vasomotor symptoms in the menopause santiago palacios
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Vasomotor symptomsVasomotor symptomsin the menopausein the menopause
Santiago Palacios
Hot flushesHot flushes
• Definition
• Epidemiological data
• Physiological changes
• Mechanism
• Clinical consequences
• Treatments
• Conclusions
DefinitionsDefinitions
• A hot flush is a sensation of warmth that is generally most intense over the face, neck and chest, with objective signs of cutaneous vasodilatation and a drop in core temperature
• Sweating, palpitations, anxiety, irritability and panic may accompany the hot flush
• The frequency, duration and intensity vary
• It is not possible to predict whether a particular woman will have hot flushes
IntensityIntensity
• Hot flushes– Mild = passing sensation of heat without
sweating– Moderate = sensation of heat with sweating,
but allows continuation of current activity– Severe = sensation of intense heat with
sweating that interferes with continuation of activity
IntensityIntensity
• Night sweats– Mild = don’t wake up, but notice them when
getting up or waking up for other reasons, or notice damp sheets/nightgown on waking
– Moderate = wakes you up because you’re hot and/or perspiring, but no action is necessary other than rearranging blankets or sheets
– Severe = wakes you up hot/perspiring and need to take action (e.g. remove night clothes, open the window, or get out of bed)
Hot flushesHot flushes
• Definition
• Epidemiological data
• Physiological changes
• Mechanism
• Clinical consequences
• Treatments
• Conclusions
Epidemiological dataEpidemiological data
• Hot flushes occur in 65% of women in Europe
• Marked variation in prevalence globally
• Are more abrupt and severe following oophorectomy
• More than 80% of women who experience hot flushes will experience them for more than1 year
• 25% of women complain of severe hot flushes
• 9% of women experience hot flushes beyond the age of 70 years
Gold EB, et al. Am J Epidemiol 2000;152:463–73
Prevalence of vasomotor symptomsPrevalence of vasomotor symptoms
Estradiol levels: absolute vs change
Regularmenstrualbleeding
Pre/perimenopause(months since last
menstrual bleeding)
Postmenopause(years since last
menstrual bleeding)
%
100
75
50
25
0
0 1 2 3–4 5–6Severity
Absence Moderate/severe
Oldenhave, et al. AJOG 1993;168:773
<1 1–3 3–6 6–12 1 2 3 4 5 6–7 8–10 >10
45.6
35.4
31.2
20.517.6
0
10
20
30
40
50
n = 12,357; SWAN = Study of Women’s Health Across the Nation
SWAN study:SWAN study:reported prevalence of vasomotor symptoms reported prevalence of vasomotor symptoms
in perimenopausal womenin perimenopausal women
Ages 40–55 years
Wo
men
rep
ort
ing
ho
t fl
us
hes
/nig
ht
sw
eats
(%
)
Race/ethnicity
African American (n = 3650)Hispanic (n = 1712)White (n = 5746)Chinese (n = 542)Japanese (n = 707))
Gold EB, et al. Am J Epidemiol 2000;152:463–73
Hot flushesHot flushes
• Definition
• Epidemiological data
• Physiological changes
• Mechanism
• Clinical consequences
• Treatments
• Conclusions
Physiological changesPhysiological changesassociated with hot flushassociated with hot flush
• Acute rise in skin temperature
• Peripheral vasodilatation
• Transient increase in heart rate
• Fluctuations in ECG baseline
• Pronounced decrease in skin resistance
• Different from response to warming
• May be provoked by warming
Sturdee DW, et al. Br Med J 1978;2:79–80
Skin temperatureSkin temperature
• The mean skin temperature increases a few degrees centigrade during the few minutes surrounding the hot flushes
• Peripheral vasodilatation, as evidenced by increased skin temperature, occurs in all body areas that have been measured
• These areas include fingers, toes, cheek, forehead, forearm, upper arm, chest, abdomen, back, calf and thigh
• Finger blood flow, hand, calf and forearm blood flow increase during hot flushes
Freedman RR. Fertil Steril 1998;70:332–7; Freedman RR. Fertil Steril 2000;74:20–3
Body temperaturesBody temperaturesduring hot flushesduring hot flushes
Adapted from Molnar. J Appl Physiol 1975;38:499–503
Tem
per
atu
re (
°C)
37
36
35
34
33
32
31
30
29
28
0 30 60 90 Time (min)
Flush Flush
RectumTympanumToeFinger
Other changesOther changes
• There is a small core temperature elevation preceding the hot flushes in 65% of symptomatic women
• Metabolic rate is increased during the period surrounding the hot flush
• Sweating occurs during 90% of hot flushes
• Heart rate increases by approximately 7–15 beats/min
Freedman RR. Fertil Steril 1998;70:332–7; Freedman RR. Fertil Steril 2000;74:20–3
External skin conductance has been found to be the most sensitive and specific marker for hot flushes
Freedman RR. Psychophysiology 1989;26:573–9
Hot flushes: subjective featuresHot flushes: subjective features
May be provoked by:
• embarrassment, stress
• temperature change
• alcohol
• caffeine, warm drink
Often premonition
Hot flushesHot flushes
• Definition
• Epidemiological data
• Physiological changes
• Mechanism
• Clinical consequences
• Treatments
• Conclusions
Mechanism of flushingMechanism of flushing
Estrogen deficiency?
But flushes do not occur in:
• pre-pubertal girls
• Turner’s syndrome(unless primed with estrogen)
• 25% of menopausal women
• older postmenopausal women
Estrogen withdrawal does not Estrogen withdrawal does not explain the etiology of hot flushesexplain the etiology of hot flushes
• There are no correlations between hot flush occurrence and plasma, urinary and vaginal levels of estrogens
• Nor are there differences in plasma levels between asymptomatic and symptomatic women
• Clonidine reduces hot flush frequency without changing circulating estrogen levels
Estrogen withdrawal is necessary to explain the occurrence of hot flushes, but is not, by itself,
sufficient to do so
Sweating threshold
Shivering threshold
ASYMPTOMATIC SYMPTOMATIC
Hot flushSweating threshold
Thermoneutral zone
Shivering thresholdTc Tc
Freedman RR. Semin Reprod Med 2005;23:117
Thermoneutral zone
Small core body temperature (Tc) elevations acting Small core body temperature (Tc) elevations acting within a reduced thermoneutral zone trigger hot within a reduced thermoneutral zone trigger hot flushes in symptomatic postmenopausal womenflushes in symptomatic postmenopausal women
Hot flushesHot flushes
• Definition
• Epidemiological data
• Physiological changes
• Mechanism
• Clinical consequences
• Treatments
• Conclusions
Impact of hot flushesImpact of hot flusheson quality of lifeon quality of life
• Interferes with work
• Interferes with daily activities
• Interferes with sleep cycles
• Results in fatigue
• Loss of concentration
• Depression
• Impacts on other members of family
• Impairs sexual function
Scharf MB, et al. Clin Ther 1997;19:304–11
Effect of unopposed estrogenEffect of unopposed estrogenon sleep quality on sleep quality
**
Mea
n n
um
ber
of
occ
urr
ence
s Mean number of hot flushesper 24 h
Mean number of hot flusheswith awakenings per night
Ages 45–60 years
*p < 0.01 compared with baseline
n = 7; treatment was CEE 0.625 mg for 27 days
Treatment days
-4 0 6 11 16 21 26
14
12
10
8
6
4
2
0
Differential diagnosis: Differential diagnosis: other clinical situationsother clinical situationsassociated with flushingassociated with flushing
• Alcohol consumption
• Carcinoid
• The dumping syndrome
• Hyperthyroidism
• Narcotic withdrawal
• Pheochromocytoma
• Medication side-effect
Flushing caused by medicationFlushing caused by medication
• Congenital absence of alcohol dehydrogenase
• Calcium channel blockers
• SERMs
• Nitroglycerine
• Monosodium glutamate
• Niacin, vancomycin
• Calcitonin
Hot flushesHot flushes
• Definition
• Epidemiological data
• Physiological changes
• Mechanism
• Clinical consequences
• Treatments
• Conclusions
Simple strategiesSimple strategies
• Wear light clothes
• Dress in layers
• Lower the room temperature
• Use air conditioners
• Drink cold beverages
• Avoid alcohol, spicy food, hot drinks, hot food
Treatments for hot flushesTreatments for hot flushes
• Hormone-based therapies
• SSRIs
• Gabapentin
• Alternative medicine approaches
Dose response to estrogen therapyDose response to estrogen therapyNumber of moderate–severe hot flushes
Adapted from Notelovitz M, et al. Obstet Gynecol 2000;95:726
Nu
mb
e r
80
70
60
50
40
30
20
10
00 1 2 3 4 5 6 7 8 9 10 11 12
** *
**
*
*
*
Placebo
0.25 mg E2
0.5 mg E2
1 mg E2
2 mg E2
Significantly (p < 0.05)different from placebo
*
Utian W, et al. Fertil Steril 2001;75:1065
CEE alone CEE + MPA
12
10
8
6
4
2
0
Ad
jus
ted
me
an n
um
ber
Week
1 2 3 4 5 6 7 8 9 10 11 12
12
10
8
6
4
2
0A
dju
ste
d m
ean
nu
mb
er
Week
1 2 3 4 5 6 7 8 9 10 11 12
Placebo
0.3 mg/day
0.45 mg/day
0.625 mg/day
Placebo
0.3/1.5 mg/day
0.45/2.5 mg/day
0.625/2.5 mg/day
Hot flush response to conjugated equineestrogen alone and with additional
medroxyprogesterone acetate
Vasomotor symptoms:Vasomotor symptoms:alternatives to HRTalternatives to HRT
• Medroxyprogesterone acetate 20–40 mg/day
• Megestrol acetate20–40 mg/day
• Norethisterone acetate5 mg/day
• Tibolone2.5 mg/day
• Clonidine transdermal100 µg/day
• SSRI/SNRIVenlafaxine37.5–75 mg/dayParoxetine10–20 mg/day
Progestins alone
Soy isoflavone • Alternative Rx • Black cohosh
Archer D. Menopausal Med 2000;8:5; Stearns et al. Lancet 2002;360:185
Other therapy
0
20
40
60
80
100
Baseline 1 2 3 4
Median hot flush score reduction Median hot flush score reduction in breast cancer patientsin breast cancer patients
Loprinzi CL, et al. Lancet Oncol 2001;2:199–204; Goldberg RM, et al. J Clin Oncol 1994;12:155–8; Barton DL, et al. J Clin Oncol 1998;16:495–500;
Quella SK, et al. J Clin Oncol 2000;18:1068–74; Quella SK, et al. Cancer 1998;82:1784–8; Loprinzi CL, et al. Lancet 2000;356:2059–63; Loprinzi CL, et al. J Clin Oncol 2002;20:1578–83
Week
Med
ian
sco
re
Placebo (n = 347)
Soy (n = 66)
Clonidine (n = 75)
Fluoxetine (n = 20)
Vitamin E (n = 57)
Venlafaxine (n = 45)
Megestrol (n = 74)
Data are not from head-to-head clinical trials
Randomized, double-blind, placebo-Randomized, double-blind, placebo-controlled trials with SSRIscontrolled trials with SSRIs
1Evans Ml, et al. Obstet Gynecol 2005;105:161–6; 2Loprinzi CL, et al. Lancet 2000;356:2059–63;3Loprinzi CL, et al. J Clin Oncol 2002;20:1578–83; 4Stearns V, et al. JAMA 2003;289:2827–34;
5Stearns V, et al. J Clin Oncol 2005;23:6919–30
SSRIs vs placeboPatients (% decrease in hot
flushes)
Venlafaxine (75 mg)1 General population 51 vs 15
Venlafaxine (75 mg)2 Breast cancer 62 vs 37
Fluoxetine (20 mg)3 Breast cancer 50 vs 32
Paroxetine (12.5 mg)4 General population 62 vs 38Paroxetine (10 mg)5 General population 40.6 vs 13.7
+ breast cancer
Gabapentin and hot flushesGabapentin and hot flushes
• A randomized, placebo-controlled trial, 12 weeks– Gabapentin (900 mg 3 divided doses) 45%
frequency
• Randomized, double-blind, placebo-controlled trial in 420 women with breast cancer– Gabapentin (300 mg s.d.) 31%
frequency
– Gabapentin (900 mg 3 divided doses) 46% frequency
and severity
Gatusso, et al. Obstet Gynecol 2003;201:337–45; Pandya KJ, et al. Lancet 2005:366:814–24
Non-proven therapyNon-proven therapyfor hot flushesfor hot flushes
• Acupuncture
• Chinese herbs
• Dong quai
• Ginseng
• Kava
• Primrose oil
• Red clover/phytoestrogens
• YogaNelson HD, et al. HRQ 05-E016-2. 2005;
Kronenberg F, et al. Ann Intern Med 2002;137:805–13
Treatment conclusionTreatment conclusion
The IMS recommends:
• Hormone therapy is the treatment of choice in women with moderate to severe hot flushes
• For women who wish to avoid estrogens or with contraindications, SSRIs, SNRIs or gabapentin are suggested
Hot flushes in men?Hot flushes in men?
• Men do not experience comparable climacteric
• Testicular failure or bilateral orchidectomy will provoke severe flushes and sweats similar to those in women
Hot flushesHot flushes
• Definition
• Epidemiological data
• Physiological changes
• Mechanism
• Clinical consequences
• Treatments
• Conclusions
Hot flush: conclusionsHot flush: conclusions
• Hot flushes are most common menopausal symptom
• Major impact on quality of life
• Estrogen is best and most logical treatment
• Of currently available alternatives, SSRIs or gabapentin seem best