The role of estrogen in differentiating the sexes may not be as clearly defined as Fitch & Denenberg would have us believe. Although their presentation of the feminizing role for estrogen was intriguing, I question whether it can be so easily categorized and wonder where the research on estrogen's masculinizing role fits into their model.
2. Since the early 1970s, it has been well established in the animal literature that testosterone becomes aromatized to estradiol (a compound structurally similar to estrogen) by the enzyme aromatase complex. It is then in this estrogen form that testosterone exerts its masculinizing effect on both the male and the female brain (MacLusky & Naftolin, 1981). In fact, estrogenic hormones are believed to be "the active agents organizing the brains of rodents" (Breedlove, 1994). Evidence for aromatization initially came from studies administrating estrogen antagonists (such as MER-25). These antagonists were found to block testosterone treatment in neonatal female rats, suggesting that "estrogen formation might play an important part in mediating the developmental effects of testosterone" (MacLusky & Naftolin, 1981).
3. Numerous studies have demonstrated that when developing female rats are exposed to exogeneous estrogen, as adults they can fail to ovulate, they are unlikely to display the feminine lordosis reflex, they are more likely to demonstrate the male-typical mounting behaviour, and they tend to possess a large, male-like sexually dimorphic nucleus of the preoptic area (Dohler et al., 1982; Hendricks, 1969; Hines, Alsum, Roy, Gorski & Goy, 1987; Mullins & Levine, 1968; Whalen & Nadler, 1963). In all of these studies, estrogen was affecting the development of mammalian feminine sexual differentiation in much the same way as early exposure to testosterone (MacLusky & Naftolin, 1981). This general model for perinatal hormone influences on sexual differentiation of brain and behaviour has not only been supported in rats, hamsters, and mice, but also in part in gerbils, dogs, guinea pigs, cattle, ferrets, sheep, marmoset, rhesus monkeys, and several avian species (see Hines, 1982, for a review).
4. Further evidence for the aromatization hypothesis comes from research on estrogen receptors in the male brain; MacLusky, Naftolin and Goldman-Rakic (1986) described estrogen receptors throughout the male brain, with the highest concentrations found in the hypothalamus-preoptic area. In these areas of high concentration, aromatase complex activity is also detected, suggesting that it is "locally-formed estrogen that may be involved in the effects of circulating androgens on the developing primate neocortex" (MacLusky et al., 1986). Support for the active role of these estrogen receptors also comes from research on Tfm male rats. These rats have severely reduced levels of androgen receptors compared to their normal siblings but show normal CNS levels of both estrogen receptors and aromatase. If androgen-specific receptor mechanisms played a role in the actions of testosterone in the developing brain, then Tfm male rats should not undergo brain sexual differentiation. In fact, these rats experience normal differentiation (MacLusky & Naftolin, 1981). Therefore, estrogen formation plays a vital and primary role in the sexual differentiation of the male central nervous system, "masculinizing" the male brain. The fact that estrogen, at least in part, exerts a masculinizing effect in both the male and the female suggests that its role is not as well defined as Fitch & Denenberg indicated in their article.
5. A question that arises from these studies implicating estrogen's role as one of masculinization is how does the developing female mammal protect itself from a masculine fate? In order to protect the developing female from the masculinizing effects of maternally- and placentally-produced estrogens, there is a plasma estrogen binding protein (fetoneonatal estrogen binding protein, or FEBP) that sequesters estrogens but not androgens (Breedlove, 1994). FEBP is known to circulate in high concentrations during the later part of gestation and then it gradually disappears over the first few weeks of postnatal life (MacLusky & Naftolin, 1981). Consequently, in females, FEBP binds to circulating estrogen rendering its action ineffective. However, in males, testosterone ignores this binding protein, enters the brain and is then intracellularly aromatized to estrogen. As FEBP cannot bind intracellularly, this intracellularly aromatized estrogen can then alter neuronal development in the male (Breedlove, 1994). Consequently, females are protected from the masculinizing effect of estrogen but males are not. Although it is certainly possible that not all estrogen is bound to FEBP and that the remaining estrogen does feminize the brain, it is necessary for studies on estrogen to include FEBP as a potential mediating factor and to then offer evidence that above and beyond the protective effect of FEBP, estrogen is still the hormone responsible for feminizing the female brain.
6. Research on estrogen in human development also questions estrogen's primarily feminizing effect. Although the aromatization hypothesis has not been confirmed in human research and there is some question of its applicability to human sexual differentiation, nevertheless, there is evidence that estrogen's role in human development can also be, in part, one of masculinization (Breedlove, 1994; Hines & Collaer, 1991; Reinisch, Ziemba-Davis & Sanders, 1991). Certainly, the enormous amount of research performed in this area does support estrogen as a partial masculinizing agent. However, estrogen's role appears to vary according to the variables being studied, the form in which it is administered to humans and the time period in which it is given (see Reinisch et al., 1991 for an excellent review of 19 studies on the behavioural effects of prenatal exposure to hormones administered for the treatment of at-risk human pregnancies).
7. One of the most intriguing but complex bodies of research on human hormones comes from studies on synthetic estrogens. Diethylstilbestrol (DES), a synthetic estrogen, has been found in both animal and human research to play mostly a masculinizing role (although there is also a subtle feminizing role) in sexual differentiation of the brain (Hines, 1982; Hines & Shipley, 1984; Reinisch et al., 1991; Schachter, 1994). For example, women exposed to DES prenatally have been found to have increased spatial skills (i.e., skills more similar to males [Meyer-Bahlburg, Feldman, Cohen & Ehrhardt, 1988]), higher prevalence of homosexuality (Ehrhardt et al., 1985) but hypomasculinized play behaviour (Meyer-Bahlburg et al., 1988). Further, this research supports the FEBP protection hypothesis in that FEBP may not recognize DES and thus would not bind it. Consequently, DES would act in a fashion similar to testosterone, providing an explanation as to the reported masculinization of females exposed to DES prenatally.
8. If it is actually estrogen and not testosterone that mediates male development and if females are protected from estrogen by FEBP but are masculinized by exogeneous estrogens, it follows that estrogen is not the powerful feminizing agent as described by Fitch & Denenberg. Certainly, Fitch & Denenberg review a wealth of research that implicates estrogen's role as a feminizing agent; however, it appears that when one takes into account the large and significant area of research on its masculinizing effect, both in males and females, it appears that estrogen's role may not be that simple. Although consideration of the aromatization hypothesis and the action of FEBP should not preclude the strong arguments in favour of estrogen's role as a feminizing agent for some variables, they need to be incorporated into Fitch & Denenberg's model of sexual differentiation of the central nervous system. It appears more likely that estrogen exerts different effects depending on the sex, the behaviour being investigated, and the critical period of development of that behaviour. There is a need to develop a more flexible model that acknowledges the paradoxical nature of estrogen.
Breedlove, S.M. (1994). Sexual differentiation of the human nervous system. Annual Review of Psychology, 45, 465-488.
Dohler, K.D., Hines, M., Coquelin, A., Davis, F., Shryne, J.E. & Gorski, R.A. (1982). Pre- and postnatal influence of diethylstilbestrol on differentiation of the sexually dimorphic nucleus in the preoptic area of the female rat brain. Neuroscience Letters, 4, 361-365.
Ehrhardt, A.A., Meyer-Bahlburg, H.F.L., Rosen, L.R., Feldman, J.F., Veridiano, N.P., Zimmerman, I. & McEwen, B.S. (1985). Sexual orientation after prenatal exposure to exogeneous estrogen. Archives of Sexual Behavior, 14, 57-77.
Fitch, R. H. & Denenberg, V.H. (1995). A Role for Ovarian Hormones in Sexual Differentiation of the Brain. PSYCOLOQUY 6(5) sex-brain.1.fitch.
Hendricks, S.E. (1969). Influence of neonatally administered hormones and early gonadectomy on rats' sexual behavior. Journal of Comparative Physiology and Psychology, 69, 408-413.
Hines, M. (1982). Prenatal gonadal hormones and sex differences in human behavior. Psychological Bulletin, 92, 56-80.
Hines, M., Alsum, P., Roy, M., Gorski, R.A. & Goy, R.W. (1987). Estrogenic contributions to sexual differentiation in the female guinea pig: Influences of diethylstilbestrol and tamoxifen on neural, behavioral and ovarian development. Hormones and Behavior, 21, 402-417.
Hines, M. & Collaer, M.L. (1991). Gonadal hormones and sexual differentiation of human behavior: Developments from research on endocrine syndromes and studies of brain structure. Annual Review of Sex Research, 4, 1-48.
Hines, M. & Shipley, C. (1984). Prenatal exposure to diethylstilbestrol (DES) and the development of sexually dimorphic cognitive abilities and cerebral lateralization. Developmental Psychology, 20, 81-94.
MacLusky, N.J., Naftolin, F. & Goldman-Rakic, P.S. (1986). Estrogen formation and binding in the cerebral cortex of the developing rhesus monkey. Proceedings of the National Academy of Science, 83, 513-516.
MacLusky, N.J. & Naftolin, F. (1981). Sexual differentiation of the central nervous system. Science, 211, 1294-1303.
Meyer-Bahlburg, H.F., Feldman, J.F., Cohen, P. & Ehrhardt, A.A. (1988). Perinatal factors in the development of gender-related play behavior: Sex hormones versus pregnancy complications. Psychiatry, 51, 260-271.
Mullins, R.F. & Levine, S. (1968). Hormonal determinants during infancy of adult sexual behavior in the male rat. Physiology and Behavior, 3, 339- 343.
Reinisch, J.M., Ziemba-Davis, D.M. & Sanders, S.A. (1991). Hormonal contributions to sexually dimorphic behavioral development in humans. Special issue: Neuroendocrine effects on brain development and cognition. Psychoneuroendocrinology, 16, 213-278.
Schachter, S.C. (1994). Handedness in women with intrauterine exposure to diethylstilbestrol. Neuropsychologia, 32, 619-623.
Whalen, R.E. & Nadler, R.D. (1963). Suppression of the development of female mating behavior by estradiol administration in infancy. Science, 141, 273-274.