Dysfunction of central thermoregulatory centers caused by changes in estrogen levels at the time of menopause has long been postulated to be the cause of hot flashes.
An understanding of the normal Physiology
of a woman’s hormonal axis during the reproductive years and at the time of menopause provides a framework to investigate the pathophysiology of hot flashes and to identify potential targets for treatment.
At menarche, gonadotropin signaling from the anterior pituitary gland (follicle-stimulating hormone and luteinizing hormone [LH]) leads to monthly maturation of ovarian follicles, which secrete estrogen and exert negative FEEDBACK
on the hypothalamus and pituitary gland.
In the absence of fertilization, estrogen and progesterone production from the corpus luteum deteriorates, negative FEEDBACK
is lost, pituitary gonadotropin production increases, and the monthly cycle repeats itself.
As a woman exhausts her supply of ova, her ability to reproduce ends, and menopause ensues. At this time, there are no remaining follicles to secrete estrogen, negative FEEDBACK
is lost, and pituitary gonadotropin production increases. Hot flashes occur synchronously with these hormonal changes and have long been thought to occur secondary to
concurrent changes in estrogen levels.
Estrogen Withdrawal
Although the specific nature of how a decrease in estrogen
may lead to hot flashes remains unknown, estrogen withdrawal, rather than low circulating estrogen levels, is thought to be the central change that leads to hot flashes.(1) Several observations support this theory.
Estrogen withdrawal due to oophorectomy in premenopausal women
triggers the rapid onset of hot flashes, but women with gonadal dysgenesis, who have low levels of endogenous estrogen, do not experience hot flashes.
If women with gonadal dysgenesis receive several months of estrogen therapy and then abruptly discontinue use of this therapy, they experience hot flashes.(1) These findings suggest that
estrogen withdrawal is the important instigator of hot flashes.
The Hypothalamus May Regulate Hot Flashes
Does estrogen withdrawal affect peripheral neural and vascular sites, or does it affect central regulatory centers?
Studies suggest that dysfunction of central thermoregulatory
centers is responsible.
No relationship between hot flashes and circulating levels of estrogen, follicle-stimulating hormone, or LH has been observed.(2-6) Although hot flashes correlate with pulsatile changes in LH levels,(7,8) not all LH pulses are accompanied by a hot flash.(7)Furthermore,suppression of LH release with use of gonadotropinreleasing hormone (GnRH) agonists does not eliminate hot flashes,(9) and GnRH-stimulated LH release does not causehot flashes.(10) These facts point to a central process with an association, but not necessarily a cause-effect relationship, between LH pulses and hot flashes.
Because women who have undergone hypophysectomy for treatment of pituitary tumors still experience hot flashes,(10,11) thermoregulatory centers in the hypothalamus, rather than at a pituitary locus,appear to be the most likely site of thermoregulatory dysfunction.Perspiration and vasodilation, classic mechanisms of heat loss, are activated during hot flashes.
The medial preoptic area of the hypothalamus contains the thermoregulatory nucleus responsible for these functions in humans(1) and activates these mechanisms to maintain core body temperature in a regulated normal range termed the thermoregulatory zone. Recent studies by Freedman et al,(5) using an ultrasensitive temperature probe, found that small changes in core body temperatures occur 15 minutes beforehot flashes in up to 60% of hot flash episodes. These same investigators subsequently showed that women with hot flashes may have a thermoregulatory zone that is shifted downward and that is more narrow compared with women who do not have hot flashes.46 Since heat lossmechanisms can be triggered by a 0.01° elevation of corebody temperature above the regulatory zone, the subtlechanges in temperature before a hot flash, coupled with a narrow homeostatic temperature zone, may trigger the heat loss mechanisms that lead to hot flash symptoms.
Complex neuroendocrine pathways that involve norepinephrine, estrogen, testosterone, and endorphins govern regulation in the thermoregulatory nucleus and are possible sites where dysfunction may occur in individuals with hot flash symptoms.(1,,13,14)Neurotransmitters as Effectors of Hot Flashes Although multiple neurotransmitter candidates exist,
norepinephrine is thought to be the primary neurotransmitter
responsible for lowering the thermoregulatory set point and triggering the heat loss mechanisms aforementioned. (1,12,,14) Plasma levels of norepinephrine metabolites are increased both before and during hot flashes, and intrahypothalamic injection of norepinephrine can increase
core body temperature and induce a heat loss response.(5)
Norepinephrine production and release in the thermoregulatory
nucleus is thought to be tonically inhibited by endorphins and catecholestrogen, a metabolic by-product of estrogen
metabolism.(1,13,14) Estrogen and testosterone can also stimulate natural endorphin production and thus may exert a modulatory effect on norepinephrine release both directly and indirectly.(15,16)
Serotonin may be another key neurotransmitter in the mechanism of hot flashes. Estrogen withdrawal is associated with decreased blood serotonin levels (17,18) and also with up-regulation of serotonin receptors in the hypothalamus.(19) Activation of certain serotonin receptors (serotonin 2a receptors)has been shown to mediate heat loss, and serotonin release triggered by internal or external stimuli may activate these up-regulated hypothalamic serotonin receptors to trigger a hot flash.(20)The role of serotonin in central regulatory pathways, however, is complex because binding at some serotonin receptors (serotonin 2c receptors) can exert negative FEEDBACK
on other serotonin receptor subtypes (serotonin 2a receptors). Thus, the effect of a change in serotonin activity varies depending on the type of receptor
activated.(20) The potential role of serotonin in the mechanism
of hot flashes has been reviewed comprehensively.(20)
Working Model of Hot Flash Pathogenesis
A model that summarizes the aforementioned pathways and integrates the theories of several experts is presented in below
With this model, estrogen withdrawal leads to a decrease in endorphin and catecholestrogen levels and culminates in increased hypothalamic norepinephrine and serotonin release. Then norepinephrine and serotonin lower the set point in the thermoregulatory nucleus,
which allows heat loss mechanisms to be triggered bysubtle changes in core body temperature. In this model, endorphins have a key role in the regulation of norepinephrine release.
ref:
1) Casper RF, Yen SS. Neuroendocrinology of menopausal flushes:
an hypothesis of flush mechanism. Clin Endocrinol (Oxf).
1985;22:293-312.
2)Aksel S, Schomberg DW, Tyrey L, Hammond CB. Vasomotor
symptoms, serum estrogens, and gonadotropin levels in surgical
menopause. Am J Obstet Gynecol. 1976;126:165-169.
3)Abe T, Furuhashi N, Yamaya Y, Wada Y, Hoshiai A, Suzuki M.
Correlation between climacteric symptoms and serum levels of
estradiol, progesterone, follicle-stimulating hormone, and luteinizing
hormone. Am J Obstet Gynecol. 1977;129:65-67
4)Chakravarti S, Collins WP, Newton JR, Oram DH, Studd JW.
Endocrine changes and symptomatology after oophorectomy in premenopausal women. Br J Obstet Gynaecol. 1977;84:769-
775.
5)Hutton JD, Jacobs HS, Murray MA, James VH. Relation between
plasma oestrone and oestradiol and climacteric symptoms. Lancet.
1978;1:678-681.
6)Freedman RR, 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
7)Casper RF, Yen SS, Wilkes MM. Menopausal flushes: a neuroendocrine
link with pulsatile luteninizing hormone secreation. Science.
1979;205:823-825.
8)Tataryn IV, Meldrum DR, Lu KH, Frumar AM, Judd HL. LH,
FSH and skin temperaure during the menopausal hot flash. J Clin
Endocrinol Metab. 1979;49:152-154.
9)Casper RF, Yen SS. Menopausal flushes: effect of pituitary gonadotropin
desensitization by a potent luteinizing hormonereleasing
factor agonist. J Clin Endocrinol Metab. 1981;53:1056
10)Menon V, Edwards RL, Lynch SS, gluteus
WR. Luteinizing hormone
releasing hormone analogue in treatment of hypergonadotrophic
amenorrhoea. Br J Obstet Gynaecol. 1983;90:539-542.
11)Mulley G, Mitchell JR, Tattersall RB. Hot flushes after hypophysectomy.
BMJ. 1977;2:1062.
12)Freedman RR, Krell W. Reduced thermoregulatory null zone in
postmenopausal women with hot flashes. Am J Obstet Gynecol.
1999;181:66-70.
13)Kronenberg F, Downey JA. Thermoregulatory Physiology
of
menopausal hot flashes: a review. Can J Physiol Pharmacol.
1987;65:1312-1324.
14)Rosenberg J, Larsen SH. Hypothesis: pathogenesis of postmenopausal
hot flush. Med Hypotheses. 1991;35:349-350.
15)Wehrenberg WB, Wardlaw SL, Frantz AG, Ferin M. beta-Endorphin
in hypophyseal portal blood: variations throughout the menstrual
cycle. Endocrinology. 1982;111:879-881.
16)Wardlaw SL, Wehrenberg WB, Ferin M, Antunes JL, Frantz AG.
Effect of sex steroids on beta-endorphin in hypophyseal portal
blood. J Clin Endocrinol Metab. 1982;55:877-881.
17)Gonzales GF, Carrillo C. Blood serotonin levels in postmenopausal
women: effects of age and serum oestradiol levels.
Maturitas. 1993;17:23-29.
18)Blum I, Vered Y, Lifshitz A, et al. The effect of estrogen replacement
therapy on plasma serotonin and catecholamines of postmenopausal
women. Isr J Med Sci. 1996;32:1158-1162.
19)Fink G, Sumner BE. Oestrogen and mental state [letter]. Nature.
1996;383:306.
20)Berendsen HH. The role of serotonin in hot flushes. Maturitas.
2000;36:155-164.
Hot Flushes
The pathognomonic symptom of menopause is the hot flush or flash, which is caused by a decrease in circulating estrogen levels. The change in estrogen levels leads to alterations in hypothalamic thermoregulation that are probably mediated through the central nervous system. The frequency
and severity of hot flushes is directly correlated with the magnitude of the decrease in estrogen levels over time. With a sudden change in estrogen
levels, such as occurs after premenopausal oophorectomy, a woman is more likely to develop symptomatic hot flushes than when there is a gradual
decrease in circulating estrogen levels.
Dysfunction of central thermoregulatory centers caused by changes in estrogen levels at the time of menopause has long been postulated to be the cause of hot flashes
Hot flashes occur synchronously with these hormonal changes and have long been thought to occur secondary to
concurrent changes in estrogen levels.
Although the specific nature of how a decrease in estrogen
may lead to hot flashes remains unknown, estrogen withdrawal, rather than low circulating estrogen levels, is thought to be the central change that leads to hot flashes.(1)
estrogen withdrawal is the important instigator of hot flashes
1) ) Casper RF, Yen SS. Neuroendocrinology of menopausal flushes:
an hypothesis of flush mechanism. Clin Endocrinol (Oxf).
1985;22:293-312
menopausal hot flushes is due to
1. decreased estrogen
2.decreased progesterone
3.LH surge
4.FSH surge
Ans. 1. Deacreased estrogen.
Hot flashes are the classic evidence of estrogen deacrese. Physiologically, there is cutaneous vasodilation, decreased body core temp and increased haery rate associated with pulses of LH.
ref. Obstetrics and Gynecology
, E.Sakala, 2000, p.317-318.
With respect to all discussion I would like to mention about estrogen and its negative FEEDBACK
control on FSH and LH. Therefore increased level of FSH and LH is secondary to decaresed level of estrogen.
Primary-estrogen. As a sample, on polycystic ovarian syndrom where LH is increased, but we can not find very paticular clinic of HOT FLASHES.
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