scholarly journals Hypothalamic Insulin-Like Growth Factor-I Receptors Are Necessary for Hormone-Dependent Luteinizing Hormone Surges: Implications for Female Reproductive Aging

Endocrinology ◽  
2010 ◽  
Vol 151 (3) ◽  
pp. 1356-1366 ◽  
Author(s):  
Brigitte J. Todd ◽  
Zaher O. Merhi ◽  
Jun Shu ◽  
Anne M. Etgen ◽  
Genevieve S. Neal-Perry
Keyword(s):  
Young Adult ◽  
Third Ventricle ◽  
Female Rats ◽  
Aged Rats ◽  
Gnrh Neuron ◽  
Middle Aged ◽  
Reproductive Senescence ◽  
Lh Surge ◽  
Neuron Activation ◽  
Igf I

Brain IGF-I receptors are required for maintenance of estrous cycles in young adult female rats. Circulating and hypothalamic IGF-I levels decrease with aging, suggesting a role for IGF-I in the onset of reproductive senescence. Therefore, the present study investigated potential mechanisms of action of brain IGF-I receptors in the regulation of LH surges in young adult and middle-aged rats. We continuously infused IGF-I, the selective IGF-I receptor antagonist JB-1, or vehicle into the third ventricle of ovariectomized young adult and middle-aged female rats primed with estradiol and progesterone. Pharmacological blockade of IGF-I receptors attenuated and delayed the LH surge in young adult rats, reminiscent of the LH surge pattern that heralds the onset of reproductive senescence in middle-aged female rats. Infusion of IGF-I alone had no effect on the LH surge but reversed JB-1 attenuation of the surge in young females. In middle-aged rats, infusion of low doses of IGF-I partially restored LH surge amplitude, and infusion of JB-1 completely obliterated the surge. Intraventricular infusion of IGF-I or JB-1 did not modify pituitary sensitivity to exogenous GnRH or GnRH peptide content in the anterior or mediobasal hypothalamus in either young or middle-aged rats. These findings support the hypothesis that brain IGF-I receptor signaling is necessary for GnRH neuron activation under estrogen-positive feedback conditions and that decreased brain IGF-I signaling in middle-aged females contributes, in part, to LH surge dysfunction by disrupting estradiol-sensitive processes that affect GnRH neuron activation and/or GnRH release.

scholarly journals Hypothalamic Molecular Changes Underlying Natural Reproductive Senescence in the Female Rat

Endocrinology ◽  
2014 ◽  
Vol 155 (9) ◽  
pp. 3597-3609 ◽  
Author(s):  
Bailey A. Kermath ◽  
Penny D. Riha ◽  
Michael J. Woller ◽  
Andrew Wolfe ◽  
Andrea C. Gore
Keyword(s):  
Estrogen Receptor ◽  
Estrogen Receptor Α ◽  
Steroid Hormone Receptors ◽  
Female Rats ◽  
Mrna Levels ◽  
Female Rat ◽  
Aged Rats ◽  
Middle Aged ◽  
Reproductive Senescence ◽  
Periventricular Nucleus

Abstract The role of the hypothalamus in female reproductive senescence is unclear. Here we identified novel molecular neuroendocrine changes during the natural progression from regular reproductive cycles to acyclicity in middle-aged female rats, comparable with the perimenopausal progression in women. Expression of 48 neuroendocrine genes was quantified within three hypothalamic regions: the anteroventral periventricular nucleus, the site of steroid positive feedback onto GnRH neurons; the arcuate nucleus (ARC), the site of negative feedback and pulsatile GnRH release; and the median eminence (ME), the site of GnRH secretion. Surprisingly, the majority of changes occurred in the ARC and ME, with few effects in anteroventral periventricular nucleus. The overall pattern was increased mRNA levels with chronological age and decreases with reproductive cycle status in middle-aged rats. Affected genes included transcription factors (Stat5b, Arnt, Ahr), sex steroid hormone receptors (Esr1, Esr2, Pgr, Ar), steroidogenic enzymes (Sts, Hsd17b8), growth factors (Igf1, Tgfa), and neuropeptides (Kiss1, Tac2, Gnrh1). Bionetwork analysis revealed region-specific correlations between genes and hormones. Immunohistochemical analyses of kisspeptin and estrogen receptor-α in the ARC demonstrated age-related decreases in kisspeptin cell numbers as well as kisspeptin-estrogen receptor-α dual-labeled cells. Taken together, these results identify unexpectedly strong roles for the ME and ARC during reproductive decline and highlight fundamental differences between middle-aged rats with regular cycles and all other groups. Our data provide evidence of decreased excitatory stimulation and altered hormone feedback with aging and suggest novel neuroendocrine pathways that warrant future study. Furthermore, these changes may impact other neuroendocrine systems that undergo functional declines with age.

scholarly journals The Increase in Signaling by Kisspeptin Neurons in the Preoptic Area and Associated Changes in Clock Gene Expression That Trigger the LH Surge in Female Rats Are Dependent on the Facilitatory Action of a Noradrenaline Input

Endocrinology ◽  
2016 ◽  
Vol 157 (1) ◽  
pp. 323-335 ◽  
Author(s):  
Bruna Kalil ◽  
Aline B. Ribeiro ◽  
Cristiane M. Leite ◽  
Ernane T. Uchôa ◽  
Ruither O. Carolino ◽  
...  
Keyword(s):  
Gene Expression ◽  
Median Eminence ◽  
Preoptic Area ◽  
Clock Genes ◽  
Third Ventricle ◽  
Female Rats ◽  
Ovariectomized Rats ◽  
Lh Surge ◽  
Clock Gene Expression

Abstract In rodents, kisspeptin neurons in the rostral periventricular area of the third ventricle (RP3V) of the preoptic area are considered to provide a major stimulatory input to the GnRH neuronal network that is responsible for triggering the preovulatory LH surge. Noradrenaline (NA) is one of the main modulators of GnRH release, and NA fibers are found in close apposition to kisspeptin neurons in the RP3V. Our objective was to interrogate the role of NA signaling in the kisspeptin control of GnRH secretion during the estradiol induced LH surge in ovariectomized rats, using prazosin, an α1-adrenergic receptor antagonist. In control rats, the estradiol-induced LH surge at 17 hours was associated with a significant increase in GnRH and kisspeptin content in the median eminence with the increase in kisspeptin preceding that of GnRH and LH. Prazosin, administered 5 and 3 hours prior to the predicted time of the LH surge truncated the LH surge and abolished the rise in GnRH and kisspeptin in the median eminence. In the preoptic area, prazosin blocked the increases in Kiss1 gene expression and kisspeptin content in association with a disruption in the expression of the clock genes, Per1 and Bmal1. Together these findings demonstrate for the first time that NA modulates kisspeptin synthesis in the RP3V through the activation of α1-adrenergic receptors prior to the initiation of the LH surge and indicate a potential role of α1-adrenergic signaling in the circadian-controlled pathway timing of the preovulatory LH surge.

scholarly journals Age-Related Effects on Right Femoral Bone of Male Wistar Rats: A Morphometric and Biomechanical Study

2021 ◽  
Author(s):  
Sheila Martins Puelker ◽  
Sonia Regina Ribeiro de Castro ◽  
Romeu Rodrigues de Souza ◽  
Laura Beatriz Mesiano Maifrino ◽  
Ricardo Aparecido Baptista Nucci ◽  
...  
Keyword(s):  
Cortical Thickness ◽  
Wistar Rats ◽  
Female Rats ◽  
Male Rats ◽  
Aged Rats ◽  
Femoral Bone ◽  
Middle Aged ◽  
Left Femur ◽  
Bone Stiffness ◽  
The Right

Abstract Introduction Study of the variations of bone characteristics with age in different animal models is important to design musculoskeletal studies. Thus, this study aimed to evaluate the bone mass, dimensions, and biomechanical parameters of the femur in young, middle-aged, and aged Wistar rats. Materials and Methods Thirty male rats (Rattus norvegicus) were divided in three groups (n = 10 per group)—3-month-old young rats, 12-month-old middle-aged rats, and 18-months-old aged rats. The right femurs were subjected sequentially to morphometric study (bone weight, cortical thickness) and biomechanical tests (maximum resistance strength and bone stiffness). Results We observed a significant increase in femur histological (cortical thickness) and biomechanical (maximum strength and bone stiffness) parameters with aging when compared with young animals. Conclusions With the advancing age, the right femoral bone of middle-aged and old animals had greater variations when compared with young animals. However, further studies with the aid of a comparison between right and left femur and other long bones in both male and female rats are needed to corroborate with our findings.

scholarly journals Pup removal suppresses estrogen-induced surges of LH secretion and activation of GnRH neurons in lactating rats

2006 ◽  
Vol 191 (1) ◽  
pp. 339-348 ◽  
Author(s):  
Atsushi Fukushima ◽  
Ping Yin ◽  
Maho Ishida ◽  
Nobuhiro Sugiyama ◽  
Jun Arita
Keyword(s):  
Third Ventricle ◽  
Acute Effect ◽  
Suppressive Effect ◽  
Female Rats ◽  
Ovariectomized Rats ◽  
Indwelling Catheter ◽  
Lh Surge ◽  
Gnrh Neurons ◽  
Double Immunohistochemical Staining ◽  
Lh Secretion

During lactation, the suckling stimulus exerts profound influences on neuroendocrine regulation in nursing rats. We examined the acute effect of pup removal on the estrogen-induced surge of LH secretion in ovariectomized lactating rats. Lactating and nonlactating cyclic female rats were given an estradiol-containing capsule after ovariectomy, and blood samples were collected through an indwelling catheter for serum LH determinations. In lactating, freely suckled ovariectomized rats, estrogen treatment induced an afternoon LH surge with a magnitude and timing comparable to those seen in nonlactating rats. Removal of pups from the lactating rats at 0900, 1100, or 1300 h, but not at 1500 h, suppressed the estrogen-induced surge that normally occurs in the afternoon of the same day. The suppressive effect of pup removal at 0900 h was completely abolished when the pups were returned by 1400 h. In contrast, pup removal was ineffective in abolishing the stimulatory effect of progesterone on LH surges. Double immunohistochemical staining for gonadotropin-releasing hormone (GnRH) and c-Fos, a marker for neuronal activation, revealed a decrease, concomitantly with the suppression of LH surges, in the number of c-Fos-immunoreactive GnRH neurons in the preoptic regions of nonsuckled rats. An LH surge was restored in nonsuckled rats when 0.1 μg oxytocin was injected into the third ventricle three times at 1-h intervals during pup removal. These results suggest that the GnRH surge generator of lactating rats requires the suckling stimulus that is not involved in nonlactating cyclic female rats.

Effects of central hypocretin-1 administration on hemodynamic responses in young-adult and middle-aged rats

2003 ◽  
Vol 981 (1-2) ◽  
pp. 143-150 ◽  
Author(s):  
Kazuyoshi Hirota ◽  
Tetsuya Kushikata ◽  
Mihoko Kudo ◽  
Tsuyoshi Kudo ◽  
Darren Smart ◽  
...  
Keyword(s):  
Young Adult ◽  
Aged Rats ◽  
Middle Aged ◽  
Hemodynamic Responses ◽  
Hypocretin 1

scholarly journals Vasoactive Intestinal Peptide Modulation of the Steroid-Induced LH Surge Involves Kisspeptin Signaling in Young but Not in Middle-Aged Female Rats

Endocrinology ◽  
2014 ◽  
Vol 155 (6) ◽  
pp. 2222-2232 ◽  
Author(s):  
Alexander S. Kauffman ◽  
Yan Sun ◽  
Joshua Kim ◽  
Azim R. Khan ◽  
Jun Shu ◽  
...  
Keyword(s):  
Vasoactive Intestinal Peptide ◽  
Suprachiasmatic Nucleus ◽  
Reproductive Age ◽  
Female Rats ◽  
Mrna Levels ◽  
Dependent Manner ◽  
Middle Aged ◽  
Lh Surge ◽  
Young Females ◽  
Gnrh Neurons

Age-related LH surge dysfunction in middle-aged rats is characterized, in part, by reduced responsiveness to estradiol (E2)-positive feedback and reduced hypothalamic kisspeptin neurotransmission. Vasoactive intestinal peptide (VIP) neurons in the suprachiasmatic nucleus project to hypothalamic regions that house kisspeptin neurons. Additionally, middle-age females express less VIP mRNA in the suprachiasmatic nucleus on the day of the LH surge and intracerebroventricular (icv) VIP infusion restores LH surges. We tested the hypothesis that icv infusion of VIP modulates the LH surge through effects on the kisspeptin and RFamide-related peptide-3 (RFRP-3; an estradiol-regulated inhibitor of GnRH neurons) neurotransmitter systems. Brains were collected for in situ hybridization analyses from ovariectomized and ovarian hormone-primed young and middle-aged females infused with VIP or saline. The percentage of GnRH and Kiss1 cells coexpressing cfos and total Kiss1 mRNA were reduced in saline-infused middle-aged compared with young females. In young females, VIP reduced the percentage of GnRH and Kiss1 cells coexpressing cfos, suggesting that increased VIP signaling in young females adversely affected the function of Kiss1 and GnRH neurons. In middle-aged females, VIP increased the percentage of GnRH but not Kiss1 neurons coexpressing cfos, suggesting VIP affects LH release in middle-aged females through kisspeptin-independent effects on GnRH neurons. Neither reproductive age nor VIP affected Rfrp cell number, Rfrp mRNA levels per cell, or coexpression of cfos in Rfrp cells. These data suggest that VIP differentially affects activation of GnRH and kisspeptin neurons of female rats in an age-dependent manner.

Relation of attenuated proestrous luteinizing hormone surges in middle-aged female rats to in vitro pituitary gonadotropin-releasing hormone responsiveness

1994 ◽  
Vol 130 (5) ◽  
pp. 540-544 ◽  
Author(s):  
Aurelia N Brito ◽  
Timothy E Sayles ◽  
Richard J Krieg ◽  
Dennis W Matt
Keyword(s):  
Luteinizing Hormone ◽  
Gonadotropin Releasing Hormone ◽  
Female Rats ◽  
Aged Rats ◽  
Middle Aged ◽  
Releasing Hormone ◽  
Young Females ◽  
Pituitary Gonadotropin ◽  
Hormone Responsiveness

Brito AN, Sayles TE, Krieg Jr RJ, Matt DW. Relation of attenuated proestrous luteinizing hormone surges in middle-aged female rats to in vitro pituitary gonadotropin-releasing hormone responsiveness. Eur J Endocrinol 1994;130:540–4. ISSN 0804–4643 Prior to the cessation of regular cyclicity, middle-aged rats display pre-ovulatory luteinizing hormone (LH) surges of reduced magnitude. The present study was designed to identify whether middle-aged female rats with attenuated proestrous LH surges have alterations in pituitary responsiveness to gonadotropin-releasing hormone (GnRH). Young (4 months old) and middle-aged (10–12 months old) regularly cycling females were catheterized and sampled on proestrus to characterize their LH surge profiles. On the next proestrus (12.00 h), pituitaries were perifused individually and exposed to three pulses of GnRH (30 nmol/l). The patterns of the proestrous LH surges revealed that 12 of 22 middle-aged rats had attenuated surges (< 7 μg/l) while the remaining 10 middle-aged females had surges that were similar to those of young rats. Pituitaries perifused on the next proestrus showed similar basal LH release among the middle-aged and young females. However, the LH secretory rates following the second and third administration of GnRH, as well as the overall GnRH-stimulated LH secretory rates, were significantly decreased in middle-aged females with previously attenuated LH surges as compared to those from the young proestrous rats. In contrast, middle-aged rats with normal LH surges had pituitary LH responses that were no different from those of young females. These results indicate that a decrease in pituitary LH responsiveness to GnRH is only apparent in middle-aged rats that display attenuated proestrous LH surges. Dennis W Matt. Department of Obstetrics and Gynecology, Medical College of Virginia, Box 980034, Richmond, VA 23298, USA

scholarly journals The Excitatory Peptide Kisspeptin Restores the Luteinizing Hormone Surge and Modulates Amino Acid Neurotransmission in the Medial Preoptic Area of Middle-Aged Rats

Endocrinology ◽  
2009 ◽  
Vol 150 (8) ◽  
pp. 3699-3708 ◽  
Author(s):  
Genevieve Neal-Perry ◽  
Diane Lebesgue ◽  
Matthew Lederman ◽  
Jun Shu ◽  
Gail D. Zeevalk ◽  
...  
Keyword(s):  
Positive Feedback ◽  
Preoptic Area ◽  
Gaba Release ◽  
Medial Preoptic Area ◽  
Aged Rats ◽  
Middle Aged ◽  
Lh Surge ◽  
Age Related ◽  
Lh Release ◽  
Estrogen Positive Feedback

Reproductive success depends on a robust and appropriately timed preovulatory LH surge. The LH surge, in turn, requires ovarian steroid modulation of GnRH neuron activation by the neuropeptide kisspeptin and glutamate and γ-aminobutyric acid (GABA) neurotransmission in the medial preoptic area (mPOA). Middle-aged females exhibit reduced excitation of GnRH neurons and attenuated LH surges under estrogen-positive feedback conditions, in part, due to increased GABA and decreased glutamate neurotransmission in the mPOA. This study tested the hypothesis that altered kisspeptin regulation by ovarian steroids plays a role in age-related LH surge dysfunction. We demonstrate that middle-aged rats exhibiting delayed and attenuated LH surges have reduced levels of Kiss1 mRNA in the anterior hypothalamus under estrogen-positive feedback conditions. Kisspeptin application directly into the mPOA rescues total LH release and the LH surge amplitude in middle-aged rats and increases glutamate and decreases GABA release to levels seen in the mPOA of young females. Moreover, the N-methyl-d-aspartate receptor antagonist MK801 blocks kisspeptin reinstatement of the LH surge. These observations suggest that age-related LH surge dysfunction results, in part, from reduced kisspeptin drive under estrogen-positive feedback conditions and that kisspeptin regulates GnRH/LH release, in part, through modulation of mPOA glutamate and GABA release.

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