Nitric oxide-heat shock protein axis in menopausal hot flushes: neglected metabolic issues of chronic inflammatory diseases associated with deranged heat shock response

Hum Reprod Update. 2017 Sep 1;23(5):600-628. doi: 10.1093/humupd/dmx020.


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.

Keywords: cardiovascular disease; cellular senescence; chronic inflammatory diseases; heat shock response; heat therapy; hot flushes; insulin resistance; menopause; obesity; thermoregulation.

Publication types

  • Review

MeSH terms

  • Animals
  • Estrogens / physiology
  • Female
  • Heat-Shock Proteins / metabolism
  • Heat-Shock Response*
  • Hot Flashes / metabolism*
  • Humans
  • Hypothalamus
  • Menopause / physiology*
  • Nitric Oxide / blood
  • Nitric Oxide / metabolism*
  • Risk Factors


  • Estrogens
  • Heat-Shock Proteins
  • Nitric Oxide