Biology 202
1998 Third Web Reports
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The Role of Estrogen in Sexual Differentiation

Elaine Bonleon de Castro

Most, if not all, species with two sexes exhibit sexually dimorphic behavior and physical characteristics. These dimorphisms can be attributed to differences in the brain, such as size or function of structure, and these brain structures can be affected by the hormones circulated throughout the organism. It has been held that the sexual dimorphisms rely only on the presence or absence of androgen, namely, testosterone, during the critical period of development for an organism; however, new research suggests that the presence of estrogen, specifically estradiol, has an active role in sexual differentiation.

Several sexual dimorphic structures in the brain have been observed in laboratory experiments. The corpus callosum in male rats is much larger than that in female rats, and this size difference is uncorrelated with total brain weight. These findings led many to investigate the relationship between human male and female corpus callosa. A paper published by de Lacoste-Utamsing and Holloway stated that the splenium of the callosum is larger in women than in men, but their finding has since been challenged by several reports stating that there exists no sexual dimorphism. Analysis done from 1982-1994 reveals a small difference of corpus callosum size in favor of males, but it is hypothesized that age, handedness, overall brain size and weight, and incorrect statistics were not taken into account. (3)

There has also been controversy in the research involving the brain region INAH-3 in humans. The heterosexual male INAH-3 is larger than that of heterosexual females; the INAH-3 in homosexual males is on the average smaller than that of heterosexual males and approximately the same size of heterosexual females. The general population has attempted to use this fact as an explanation of the biological basis of homosexuality, though the differences in structure may not be causally related to the sexual orientation of the man. Because we can only observe behaviors when doing experiments with lab animals, the data cannot firmly establish a basis for sexual orientation.

The traditional view on sexual differentiation is that organizational effects from hormones which occur during neonatal development are the master plan for the organisms sex and corresponding behaviors and characteristics. Exposure to androgen, namely, testosterone, would result in a male organism, while exposure to neither androgen nor estrogen would result in the default sex: female.

Characteristics resulting from organizational effects include formation of genitalia and traits such as aggression. Some studies have correlated aggression in preschool boys to organizational effects of androgen. Activational effects are defined as effects which occur in the adult organism, and include reproductive and social behaviors. In the rat, such behaviors include mounting (male) and lordosis (female).

In the rat, it has been held that adult sexual behavior depends solely on organizational effects. A female treated with testosterone shortly after birth or an intact male will exhibit male behaviors no matter what activational effects may be manipulated later in life. An intact female or a neonatally castrated male will exhibit female behaviors.

The most recent research on rat brain sexual dimorphisms suggests that estrogen, namely, estradiol, has an active effect on differentiation. This contradicts previous research which states that lack of hormones causes feminization, and the female sex is developed by default in a passive mechanism. (3) It has also been shown that the sensitive period for estrogen related processes occurs at a later time than that of testosterone related processes. The definitions of organizational and activational effects have also been questioned, as some permanent changes are instilled late in life, and some temporary effects are enacted very early in development. (3, 4)

In rats, a region known as the sexually dimorphic nucleus of the preoptic area (SDN-POA) is larger in males, and administering testosterone to a female rat can increase the size of her SDN-POA. (2) The SDN-POA was said to develop in a female fashion without hormones. More recent experiments concur that a female rat pup treated with androgen will develop a larger SDN-POA, similar in size to that of a male. However, the absence of estrogen (caused by the administration of an estrogen antagonist) caused the size of the SDN-POA to decrease. This is some evidence that estrogen does not play a passive role in the critical period. This is also an example of defeminization without masculinization. (3)

It has also been noted that in male rat pups, testosterone is secreted by the testes, but it is converted to estrogen within neurons before causing developmental effects in males. Although female rat pups are also exposed to estrogen during this period, they are not masculinized; instead, they are protected by alpha-fetoprotein (AFP), which binds to estrogen and prevents it from entering the cells. Levels of AFP reach a maximum during the same period that testosterone and other androgens cause maximum masculinization. When administering synthetic estrogen (diethylstilbestrol), the SDN-POA still increases in size because this hormone does not bind to AFP. The ovaries in female rat pups do not take an active role until the AFP levels have already declined. Thus, both sexes of rat pups are exposed to estrogen which causes masculine development, except females are protected by AFP. Also, estrogen biosynthesis holds a crucial role in sexual differentiation. This data contradicts the hypotheses that claim female development is a default mechanism (since an extra process is required to keep a pup from masculinization) and that testosterone is the critical factor in sexual differentiation.

The presence or absence of ovaries during development makes a significant difference in behaviors as well. A greater lordosis response is seen in intact females who have received testosterone versus females who had neonatal ovariectomies, received testosterone, and were primed with estrogen and progesterone.

Greater proceptive behavior (such as ear-wiggling and hopping to attract the attention of the male) was seen in females who had post-pubertal ovariectomies compared to those who had neonatal ovariectomies. Males who had testes removed and ovaries transplanted into them also had stronger female proceptive behaviors than those who only had testes removed.

Non-reproductive behavior, such as behavior in open fields and plus mazes, was also affected by neonatal ovariectomies. Females who had ovariectomies behaved as males in open fields, which would not be expected under the hypothesis that absence of hormone would lead to a female development. Meanwhile, androgen blockage in males did not feminize their behavior in plus mazes. These show that particular female behaviors are under the control of ovarian hormones. Estrogen biosynthesis was also seen when castrated male rats attempted to learn behaviors associated with going through mazes. When estradiol was deposited in the hippocampus or cortex, maze learning behavior was reacquired in a male fashion.

Other brain structures are also sexually dimorphic in rats, and are currently being investigated in humans. An asymmetry of the cerebral cortex is seen -- it is thicker in the right hemisphere than in the left in male rats, with an opposite thickness ratio for female rats. Neonatal ovariectomy results in an overall thicker cortex compared to intact females. The development of cortical neurotransmitter systems ends earlier in female rats than in male rats. The direction of hippocampal dendritic anatomy varies depending on the sex of the rat, and the density of the dendritic spine varies in females according to the estrus cycle, which suggests a correspondence between estrogen levels and neuronal structure. Male rats have a larger absolute cross-sectional callosal area than females in absolute and relative measurements, and the neonatal removal of ovarian hormones leads to callosal enlargement; these effects can be countered by the administration of estrogen.

These experimental data strongly suggest that ovarian hormones, especially estrogen, contribute to the sexual differentiation process in ways comparable to testosterones masculinization effects. Other factors to consider in the sexual dimorphisms of a species, particularly humans, include age, handedness, and environment. A normal male requires exposure to androgens during his critical period in development; a normal female must be exposed to ovarian hormones, including estrogen and any accompanying factors such as alpha-fetoprotein. Lack of hormone exposure does not lead to feminization as a default process. Experimental data on the sexually dimorphic nucleus of the preoptic area (SDN-POA) and the corpus callosum in rats consistently show these developments as reliant on both androgens and estrogens. Whether or not these data correspond to human sexual differentiation has yet to be determined.

References

(1) Measuring and Understanding Sex Differences in the Brain Timothy J. DeVoogd

A course page in which DeVoogd describes the sexual dimorphisms in the brains of songbirds and the attempts to determine the hormonal effects on these structures.

(2) Biological Bases of Behavior: Psychosexual Differentiation, University of Plymouth- Department of Psychology

Lecture support material on the traditional view of sexual differentiation in rats. Includes graphs and illustrations of sexual behaviors associated with rats, preschool children, and CAH patients.

(3) A Role for Ovarian Hormones in Sexual Differentiation of the Brain R. H. Fitch & V. H. Denenberg

Extensive research data and conclusions on the effects of estrogen on developing and mature rats, with analysis on past research done on other animals including humans.

(4) ISBN 1997: ABSTRACTS: ESTROGEN SYMPOSIUM

A collection of abstracts including An Overview on the Role of Estrogen in Development and Sexual Differentiation of the Brain: Re-Examining the Neutral Female Phenotype (R. H. Fitch), Estrogen-Related Changes in Spatial Learning, Hippocampal Size, and Cell Proliferation in the Adult Female Meadow Vole (Galea, McEwen), and Estrogen and the Female Brain Across the Lifespan (Cowell).

(5) Sex Differences in the Functional Organization of the Brain for Language

1995 Nature, 373, 607-609- by Shaywitz, Shaywitz, Pugh, Constable, Skudlarski, Bronen, Fulbright, Fletcher, Shankweiler, Katz , and Gore

An abstract which addresses the question of sex differences in the language centers of the human brain. These differences manifest themselves in lateralization between males and females.

(6) Neural development and the influence of sex, hormones, and the environment

A faculty page in which Juraska describes her research in the cerebral cortex and hippocampus of rats, and the differences of these structures between the sexes.


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