Vasomotor symptoms in the menopause Santiago Palacios

Hot flushes Definition Epidemiological data Physiological changes Mechanism Clinical consequences Treatments Conclusions

Definitions 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

Intensity 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

Intensity 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 flushes Definition Epidemiological data Physiological changes Mechanism Clinical consequences Treatments Conclusions

Epidemiological 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 than 1 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 symptoms Estradiol levels: absolute vs change Regular menstrual bleeding Pre/perimenopause (months since last menstrual bleeding) Postmenopause (years since last menstrual bleeding) % –45–6 Severity Absence Moderate/ severe Oldenhave, et al. AJOG 1993;168:773 <1 1–3 3–6 6– –7 8–10 >10

n = 12,357; SWAN = Study of Women’s Health Across the Nation SWAN study: reported prevalence of vasomotor symptoms in perimenopausal women Ages 40–55 years Women reporting hot flushes/night sweats (%) 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 flushes Definition Epidemiological data Physiological changes Mechanism Clinical consequences Treatments Conclusions

Physiological changes associated 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 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 temperatures during hot flushes Adapted from Molnar. J Appl Physiol 1975;38:499–503 Temperature (°C) Time (min) Flush Rectum Tympanum Toe Finger

Other 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 features May be provoked by: embarrassment, stress temperature change alcohol caffeine, warm drink Often premonition

Hot flushes Definition Epidemiological data Physiological changes Mechanism Clinical consequences Treatments Conclusions

Mechanism 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 explain 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 ASYMPTOMATICSYMPTOMATIC Hot flush Sweating threshold Thermoneutral zone Shivering threshold TcTc Tc Tc Freedman RR. Semin Reprod Med 2005;23:117 Thermoneutral zone Small core body temperature (Tc) elevations acting within a reduced thermoneutral zone trigger hot flushes in symptomatic postmenopausal women

Hot flushes Definition Epidemiological data Physiological changes Mechanism Clinical consequences Treatments Conclusions

Impact of hot flushes on 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 estrogen on sleep quality * * Mean number of occurrences Mean number of hot flushes per 24 h Mean number of hot flushes with awakenings per night Ages 45–60 years *p < 0.01 compared with baseline n = 7; treatment was CEE mg for 27 days Treatment days

Differential diagnosis: other clinical situations associated with flushing Alcohol consumption Carcinoid The dumping syndrome Hyperthyroidism Narcotic withdrawal Pheochromocytoma Medication side-effect

Flushing caused by medication Flushing caused by medication Congenital absence of alcohol dehydrogenase Calcium channel blockers SERMs Nitroglycerine Monosodium glutamate Niacin, vancomycin Calcitonin

Hot flushes Definition Epidemiological data Physiological changes Mechanism Clinical consequences Treatments Conclusions

Simple 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 flushes Hormone-based therapies SSRIs Gabapentin Alternative medicine approaches

Dose response to estrogen therapy Number of moderate–severe hot flushes Adapted from Notelovitz M, et al. Obstet Gynecol 2000;95:726 Number * ******* ****** 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 aloneCEE + MPA Adjusted mean number Week Adjusted mean number Week Placebo 0.3 mg/day 0.45 mg/day 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 equine estrogen alone and with additional medroxyprogesterone acetate

Vasomotor symptoms: alternatives to HRT Medroxyprogesterone acetate 20–40 mg/day Megestrol acetate 20–40 mg/day Norethisterone acetate 5 mg/day Tibolone 2.5 mg/day Clonidine transdermal 100 µg/day SSRI/SNRI Venlafaxine 37.5–75 mg/day Paroxetine 10–20 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

Median hot flush score reduction in 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 Median score 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- controlled trials with SSRIs 1 Evans Ml, et al. Obstet Gynecol 2005;105:161–6; 2 Loprinzi CL, et al. Lancet 2000;356:2059–63; 3 Loprinzi CL, et al. J Clin Oncol 2002;20:1578–83; 4 Stearns V, et al. JAMA 2003;289:2827–34; 5 Stearns V, et al. J Clin Oncol 2005;23:6919–30 SSRIs vs placebo Patients(% decrease in hot flushes) Venlafaxine (75 mg) 1 General population51 vs 15 Venlafaxine (75 mg) 2 Breast cancer62 vs 37 Fluoxetine (20 mg) 3 Breast cancer50 vs 32 Paroxetine (12.5 mg) 4 General population62 vs 38 Paroxetine (10 mg) 5 General population40.6 vs breast cancer

Gabapentin 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 therapy for hot flushes Acupuncture Chinese herbs Dong quai Ginseng Kava Primrose oil Red clover/phytoestrogens Yoga Nelson HD, et al. HRQ 05-E ; Kronenberg F, et al. Ann Intern Med 2002;137:805–13

Treatment 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? Men do not experience comparable climacteric Testicular failure or bilateral orchidectomy will provoke severe flushes and sweats similar to those in women

Hot flushes Definition Epidemiological data Physiological changes Mechanism Clinical consequences Treatments Conclusions

Hot 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