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Cardiovascular diseases (CVD) and neurodegenerative disorders (ND), such as Alzheimer’s disease (AD), are highly prevalent conditions in postmenopausal women. Recent evidence suggests the existence of an intimate cross-talk between the heart and the brain, resulting from a complex network of the autonomic nervous system and it has been suggested a role of decreases in oestrogen-related signalling during the transition into menopause. This review by Schwarz et al. [1] provides up to date evidence supporting how changes in circulating oestrogen levels during the transition to menopause may trigger autonomic dysfunction, thus promoting cardiovascular and cognitive decline in women, particularly on the role of oestrogens in sympathoexcitation [2]. Improving the understanding of the contribution of the autonomic nervous system on the development, maintenance and/or progression of both cardiovascular and cognitive dysfunction during the menopausal transition should help improve the clinical management of elderly women.


Cerebral ageing in women differs from that in men, and female-specific hormones significantly impact cardiovascular health, autonomic function, and cognition in later life. The main symptoms of the perimenopause originate in the central nervous system (CNS), including vasomotor instability, diaphoresis, insomnia, high blood pressure, depression, and a decline in cognitive function, which can persist into postmenopausal stages [3].  Estradiol, a lipophilic steroid, can diffuse through the blood brain barrier to regulate various female homeostatic systems and intrinsic behaviour. Three estrogen receptor subtypes have been described: estrogen receptor alpha (ER-α); estrogen receptor beta (ER-β); and G-protein-coupled estrogen receptor 1 (GPER), a plasma membrane-bound G-protein-coupled receptor that mediates rapid estrogen non-genomic actions by activating several protein kinases. ER-α and ER-β exhibit a wide distribution within the CNS.

Epidemiological evidence supports the connection between premature ovarian insufficiency, menopause and premenopausal women who have undergone oophorectomy with the risk of cognitive decline. Non-estrogen sex female hormones, progesterone and FSH, also play an important role  on autonomic regulation. Progesterone, acts with estrogen to regulate multiple non-reproductive physiological functions, in particular cognition and neuroprotection. Progesterone and its neuroactive metabolites, activate multiple receptors, mediating both genomic and non-genomic actions within brain cells. Non-genomic actions of progesterone and its steroids derivates on GABA receptors can modulate brain activity. Preclinical evidence suggests that progesterone, similar to estrogen, exhibits neuro- protective actions against neurodegenerative processes.

Another important field of investigation is the role of increased circulating FSH levels during the perimenopausal phase and its association with the onset of cognitive decline, bone loss, visceral adiposity accumulation and cardiovascular risk. Early estrogen therapy (ET) has been proposed as a promising intervention to prevent cardiovascular events and cognitive decline [4,5], possibly by increasing brain glucose metabolism and attenuating aging-associated neuroinflammation and oxidative stress [6]. However, controversy remains regarding the optimal therapeutic window for the beneficial effects of ET [7]. In the present commented review, Schwarz et al. [1] points out to the need for future studies in order to understand the specific cellular and molecular mechanisms underlying high circulating FSH, FSHR signalling, and estrogen and progesterone-mediated changes within the CNS.

Prof. Sonia Cerdas Pérez, MD
University of Costa Rica
Department of Endocrinology, Hospital Cima San José, Costa Rica
President of the Costa Rican Society of Gynecological Endocrinology (AGE)


  1. Schwarz KG, Vicencio SC, Inestrosa NC, Villaseca P, Del Rio R. Autonomic nervous system dysfunction throughout menopausal transition: A potential mechanism underpinning cardiovascular and cognitive alterations during female ageing. J Physiol. 2023 Dec 8. doi: 10.1113/JP285126.
  2. El Khoudary SR, Aggarwal B, Beckie TM, et al.; American Heart Association Prevention Science Committee of the Council on Epidemiology and Prevention; and Council on Cardiovascular and Stroke Nursing. Menopause Transition and Cardiovascular Disease Risk: Implications for Timing of Early Prevention: A Scientific Statement From the American Heart Association. Circulation. 2020;142(25):e506-e532.
  3. Brinton RD, Yao J, Yin F, Mack WJ, Cadenas E. Perimenopause as a neurological transition state. Nat Rev Endocrinol. 2015;11(7):393-405.
  4. Guo H, Liu M, Zhang L, et al. The Critical Period for Neuroprotection by Estrogen Replacement Therapy and the Potential Underlying Mechanisms. Curr Neuropharmacol. 2020;18(6):485-500.
  5. Maki PM. Critical window hypothesis of hormone therapy and cognition: a scientific update on clinical studies. Menopause. 2013;20(6):695-709.
  6. Villaseca P, Cisternas P, Inestrosa NC. Menopause and development of Alzheimer’s disease: Roles of neural glucose metabolism and Wnt signaling. Front Endocrinol (Lausanne). 2022;13:1021796.
  7. Mills ZB, Faull RLM, Kwakowsky A. Is Hormone Replacement Therapy a Risk Factor or a Therapeutic Option for Alzheimer’s Disease? Int J Mol Sci. 2023;24(4):3205.

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