Gonadal hormones exert effects on the nervous system and consequently on behavior that depend on the stage of development of the organism. During critical developmental periods, gonadal hormones produce permanent changes in the organization of neuronal circuitry that results in sexual differentiation of behavior. In the adult, gonadal hormones can activate gender-typical behaviors, but the behaviors do not persist in the absence of the hormone, and structural changes in the brain are not produced.
One gene determines whether the fetal animal or human will differentiate into a male or a female adult. Sexual dimorphism includes obvious body characteristics such as the form of the external genitalia as well as the organization of various neural systems and is determined by whether the sperm contributes an X or a Y sex chromosome when it fertilizes the egg. If the sperm contains an X chromosome, the resulting XX mix causes the fetus to develop as a phenotypic female. When the ovaries begin to secrete gonadotropins, the secondary sex characteristics and the brain will be feminine. If the sex chromosomes are XY, testis will develop, and the secondary sex characteristics and the brain will be masculine.
The critical gene that determines whether or not the go-nads will become either ovaries or testes is located in the middle of the short arm of the Y chromosome. The gene is called the sex-determining region of Y and encodes for production of testes-determining factor (TDF). The presence of TDF causes the testes to develop. The testes in turn secrete two hormones that are responsible for the phenotypic development of the fetus as a male. If these hormones are lacking, no signals are sent to alter the intrinsic default developmental sequence, and the fetus develops as a female. Testosterone, secreted by the Leydig cells of the testes, changes the sex organs, mammary gland anlage, and nervous system into the male pattern. The second hormone is secreted by the Sertoli cells of the testes and is called Mul-lerian duct-inhibiting hormone (MIS). MIS causes the tissues that would become the oviducts, uterus, cervix, and vagina to be resorbed.
Although conducted before the discovery of MIS, an early experiment by Phoenix, Goy, Gerall, and Young serves to distinguish the roles of these two hormones and demonstrates the importance of testosterone for masculization of adult behavior. Fetuses of both sexes are exposed to high estrogen levels from the mother's circulation. Thus the primary secretion of the fetal ovaries is reinforced by estrogen from the mother. Phoenix and colleagues wondered what would happen if female fetuses were exposed to higher than normal levels of testosterone. To answer this question, they injected large amounts of testosterone into pregnant guinea pigs. The external genitalia were unequivocally male, but the internal genitalia were female. These animals were now pseudohermaphroditic. The explanation of this phenomenon is that the external genitalia were shaped as male by the influence of the testosterone; however, the oviducts, uterus, cervix, and vagina existed because these guinea pigs were not exposed to the second testicular hormone, MIS, so development of the internal genitalia proceeded according to the default female plan.
The second observation was more important. In normal adult female guinea pigs, administration of estrogen and progesterone produces strong lordosis when the female is mounted by the male. Lordosis is a gender-specific behavior activated in the adult female by the presence of estrogens in the circulation. Phoenix and colleagues found that the female guinea pigs exposed to testosterone in utero demonstrated little lordotic behavior when injected with estrogen and progesterone as adults. However, although they had functioning ovaries, they displayed as much mounting behavior as male litter mates when injected with testosterone. Mounting behavior is often used as an experimental index of the male behavior pattern and is seldom seen in normal adult females, even with testosterone injections. Prenatal exposure to testosterone may have not only produced masculine external genitalia but may also have changed parts of the circuitry of the brain to the masculine pattern.
There are relatively short critical periods in the development of the animal when manipulation of levels of sex steroids makes a difference in development of adult patterns of sexual behavior. Rats have a 21-day gestation period. The testes appear on the 13th day of embryonic life and secrete androgens until the 10th day after birth. Androgen secretion then virtually ceases until puberty. Castration at the day of birth causes male rats to display female sexual behavior as adults when injected with estrogen and progesterone and mounted by normal males. Male rat pups castrated after postnatal day 10 will not display lordosis as adults. This suggests that there is a short critical period when the brain is influenced by testosterone to develop circuitry for male sexual behavior.
Furthermore, the anterior pituitary of both males and females secretes luteinizing hormone (LH) and follicle-stimulating hormone (FSH). As noted previously, release of hormones from the anterior pituitary is under control of the hypothalamus. In males, LH and FSH are released at a steady rate, but in females, the release of these hormones is cyclical, and their levels are related to the cyclical activation of the reproductive organs. If male rats are castrated shortly after birth, cyclical release of LH and FSH will occur. If ovaries are implanted into adult genetic males that were castrated within 1 day of birth, these ovaries can cyclically ovulate, and the host male rats demonstrate behavior normally shown by females in estrus.
Exposure to higher-than-normal levels of androgens at critical periods clearly can produce male behavior in genetic females, and lack of exposure to these hormones can feminize genetic males. Thus females exposed to high levels of testosterone during the critical developmental periods will exhibit mounting behavior at a rate similar to that of genetic males, and males lacking testosterone during the critical period will fail to exhibit mounting behavior, but will exhibit lordosis when exposed as adults to estrogen. A correlated observation to the results of these experimental manipulations is that in normal males and females, exposure to homotypic hormones (i.e., hormones appropriate to the sex of the animal) can trigger sex-specific behaviors (e.g., lordosis on exposure of a normal female to estrogen and progesterone). These observations suggest that the brain (1) must be responsive to sex steroids, and (2) there should be differences in organization of at least some parts of the brain between males and females.
For the central nervous system to respond to gonadal hormones, receptors for androgens, estrogen, and progesterone must exist in neural tissue. Such receptors are located in neurons found in several regions of the central nervous system of the rat and monkey. These areas include not only the hypothalamus, but also the frontal and cingulate cortex, amygdala, hippocampus, midbrain, and spinal cord. Unlike receptors for neurotransmitters, receptors for sex steroids are typically found in the cell nucleus, not in the cell-limiting membrane. Therefore, rather than changing plasma membrane properties, gonadal hormones influence DNA and the transcription of genes. This action permits these hormones potentially to exert influence over many functions of the cell.
The presence of receptors for the different gonadal hormones in the brain differs between the sexes. For example, it was noted previously that in females LH is released in relationship to the cyclical activation of the reproductive organs, whereas in males LH release is continuous at a steady level. Release of LH is regulated by neurosecretory cells of the anterior pituitary that secrete LH-releasing hormone (LHRH). The LHRH neurosecretory cells do not have sex-steroid receptors. These cells, however, receive neural input from neurons in the preoptic area of the hypothalamus. These preoptic neurons do have receptors for estrogen. Thus in normal females, as the ovarian follicles grow, the secreted estrogen stimulates neurons in the preoptic hypothalamus, which in turn stimulate LHRH neurosecretory cells to produce LH. In the brains of genetic females that have been exposed to high levels of androgens either prenatally or immediately postnatally, the preoptic cells do not express estrogen receptors and do not respond to estrogen activation. Therefore, the male pattern of LH secretion ensues.
The structure of the brain differs between males and females. The most obvious example is the sexually dimorphic nucleus located in the preoptic area of the hypothalamus. This nucleus is much larger in males. Unfortunately, its function is not known. Raisman and Field observed differ ences in organization of input to the preoptic area of the hypothalamus.
In addition to their influence on reproductive behaviors, the gonadal hormones also may have organizing and triggering effects on other types of behavior. For example, aggression between males is positively related to testosterone levels, whether the males are competing for a female. These effects may be related to neural events taking place in the medial and preoptic hypothalamus. Aggressive play is much more prevalent in male animals, and the incidence of this form of play is sharply reduced in male rats if they are castrated before postnatal day 6, but not if they are castrated later in life. Conversely, female rats given large doses of testosterone within the first 6 days of life exhibit as much aggressive play as males when this activity develops several weeks later. Similar findings have been reported for monkeys, but the manipulations must be made prenatally.
In summary, gonadal hormones have the capability of organizing behaviors if administered during certain critical periods of development of the organism. Presumably, this organization is due to the influence of these hormones on the developing brain circuitry, but the exact causal sequence between hormonal release and final brain circuit is not known. The exact timing of the critical periods when go-nadal hormones can permanently influence behavior varies according to species, but critical periods occur either late during gestation or immediately after birth. The behaviors organized are those related to sexual activity but also include other behavioral patterns, particularly those reflecting aggression. Exposure to gonadal hormones also can activate behaviors such as mounting or lordosis in adults if appropriate sensory events, such as a receptive female in the case of male mounting behavior, are present. Gonadal hormones also influence the actual morphology of the sexual organs and secondary sex characteristics. Alterations in external sex characteristics might also influence behavioral expression, particularly in humans for whom sex roles are heavily influenced by gender assignment based on external appearance and consequent social learning.
Michael L. Woodruff
East Tennessee State University, Johnson City
See also: Behavioral Genetics; General Adaptation
Syndrome; Homeostasis; Neurochemistry; Pituitary; Stress Consequences; Transsexualism; Weight Control
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