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MON-209 Systemic and Hypothalamic Hyperandrogenism Emerges Following Elimination of Ovarian and Extra-Ovarian Sources of Estradiol in Female Marmoset Monkeys

In female nonhuman primates, ovarian and extra-ovarian estradiol (E(2)) contribute components of negative and positive feedback regulation of pituitary gonadotropin, as well as sexually receptive behavior. Little is known, however, about accompanying changes in brain steroid hormone content, particu...

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Autores principales: Kraynak, Marissa, Goy, Robinson, Kapoor, Amita, Levine, Jon, Abbott, David
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Endocrine Society 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6550761/
http://dx.doi.org/10.1210/js.2019-MON-209
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author Kraynak, Marissa
Goy, Robinson
Kapoor, Amita
Levine, Jon
Abbott, David
author_facet Kraynak, Marissa
Goy, Robinson
Kapoor, Amita
Levine, Jon
Abbott, David
author_sort Kraynak, Marissa
collection PubMed
description In female nonhuman primates, ovarian and extra-ovarian estradiol (E(2)) contribute components of negative and positive feedback regulation of pituitary gonadotropin, as well as sexually receptive behavior. Little is known, however, about accompanying changes in brain steroid hormone content, particularly at the level of the hypothalamus. As part of a larger study investigating ovarian and extra-ovarian E(2) regulation of reproductive, sexual and metabolic function, 13 adult female marmosets housed with well-established male pairmates were ovariectomized (OVX) and immediately assigned to one of three treatment groups: E(2) SC capsule replacement (E2, n=5, mimicking peri-ovulatory circulating E(2) levels), vehicle (VEH, n=4, daily PO 1ml/kg Ensure®), and aromatase inhibition (LET, n=4, daily PO 1mg/kg letrozole). At necropsy 8-9 months following treatment onset, plasma samples were obtained and hemi-hypothalami were harvested. Tissues and samples were placed in liquid nitrogen and frozen at -80C until assayed by LC-MS/MS (steroid hormones) or RIA (gonadotropin). LET females exhibited elevated (p=0.05) post-OVX circulating CG levels (marmoset LH equivalent) compared to E2 females. Circulating E(2) levels were similarly diminished (p=0.01) in VEH and LET female groups compared to E2 females, while circulating levels of DHEA were comparably elevated (p<0.001) in VEH and LET compared to E2 females. Increased DHEA likely reflects absence of E(2)-inhibition of adrenal androgen biosynthesis and development of a zona reticularis. Circulating levels of testosterone (T), androstenedione (A(4)), progesterone (P(4)) and 17-hydroxyP(4) (17OHP) were comparable between all three female groups. Changes in hypothalamic steroids, however, differed from circulating levels. Hypothalamic E(2) was diminished (p<0.001) only in LET compared to E2 and VEH females. In contrast, hypothalamic A(4) was increased in both VEH (p=0.03) and LET (p=0.05) compared to E2 females, while hypothalamic DHEA was increased (p=0.04) only in VEH compared to E2 and LET females. Hypothalamic T, P(4) and 17OHP were comparable across treatment groups, not surprisingly producing a diminished (p<0.001) E(2):T ratio in LET versus E2 females. Taken together, these results suggest E(2) inhibition of adrenal and hypothalamic androgen biosynthesis and reveal potential contribution of hypothalamic E(2) and androgens to physiological and behavioral function, translationally relevant when E(2) production or action is impaired, such as in women with polycystic ovary syndrome.
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spelling pubmed-65507612019-06-13 MON-209 Systemic and Hypothalamic Hyperandrogenism Emerges Following Elimination of Ovarian and Extra-Ovarian Sources of Estradiol in Female Marmoset Monkeys Kraynak, Marissa Goy, Robinson Kapoor, Amita Levine, Jon Abbott, David J Endocr Soc Reproductive Endocrinology In female nonhuman primates, ovarian and extra-ovarian estradiol (E(2)) contribute components of negative and positive feedback regulation of pituitary gonadotropin, as well as sexually receptive behavior. Little is known, however, about accompanying changes in brain steroid hormone content, particularly at the level of the hypothalamus. As part of a larger study investigating ovarian and extra-ovarian E(2) regulation of reproductive, sexual and metabolic function, 13 adult female marmosets housed with well-established male pairmates were ovariectomized (OVX) and immediately assigned to one of three treatment groups: E(2) SC capsule replacement (E2, n=5, mimicking peri-ovulatory circulating E(2) levels), vehicle (VEH, n=4, daily PO 1ml/kg Ensure®), and aromatase inhibition (LET, n=4, daily PO 1mg/kg letrozole). At necropsy 8-9 months following treatment onset, plasma samples were obtained and hemi-hypothalami were harvested. Tissues and samples were placed in liquid nitrogen and frozen at -80C until assayed by LC-MS/MS (steroid hormones) or RIA (gonadotropin). LET females exhibited elevated (p=0.05) post-OVX circulating CG levels (marmoset LH equivalent) compared to E2 females. Circulating E(2) levels were similarly diminished (p=0.01) in VEH and LET female groups compared to E2 females, while circulating levels of DHEA were comparably elevated (p<0.001) in VEH and LET compared to E2 females. Increased DHEA likely reflects absence of E(2)-inhibition of adrenal androgen biosynthesis and development of a zona reticularis. Circulating levels of testosterone (T), androstenedione (A(4)), progesterone (P(4)) and 17-hydroxyP(4) (17OHP) were comparable between all three female groups. Changes in hypothalamic steroids, however, differed from circulating levels. Hypothalamic E(2) was diminished (p<0.001) only in LET compared to E2 and VEH females. In contrast, hypothalamic A(4) was increased in both VEH (p=0.03) and LET (p=0.05) compared to E2 females, while hypothalamic DHEA was increased (p=0.04) only in VEH compared to E2 and LET females. Hypothalamic T, P(4) and 17OHP were comparable across treatment groups, not surprisingly producing a diminished (p<0.001) E(2):T ratio in LET versus E2 females. Taken together, these results suggest E(2) inhibition of adrenal and hypothalamic androgen biosynthesis and reveal potential contribution of hypothalamic E(2) and androgens to physiological and behavioral function, translationally relevant when E(2) production or action is impaired, such as in women with polycystic ovary syndrome. Endocrine Society 2019-04-30 /pmc/articles/PMC6550761/ http://dx.doi.org/10.1210/js.2019-MON-209 Text en Copyright © 2019 Endocrine Society https://creativecommons.org/licenses/by-nc-nd/4.0/ This article has been published under the terms of the Creative Commons Attribution Non-Commercial, No-Derivatives License (CC BY-NC-ND; https://creativecommons.org/licenses/by-nc-nd/4.0/).
spellingShingle Reproductive Endocrinology
Kraynak, Marissa
Goy, Robinson
Kapoor, Amita
Levine, Jon
Abbott, David
MON-209 Systemic and Hypothalamic Hyperandrogenism Emerges Following Elimination of Ovarian and Extra-Ovarian Sources of Estradiol in Female Marmoset Monkeys
title MON-209 Systemic and Hypothalamic Hyperandrogenism Emerges Following Elimination of Ovarian and Extra-Ovarian Sources of Estradiol in Female Marmoset Monkeys
title_full MON-209 Systemic and Hypothalamic Hyperandrogenism Emerges Following Elimination of Ovarian and Extra-Ovarian Sources of Estradiol in Female Marmoset Monkeys
title_fullStr MON-209 Systemic and Hypothalamic Hyperandrogenism Emerges Following Elimination of Ovarian and Extra-Ovarian Sources of Estradiol in Female Marmoset Monkeys
title_full_unstemmed MON-209 Systemic and Hypothalamic Hyperandrogenism Emerges Following Elimination of Ovarian and Extra-Ovarian Sources of Estradiol in Female Marmoset Monkeys
title_short MON-209 Systemic and Hypothalamic Hyperandrogenism Emerges Following Elimination of Ovarian and Extra-Ovarian Sources of Estradiol in Female Marmoset Monkeys
title_sort mon-209 systemic and hypothalamic hyperandrogenism emerges following elimination of ovarian and extra-ovarian sources of estradiol in female marmoset monkeys
topic Reproductive Endocrinology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6550761/
http://dx.doi.org/10.1210/js.2019-MON-209
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