.(24)

The sample size would give 80%
power to detect at least a 50%
reduction in hot flush scores.
Determining the optimal
paroxetine dose is difficult:
impressive reductions were seen
in the first 3 weeks as the dose
was increased but longer term
data are not available.


A lower paroxetine dose than
used in the trial above was
effective, but longer term data are
lacking.
6
Medicines Q&As
Ref
Study design and treatment
Results


(26)



Case reports
Sertraline 25mg – 100mg daily
5 men with prostate cancer and
experiencing hot flushes.



(27)



Pilot study.
Venlafaxine 12.5mg bd for 4 weeks.
Five men receiving ADT for prostate
cancer and 23 women with a history of
breast cancer.




(28)





(21)

Pilot study.
Venlafaxine 12.5mg bd for 4 weeks.
21 men receiving ADT and with at least
14 hot flushes/week. 16 men had
evaluable data.

Randomised, double-blind, doubledummy 8 week study.
Venlafaxine SR 75mg/day (n=102),
MPA 20mg/day (n=108) or cyproterone
acetate 100mg/day (n=101).
309 men treated with leuprorelin
11.25mg who, after 6 months of
treatment, experienced ≥14 hot flushes





Case 1: Patient was initiated on sertraline 25mg daily which was raised to 100mg daily over 6
weeks. A significant decrease in the frequency (from 5-10 per day to 3-5 per day) and intensity of
hot flushes occurred.
Case 2: Sertraline 100mg daily improved the quality of life of the patient who had been experiencing
a few hot flushes each day and was being woken once or twice a night by the flushes.
Case 3: Sertraline 100mg daily reduced the number of hot flushes in a patient who was woken 1-2
times per night because of them. A 50mg daily dose maintained the positive effects.
Case 4: Patient experienced hot flushes with drenching sweats several times a day. With a dose of
sertraline 100mg daily the frequency of the flushes fell from 8 to 2 per day, with the mean duration
reduced from 2-3 minutes to less than 1.
Case 5: A patient who experienced distressing hot flushes several times a day and was awakened
several times night was treated with sertraline 125mg daily. Although no decrease in the frequency
and intensity of the flushes was reported, he did not complain about them as much.
The number of hot flushes fell from a baseline average of 6.6 hot flushes per day (range 3.1 to 33.9)
to 5.7 after week 1 and to 4.3 (range 0 to 19) at the end of the study period.
Fifteen patients reported ≥50% reduction in the number of hot flushes, and the incidence of
severe/very severe was reduced from an average of 1.4 to 0.1 per day (p<0.0002).
Overall, 19 patients (68%) thought that venlafaxine reduced hot flush activity and 18 (64%) would
want to continue with the therapy.
During the baseline period an average of 10 hot flushes per day were reported (range 0.7 to 33.9),
which fell to 7 by week 1 and to 6 (range 0 to 15) by the end of the treatment period.
Hot flush activity decreased significantly in all but 5 patients during the first treatment week and by
the end of week 4, 13 men reported a reduction in hot flush activity.
A number of side effects occurred, including appetite loss, sleepiness, constipation, dizziness,
tiredness, dry mouth, abnormal sweating, but the incidence was lower at week 4 than at baseline
and three patients discontinued because of adverse gastric reactions, including severe nausea.
At the end of the study, 11 of the 21 men who started the study perceived a benefit from venlafaxine
and wished to continue taking it.
At baseline hot flushes were described as: mild (20.1%), moderate (43.4%) and severe (36.6%).
The median (mean) weekly number of hot flushes was 33 (44.4). The daily hot flush score was 7.6
(10.5).
Results at week 4 are below. Pairwise comparisons of treatment groups confirmed that the
decreases in hot flush scores were significantly larger in the cyproterone and MPA groups than in
the venlafaxine group. There was no significant difference between the cyproterone and MPA
groups.
Overall, after 4 weeks of treatment, 70.9% had an improvement of at least 50% in their hot-flush
Available through NICE Evidence Search at www.evidence.nhs.uk
Comments

These limited case reports show
that sertraline is effective in
reducing hot flushes, but the data
are limited by the lack of detail
and small patient numbers; a
larger study would be required.

Although the patient numbers are
too small to draw firm conclusions
on subsets, there did not appear
to be any differences between the
responses of the men and
women.

Both of the venlafaxine studies
are too short to draw firm
conclusions regarding the longterm efficacy of it for hot flushes.

All patients received 2 tablets in
the morning and one in the
evening from weeks 1-8, then one
tablet twice a day, to account for
venlafaxine dosing and
discontinuation (37.5mg/day
during weeks 9 and 10).
The primary goal of 351 patients,

7
Medicines Q&As
Ref
Study design and treatment

in the week before enrolment. Patients
receiving SSRIs, steroid hormones,
clonidine and gabapentin were excluded.
The primary endpoint was the change in
hot flush score after 4 weeks of
treatment. Daily hot flushes were
assessed using the validated Mayo
Clinic hot flush diary, with the score =
number of hot flushes x average severity
(mild =1, very severe = 4).
Results



score and 22.7% reported a complete absence of hot flushes. Improvements for venlafaxine were
significantly lower than in the other two groups (p=0.0006).
EORTC Quality of life questionnaires were completed but the only significant difference was in the
emotional functional scale, which was significantly better with venlafaxine.
60-84.1% of patients treated with cyproterone or MPA rated their treatment as good, compared to
28.4 to 33.7% in the venlafaxine group (p<0.0001).
The rate of adverse events and discontinuation due to AEs did not differ significantly between the
three groups.
Results
Overall
Venlafaxine
Cyproterone
MPA
Median score at randomisation
7.6
6.9
6.5
9.6
7.5 (12.7).
P<0.0001 vs.
venlafaxine
4 week median (mean) weekly
number of hot flushes
9.0 (15.7)
21.0 (26.6)
4.0 (1.8)
P<0.0001 vs.
venlafaxine
4 week median (mean) daily hot
flush score
1.6 (3.6)
4.0 (6.5)
0.9 (1.8)
1.3 (2.7)
-47.2%
(-74.3 to -2.5)
3.6
-94.5%
(-100 to -74.5)
0
-83.7%
(-98.9 to -64.3)
0.3
Median relative change in daily hot
flush score from 4 to 8 weeks
-6.7%
(-50 to -38.3)
-13.5%
(-88.9 to 0)
-34.1%
(-96.8 to 0)
Median relative change in daily hot
flush score from baseline to 8 weeks
-56.7%
(-80.9 to -21.7)
-100%
(-100 to -83.5)
-97.3%
(-100 to -77.8)
Adverse events
66
75
60
AEs related to study med
26 (39.4%)
36 (48%)
18 (30%)
Patients with ≥1 AE leading to
discontinuation
7 (6.9%)
8 (8%)
9 (8.4%)
4 week median relative change in
daily hot flush score from baseline
8 week median score

Comments
-



to take into account a 14%
dropout rate, was not reached.
No placebo group was included
due to the availability of data for
the study drugs vs. placebo.
There was an imbalance in the
median hot flush score at
randomisation, with a higher score
and more patients requesting hot
flush treatment in the MPA group;
this may have affected the results.
Data are only available for 8
weeks of treatment; long-term
data on efficacy and safety are
needed.
Hot flush score: total number of mild hot flushes + 2 x total number of moderate hot flushes + 3 x total number of severe hot flushes + 4 x total number of very severe hot flushes recorder in a given
week and divided by the number of days the symptoms were recorded on.
Available through NICE Evidence Search at www.evidence.nhs.uk
8
Medicines Q&As
Summary





There are a number of treatments which have been studied for the treatment of hot flushes in
men undergoing androgen deprivation therapy, most are unlicensed for this indication, such
as clonidine, gabapentin, medroxyprogesterone acetate, megestrol and SSRIs, while
cyproterone is licensed for this.
There are few well designed, randomised studies. Some data come from smaller open-label
or pilot studies or case reports, which were not placebo-controlled and have not been well
reported.
Many of the studies are short, do not carry the strength of a longer, prospective, randomised,
placebo-controlled trial and may prevent firm conclusions being drawn.
One short randomised, comparative study has been carried out and showed that cyproterone
acetate and medroxyprogesterone were significantly more effective than venlafaxine in
reducing the severity and frequency of hot flushes.
Optimum doses of the individual drugs may be difficult to determine, and it may be a case of
starting with a low dose and titrating upwards until hot flushes are controlled, or until adverse
events lead to discontinuation. Bear in mind that patient variability means that one specific
treatment may not be suitable for every patient.
Limitations


Of the treatments listed in the Q&A, only cyproterone is licensed for the treatment of hot
flushes in men who are treated with LHRH agonists or who have undergoing orchiectomy.(12)
Interactions, contraindications, precautions, adverse events etc. of each therapy are not
discussed in this Q&A, but information can be found via the electronic Medicines
Compendium.
References
(1) Prostate cancer. Diagnosis and treatment. NICE clinical guideline 58. February 2008.
National Collaborating Centre for Cancer www.nice.org.uk
(2) Baum NH, Torti DC. Managing hot flashes in men being treated for prostate cancer. Geriatrics
2007; 62(11):18-21.
(3) Nishiyama T, Kanazawa S, Watanabe R et al. Influence of hot flashes on quality of life in
patients with prostate cancer treated with androgen deprivation therapy. Int J Urol 2004;
11:735-741.
(4) Kattan MW. Measuring hot flashes in men treated with hormone ablation therapy: an unmet
need. Urol Nurs 2006; 26(1):13-18.
(5) Bagrodia A, DiBlasio CJ, Wake RW et al. Adverse effects of androgen deprivation therapy in
prostate cancer: Current management issues. Indian J Urol 2009; 25(2):169-176.
(6) Sicat BL, Brokaw DK. Nonhormonal alternatives for the treatment of hot flashes.
Pharmacotherapy 2004; 24(1):79-83.
(7) Spetz A-C, Zetterlund E-L, Varenhost E et al. Incidence and management of hot flashes in
prostate cancer. Journal of Supportive Oncology 2003; 1:263-273.
(8) Alekshun TJ, Patterson SG. Management of hot flashes in men with prostate cancer being
treated with androgen deprivation therapy. Supportive Cancer Therapy 2006; 4(1):30-37.
(9) Fitzpatrick LA, Santen RJ. Hot flashes: the old and the new, what is really true? Mayo Clin
Proc 2002; 77(11):1155-1158.
Available through NICE Evidence Search at www.evidence.nhs.uk
9
Medicines Q&As
(10) Naoe M, Ogawa Y, Shichijo T et al. Pilot evaluation of selective serotonin reuptake inhibitor
antidepressants in hot flash patients under androgen-deprivation therapy for prostate cancer.
Prost Can Prostat Dis 2006; 9:275-278.
(11) Prostate cancer: diagnosis and treatment. Clinical guideline 175. January 2014. National
Institute for Health and Care Excellence www.guidance.nice.org.uk/cg175
(12) Summary of Product Characteristics. Cyprostat 100mg. Date of revision of the text:
18/12/2012. Bayer PLC. www.emc.medicines.org.uk
(13) Bressler LR, Murphy CM, Shevrin DH et al. Use of clonidine to treat hot flashes secondary to
leuprolide or goserelin. Ann Pharmacother 1993; 27:182-185.
(14) Loprinzi CL, Goldberg RM, O'Fallon JR et al. Transdermal clonidine for ameliorating postorchiectomy hot flashes. J Urol 1994; 151:634-636.
(15) Parra RO, Gregory JG. Treatment of post-orchiectomy hot flashes with transdermal
administration of clonidine. J Urol 1990; 143:753-754.
(16) Loprinzi CL, Dueck AC, Khoyratty BS et al. A phase III randomized, double-blind, placebocontrolled trial of gabapentin in the management of hot flashes in men (N00CB). Ann Oncol
2009; 20:542-549.
(17) Moraska AR, Atherton PJ, Szydlo DW et al. Gabapentin for the management of hot flashes in
prostate cancer survivors: a longitudinal continuation study - NCCTG trial N00CB. Journal of
Supportive Oncology 2010; 8:128-132.
(18) Brosman SA. Depo-Provera as treatment for 'hot flashes' in men on androgen ablation
therapy. Abstract 877. J Urol 1995; 153(April Supplement):448A.
(19) Langenstroer P, Kramer B, Cutting B et al. Parenteral medroxyprogesterone for the
management of luteinizing hormone releasing hormone induced hot flashes in men with
advanced prostate cancer. J Urol 2005; 174:642-645.
(20) Summary of Product Characteristics. Depo-Provera 150mg/mL injection. Date of revision of
the text: 08/2010. Pharmacia Limited www.emc.medicines.org.uk
(21) Irani J, Saloman L, Oba R et al. Efficacy of venlafaxine, medroxyprogesterone acetate, and
cyproterone acetate for the treatment of vasomotor hot flushes in men taking gonadotrophinreleasing hormone analogues for prostate cancer: a double-blind, randomised trial. Lancet
2010; 11:147-154.
(22) Loprinzi CL, Michalak JC, Quella SK et al. Megestrol acetate for the prevention of hot flashes.
N Engl J Med 1994; 331:347-352.
(23) Quella SK, Loprinzi CL, Sloan JA et al. Long term use of megestrol acetate by cancer
survivors for the treatment of hot flashes. Cancer 1998; 82:1784-1788.
(24) Summary of Product Characteristics. Megace 160mg tablets. Date of revision of the text:
January 2013. Bristol-Myers Pharmaceuticals. www.emc.medicines.org.uk
(25) Loprinzi CL, Barton DL, Carpenter LA et al. Pilot evaluation of paroxetine for treating hot
flashes in men. Mayo Clin Proc 2004; 79(10):1247-1251.
(26) Roth AJ, Scher HI. Sertraline relieves hot flashes secondary to medical castration as
treatment of advanced prostate cancer. Psychooncology 1998; 7:129-132.
Available through NICE Evidence Search at www.evidence.nhs.uk
10
Medicines Q&As
(27) Loprinzi CL, Pisansky TM, Fonseca R et al. Pilot evaluation of venlafaxine hydrochloride for
the therapy of hot flashes in cancer survivors. J Clin Oncol 1998; 16:2377-2381.
(28) Quella SK, Loprinzi CL, Sloan J et al. Pilot evaluation of venlafaxine for the treatment of hot
flashes in men undergoing androgen ablation therapy for prostate cancer. J Urol 1999;
162:98-102.
Quality Assurance
Prepared by
Lekha Shah, Principal pharmacist, London Medicines Information Service (Northwick Park Hospital)
(Based on earlier work by Alexandra Denby)
Date Prepared
November 2013 [Updated February 2014]
Checked by
Alexandra Denby, Regional MI Manager, London Medicines Information Service (Northwick Park
Hospital)
Date of check
6th January 2014
Email contact
nwlh-tr.medinfo@nhs.net
Search strategy
 Embase: *HOT FLUSH/si [Side Effect] AND *PROSTATE CANCER/[Limit to: Publication Year
2011 – Current]
 Embase: HOT FLUSH/dt [dt=Drug Therapy] AND *PROSTATE CANCER [Limit to: Publication
Year 2011 – Current]
 Embase: HOT FLUSH/dt [dt=Drug Therapy] AND [MEDROXYPROGESTERONE/ OR
MEDROXYPROGESTERONE ACETATE/ OR MEGESTROL/ OR GABAPENTIN/ OR
PAROXETINE/ OR SERTRALINE/ OR FLUOXETINE/ OR VENLAFAXINE/ CLONIDINE/] [Limit to:
Male] [Limit to: Publication Year 2011 – Current]
 Medline: HOT FLASHES/dt [dt=Drug Therapy AND *PROSTATIC NEOPLASMS/ [Limit to:
Publication Year 2011 – Current]
 Medline: *PROSTATIC NEOPLASMS/ AND [MEDROXYPROGESTERONE/ OR
MEDROXYPROGESTERONE ACETATE/ OR MEGESTROL/ gabapentin.af OR SERTRALINE/
OR FLUOXETINE/ OR PAROXETINE/ OR venlafaxine.af OR CLONIDINE/] [Limit to: Humans and
English Language and Publication Year 2011 - Current]
 Medline: HOT FLASHES/dt [dt=Drug Therapy] AND [MEDROXYPROGESTERONE/ OR
MEGESTROL/ gabapentin.af OR SERTRALINE/ OR FLUOXETINE/ OR venlafaxine.af OR
CLONIDINE/] AND MALE/ / [Limit to: Publication Year 2011 – Current]
 In-house database/ resources (MIDatabank)
Available through NICE Evidence Search at www.evidence.nhs.uk
11