Oestrogens: Structure, Mechanisms of Action and Role in Mood and Cognition

Abstract

Oestrogens are steroid hormones that act through specific receptors in the brain to influence a variety of functions, including mood and cognition. The best‐known and most potent endogenous oestrogen is 17β‐oestradiol (17β‐E2). Oestrogen actions in the brain include alterations of neuronal excitability, neurotransmitter synthesis and metabolism, neuronal development, morphology and survival as well as connectivity between different brain areas so as to generate behaviours that are appropriate to internal (physiological) and external (environmental) demands. In the so‐called classical mode of action, oestrogens bind to specific receptors located in the cell nucleus that regulate gene transcription and ultimately protein synthesis. Such receptors are widely distributed in the brain and peripheral tissues such as breast, uterus, bone, liver and heart. Oestrogen actions mediated by nuclear receptors only become detectable after several hours. In contrast, more recently described membrane‐bound receptors allow oestrogens to rapidly alter the excitability of neuronal and nonneuronal membranes. Thus, oestrogens have the potential to influence brain function through slow‐ and/or fast‐acting modes. Knowledge about how and what brain structures and functions are responsive to oestrogens over the entire lifespan is key to informing future improvements in women's health, from adolescence through to old age.

  • Oestrogens are steroid hormones that modulate neuronal structure, activity and function; the term ‘oestrogen’ refers to both naturally produced hormones and synthetic analogues.
  • Modern industrial products contain a variety of chemicals with oestrogen‐like properties. These so‐called endocrine disruptor compounds are considered to be environmental health hazards.
  • Oestrogen secretion starts during early development, varies cyclically from puberty onwards and gradually diminishes with age (menopause in women).
  • Oestrogens and oestrogen‐like compounds bind to oestrogen receptors located in either the plasma membrane or cell nucleus that lead to rapid changes in neuronal excitability and slow‐onset changes in protein synthesis, respectively.
  • Both the rapid and slow modes of oestrogen action contribute to the regulation of complex behaviours such as mood and cognition.
  • Oestrogens have wide therapeutic applications, for example in contraception and management of postmenopausal symptoms, but their prescription requires careful tailoring to individual needs and potential risk factors.
  • Phytoestrogens are natural (plant) compounds. Although they are widely promoted in alternative medicine, their efficacy is questionable.

Keywords: oestrogen; oestrogen receptors; mechanisms of oestrogen action; neuron structure and function; sexual differentiation of the brain; contraception; ageing; hormone replacement therapy; anxiety; depression; cognitive performance

Figure 1. Structural formulae of the naturally occurring gonadal steroids: (a) testosterone, (b) 17β‐oestradiol, which is derived from testosterone through the action of the enzyme aromatase and (c) equilenin. Structure of the ‘steroid backbone’, labelled according to convention, is shown in the top left‐hand corner of the illustration. Three representative members of the phyto‐oestrogen family, coumestrol, genistein and resveratrol, are shown in (d–f); these plant‐derived oestrogens display weak potencies at the oestrogen receptor. The chemical formula of diethylstilboestrol, a highly potent synthetic nonsteroidal oestrogen, is depicted in (g); DES was originally used to prevent spontaneous abortions, but it is no longer used as a therapeutic agent because of its highly carcinogenic nature Arnal et al., (). The structures of two common nonsteroidal ‘endocrine disrupter compounds’, bisphenol A and DDT, are represented in (h) and (i), respectively; the use of EDCs is now prohibited in most countries. Tamoxifen (j), ICI 182780 (k) and raloxifene (l) serve as examples of nonsteroidal ‘designer oestrogens’ or ‘selective oestrogen receptor modulators’. Tamoxifen is used for the treatment of oestrogen‐dependent breast cancers. ICI 182780 shows greater oestrogen receptor selectivity than tamoxifen and shows considerable potential as a therapeutic agent. Raloxifene was recently approved for use in the prevention of osteoporosis. The structure of 3βAdiol is shown in (m); this compound is reportedly an endogenous oestrogen that shows higher affinity for ERβ than ERα. The inset (top left‐hand corner) shows the structure of the basic ‘steroid rings’.
Figure 2. Schematic representation of the ovarian cycle in women, based on an average cycle length of 28 days with ovulation occurring on day 14. Note that oestradiol concentrations gradually rise with increasing size of the developing ovarian follicle and reach a peak just before ovulation before declining. The secretory profile of progesterone follows that of the development of the corpus luteum; progesterone levels plummet when the corpus luteum regresses, and this is accompanied by the menstrual bleeding due to sloughing of the endometrium lining the walls of the uterus.
Figure 3. Schematic distribution of ER isoforms (α and β) in the brain, based on published maps generated by immunocytochemistry and in situ hybridisation histochemistry. The map is not comprehensive; it only shows a selection of brain areas relevant to the subject of this article. More complete data can be found at https://www.proteinatlas.org/humanproteome/brain (human brain) and https://portal.brain‐map.org (human and mouse brains). The number of pluses refers to the relative abundance of each isoform. Only those areas of the brain relevant to functions discussed in this article are shown. Several hypothalamic nuclei express one or both ER isoforms; of particular relevance are the preoptic area, which is responsible for the control of sex steroid secretion, and the ventromedial nucleus, which is strongly implicated in the regulation of sexual behaviour.
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References

Andreano JM, Touroutoglou A, Dickerson B, et al. (2018) Hormonal cycles, brain network connectivity, and windows of vulnerability to affective disorder. Trends in Neurosciences 41: 660–676.

Arnal JF, Lenfant F, Flouriot G, et al. (2012) From in vivo gene targeting of oestrogen receptors to optimization of their modulation in menopause. British Journal of Pharmacology 165: 57–66.

Arnold AP (2017) A general theory of sexual differentiation. Journal of Neuroscience Research 95: 291–300.

Arnold AP (2020) Sexual differentiation of brain and other tissues: five questions for the next 50 years. Hormones and Behavior 120: 104691. DOI: 10.1016/j.yhbeh.2020.104691.

Azcoitia I, Barreto GE and Garcia‐Segura LM (2019) Molecular mechanisms and cellular events involved in the neuroprotective actions of estradiol. Analysis of sex differences. Frontiers in Neuroendocrinology 55: 100787. DOI: 10.1016/j.yfrne.2019.100787.

Barton M, Filardo EJ, Lolait SJ, et al. (2018) Twenty years of the G protein‐coupled estrogen receptor GPER: historical and personal perspectives. Journal of Steroid Biochemistry and Molecular Biology 176: 4–15.

Bayer J, Gläscher J, Finsterbusch J, et al. (2018) Linear and inverted U‐shaped dose‐response functions describe estrogen effects on hippocampal activity in young women. Nature Communications 9: 1220. DOI: 10.1038/s41467‐018‐03679‐x.

Boulware MI, Kent BA and Frick KM (2012) The impact of age‐related ovarian hormone loss on cognitive and neural function. Current Topics in Behavioral Neuroscience 10: 165–184.

Döllen G (2017) Setting the mood for love. Nature Neuroscience 20: 379–380.

Engler‐Chiurazzi EB, Brown CM, Povroznik JM and Simpkins JW (2018) Estrogens as neuroprotectants: estrogenic actions in the context of cognitive aging and brain injury. Progress in Neurobiology 157: 188–211.

Gershoni M and Pietrokovski S (2017) The landscape of sex‐differential transcriptome and its consequent selection in human adults. BMC Biology 15: 7. DOI: 10.1186/s12915‐017‐0352‐z.

Hines M (2011) Gender development and the human brain. Annual Reviews of Neuroscience 34: 69–88.

Inoue S, Yang R, Tantry A, et al. (2019) Periodic remodeling in a neural circuit governs timing of female sexual behavior. Cell 179: 1393–1408.

Kimura D (1999) Sex and Cognition. MIT Press: Cambridge, MA.

Lanza di Scalea T and Pearlstein T (2019) Premenstrual dysphoric disorder. Medical Clinics of North America 103: 613–628.

LeGates TA, Kvarta MD and Thompson SM (2019) Sex differences in antidepressant efficacy. Neuropsychopharmacology 44: 140–154.

Luine V (2014) Estradiol and cognitive function: past, present and future. Hormones and Behavior 66: 602–618.

Manson JE, Chlebowski RT, Stefanick ML, et al. (2013) Menopausal hormone therapy and health outcomes during the intervention and extended poststopping phases of the Women's Health Initiative randomized trials. Journal of the American Medical Association 310: 1353–1368.

Marrocco J and McEwen BS (2016) Sex in the brain: hormones and sex differences. Dialogues in Clinical Neuroscience 18: 373–383.

McCarthy MM, Woolley CS and Arnold AP (2017) Incorporating sex as a biological variable in neuroscience: what do we gain? Nature Reviews in Neuroscience 18: 707–708.

McCarthy MM (2019) Is sexual differentiation of brain and behavior epigenetic? Current Opinion in Behavioral Science 25: 83–88.

Merlo S, Spampinato SF and Sortino MA (2017) Estrogen and Alzheimer's disease: still an attractive topic despite disappointment from early clinical results. European Journal of Pharmacology 817: 51–58.

Miles C, Green R and Hines M (2006) Estrogen treatment effects on cognition, memory and mood in male‐to‐female transsexuals. Hormones and Behavior 50: 708–717.

Morselli E, Frank AP, Santos RS, et al. (2016) Sex and gender: critical variables in preclinical and clinical medical research. Cell Metabolism 24: 203–209.

NAMS 2017 Hormone Therapy Position Statement Advisory Panel (2017) The 2017 hormone therapy position statement of The North American Menopause Society. Menopause 24: 728–753.

Norton J, Carrière I, Pérès K, et al. (2019) Sex‐specific depressive symptoms as markers of pre‐Alzheimer dementia: findings from the Three‐City cohort study. Translational Psychiatry 9: 291. DOI: 10.1038/s41398‐019‐0620‐5.

Ogawa S, Tsukahara S, Choleris E and Vasudevan N (2018) Estrogenic regulation of social behavior and sexually dimorphic brain formation. Neuroscience and Biobehavioral Reviews 110: 46–59. DOI: 10.1016/j.neubiorev.2018.10.012.

Patchev VK, Bachurin SO, Albers M, et al. (2008) Neurotrophic estrogens: essential profile and endpoints for drug discovery. Drug Discovery Today 13: 734–747.

Riggs BL and Hartmann LC (2003) Selective estrogen‐receptor modulators – mechanisms of action and application to clinical practice. New England Journal of Medicine 348: 618–629.

Ritchie SJ, Cox SR, Shen X, et al. (2018) Sex differences in the adult human brain: evidence from 5216 UK Biobank participants. Cerebral Cortex 28: 2959–2975.

Sánchez FJ and Vilain E (2010) Genes and brain sex differences. Progress in Brain Research 186: 65–76.

Schiller CE, Johnson SL, Abate AC, et al. (2016) Reproductive steroid regulation of mood and behavior. Comprehensive Physiology 6: 1135–1160.

Sheppard PAS, Choleris E and Galea LAM (2019) Structural plasticity of the hippocampus in response to estrogens in female rodents. Molecular Brain 12: 22. DOI: 10.1186/s13041‐019‐0442‐7.

Sherwin BB (2012) Estrogen and cognitive functioning in women: lessons we have learned. Behavioral Neuroscience 126: 123–127.

Sramek J (2016) Sex differences in the psychopharmacological treatment of depression. Dialogues in Clinical Neuroscience 18: 447–457.

Thornton J, Zehr JL and Loose MD (2009) Effects of prenatal androgens on rhesus monkeys: a model system to explore the organizational hypothesis in primates. Hormones and Behavior 55: 633–645.

Tibrewal M, Cheng B, Dohare P, et al. (2018) Disruption of interneuron neurogenesis in premature newborns and reversal with estrogen treatment. Journal of Neuroscience 38: 1100–1113.

Tschiffely AE, Schuh RA, Prokai‐Tatrai K, et al. (2018) An exploratory investigation of brain‐selective estrogen treatment in males using a mouse model of Alzheimer's disease. Hormones and Behavior 98: 16–21.

Tunç B, Solmaz B, Parker D, et al. (2016) Establishing a link between sex‐related differences in the structural connectome and behaviour. Philosophical Transactions of the Royal Society of London B Biological Sciences 371: 20150111.

Viña J and Lloret A (2010) Why women have more Alzheimer's disease than men: gender and mitochondrial toxicity of amyloid‐beta peptide. Journal of Alzheimer's Disease 20 (Suppl 2): S527–S533.

Walf AA, Paris JJ, Rhodes ME, Simpkins JW and Frye CA (2011) Divergent mechanisms for trophic actions of estrogens in the brain and peripheral tissues. Brain Research 1379: 119–136.

Wellman CL, Bangasser DA, Bollinger JL, et al. (2018) Sex differences in risk and resilience: stress effects on the neural substrates of emotion and motivation. Journal of Neuroscience 38: 9423–9432.

Wisniewski AB, Prendeville MT and Dobs AS (2005) Handedness, functional cerebral hemispheric lateralization, and cognition in male‐to‐female transsexuals receiving cross‐sex hormone treatment. Archives of Sexual Behavior 34: 167–172.

Further Reading

Ainsworth C (2015) Sex redefined: the idea of 2 sexes is overly simplistic. Nature 518: 288–291.

Bennesch MA and Picard D (2015) Tipping the balance: ligand‐independent activation of steroid receptors. Molecular Endocrinology 29: 349–363.

Brinton RD (2015) Perimenopause as a neurological transition state. Nature Reviews in Endocrinology 11: 393–405.

Chavira BS, Kablinger AS and Rahmani E (2019) Should we prescribe different dosages of psychotropic medications to men and women? Psychiatric Times 36 (5) https://www.google.com/search?client=firefox‐b‐e&q=Should+we+prescribe+different+dosages+of+psychotropic+medications+to+men+and+women.

Charney DS, Buxbaum JD, Sklar P and Nestler EJ (eds) (2018) Neurobiology of Mental Illness, 5th edn. Oxford University Press: New York.

Clark JA, Alves S, Gundlah C, et al. (2012) Selective estrogen receptor‐beta (SERM beta) compounds modulate raphe nuclei tryptophan hyroxylase‐1 (TPH‐1) mRNA expression and cause antidepressant‐like effects in the forced swim test. Neuropharmacology 63: 1051–1063.

Danska JS (2014) Sex matters for mechanism. Science Translation‐al Medicine 6: 1–3.

Gasbarri A, Tavares MCH, Rodrigues RC, et al. (2012) Estrogen, cognitive functions and emotion: an overview on humans, non‐human primates and rodents in reproductive age. Reviews in the Neurosciences 23: 587–606.

Gould SJ (1980) The Panda's Thumb, pp 152–159. W.W. Norton & Company: New York.

Henderson VW (2010) Action of estrogens in the aging brain: dementia and cognitive aging. Biochimica et Biophysica Acta 1800: 1077–1083.

Joel D and McCarthy MM (2017) Incorporating sex as a biological variable in neuropsychiatric research: where are we now and where should we be? Neuropsychopharmacology 42: 379–385.

May M (2016) Sex on the brain. Nature Medicine 22: 1370–1372.

McCarthy MM, Nugent BM and Lenz KM (2017) Neuroimmunology and neuroepigenetics in the establishment of sex differences in the brain. Nature Reviews in Neuroscience 18: 471–484.

Meyer‐Bahlburg HFL (2013) Sex steroids and variants of gender identity. Endocrinology and Metabolism Clinics of North America 42: 435–452.

Nelson RJ and Kriegsfeld LJ (2016) An Introduction to Behavioral Endocrinology, 5th edn. Sinauer Associates, Inc.: Sunderland, MA.

Oxford University Press Oxford Series in Behavioral Neuroendocrinology. Oxford University Press: New York. https://global.oup.com/academic/content/series/o/oxford‐series‐in‐behavioral‐neuroendocrinology‐osbn/?cc=de&lang=en&.

Patchev VK and Almeida OFX (1999) Steroid‐dependent Organization of Neuroendocrine Functions. Landes Bioscience: Georgetown, TX.

Shansky RM (2019) Are hormones a “female problem” for animal research? Science 364: 825–826.

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Almeida, Osborne FX, and Patchev, Vladimir K(Aug 2020) Oestrogens: Structure, Mechanisms of Action and Role in Mood and Cognition. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0029144]