Estrogen receptor (ESR) 2 partially offsets the absence of ESR1 in gonadotropes of pituitary-specific Esr1 knockout female mice

Abstract

Estrogen receptor 1 and 2 (ESR1 and 2) mediate estrogen (E) action on gonadotrope function. While much is known about the effects of ESR1 on the gonadotrope, there is still some controversy regarding the effects of ESR2. To investigate the role of ESR2 in the gonadotrope, 45-day-old female mice of two different genotypes were used: wild type (WT) and pituitary (gonadotropes and thyrotropes)-specific Esr1 knockout (KO). All mice were ovariectomized (OVX) and 15 days later injected over 3 days with 2.5 mg 17b-estradiol (E 2 ), 0.2 mg of the selective ESR1 or 2 agonists, propylpyrazole triol and diarylpropionitrile, respectively, or 0.1 ml oil. The day after treatment, anterior pituitary glands were dissected out for evaluation of gonadotrope ultrastructural morphology and pituitary immunohistochemical expression of progesterone receptor (Pgr (Pr)). Blood was collected and serum LH levels were assessed. Activation of ESR1 in WT mice resulted in the following: i) uterine ballooning and vaginal cornification, ii) negative feedback on LH secretion, iii) increased number of homogeneous (functional) gonadotropes, and iv) pituitary Pgr expression (35.9G2.0% of pituitary cells). Activation of ESR1 in KO mice induced normal uterine, vaginal, and LH secretion responses, but failed to increase the number of functional gonadotropes, and induced significantly lower Pgr expression (21.0G3.0% of pituitary cells) than in WT mice. Whilst activation of ESR2 had no significant effects in WT mice, it doubled the number of functional gonadotropes exhibited by KO mice injected with oil. It is concluded that E 2 exerted its action in KO mouse gonadotropes via ESR2.

Health benefits attributed to 17α-estradiol, a lifespan-extending compound, are mediated through estrogen receptor α

“…There are a few notable caveats to our studies. First, we utilized constitutive global ERα KO mice, which have been shown to display varying degrees of compensatory ERβ activity due to the absence of ERα during development [101,102]. However, if compensatory ERβ expression was playing a role in our study, we would not see a complete attenuation of 17α-E2 mediated effects.…”

Health benefits attributed to 17α-estradiol, a lifespan-extending compound, are mediated through estrogen receptor α

“…There are a few notable caveats to our studies. First, we utilized constitutive global ERα KO mice, which have been shown to display varying degrees of compensatory ERβ activity due to the absence of ERα during development [132,133]. However, if compensatory ERβ expression was playing a role in our study, we likely would not see a complete attenuation of 17α-E2 mediated effects.…”

Gene expression profiling of key genes in hypothalamus–pituitary–gonad axis of rare minnow Gobiocypris rarus in response to EE2

“…The pituitaryspecific Esr1 KO mice indicated the presence of both estrogen positive feedback and estrogen negative feedback in the reproductive regulation of the gonadotrope (Singh et al, 2009). In C57BL/6 mice, the effect of estrogen on the gonadotrope is exerted mainly through the activation of Esr1 in the pituitary and Esr2 can partially offset the absence of Esr1 in gonadotropes in female mice by pituitary-specific Esr1 knockout (Sanchez-Criado et al, 2012). In the sea bass, in situ hybridization studies demonstrated that esr1 was profusely expressed in the main neuroendocrine areas, such as the preoptic area and hypothalamus and also was expressed in the Fshβ and Lhβ cells, suggesting involvement of Esr1 in the modulation of the hypophysiotropic neurons and direct control of gonadotropin hormone synthesis by estrogens (Muriach et al, 2008b).…”