Faculty Opinions recommendation of Positive, but not negative feedback actions of estradiol in adult female mice require estrogen receptor α in kisspeptin neurons.

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.

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

Journal of Neuroscience ◽

10.1523/jneurosci.2428-17.2017 ◽

2017 ◽

Vol 38 (5) ◽

pp. 1061-1072 ◽

Cited By ~ 15

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

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

Journal of Endocrinology ◽

10.1677/joe.1.06965 ◽

2006 ◽

Vol 191 (1) ◽

pp. 309-317 ◽

Cited By ~ 28

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.

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Effects of Neuron-Specific Estrogen Receptor (ER) α and ERβ Deletion on the Acute Estrogen Negative Feedback Mechanism in Adult Female Mice

Endocrinology ◽

10.1210/en.2013-1943 ◽

2014 ◽

Vol 155 (4) ◽

pp. 1418-1427 ◽

Cited By ~ 26

Author(s):

Rachel Y. Cheong ◽

Robert Porteous ◽

Pierre Chambon ◽

István Ábrahám ◽

Allan E. Herbison

Keyword(s):

Estrogen Receptor ◽

Adult Female ◽

Negative Feedback ◽

Feedback Mechanism ◽

Mutant Mice ◽

Estrous Cycles ◽

Female Mice ◽

Negative Feedback Mechanism ◽

Gnrh Neurons ◽

Lh Secretion

The negative feedback mechanism through which 17β-estradiol (E2) acts to suppress the activity of the GnRH neurons remains unclear. Using inducible and cell-specific genetic mouse models, we examined the estrogen receptor (ER) isoforms expressed by neurons that mediate acute estrogen negative feedback. Adult female mutant mice in which ERα was deleted from all neurons in the neonatal period failed to exhibit estrous cycles or negative feedback. Adult mutant female mice with neonatal neuronal ERβ deletion exhibited normal estrous cycles, but a failure of E2 to suppress LH secretion was seen in ovariectomized mice. Mutant mice with a GnRH neuron–selective deletion of ERβ exhibited normal cycles and negative feedback, suggesting no critical role for ERβ in GnRH neurons in acute negative feedback. To examine the adult roles of neurons expressing ERα, an inducible tamoxifen-based Cre-LoxP approach was used to ablate ERα from neurons that express calmodulin kinase IIα in adults. This resulted in mice with no estrous cycles, a normal increase in LH after ovariectomy, but an inability of E2 to suppress LH secretion. Finally, acute administration of ERα- and ERβ-selective agonists to adult ovariectomized wild-type mice revealed that activation of ERα suppressed LH secretion, whereas ERβ agonists had no effect. This study highlights the differences in adult reproductive phenotypes that result from neonatal vs adult ablation of ERα in the brain. Together, these experiments expand previous global knockout studies by demonstrating that neurons expressing ERα are essential and probably sufficient for the acute estrogen negative feedback mechanism in female mice.

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

Endocrinology ◽

10.1210/en.2014-1128 ◽

2014 ◽

Vol 155 (8) ◽

pp. 2986-2995 ◽

Cited By ~ 34

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.

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

Journal of the American Heart Association ◽

10.1161/jaha.119.013895 ◽

2020 ◽

Vol 9 (5) ◽

Cited By ~ 3

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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Evidence that Orphanin FQ Mediates Progesterone Negative Feedback in the Ewe

Endocrinology ◽

10.1210/en.2013-1274 ◽

2013 ◽

Vol 154 (11) ◽

pp. 4249-4258 ◽

Cited By ~ 8

Author(s):

Casey C Nestor ◽

Lique M. Coolen ◽

Gail L. Nesselrod ◽

Miro Valent ◽

John M. Connors ◽

...

Keyword(s):

Estrogen Receptor ◽

Negative Feedback ◽

Luteal Phase ◽

Arcuate Nucleus ◽

Pulse Amplitude ◽

Estrogen Receptor Α ◽

Pulse Frequency ◽

Orphanin Fq ◽

High Degree ◽

Lh Secretion

Orphanin FQ (OFQ), a member of the opioid family, is found in many areas of the hypothalamus and, when given centrally OFQ inhibits episodic LH secretion in rodents and sheep. Because GnRH neurons are devoid of the appropriate receptors to mediate steroid negative feedback directly, neurons that release OFQ may be involved. Using immunocytochemistry, we first determined that most OFQ neurons in the arcuate nucleus (ARC) and other hypothalamic regions of luteal phase ewes contained both estrogen receptor α and progesterone (P) receptor. Given a similar high degree of steroid receptor colocalization in other ARC subpopulations, we examined whether OFQ neurons of the ARC contained those other neuropeptides and neurotransmitters. OFQ did not colocalize with kisspeptin, tyrosine hydroxylase, or agouti-related peptide, but all ARC OFQ neurons coexpressed proopiomelanocortin. To test for a role for endogenous OFQ, we examined the effects of an OFQ receptor antagonist, [Nphe1,Arg14,Lys15]Nociceptin-NH2 (UFP-101) (30 nmol intracerebroventricular/h), on LH secretion in steroid-treated ewes in the breeding season and ovary-intact ewes in anestrus. Ovariectomized ewes with luteal phase concentrations of P and estradiol showed a significant increase in LH pulse frequency during infusion of UFP-101 (4.5 ± 0.5 pulses/6 h) compared with saline infusion (2.6 ± 0.4 pulses/6 h), whereas ewes implanted with only estradiol did not. Ovary-intact anestrous ewes displayed no significant differences in LH pulse amplitude or frequency during infusion of UFP-101. Therefore, we conclude that OFQ mediates, at least in part, the negative feedback action of P on GnRH/LH pulse frequency in sheep.

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