Treatment of hot flashes presented in Egyptian society of menopause conference on 8 .1.2015

1. Treatment of hot flashes
Aboubakr Elnashar
Banha university Hospital, Egypt
AboubakrElnashar

2. CONTENTS
1. INTRODUCTION
Clinical manifestations
Pathophysiology
Rate
Prevalence
Risk factors
2. ASSESSMENT
3. TREATMENT
4. TREATMENT OF INTRACTABLE HOT
FLUSHES
SUMMARY AND RECOMMENDATIONS
4
AboubakrElnashar

3. 1. INTRODUCTION
Clinical manifestations
Sudden sensation of heat centered on the face
and upper chest that rapidly becomes generalized.
The sensation of heat lasts 2-4 mins
Often associated with profuse perspiration and
occasionally palpitations
Often followed by chills and shivering.
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4. Thermoregulatory dysfunction
inappropriate peripheral vasodilatation: increased
digital and cutaneous blood flow and perspiration:
rapid heat loss and a decrease in core body
temperature below normal.
Shivering then occurs as a normal mechanism to
restore the core temperature to normal
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5. Rate
Usually: several times/d
1-2/d
1/h during the day and night: arousal from
sleep: sleep disturbances
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6. Prevalence
Before the perimenopausal transition: 14-51%
Perimenopause: 35-50%
After menopause: 30 to 80%
[NIH, 2005].
It is generally believed that hot flashes do not
occur in premenopausal women
{serum estrogen concentrations are never very low,
even during the menstrual period}. However, the
large observational SWAN study found that 20% of
premenopausal women reported hot flashes
[Gold et al, 2009].
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7. In a longitudinal study of women traversing the
perimenopausal transition, annual serum FSH
concentrations, but not other hormones (estradiol,
testosterone, DHEA-S), when collectively modeled
longitudinally, were associated with both the
prevalence and frequency of vasomotor symptoms
[Huang et al, 2009].
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8. Duration
≥80%: ≥one year.
Untreated: stop spontaneously within a few
years of onset in most women
Persistent hot flashes
12 to 15% for women in their sixties
9% after age 70 years
The prevalence (or reporting) of hot flashes is
quite variable across cultures.
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9. Pathophysiology
Not clearly understood
(Bachmann, 2005).
Dysfunction of central thermoregulatory centers in
the hypothalamus
Estrogens.
play a vital role
withdrawal or rapid fluctuation in levels, rather than
low concentration
(Overlie, 2002).
{Turner syndrome who lack normal estrogen levels, do not experience hot
flashes unless first exposed to estrogen and then withdrawn from treatment}.
Neurotransmitters.
changes in neurotransmitter levels
(Pinkerton, 2009).
Norepinephrine. Serotonin.
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10. Risk factors
In the Study of Women's Health Across the Nation
(SWAN)
Less often
Japanese and Chinese
More often
African-American compared to Caucasian
[Gold et al, 2006].
0
20
40
60
80
100
USA Canada Europe Japan Other
Asian
Africa Middle
East
Frequenciesofhotflushes(%)
Low estimate High estimate
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11. High BMI
Although obese women have higher endogenous levels of circulating
estrone {increased peripheral conversion of androstenedione to estrone in
adipose tissue}
[whiteman, 2003].
Smoking
[Gold et al, 2000].
Less physical activity
Sociodemographic factors
less than a high school education
difficulty paying for basics
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12. Score Calculation Interpretation
Severity score = (number of
mild hot flashes/day × 1) +
(number of moderate hot
flashes/day × 2) + (number of
severe hot flashes/day × 3) +
(number of very severe hot
flashes/day × 4)/total number
of hot flashes/day
Some trial methodologies deviate from this formula
slightly, excluding hot flashes in the very severe
category and including them in the severe category
Higher scores indicate
worse symptoms
There is no maximum
score since the score is
patient dependent for both
number and severity
2. ASSESSMENT
Hot Flash Score
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13. Score Calculation Interpretation
Assesses four subcomponents
of both symptoms and quality
of life: psychological (possible
score 0-33), somatic (0-21),
vasomotor symptoms (0-6),
and sexual (0-3)
Total score can range
from 0-63
Higher scores indicate
worse symptoms
For the vasomotor
subscore, a score of 0-2
indicates no or mild hot
flashes and 3-6 indicates
moderate-to-severe hot
flashes
Greene Climacteric Score
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14. Score Calculation Interpretation
Assesses 11 subcomponents: hot flashes,
sweating, insomnia, nervousness,
depression, vertigo, tiredness, joint ache,
headache, palpitations, and vaginal
dryness
All are scored from 0-3 based on
symptoms: 0 = none, 1 = weak, 2 =
moderate, 3 = strong
Hot flash score is multiplied by 4; sweating,
insomnia, and nervousness scores are multiplied
by 2; then all subcomponents are added together
for the total score
Total score
can range
from 0-51
Higher scores
indicate
worse
symptoms
Modified Kupperman Index
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15. A. Hormonal
1. Estrogen
2. Progestin
3. Tibolone
4. Bioidentical hormones
B. Non-hormonal
I. CNS agents
1. SSRI
2. Gabapentin
II. CAM
1. Acupuncture
2. Phytoestrogen
3. Phytoprogestin
4. Lifestyle Changes
4. TREATMENT
AboubakrElnashar

16. A. Hormonal
1. ESTROGEN
Indication
 Moderate-to-severe hot flashes: Short-term
[NAMS, 2010].
Long-term use for prevention of disease is no
longer recommended.
Mild hot flashes: do not usually require any
pharmacologic intervention.
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17. Effectiveness.
Systemic ET
Most effective tt for VMS
•stop hot flashes completely in 80%
•reduce their frequency and severity in the
remainder
[Maclennan et al Cochrane Database Syst Rev 2004].
Only therapy currently approved by the FDA
(Shifren, 2010).
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18. Route.
Oral, parenteral, topical, vaginal, or transdermal:
similar effects.
Oral:
Most popular, although
Transdermal
±safer {avoid liver’s1st pass effect}
≥convenience {less frequent administration
(once or twice weekly)}.
similar efficacy {all absorbed from GIT primarily as estrone
sulfate, which is continuously desulfated and converted to E2}: even
though oral estrogen is administered in a single daily dose, the resulting
serum E2 vary little between doses.
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19. The effective daily dose-equivalents:
CEE and 17-beta estradiol (oral or transdermal):
equally effective for the tt of hot flashes
[Nelson, 2004, SR].
Daily dose
1 mgmicronized 17-beta-estradiol
50 mcgtransdermal 17-beta-estradiol
1.25 mgpiperazine estrone sulfate
0.625 mgconjugated equine estrogens
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20.  Lower doses ± effective in select patients.
CEE (0.3 mg),
Oral 17-beta estradiol (0.5 mg)
Transdermal 17-beta estradiol (25 mcg patch)
[Ettinger, 2005].
Transdermal estradiol [14 mcg/day]) : more
effective than placebo
[Bachmann et al, 2007].
AboubakrElnashar

21. Estradiol: Benefits on Vasomotor Symptoms
• Dose–response effect for reducing moderate-to-severe hot flushes
(n=333)
Notelovitz et al 2000
*p<0.05, ***p<0.001 vs. placebo
*
*
Meannumberofmoderate-to-
severehotflushesperweek
Weeks
0
10
20
30
40
50
60
70
80
0 1 2 3 4 5 6 7 8 9 10 11 12
Placebo
0.25 mg Estradiol
0.5 mg Estradiol
1 mg Estradiol
2 mg Estradiol
***
***
***
*
*
*
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22. Regimen
Continuous estrogen therapy:
recommended
{When given for 25 days of each month or for 3 of
every 4 ws: hot flashes often recur during the E free-
period}.
In women with a uterus:
E should be given with a progestin {prevent
endometrial hyperplasia}.
Doses and route of administration
can be changed relative to patient preference.
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23. Uterus
Sequential therapy without tablet break
Regular bleeding at end of cycle
How is HRT Given?
Continuous Sequential HRT
Estrogen
Progestogen
Day 14
De Villiers TJ et al. 2013.
.
Continuous Estrogen
Estrogen
No tablet break
No bleeding as no uterus
Uterus
Continuous Combined HRT
Estrogen
Progestogen
Day 14 Combined therapy without tablet break
No bleeding at end of cycle
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24. Estrogen contraindications:
Undiagnosed abnormal genital bleeding
Known, suspected, or history of breast cancer
Known or suspected E-dependent neoplasia
Active DVT, pulmonary embolism, or history of
these conditions
Active or recent (within the past year) arterial
thromboembolic disease (stroke or MI)
Liver dysfunction or disease
Known hypersensitivity to the ingredients of E
preparation
Known or suspected pregnancy.
AboubakrElnashar

25. When prescribing of HRT:
 Timing:
 Sooner is better
 Maintain the beneficial action of E on the woman’s body
with an early start, whenever she needs it
 Personalization:
 Tailor the type, dose, and route of HRT for each individual
woman to achieve control of E-deficiency symptoms.
 There will never be one preparation that suits all women.
Select the right dose for the right woman.
 Balance the benefits vs. the risks
At both the initiation of therapy and over time.
 With age:
Continuation and tapering the dose
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26. 2. Progestin
Progestin alone
Somewhat effective for tt of hot flashes {inhibit GnT
secretion and increase endogenous hypothalamic
opioid peptide activity}.
Combined with E:
Protect against E-induced endometrial hyperplasia.
Slightly more effective than E alone in ameliorating
hot flashes.
AboubakrElnashar

27. When: E is contraindicated
History of venous thromboembolism or
Breast cancer.
Adverse effects:
Vaginal bleeding
Wt gain
Transient increase in hot flashes for 1-2 w
Megestrol acetate: glucocorticoid-like activity:
adrenal insufficiency after it is discontinued.
±attenuate E beneficial effects on lipids and blood
flow.
Progestins provide no meaningful increase in
estrogen’s benefits to bone. AboubakrElnashar

28. Role of Progestogens in HRT
Writing Group for the PEPI Trial. JAMA 1996;275:370–5.
PEPI Trial: multicenter RCT : Results of Endometrial Biopsy
Adding a progestogen is needed to safeguard the
endometrium
Placebo CEE
alone
CEE+MPA
sequential
CEE+MPA
continuous
119 119 118 120
Normal 98% 38% 95% 99%
Simple
hyperplasia
1% 28% 3% 1%
Complex
hyperplasia
1% 23% 2% 0%
Atypia 0% 12% 0% 0%
Adenocarcinoma 1% 0% 0% 0%
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29. DMPA :
Single dose of 400 mg: 80% reduction of hot
flushes
Greater efficacy with fewer side effects.
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30. 3. Tibolone
Synthetic steroid: 17 OH -7 methyl norpregn
Action
3 metabolites, each with different binding affinity to
the E, P & A receptors.
Weak estrogenic, progestagenic & androgenic
(Gonadomimetic)
It is anti E on the endometrium & E on the vagina
2.5 mg/d
AboubakrElnashar

31. Widely used in Europe and other countries for
nearly 20 years
Reduces VMS when compared to placebo
[NAMS, 2004]
 Beneficial effect on BMD.
Modest effect for symptoms of sexual dysfunction.
AboubakrElnashar

32. Compared to placebo:
Tibolone:
More effective in relieving the frequency of VMS
Increased vaginal bleeding
Compared to equipotent doses of combined HT:
Tibolone
Reduced vaginal bleeding
Less effective in relieving the frequency of VMS
(Formoso et al, 2012: Cochrane Database Syst Rev)
AboubakrElnashar

33. Long term safety:
•RCT of 3098 women with breast cancer and
menopausal symptoms was halted after 3.1 y
{increased tumour recurrence} .
•RCT of 4506 of osteoporotic women with negative
mammograms
Reduction in breast cancer compared to placebo
after 2.8 y
An excess risk of stroke in women whose mean
age was over 60 y.
(Formoso et al, 2012: Cochrane Database Syst Rev)AboubakrElnashar

34. No clear evidence of a tibolone effect on
endometrial cancer compared with placebo.
No evidence of a difference in long term safety
between tibolone and combined HT.
Similar concerns may exist for EP therapy but
overall benefit-risk profile
better known
more directly related to women with menopausal
symptoms.
(Formoso et al, 2012: Cochrane Database Syst Rev)
AboubakrElnashar

35. 4. Bioidentical Hormones
BH:
Molecule identical to a hormone produced by the
human body
BHRT
A set of diagnostic, prescribing, preparation and
marketing practices including compounding (the
preparation of custom-mixed hormones by a pharmacist, according to a
prescription), saliva testing, and efforts to counter the
effects of aging rather than relieving the symptoms of
menopause. AboubakrElnashar

36. FDA-Approved Products.
Various routes of administration: constant, low
levels of hormones
Proven efficacy at relieving menopausal symptoms
Endometrial safety profiles.
Non-FDA-Approved Products.
Available by prescription for those who cannot
tolerate FDA-approved products.
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37. Individualized compounds:
Based on salivary hormone testing.
Safe and effective
Unfortunately, salivary testing has tremendous inter-
and intrapatient variability and has been found to
lack correlation with serum hormone levels
(Boothby, 2004).
No rigorous RCTs regarding safety or efficacy:
cannot be assumed to be safer than conventional
pharmaceutical E or P.
Adequate endometrial protection is needed if
compounded estrogens are prescribed
(Pinkerton, 2009).
AboubakrElnashar

38. B. Non hormonal
I. CNS agents
1. SSRI
2. Gabapentin
II. CAM
1. Acupuncture
2. Phytoestrogen
3. Phytoprogestin
4. Lifestyle Changes
AboubakrElnashar

39. B. Non hormonal
 Mild hot flashes: usually do not seek or require
pharmacologic intervention.
 However, women often try
{NAMS; 2004]
1. Lifestyle changes
(keeping the core body temp cool and regular exercise),
either alone or combined with
2. Nonprescription therapies
(soy foods, isoflavone supplements (from either soy or red
clover, black cohosh, or vitamin E).
 Neither exercise nor nonprescription therapies
have proven benefit.
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40. Non hormonal tts:
No FDA-approval for tt of hot flashes
Long-term studies: not available.
Short-term trials: available
Indication:
1. Women decline HT
2. E is contraindicated.
{many side effects or ineffectiveness compared with
HT: limits their routine use
AboubakrElnashar

41. I. Central Nervous System Agents
1. Selective Serotonin-Reuptake Inhibitors(SSRI).
selective serotonin norepinephrine reuptake
inhibitors (SNRIs)
RCT with the antidepressants
Venlafaxine (Effexor)
Fluoxetine (Prozac, Sarafem)
Paroxetine (Paxil), and
Desvenlafaxine (Pristiq)
: modest improvement in hot flashes compared with
placebo.
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42. AboubakrElnashar

43. Benefits of SSRIs should be balanced against
drug side effects: nausea, diarrhea, headache,
insomnia, fatigue, and sexual dysfunction.
SSRIs must be used with caution in women with
breast cancer receiving adjuvant tamoxifen {SSRIs
and some SNRIs reduce the metabolism of
tamoxifen to its most active metabolite, endoxifen},
Reserve SSRI tt of hot flushes for women with
breast cancer receiving aromatase inhibitors or no
adjuvant tt.
AboubakrElnashar

44. 2. Gabapentin (Neurontin)
structurally related to
neurotransmitter gamma amino butyric acid
(GABA)
Mechanism of action:
unknown.
Uses:
seizure disorders
post-herpetic neuralgia
other indications as well. (Brown, 2009).
AboubakrElnashar

45. Pooled analyses (Lobrinzi et al, 2009)
of 7 trials of antidepressants and 3 trials of
Gabapentin
[Pandya et al, 2005 ].
The mean reduction in hot flash score with
placebo: 24%.
The additional hot flash score reductions Vs
placebo for
Paroxetine: 41%
Gabapentin: 36%
Venlafaxine: 33%
Fluoxetine: 13%
Although these agents do not appear to be as
effective as E for hot flashes, they are significantly
better than placebo.
AboubakrElnashar

46. II. Complementary and Alternative Medicine
(CAM)
Prevalence of use in postmenopausal women
50 to 75% [Keenan et al, 2003]
Increasing (Newton, 2002).
Higher in breast cancer patients.
Safety and efficacy
Not well established.
Soy and black cohosh: no more effective than
placebo AboubakrElnashar

47. HRT remains the most effective therapy for VMS
(Newton et al. 2006)
 No significant efficacy of botanicals in reducing VMS
Baseline 3 months 6 months 12 months
0
1
2
3
4
5
6
7
8
Vasomotorsymptomsperday
Black Cohosh
Multibotanical
Multibotanical + soy
HRT: CEE +/- MPA
Placebo
AboubakrElnashar

48. Meta-analysis of 43 trials [Nelson et al, 2006]:
Mean difference in number of hot flashes/d
compared to placebo
Gabapentin: -2.05
SSRIs/SNRIs: -1.13
Clonidine: -0.95
Red clover isoflavone extracts: did not show a
significant reduction in hot flashes
AboubakrElnashar

49.  Acupuncture.
 10 or 12 sessions: Significant decrease in hot
flash frequency and intensity.
 small study groups
data from only short-term therapy and followup.
(Borud, 2009; Kim, 2010).
MA of 5 trials comparing acupuncture to sham
acupuncture: reductions in severity and frequency of
hot flashes with both therapies.
[Cho SH, Whang, 2009].
Women with breast cancer, acupuncture: not
effective therapy for hot flashes
[Lee, 2009].
AboubakrElnashar

50. Phytoestrogens
Nonsteroidal compounds that occur naturally in
many plants, fruits, and vegetables
Action
estrogenic and antiestrogenic properties
Types:
isoflavones, coumestans, or lignans.
Two types of isoflavones, genistein and daidzein,
are found in soybeans, chickpeas, and lentils, and
are thought to be the most potent estrogens of the
phytoestrogens (although they are much weaker
than human estrogens).
No more effective than placebo for hot flashes.
AboubakrElnashar

51. 3. Lifestyle Changes
A. Practices that lower core body temperature
using a fan
dressing in layers
ingestion of cold foods and beverages.
taking cool showers
±temporarily help.
C. Meditation, smoking cessation, and weight loss
Weight loss
{obesity is a risk factor for hot flashes}. may help reduce hot
flashes [Huang et al,2010].
± helpful
AboubakrElnashar

52. C. Relaxation techniques
 Paced respiration: reduce frequency.
(Irvin et al, 1996; Freedman and Woodward, 1992)
Relaxation: significant reductions in intensity,
tension, anxiety, and depression
{decreased central sympathetic tone}.
Relaxation therapy and stress management:
Not effective
[Nedrow, 2006].
Exercise:
No beneficial effect on hot flashes
{ exercise raises core body temperature, thereby
triggering hot flashes}
AboubakrElnashar

53. 4. TREATMENT OF INTRACTABLE HOT FLASHES
Define
continuing occurrence of hot flashes despite the
administration of what should be an effective dose of
E.
Treatment
1. Determine if they are taking drugs that can
 decrease the absorption of E (eg, broad-
spectrum antibiotics) or
 increase hepatic enzyme activity: increase the
metabolism of E (eg, barbiturates,
anticonvulsants, or tranquilizers).
Stopping or replacing these drugs may be helpful.
AboubakrElnashar

54. 2. Changing the route of E administration from oral
to transdermal may result in control of hot flashes
by bypassing the liver.
Titration of patch size until plasma estradiol levels
reach 120 pg/mL may be helpful. However, there
are no clinical trial data to support this approach.
AboubakrElnashar

55. 3. Other potential causes of flushes or night sweats
(hyperthyroidism, underlying malignancy, infection,
SSRIs)
4. Finally, for women who are receiving very high
doses of E in an unsuccessful attempt to stop their
hot flashes, stopping E altogether for one to two
weeks and then restarting at the usual dose may be
effective.
This will give the woman a chance to compare the
severity of hot flashes on and off E. She may decide
that, although the flashes have not completely
disappeared, E is beneficial and she may tolerate
the residual flashes better.
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56. AboubakrElnashar

57. SUMMARY AND RECOMMENDATIONS
HRT remains the most effective therapy for VMS
Use lowest effective dose of E
More favorable if tt is started earlier in menopause
For postmenopausal women with moderate-to-
severe VMS (and no history of breast cancer or
CVD): short-term E therapy is the tt of choice
(Grade 2B)..
.
AboubakrElnashar

58. Short-term therapy is considered to be two to
three years and generally not more than five years.
For women with moderate-to-severe hot flashes in
whom E is contraindicated or not well tolerated, or
for women who have stopped E and are
experiencing recurrent symptoms but wish to avoid
resuming E: Gabapentin, SNRI, or SSRI (Grade
2B).
AboubakrElnashar

59. For women with predominantly nighttime
symptoms: single bedtime dose of Gabapentin
{soporific effect of gabapentin while minimizing
daytime sedation}.
For women with predominantly daytime
symptoms: SNRI/SSRI {less sedating than
Gabapentin}. These drugs should be used with caution in women
with breast cancer who are taking tamoxifen.
AboubakrElnashar

60. Since hot flashes gradually subside without
therapy in most postmenopausal women, any drug
can be gradually tapered after one to two years of
administration.
For women with breast cancer and hot flashes: no
phytoestrogens and black cohosh (Grade 2C).
AboubakrElnashar

61. Thank you
AboubakrElnashar