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 Release of Norepinephrine in the Preoptic Area Activates Anteroventral Periventricular Nucleus Neurons and Stimulates the Surge of Luteinizing Hormone

Endocrinology ◽  
2013 ◽  
Vol 154 (1) ◽  
pp. 363-374 ◽  
Author(s):  
Raphael E. Szawka ◽  
Maristela O. Poletini ◽  
Cristiane M. Leite ◽  
Marcelo P. Bernuci ◽  
Bruna Kalil ◽  
...  
Keyword(s):  
Positive Feedback ◽  
Preoptic Area ◽  
Lh Surge ◽  
Ovx Rats ◽  
Selective Lesion ◽  
Periventricular Nucleus ◽  
Reverse Microdialysis ◽  
Fos Expression ◽  
Lh Secretion

The role of norepinephrine (NE) in regulation of LH is still controversial. We investigated the role played by NE in the positive feedback of estradiol and progesterone. Ovarian-steroid control over NE release in the preoptic area (POA) was determined using microdialysis. Compared with ovariectomized (OVX) rats, estradiol-treated OVX (OVX+E) rats displayed lower release of NE in the morning but increased release coincident with the afternoon surge of LH. OVX rats treated with estradiol and progesterone (OVX+EP) exhibited markedly greater NE release than OVX+E rats, and amplification of the LH surge. The effect of NE on LH secretion was confirmed using reverse microdialysis. The LH surge and c-Fos expression in anteroventral periventricular nucleus neurons were significantly increased in OVX+E rats dialyzed with 100 nm NE in the POA. After Fluoro-Gold injection in the POA, c-Fos expression in Fluoro-Gold/tyrosine hydroxylase-immunoreactive neurons increased during the afternoon in the A2 of both OVX+E and OVX+EP rats, in the locus coeruleus (LC) of OVX+EP rats, but was unchanged in the A1. The selective lesion of LC terminals, by intracerebroventricular N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine, reduced the surge of LH in OVX+EP but not in OVX+E rats. Thus, estradiol and progesterone activate A2 and LC neurons, respectively, and this is associated with the increased release of NE in the POA and the magnitude of the LH surge. NE stimulates LH secretion, at least in part, through activation of anteroventral periventricular neurons. These findings contribute to elucidation of the role played by NE during the positive feedback of ovarian steroids.

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.

Characterizing the neuroendocrine and ovarian defects of androgen receptor-knockout female mice

2013 ◽  
Vol 305 (6) ◽  
pp. E717-E726 ◽  
Author(s):  
Xiaobing B. Cheng ◽  
Mark Jimenez ◽  
Reena Desai ◽  
Linda J. Middleton ◽  
Shai R. Joseph ◽  
...  
Keyword(s):  
Androgen Receptor ◽  
Negative Feedback ◽  
Positive Feedback ◽  
Growth Patterns ◽  
Corpora Lutea ◽  
Preovulatory Follicle ◽  
Lh Surge ◽  
Antral Follicles ◽  
Female Mice ◽  
Follicle Diameter

Homozygous androgen receptor (AR)-knockout (ARKO) female mice are subfertile due to both intra- and extraovarian (neuroendocrine) defects as defined by ovary transplantation. Using ARKO mice, this study set out to reveal the precise AR-regulated pathways required for optimal androgen-regulated ovulation and fertility. ARKO females exhibit deficient neuroendocrine negative feedback, with a reduced serum luteinizing hormone (LH) response to ovariectomy (OVX) ( P < 0.01). Positive feedback is also altered as intact ARKO females, at late proestrus, exhibit an often mistimed endogenous ovulatory LH surge. Furthermore, at late proestrus, intact ARKO females display diminished preovulatory serum estradiol (E2; P < 0.01) and LH ( P < 0.05) surge levels and reduced Kiss1 mRNA expression in the anteroventral periventricular nucleus ( P < 0.01) compared with controls. However, this reduced ovulatory LH response in intact ARKO females can be rescued by OVX and E2 priming or treatment with endogenous GnRH. These findings reveal that AR regulates the negative feedback response to E2, E2-positive feedback is compromised in ARKO mice, and AR-regulated negative and positive steroidal feedback pathways impact on intrahypothalamic control of the kisspeptin/GnRH/LH cascade. In addition, intraovarian AR-regulated pathways controlling antral to preovulatory follicle dynamics are disrupted because adult ARKO ovaries collected at proestrus have small antral follicles with reduced oocyte/follicle diameter ratios ( P < 0.01) and increased proportions of unhealthy large antral follicles ( P < 0.05) compared with controls. As a consequence of aberrant follicular growth patterns, proestrus ARKO ovaries also exhibit fewer preovulatory follicle ( P < 0.05) and corpora lutea numbers ( P < 0.01). However, embryo development to the blastocyst stage is unchanged in ARKO females, and hence, the subfertility is a consequence of reduced ovulations and not altered embryo quality. These findings reveal that the AR has a functional role in neuroendocrine regulation and timing of the ovulatory LH surge as well as antral/preovulatory follicle development.

Estrogen regulation of the molecular phenotype and active translatome of AVPV kisspeptin neurons

Endocrinology ◽  
2021 ◽  
Author(s):  
Shannon B Z Stephens ◽  
Alexander S Kauffman
Keyword(s):  
Positive Feedback ◽  
Molecular Mechanisms ◽  
Hormone Secretion ◽  
Feedback Regulation ◽  
Rna Seq ◽  
Molecular Phenotype ◽  
Estrogen Regulation ◽  
Physiological Processes ◽  
Estrogen Effects

Abstract In females, ovarian estradiol (E2) exerts both negative and positive feedback regulation on the neural circuits governing reproductive hormone secretion, but the cellular and molecular mechanisms underlying this remain poorly understood. In rodents, ERα-expressing kisspeptin neurons in the hypothalamic anteroventral periventricular region (AVPV) are prime candidates to mediate E2 positive feedback induction of preovulatory GnRH and LH surges. E2 stimulates AVPV Kiss1 expression, but the full extent of estrogen effects in these neurons is unknown; whether E2 stimulates or inhibits other genes in AVPV Kiss1 cells has not been determined. Indeed, understanding of the function(s) of AVPV kisspeptin cells is limited, in part, by minimal knowledge of their overall molecular phenotype, as only a few genes are currently known to be co-expressed in AVPV Kiss1 cells. To provide a more detailed profiling of co-expressed genes in AVPV Kiss1 cells, including receptors and other signaling factors, and test how these genes respond to E2, we selectively isolated actively-translated mRNAs from AVPV Kiss1 cells of female mice and performed RNA-Seq. This identified &gt;13,000 mRNAs co-expressed in AVPV Kiss1 cells, including multiple receptor and ligand transcripts positively or negatively regulated by E2. We also performed RNAscope to validate high co-expression of several transcripts identified by RNA-Seq, including Pdyn (prodynorphin), Penk (proenkephalin), Vgf (VGF), and Cartpt (CART), in female AVPV Kiss1 cells. Given the important role of AVPV kisspeptin cells in positive feedback, E2 effects on identified genes may relate to the LH surge mechanism and/or other physiological processes involving these AVPV kisspeptin cells.

scholarly journals KNDy (Kisspeptin/Neurokinin B/Dynorphin) Neurons Are Activated during Both Pulsatile and Surge Secretion of LH in the Ewe

Endocrinology ◽  
2012 ◽  
Vol 153 (11) ◽  
pp. 5406-5414 ◽  
Author(s):  
Christina M. Merkley ◽  
Katrina L. Porter ◽  
Lique M. Coolen ◽  
Stanley M. Hileman ◽  
Heather J. Billings ◽  
...  
Keyword(s):  
Negative Feedback ◽  
Positive Feedback ◽  
Neurokinin B ◽  
Lh Surge ◽  
Short And Long Term ◽  
Positive And Negative Feedback ◽  
Kndy Neurons ◽  
Lh Secretion

Abstract KNDy (kisspeptin/neurokinin B/dynorphin) neurons of the arcuate nucleus (ARC) appear to mediate the negative feedback actions of estradiol and are thought to be key regulators of pulsatile LH secretion. In the ewe, KNDy neurons may also be involved with the positive feedback actions of estradiol (E2) to induce the LH surge, but the role of kisspeptin neurons in the preoptic area (POA) remains unclear. The goal of this study was to identify which population(s) of kisspeptin neurons is (are) activated during the LH surge and in response to the removal of E2-negative feedback, using Fos as an index of neuronal activation. Dual-label immunocytochemistry for kisspeptin and Fos was performed on sections containing the ARC and POA from ewes during the luteal phase of the estrous cycle, or before or after the onset of the LH surge (experiment 1), and from ovary-intact, short-term (24 h) and long-term (&gt;30 d) ovariectomized (OVX) ewes in anestrus (experiment 2). The percentage of kisspeptin neurons expressing Fos in both the ARC and POA was significantly higher during the LH surge. In contrast, the percentage of kisspeptin/Fos colocalization was significantly increased in the ARC, but not POA, after both short- and long-term E2 withdrawal. Thus, POA kisspeptin neurons in the sheep are activated during, and appear to contribute to, E2-positive feedback, whereas ARC kisspeptin (KNDy) neurons are activated during both surge and pulsatile modes of secretion and likely play a role in mediating both positive and negative feedback actions of E2 on GnRH secretion in the ewe.

scholarly journals Kisspeptin Neurons and Estrogen–Estrogen Receptor α Signaling: Unraveling the Mystery of Steroid Feedback System Regulating Mammalian Reproduction

2021 ◽  
Vol 22 (17) ◽  
pp. 9229
Author(s):  
Yoshihisa Uenoyama ◽  
Naoko Inoue ◽  
Sho Nakamura ◽  
Hiroko Tsukamura
Keyword(s):  
Estrogen Receptor ◽  
Positive Feedback ◽  
Arcuate Nucleus ◽  
Feedback System ◽  
Estrogen Receptor Α ◽  
Pulsatile Gnrh ◽  
Periventricular Nucleus ◽  
Gnrh Release ◽  
Estrogen Positive Feedback

Estrogen produced by ovarian follicles plays a key role in the central mechanisms controlling reproduction via regulation of gonadotropin-releasing hormone (GnRH) release by its negative and positive feedback actions in female mammals. It has been well accepted that estrogen receptor α (ERα) mediates both estrogen feedback actions, but precise targets had remained as a mystery for decades. Ever since the discovery of kisspeptin neurons as afferent ERα-expressing neurons to govern GnRH neurons, the mechanisms mediating estrogen feedback are gradually being unraveled. The present article overviews the role of kisspeptin neurons in the arcuate nucleus (ARC), which are considered to drive pulsatile GnRH/gonadotropin release and folliculogenesis, in mediating the estrogen negative feedback action, and the role of kisspeptin neurons located in the anteroventral periventricular nucleus-periventricular nucleus (AVPV-PeN), which are thought to drive GnRH/luteinizing hormone (LH) surge and consequent ovulation, in mediating the estrogen positive feedback action. This implication has been confirmed by the studies showing that estrogen-bound ERα down- and up-regulates kisspeptin gene (Kiss1) expression in the ARC and AVPV-PeN kisspeptin neurons, respectively. The article also provides the molecular and epigenetic mechanisms regulating Kiss1 expression in kisspeptin neurons by estrogen. Further, afferent ERα-expressing neurons that may regulate kisspeptin release are discussed.

The role of sex steroid receptors in sheep female reproductive physiology

2004 ◽  
Vol 16 (4) ◽  
pp. 385 ◽  
Author(s):  
A. Meikle ◽  
C. Tasende ◽  
C. Sosa ◽  
E. G. Garófalo
Keyword(s):  
Steroid Receptors ◽  
Post Partum ◽  
Progesterone Receptors ◽  
Reproductive Physiology ◽  
Receptor Expression ◽  
Present Review ◽  
Sex Steroid ◽  
Receptor Subtypes ◽  
Luteal Function

Cell responsiveness to steroid hormones is related to the number and affinity of its receptors, thus factors affecting steroid expression will influence tissue sensitivity and functionality. The present review discusses the role of oestrogen and progesterone receptors in sheep female reproductive physiology. The mechanism of steroid hormone action in the target cell is introduced first; the tissue distribution, physiological functions and regulation of oestrogen receptor subtypes and progesterone receptor isoforms in ruminants are reported. The role of steroid receptors in target tissues (with emphasis on the uterus and pituitary gland) during different physiological events is addressed in an attempt to clarify oestrogen and progesterone actions in different developmental and reproductive stages: prepubertal period, oestrous cycle, pregnancy, post-partum period and seasonal anoestrus. The present review shows how the distinct reproductive stages are accompanied by dramatic changes in uterine receptor expression. The role of oestrogen and progesterone receptors in the molecular mechanism responsible for premature luteolysis that results in subnormal luteal function is discussed. Finally, the effect of nutrition on sex steroid receptor expression and the involvement on reproductive performance is reported.

ZUR BEDEUTUNG DES HYPOPHYSÄREN LUTEINISIERUNGSHORMONS FÜR SCHWANGERSCHAFT, GEBURT UND LACTATION BEI DER RATTE

1970 ◽  
Vol 65 (3_Suppl) ◽  
pp. S5-S32 ◽  
Author(s):  
K. Loewit
Keyword(s):  
Luteinizing Hormone ◽  
Early Pregnancy ◽  
Hydroxysteroid Dehydrogenase ◽  
The State ◽  
Termination Of Pregnancy ◽  
Progesterone Level ◽  
Corpora Lutea ◽  
Regulatory Properties ◽  
Duration Of Pregnancy

ABSTRACT The role of luteinizing hormone (LH) for the maintenance of pregnancy, parturition and lactation was investigated by immunological and histochemical methods in the rat. Neutralisation of endogenous rat-LH with Rabbit-Anti-Bovine-LH-Serum (selective hypophysectomy) from days 7-12 of pregnancy resulted in reabsorption of the foetuses and the reappearance of strong 20α-hydroxysteroid-dehydrogenase (20α-OHSD) activity in the corpora lutea (CL) of pregnancy, which normally show no such activity at that time. This effect could be prevented in part by concurrent pregnenolone administration and fully by progesterone, but was not influenced by oestrogen or prolactin. It is concluded that in early pregnancy LH is the main luteotrophic hormone in the rat even though prolactin might act synergistically with it. Antiserum treatment after the 12th day of gestation had no influence on the state or duration of pregnancy or on parturition. LH-injections during the first half of pregnancy had no luteolytic effects i. e. they did not activate 20α-OHSD activity. After day 16 they advanced the reappearance of the enzyme, but delayed parturition or resulted in stillbirths. Neither LH nor antiserum seemed to alter lactation. Since progesterone prevented both the termination of pregnancy and the recurrence of 20α-OHSD activity, it should have some regulatory properties on the enzyme. It is discussed whether the gonadotrophin-dependent progesterone level could regulate the 20α-OHSD activity rather than result from it.

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