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


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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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]