Steinach and Young, Discoverers of the Effects of Estrogen on Male Sexual Behavior and the “Male Brain”

This Accepted Manuscript has not been copyedited and formatted. The final version may differ from this version. Research Article: History of Neuroscience | History, Teaching, and Public Awareness Steinach and Young, discoverers of the effects of estrogen on male sexual behavior and the “male brain” History of estrogen and the male brain Per Södersten Section of Applied Neuroendocrinology, Karolinska Institutet, S-141 04 Huddinge, Sweden DOI: 10.1523/ENEURO.0058-15.2015 Received: 30 May 2015 Revised: 16 October 2015 Accepted: 20 October 2015 Published: 2 November 2015 Author contributions: P.S. wrote the paper. Conflict of Interest: Authors report no conflict of interest. Correspondence should be addressed to either Karolinska Institutet, Section of Applied Neuroendocrinology, S-141 04 Huddinge, Sweden, Email: [email protected] Cite as: eNeuro 2015; 10.1523/ENEURO.0058-15.2015 Alerts: Sign up at eneuro.org/alerts to receive customized email alerts when the fully formatted version of this article is published. Accepted manuscripts are peer-reviewed but have not been through the copyediting, formatting, or proofreading process. This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution and reproduction in any medium provided that the original work is properly attributed. Copyright © 2015 Society for Neuroscience eNeuro http://eneuro.msubmit.net eN-HON-0058-15R2 Steinach and Young, discoverers of the effects of estrogen on male sexual behavior and the "male brain" This is a confidential document and must not be discussed with others, forwarded in any form, or posted on websites without the express written consent of eNeuro. 1 Steinach and Young, discoverers of the effects of estrogen on male sexual behavior and 2 the “male brain” 3 Abbreviated Title: History of estrogen and the male brain 4 P. Södersten, Karolinska Institutet, Section of Applied Neuroendocrinology, S-141 04 5 Huddinge, Sweden, Email: [email protected] 6 Figures: 3 7 Abstract: 225 words 8 Significance Statement: 108 words 9 Introduction: 326 words 10 Discussion: Major part of the manuscript 11 Acknowledgments: I thank Ann-Mari Dumanski and Göran K. Hansson of the Medical 12 Nobel Institute for permission to read and translate the evaluation of Steinach for the Nobel 13 Prize, David Crews, Cheryl Logan, and Rudolf Werner Soukup for advice, Thore Grimm of 14 the Bayer Company, Berlin, for outlining the history of 17β EB, the Endocrine Society for 15 permission to redraw the data in Phoenix et al. (1959) as Fig. 1, Springer for permission to 16 reproduced Fig. 2 from Hohlweg et al. (1962), and John Wiley for permission to reproduce 17 Fig. 1A from Olster and Blaustein (1990). 18 Conflict of Interest: No 19 Funding Sources: None 1 20 Abstract 21 In the 1930s Eugen Steinach´s group found that estradiol induces lordosis in castrated rats and 22 reduces the threshold dose of testosterone necessary for induction of ejaculation, and that 23 estradiol-treated intact rats display lordosis as well as mounting and ejaculation. The bisexual, 24 estrogen-sensitive male had been demonstrated. Another major, albeit contrasting, discovery 25 was made in the 1950s, when William Young´s group reported that male guinea pigs and 26 prenatally testosterone-treated female guinea pigs are relatively insensitive to estrogen when 27 tested for lordosis as adults. Reduced estrogen-sensitivity was part of the new concept of 28 organization of the neural tissues mediating sexual behavior of females, into tissues similar to 29 those of males. The importance of neural organization by early androgen stimulation was 30 realized immediately and led to the discovery of a variety of sex difference in the brain of 31 adult animals. By contrast, the importance of metabolism of testosterone into estrogen in the 32 male was recognized only after a delay. While the finding that males are sensitive to estrogen 33 was based on Bernhard Zondek´s discovery in 1934 that testosterone is metabolized to 34 estrogen in males, the finding that males are insensitive to estrogen was based on the 35 hypothesis that testosterone - male sexual behavior is the typical relationship in the male. It is 36 suggested that this difference in theoretical framework explains the discrepancies in some of 37 the reported results. 38 39 40 41 42 2 43 Significance Statement 44 In 1936, the importance of estrogen in male sexual behavior was discovered. This finding 45 went unnoticed when estrogen´s effect in the male was re-discovered in the early 1970s; the 46 original report of the effect of estrogen in the male in 1936 was found only in 2012. An 47 equally significant discovery was made in 1959, when it was found that prenatal treatment 48 with testosterone organizes the brain of a female into a male brain and permanently decreases 49 behavioral estrogen sensitivity. Males cannot be both sensitive and insensitive to estrogens 50 and this inconsistency may have contributed to the long latency before the significance of 51 estrogen in the male was recognized. 3 52 Introduction 53 The hypothesis that estrogen, formed in the brain from testosterone in the circulation, is 54 important for sexual behavior in male rats is often dated to 1970 (McDonald et al., 1970). 55 However, the idea was launched 34 years earlier in a report by Steinach et al. (1936; 56 translated in Södersten et al., 2014), which was not mentioned when the effect of estrogen 57 was re-discovered in the early 1970s (Södersten, 2012). Thus, the original paper, which 58 demonstrated that a behaviorally ineffective dose of estradiol benzoate (EB) synergizes with a 59 likewise behaviorally ineffective dose of testosterone in restoring ejaculation in castrated rats, 60 hibernated for a long time although it was reviewed in detail in 1938 when Steinach was 61 nominated for the seventh time for the Nobel Prize (Liljestrand, 1938). In evaluating 62 Steinach´s work, including the finding that EB stimulates female sexual behavior in male rats, 63 the Nobel Prize committee acknowledged the behavioral bipotential of the sexes as one of 64 Steinach´s major contributions (Liljestrand, 1938). 65 Steinach´s hypothesis that the behavioral sex of an animal is reversible by treatment with 66 the hormones of the opposite sex was challenged in the 1950s, when it was discovered that 67 the behavioral sensitivities to gonadal hormones are unequally distributed both within and 68 between the sexes (Grunt and Young, 1952; Phoenix et al., 1959). Most important, these 69 authors demonstrated that the sensitivities to gonadal hormones of adult animals are 70 determined by exposure to testosterone in early development. This discovery stimulated the 71 search for sex differences in the brain which are causally related to sex differences in sexual 72 behavior. This was a major step ahead; the field flourished focusing on the following key 73 concepts: hormone specificity, tissue sensitivity, activation and organization of the tissues 74 mediating mating behavior, and the associated idea that males are relatively insensitive to 75 estrogen (Phoenix et al., 1959; Young, 1961). 4 76 It is suggested that the emergence of these ideas is why the significance of Steinach´s work 77 was not recognized immediately by behavioral neuroendocrinologists. 78 Discovery of the Effects of Estrogen in Male Rats 79 When in the 1930s, synthetic gonadal hormones replaced transplantation of the gonads, the 80 method that Steinach had used to demonstrate sex reversal of reproductive behavior and 81 anatomy, his group published two studies on the effects of estrogen in male rats. 82 Lordosis in castrated rats and lordosis and ejaculation in intact rats 83 In the first study, Kun (1934) castrated rats at 4-6 months of age and 3-11 months later, the 84 rats were injected once with EB, and tested with males 48 hours later. With 2.9 μg EB, only 1 85 of 4 rats showed lordosis, but with 5.8 μg EB or more, all rats responded. Intact, sexually 86 active rats injected with a higher dose, 23.2 μg EB, also showed lordosis when tested with 87 males and continued ejaculating when tested with females; their bisexual behavior was 88 highlighted in the title of the paper. 89 Although the behavior was reported as all-or-none rather than quantitatively in these 90 experiments, it should be recognized that at the time, many scientists questioned whether 91 behavior can be measured at all and even if it is possible to use mathematical model in 92 biology (Beach, 1981; Södersten, 2012). Despite these constraints, the methods permitted the 93 demonstration that the dose of EB necessary for induction of lordosis in intact rats is higher 94 than the dose needed in castrated rats, a finding that has been replicated using modern 95 methods (Butler et al., 2001). 96 A note of hormone doses is appropriate at the beginning of this overview. The ovarian 97 hormone that produces estrus was referred to as Folliculin, estrin, Progynon, or theelin 98 (theelus is the Greek for female). The Schering AG launched 17β estradiol benzoate (17β 5 99 EB), Progynon, in 1928. One “dragée” contained 250 ME estradiol [1,3,5(10)-estratrien- 100 3,17β-diol]. The ME (Mäuseeinheit - Mouse Unit, MU) was subsequently replaced by IE 101 (Internationale Einheit - International Unit, IU). Because the effect of the estrogen 102 preparations varied depending on their purity and the maintenance conditions of the animals 103 the doses used in the different experiments are not necessarily comparable. Progynon B, 1 mg 104 17β EB (50.000 - 80.000 IU)/ml oil was launched in 1932. This is the EB commonly used in 105 behavioral research.

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