Sexually dimorphic expression of estrogen receptor β in the anteroventral periventricular nucleus of the rat preoptic area: Implication in luteinizing hormone surge

Abstract

Striking sex difference was detected in the expression of estrogen receptor (ER)␤E strogen plays critical roles in sexual differentiation of the developing brain and sex-specific regulation of reproductive neuroendocrinology in adults (1, 2). Cellular estrogen signaling is conveyed by nuclear estrogen receptors (ERs), which include the classical ER␣ as well as the recently cloned ER␤ (3). Both ERs are expressed in the preoptic area (POA), hypothalamus and limbic structures, which have been implicated in the regulation of reproduction (4-6). It is unclear, however, whether ER␤, like ER␣ (7), is expressed in a sex-specific manner (8, 9). Furthermore, the presence of both ERs in the same neurons could alter the specificity of the transcription by forming heterodimers (10) and might produce different responses to estrogen in different cells, depending on the ratios of ER␣ and ER␤ (11).Disruption of either ER␣ or ER␤ affects various aspects of reproduction. Female and male ER␣ knockout mice are infertile (12), and ER␤ knockout females have a reduced fecundity (13). Anovulation and polycystic or hemorrhagic ovary are present in the ER␣ knockouts (14). Reductions of ovulatory capacity and polycystic ovary occur in the ER␤ knockouts (13). The syndrome may be caused, at least partially, by the impairment in the central mechanism for the secretion of luteinizing hormone.The anteroventral periventricular nucleus (AVPV) is sexually dimorphic with over three times as many dopaminergic neurons in the female rat compared with males (15), and this supports the importance of this brain region in the control of estrous cyclicity, which is absent in males. Indeed, small lesions confined to the AVPV block the cyclic release of luteinizing hormone in female rat and results in anovulatory, persistent estrous state (16).Implantation of microcannulae containing antiestrogens into the AVPV suppressed spontaneous luteinizing hormone surges (17).In the present study, striking sex difference, detected in the ER␤ expression in the AVPV, was reversed by altering neonatal steroid environment. ER␤ mRNA and ER␣ immunoreactivity colocalized in many AVPV cells, some of which would be dopaminergic in nature. Infusion of ER␤ antisense oligonucleotides prolonged vaginal estrus and was accompanied by a 50% reduction of ER␤ immunoreactivity. Materials and MethodsSubjects. Female and male Sprague-Dawley rats (Saitama Experimental Animals, Saitama, Japan) were used on postnatal d 7, 14, 21, 35, or 60 (d 1 ϭ the day of birth) for brain morphometry. They were maintained in a controlled environment at 23°C with a 12-hr light͞12-h dark cycle (lights on at 11 a.m.). The weaning occurred on d 21. Free access to laboratory chow and water was allowed thereafter. A cohort of animals underwent endocrine manipulations as neonates or pups: males were orchidectomized under hypothermia on d 1; females received daily s.c. injections of 10 g 17␤-estradiol benzoate (Sigma) in oil on d 1 through d 10. All juvenile males and females were used without gonadectomy.ER␤ mRNA ...

Age-related changes in the expression of ER-β mRNA in the female rat brain

“…It is possible that the decreased ER-β concentration influences the total number of available receptors, leading to a diminished responsiveness to estrogen. Moreover, it has been reported that the ER-α protein and the ER-β mRNA are co-localized in neurons in the rat brain (Shughrue et al, 1998;Orikasa et al, 2002), and the activity of estrogenic compounds may depend, in part, on whether a cell contains ER-α, β, or both. In addition, it is known that ERs form homo-or heterodimers (Cowley et al, 1997;Pace et al, 1997;Pettersson et al, 1997;Ogawa et al, 1998;Matsuda et al, 2002).…”

“…Both ER-α and ER-β mRNA are abundant in the same brain regions: the preoptic area, bed nucleus of the stria terminalis and medial amygdala (Simerly et al, 1990;Shughrue et al, 1997). ER-β mRNA was shown to be co-expressed with ER-α immunoreactivity in the same neuron in several brain regions: the bed nucleus of the stria terminalis, medial amygdaloid nucleus, periventricular preoptic nucleus, medial preoptic nucleus, and anteroventral periventricular nucleus (Shughrue et al, 1998;Orikasa et al, 2002). In addition, in vitro studies have shown that ER-β can form heterodimers with ER-α (Cowley et al, 1997;Pace et al, 1997;Pettersson et al, 1997;Ogawa et al, 1998;Matsuda et al, 2002), 5 suggesting that estrogen may differentially modulate the activity of certain neuronal populations depending on whether the cells express ER-α, ER-β or both (Shughrue et al, 1998).…”

Developmental programming and endocrine disruptor effects on reproductive neuroendocrine systems

“…The AVPV is a small preoptic brain region that is abundant in nuclear hormone receptors such as ERα [25], ERβ [108,26], AR [143], and PR [122] in a sexually dimorphic manner (ERα [27], ERβ [108], PR [122]). The AVPV of rats is larger in female than male rodents [18,43,150], due to influences of both estradiol and testosterone during the early postnatal (and possibly prenatal) periods [43,150,142].…”

“…A frequent target of study in endocrine disruption work is the ERβ, the expression of which is not only sexually dimorphic [108], but whose expression is affected in the adult hypothalamus by prenatal exposure to EDCs. Effects on hypothalamic ERβ expression have been shown for a phytoestrogen (daidzein; [124]) an organochlorine pesticide (methoxychlor; [154], and PCBs [134].…”

Neural mechanisms underlying sex-specific behaviors in vertebrates

“…Interestingly, most sexually dimorphic neural structures were found to express differential levels of gonadal steroid hormone receptors [15][16][17] and were described as components of the vomeronasal system, a sensory system thought to process pheromone information and required for sexual and aggressive responses [12][13][14].…”