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Differential role of estrogen receptor isoforms in sex-specific brain organization

Institute of Experimental Endocrinology, School of Medicine Charité, Humboldt University, Berlin, Germany

¹Correspondence: Institute of Experimental Endocrinology, School of Medicine Charité, Schumannstr. 20/21, 10117 Berlin, Germany. E-mail: Alexandre.Patchev{at}Charite.de

SPECIFIC AIMS

Activation of estrogen receptors (ER) in the neonatal female rat brain results in irreversible alterations in female gonadal function and sexual behavior in adulthood. The two major ER isoforms, and ß, are coexpressed in several brain areas involved in control of reproductive functions, yet their individual role in sex-specific brain organization has not been elucidated. In the present study we used the paradigm of transient exposure of female rats during a critical neonatal "window of time" to highly selective agonists of ER and ERß to examine individual contribution of each ER isoform to defeminization of various aspects of neuroendocrine control of reproduction in adulthood.

PRINCIPAL FINDINGS

1. Neonatal activation of ER completely reproduces defeminizing effects of estradiol
Neonatal treatment with the ER-selective agonist ZK 281471 (3,17ß-dihydroxy-19-nor-17-pregna-1,3,5(10)-triene-21,16-lactone) significantly decreased frequency of ovarian cycles and prolonged estrus duration.

Female sexual receptivity was severely disrupted, as disclosed by abolition of lordosis behavior, and the animals were refractory to induction of sexual behavior by estradiol priming (Fig. 1 ).

View larger version (24K): [in this window] [in a new window]   Figure 1. Female sexual behavior in random cycling, and ovariectomized and estradiol-primed adult rats neonatally treated with estradiol (solid bars) or ER- (ZK 281471; hatched bars) or ERß-selective agonists (ZK 281738; cross-hatched bars). Data represent mean ± SE of 12 individuals per treatment group; *significant differences from rats receiving neonatal vehicle treatment (open bars).

Exposure to the ER-selective agonist significantly influenced sex-specific features of two sexually dimorphic brain nuclei: neuronal density in the anteroventral paraventricular nucleus (AVPV) was decreased and nuclear volume of the sexually dimorphic nucleus of the preoptic area (SDN-POA) was enlarged, thus resembling those measured in intact males (Fig. 2 ).

View larger version (17K): [in this window] [in a new window]   Figure 2. Morphometric comparison of the volume of the SDN-POA in adult rats subjected to neonatal treatment with either estradiol (solid bars) or ER- (ZK 281471; hatched bars) or ERß-selective agonists (ZK 281738; cross-hatched bars). Vehicle-treated age-matched females (open bars) and males (shaded bars) were used as reference (n=5/group). Data are shown as mean ± SE; *significant changes as compared with vehicle-treated females.

2. Defeminizing consequences of neonatal activation of ERß are confined to disturbance of cyclic ovarian activity, not female sexual behavior
Treatment of neonatal females with the ERß-selective agonist ZK 281738 (8ß-vinyl-estra-1,3,5(10)-triene-3,17ß-diol) led to disruption of cyclic ovarian activity and manifestation of persistent estrus in adulthood.

Signs of morphological defeminization following neonatal activation of ERß were documented in the AVPV, whose neuronal density decreased to male-like values.

ERß activation during neonatal development failed to affect female sexual receptivity, inducibility of lordosis behavior by estradiol, and female-specific small volume of the SDN-POA (Figs. 1 , 2) .

CONCLUSIONS AND SIGNIFICANCE

Estrogens derived from biotransformation of perinatally secreted testicular androgens account for male-specific organization of neural circuitry, which controls gonadal activity and sexual behavior in the rat. Accordingly, exposure of newborn females to ER agonists results in persisting alterations in the regulation of female gonadal function and reproductive behavior. These are known as defeminization, and best exemplified by disruption of cyclic gonadotropin secretion and ovarian activity and suppression of sexual receptivity. Susceptibility of reproduction-relevant neuronal populations to perinatal modification of ER signaling is further illustrated by alterations in two sexually dimorphic brain structures: female-specific high neuronal density of the AVPV and the small volume of the SDN-POA converted to male-like values after estrogen administration in female neonates.

Copresence of ER and ERß in several neuronal populations involved in the control of reproductive functions is well documented. However, their specific contribution to the process of defeminization has not been comprehensively investigated. Although the reproductive phenotype of transgenic animals with targeted disruption of individual ER isoforms is suggestive of changes in relevant neuroendocrine mechanisms, conclusions may be biased by very early onset of aberrant ER signaling not only in the developing brain, but also the entire reproductive axis. Pharmacological studies using phytoestrogens and similar endpoint parameters have documented disruption of cyclic ovarian activity and masculinization of the SDN-POA; however, poor ER isoform selectivity of these compounds and the high doses used preclude strict discrimination of ERß and ER signaling.

The study described here combines a "classic" experimental paradigm of neuroendocrine defeminization with ER agonists that display 300- (ZK 281471) and 190-fold (ZK 281738) preference for the - and ß-isoform, respectively, and pharmacological potency comparable to that of the shared natural ligand estradiol. The results indicate that 1) neonatal activation of each of the two ER isoforms in the rat can independently disrupt cyclic activity of the female gonadal axis; 2) these effects are associated with morphological defeminization of the putative LH "surge generator", the hypothalamic AVPV; 3) isolated activation of ER, but not ERß, irreversibly abolishes female sexual receptivity and estrogen-mediated induction of lordosis behavior; 4) coincident morphological defeminization of the SDN-POA, a neuronal population reportedly involved in control of sexual behavior, by an ER- but not ERß-selective agonist points to ER in this nucleus as a major mediator of behavioral organization by estrogens.

Taken together, the data suggest that although both ER isoforms are copresent in brain structures subject to sex-specific hormonal organization, they differentially shape neural circuits that determine sex-specific patterns of gonadal secretions and reproductive behavior. Thus, perinatal exposure of the female brain to inappropriate doses of either ER- or ERß-preferring agonists may result in disturbed ovarian cyclicity, however, activation of ER appears to be instrumental for impairment of female sexual behavior. Explanations of these dissociated effects remain speculative. Lack of behavioral defeminization following selective ERß activation may reflect "sparing" of ER-responsive components of the complex circuitry that integrates sensory and motor signals leading to lordosis behavior. On the other hand, although disruption of ovarian cycle by either ER isoform activation is apparently associated with defeminization of the AVPV, a structure believed to act as "LH surge generator," it is unclear whether effects of ER and ERß converge on overlapping downstream targets in this highly heterogeneous neuronal population. Thus, identification of the neurochemical phenotype and projections of ER- and ERß-expressing neurons in areas involved in the regulation of gonadotropin secretion, but also changes in neuropeptide/transmitter synthesis and release in these regions upon selective activation of individual ER isoforms, is a task that warrants further attention.

View larger version (30K): [in this window] [in a new window]   Figure 3. Schematic diagram showing the presumptive roles of ER-isoforms in the process of sex-specific brain differentiation. The columns represent the consequences of selective neonatal ER-isoform activation in female rats (F+ER, F+ERß) for cyclic gonadal activity, estrogen sensitivity and lordosis behavior in terms of "all-or-none-effects" (i.e., "maximal" female (F) vs. "minimal" male (M) pattern).

FOOTNOTES

To read the full text of this article, go to http://www.fasebj.org/cgi/doi/10.1096/fj.04-1959fje;

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