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Differential Expression of Estrogen Receptors in the Hypothalamus Underlies the Bimodal Effects of Estradiol on Luteinizing Hormone Release

Low 17β-estradiol (E2) levels suppress luteinizing hormone (LH) release, while high E(2) stimulates an LH surge in the positive-feedback required for ovulation. Kisspeptin (Kp) neurons in the anteroventral periventricular (AVPV) and arcuate (ARC) nuclei of hypothalamus have been implicated in E2 pos...

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Autores principales: Henriques, Patricia Costa, Aquino, Nayara Soares Sena, Araújo-Lopes, Roberta, Silva, Juneo Freitas, Coimbra, Candido Celso, Franci, Celso Rodrigues, Szawka, Raphael Escorsim
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Oxford University Press 2021
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Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8090696/
http://dx.doi.org/10.1210/jendso/bvab048.1092
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author Henriques, Patricia Costa
Aquino, Nayara Soares Sena
Araújo-Lopes, Roberta
Silva, Juneo Freitas
Coimbra, Candido Celso
Franci, Celso Rodrigues
Szawka, Raphael Escorsim
author_facet Henriques, Patricia Costa
Aquino, Nayara Soares Sena
Araújo-Lopes, Roberta
Silva, Juneo Freitas
Coimbra, Candido Celso
Franci, Celso Rodrigues
Szawka, Raphael Escorsim
author_sort Henriques, Patricia Costa
collection PubMed
description Low 17β-estradiol (E2) levels suppress luteinizing hormone (LH) release, while high E(2) stimulates an LH surge in the positive-feedback required for ovulation. Kisspeptin (Kp) neurons in the anteroventral periventricular (AVPV) and arcuate (ARC) nuclei of hypothalamus have been implicated in E2 positive- and negative-feedback effects, respectively. However, how E2 differentially regulates these two neuronal populations remains unknown. We investigated whether neurons in the AVPV and ARC are differently responsive to changes in E2 levels and the regulatory role of estrogen receptors (ERs). Ovariectomized (OV) rats received oil or E2 at doses of 4 (OVE-4), 40 (OVE-40), or 80 (OVE-80) µg/kg. Rats on diestrus (DI) and proestrus (PRO) were used as physiological controls. OV rats were also treated with 0.02, 0.2 or 2.0 mg/kg of propyl pyrazole triol (PPT), or 6 mg/kg of diarylpropionitrile (DPN). Serial blood samples were collected for hormonal measurements. Brains were processed for immunohistochemistry and qPCR analyses in the AVPV and ARC. The E2 doses gradually increased plasma E2(,) with PRO levels being attained in OVE-80 rats. OVE-80 rats displayed a PRO-like LH surge, while LH levels were constantly suppressed in OVE-4 rats. Progesterone receptor (PR) was used as an index of E2 responsiveness. PR expression was increased in the AVPV of PRO and OVE-80 rats, associated with c-Fos expression and occurrence of LH surge. In the ARC, both low and high E2 induced PR expression and reduced the number of Kp-immunoreactive (ir) neurons, consistent with the negative feedback effects on LH. E2 at 4 or 80 µg/kg equally induced PR expression in 90% of ARC Kp-ir neurons. Despite the higher sensitivity to E2 in the ARC, the percentage of neurons expressing ERα was lower in the ARC compared with AVPV. However, Esr1 expression was 2-fold higher in the ARC than in AVPV for low E2 levels, whereas both Esr1 and Esr2 were more expressed in the AVPV under high E2 status. Notably, Esr1/Esr2 ratio was twice as high in the ARC as in the AVPV regardless of E2 levels, suggesting a stronger ERβ inhibition over ERα in the AVPV. Accordingly, ERα selective activation with PPT increased PR in the ARC at the doses of 0.2 and 2.0 mg/kg, reducing plasma LH, while only the highest dose was able to stimulate PR expression in the AVPV. ERβ activation with DPN, in turn, had no effect in OV rats but amplified the induction of AVPV PR and the size of the LH surge in OVE-80 rats. Thus, we provide evidence that ARC and AVPV neurons are responsive to low and high E2 levels, respectively. ARC is 10 times more sensitive to ERα activation than AVPV, whereas ERβ positively modulates AVPV responsiveness to high E2. These differential responses to E2 seem to be related to differences in the relative Esr1 and Esr2 expression in the ARC and AVPV. Our findings suggest that hypothalamic differences in the relative expression of ERs play a key role in the bimodal regulation of LH release by E2.
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spelling pubmed-80906962021-05-12 Differential Expression of Estrogen Receptors in the Hypothalamus Underlies the Bimodal Effects of Estradiol on Luteinizing Hormone Release Henriques, Patricia Costa Aquino, Nayara Soares Sena Araújo-Lopes, Roberta Silva, Juneo Freitas Coimbra, Candido Celso Franci, Celso Rodrigues Szawka, Raphael Escorsim J Endocr Soc Neuroendocrinology and Pituitary Low 17β-estradiol (E2) levels suppress luteinizing hormone (LH) release, while high E(2) stimulates an LH surge in the positive-feedback required for ovulation. Kisspeptin (Kp) neurons in the anteroventral periventricular (AVPV) and arcuate (ARC) nuclei of hypothalamus have been implicated in E2 positive- and negative-feedback effects, respectively. However, how E2 differentially regulates these two neuronal populations remains unknown. We investigated whether neurons in the AVPV and ARC are differently responsive to changes in E2 levels and the regulatory role of estrogen receptors (ERs). Ovariectomized (OV) rats received oil or E2 at doses of 4 (OVE-4), 40 (OVE-40), or 80 (OVE-80) µg/kg. Rats on diestrus (DI) and proestrus (PRO) were used as physiological controls. OV rats were also treated with 0.02, 0.2 or 2.0 mg/kg of propyl pyrazole triol (PPT), or 6 mg/kg of diarylpropionitrile (DPN). Serial blood samples were collected for hormonal measurements. Brains were processed for immunohistochemistry and qPCR analyses in the AVPV and ARC. The E2 doses gradually increased plasma E2(,) with PRO levels being attained in OVE-80 rats. OVE-80 rats displayed a PRO-like LH surge, while LH levels were constantly suppressed in OVE-4 rats. Progesterone receptor (PR) was used as an index of E2 responsiveness. PR expression was increased in the AVPV of PRO and OVE-80 rats, associated with c-Fos expression and occurrence of LH surge. In the ARC, both low and high E2 induced PR expression and reduced the number of Kp-immunoreactive (ir) neurons, consistent with the negative feedback effects on LH. E2 at 4 or 80 µg/kg equally induced PR expression in 90% of ARC Kp-ir neurons. Despite the higher sensitivity to E2 in the ARC, the percentage of neurons expressing ERα was lower in the ARC compared with AVPV. However, Esr1 expression was 2-fold higher in the ARC than in AVPV for low E2 levels, whereas both Esr1 and Esr2 were more expressed in the AVPV under high E2 status. Notably, Esr1/Esr2 ratio was twice as high in the ARC as in the AVPV regardless of E2 levels, suggesting a stronger ERβ inhibition over ERα in the AVPV. Accordingly, ERα selective activation with PPT increased PR in the ARC at the doses of 0.2 and 2.0 mg/kg, reducing plasma LH, while only the highest dose was able to stimulate PR expression in the AVPV. ERβ activation with DPN, in turn, had no effect in OV rats but amplified the induction of AVPV PR and the size of the LH surge in OVE-80 rats. Thus, we provide evidence that ARC and AVPV neurons are responsive to low and high E2 levels, respectively. ARC is 10 times more sensitive to ERα activation than AVPV, whereas ERβ positively modulates AVPV responsiveness to high E2. These differential responses to E2 seem to be related to differences in the relative Esr1 and Esr2 expression in the ARC and AVPV. Our findings suggest that hypothalamic differences in the relative expression of ERs play a key role in the bimodal regulation of LH release by E2. Oxford University Press 2021-05-03 /pmc/articles/PMC8090696/ http://dx.doi.org/10.1210/jendso/bvab048.1092 Text en © The Author(s) 2021. Published by Oxford University Press on behalf of the Endocrine Society. https://creativecommons.org/licenses/by-nc-nd/4.0/This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs licence (http://creativecommons.org/licenses/by-nc-nd/4.0/ (https://creativecommons.org/licenses/by-nc-nd/4.0/) ), which permits non-commercial reproduction and distribution of the work, in any medium, provided the original work is not altered or transformed in any way, and that the work is properly cited. For commercial re-use, please contact journals.permissions@oup.com
spellingShingle Neuroendocrinology and Pituitary
Henriques, Patricia Costa
Aquino, Nayara Soares Sena
Araújo-Lopes, Roberta
Silva, Juneo Freitas
Coimbra, Candido Celso
Franci, Celso Rodrigues
Szawka, Raphael Escorsim
Differential Expression of Estrogen Receptors in the Hypothalamus Underlies the Bimodal Effects of Estradiol on Luteinizing Hormone Release
title Differential Expression of Estrogen Receptors in the Hypothalamus Underlies the Bimodal Effects of Estradiol on Luteinizing Hormone Release
title_full Differential Expression of Estrogen Receptors in the Hypothalamus Underlies the Bimodal Effects of Estradiol on Luteinizing Hormone Release
title_fullStr Differential Expression of Estrogen Receptors in the Hypothalamus Underlies the Bimodal Effects of Estradiol on Luteinizing Hormone Release
title_full_unstemmed Differential Expression of Estrogen Receptors in the Hypothalamus Underlies the Bimodal Effects of Estradiol on Luteinizing Hormone Release
title_short Differential Expression of Estrogen Receptors in the Hypothalamus Underlies the Bimodal Effects of Estradiol on Luteinizing Hormone Release
title_sort differential expression of estrogen receptors in the hypothalamus underlies the bimodal effects of estradiol on luteinizing hormone release
topic Neuroendocrinology and Pituitary
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8090696/
http://dx.doi.org/10.1210/jendso/bvab048.1092
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