Cortisol and the menopause 2021

Inspired by Cagnacci et al 2021.[1]

Professor Angelo Cagnacci presenting at the BMAS Autumn Scientific Meeting in 2019.

RCT – randomised controlled trial
HRT – homone replacement therapy
CVD – cardiovascular disease
ROS – reactive oxygen species (a form of free radicals)
NO – nitrous oxide

key to acronyms

This is the third and probably the last paper to come from the (n=75) 3-arm RCT (HRT vs acupuncture vs phytoestrogens) run by Professor Angelo Cagnacci from Genoa, Italy.[2,3]

I have written 2 previous blogs on this research already:

Professor Cagnacci presented all this data at the BMAS Autumn Scientific meeting in 2019, so those of us there were a year ahead of the publication of the risk reduction data (second blog listed above). He mentioned that serum cortisol increased at the time of a hot flush and discussed the physiological mechanisms by which this could play a role in the increased CVD risk in the longer term through an increase in blood pressure, insulin resistance and dyslipidaemia.[4] He told us that aortic atherosclerotic plaque calcification increases with severity of vasomotor symptoms (the paper quoted correlated length of history of vasomotor symptoms with aortic calcification – age was accounted for as a covariate in linear regression),[5] and that there is roughly a 30% increased risk of CVD in women with vasomotor symptoms compared with those who do not have them.[6]

Is there a causative link between vasomotor symptoms and risk factors for cardiovascular disease?

But the big question is whether or not there is a causative link between vasomotor symptoms and CVD risk factors, or whether these are merely associations. If there is a causative link of course, then by treating the hot flushes we could potentially reduce long-term CVD risk.

He discussed two factors that could mediate a causative link – oxidative stress and cortisol. Briefly, hot flushes are associated with an increase in metabolism and therefore with oxygen use. This leads to an increase in excess ROS, which need to be mopped up by antioxidants. Data shows that an increase in Greene’s vasomotor subscale score is associated with a reduction in serum antioxidant levels.[7] The presence of excess ROS impedes endothelial production of NO, and this can be protected to some degree by dihydrofolate reductase.[8,9]

Prof Angelo went on to demonstrate that administration of folate, which is an antioxidant, to postmenopausal women led to a reduction in both oxidative stress and blood pressure.[10]

So, what about cortisol? We know that serum cortisol rises every time there is a hot flush,[11] and that depression, which is more common during the menopause, is associated with higher levels of cortisol.[12] Not only that, but reduced sleep time, which can be caused by nocturnal hot flushes, results in a rise in cortisol the following day.[13] In 2011, Prof Angelo’s team demonstrated that the Greene Climacteric Scale score is associated associated with 24-hour urinary cortisol.[14]

Finally, we come to the current study, which reports the 24-hour urinary cortisol results from his team’s 3-arm RCT of HRT vs acupuncture vs phytoestrogens. This demonstrated that baseline cortisol correlated with the Greene Climacteric Scale score and that the reduction in symptom score also correlated with the reduction in 24-hour urinary cortisol.

the reduction in symptoms correlated with the reduction in cortisol

The question of causation or association is still not answered; however, this is all pointing towards the strong likelihood that a reduction in the severity of climacteric symptoms may well reduce long-term disease risk in menopausal women.

But wait, the Greene Climacteric Scale includes subscales for not only vasomotor symptoms, but depression, anxiety, somatisation, and sexuality as well. The results of this study seem to indicate that the change in 24-hour cortisol values is more related to depression, anxiety and somatisation than to vasomotor symptoms, and to depression in particular. That is not a particular setback though since acupuncture seems to improve mood and well-being, as well as anxiety on occasions.

I am very grateful to Prof Angelo for drawing this important field to my attention. We have been treating vasomotor symptoms with acupuncture for many years, but until recently I had not ever considered the possibility that this might reduce the risk of related chronic disease. I just thought I was relieving a symptom!

That reminds me of the very large retrospective cohort studies that have observed reduced risks associated with acupuncture use in a variety of health conditions. Again, these do not demonstrate causation, but that possibility is looking ever more plausible thanks to the diligent work of researchers like Prof Angelo and this team.


1          Cagnacci A, Xholli A, Fontanesi F, et al. Treatment of menopausal symptoms: concomitant modification of cortisol. Menopause Published Online First: 11 October 2021. doi:10.1097/GME.0000000000001875

2          Palma F, Fontanesi F, Facchinetti F, et al. Acupuncture or phy(F)itoestrogens vs. (E)strogen plus progestin on menopausal symptoms. A randomized study. Gynecol Endocrinol Off J Int Soc Gynecol Endocrinol 2019;0:1–4. doi:10.1080/09513590.2019.1621835

3          Palma F, Fontanesi F, Neri I, et al. Blood pressure and cardiovascular risk factors in women treated for climacteric symptoms with acupuncture, phytoestrogens, or hormones. Menopause 2020;27:1060–5. doi:10.1097/GME.0000000000001626

4          Cagnacci A, Cannoletta M, Palma F, et al. Menopausal symptoms and risk factors for cardiovascular disease in postmenopause. Climacteric 2012;15:157–62. doi:10.3109/13697137.2011.617852

5          Thurston RC, Kuller LH, Edmundowicz D, et al. History of hot flashes and aortic calcification among postmenopausal women. Menopause 2010;17:256–61. doi:10.1097/gme.0b013e3181c1ad3d

6          Muka T, Oliver-Williams C, Colpani V, et al. Association of Vasomotor and Other Menopausal Symptoms with Risk of Cardiovascular Disease: A Systematic Review and Meta-Analysis. PloS One 2016;11:e0157417. doi:10.1371/journal.pone.0157417

7          Cagnacci A, Cannoletta M, Palma F, et al. Relation between oxidative stress and climacteric symptoms in early postmenopausal women. Climacteric 2015;18:631–6. doi:10.3109/13697137.2014.999659

8          Crabtree MJ, Channon KM. Synthesis and recycling of tetrahydrobiopterin in endothelial function and vascular disease. Nitric Oxide Biol Chem 2011;25:81–8. doi:10.1016/j.niox.2011.04.004

9          Crabtree MJ, Hale AB, Channon KM. Dihydrofolate reductase protects endothelial nitric oxide synthase from uncoupling in tetrahydrobiopterin deficiency. Free Radic Biol Med 2011;50:1639–46. doi:10.1016/j.freeradbiomed.2011.03.010

10        Cagnacci A, Cannoletta M, Xholli A, et al. Folate administration decreases oxidative status and blood pressure in postmenopausal women. Eur J Nutr 2015;54:429–35. doi:10.1007/s00394-014-0726-8

11        Meldrum DR, Tataryn IV, Frumar AM, et al. Gonadotropins, estrogens, and adrenal steroids during the menopausal hot flash. J Clin Endocrinol Metab 1980;50:685–9. doi:10.1210/jcem-50-4-685

12        Mortola JF, Liu JH, Gillin JC, et al. Pulsatile rhythms of adrenocorticotropin (ACTH) and cortisol in women with endogenous depression: evidence for increased ACTH pulse frequency. J Clin Endocrinol Metab 1987;65:962–8. doi:10.1210/jcem-65-5-962

13        Spiegel K, Leproult R, Van Cauter E. Impact of sleep debt on metabolic and endocrine function. Lancet 1999;354:1435–9. doi:10.1016/S0140-6736(99)01376-8

14        Cagnacci A, Cannoletta M, Caretto S, et al. Increased cortisol level: a possible link between climacteric symptoms and cardiovascular risk factors. Menopause 2011;18:273–8. doi:10.1097/gme.0b013e3181f31947

Declaration of interests MC