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.

scholarly journals Absent Progesterone Signaling in Kisspeptin Neurons Disrupts the LH Surge and Impairs Fertility in Female Mice

Endocrinology ◽  
2015 ◽  
Vol 156 (9) ◽  
pp. 3091-3097 ◽  
Author(s):  
Shannon B. Z. Stephens ◽  
Kristen P. Tolson ◽  
Melvin L. Rouse ◽  
Matthew C. Poling ◽  
Minako K. Hashimoto-Partyka ◽  
...  
Keyword(s):  
Positive Feedback ◽  
Progesterone Receptors ◽  
Sex Steroid ◽  
Corpora Lutea ◽  
Neuronal Activation ◽  
Estrogen Regulation ◽  
Lh Surge ◽  
Normal Fertility ◽  
Periventricular Nucleus

Kisspeptin, encoded by Kiss1, stimulates GnRH neurons to govern reproduction. In rodents, estrogen-sensitive kisspeptin neurons in the anterior ventral periventricular nucleus and neighboring periventricular nucleus are thought to mediate sex steroid-induced positive feedback induction of the preovulatory LH surge. These kisspeptin neurons coexpress estrogen and progesterone receptors and display enhanced neuronal activation during the LH surge. However, although estrogen regulation of kisspeptin neurons has been well studied, the role of progesterone signaling in regulating kisspeptin neurons is unknown. Here we tested whether progesterone action specifically in kisspeptin cells is essential for proper LH surge and fertility. We used Cre-lox technology to generate transgenic mice lacking progesterone receptors exclusively in kisspeptin cells (termed KissPRKOs). Male KissPRKOs displayed normal fertility and gonadotropin levels. In stark contrast, female KissPRKOs displayed earlier puberty onset and significant impairments in fertility, evidenced by fewer births and substantially reduced litter size. KissPRKOs also had fewer ovarian corpora lutea, suggesting impaired ovulation. To ascertain whether this reflects a defect in the ability to generate sex steroid-induced LH surges, females were exposed to an estradiol-positive feedback paradigm. Unlike control females, which displayed robust LH surges, KissPRKO females did not generate notable LH surges and expressed significantly blunted cfos induction in anterior ventral periventricular nucleus kisspeptin neurons, indicating that progesterone receptor signaling in kisspeptin neurons is required for normal kisspeptin neuronal activation and LH surges during positive feedback. Our novel findings demonstrate that progesterone signaling specifically in kisspeptin cells is essential for the positive feedback induction of normal LH surges, ovulation, and normal fertility in females.

scholarly journals Genetic dissection of the different roles of hypothalamic kisspeptin neurons in regulating female reproduction

2018 ◽  
Author(s):  
Luhong Wang ◽  
Charlotte Vanacker ◽  
Laura L. Burger ◽  
Tammy Barnes ◽  
Yatrik M. Shah ◽  
...  
Keyword(s):  
Negative Feedback ◽  
Knockout Mice ◽  
Positive Feedback ◽  
Gonadotropin Releasing Hormone ◽  
Genetic Dissection ◽  
Female Reproduction ◽  
Releasing Hormone ◽  
Gnrh Neurons ◽  
Reproductive Cycles ◽  
The Brain

AbstractThe brain regulates fertility through gonadotropin-releasing hormone (GnRH) neurons. Estradiol induces negative feedback on pulsatile GnRH/luteinizing hormone (LH) release and positive feedback generating preovulatory GnRH/LH surges. Negative and positive feedback are postulated to be mediated by kisspeptin neurons in arcuate and anteroventral periventricular (AVPV) nuclei, respectively. Kisspeptin-specific ERα knockout mice exhibit disrupted LH pulses and surges. This knockout approach is neither location-specific nor temporally-controlled. We utilized CRISPR-Cas9 to disrupt ERα in adulthood. Mice with ERα disruption in AVPV kisspeptin neurons have typical reproductive cycles but blunted LH surges, associated with decreased excitability of these neurons. Mice with ERα knocked down in arcuate kisspeptin neurons showed disrupted cyclicity, associated with increased glutamatergic transmission to these neurons. These observations suggest activational effects of estradiol regulate surge generation and maintain cyclicity through AVPV and arcuate kisspeptin neurons, respectively, independent from its role in the development of hypothalamic kisspeptin neurons or puberty onset.Significant StatementThe brain regulates fertility through gonadotropin-releasing hormone (GnRH) neurons. Ovarian estradiol regulates GnRH pulses (negative feedback) and the GnRH surge release that ultimately triggers ovulation (positive feedback). Kisspeptin neurons in the arcuate and anteroventral periventricular nuclei are postulated to convey negative and positive feedback to GnRH neurons, respectively. Kisspeptin-specific ERα knockout mice exhibited disrupted negative and positive feedback. However, it is not clear what roles each kisspeptin population plays, and not possible to separate their roles during development vs adulthood in this model. Here we utilized CRISPR-Cas9 to disrupt ERα in each population in adulthood. We found activational effects of estradiol regulate surge generation and maintain cyclicity through AVPV and arcuate kisspeptin neurons, respectively, independent from estradiol action during development.

CONVERSION OF PROGESTERONE TO 5α- AND 5β-REDUCED METABOLITES IN THE BRAIN OF THE HEN AND ITS POTENTIAL ROLE IN THE INDUCTION OF THE PREOVULATORY RELEASE OF LUTEINIZING HORMONE

1980 ◽  
Vol 86 (3) ◽  
pp. 459-464 ◽  
Author(s):  
P. J. SHARP ◽  
R. MASSA
Keyword(s):  
Luteinizing Hormone ◽  
Pituitary Gland ◽  
Positive Feedback ◽  
Potential Role ◽  
Laying Hen ◽  
Feedback Effect ◽  
Lh Release ◽  
The Brain ◽  
Positive Feedback Effect

In the laying hen, progesterone was shown to be converted in vitro in the pituitary gland and the hypothalamus to 5β-pregnane-3,20-dione (5β-DHP), 5β-pregnan-3α-ol-20-one (5β,3α-ol) and 5α-pregnane-3,20-dione (5α-DHP) and in the hyperstriatum dorsale to 5β-DHP and 5β,3α-ol. The conversion of progesterone to 5β-reduced metabolites was greater in the hyperstriatum dorsale than in the hypothalamus (P<0·001) and greater in the hypothalamus than in the pituitary gland (P <0·01). The conversion of progesterone to 5β-reduced metabolites was greater than its conversion to 5α-DHP in the pituitary gland (P <0·01) and the hypothalamus (P < 0·001). The possibility was investigated that 5α-DHP and 5β-DHP may act as metabolic intermediaries in the mechanism by which progesterone exerts a positive feedback effect on LH release. Progesterone, 5α-DHP and 5β-DHP were injected into laying hens at doses of 0·05,0·25 and 1·25 mg/kg and the changes in the concentration of plasma LH were followed for 4 h thereafter. Secretion of LH was stimulated after treatment with progesterone or 5α-DHP but not 5β-DHP. Progesterone stimulated LH release more effectively than did 5α-DHP, since an increase in the concentration of plasma LH was observed after 0·25 mg progesterone/kg but not after the same dose of 5α-DHP. It was concluded that in the hen 5α-DHP is unlikely to play a role in the induction of the preovulatory release of LH.

OVARIAN STEROID EFFECTS ON GONADOTROPHIN OUTPUT, AND ON THE INCORPORATION OF 35S FROM METHIONINE INTO PROTEIN OF DISCRETE BRAIN AREAS AND THE ANTERIOR PITUITARY

1977 ◽  
Vol 85 (2) ◽  
pp. 279-290
Author(s):  
M. B. ter Haar ◽  
P. C. B. MacKinnon
Keyword(s):  
Luteinizing Hormone ◽  
Median Eminence ◽  
Anterior Pituitary ◽  
Preoptic Area ◽  
Ovarian Hormones ◽  
Female Rats ◽  
Brain Areas ◽  
Lh Surge ◽  
Progesterone Metabolites ◽  
The Brain

ABSTRACT The effects of various ovarian hormones administered on the morning of pro-oestrus on gonadotrophin levels and the incorporation of 35S from methionine into protein of discrete areas of the brain and the anterior pituitary were investigated at 15.00 h of the same day in female rats. The hormones which were investigated in this study could be divided in general into two groups according to their actions. The first group, consisting of oestradiol-17β and progesterone, tended to advance the preovulatory surge of luteinizing hormone (LH) by 3–6 h from 18.00–21.00 h, together with the peaks of [35S] incorporation in the median eminence area and the anterior pituitary which normally accompany the LH surge. The second group, consisting of the LH-stimulated reduced progesterone metabolites, 5α-pregnane-3,20-dione (pregnanedione) and 20α-hydroxypregn-4-en-3-one (dihydroprogesterone), tended to inhibit serum gonadotrophin levels as well as inhibiting the pro-oestrous increase of [35S] incorporation in the median eminence area and in the amygdala, but not in the preoptic area and the anterior pituitary. On the afternoon of pro-oestrus in intact animals, luteinizing hormonereleasing hormone or LH administration had the same effect on [35S]incorporation in the brain as did the progesterone metabolites, though this effect was not observed if the animals had been ovariectomized a few hours beforehand. It is suggested that certain ovarian hormones are involved in the neural events which induce the pre-ovulatory LH surge, while others are associated with neural events which terminate the stimulus for the LH surge.

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.

scholarly journals Neuroprogesterone signals through Src kinase within RP3V neurons to induce the luteinizing hormone surge in female rats

2019 ◽  
Author(s):  
Timbora Chuon ◽  
Micah Feri ◽  
Claire Carlson ◽  
Sharity Ondrejik ◽  
Paul Micevych ◽  
...  
Keyword(s):  
Luteinizing Hormone ◽  
Neural Circuits ◽  
Third Ventricle ◽  
Progesterone Receptors ◽  
Female Rats ◽  
Estradiol Treatment ◽  
Lh Surge ◽  
Src Inhibitor ◽  
Luteinizing Hormone Surge

ABSTRACTNeural circuits in female rats are exposed to estradiol and sequential progesterone to regulate the luteinizing hormone (LH) surge and thus ovulation. Estradiol induces progesterone receptors (PGRs) in rostral periventricular region of the third ventricle (RP3V) kisspeptin neurons, and positive feedback estradiol concentrations induce neuroprogesterone (neuroP) synthesis in hypothalamic astrocytes that signal to PGRs expressed in kisspeptin neurons to trigger the LH surge. We tested the hypothesis that neuroP-PGR signals through Src family kinase (Src) to trigger the LH surge. As in vitro, PGR and Src are co-expressed in RP3V neurons. Estradiol treatment increased the number of PGR immunopositive cells and PGR and Src colocalization. Infusion of the Src inhibitor (PP2) into the RP3V, attenuated the LH surge measured by ELISA in trunk blood collected 53 hours post-EB injection. While PP2 reduced the LH surge in 50 μg EB treated ovariectomized/adrenalectomized (ovx/adx) rats, activation of either PGR or Src in 2μg EB primed animals significantly elevated LH concentrations compared with DMSO treated ovx/adx rats. These results support the importance of Src in the estradiol and neuroP triggering of the LH surge.

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.

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