Estrogens and female developing brain: two sides of the coin

Literature review




estrogens, xenoestrogens, bisphenol A, alpha-fetoprotein, hyperandrogenism, sex differentiation, brain development, reproduction, female, rat


The review highlights current views and hypotheses on the pathogenetic role of natural and xenoestrogens in the disorders of programming of neuroendocrine regulation of reproduction, alaptation, and various forms of instinctive behavior (reproductive, eating, parental, etc.) in the perinatal period of development of the female brain. Catecholestrogens, which are formed in the brain as a result of sequential metabolic conversions of testosterone, are involved in exogenous or endogenous androgen-induced defeminization of hypothalamic control of ovulation in early female ontogenesis. In the research on female animals with a knocked out gene of alpha-fetoprotein, the protective role of this protein against the possible pathogenic effect of placental estrogens on the developing brain of female fetuses was proved. The damaging effect of phytoestrogens (genistein, coumestrol) in the early postnatal period on the formation of ovulatory cycles has been shown. Evidence from studies in rodents and other animal species, supported by clinical observations, indicate the potential damaging effect of exposure to low levels of environmental xenoestrogens
on the developing brain, in particular on its sexual differentiation and the hypothalamic-pituitary-adrenal axis. The potential hazard of the perinatal exposure to low doses of bisphenol A for the formation of estrogen receptors in the hypothalamus and amygdala of the female brain, sexual behavior and ovulation is discussed. Special attention is paid to the possible physiological role of natural estrogens in the formation of the female neuroendocrine system during puberty. It was concluded that in the early stages of female life, estrogens play a different role in the programming of the neuroendocrine system and behavior, depending on the period of individual development.

Author Biography

A.G. Reznikov, NAMS of Ukraine; SI “V.P. Komisarenko Institute of Endocrinology and Metabolism of the NAMS of Ukraine”, Kyiv

MD, professor, academician of the NAMS of Ukraine, corresponding member of the NAS of Ukraine;

Head of the Department of Endocrinology of Reproduction and Adaptation


The estrogen elixer: A History of hormone replacement in America. Baltimore: The Johns Hopkins Press. 2007

Veler, C.D., Thayer, S., Doisy, E.A. “The preparation of the crystallinefollicular ovarian hormone: theelin.” J Biol Chem 87 (1930): 357–71.

Butenandt, A. “Uber progynon ein krytallisiertes weibliches exualhormon.” Die Naturwissenschaften 17 (1929): 879.

Huffman, M.N., Thayer, S.A., Doisy, E.A. “The isolation of a-dihydrotheelin from human placenta.” J Biol Chem 133 (1940): 567–71.

Reznikov, A. “Hormonal impact on tumor growth and progression.” Exp Oncol 37.3 (2015): 162–72.

Gibson, D.A., Simitsidellis, I., Collins, F., Saunders, P.T.K. “Androgens, oestrogens and endometrium: a fine balance between perfection and pathology.” J Endocrinol 246.3 (2020): R75-R93.

Haddow, A., Watkinson, J.M., Paterson, E., Koller, P.C. “Influence of synthetic oestrogens on advanced malignant disease.” Br Med J 2.4368 (1944): 393–8.

Jordan, V.G. “The new biology of estrogen-induced apoptosis applied to treat and prevent breast cancer.” Endocr Relat Cancer 22.1 (2015): R1–31.

Barker, D.J. “The developmental origins of chronic adult disease.” Acta Paediatr Suppl 93 (2004): 26–33.

Bakker, J., De Mees, C., Douhard, Q., et al. “Alpha-fetoprotein protects the developing female mouse brain from masculinization and defeminization by estrogens.” Nat Neurosci 9.2 (2006): 220–6.

De Boo, H.A., Harding, J.E. “The developmental origins of adult disease (Barker) hypothesis.” Aust NZ J Obstet Gynaecol 46 (2006): 4–14.

Baraboy, V.A., Reznikov, O.G. Physiology, biochemistry and psychology of Stress. Kyiv. Interservice (2013).

Perets, O.V., Sergienko, L.Y., Seliukova, N.Y., et al. “Potentiating effect of excessive consumption of fructose on obesity development in offspring of mothers stressed during pregnancy.” Problemy Endokrynnoi Patologii 4 (2016): 83–90.

Vaiserman, A.M. “Epigenetic programming by early-life stress: evidence from human populations.” Dev Dyn 244.3 (2015): 254–65.

Wang, Y., Wu, H., Sun, Z.S. “The biological basis of sexual orientation: How hormonal, genetic, and environmental factors influence to whom we are sexually attracted.” Front Neuroendocrinol 55 (2019): 100798.

Goyal, D., Limesand, S.W., Goyal, R. “Epigenetic responses and the developmental origins of health and disease.” J Endocrinol 242.1 (2019): T105–T119.

Carrillo, B., Collado, P., Díaz, F., et al. “Physiological and brain alterations produced by high-fat diet in male and female rats can be modulated by increased levels of estradiol during critical periods of development.” Nutr Neurosci 22.1 (2019): 29–39.

Ganna, A., Verweij, K.J.H., Nivard, M.l.G., et al. “Large-scale GWAS reveals insights into the genetic architecture of same-sex sexual behavior.” Science 365.6456 (2019): eaat7693.

Dorner, G. Hormones and brain differentiation. Amsterdam. Elsevier Sci (1976).

Reznikov, A.G. Sex hormones and the brain differentiation. Kyiv. Naukova dumka (1982).

Reznikov, O.G. “Perinatal programming of disorders of endocrine functions and behavior.” Kyiv. Naukova dumka (2019).

Reinisch, J.M., Sanders, S.A. “Prenatal gonadal steroidal influences on gender-related behavior.” Progr Brain Res 61 (1984): 407–16.

Nordenström, A., Falhammar, H. “Management of endocrine disease: Diagnosis and management of the patient with non-classic CAH due to 21-hydroxylase deficiency.” Eur J Endocrinol 180.3 (2019): R127–R145.

Tatarchuk, T.F.., Kosei, N.V., Tutchenko, T.M., Hlamazda, M.I. “Optimization of ovarian function and metabolic status in syndrome of polycystic ovaries.” Reprod Endocr 2.52 (2020): 18–22.

Dittmann, R.W., Kappes, M.E., Kappes, M.H. “Sexual behavior in adolescent and adult females with congenital adrenal hyperplasia.” Psychoneuroendocrinol 17 (1992): 153–70.

Meyer-Bahlburg, H.F., Dolezal, C., Baker, S.W., New, M.I. “Sexual orientation in women with classical or non-classical congenital adrenal hyperplasia as a function of degree of prenatal androgen excess.” Arch Sex Behav 37.1 (2008): 85–99.

Abruzzese, G.A., Heber, M.F., Ferreira, S.R., et al. “Prenatal androgen exposure affects ovarian lipid metabolism and steroid biosynthesis in rats.” J Endocrinol 247.3 (2020): 239–50.

Ehrhardt, A.A., Meyer-Bahlburg, F.L., Rosen, L.R. “Sexual orientation after prenatal exposure to exogenous estrogen.” Arch Sex Behav 14 (1985): 57–77.

Bakker, J., De Mees, C., Douhard, Q., et al. “Alpha-fetoprotein protects the developing female mouse brain from masculinization and defeminization by estrogens.” Nat Neurosci 9.2 (2006): 220–6.

Nosenko, N.D., Reznikov, A.G. “Sexual differentiation of the brain as a manifestation of its plasticity.” Neurophysiology 33.2 (2001): 125–34.

Reznikov, A.G. Hormone-neurotransmitter imprinting in the neuroendocrine control of reproduction. New York. Harwood Academic Publishers (1994).

Simpson, E., Santen, R.J. “Celebrating 75 years of oestradiol.” J Mol Endocr 55.3 (2015): T1–T20.

McEwen, B., Coirini, H., Westlund-Danielsson, A., et al. “Steroid hormones as mediators of neural plasticity.” J Steroid Biochem Mol Biol 39 (1991): 223–32.

Naftolin, F. “Brain aromatization of androgens.” J Reprod Med 39.4 (1994): 257–61.

Reznikov, A.G., Nosenko, N.D. “It is possible that noradrenaline is the biogenic monoamine responsible for androgen-dependent sexual brain differentiation.” Exp Clin Endocrinol 81.1 (1983): 91–3.

Reznikov, A.G., Nosenko, N.D. “Prevention of the anovulatory syndrome and testosterone-induced rise in catecholamine level in the hypothalamus of newborn rats with steroid aromatase inhibitors.” Exp Clin Endocrinol 90.2 (1987): 185–9.

Reznikov, A.G., Nosenko, N.D., Tarasenko, L.V. “Augmentation of the sterilizing effect of neonatal androgenization with tropolone, a catechol- O-methyltransferase inhibitor, in female rats.” Neuroendocrinology 52.5 (1990): 455–9.

Chistyakova, E.Y., Somova, O.V., Karpenko, N.O. “The hormonal state and fertility of female rats phitoestrogenized during suckling.” Visnyk Problem Biologii i Medytsyny 1.87 (2011): 122–4.

Whitten, P.L., Lewis, C., Naftolin, F. “A phytoestrogen diet induces the premature anovulatory syndrome in lactationally exposed female rats.” Biol Reprod 49 (1993): 1117–21.

Jefferson, W.N., Padilla-Banks, E., Goulding, E.H., et al. “Neonatal exposure to genistein disrupts ability of female mouse reproductive tract to support embryo development and implantation.” Biol Reprod 80 (2009): 425–31.

Reznikov, O.G., Sachynska, O.V., Polyakova, L.I., et al. “Long-term effects of prenatal exposure of male rats to dibutylphthalate on various parts of the reproductive system.” Fiziologichnyi Zhurnal 65.3 Suppl. (2019): 100–1.

Balakrishnan, B., Henare, K., Thorstensen, E.B., et al. “Transfer of bisphenol A across the human placenta.” Am J Obstet Gynecol 202.4 (2010): 393.e1–7.

Cao, J., Rebuli, M.E., Rogers, J., et al. “Prenatal bisphenol A exposure alters sex-specific estrogen receptor expression in the neonatal rat hypothalamus and amygdala.” Toxicol Sci 133.1 (2013): 157–73.

Rebuli, M.E., Cao, J., Sluzas, E., et al. “Investigation of the effects of subchronic low dose oral exposure to bisphenol A (BPA) and ethinyl estradiol (EE) on estrogen receptor expression in the juvenile and adult female rat hypothalamus.” Toxicol Sci 140.1 (2014): 190–203.

Arambula, S.E., Belcher, S.M., Planchart, A., et al. “Impact of low dose oral exposure to bisphenol A (BPA) on the neonatal rat hypothalamic and hippocampal transcriptome: A CLARITY-BPA Consortium Study.” Endocrinology 157.10 (2016): 3856–72.

Roepke, T.A., Yang, J.A., Yasrebi, A., et al. “Regulation of arcuate genes by developmental exposures to endocrine-disrupting compounds in female rats.” Reprod Toxicol 62 (2016): 18–26.

Talsness, C., Fialkowski, O., Gericke, C., et al. “The effects of low and high doses of bisphenol A on the reproductive system of female and male rat offspring.” Congen Anomal 40 (2000): S94–S107.

Rubin, B.S., Murray, M.K., Bamassa, D.A., et al. “Perinatal exposure to low doses of bisphenol A affects body weight, patterns of estrous cyclicity, and plasma LH levels.” Environ Health Perspect 109.7 (2001): 675–80.

Palanza, P., Howdeshell, K.L., Parmigiani, S., vom Saal, F.S. “Exposure to a low dose of bisphenol A during fetal life or in adulthood alters maternal behavior in mice.” Environ Health Perspect 110 Suppl. 3 (2002): 415–22.

Della Seta, D., Minder, I., Dessi-Fulgheri, F., Farabollini, F. “Bisphenol-A exposure during pregnancy and lactation affects maternal behavior in rats.” Brain Res Bull 65.3 (2005): 255–60.

Ryan, B.C., Vandenbergh, J.G. “Developmental exposure to environmental estrogens alters anxiety and spatial memory in female mice.” Horm Behav 50.1 (2006): 85–93.

Hass, U., Christiansen, S., Boberg, J., et al. “Low-dose effect of developmental bisphenol A exposure on sperm count and behaviour in rat.” Andrology 4.4 (2016): 594–607.

Kubo, K., Arai, O., Omura, M., et al. “Low dose effects of bisphenol A on sexual differentiation of the brain and behavior in rats.” Neurosci Res 45 (2003): 345–56.

Rubin, B.S., Lenkowski, J.R., Schaeberle, C.M., et al. “Evidence of altered brain sexual differentiation in mice exposed perinatally to low, environmentally relevant levels of bisphenol A.” Endocrinology 147.8 (2006): 3681–91.

De Kloet, E.R., Joëls, M., Holsboer, F. “Stress and the brain: from adaptation to disease.” Nature Rev Neuroscience 6 (2005): 463–75.

Harley, K.G., Gunier, R.B., Kogut, K., et al. “Prenatal and early childhood bisphenol A concentrations and behavior in school-aged children.” Environ Res 126 (2013): 43–50.

Rochester, J.R., Bolden, A.L., Kwiatkowski, C.F. “Prenatal exposure to bisphenol A and hyperactivity in children: a systematic review and meta-analysis.” Environ Intern 114 (2018): 343–56.

Giesbrecht, G.F., Ejaredar, M., Liu, J., et al. “Prenatal bisphenol A exposure and dysregulation of infant hypothalamic-pituitary-adrenal axis function: findings from the APrON cohort study.” Environ Health 16.1 (2017): 47.

Bakker, J., Baum, M.J. “Role for estradiol in female-typical brain and behavioral sexual differentiation.” Front Neuroendocrinol 29.1 (2008): 1–16.






Analytical review