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

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.

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

Reproduction ◽

10.1530/rep-11-0214 ◽

2012 ◽

Vol 143 (4) ◽

pp. 549-558 ◽

Cited By ~ 15

Author(s):

José E Sánchez-Criado ◽

Kourtney Trudgen ◽

Yolanda Millán ◽

Alfonso Blanco ◽

José Monterde ◽

...

Keyword(s):

Estrogen Receptor ◽

Pituitary Cells ◽

Immunohistochemical Expression ◽

Female Mice ◽

Serum Lh ◽

Pituitary Glands ◽

17Β Estradiol ◽

Lh Secretion ◽

Estrogen Receptor 1

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 μg 17β-estradiol (E2), 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 (35.9±2.0% 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 (21.0±3.0% 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 E2 exerted its action in KO mouse gonadotropes via ESR2.

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Theca-Specific Estrogen Receptor-α Knockout Mice Lose Fertility Prematurely

Endocrinology ◽

10.1210/en.2008-1774 ◽

2009 ◽

Vol 150 (8) ◽

pp. 3855-3862 ◽

Cited By ~ 53

Author(s):

Sungeun Lee ◽

Dong-Wook Kang ◽

Susan Hudgins-Spivey ◽

Andree Krust ◽

Eun-Young Lee ◽

...

Keyword(s):

Estrogen Receptor ◽

Knockout Mice ◽

Critical Role ◽

Serum Testosterone ◽

Estrogen Receptor Α ◽

Corpora Lutea ◽

Wild Type ◽

Female Reproduction ◽

Estrogen Action ◽

Theca Cells

Estrogen receptor-α (Esr1) mediates estrogen action in regulating at all levels of the hypothalamic-pituitary-ovarian axis. Whereas the importance of Esr1 in hypothalamus and pituitary has been demonstrated by loss of fertility in the neuron- and pituitary-specific Esr1 knockout mice, whether Esr1 plays a critical role in the ovary remains to be determined. In the ovary, Esr1 is mainly expressed in the theca/interstitial cells and germinal epithelium and thus is believed to mediate estrogen action in these cells. In this study, we assessed the importance of Esr1 in the ovarian theca cells in regulating female reproduction. The Cre-LoxP approach was used to selectively delete the Esr1 gene in the theca cells, and the reproductive consequence of the deletion was measured. Adolescent theca-specific Esr1 knockout (thEsr1KO) mice (<4 months of age) are fertile and cycling. However, they begin to display an erratic pattern of estrous cycles and become infertile before they reach the age of 6 months. The ovaries of thEsr1KOmice (≥4 months) have fewer corpora lutea but more antral follicles than the age-matching wild-type mice. The numbers of 17-hydroxylase-expressing cells are largely increased in the interstitium of the thEsr1KO mouse ovary. Interestingly, whereas basal levels of serum testosterone and FSH were mildly elevated, LH level was either markedly lower or undetectable in the thEsr1KO mice. When superstimulated by exogenous gonadotropins, thEsr1KO mice released significantly fewer oocytes that wild-type littermates and developed multiple hemorrhagic cysts. Taken together, this study demonstrates that theca Esr1 plays a critical role in regulating female reproduction.

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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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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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