scholarly journals The bi-modal effects of estradiol on gonadotropin synthesis and secretion in female mice are dependent on estrogen receptor-α

2006 ◽  
Vol 191 (1) ◽  
pp. 309-317 ◽  
Author(s):  
Jonathan Lindzey ◽  
Friederike L Jayes ◽  
Mariana M Yates ◽  
John F Couse ◽  
Kenneth S Korach
Keyword(s):  
Estrogen Receptor ◽  
Negative Feedback ◽  
Primary Cultures ◽  
Estrogen Receptor Α ◽  
High Plasma ◽  
Pituitary Cells ◽  
Gonadotropin Secretion ◽  
Female Mice ◽  
Positive Effects

Depending on the estrous/menstrual cycle stage in females, ovarian-derived estradiol (E2) exerts either a negative or a positive effect on the hypothalamic–pituitary axis to regulate the synthesis and secretion of pituitary gonadotropins, LH, and FSH. To study the role of estrogen receptor-α (ERα) mediating these effects, we assessed the relevant parameters in adult wild-type (WT) and ERα-null (αERKO) female mice in vivo and in primary pituitary cell cultures. The αERKO mice exhibited significantly higher plasma and pituitary LH levels relative to WT females despite possessing markedly high levels of circulating E2. In contrast, hypothalamic GnRH content and circulating FSH levels were comparable between genotypes. Ovariectomy led to increased plasma LH in WT females but no further increase in αERKO females, while plasma FSH levels increased in both genotypes. E2 treatment suppressed the high plasma LH and pituitary Lhb mRNA expression in ovariectomized WT females but had no effect in αERKO. In contrast, E2 treatments only partially suppressed plasma FSH in ovariectomized WT females, but this too was lacking in αERKO females. Therefore, negative feedback on FSH is partially E2/ERα mediated but more dependent on ovarian-derived inhibin, which was increased threefold above normal in αERKO females. Together, these data indicate that E2-mediated negative feedback is dependent on functional ERα and acts to primarily regulate LH synthesis and secretion. Studies in primary cultures of pituitary cells from WT females revealed that E2 did not suppress basal or GnRH-induced LH secretion but instead enhanced the latter response, indicating that the positive influence of E2 on gonadotropin secretion may occur at the level of the pituitary. Once again this effect was lacking in αERKO gonadotropes in culture. These data indicate that the aspects of negative and positive effects of E2 on gonadotropin secretion are ERα dependent and occur at the level of the hypothalamus and pituitary respectively.

scholarly journals Positive, But Not Negative Feedback Actions of Estradiol in Adult Female Mice Require Estrogen Receptor α in Kisspeptin Neurons

Endocrinology ◽  
2015 ◽  
Vol 156 (3) ◽  
pp. 1111-1120 ◽  
Author(s):  
Sharon L. Dubois ◽  
Maricedes Acosta-Martínez ◽  
Mary R. DeJoseph ◽  
Andrew Wolfe ◽  
Sally Radovick ◽  
...  
Keyword(s):  
Estrogen Receptor ◽  
Adult Female ◽  
Negative Feedback ◽  
Positive Feedback ◽  
Estrogen Receptor Α ◽  
Female Mice ◽  
Lh Secretion ◽  
Express Estrogen Receptor ◽  
Specific Deletion

Abstract Hypothalamic kisspeptin (Kiss1) neurons express estrogen receptor α (ERα) and exert control over GnRH/LH secretion in female rodents. It has been proposed that estradiol (E2) activation of ERα in kisspeptin neurons in the arcuate nucleus (ARC) suppresses GnRH/LH secretion (negative feedback), whereas E2 activation of ERα in kisspeptin neurons in the anteroventral periventricular nucleus (AVPV) mediates the release of preovulatory GnRH/LH surges (positive feedback). To test these hypotheses, we generated mice bearing kisspeptin cell–specific deletion of ERα (KERαKO) and treated them with E2 regimens that evoke either negative or positive feedback actions on GnRH/LH secretion. Using negative feedback regimens, as expected, E2 effectively suppressed LH levels in ovariectomized (OVX) wild-type (WT) mice to the levels seen in ovary-intact mice. Surprisingly, however, despite the fact that E2 regulation of Kiss1 mRNA expression was abrogated in both the ARC and AVPV of KERαKO mice, E2 also effectively decreased LH levels in OVX KERαKO mice to the levels seen in ovary-intact mice. Conversely, using a positive feedback regimen, E2 stimulated LH surges in WT mice, but had no effect in KERαKO mice. These experiments clearly demonstrate that ERα in kisspeptin neurons is required for the positive, but not negative feedback actions of E2 on GnRH/LH secretion in adult female mice. It remains to be determined whether the failure of KERαKO mice to exhibit GnRH/LH surges reflects the role of ERα in the development of kisspeptin neurons, in the active signaling processes leading to the release of GnRH/LH surges, or both.

scholarly journals Carbon Black Nanoparticles Selectively Alter Follicle-Stimulating Hormone Expression in vitro and in vivo in Female Mice

2021 ◽  
Vol 15 ◽  
Author(s):  
Charlotte Avet ◽  
Emmanuel N. Paul ◽  
Ghislaine Garrel ◽  
Valérie Grange-Messent ◽  
David L’Hôte ◽  
...  
Keyword(s):  
Carbon Black ◽  
Follicle Stimulating Hormone ◽  
Primary Cultures ◽  
Pituitary Cells ◽  
Intratracheal Administration ◽  
Female Mice ◽  
Carbon Black Nanoparticles ◽  
Stimulating Hormone

Toxic effects of nanoparticles on female reproductive health have been documented but the underlying mechanisms still need to be clarified. Here, we investigated the effect of carbon black nanoparticles (CB NPs) on the pituitary gonadotropins, luteinizing hormone (LH) and follicle-stimulating hormone (FSH), which are key regulators of gonadal gametogenesis and steroidogenesis. To that purpose, we subjected adult female mice to a weekly non-surgical intratracheal administration of CB NPs at an occupationally relevant dose over 4 weeks. We also analyzed the effects of CB NPs in vitro, using both primary cultures of pituitary cells and the LβT2 gonadotrope cell line. We report here that exposure to CB NPs does not disrupt estrous cyclicity but increases both circulating FSH levels and pituitary FSH β-subunit gene (Fshb) expression in female mice without altering circulating LH levels. Similarly, treatment of anterior pituitary or gonadotrope LβT2 cells with increasing concentrations of CB NPs dose-dependently up-regulates FSH but not LH gene expression or release. Moreover, CB NPs enhance the stimulatory effect of GnRH on Fshb expression in LβT2 cells without interfering with LH regulation. We provide evidence that CB NPs are internalized by LβT2 cells and rapidly activate the cAMP/PKA pathway. We further show that pharmacological inhibition of PKA significantly attenuates the stimulatory effect of CB NPs on Fshb expression. Altogether, our study demonstrates that exposure to CB NPs alters FSH but not LH expression and may thus lead to gonadotropin imbalance.

scholarly journals Estrogen-Negative Feedback and Estrous Cyclicity Are Critically Dependent Upon Estrogen Receptor-α Expression in the Arcuate Nucleus of Adult Female Mice

Endocrinology ◽  
2014 ◽  
Vol 155 (8) ◽  
pp. 2986-2995 ◽  
Author(s):  
Shel-Hwa Yeo ◽  
Allan E. Herbison
Keyword(s):  
Estrogen Receptor ◽  
Negative Feedback ◽  
Arcuate Nucleus ◽  
Critical Role ◽  
Estrogen Receptor Α ◽  
Feedback Mechanism ◽  
Neuron Activity ◽  
Female Mice ◽  
Negative Feedback Mechanism ◽  
Estrous Cyclicity

The location and characteristics of cells within the brain that suppress GnRH neuron activity to contribute to the estrogen-negative feedback mechanism are poorly understood. Using adeno-associated virus (AAV)-mediated Cre-LoxP recombination in estrogen receptor-α (ERα) floxed mice (ERαflox/flox), we aimed to examine the role of ERα-expressing neurons located in the arcuate nucleus (ARN) in the estrogen-negative feedback mechanism. Bilateral injection of AAV-Cre into the ARN of ERαflox/flox mice (n = 14) resulted in the time-dependent ablation of up to 99% of ERα-immunoreactive cell numbers throughout the rostrocaudal length of the ARN. These mice were all acyclic by 5 weeks after AAV-Cre injections with most mice in constant estrous. Control wild-type mice injected with AAV-Cre (n = 13) were normal. Body weight was not altered in ERαflox/flox mice. After ovariectomy, a significant increment in LH secretion was observed in all genotypes, although its magnitude was reduced in ERαflox/flox mice. Acute and chronic estrogen-negative feedback were assessed by administering 17β-estradiol to mice as a bolus (LH measured 3 h later) or SILASTIC brand capsule implant (LH measured 5 d later). This demonstrated that chronic estrogen feedback was absent in ERαflox/flox mice, whereas the acute feedback was normal. These results reveal a critical role for ERα-expressing cells within the ARN in both estrous cyclicity and the chronic estrogen negative feedback mechanism in female mice. This suggests that ARN cells provide a key indirect, transsynpatic route through which estradiol suppresses the activity of GnRH neurons.

scholarly journals Pituitary Gonadotroph Estrogen Receptor-α Is Necessary for Fertility in Females

Endocrinology ◽  
2007 ◽  
Vol 149 (1) ◽  
pp. 20-27 ◽  
Author(s):  
Mary C. Gieske ◽  
Hyun Joon Kim ◽  
Sandra J. Legan ◽  
Yongbum Koo ◽  
Andree Krust ◽  
...  
Keyword(s):  
Estrogen Receptor ◽  
Estrogen Receptor Α ◽  
Pituitary Cells ◽  
Female Reproduction ◽  
Estrogen Action ◽  
Α Subunit ◽  
Female Mice ◽  
Reproductive Axis ◽  
Serum Lh ◽  
Estrous Cyclicity

Estrogens play a central role in regulating female reproduction throughout the reproductive axis, and the pituitary is one of the major targets of estrogen action. We hypothesized that estrogen receptor α (ERα) mediates estrogen action in the pituitary gonadotroph. To test this hypothesis, we generated a mouse line with a selective ERα deletion in the gonadotropin α-subunit (αGSU)-expressing pituitary cells (pituitary-specific ERα knockout; ERαflox/flox αGSUcre). Although the ERαflox/flox αGSUcre female mice maintain a basal level of serum LH and FSH and their ovulatory capacity is comparable to that in controls, they do not display regular estrous cycles and are infertile, indicating a potential disorder in regulating LH and/or FSH secretion. The ERαflox/flox αGSUcre female mice express equivalent levels of LHβ and αGSU mRNA compared with wild-type mice as determined by microarray analysis. Taken together, these findings indicate that pituitary gonadotroph ERα carries out the effects of estrogens with regard to estrous cyclicity and ultimately fertility.

Multiple forms of estrogen receptor-α in cerebral blood vessels: regulation by estrogen

2003 ◽  
Vol 284 (1) ◽  
pp. E184-E192 ◽  
Author(s):  
Chris Stirone ◽  
Sue P. Duckles ◽  
Diana N. Krause
Keyword(s):  
Estrogen Receptor ◽  
Blood Vessels ◽  
Estrogen Receptor Α ◽  
26S Proteasome ◽  
Target Tissue ◽  
Female Rat ◽  
Cerebral Vasculature ◽  
Cerebral Blood Vessels ◽  
Multiple Forms

The cerebral vasculature is an important target tissue for estrogen, as evidenced by significant effects of estrogen on vascular reactivity and protein levels of endothelial nitric oxide synthase and prostacyclin synthase. However, the presence, localization, and regulation of estrogen receptors in the cerebral vasculature have not been investigated. In this study, we identified the presence of estrogen receptor-α (ER-α) in female rat cerebral blood vessels and localized this receptor to both smooth muscle and endothelial cells by use of immunohistochemistry and confocal microscopy. With immunoblot analysis, multiple forms of ER-α were detected at 110, 93, 82, 50, and 45 kDa in addition to a relatively weak band corresponding to the 66-kDa putative unmodified receptor. The 82-kDa band was identified as Ser118-phosphorylated ER-α, whereas the 50-kDa band lacks the normal NH2 terminus, suggestive of an ER-α splice variant. Lower molecular mass bands persisted after in vivo inhibition of 26S proteasome activity with lactacystin, whereas the 110- and 93-kDa bands increased. All forms of ER-α in cerebral vessels were decreased after ovariectomy but significantly increased after chronic estrogen exposure in vivo.

scholarly journals Glutamatergic Transmission to Hypothalamic Kisspeptin Neurons Is Differentially Regulated by Estradiol through Estrogen Receptor α in Adult Female Mice

2017 ◽  
Vol 38 (5) ◽  
pp. 1061-1072 ◽  
Author(s):  
Luhong Wang ◽  
Laura L. Burger ◽  
Megan L. Greenwald-Yarnell ◽  
Martin G. Myers ◽  
Suzanne M. Moenter
Keyword(s):  
Estrogen Receptor ◽  
Adult Female ◽  
Estrogen Receptor Α ◽  
Glutamatergic Transmission ◽  
Female Mice

scholarly journals Nuclear Activation Function 2 Estrogen Receptor α Attenuates Arterial and Renal Alterations Due to Aging and Hypertension in Female Mice

2020 ◽  
Vol 9 (5) ◽  
Author(s):  
Emmanuel Guivarc'h ◽  
Julie Favre ◽  
Anne‐Laure Guihot ◽  
Emilie Vessières ◽  
Linda Grimaud ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Estrogen Receptor ◽  
Angiotensin Ii ◽  
Systolic Blood Pressure ◽  
Vascular Reactivity ◽  
Nuclear Gene ◽  
Estrogen Receptor Α ◽  
Protective Effects ◽  
Wild Type ◽  
Female Mice

Background The cardiovascular protective effects of estrogens in premenopausal women depend mainly on estrogen receptor α (ERα). ERα activates nuclear gene transcription regulation and membrane‐initiated signaling. The latter plays a key role in estrogen‐dependent activation of endothelial NO synthase. The goal of the present work was to determine the respective roles of the 2 ERα activities in endothelial function and cardiac and kidney damage in young and old female mice with hypertension, which is a major risk factor in postmenopausal women. Methods and Results Five‐ and 18‐month‐old female mice lacking either ERα (ERα −/− ), the nuclear activating function AF2 of ERα (AF2°), or membrane‐located ERα (C451A) were treated with angiotensin II (0.5 mg/kg per day) for 1 month. Systolic blood pressure, left ventricle weight, vascular reactivity, and kidney function were then assessed. Angiotensin II increased systolic blood pressure, ventricle weight, and vascular contractility in ERα −/− and AF2° mice more than in wild‐type and C451A mice, independent of age. In both the aorta and mesenteric resistance arteries, angiotensin II and aging reduced endothelium‐dependent relaxation in all groups, but this effect was more pronounced in ERα −/− and AF2° than in the wild‐type and C451A mice. Kidney inflammation and oxidative stress, as well as blood urea and creatinine levels, were also more pronounced in old hypertensive ERα −/− and AF2° than in old hypertensive wild‐type and C451A mice. Conclusions The nuclear ERα‐AF2 dependent function attenuates angiotensin II–dependent hypertension and protects target organs in aging mice, whereas membrane ERα signaling does not seem to play a role.

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