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GnRH network at earlier stages of development ( Gore, 2008 ); a phenom-
enon that takes place during the process of brain sex differentiation. Indeed,
the timing of puberty and different adult reproductive traits are sexually
dimorphic, and manifest as the late expression of the specific determination
of the brain circuitries involved in the control of the HPG axis during critical
developmental windows. In rodents, brain sex differentiation takes place dur-
ing a period spanning from late embryonic to early postnatal age ( Gore, 2008;
Morris, Jordan, & Breedlove, 2004 ). Accordingly, experimental manipula-
tions during this age-window that perturb the normal process of brain sex dif-
ferentiation can alter the timing of puberty and/or disrupt the function of the
adult gonadotropic system. For instance, neonatal androgenization of female
rodents prevents the capacity of estrogen to induce positive feedback and
hence to evoke the preovulatory surges of gonadotropins in adulthood that
are the hormonal drive for ovulation.
Given its paramount importance in the timing of puberty and the reg-
ulation of adult reproductive function, the process of sexual differentiation
of the hypothalamic Kiss1 system during early developmental periods has
been the subject of analysis, especially in rodents. Initial studies already
documented that the Kiss1 neuronal population in the RP3V in the rat is
sexually dimorphic, with females having much greater numbers of Kiss1
neurons than males. Moreover, RP3V Kiss1 neurons appeared to be sensi-
tive to the organizing actions of sex steroids during the window of sexual
maturation of the brain ( Kauffman et al., 2007 ). Thus, neonatal exposure
of female rats to high doses of androgen caused the complete “masculiniza-
tion” of the pattern of Kiss1 mRNA expression at the RP3V in adulthood;
namely, androgenized females showed much lower Kiss1 mRNA levels than
cyclic female rats ( Kauffman et al., 2007 ). Moreover, exposure to estradiol as
adults failed to increase Kiss1 mRNA levels in the RP3V of neonatally
androgenized females, in contrast to the clear stimulatory responses observed
in cyclic females ( Kauffman et al., 2007 ). Those observations were the first to
demonstrate the sensitivity of the hypothalamic Kiss1 system to the organiz-
ing actions of endogenous (and eventually exogenous) sex steroids
( Navarro & Tena-Sempere, 2008 ). In good agreement, later analyses in
a -fetoprotein (AFP) knock-out mice, in which the congenital lack of this
scavenger protein of circulating estrogens causes an excessive estrogenic
input during early development, showed that sexual differentiation and
function of the hypothalamic Kiss1 system is also severely disrupted in these
mice ( Gonzalez-Martinez, De Mees, Douhard, Szpirer, & Bakker, 2008 ).
Furthermore, neonatal exposures to synthetic estrogens, known to alter the
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