PMID- 28903474
OWN - NLM
STAT- MEDLINE
DCOM- 20180130
LR  - 20220317
IS  - 1460-2369 (Electronic)
IS  - 1355-4786 (Linking)
VI  - 23
IP  - 5
DP  - 2017 Sep 1
TI  - Nitric oxide-heat shock protein axis in menopausal hot flushes: neglected 
      metabolic issues of chronic inflammatory diseases associated with deranged heat 
      shock response.
PG  - 600-628
LID - 10.1093/humupd/dmx020 [doi]
AB  - BACKGROUND: Although some unequivocal underlying mechanisms of menopausal hot 
      flushes have been demonstrated in animal models, the paucity of similar 
      approaches in humans impedes further mechanistic outcomes. Human studies might 
      show some as yet unexpected physiological mechanisms of metabolic adaptation that 
      permeate the phase of decreased oestrogen levels in both symptomatic and 
      asymptomatic women. This is particularly relevant because both the severity and 
      time span of hot flushes are associated with increased risk of chronic 
      inflammatory disease. On the other hand, oestrogen induces the expression of heat 
      shock proteins of the 70 kDa family (HSP70), which are anti-inflammatory and 
      cytoprotective protein chaperones, whose expression is modulated by different 
      types of physiologically stressful situations, including heat stress and 
      exercise. Therefore, lower HSP70 expression secondary to oestrogen deficiency 
      increases cardiovascular risk and predisposes the patient to 
      senescence-associated secretory phenotype (SASP) that culminates in chronic 
      inflammatory diseases, such as obesities, type 2 diabetes, neuromuscular and 
      neurodegenerative diseases. OBJECTIVE AND RATIONALE: This review focuses on HSP70 
      and its accompanying heat shock response (HSR), which is an anti-inflammatory and 
      antisenescent pathway whose intracellular triggering is also oestrogen-dependent 
      via nitric oxide (NO) production. The main goal of the manuscript was to show 
      that the vasomotor symptoms that accompany hot flushes may be a disguised clue 
      for important neuroendocrine alterations linking oestrogen deficiency to the 
      anti-inflammatory HSR. SEARCH METHODS: Results from our own group and recent 
      evidence on hypothalamic control of central temperature guided a search on PubMed 
      and Google Scholar websites. OUTCOMES: Oestrogen elicits rapid production of the 
      vasodilatory gas NO, a powerful activator of HSP70 expression. Whence, part of 
      the protective effects of oestrogen over cardiovascular and neuroendocrine 
      systems is tied to its capacity of inducing the NO-elicited HSR. The hypothalamic 
      areas involved in thermoregulation (infundibular nucleus in humans and arcuate 
      nucleus in other mammals) and whose neurons are known to have their function 
      altered after long-term oestrogen ablation, particularly kisspeptin-neurokinin 
      B-dynorphin neurons, (KNDy) are the same that drive neuroprotective expression of 
      HSP70 and, in many cases, this response is via NO even in the absence of 
      oestrogen. From thence, it is not illogical that hot flushes might be related to 
      an evolutionary adaptation to re-equip the NO-HSP70 axis during the downfall of 
      circulating oestrogen. WIDER IMPLICATIONS: Understanding of HSR could shed light 
      on yet uncovered mechanisms of menopause-associated diseases as well as on 
      possible manipulation of HSR in menopausal women through physiological, 
      pharmacological, nutraceutical and prebiotic interventions. Moreover, decreased 
      HSR indices (that can be clinically determined with ease) in perimenopause could 
      be of prognostic value in predicting the moment and appropriateness of starting a 
      HRT.
CI  - (c) The Author 2017. Published by Oxford University Press on behalf of the European 
      Society of Human Reproduction and Embryology. All rights reserved. For 
      Permissions, please email: journals.permissions@oup.com
FAU - Miragem, Antonio Azambuja
AU  - Miragem AA
AD  - Laboratory of Cellular Physiology, Department of Physiology, Federal University 
      of Rio Grande do Sul, Rua Sarmento Leite 500, ICBS, 2nd Floor, Suite 350, Porto 
      Alegre, RS 90050-170, Brazil.
AD  - Federal Institute of Education, Science and Technology 'Farroupilha', Rua Uruguai 
      1675, Santa Rosa, RS 98900-000, Brazil.
FAU - Homem de Bittencourt, Paulo Ivo Jr
AU  - Homem de Bittencourt PI Jr
AD  - Laboratory of Cellular Physiology, Department of Physiology, Federal University 
      of Rio Grande do Sul, Rua Sarmento Leite 500, ICBS, 2nd Floor, Suite 350, Porto 
      Alegre, RS 90050-170, Brazil.
LA  - eng
PT  - Journal Article
PT  - Review
PL  - England
TA  - Hum Reprod Update
JT  - Human reproduction update
JID - 9507614
RN  - 0 (Estrogens)
RN  - 0 (Heat-Shock Proteins)
RN  - 31C4KY9ESH (Nitric Oxide)
SB  - IM
MH  - Animals
MH  - Estrogens/physiology
MH  - Female
MH  - Heat-Shock Proteins/metabolism
MH  - *Heat-Shock Response
MH  - Hot Flashes/*metabolism
MH  - Humans
MH  - Hypothalamus
MH  - Menopause/*physiology
MH  - Nitric Oxide/blood/*metabolism
MH  - Risk Factors
OTO - NOTNLM
OT  - cardiovascular disease
OT  - cellular senescence
OT  - chronic inflammatory diseases
OT  - heat shock response
OT  - heat therapy
OT  - hot flushes
OT  - insulin resistance
OT  - menopause
OT  - obesity
OT  - thermoregulation
EDAT- 2017/09/15 06:00
MHDA- 2018/01/31 06:00
CRDT- 2017/09/15 06:00
PHST- 2016/03/24 00:00 [received]
PHST- 2017/06/28 00:00 [accepted]
PHST- 2017/09/15 06:00 [entrez]
PHST- 2017/09/15 06:00 [pubmed]
PHST- 2018/01/31 06:00 [medline]
AID - 3978711 [pii]
AID - 10.1093/humupd/dmx020 [doi]
PST - ppublish
SO  - Hum Reprod Update. 2017 Sep 1;23(5):600-628. doi: 10.1093/humupd/dmx020.