Roslyn Holly Fitch (1995) Studying the Complexity of Sexual Differentiation. Psycoloquy: 6(25) Sex Brain (5)

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Psycoloquy 6(25): Studying the Complexity of Sexual Differentiation

Reply to Forgie on Fitch & Denenberg on Sex-Brain

Roslyn Holly Fitch
Center for Molecular and Behavioral Neuroscience
Rutgers University
197 University Ave.
Newark, NJ 07102

Victor H. Denenberg
Biobehavioral Sciences Graduate Degree Program
University of Connecticut
Storrs, CT 06269-4154


Forgie (1995) notes the complexity of the feminization process, and suggests that Fitch and Denenberg (1995) take a narrow view in presenting data concerning the role of ovarian hormones in development of the female brain. While recognizing the importance of a comprehensive view towards sexual differentiation, we note that: (1) a researcher may focus on a delineated dataset without asserting, by default, that other factors are unimportant; (2) our target article encompasses references which specifically expand the definition of feminization (e.g., to include cyclic ovarian effects on neurochemistry and neurophysiology) and; (3) our findings are not inconsistent with data she presents.


corpus callosum, development, estrogen, feminization, ovaries, sensitive period.
1. The main point made by Forgie (1995) is to emphasize that other factors influence the feminization process besides exposure to ovarian hormones in a circumscribed pre-pubertal period: specifically, an XX genotype, an absence of exposure to high levels of testicular androgens (or estrogens) in the perinatal period, and exposure to ovarian steroids prepubertally and throughout adulthood (presumably including cyclic activational effects). These factors basically define a female. She describes our failure to address these variables as "over-simplified," "misleading," short-sighted," and "perpetuating a myth of `single' causal factors." Though she agrees with what we have written, she apparently views our failure to go far enough as a fatal flaw, and states that "only when we begin to acknowledge and understand the importance of the interactions of all these factors (which include different neural systems, different components of the same system, the state of the nervous system at the time each event occurs, knowledge of all prior events that have occurred, and other hormonal and genetic factors) over the life span of the animal will we begin to understand the true underpinnings of sexually dimorphic differentiation of brain and behavior" (Forgie, 1995, par. 5).

2. Although her point is technically valid, it is nevertheless true that each researcher cannot experimentally address every variable that might affect a system under study. Most researchers understand that a multiplicity of factors influence sexual differentiation, yet may select a subset of these variables to study over a period of years in attempts to understand the relationships and dynamics of these selected variables. This reflects a standard rule of science, which is to reduce complexity to simplicity. With respect to sexual differentiation, the original hypothesis that testosterone exposure produced a male, while a female developed by default in the absence of androgen, was an elegant simplification (NOT over-simplification) that advanced our understanding of sexual differentiation enormously. We now recognize that this hypothesis is inadequate to account for experimental observations, and that ovarian hormones play an active role as well. Still, there are as-yet-unstudied variables which will, in all likelihood, one day be added to the standard model of sexual differentiation. We comment in our target article, for example, that "several key parameters have been found which interact with sex differences in the human CC [corpus callosum]: age, CC region, degree of hand preference, and direction of hand preference" (Fitch and Denenberg, 1995, par. 53). We note that our studies on sexual differentiation of the rat callosum have not yet examined the role of these or equivalent variables.

3. This said, it is apparent that our experimental findings are not at odds with those of Forgie. She notes that exposure of female rats to neonatal testosterone propionate (TP) was sufficient to produce a male-like pattern of dopaminergic (DA) responsiveness to amphetamine (AMPH), while castration of males produced a female-like pattern, arguing that an early absence of androgen remains a pivotal feminizing factor (Forgie and Stewart, 1993, 1994; Forgie, 1995). Similarly, we found that exposure to TP in the early neonatal period was sufficient to masculinize callosal size in female rats even with the ovaries intact, and state that "testosterone exposure in infancy combined with handling stimulation is sufficient to enlarge the female callosum to the size of the male" (Fitch and Denenberg, 1995, par. 55). We also found that a combination of prenatal and postnatal androgen removal in males reduced callosal size to that seen in females (Fitch et al., 1991a; Fitch and Denenberg, 1995). Consistent with these results, we suggest in our target article that ovarian hormones play a parallel -- not over-riding -- role in relation to the masculinization process.

4. Forgie also found that, in the absence of early androgen exposure, prepubertal removal of the ovaries exerted defeminizing effects on DA responsiveness to AMPH (Forgie and Stewart, 1994). It is not clear from the current commentary (Forgie, 1995) when these females were ovariectomized, and whether any differences in sensitive period to the effects of TP treatment versus ovariectomy on DA responsiveness were investigated. Nevertheless, her results are not incompatible with our findings or conclusions, since we found ovariectomy on postnatal day 8 (P8), 12 or 16 to exert defeminizing effects on callosal size in the absence of early androgen exposure (Fitch et al., 1991b; Mack et al., 1993; Fitch and Denenberg, 1995).

5. Interestingly, though we did not discuss this observation in our target article, the effects of removing exposure to gonadal hormones in males (via prenatal treatment with flutamide and P1 castration; Fitch et al., 1991a) and in females (via P8, 12, or 16 ovariectomy; Fitch et al., 1991b) did NOT result in callosa of equivalent size, as one might expect (representing gonadally "ahormonal" preparations differing in genotype). These differential outcomes may represent the effects of sexually dimorphic hormone receptor populations or other unknown factors of genetic origin, interacting differentially with later hormone exposure (or the absence of gonadal hormones). Such would not be inconsistent with Forgie's report of sexual dimorphism in the DA system prior to embryonic day 17 (Forgie, 1995), nor her assertion that the expression of sexual dimorphism in the nervous system depends on all prior events (including genetic factors) in an interactive fashion.

6. Next, though we did not find evidence of circulating hormonal effects on callosal size, we did attempt to pull in this literature which has typically not been included in discussions of sexual differentiation. We state that "the cyclic nature of the female brain has its roots in the way the brain was organized initially. Thus, cyclicity per se is a permanent (organizational) feature of the female brain. In as much as cyclic hormonal changes induce specific neural alterations [such as variations in AMPH induced release of DA over the estrous cycle; Becker and Cha, 1989), such effects characterize the female brain and thus would appear to fall under the rubric of sexual differentiation" (Fitch and Denenberg, 1995, par. 6).

7. Finally, we would emphasize again the main and heretofore relatively over-looked point that ovarian hormones do contribute significantly to the development of the female brain. In this regard, we and Forgie appear to be in agreement.


Becker, J.B. & Cha, J. (1989) Estrous-cycle variation in amphetamine induced behaviors and striatal dopamine release assessed with microdialysis. Behavioral Brain Research 35: 117-125.

Fitch, R.H., Cowell, P.E., Schrott, L.M. & Denenberg, V.H. (1991a) Corpus callosum: perinatal anti-androgen and callosal demasculinization. International Journal of Developmental Neuroscience 9: 35-38.

Fitch, R.H., Cowell, P.E., Schrott, L.M. & Denenberg, V.H. (1991b) Corpus callosum: ovarian hormones and feminization. Brain Research 542: 313-317.

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.

Forgie, M.L. (1995) Are Ovarian Secretions All That Females "Need"? PSYCOLOQUY 6(5) sex-brain.3.forgie.

Forgie, M.L. & Stewart, J. (1994) Effect of prepubertal ovariectomy on amphetamine-induced locomotion in adult female rats. Hormones and Behavior 28: 241-260.

Forgie, M.L. & Stewart, J. (1993) Sex differences in amphetamine- induced locomotor activity in adult rats: Role of testosterone exposure in the neonatal period. Pharmacology Biochemistry & Behavior 46: 637-645.

Mack, C.M., Fitch, R.H., Cowell, P.E., Schrott, L.M. & Denenberg, V.H. (1993) Ovarian estrogen acts to feminize the rat's corpus callosum. Developmental Brain Research 71: 115-119.

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