Subscribe to RSS
DOI: 10.1055/s-2005-869479
Pathophysiology and Treatment of Menopausal Hot Flashes
Publication History
Publication Date:
25 April 2005 (online)
ABSTRACT
Hot flashes are the most common symptom of menopause. Although the appearance of hot flashes coincides with estrogen withdrawal, this does not entirely explain the phenomenon because estrogen levels do not differ between symptomatic and asymptomatic women. Luteinizing throughout? hormone pulses do not produce hot flashes nor do changes in endogenous opiates. Recent studies suggest that hot flashes are triggered by small elevations in core body temperature (Tc) acting within a reduced thermoneutral zone in symptomatic postmenopausal women. This narrowing may be due to elevated central noradrenergic activation, a contention supported by observations that clonidine and some relaxation procedures ameliorate hot flashes. Because hot flashes are triggered by Tc elevations, procedures to reduce Tc, such as lowering ambient temperature, are beneficial. Estrogen ameliorates hot flashes by increasing the Tc sweating threshold, although the underlying mechanism is not known. Recent studies of hot flashes during sleep call into question their role in producing sleep disturbance.
KEYWORDS
Hot flashes - menopause - thermoregulation - sleep
REFERENCES
- 1 Avis N E, Crawford S L, McKinlay S M. Psychosocial, behavioral, and health factors related to menopause symptomatology. Womens Health. 1997; 3 103-120
- 2 Feldman B M, Voda A, Groseth E. The prevalence of hot flash and associated variables among perimenopausal women. Res Nurs Health. 1985; 8 261-268
- 3 Kronenberg F. Hot flashes: epidemiology and physiology. Ann N Y Acad Sci. 1990; 592 52-86
- 4 Gold E B, Sternfeld B, Kelsey J L et al.. Relation of demographic and lifestyle factors to symptoms in a multi-racial/ethnic population of women 40-55 years of age. Am J Epidemiol. 2000; 152 463-473
- 5 Whiteman M K, Staropoli C A, Lengenberg P W, McCarter R J, Kjerulff K H, Flaws J H. Smoking, body mass, and hot flashes in midlife women. Obstet Gynecol. 2003; 101 264-272
- 6 Freedman R R. Editorial: hot flash trends and mechanisms. Menopause. 2002; 9 151-152
- 7 Jessen A B, Toubro S, Astrup A. Effect of chewing gum containing nicotine and caffeine on energy expenditure and substrate utilization in men. Am J Clin Nutr. 2003; 77 1442-1447
- 8 Freedman R R. Biochemical, metabolic, and vascular mechanisms in menopausal hot flushes. Fertil Steril. 1998; 70 1-6
- 9 Molnar G W. Body temperature during menopausal hot flashes. J Appl Physiol: Respir Environ Exercise Physiol. 1975; 38 499-503
- 10 Kronenberg F, Cote L J, Linkie D M, Dyrenfurth I, Downey J A. Menopausal hot flashes: thermoregulatory, cardiovascular, and circulating catecholamine and LH changes. Maturitas. 1984; 6 31-43
- 11 Tataryn I V, Lomax P, Bajorek J G, Chesarek W, Meldrum D R, Judd H L. Postmenopausal hot flushes: a disorder of thermoregulation. Maturitas. 1980; 2 101-107
- 12 Ginsburg J, Swinhoe J, O'Reilly B. Cardiovascular responses during the menopausal hot flush. Br J Obstet Gynaecol. 1981; 88 925-930
- 13 Freedman R R. Laboratory and ambulatory monitoring of menopausal hot flashes. Psychophysiology. 1989; 26 573-579
- 14 Freedman R R, Woodward S, Norton D. Laboratory and ambulatory monitoring of menopausal hot flushes: comparison of symptomatic and asymptomatic women. J Psychophysiol. 1992; 6 162-166
- 15 de Bakker I PM, Everaerd W. Measurement of menopausal hot flushes: validation and cross-validation. Maturitas. 1996; 25 87-98
- 16 Carpenter J S, Andrykowski M A, Freedman R R, Munn R. Feasibility and psychometrics of an ambulatory hot flash monitoring device. Menopause. 1999; 6 209-215
- 17 Molnar G W, Read R C. Studies during open heart surgery on the special characteristics of rectal temperature. J Appl Physiol. 1974; 36 333-336
- 18 Shiraki K, Nobuhide K, Sagawa S. Esophageal and tympanic temperature responses to core blood temperature changes during hyperthermia. J Appl Physiol. 1986; 61 98-102
- 19 Freedman R R, Norton D, Woodward S, Cornelissen G. Core body temperature and circadian rhythm of hot flashes in menopausal women. J Clin Endocrinol Metab. 1995; 80 2354-2358
- 20 Freedman R R, Woodward S. Core body temperature during menopausal hot flushes. Fertil Steril. 1996; 65 1141-1144
- 21 Nelson H D. Commonly used types of postmenopausal estrogen for treatment of hot flashes. JAMA. 2004; 291 1610-1620
- 22 Askel S, Schomberg D W, Tyrey L, Hammond C B. Vasomotor symptoms, serum estrogens, gonadotropin levels in surgical menopause. Am J Obstet Gynecol. 1976; 126 165-169
- 23 Stone S C, Mickal A, Rye F, Rye P H. Postmenopausal symptomatology, maturation index, and plasma estrogen levels. Obstet Gynecol. 1975; 45 625-627
- 24 Hutton J D, Jacobs H S, Murray M AF, James V HT. Relation between plasma esterone and estradiol and climacteric symptoms. Lancet. 1978; 1 678-681
- 25 Schindler A E, Muller D, Keller E, Goser R, Runkel F. Studies with clonidine (Dixarit) in menopausal women. Arch Gynecol. 1979; 227 341-347
- 26 Casper R F, Yen S SC, Wilkes M M. Menopausal flushes: a neuroendocrine link with pulsatile luteinizing hormone secretion. Science. 1979; 205 823-825
- 27 Tataryn I V, Meldrum D R, Lu K H, Frumar A M, Judd H L. LH, FSH, and skin temperature during menopausal hot flush. J Clin Endocrinol Metab. 1979; 49 152-154
- 28 Gambone J, Meldrum D R, Laufer L, Chang R J, Lu J KH, Judd H L. Further delineation of hypothalamic dysfunction responsible for menopausal hot flashes. J Clin Endocrinol Metab. 1984; 59 1092-1102
- 29 Casper R F, Yen S SC. Menopausal flushes: effect of pituitary gonadotropin desensitization by a potent luteinizing hormone releasing factor agonist. J Clin Endocrinol Metab. 1981; 53 1056-1058
- 30 DeFazio J, Meldrum D R, Laufer L et al.. Induction of hot flashes in premenopausal women treated with a long-acting GnRH agonist. J Clin Endocrinol Metab. 1983; 56 445-448
- 31 Meldrum D R, Erlik Y, Lu J KH, Judd H L. Objectively recorded hot flushes in patients with pituitary insufficiency. J Clin Endocrinol Metab. 1981; 52 684-687
- 32 Mulley G, Mitchell R A, Tattersall R B. Hot flushes after hypophysectomy. BMJ. 1977; 2 1062
- 33 Lightman S L, Jacobs H S, Maguire A K, McGarrick G, Jeffcoate S L. Climacteric flushing: clinical and endocrine response to infusion of naloxone. Br J Obstet Gynaecol. 1981; 88 919-924
- 34 DeFazio J, Vorheugen C, Chetkowski R, Nass T, Judd H L, Meldrum D R. The effects of naloxone on hot flashes and gonadotropin secretion in postmenopausal women. J Clin Endocrinol Metab. 1984; 58 578-581
- 35 Tepper R, Neri A, Kaufman H, Schoenfield A, Ovadia J. Menopausal hot flushes and plasma β-endorphins. Obstet Gynecol. 1987; 70 150-152
- 36 Genazzani A R, Petraglia F, Facchinetti F, Facchini V, Volpe A, Alessandrini G. Increase of proopiomelanocortin-related peptides during subjective menopausal flushes. Am J Obstet Gynecol. 1984; 149 775-779
- 37 Brűck K, Zeisberger E. Adaptive changes in thermoregulation and their neuropharmacological basis. In: Schönbaum E, Lomax P Thermoregulation: Physiology and Biochemistry New York; Pergamon 1990: 255-307
- 38 Insel P A, Motulsky H J. Physiologic and pharmacologic regulation of adrenergic receptors. In: Insel PA Adrenergic Receptors in Man New York; Marcel Dekker 1987: 201-236
- 39 Kopin I J, Blombery P, Ebert M H et al.. Disposition and metabolism of MHPG-CD3 in humans: plasma MHPG as the principal pathway of norepinephrine metabolism and as an important determinant in CSF levels of MHPG. In: Usdin E, et al Frontiers in Biochemical and Pharmacological Research in Depression New York; Raven Press 1984: 57-68
- 40 Freedman R R, Woodward S. Elevated α2-adrenergic responsiveness in menopausal hot flushes: pharmacologic and biochemical studies. In: Lomax P, Schönbaum E Thermoregulation: The Pathophysiological Basis of Clinical Disorders Basel; Karger 1992: 6-9
- 41 Lambert G W, Kaye D M, Vaz M et al.. Regional origins of 3-methoxy-4-hydroxyphenylglycol in plasma: effects of chronic sympathetic nervous activation and denervation and acute reflex sympathetic stimulation. J Auton Nerv Syst. 1995; 55 169-178
- 42 Clayden J R, Bell J W, Pollard P. Menopausal flushing: double blind trial of a non- hormonal medication. BMJ. 1974; 1 409-412
- 43 Laufer L R, Erlik Y, Meldrum D R, Judd H L. Effects of clonidine on hot flushes in postmenopausal women. Obstet Gynecol. 1982; 60 583-589
- 44 Goldberg M, Robertson D. Yohimbine: a pharmacological probe for study of α2- adrenoceptor. Pharmacol Rev. 1983; 35 143-180
- 45 Freedman R R, Woodward S, Sabharwal S C. Adrenergic mechanism in menopausal hot flushes. Obstet Gynecol. 1990; 76 573-578
- 46 Sastre M, Garcia-Sevilla J A. Density of alpha-2A adrenoceptors and Gi proteins in the human brain: ratio of high-affinity agonist sites to antagonist sites and effect of age. J Pharmacol Exp Ther. 1994; 269 1062-1072
- 47 Starke K, Gothert M, Kilbringer H. Modulation of neurotransmitter release of presynaptic autoreceptors. Physiol Rev. 1989; 69 864-989
- 48 Charney D S, Heninger G R, Sternberg D E. Assessment of α2-adrenergic autoreceptor function in humans: effects of oral yohimbine. Life Sci. 1982; 30 2033-2041
- 49 Etgen A M, Ansonoff M A, Quesada A. Mechanisms of ovarian steroid regulation of norepinephrine receptor-mediated signal transduction in the hypothalamus: implications for female reproductive physiology. Horm Behav. 2001; 40 169-177
- 50 Ansonoff M A, Etgen A M. Receptor phosphorylation mediates estradiol reduction of alpha 2-adrenoceptor coupling to G protein in the hypothalamus of female rats. Endocrine. 2001; 14 165-174
- 51 Savage M V, Brengelmann G L. Control of skin blood flow in the neutral zone of human body temperature regulation. J Appl Physiol. 1996; 80 1249-1257
- 52 Kronenberg F, Barnard R M. Modulation of menopausal hot flashes by ambient temperature. J Therm Biol. 1992; 17 43-49
- 53 Freedman R R, Woodward S. Altered shivering threshold in postmenopausal women with hot flashes. Menopause. 1995; 2 163-168
- 54 Freedman R R, Krell W. Reduced thermoregulatory null zone in postmenopausal women with hot flashes. Am J Obstet Gynecol. 1999; 181 66-70
- 55 Freedman R R. Core body temperature variation in symptomatic and asymptomatic postmenopausal women: brief report. Menopause. 2002; 9 399-401
- 56 Freedman R R, Dinsay R. Clonidine raises the sweating threshold in symptomatic but not in asymptomatic postmenopausal women. Fertil Steril. 2000; 74 20-23
- 57 Freedman R R, Blacker C M. Estrogen raises the sweating threshold in postmenopausal women with hot flashes. Fertil Steril. 2002; 77 487-490
- 58 Albright D L, Voda A M, Smolensky M H, His B, Decker M. Circadian rhythms in hot flashes in natural and surgically induced menopause. Chronobiol Int. 1989; 6 279-284
- 59 Owens J F, Matthews K A. Sleep disturbance in healthy middle-aged women. Maturitas. 1998; 30 41-50
- 60 Kuh D L, Wadsworth M, Hardy R. Women's health in midlife: the influence of the menopause, social factors and health in earlier life. Br J Obstet Gynaecol. 1997; 104 923-933
- 61 Baker A, Simpson S, Dawson D. Sleep disruption and mood changes associated with menopause. J Psychosom Res. 1997; 43 359-369
- 62 Dennerstein L, Dudley E C, Hopper J L, Guthrie J R, Burger H G. A prospective population-based study of menopausal symptoms. Obstet Gynecol. 2000; 96 351-358
- 63 Kravtiz H M, Ganz P A, Bromberger J, Powell L H, Sutton-Terrell K, Meyer P M. Sleep difficulty in women in midlife: a community survey of sleep and the menopausal transition. Menopause. 2003; 10 19-28
- 64 Erlik Y, Tataryn I V, Meldrum D R, Lomax P, Bajorek J G, Judd H L. Association of waking episodes with menopausal hot flushes. JAMA. 1981; 245 1741-1744
- 65 Woodward S, Freedman R R. The thermoregulatory effects of menopausal hot flashes on sleep. Sleep. 1994; 17 497-501
- 66 Freedman R R, Roehrs T A. Lack of sleep disturbance from menopausal hot flashes. Fertil Steril. 2004; 82 138-144
- 67 Young T, Rabago D, Zgierska A, Austin D, Finn L. Objective and subjective sleep quality in premenopausal, perimenopausal, and postmenopausal women in the Wisconsin cohort study. Sleep. 2003; 26 667-672
- 68 Writing Group for the Women's Health Initiative Investigators . Risks and benefits of estrogen plus progestins in healthy postmenopausal women: principal results from the Women's Health Initiative randomized controlled trial. JAMA. 2002; 288 321-333
- 69 The Women's Health Initiative Steering Committee . Effects of conjugated equine estrogen in postmenopausal women with hysterectomy: the Women's Health Initiative randomized controlled trial. JAMA. 2004; 291 1701-1712
- 70 Archer D F. Lower doses of oral estrogen and progestogens as treatment for postmenopausal women. Semin Reprod Med. 2005; 23 188-195
- 71 Germaine L M, Freedman R R. Behavioral treatment of menopausal hot flashes: evaluation by objective methods. J Consult Clin Psychol. 1984; 52 1072-1079
- 72 Freedman R R, Woodward S. Behavioral treatment of menopausal hot flushes: evaluation by ambulatory monitoring. Am J Obstet Gynecol. 1992; 167 436-439
- 73 Freedman R R, Woodward S, Brown B, Javaid J I, Pandey G N. Biochemical and thermoregulatory effects of behavioral treatment for menopausal hot flashes. Menopause. 1995; 2 211-218
- 74 Irvin J H, Domar A D, Clark C, Zuttermeister P C, Friedman R. The effects of relaxation response training on menopausal symptoms. J Psychosom Obstet Gynecol. 1996; 17 202-207
- 75 Wijima K, Melin A, Nedstrand E, Hammar M. Treatment of menopausal symptoms with applied relaxation: a pilot study. J Behav Ther Exp Psychiatry. 1997; 28 251-261
- 76 Kronenberg F, Fugh-Berman A. Complementary and alternative medicine for menopausal symptoms: a review of randomized, controlled trials. Ann Intern Med. 2002; 137 805-813
- 77 Stearns V, Beebe K L, Iyengar M, Dube E. Paroxetine controlled release in the treatment of menopausal hot flashes: a randomized controlled trial. JAMA. 2003; 289 2827-2834
- 78 Loprinzi C L, Sloan J A, Perez E A et al.. Phase III evaluation of fluoxetine for treatment of hot flashes. J Clin Oncol. 2002; 20 1578-1583
- 79 Loprinzi C L, Kugler J W, Sloan J A et al.. Venlafaxine in management of hot flashes in survivors of breast cancer: a randomized controlled trial. Lancet. 2000; 356 2059-2063
- 80 Nagamani M, Kelver M E, Smith E R. Treatment of menopausal hot flashes with transdermal administration of clonidine. Am J Obstet Gynecol. 1987; 156 561-565
- 81 Pandya K J, Raubertas R F, Flynn P J et al.. Oral clonidine in post-menopausal patients with breast cancer experiencing tamoxifen induced hot flashes: a University of Rochester Cancer Center Community Clinical Oncology Program study. Ann Intern Med. 2000; 132 788-793
- 82 Goldberg R M, Loprinzi C L, O'Fallon J R et al.. Transdermal clonidine for ameliorating tamoxifen-induced hot flashes. J Clin Oncol. 1994; 12 155-158
- 83 Guttuso Jr T, Kurlan R, McDermott M P, Keiburtz K. Gabapentin's effects on hot flashes in postmenopausal women: a randomized controlled trial. Obstet Gynecol. 2003; 101 337-345
Robert R FreedmanPh.D.
Obstetrics and Gynecology, and Psychiatry and Behavioral Neurosciences, Wayne State University School of Medicine
C. S. Mott Center, 275 E. Hancock Avenue
Detroit, MI 48201
Email: aa2613@wayne.edu