scholarly journals RP3V kisspeptin neurons mediate neuroprogesterone induction of the luteinizing hormone surge in female rat

2019 ◽  
Author(s):  
Lauren K. Delhousay ◽  
Timbora Chuon ◽  
Melinda Mittleman-Smith ◽  
Paul Micevych ◽  
Kevin Sinchak
Keyword(s):  
Luteinizing Hormone ◽  
Steroid Receptors ◽  
Estradiol Benzoate ◽  
Estrogen Receptor Α ◽  
Medial Septum ◽  
Subsequent Treatment ◽  
Antisense Oligodeoxynucleotide ◽  
Female Rat ◽  
Lh Surge ◽  
Gnrh Neurons

ABSTRACTTo induce ovulation, neural circuits are sequentially activated by estradiol and progesterone. In female rodents, estradiol-induced neuroprogesterone, synthesized in astrocytes, is essential for the luteinizing hormone (LH) surge and subsequently, ovulation. However, the gonadotropin-releasing hormone (GnRH) neurons do not express the steroid receptors necessary for reproduction: progesterone receptors (PGR) or estrogen receptor-α (ERα). Steroid information is transduced by rostral periventricular (RP3V) kisspeptin neurons that express ERα and PGR and innervate GnRH neurons in the diagonal band of Broca (DBB) and the medial septum. In this study, we tested the hypothesis that estradiol induced neuroprogesterone needed for the LH surge is mediated by kisspeptin. Neuroprogesterone synthesis was inhibited with aminoglutethimide (AGT; s.c.) in 17β-estradiol benzoate (EB)-primed, ovariectomized (ovx) and adrenalectomized (adx) rats. Kisspeptin-10 (20 nmol/µl) was infused into the DBB, trunk blood was collected 53 hours post-EB injection, and serum LH levels were analyzed by ELISA. AGT inhibition of neuroprogesterone synthesis blocked the EB-induced LH surge. Subsequent treatment with either progesterone or DBB kisspeptin-10 infusion restored the LH surge. Kisspeptin restored the LH surge, which was blocked by DBB infusion of kisspeptin receptor (GPR54) antagonist (kisspeptin-234). Finally, knockdown of kisspeptin protein levels in the RP3V with kisspeptin antisense oligodeoxynucleotide (ODN) significantly lowered LH levels in EB-primed rats compared to scrambled ODN, demonstrating the importance of endogenous RP3V kisspeptin for the LH surge. These results support the hypothesis that neuroprogesterone induces both kisspeptin release from RP3V neurons impacting the LH surge.

Progesterone receptors in AVPV kisspeptin neurons are sufficient for positive feedback induction of the LH surge

Endocrinology ◽  
2021 ◽  
Author(s):  
Margaret A Mohr ◽  
Lourdes A Esparza ◽  
Paige Steffen ◽  
Paul E Micevych ◽  
Alexander S Kauffman
Keyword(s):  
Luteinizing Hormone ◽  
Transgenic Mice ◽  
Positive Feedback ◽  
Progesterone Receptors ◽  
Critical Importance ◽  
Estrogen And Progesterone Receptors ◽  
Lh Surge ◽  
Normal Fertility ◽  
Gnrh Neurons ◽  
The Brain

Abstract Kisspeptin, encoded by Kiss1, stimulates GnRH neurons to govern reproduction. In female rodents, estrogen-sensitive kisspeptin neurons in the rostral anteroventral periventricular (AVPV) hypothalamus are thought to mediate estradiol (E2)-induced positive feedback induction of the preovulatory luteinizing hormone (LH) surge. AVPV kisspeptin neurons co-express estrogen and progesterone receptors (PGR) and are activated during the LH surge. While E2 effects on kisspeptin neurons have been well-studied, progesterone’s regulation of kisspeptin neurons is less understood. Using transgenic mice lacking PGR exclusively in kisspeptin cells (termed KissPRKOs), we previously demonstrated that progesterone action specifically in kisspeptin cells is essential for ovulation and normal fertility. Unlike control females, KissPRKO females did not generate proper LH surges, indicating that PGR signaling in kisspeptin cells is required for proper positive feedback. However, since PGR was knocked out from all kisspeptin neurons in the brain, that study was unable to determine the specific kisspeptin population mediating PGR action on the LH surge. Here, we used targeted Cre-mediated AAV technology to re-introduce PGR selectively into AVPV kisspeptin neurons of adult KissPRKO females, and tested whether this rescues occurrence of the LH surge. We found that targeted upregulation of PGR in kisspeptin neurons exclusively in the AVPV is sufficient to restore proper E2-induced LH surges in KissPRKO females, suggesting that this specific kisspeptin population is a key target of the necessary progesterone action for the surge. These findings further highlight the critical importance of progesterone signaling, along with E2 signaling, in the positive feedback induction of LH surges and ovulation.

Expression of estrogen receptor-α and c-Fos in adrenergic neurons of the female rat during the steroid-induced LH surge

2000 ◽  
Vol 875 (1-2) ◽  
pp. 56-65 ◽  
Author(s):  
Eun-Joo Lee ◽  
Constance T Moore ◽  
Somaya Hosny ◽  
Adrian Centers ◽  
Lothar Jennes
Keyword(s):  
Estrogen Receptor ◽  
Estrogen Receptor Α ◽  
Female Rat ◽  
Lh Surge ◽  
Adrenergic Neurons

scholarly journals Estradiol Dose-Dependent Regulation of Membrane Estrogen Receptor-α, Metabotropic Glutamate Receptor-1a, and Their Complexes in the Arcuate Nucleus of the Hypothalamus in Female Rats

Endocrinology ◽  
2013 ◽  
Vol 154 (9) ◽  
pp. 3251-3260 ◽  
Author(s):  
Matthew Mahavongtrakul ◽  
Martha P. Kanjiya ◽  
Maribel Maciel ◽  
Shrey Kanjiya ◽  
Kevin Sinchak
Keyword(s):  
Estrogen Receptor ◽  
Glutamate Receptor ◽  
Arcuate Nucleus ◽  
Metabotropic Glutamate Receptor ◽  
Estradiol Benzoate ◽  
Estrogen Receptor Α ◽  
Female Rats ◽  
Female Rat ◽  
Metabotropic Glutamate ◽  
Dose Dependent

Sexual receptivity in the female rat is dependent on dose and duration of estradiol exposure. A 2 μg dose of estradiol benzoate (EB) primes reproductive behavior circuits without facilitating lordosis. However, 50 μg EB facilitates lordosis after 48 hours. Both EB doses activate membrane estrogen receptor-α (mERα) that complexes with and signals through metabotropic glutamate receptor-1a (mGluR1a). This mERα-mGluR1a signaling activates a multisynaptic lordosis-inhibiting circuit in the arcuate nucleus (ARH) that releases β-endorphin in the medial preoptic nucleus (MPN), activating μ-opioid receptors (MOP). MPN MOP activation is maintained, inhibiting lordosis for 48 hours by 2 μg EB, whereas 50 μg EB at 48 hours deactivates MPN MOP, facilitating lordosis. We hypothesized that 50 μg EB down-regulates ERα and mERα-mGluR1a complexes in the ARH to remove mERα-mGluR1a signaling. In experiment I, 48 hours after 2 μg or 50 μg EB, the number of ARH ERα-immunopositive cells was reduced compared with controls. In experiment II, compared with oil controls, total ARH ERα protein was decreased 48 hours after 50 μg EB, but the 2 μg dose was not. These results indicate that both EB doses reduced the total number of cells expressing ERα, but 2 μg EB may have maintained or increased ERα expressed per cell, whereas 50 μg EB appeared to reduce total ERα per cell. In experiment III, coimmunoprecipitation and Western blot revealed that total mERα and coimmunoprecipitated mERα with mGluR1a were greater 48 hours after 2 μg EB treatment vs rats receiving 50 μg EB. These results indicate 2 μg EB maintains but 50 μg EB down-regulates mERα-mGluR1a to regulate the lordosis circuit activity.

scholarly journals Genetic Deletion of Esr1 in the Mouse Preoptic Area Disrupts the LH Surge and Estrous Cyclicity

Endocrinology ◽  
2019 ◽  
Vol 160 (8) ◽  
pp. 1821-1829 ◽  
Author(s):  
Robert Porteous ◽  
Allan E Herbison
Keyword(s):  
Estrogen Receptor ◽  
Third Ventricle ◽  
Estrogen Receptor Α ◽  
Adeno Associated Virus ◽  
Estrous Cycles ◽  
Lh Surge ◽  
Periventricular Nucleus ◽  
Gnrh Neurons ◽  
Estrous Cyclicity ◽  
Periventricular Area

Abstract Estrogen receptor α (ESR1) is critical for the generation of the preovulatory LH surge. Experiments in rodents have indicated a role for neurons located in the anteroventral periventricular area and preoptic periventricular nucleus [termed the rostral periventricular area of the third ventricle (RP3V)] in surge generation. In the current study, we aimed to examine whether ESR1 expressed by RP3V neurons was necessary for the LH surge. The estrous cycles of mice with estrogen receptor α (Esr1) exon 3 flanked by LoxP sites (Esr1 flox) and controls were monitored before and after bilateral stereotactic injection of adeno-associated virus encoding Cre recombinase into the RP3V. This resulted in 84% and 72% decreases in ESR1-immunoreactive cell numbers in the anteroventral periventricular area and preoptic periventricular nucleus, respectively, with no changes in the arcuate nucleus. Beginning three weeks after the adeno-associated virus injection, Esr1 flox mice began to show a loss of estrous cyclicity going, primarily, into constant estrus. Wild-type mice and Esr1 flox mice with injections outside the RP3V or unilateral ablations of ESR1 continued to exhibit normal estrous cycles. Mice were then gonadectomized and given an estradiol replacement regimen to generate the LH surge. This resulted in an absence of cFOS expression in GnRH neurons (1 ± 1% vs 28 ± 4% of GnRH neurons; P < 0.01) and markedly reduced LH surge levels (2.5 ± 0.6 vs 9.1 ± 1.0 ng/mL; P < 0.01) in Esr1 flox mice compared with controls. These results demonstrate that neurons expressing ESR1 within the RP3V are critical for the generation of the LH surge and estrous cyclicity in the mouse.

A reevaluation of the refractory period following the estrogen-induced luteinizing hormone surge in the rhesus monkey

1980 ◽  
Vol 58 (8) ◽  
pp. 995-998
Author(s):  
Richard F. Weick
Keyword(s):  
Luteinizing Hormone ◽  
Rhesus Monkey ◽  
Refractory Period ◽  
Rhesus Monkeys ◽  
Estradiol Benzoate ◽  
Intact Female ◽  
Lh Surge ◽  
Female Rhesus ◽  
Luteinizing Hormone Surge ◽  
Estradiol 17Β

A refractory period of 6-8 days following the estrogen-induced luteinizing hormone (LH) surge in the rhesus monkey has been reported, the estrogen having been applied as injections of estradiol benzoate. This was reinvestigated using Silastic capsules filled with estradiol-17β. Mature intact female rhesus monkeys were given two successive exposures to estrogen, each of 48 h duration. In one experiment the second exposure started 4 days after the capsules were first implanted (2 days after removal), in the second experiment, 3 days after implantation (1 day after removal). LH surges were seen in response to both estrogen treatments in both experiments. The results suggest that a period of exposure to relatively low estrogen levels is required before a second LH surge can be elicited. This period of time can be as short as 24 h.

scholarly journals Optogenetic Activation of Arcuate Kisspeptin Neurons Generates a Luteinizing Hormone Surge-Like Secretion in an Estradiol-Dependent Manner

2021 ◽  
Vol 12 ◽  
Author(s):  
Xian-Hua Lin ◽  
Geffen Lass ◽  
Ling-Si Kong ◽  
Hui Wang ◽  
Xiao-Feng Li ◽  
...  
Keyword(s):  
Luteinizing Hormone ◽  
Brain Area ◽  
Estradiol Benzoate ◽  
Dependent Manner ◽  
Lh Surge ◽  
Expected Time ◽  
17Β Estradiol ◽  
Stimulation Period ◽  
Lh Release ◽  
Lh Secretion

Traditionally, the anteroventral periventricular (AVPV) nucleus has been the brain area associated with luteinizing hormone (LH) surge secretion in rodents. However, the role of the other population of hypothalamic kisspeptin neurons, in the arcuate nucleus (ARC), has been less well characterized with respect to surge generation. Previous experiments have demonstrated ARC kisspeptin knockdown reduced the amplitude of LH surges, indicating that they have a role in surge amplification. The present study used an optogenetic approach to selectively stimulate ARC kisspeptin neurons and examine the effect on LH surges in mice with different hormonal administrations. LH level was monitored from 13:00 to 21:00 h, at 30-minute intervals. Intact Kiss-Cre female mice showed increased LH secretion during the stimulation period in addition to displaying a spontaneous LH surge around the time of lights off. In ovariectomized Kiss-Cre mice, optogenetic stimulation was followed by a surge-like secretion of LH immediately after the stimulation period. Ovariectomized Kiss-Cre mice with a low dose of 17β-estradiol (OVX+E) replacement displayed a surge-like increase in LH release during period of optic stimulation. No LH response to the optic stimulation was observed in OVX+E mice on the day of estradiol benzoate (EB) treatment (day 1). However, after administration of progesterone (day 2), all OVX+E+EB+P mice exhibited an LH surge during optic stimulation. A spontaneous LH surge also occurred in these mice at the expected time. Taken together, these results help to affirm the fact that ARC kisspeptin may have a novel amplificatory role in LH surge production, which is dependent on the gonadal steroid milieu.

scholarly journals Kisspeptin Is Essential for the Full Preovulatory LH Surge and Stimulates GnRH Release from the Isolated Ovine Median Eminence

Endocrinology ◽  
2011 ◽  
Vol 152 (3) ◽  
pp. 1001-1012 ◽  
Author(s):  
Jeremy T. Smith ◽  
Qun Li ◽  
Kai Sing Yap ◽  
Muhammad Shahab ◽  
Antonia K. Roseweir ◽  
...  
Keyword(s):  
Median Eminence ◽  
Positive Feedback ◽  
Estradiol Benzoate ◽  
Portal System ◽  
Neuronal Tracing ◽  
Lh Surge ◽  
External Zone ◽  
Gnrh Secretion ◽  
Gnrh Neurons ◽  
Gnrh Release

Kisspeptins are the product of the Kiss1 gene and potently stimulate GnRH secretion. In sheep, Kiss1 mRNA-expressing cells are found in the arcuate nucleus (ARC) and dorsal-lateral preoptic area and both appear to mediate the positive feedback effect of estradiol to generate the preovulatory GnRH/LH surge. To determine the role of kisspeptin in transmitting estrogen-positive feedback in the hypothalamus, we administered the kisspeptin antagonist p-271 to ewes subjected to an estradiol benzoate-induced LH surge. Kisspeptin antagonist treatment significantly attenuated these LH surges. We further examined the response to kisspeptin treatment prior to the LH surge. Kisspeptin significantly stimulated GnRH secretion into the hypophysial portal system, but the response to kisspeptin was similar in luteal and late-follicular phase ewes. Kiss1r mRNA expression in GnRH neurons was also similar across the estrous cycle. To examine alternative pathways for kisspeptin stimulation of GnRH neurons, we examined the origin of kisspeptin neuronal fibers in the external zone of the median eminence (ME) using neuronal tracing and immunohistochemical techniques. ARC populations of kisspeptin neurons project fibers to the ME. Finally, we showed kisspeptin stimulates GnRH release from ovine ME-cultured explants. This suggests direct kisspeptin to GnRH terminal-to-terminal communication within the ME. Overall, these data indicate an essential role for kisspeptin in receiving stimulatory estrogen signals and generating the full positive feedback GnRH/LH surge. Kisspeptin neurons of the ARC project to the external zone of the ME and kisspeptin acts upon the GnRH fibers at this level.

Neurophysiological control of the secretion of gonadotrophin-releasing hormone and luteinizing hormone in the sheep--a review

1991 ◽  
Vol 3 (2) ◽  
pp. 137 ◽  
Author(s):  
JC Thiery ◽  
GB Martin
Keyword(s):  
Luteinizing Hormone ◽  
Steroid Receptors ◽  
Pulse Amplitude ◽  
Pulse Frequency ◽  
Neural Pathways ◽  
Releasing Hormone ◽  
Diagonal Band ◽  
Gonadotrophin Secretion ◽  
Gnrh Neurons ◽  
Gonadotrophin Releasing Hormone

The anterior pituitary gland secretes pulses of luteinizing hormone (LH) in response to pulses of gonadotrophin-releasing hormone (GnRH) released into the hypophysial portal blood by the hypothalamus. The pulsatile nature of the secretions is very important because the frequency of the pulses is directly related to the activity of the GnRH neurons. We can therefore take advantage of this phenomenon to develop mechanistic interpretations of responses to experimental treatments designed to unravel the neural pathways that influence what is, arguably, the most important individual signal controlling the activity of the reproductive system. We might also resolve the disagreements in the literature covering the neuropharmacology of gonadotrophin secretion. In this review, we describe work towards this end in the sheep. Most (95%) of the 2500 GnRH cell bodies in the sheep brain are located in a region covering the anterior hypothalamus, the medial preoptic area, the diagonal band of Broca, and the septum. The axons of up to 50% of these cells terminate in the organum vasculosum of the lamina terminalis. The remainder terminate in the median eminence and form the final common pathway for the many factors that affect gonadotrophin secretion. Among the factors known to affect the frequency of the pulses (or the activity of the GnRH neurons) are nutrition, pheromones, photoperiod and gonadal steroids (negative and positive feedback). Factors that affect GnRH pulse amplitude are more difficult to determine because variations in pituitary responsiveness prevent the use of LH patterns as a 'bioassay'. Techniques developed recently have allowed the direct measurement of GnRH pulse amplitude and revealed inhibitory effects of oestradiol, but we do not know whether this effect is due to a reduction in the amount of GnRH released by each neurone or a reduction in the number of neurones releasing a pulse. It is unlikely that the factors that alter pulse frequency do so by directly affecting the GnRH cells. For example, it is obvious that other cells, with specific receptors for pheromonal or nutritional stimuli, formulate a signal that is transferred to the GnRH cells via interneurones. Similarly, it is likely that a hypothalamic clock intervenes between photoperiodic inputs and GnRH output. Opioidergic neurons have been proposed as a link in this system, but the complexity of their action makes it unlikely that they directly affect the GnRH neurons. The responses to steroids are simple and rapid, but steroid receptors have not been found in GnRH cells, so at least one other set of interneurones is involved.(ABSTRACT TRUNCATED AT 400 WORDS)

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