- Email: [email protected]
On estrogenic masculinization of the human brain and behavior
Hormones and Behavior 97 (2018) 1–2
Contents lists available at ScienceDirect
Hormones and Behavior journal homepage: www.elsevier.com/locate/yhbeh
On estrogenic masculinization of the human brain and behavior
MARK
A R T I C L E I N F O Keywords: Estrogen Masculinization Hormones Neurodevelopment Endocrine disruptor Sex hormone-binding globulin
Motta-Mena and Puts (2017) have recently reviewed the endocrinological substrates of human female sexuality. We feel that it is necessary to point out a shortcoming in their review, since their claim that estrogen “has a limited role, if any, in masculinizing the human brain and behavior” does not stand up to close scrutiny, especially when applied to females. The first line of evidence used by the authors to support this argument concerns the putatively low binding affinity for estrogen that human alpha-fetoprotein (AFP) has. However, this is insufficient evidence for the argument that “then ovarian estrogens would presumably cross the bloodbrain barrier and masculinize the human female brain”. The authors disregard that the sex hormone-binding globulin (SHBG) has a similar function to rodent AFP in humans, binding to endogenous estrogens with high affinity (Hong et al., 2015; Varshney and Nalvarte, 2017). Motta-Mena and Puts's (2017) second line of evidence is based on genetically male (46, XY) CAIS individuals who develop feminine gender expression despite producing normal-to-high male levels of testosterone. This line of evidence is based on genetic males and cannot be extrapolated to females (cf. Koebele and Bimonte-Nelson, 2015). As third line of evidence, Motta-Mena and Puts state that human males with mutations rendering the aromatase enzyme dysfunctional typically present as normal males. This claim is based on a sample size of two men (Grumbach and Auchus, 1999), which is inadequate to draw wider conclusions. Cooke et al. (2017) helpfully review several more cases to support this hypothesis. This line of evidence, however, also concerns men and cannot be extrapolated to females. Recent reviews have argued that estrogen aromatized through testosterone is required for masculinization of the male brain (Cooke et al., 2017; Varshney and Nalvarte, 2017). However, Motta-Mena and Puts's (2017) review—especially the second and third points discussed above—rightfully calls for a critical readjustment of that hypothesis in human males. What we highlight is that in rats and supposedly in humans, brain masculinization occurring when testosterone is aromatized into estrogen affects the size of the hypothalamic preoptic area SDN-POA (Cooke et al., 2017; Morris et al., 2004). This area controls sexual behavior and is larger in males than in females due to cell death occurring naturally after 4 years postnatally (Morris et al., 2004; Swaab and Hofman, 1988). Treating developing female rats with estradiol or other estrogens—including the xenoestrogens genistein and zearalenone—increases the volume of the SDN-POA, reducing female-typical sexual behavior and increasing male-typical sexual behavior (de Jonge et al., 1988; Döhler et al., 1984; Faber and Hughes, 1991; MacLusky and Naftolin, 1981). These findings correspond with the effect of prenatal diethylstilbestrol (DES) exposure on women. A synthetic estrogen, prenatal DES exposure increases women's likelihood of behaving bisexually or homosexually in adulthood, indicating heightened brain masculinization (Ehrhardt et al., 1985; Meyer-Bahlburg et al., 1995; cf. similar findings in rhesus monkeys by Goy and Deputte, 1996). Whether DES exposure affects the size of the SDN-POA in humans is not known, but in female rats, pre- and postnatal treatment with DES increases SDN-POA size to match that of a male (Döhler et al., 1984; Tarttelin and Gorski, 1988). Importantly, while SHBG has high binding affinity to endogenous estrogens, it has low or zero binding affinity to a number of xenoestrogens, including DES and genistein, which bind to estrogen receptors with moderate to strong affinity (Hong et al., 2015). This can potentially lead to heightened estrogenic masculinization in women, as in those exposed to DES. Taken together, these observations question Motta-Mena and Puts's (2017) conclusion that estrogen “has a limited role, if any, in masculinizing the human brain and behavior”. References Cooke, P.S., Nanjappa, M.K., Ko, C., Prins, G.S., Hess, R.A., 2017. Estrogens in male physiology. Physiol. Rev. 97, 995–1043. http://dx.doi.org/10.1152/physrev.00018.2016. Döhler, K.D., Coquelin, A., Davis, F., Hines, M., Shryne, J.E., Gorski, R.A., 1984. Pre-and postnatal influence of testosterone propionate and diethylstilbestrol on differentiation of the sexually dimorphic nucleus of the preoptic area in male and female rats. Brain Res. 302, 291–295. Ehrhardt, A.A., Meyer-Bahlburg, H.F., Rosen, L.R., Feldman, J.F., Veridiano, N.P., Zimmerman, I., McEwen, B.S., 1985. Sexual orientation after prenatal exposure to exogenous estrogen. Arch. Sex. Behav. 14, 57–77. http://dx.doi.org/10.1016/j.yhbeh.2017.07.017 Received 26 June 2017; Accepted 29 July 2017 0018-506X/ © 2017 Elsevier Inc. All rights reserved.
Hormones and Behavior 97 (2018) 1–2 Faber, K.A., Hughes Jr., C.L., 1991. The effect of neonatal exposure to diethylstilbestrol, genistein, and zearalenone on pituitary responsiveness and sexually dimorphic nucleus volume in the castrated adult rat. Biol. Reprod. 45, 649–653. Goy, R.W., Deputte, B.L., 1996. The effects of diethylstilbestrol (DES) before birth on the development of masculine behavior in juvenile female rhesus monkeys. Horm. Behav. 30, 379–386. Grumbach, M.M., Auchus, R.J., 1999. Estrogen: consequences and implications of human mutations in synthesis and action. J. Clin. Endocrinol. Metab. 84, 4677–4694. Hong, H., Branham, W.S., Ng, H.W., Moland, C.L., Dial, S.L., Fang, H., ... Tong, W., 2015. Human sex hormone-binding globulin binding affinities of 125 structurally diverse chemicals and comparison with their binding to androgen receptor, estrogen receptor, and α-fetoprotein. Toxicol. Sci. 143, 333–348. http://dx.doi.org/10.1093/toxsci/kfu231. de Jonge, F.H., Muntjewerff, J.W., Louwerse, A.L., Van de Poll, N.E., 1988. Sexual behavior and sexual orientation of the female rat after hormonal treatment during various stages of development. Horm. Behav. 22, 100–115. Koebele, S.V., Bimonte-Nelson, H.A., 2015. Trajectories and phenotypes with estrogen exposures across the lifespan: what does Goldilocks have to do with it? Horm. Behav. 74, 86–104. http://dx.doi.org/10.1016/j.yhbeh.2015.06.009. MacLusky, N.J., Naftolin, F., 1981. Sexual differentiation of the central nervous system. Science 211 (4488), 1294–1302. Meyer-Bahlburg, H.F., Ehrhardt, A.A., Rosen, L.R., Gruen, R.S., Veridiano, N.P., Vann, F.H., Neuwalder, H.F., 1995. Prenatal estrogens and the development of homosexual orientation. Dev. Psychol. 31, 12–21. Morris, J.A., Jordan, C.L., Breedlove, S.M., 2004. Sexual differentiation of the vertebrate nervous system. Nat. Neurosci. 7, 1034–1039. Motta-Mena, N.V., Puts, D.A., 2017. Endocrinology of human female sexuality, mating, and reproductive behavior. Horm. Behav. 91, 19–35. http://dx.doi.org/10.1016/j.yhbeh.2016.11. 012. Swaab, D.F., Hofman, M.A., 1988. Sexual differentiation of the human hypothalamus: ontogeny of the sexually dimorphic nucleus of the preoptic area. Dev. Brain Res. 44, 314–318. Tarttelin, M.F., Gorski, R.A., 1988. Postnatal influence of diethylstilbestrol on the differentiation of the sexually dimorphic nucleus in the rat is as effective as perinatal treatment. Brain Res. 456, 271–274. Varshney, M., Nalvarte, I., 2017. Genes, gender, environment, and novel functions of estrogen receptor beta in the susceptibility to neurodevelopmental disorders. Brain Sci. 7, 24. http:// dx.doi.org/10.3390/brainsci7030024.
Severi Luoto,,, Markus J. Rantala, English, Drama and Writing Studies, University of Auckland, 1010 Auckland, New Zealand School of Psychology, University of Auckland, 1010 Auckland, New Zealand Department of Biology, University of Turku, FIN-20014 Turku, Finland Turku Brain and Mind Center, University of Turku, FIN-20014 Turku, Finland E-mail address: [email protected]
⁎
Corresponding author at: English, Drama and Writing Studies, University of Auckland, 1010 Auckland, New Zealand.
2
Contents lists available at ScienceDirect
Hormones and Behavior journal homepage: www.elsevier.com/locate/yhbeh
On estrogenic masculinization of the human brain and behavior
MARK
A R T I C L E I N F O Keywords: Estrogen Masculinization Hormones Neurodevelopment Endocrine disruptor Sex hormone-binding globulin
Motta-Mena and Puts (2017) have recently reviewed the endocrinological substrates of human female sexuality. We feel that it is necessary to point out a shortcoming in their review, since their claim that estrogen “has a limited role, if any, in masculinizing the human brain and behavior” does not stand up to close scrutiny, especially when applied to females. The first line of evidence used by the authors to support this argument concerns the putatively low binding affinity for estrogen that human alpha-fetoprotein (AFP) has. However, this is insufficient evidence for the argument that “then ovarian estrogens would presumably cross the bloodbrain barrier and masculinize the human female brain”. The authors disregard that the sex hormone-binding globulin (SHBG) has a similar function to rodent AFP in humans, binding to endogenous estrogens with high affinity (Hong et al., 2015; Varshney and Nalvarte, 2017). Motta-Mena and Puts's (2017) second line of evidence is based on genetically male (46, XY) CAIS individuals who develop feminine gender expression despite producing normal-to-high male levels of testosterone. This line of evidence is based on genetic males and cannot be extrapolated to females (cf. Koebele and Bimonte-Nelson, 2015). As third line of evidence, Motta-Mena and Puts state that human males with mutations rendering the aromatase enzyme dysfunctional typically present as normal males. This claim is based on a sample size of two men (Grumbach and Auchus, 1999), which is inadequate to draw wider conclusions. Cooke et al. (2017) helpfully review several more cases to support this hypothesis. This line of evidence, however, also concerns men and cannot be extrapolated to females. Recent reviews have argued that estrogen aromatized through testosterone is required for masculinization of the male brain (Cooke et al., 2017; Varshney and Nalvarte, 2017). However, Motta-Mena and Puts's (2017) review—especially the second and third points discussed above—rightfully calls for a critical readjustment of that hypothesis in human males. What we highlight is that in rats and supposedly in humans, brain masculinization occurring when testosterone is aromatized into estrogen affects the size of the hypothalamic preoptic area SDN-POA (Cooke et al., 2017; Morris et al., 2004). This area controls sexual behavior and is larger in males than in females due to cell death occurring naturally after 4 years postnatally (Morris et al., 2004; Swaab and Hofman, 1988). Treating developing female rats with estradiol or other estrogens—including the xenoestrogens genistein and zearalenone—increases the volume of the SDN-POA, reducing female-typical sexual behavior and increasing male-typical sexual behavior (de Jonge et al., 1988; Döhler et al., 1984; Faber and Hughes, 1991; MacLusky and Naftolin, 1981). These findings correspond with the effect of prenatal diethylstilbestrol (DES) exposure on women. A synthetic estrogen, prenatal DES exposure increases women's likelihood of behaving bisexually or homosexually in adulthood, indicating heightened brain masculinization (Ehrhardt et al., 1985; Meyer-Bahlburg et al., 1995; cf. similar findings in rhesus monkeys by Goy and Deputte, 1996). Whether DES exposure affects the size of the SDN-POA in humans is not known, but in female rats, pre- and postnatal treatment with DES increases SDN-POA size to match that of a male (Döhler et al., 1984; Tarttelin and Gorski, 1988). Importantly, while SHBG has high binding affinity to endogenous estrogens, it has low or zero binding affinity to a number of xenoestrogens, including DES and genistein, which bind to estrogen receptors with moderate to strong affinity (Hong et al., 2015). This can potentially lead to heightened estrogenic masculinization in women, as in those exposed to DES. Taken together, these observations question Motta-Mena and Puts's (2017) conclusion that estrogen “has a limited role, if any, in masculinizing the human brain and behavior”. References Cooke, P.S., Nanjappa, M.K., Ko, C., Prins, G.S., Hess, R.A., 2017. Estrogens in male physiology. Physiol. Rev. 97, 995–1043. http://dx.doi.org/10.1152/physrev.00018.2016. Döhler, K.D., Coquelin, A., Davis, F., Hines, M., Shryne, J.E., Gorski, R.A., 1984. Pre-and postnatal influence of testosterone propionate and diethylstilbestrol on differentiation of the sexually dimorphic nucleus of the preoptic area in male and female rats. Brain Res. 302, 291–295. Ehrhardt, A.A., Meyer-Bahlburg, H.F., Rosen, L.R., Feldman, J.F., Veridiano, N.P., Zimmerman, I., McEwen, B.S., 1985. Sexual orientation after prenatal exposure to exogenous estrogen. Arch. Sex. Behav. 14, 57–77. http://dx.doi.org/10.1016/j.yhbeh.2017.07.017 Received 26 June 2017; Accepted 29 July 2017 0018-506X/ © 2017 Elsevier Inc. All rights reserved.
Hormones and Behavior 97 (2018) 1–2 Faber, K.A., Hughes Jr., C.L., 1991. The effect of neonatal exposure to diethylstilbestrol, genistein, and zearalenone on pituitary responsiveness and sexually dimorphic nucleus volume in the castrated adult rat. Biol. Reprod. 45, 649–653. Goy, R.W., Deputte, B.L., 1996. The effects of diethylstilbestrol (DES) before birth on the development of masculine behavior in juvenile female rhesus monkeys. Horm. Behav. 30, 379–386. Grumbach, M.M., Auchus, R.J., 1999. Estrogen: consequences and implications of human mutations in synthesis and action. J. Clin. Endocrinol. Metab. 84, 4677–4694. Hong, H., Branham, W.S., Ng, H.W., Moland, C.L., Dial, S.L., Fang, H., ... Tong, W., 2015. Human sex hormone-binding globulin binding affinities of 125 structurally diverse chemicals and comparison with their binding to androgen receptor, estrogen receptor, and α-fetoprotein. Toxicol. Sci. 143, 333–348. http://dx.doi.org/10.1093/toxsci/kfu231. de Jonge, F.H., Muntjewerff, J.W., Louwerse, A.L., Van de Poll, N.E., 1988. Sexual behavior and sexual orientation of the female rat after hormonal treatment during various stages of development. Horm. Behav. 22, 100–115. Koebele, S.V., Bimonte-Nelson, H.A., 2015. Trajectories and phenotypes with estrogen exposures across the lifespan: what does Goldilocks have to do with it? Horm. Behav. 74, 86–104. http://dx.doi.org/10.1016/j.yhbeh.2015.06.009. MacLusky, N.J., Naftolin, F., 1981. Sexual differentiation of the central nervous system. Science 211 (4488), 1294–1302. Meyer-Bahlburg, H.F., Ehrhardt, A.A., Rosen, L.R., Gruen, R.S., Veridiano, N.P., Vann, F.H., Neuwalder, H.F., 1995. Prenatal estrogens and the development of homosexual orientation. Dev. Psychol. 31, 12–21. Morris, J.A., Jordan, C.L., Breedlove, S.M., 2004. Sexual differentiation of the vertebrate nervous system. Nat. Neurosci. 7, 1034–1039. Motta-Mena, N.V., Puts, D.A., 2017. Endocrinology of human female sexuality, mating, and reproductive behavior. Horm. Behav. 91, 19–35. http://dx.doi.org/10.1016/j.yhbeh.2016.11. 012. Swaab, D.F., Hofman, M.A., 1988. Sexual differentiation of the human hypothalamus: ontogeny of the sexually dimorphic nucleus of the preoptic area. Dev. Brain Res. 44, 314–318. Tarttelin, M.F., Gorski, R.A., 1988. Postnatal influence of diethylstilbestrol on the differentiation of the sexually dimorphic nucleus in the rat is as effective as perinatal treatment. Brain Res. 456, 271–274. Varshney, M., Nalvarte, I., 2017. Genes, gender, environment, and novel functions of estrogen receptor beta in the susceptibility to neurodevelopmental disorders. Brain Sci. 7, 24. http:// dx.doi.org/10.3390/brainsci7030024.
Severi Luoto,,, Markus J. Rantala, English, Drama and Writing Studies, University of Auckland, 1010 Auckland, New Zealand School of Psychology, University of Auckland, 1010 Auckland, New Zealand Department of Biology, University of Turku, FIN-20014 Turku, Finland Turku Brain and Mind Center, University of Turku, FIN-20014 Turku, Finland E-mail address: [email protected]
⁎
Corresponding author at: English, Drama and Writing Studies, University of Auckland, 1010 Auckland, New Zealand.
2