scholarly journals Maternal sympathetic stress impairs follicular development and puberty of the offspring

Reproduction ◽  
2014 ◽  
Vol 148 (2) ◽  
pp. 137-145 ◽  
Author(s):  
Rafael Barra ◽  
Gonzalo Cruz ◽  
Artur Mayerhofer ◽  
Alfonso Paredes ◽  
Hernán E Lara
Keyword(s):  
Cold Stress ◽  
Plasma Levels ◽  
Polycystic Ovary ◽  
Sympathetic Innervation ◽  
Follicular Development ◽  
Sympathetic Nerves ◽  
Adult Rats ◽  
Compensatory Response ◽  
Pregnant Rats ◽  
Sympathetic Stress

Chronic cold stress applied to adult rats activates ovarian sympathetic innervation and develops polycystic ovary (PCO) phenotype. The PCO syndrome in humans originates during early development and is expressed before or during puberty, which suggests that the condition derived from in utero exposure to neural- or metabolic-derived insults. We studied the effects of maternal sympathetic stress on the ovarian follicular development and on the onset of puberty of female offspring. Timed pregnant rats were exposed to chronic cold stress (4 °C, 3 h/daily from 1000 to 1300 h) during the entire pregnancy. Neonatal rats exposed to sympathetic stress during gestation had a lower number of primary, primordial, and secondary follicles in the ovary and a lower recruitment of primary and secondary follicles derived from the primordial follicular pool. The expression of the FSH receptor and response of the neonatal ovary to FSH were reduced. A decrease in nerve growth factor (NGF) mRNA was found without change in the low-affinity NGF receptor. The FSH-induced development of secondary follicles was decreased. At puberty, estradiol plasma levels decreased without changes in LH plasma levels. Puberty onset (as shown by the vaginal opening) was delayed. Ovarian norepinephrine (NE) was reduced; there was no change in its metabolite, 3-methoxy-4-hydroxyphenylglycol, in stressed rats and no change in NE turnover. The changes in ovarian NE in prepubertal rats stressed during gestation could represent a lower development of sympathetic nerves as a compensatory response to the chronically increased NE levels during gestation and hence participate in delaying reproductive performance in the rat.

scholarly journals In vivo blockade of ovarian sympathetic activity by Neosaxitoxin prevents polycystic ovary in rats

2020 ◽  
Vol 244 (3) ◽  
pp. 523-533
Author(s):  
Miguel del Campo ◽  
Néstor Lagos ◽  
Hernán Lara
Keyword(s):  
Plasma Levels ◽  
Polycystic Ovary ◽  
Follicular Development ◽  
Sympathetic Nerves ◽  
Estradiol Valerate ◽  
Plasma Testosterone ◽  
Corpora Lutea ◽  
Follicular Cyst ◽  
Estrous Cycling

A high sympathetic tone is observed in the development and maintenance of the polycystic ovary (PCO) phenotype in rats. Neosaxitoxin (NeoSTX) specifically blocks neuronal voltage-dependent Na+ channels, and we studied the capacity of NeoSTX administered into the ovary to block sympathetic nerves and PCO phenotype that is induced by estradiol valerate (EV). The toxin was administered with a minipump inserted into the bursal cavity using two protocols: (1) the same day as EV administration and (2) 30 days after EV to block the final step of cyst development and maintenance of the condition. We studied the estrous cycling activity, follicular morphology, steroid plasma levels, and norepinephrine concentration. NeoSTX administered together with EV decreased NA intraovarian levels that were induced by EV, increased the number of corpora lutea, decreased the number of follicular cyst found after EV administration, and decreased the previously increased testosterone plasma levels induced by the PCO phenotype. Estrous cycling activity also recovered. NeoSTX applied after 30 days of EV administration showed near recovery of ovary function, suggesting that there is a specific window in which follicular development could be protected from cystic development. In addition, plasma testosterone levels decreased while those of progesterone increased. Our data strongly suggest that chronic inhibition of sympathetic nerves by a locally applied long-lasting toxin is a new tool to manage the polycystic phenotype in the rat and could be applied to other mammals depending on sympathetic nerve activity.

Acute cold stress in rheumatoid arthritis inadequately activates stress responses and induces an increase of interleukin 6

2008 ◽  
Vol 68 (4) ◽  
pp. 572-578 ◽  
Author(s):  
R H Straub ◽  
G Pongratz ◽  
H Hirvonen ◽  
T Pohjolainen ◽  
M Mikkelsson ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Stress Response ◽  
Cold Stress ◽  
Stress Responses ◽  
Plasma Levels ◽  
Acute Stress ◽  
Whole Body ◽  
Cold Therapy ◽  
Before And After ◽  
Sympathetic Stress

Objective:Acute stress in patients with rheumatoid arthritis (RA) should stimulate a strong stress response. After cryotherapy, we expected to observe an increase of hormones of the adrenal gland and the sympathetic nervous system.Methods:A total of 55 patients with RA were recruited for whole-body cryotherapy at −110°C and −60°C, and local cold therapy between −20°C and −30°C for 7 days. We measured plasma levels of steroid hormones, neuropeptide Y (sympathetic marker), and interleukin (IL)6 daily before and after cryotherapy.Results:In both therapy groups with/without glucocorticoids (GC), hormone and IL6 levels at baseline and 5 h after cold stress did not change over 7 days of cryotherapy. In patients without GC, plasma levels of cortisol and androstenedione were highest after −110°C cold stress followed by −60°C or local cold stress. The opposite was found in patients under GC therapy, in whom, unexpectedly, −110°C cold stress elicited the smallest responses. In patients without GC, adrenal cortisol production increased relative to other adrenal steroids, and again the opposite was seen under GC therapy with a loss of cortisol and an increase of dehydroepiandrosterone. Importantly, there was no sympathetic stress response in both groups. Patients without GC and −110°C cold stress demonstrated higher plasma IL6 compared to the other treatment groups (not observed under GC), but they showed the best clinical response.Conclusions:We detected an inadequate stress response in patients with GC. It is further shown that the sympathetic stress response was inadequate in patients with/without GC. Paradoxically, plasma levels of IL6 increased under strong cold stress in patients without GC. These findings confirm dysfunctional stress axes in RA.

scholarly journals Role of ovarian sympathetic nerves and cholinergic local system during cold stress

2019 ◽  
Vol 242 (2) ◽  
pp. 115-124 ◽  
Author(s):  
Raul Riquelme ◽  
Freddy Ruz ◽  
Artur Mayerhofer ◽  
Hernán E Lara
Keyword(s):  
Cold Stress ◽  
Polycystic Ovary ◽  
Recovery Period ◽  
Sympathetic Nerves ◽  
Plasma Testosterone ◽  
Corpora Lutea ◽  
Estrous Cyclicity ◽  
Rat Ovary ◽  
The Impact ◽  
Second Period

An increase in the sympathetic tone in the rat ovary induces a polycystic ovary (PCOS-like) phenotype. No information exists about its impact on fertility. In contrast, increased follicular development and improved fertility in rats were found after pharmacological inhibition of acetylcholinesterase, which increased intraovarian acetylcholine (ACh). Now, we studied the impact of sympathetic stress, followed by a recovery period without stress, on the cholinergic and noradrenergic systems of the rat ovary and on fertility. To activate ovarian sympathetic nerves, female Sprague–Dawley rats were exposed to cold stress (4°C/3 h day for 28 days; first period), followed by a 28-day period without cold stress (second period). No changes in estrous cyclicity during the first period was found. At the end of this period, ovarian levels of NA and ACh were increased. Morphometric analysis showed lower numbers of secondary and antral follicles, enhanced follicular atresia and fewer corpora lutea. Plasma progesterone was lower and testosterone was higher than that in controls. At end of the second period, ovarian ACh levels had returned to control levels, but NA levels remained elevated. The second period was also characterized by the presence of cystic follicles in the ovary, by elevated plasma testosterone and estradiol levels, while progesterone levels were decreased. Estrous cyclicity and ovulation during that period were irregular and fertility decreased. Thus, cold stress initially activated both ovarian noradrenergic and cholinergic system. After stress, the ovary did not fully recover and activation of the noradrenergic system persisted and correlated with cystic ovarian morphology and decreased fertility.

Fetal programming by androgen excess in rats affects ovarian fuel sensors and steroidogenesis

2019 ◽  
Vol 10 (6) ◽  
pp. 645-658 ◽  
Author(s):  
Giselle Adriana Abruzzese ◽  
Maria Florencia Heber ◽  
Fiorella Campo Verde Arbocco ◽  
Silvana Rocio Ferreira ◽  
Alicia Beatriz Motta
Keyword(s):  
Fetal Programming ◽  
Polycystic Ovary ◽  
Follicular Development ◽  
Female Offspring ◽  
Mrna Levels ◽  
Androgen Excess ◽  
Ovary Syndrome ◽  
Pregnant Rats ◽  
Reproductive Disorder ◽  
Main Factors

AbstractFetal programming by androgen excess is hypothesized as one of the main factors contributing to the development of polycystic ovary syndrome (PCOS). PCOS is more than a reproductive disorder, as women with PCOS also show metabolic and other endocrine alterations. Since both ovarian and reproductive functions depend on energy balance, the alterations in metabolism may be related to reproductive alterations. The present study aimed to evaluate the effect of androgen excess during prenatal life on ovarian fuel sensors and its consequences on steroidogenesis. To this end, pregnant rats were hyperandrogenized with testosterone and the following parameters were evaluated in their female offspring: follicular development, PPARG levels, adipokines (including leptin, adiponectin, and chemerin as ovarian fuel sensors), serum gonadotropins (LH and FSH), the mRNA of their ovarian receptors, and the expression of steroidogenic mediators. At 60 days of age, the prenatally hyperandrogenized (PH) female offspring displayed both an irregular ovulatory phenotype and an anovulatory phenotype with altered follicular development and the presence of cysts. Both PH groups showed altered levels of both proteins and mRNA of PPARG and a different expression pattern of the adipokines studied. Although serum gonadotropins were not impaired, there were alterations in the mRNA levels of their ovarian receptors. The steroidogenic mediators Star, Cyp11a1, Cyp17a1, and Cyp19a1 were altered differently in each of the PH groups. We concluded that androgen excess during prenatal life leads to developmental programming effects that affect ovarian fuel sensors and steroidogenesis in a phenotype-specific way.

scholarly journals Gestational stress, placental norepinephrine transporter and offspring fertility

Reproduction ◽  
2017 ◽  
Vol 153 (2) ◽  
pp. 147-155 ◽  
Author(s):  
Beatriz Piquer ◽  
Jose L Fonseca ◽  
Hernán E Lara
Keyword(s):  
Cold Stress ◽  
Norepinephrine Transporter ◽  
Reproductive Capacity ◽  
Maternal Circulation ◽  
Pregnant Rats ◽  
Protein Levels ◽  
Body Weights ◽  
Generation Progeny ◽  
Gestational Stress ◽  
Sympathetic Stress

Chronic cold stress produces adrenergic overload that can affect fetal development. The placental norepinephrine transporter (NET) clears norepinephrine (NE) from both maternal circulation and the fetus during gestation. If this system fails, NE clearance can be reduced, leading to high fetal exposure to NE. The main aim of this study was to determine the changes in NET expression during gestation and their relationship with the functional capacity of NET to transport NE under stressful conditions. Additionally, this study correlated these findings with the reproductive capacity of 2nd-generation progeny. Pregnant rats were subjected to chronic cold stress at 4°C for 3 h each day throughout their pregnancies. We found that exposure of pregnant rats to sympathetic stress caused the following effects: increased NE and corticosterone levels throughout pregnancy, decreased capacity of the placenta to clear NE from the fetus to the mother’s circulation, altered NET protein levels depending on the sex of the fetus and increased placental and body weights of pups. For the first time, we also described the disrupted fertility of progeny as adults. Increased NE plasma levels during pregnancy under sympathetic stress conditions correlated with decreased NET functionality that provoked changes in the development of progeny and their fertility in adulthood.

scholarly journals Role of RFRP-3 in the development of cold stress-induced polycystic ovary phenotype in rats

2018 ◽  
Vol 239 (1) ◽  
pp. 81-91 ◽  
Author(s):  
V Squicciarini ◽  
R Riquelme ◽  
K Wilsterman ◽  
G E Bentley ◽  
H E Lara
Keyword(s):  
Cold Stress ◽  
Polycystic Ovary ◽  
Follicular Development ◽  
Sprague Dawley ◽  
Ovarian Steroid ◽  
Sprague Dawley Rats ◽  
Mrna Expression Analysis

RFamide-related peptide (RFRP-3) is a regulator of GnRH secretion from the brain, but it can also act in human ovary to influence steroidogenesis. We aimed to study the putative local role of RFRP-3 in the ovary and its potential participation in the development of a polycystic ovary phenotype induced by chronic sympathetic stress (cold stress). We used adult Sprague–Dawley rats divided into control and stressed groups. In both groups, we studied the effect of intraovarian exposure to RFRP-3 on follicular development and plasma ovarian steroid concentrations. We also tested the effect of RFRP-3 on ovarian steroid production in vitro. Chronic in vivo intraovarian exposure to RFRP-3 decreased basal testosterone concentrations and cold stress-induced progesterone production by the ovary. In vitro, RFRP-3 decreased hCG-induced ovarian progesterone and testosterone secretion. Immunohistochemistry and mRNA expression analysis showed a decrease in Rfrp and expression of its receptor in the ovary of stressed rats, a result which is in line with the increased testosterone levels found in stressed rats. In vivo application of RFRP-3 recovered the low levels of secondary and healthy antral follicles found in stressed rats. Taken together, our data indicate a previously unknown response of hypothalamic and ovarian RFRP-3 to chronic cold stress, influencing ovarian steroidogenesis and follicular dynamics. Thus, it is likely that RFRP-3 modulation in the ovary is a key component of development of the polycystic ovary phenotype.

scholarly journals Sympathetic innervation regulates macrophage activity in rats with polycystic ovary

2018 ◽  
Vol 238 (1) ◽  
pp. 33-45 ◽  
Author(s):  
Florencia Figueroa ◽  
Gisela Mendoza ◽  
Darío Cardozo ◽  
Fabián Mohamed ◽  
Liliana Oliveros ◽  
...  
Keyword(s):  
Culture Media ◽  
Polycystic Ovary ◽  
Sympathetic Innervation ◽  
Endocrine Function ◽  
Estradiol Valerate ◽  
Tunel Staining ◽  
Low Grade ◽  
Mrna Levels ◽  
Adult Rats

Polycystic ovarian syndrome (PCOS) is a low-grade inflammatory disease characterized by hyperandrogenism and ovarian hyperinnervation. The aim of this work is to investigate whether in vivo bilateral superior ovarian nerve (SON) section in adult rats with estradiol valerate-induced PCOS (PCO rats) affects macrophage spleen cells (MФ) and modifies the steroidogenic ability of their secretions. Culture media of MФ from PCO rats and PCO rats with SON section (PCO-SON rats) were used to stimulate in vitro intact ovaries. Compared with macrophages PCO, macrophages from PCO-SON rats released less tumor necrosis factor-α and nitric oxide, expressed lower Bax and Nfkb mRNA and showed reduced TUNEL staining. Also, in PCO rats, the SON section decreased kisspeptin and nerve growth factor mRNA expressions, without changes in Trka receptor mRNA levels. Macrophage secretions from PCO-SON rats decreased androstenedione and stimulated progesterone release in PCO ovaries, compared to macrophage secretions from PCO rats. No changes were observed in ovarian estradiol response. These findings emphasize the importance of the SON in spleen MΦ, since its manipulation leads to secondary modifications of immunological and neural mediators, which might influence ovarian steroidogenesis. In PCO ovaries, the reduction of androstenedione and the improvement of progesterone release induced by PCO-SON MΦ secretion, might be beneficial considering the hormonal anomalies characteristic of PCOS. We present functional evidence that modulation of the immune-endocrine function by peripheral sympathetic nervous system might have implications for understanding the pathophysiology of PCOS.

Fetal programming by androgen excess impairs liver lipid content and PPARg expression in adult rats

2021 ◽  
pp. 1-10
Author(s):  
Aimé Florencia Silva ◽  
Giselle Adriana Abruzzese ◽  
María José Ferrer ◽  
María Florencia Heber ◽  
Silvana Rocío Ferreira ◽  
...  
Keyword(s):  
Lipid Content ◽  
Fetal Programming ◽  
Polycystic Ovary ◽  
Liver Lipid ◽  
Adult Life ◽  
Androgen Excess ◽  
Adult Rats ◽  
Pregnant Rats ◽  
Adult Age ◽  
Liver Lipid Content

Abstract It is known that prenatal hyperandrogenization induces alterations since early stages of life, contributing to the development of polycystic ovary syndrome affecting the reproductive axis and the metabolic status, thus promoting others associated disorders, such as dyslipidemia, insulin resistance, liver dysfunction, and even steatosis. In this study, we aimed to evaluate the effect of fetal programming by androgen excess on the hepatic lipid content and metabolic mediators at adult life. Pregnant rats were hyperandrogenized with daily subcutaneous injections of 1 mg of free testosterone from days 16 to 19 of pregnancy. The prenatally hyperandrogenized (PH) female offspring displayed two phenotypes: irregular ovulatory phenotype (PHiov) and anovulatory phenotype (PHanov), with different metabolic and endocrine features. We evaluated the liver lipid content and the main aspect of the balance between fatty acid (FA) synthesis and oxidation. We investigated the status of the peroxisomal proliferator-activated receptors (PPARs) alpha and gamma, which act as lipid mediators, and the adipokine chemerin, one marker of liver alterations. We found that prenatal hyperandrogenization altered the liver lipid profile with increased FAs levels in the PHanov phenotype and decreased cholesterol content in the PHiov phenotype. FA metabolism was also disturbed, including decreased mRNA and protein PPARgamma levels and impaired gene expression of the main enzymes involved in lipid metabolism. Moreover, we found low chemerin protein levels in both PH phenotypes. In conclusion, these data suggest that prenatal hyperandrogenization exerts a negative effect on the liver and alters lipid content and metabolic mediators’ expression at adult age.

scholarly journals Locus Coeruleus Mediates Cold Stress-Induced Polycystic Ovary in Rats

Endocrinology ◽  
2008 ◽  
Vol 149 (6) ◽  
pp. 2907-2916 ◽  
Author(s):  
Marcelo P. Bernuci ◽  
Raphael E. Szawka ◽  
Cleyde V. V. Helena ◽  
Cristiane M. Leite ◽  
Hernán E. Lara ◽  
...  
Keyword(s):  
Tyrosine Hydroxylase ◽  
Cold Stress ◽  
Locus Coeruleus ◽  
Acute Stress ◽  
Polycystic Ovary ◽  
Ovarian Response ◽  
Sympathetic Nerves ◽  
Neuron Activity ◽  
Morphological Alterations

Previous reports about the rat ovary have shown that cold stress promotes ovarian morphological alterations related to a polycystic ovary (PCO) condition through activation of the ovarian sympathetic nerves. Because the noradrenergic nucleus locus coeruleus (LC) is activated by cold stress and synaptically connected to the preganglionic cell bodies of the ovarian sympathetic pathway, this study aimed to evaluate the LC’s role in cold stress-induced PCO in rats. Ovarian morphology and endocrine and sympathetic functions were evaluated after 8 wk of chronic intermittent cold stress (4 C, 3 h/d) in rats with or without LC lesion. The effect of acute and chronic cold stress upon the LC neuron activity was confirmed by Fos protein expression in tyrosine hydroxylase-immunoreactive neurons. Cold stress induced the formation of follicular cysts, type III follicles, and follicles with hyperthecosis alongside increased plasma estradiol and testosterone levels, irregular estrous cyclicity, and reduced ovulation. Considering estradiol release in vitro, cold stress potentiated the ovarian response to human chorionic gonadotropin. Ovarian norepinephrine (NE) was not altered after 8 wk of stress. However, LC lesion reduced NE activity in the ovary of cold-stressed rats, but not in controls, and prevented all the cold stress effects evaluated. Cold stress increased the number of Fos/tyrosine hydroxylase-immunoreactive neurons in the LC, but this effect was more pronounced for acute stress as compared with chronic stress. These results show that cold stress promotes PCO in rats, which apparently depends on ovarian NE activity that, under this condition, is regulated by the noradrenergic nucleus LC.

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