The ZRT Laboratory Blog


Posted by Dr. Kate Placzek on Friday, 03 June 2016

Menopause – Is It All In Your Head?

Book and article on estrogen and hormones












Perimenopausal Stages & Symptoms







Brain Neurotransmitters diagram

Neurological Nature of the Perimenopausal Transition


Estradiol – The Master Regulator


A Network of Estrogen Receptors



Changes in the organization of the estrogen receptor network within the brain or alterations of circulating estradiol levels can elicit profound consequences on neural circuit function. One such example of a functional consequence of decreasing estradiol levels is perimenopause, when the estrogen receptor network undergoes uncoupling from the bioenergetics system, giving rise to a hypometabolic state associated with neurological dysfunction.[7] Some experts present convincing evidence that hypometabolic states are intimately linked with vasomotor and mood symptoms in perimenopause.

Perimenopausal Symptoms in the Context of Compromised Bioenergetics

Experienced by approximately 80% of women during perimenopause, hot flashes commonly co-occur with other neurological symptoms, such as sleep disturbances, mood changes, pain, and decline in cognitive function.[4] Characterized by the onset of intense and troublesome rises in body temperature, hot flashes are complex and poorly understood.

Increasing evidence suggests a tight-knit relationship between hot flashes and impaired glucose homeostasis. Glucose levels and the degree of insulin resistance correlate with frequency of hot flashes.[8] [9] Furthermore, fluctuating levels of estradiol coincide with a decline in brain bioenergetics and shift towards a metabolically compromised phenotype, an effect that can be rescued with hormone replacement therapy (HRT).[7] In symptomatic female patients receiving HRT during perimenopause, glucose metabolism is preserved in brain regions with estrogen-dependent neurological functions, an effect not observed in symptomatic patients without HRT.[10] [11]


The Neuroendocrine Nature of Hot Flashes


As estradiol declines, brain norepinephrine levels increase, thus inducing a narrowing of the thermoneutral zone.[14] Additionally, decreased estradiol consequently results in upregulation of monoamine oxidase-A (MAO-A) levels in the brain - the enzyme responsible for degradation of serotonin.[15] In neurochemical terms, as estradiol decreases, serotonin turnover is increased. Serotonin is a potent thermoregulatory agent that modulates hot flashes in an opposite manner from norepinephrine. Therefore, putatively reduced serotonin function during perimenopause and an abundance of norepinephrine signaling appear to have vasomotor manifestations in the context of a declining hormonal environment. 

With regard to cognition and mood, administration of transdermal estradiol reverses the heightened emotional activation and reduced activation of working memory with acute tryptophan depletion in menopausal women.[17] This and other studies further highlight and support the magnitude of positive effects estrogen has on cognition and mood via modulation of serotonergic function.[18]

"The Change"






Learn about Neurotransmitter Testing

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[1]   Hall L, Callister LC, Berry JA, Matsumura G: Meanings of menopause: cultural influences on perception and management of menopause. J Holist Nurs 2007;25:106-118.

[2]   Weber MT, Maki PM, McDermott MP: Cognition and mood in perimenopause: a systematic review and meta-analysis. J Steroid Biochem Mol Biol 2014;142:90-98.

[3]   Judd FK, Hickey M, Bryant C: Depression and midlife: are we overpathologising the menopause? J Affect Disord 2012;136:199-211.

[4]   Brinton RD, Yao J, Yin F, Mack WJ, Cadenas E: Perimenopause as a neurological transition state. Nat Rev Endocrinol 2015;11:393-405.

[5]   Hara Y, Waters EM, McEwen BS, Morrison JH: Estrogen Effects on Cognitive and Synaptic Health Over the Lifecourse. Physiol Rev 2015;95:785-807.

[6]   Fischer B, Gleason C, Asthana S: Effects of hormone therapy on cognition and mood. Fertil Steril 2014;101:898-904.

[7]   Rettberg JR, Yao J, Brinton RD: Estrogen: a master regulator of bioenergetic systems in the brain and body. Front Neuroendocrinol 2014;35:8-30.

[8]   Mendez P, Wandosell F, Garcia-Segura LM: Cross-talk between estrogen receptors and insulin-like growth factor-I receptor in the brain: cellular and molecular mechanisms. Front Neuroendocrinol 2006;27:391-403.

[9]   Thurston RC, El Khoudary SR, Sutton-Tyrrell K, Crandall CJ, Sternfeld B, Joffe H, Gold EB, Selzer F, Matthews KA: Vasomotor symptoms and insulin resistance in the study of women's health across the nation. J Clin Endocrinol Metab 2012;97:3487-3494.


[11]   Rasgon NL, Geist CL, Kenna HA, Wroolie TE, Williams KE, Silverman DH: Prospective randomized trial to assess effects of continuing hormone therapy on cerebral function in postmenopausal women at risk for dementia. PLoS One 2014;9:e89095.

[12]   Rasgon NL, Kenna HA, Geist C, Small G, Silverman D: Cerebral metabolic patterns in untreated postmenopausal women with major depressive disorder. Psychiatry Res 10-30-2008;164:77-80.

[13]   Barth C, Villringer A, Sacher J: Sex hormones affect neurotransmitters and shape the adult female brain during hormonal transition periods. Front Neurosci 2015;9:37.

[14]   Shanmugan S, Epperson CN: Estrogen and the prefrontal cortex: towards a new understanding of estrogen's effects on executive functions in the menopause transition. Hum Brain Mapp 2014;35:847-865.

[15]   Freedman RR: Menopausal hot flashes: mechanisms, endocrinology, treatment. J Steroid Biochem Mol Biol 2014;142:115-120.

[16]   Rekkas PV, Wilson AA, Lee VW, Yogalingam P, Sacher J, Rusjan P, Houle S, Stewart DE, Kolla NJ, Kish S, Chiuccariello L, Meyer JH: Greater monoamine oxidase a binding in perimenopausal age as measured with carbon 11-labeled harmine positron emission tomography. JAMA Psychiatry 2014;71:873-879.

[17]   Epperson CN, Amin Z, Ruparel K, Gur R, Loughead J: Interactive effects of estrogen and serotonin on brain activation during working memory and affective processing in menopausal women. Psychoneuroendocrinology 2012;37:372-382.

[18]   Raz L, Hunter LV, Dowling NM, Wharton W, Gleason CE, Jayachandran M, Anderson L, Asthana S, Miller VM: Differential effects of hormone therapy on serotonin, vascular function and mood in the KEEPS. Climacteric 2016;19:49-59.

[19]   Wilson RS, Leurgans SE, Boyle PA, Bennett DA: Cognitive decline in prodromal Alzheimer disease and mild cognitive impairment. Arch Neurol 2011;68:351-356.

Tagged in: Menopause Neurotransmitters Estrogen BHRT