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Summary

Even though vasomotor symptoms (VMS) and migraine are highly prevalent and often coexist during the menopause transition, interactions between the two are understudied, and it is possible there are shared physiologic mechanisms. The authors of this study investigated potential associations between VMS and migraine using the longitudinal Study of Women’s Health Across the Nation (SWAN).[1] They included 467 women with a self-reported history of migraine diagnosis made by a medical provider, and 2,466 women without a migraine diagnosis served as controls. VMS (assessed as number of days hot flashes and night sweats were experienced in the prior two weeks and converted to a mean symptom frequency) were self-reported at baseline and annually during follow up which varied between 2 and 10 years with greater than half of the women completing all 10 assessment. Vaginal dryness symptoms, also related to menopause, but without vasomotor origin, were also assessed using a frequency score. For an additional control comparison, the authors further examined the association of VMS and vaginal dryness with back pain, another pain disorder, to investigate the specificity of the association of VMS and migraine. Study results showed that a prior diagnosis of migraine predicted a higher frequency of hot flashes (p = 0.0036) and night sweats (p = 0.0138) after adjusting for all covariates. Significant interactions between migraine diagnosis and reproductive stage were noted, with higher frequencies of VMS in women with migraine, particularly in perimenopause. There was no association between migraine diagnosis and vaginal dryness. In a small subgroup of women with back pain, no association between back pain and hot flashes or night sweats was identified when compared to women with no back pain. The authors theorize that declining estrogen levels during the menopause transition are associated with hypothalamic changes which may explain the increased frequency of both VMS and migraine during this time frame.

Commentary

This study provides evidence for a link between VMS and migraine which are associated with estrogen depletion in the menopause transition and declining estrogen levels, respectively. Although there are some limitations in the current study which are acknowledged by the authors, including that this was a secondary analysis, and the study was not designed to track migraine, its characteristics or associated symptoms, the authors are to be congratulated on identifying this association. Defining potential shared mechanisms between these two conditions is a critical issue that needs to be addressed. VMS are thought to relate to thermoregulatory dysfunction associated with menopause. Thermal control is regulated by the hypothalamus, and hot flushes associated with ovarian estrogen depletion at menopause are the result of presumed narrowing of the so called “thermoneutral zone,” below and above which shivering or sweating occur, respectively, in order to maintain stable core body temperature. Marked hypertrophic changes in the hypothalamic KNDy (kisspeptin, neurokinin B and dynorphin) neuronal pathways have been noted in postmortem studies of postmenopausal women, and based on preliminary data in an animal model using cynomolgus monkeys, these pathways may be involved in the generation of hot flashes.[2] A potential shared mechanistic pathway for VMS and migraine involves the orexinergic neurons in the hypothalamus that associate with sleep and wakefulness, anxiety, and thermoregulation.[3] In preclinical studies, blockade of orexin receptors inhibits meningeal artery dilatation in response to trigeminal activation and inhibits cortical spreading depression associated with migraine.[4,5] Notably, orexin antagonists also reduce increases in tail skin temperature, the rodent equivalent of the hot flash.[6] Additionally, there is cross talk between kisspeptin and orexigenic neuronal pathways in the hypothalamus, and data suggest that certain hypothalamic orexigenic neuronal pathways involving neuroprotein Y must be intact for normal function of kisspeptin neurons.[7] Based on these interactions, and since postmenopausal women are known to have elevated levels of orexin, and estrogen therapy reduces orexin levels[8], the relationships among VMS, orexin, KNDy neurons, and estrogen require further investigation. The authors of the current study also posit that trait endothelial vascular abnormalities may predispose some women to migraine and to more severe VMS. There is evidence for endothelial dysfunction in some women with VMS, potentially conferring increased risk for cardiovascular disease.[9] Similarly, migraine has been associated with long-term cardiovascular risk, possibly through shared vascular vulnerability and endothelial dysfunction, mutual associations with hypertension and hyperlipidemia, or genetic factors.[10] Interestingly, there is also an association of migraine with gestational hypertension and preeclampsia, additional female-specific risks for cardiovascular disease.[10] Where does this leave us, and what are next steps? There is still uncertainty regarding the exact mechanisms responsible for the generation of VMS, let alone the myriad factors that affect the expression of these symptoms such as race, ethnicity, mood disorders, adverse childhood experiences, current abuse, and other sociocultural determinates of health and wellbeing. Accumulating evidence supporting female-specific variations in cardiovascular risk is convincing. The future research agenda requires additional study of the underlying physiologic mechanisms responsible for the generation of VMS, potential shared pathways with migraine, and the associations of each with cardiovascular disease risk in women.

Author(s)

  • Stephanie S. Faubion
    Professor of Medicine, Mayo Clinic, Rochester, MN

    Bill and Penny George Director of the Mayo Clinic Center for Women’s Health

    Medical Director, North American Menopause Society

Citations

  1. Maleki N, Cheng YC, Tu, Y, Locascio JJ. Longitudinal course of vasomotor symptoms in perimenopausal migraineurs. Ann Neurol 2019;85(6):865-874.
    https://www.ncbi.nlm.nih.gov/pubmed/30937949
  2. Rance NE, Dacks PA, Mittelman-Smith MA, Romanovsky AA, Krajewski-Hall SJ. Modulation of body temperature and LH secretion by hypothalamic KNDy (kisspeptin, neurokinin B and dynorphin) neurons: a novel hypothesis on the mechanism of hot flushes. Front Neuroendocrinol 2013;34:211–227.
    https://www.ncbi.nlm.nih.gov/pubmed/23872331
  3. Zhang XY, Yu L, Zhuang QX, Zhu JN, Wang JJ. Central functions of the orexinergic system. Neurosci Bull. 2013;29(3):355-65.
    https://www.ncbi.nlm.nih.gov/pubmed/23299718
  4. Schulte L, May A. Of generators, networks and migraine attacks. Cur Opin Neurol. 2017. 30(3):241–245.
    https://www.ncbi.nlm.nih.gov/pubmed/28240611
  5. Hoffmann J, Supronsinchai W, Akerman S, et al. Evidence for orexinergic mechanisms in migraine. Neurobiol Dis 2015; 74:137–143.
    https://www.ncbi.nlm.nih.gov/pubmed/25447225
  6. Federici LM, Caliman IF, Molosh AI. Hypothalamic orexin’s role in exacerbated cutaneous vasodilation responses to an anxiogenic stimulus in a surgical menopause model. Psychoneuroendocrinology. 2016 Mar; 65: 127–137.
    https://www.ncbi.nlm.nih.gov/pubmed/26765933
  7. Wahab F, Atika B, Ullah F. Metabolic impact on the hypothalamic kisspeptin-Kiss1r signaling pathway. Front Endocrinol 2018; 9:123.
    https://www.ncbi.nlm.nih.gov/pubmed/29643834
  8. El-Sedeek MS, Korish AA, Deef MM. Plasma orexin-A levels in postmenopausal women: possible interaction with estrogen and correlation with cardiovascular risk status. BJOG 2010;117(4):488-92.
    https://www.ncbi.nlm.nih.gov/pubmed/20105164
  9. Thurston RC, Chang Y, Barinas-Mitchell E, Jennings JR, von Känel R, Landsittel DP, Matthews KA. Physiologically assessed hot flashes and endothelial function among midlife women. Menopause 2017;24:886–893.
    https://www.ncbi.nlm.nih.gov/pubmed/28399007
  10. Linstra KM, Ibrahimi K, Terwindt GM. Migraine and cardiovascular disease in women. Maturitas. 2017;97:28-31.
    https://www.ncbi.nlm.nih.gov/pubmed/28159058
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