scholarly journals Prenatal Androgenization Alters the Development of GnRH Neuron and Preoptic Area RNA Transcripts in Female Mice

Endocrinology ◽  
2020 ◽  
Vol 161 (11) ◽  
Author(s):  
Laura L Burger ◽  
Elizabeth R Wagenmaker ◽  
Chayarndorn Phumsatitpong ◽  
David P Olson ◽  
Suzanne M Moenter
Keyword(s):  
Protein Synthesis ◽  
Oxidative Phosphorylation ◽  
Polycystic Ovary ◽  
Affinity Purification ◽  
Developmental Trajectory ◽  
Late Gestation ◽  
Gnrh Neuron ◽  
Altered Expression ◽  
Increased Risk ◽  
Gnrh Neurons

Abstract Polycystic ovary syndrome (PCOS) is the most common form of infertility in women. The causes of PCOS are not yet understood and both genetics and early-life exposure have been considered as candidates. With regard to the latter, circulating androgens are elevated in mid–late gestation in women with PCOS, potentially exposing offspring to elevated androgens in utero; daughters of women with PCOS are at increased risk for developing this disorder. Consistent with these clinical observations, prenatal androgenization (PNA) of several species recapitulates many phenotypes observed in PCOS. There is increasing evidence that symptoms associated with PCOS, including elevated luteinizing hormone (LH) (and presumably gonadotropin-releasing hormone [GnRH]) pulse frequency emerge during the pubertal transition. We utilized translating ribosome affinity purification coupled with ribonucleic acid (RNA) sequencing to examine GnRH neuron messenger RNAs from prepubertal (3 weeks) and adult female control and PNA mice. Prominent in GnRH neurons were transcripts associated with protein synthesis and cellular energetics, in particular oxidative phosphorylation. The GnRH neuron transcript profile was affected more by the transition from prepuberty to adulthood than by PNA treatment; however, PNA did change the developmental trajectory of GnRH neurons. This included families of transcripts related to both protein synthesis and oxidative phosphorylation, which were more prevalent in adults than in prepubertal mice but were blunted in PNA adults. These findings suggest that prenatal androgen exposure can program alterations in the translatome of GnRH neurons, providing a mechanism independent of changes in the genetic code for altered expression.

scholarly journals Investigating the NPY/AgRP/GABA to GnRH Neuron Circuit in Prenatally Androgenized PCOS-Like Mice

2020 ◽  
Vol 4 (11) ◽  
Author(s):  
Christopher J Marshall ◽  
Melanie Prescott ◽  
Rebecca E Campbell
Keyword(s):  
Polycystic Ovary ◽  
Reproductive Function ◽  
Receptor Expression ◽  
Late Gestation ◽  
Gnrh Neuron ◽  
Androgen Excess ◽  
Neuron Circuit ◽  
Gaba Neurons ◽  
Gnrh Neurons ◽  
Prenatal Androgen

Abstract Polycystic ovary syndrome (PCOS), the most common form of anovulatory infertility, is associated with altered signaling within the hormone-sensitive neuronal network that regulates gonadotropin-releasing hormone (GnRH) neurons, leading to a pathological increase in GnRH secretion. Circuit remodeling is evident between GABAergic neurons in the arcuate nucleus (ARN) and GnRH neurons in a murine model of PCOS. One-third of ARN GABA neurons co-express neuropeptide Y (NPY), which has a known yet complex role in regulating GnRH neurons and reproductive function. Here, we investigated whether the NPY-expressing subpopulation (NPYARN) of ARN GABA neurons (GABAARN) is also affected in prenatally androgenized (PNA) PCOS-like NPYARN reporter mice [Agouti-related protein (AgRP)-Cre;τGFP]. PCOS-like mice and controls were generated by exposure to di-hydrotestosterone or vehicle (VEH) in late gestation. τGFP-expressing NPYARN neuron fiber appositions with GnRH neurons and gonadal steroid hormone receptor expression in τGFP-expressing NPYARN neurons were assessed using confocal microscopy. Although GnRH neurons received abundant close contacts from τGFP-expressing NPYARN neuron fibers, the number and density of putative inputs was not affected by prenatal androgen excess. NPYARN neurons did not co-express progesterone receptor or estrogen receptor α in either PNA or VEH mice. However, the proportion of NPYARN neurons co-expressing the androgen receptor was significantly elevated in PNA mice. Therefore, NPYARN neurons are not remodeled by prenatal androgen excess like the wider GABAARN population, indicating GABA-to-GnRH neuron circuit remodeling occurs in a presently unidentified non-NPY/AgRP population of GABAARN neurons. NPYARN neurons do, however, show independent changes in the form of elevated androgen sensitivity.

scholarly journals Prenatal androgen treatment does not alter the firing activity of hypothalamic arcuate kisspeptin neurons in female mice

2021 ◽  
Author(s):  
Amanda G Gibson ◽  
Jennifer Jaime ◽  
Laura L Burger ◽  
Suzanne M Moenter
Keyword(s):  
Firing Rate ◽  
Polycystic Ovary ◽  
Developmental Trajectory ◽  
Dependent Manner ◽  
Gnrh Neuron ◽  
Neuron Firing ◽  
Firing Rates ◽  
Gnrh Neurons ◽  
Kndy Neurons

Neuroendocrine control of reproduction is disrupted in many individuals with polycystic ovary syndrome, who present with increased luteinizing hormone (LH), and presumably gonadotropin-releasing hormone (GnRH), release frequency, and high androgen levels. Prenatal androgenization (PNA) recapitulates these phenotypes in primates and rodents. Female offspring of mice injected with dihydrotestosterone (DHT) on gestational D16-18 exhibit disrupted estrous cyclicity, increased LH and testosterone, and increased GnRH neuron firing rate as adults. PNA also alters the developmental trajectory of GnRH neuron firing rates, markedly blunting the prepubertal peak in firing that occurs in 3wk-old controls. GnRH neurons do not express detectable androgen receptors and are thus probably not the direct target of DHT. Rather, PNA likely alters GnRH neuronal activity by modulating upstream neurons, such as hypothalamic arcuate neurons co-expressing kisspeptin, neurokinin B (gene Tac2), and dynorphin, aka KNDy neurons. We hypothesized PNA treatment changes firing rates of KNDy neurons in a similar age-dependent manner as GnRH neurons. We conducted targeted extracellular recordings (0.5-2h) of Tac2-identified KNDy neurons from control and PNA mice at 3wks of age and in adulthood. About half of neurons were quiescent (<0.005Hz). Long-term firing rates of active cells varied, suggestive of episodic activity, but were not different among groups. Short-term burst firing was also similar. We thus reject the hypothesis that PNA alters the firing rate of KNDy neurons. This does not preclude altered neurosecretory output of KNDy neurons, involvement of other neuronal populations, or in-vivo networks as critical drivers of altered GnRH firing rates in PNA mice.

scholarly journals Prenatal Androgenization of Female Mice Programs an Increase in Firing Activity of Gonadotropin-Releasing Hormone (GnRH) Neurons That Is Reversed by Metformin Treatment in Adulthood

Endocrinology ◽  
2010 ◽  
Vol 152 (2) ◽  
pp. 618-628 ◽  
Author(s):  
Alison V. Roland ◽  
Suzanne M. Moenter
Keyword(s):  
Polycystic Ovary ◽  
Neuron Activity ◽  
Metformin Treatment ◽  
Ampk Activation ◽  
Gnrh Neuron ◽  
Firing Activity ◽  
Ovary Syndrome ◽  
Estrous Cycles ◽  
Compound C ◽  
Gnrh Neurons

Abstract Prenatal androgenization (PNA) of female mice with dihydrotestosterone programs reproductive dysfunction in adulthood, characterized by elevated luteinizing hormone levels, irregular estrous cycles, and central abnormalities. Here, we evaluated activity of GnRH neurons from PNA mice and the effects of in vivo treatment with metformin, an activator of AMP-activated protein kinase (AMPK) that is commonly used to treat the fertility disorder polycystic ovary syndrome. Estrous cycles were monitored in PNA and control mice before and after metformin administration. Before metformin, cycles were longer in PNA mice and percent time in estrus lower; metformin normalized cycles in PNA mice. Extracellular recordings were used to monitor GnRH neuron firing activity in brain slices from diestrous mice. Firing rate was higher and quiescence lower in GnRH neurons from PNA mice, demonstrating increased GnRH neuron activity. Metformin treatment of PNA mice restored firing activity and LH to control levels. To assess whether AMPK activation contributed to the metformin-induced reduction in GnRH neuron activity, the AMPK antagonist compound C was acutely applied to cells. Compound C stimulated cells from metformin-treated, but not untreated, mice, suggesting that AMPK was activated in GnRH neurons, or afferent neurons, in the former group. GnRH neurons from metformin-treated mice also showed a reduced inhibitory response to low glucose. These studies indicate that PNA causes enhanced firing activity of GnRH neurons and elevated LH that are reversible by metformin, raising the possibility that central AMPK activation by metformin may play a role in its restoration of reproductive cycles in polycystic ovary syndrome.

scholarly journals Prenatal androgen exposure causes a sexually dimorphic transgenerational increase in offspring susceptibility to anxiety disorders

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Sanjiv Risal ◽  
Maria Manti ◽  
Haojiang Lu ◽  
Romina Fornes ◽  
Henrik Larsson ◽  
...  
Keyword(s):  
Anxiety Disorders ◽  
Maternal Obesity ◽  
Polycystic Ovary ◽  
Female Offspring ◽  
Male Offspring ◽  
Late Gestation ◽  
Male Germline ◽  
Androgen Exposure ◽  
Increased Risk ◽  
Female Germline

AbstractIf and how obesity and elevated androgens in women with polycystic ovary syndrome (PCOS) affect their offspring’s psychiatric health is unclear. Using data from Swedish population health registers, we showed that daughters of mothers with PCOS have a 78% increased risk of being diagnosed with anxiety disorders. We next generated a PCOS-like mouse (F0) model induced by androgen exposure during late gestation, with or without diet-induced maternal obesity, and showed that the first generation (F1) female offspring develop anxiety-like behavior, which is transgenerationally transmitted through the female germline into the third generation of female offspring (F3) in the androgenized lineage. In contrast, following the male germline, F3 male offspring (mF3) displayed anxiety-like behavior in the androgenized and the obese lineages. Using a targeted approach to search for molecular targets within the amygdala, we identified five differentially expressed genes involved in anxiety-like behavior in F3 females in the androgenized lineage and eight genes in the obese lineage. In mF3 male offspring, three genes were dysregulated in the obese lineage but none in the androgenized lineage. Finally, we performed in vitro fertilization (IVF) using a PCOS mouse model of continuous androgen exposure. We showed that the IVF generated F1 and F2 offspring in the female germline did not develop anxiety-like behavior, while the F2 male offspring (mF2) in the male germline did. Our findings provide evidence that elevated maternal androgens in PCOS and maternal obesity may underlie the risk of a transgenerational transmission of anxiety disorders in children of women with PCOS.

Metabolic Syndrome During Menopause

2019 ◽  
Vol 17 (6) ◽  
pp. 595-603 ◽  
Author(s):  
Sezcan Mumusoglu ◽  
Bulent Okan Yildiz
Keyword(s):  
Insulin Resistance ◽  
Metabolic Syndrome ◽  
Central Obesity ◽  
Polycystic Ovary ◽  
Ovary Syndrome ◽  
Natural Menopause ◽  
The Metabolic Syndrome ◽  
Increased Risk ◽  
Aging Women

The metabolic syndrome (MetS) comprises individual components including central obesity, insulin resistance, dyslipidaemia and hypertension and it is associated with an increased risk of cardiovascular disease (CVD) and type 2 diabetes mellitus (T2DM). The menopause per se increases the incidence of MetS in aging women. The effect(s) of menopause on individual components of MetS include: i) increasing central obesity with changes in the fat tissue distribution, ii) potential increase in insulin resistance, iii) changes in serum lipid concentrations, which seem to be associated with increasing weight rather than menopause itself, and, iv) an association between menopause and hypertension, although available data are inconclusive. With regard to the consequences of MetS during menopause, there is no consistent data supporting a causal relationship between menopause and CVD. However, concomitant MetS during menopause appears to increase the risk of CVD. Furthermore, despite the data supporting the association between early menopause and increased risk of T2DM, the association between natural menopause itself and risk of T2DM is not evident. However, the presence and the severity of MetS appears to be associated with an increased risk of T2DM. Although the mechanism is not clear, surgical menopause is strongly linked with a higher incidence of MetS. Interestingly, women with polycystic ovary syndrome (PCOS) have an increased risk of MetS during their reproductive years; however, with menopausal transition, the risk of MetS becomes similar to that of non-PCOS women.

scholarly journals Association between age of cannabis initiation and gray matter covariance networks in recent onset psychosis

2021 ◽  
Author(s):  
Nora Penzel ◽  
◽  
Linda A. Antonucci ◽  
Linda T. Betz ◽  
Rachele Sanfelici ◽  
...  
Keyword(s):  
Gray Matter ◽  
Inferior Frontal Gyrus ◽  
Brain Networks ◽  
Developmental Trajectory ◽  
Cannabis Use ◽  
Brain Maturation ◽  
Confounding Factors ◽  
Recent Onset ◽  
Increased Risk ◽  
Structural Brain

AbstractCannabis use during adolescence is associated with an increased risk of developing psychosis. According to a current hypothesis, this results from detrimental effects of early cannabis use on brain maturation during this vulnerable period. However, studies investigating the interaction between early cannabis use and brain structural alterations hitherto reported inconclusive findings. We investigated effects of age of cannabis initiation on psychosis using data from the multicentric Personalized Prognostic Tools for Early Psychosis Management (PRONIA) and the Cannabis Induced Psychosis (CIP) studies, yielding a total sample of 102 clinically-relevant cannabis users with recent onset psychosis. GM covariance underlies shared maturational processes. Therefore, we performed source-based morphometry analysis with spatial constraints on structural brain networks showing significant alterations in schizophrenia in a previous multisite study, thus testing associations of these networks with the age of cannabis initiation and with confounding factors. Earlier cannabis initiation was associated with more severe positive symptoms in our cohort. Greater gray matter volume (GMV) in the previously identified cerebellar schizophrenia-related network had a significant association with early cannabis use, independent of several possibly confounding factors. Moreover, GMV in the cerebellar network was associated with lower volume in another network previously associated with schizophrenia, comprising the insula, superior temporal, and inferior frontal gyrus. These findings are in line with previous investigations in healthy cannabis users, and suggest that early initiation of cannabis perturbs the developmental trajectory of certain structural brain networks in a manner imparting risk for psychosis later in life.

scholarly journals Relationships Between Biochemical Markers of Hyperandrogenism and Metabolic Parameters in Women with Polycystic Ovary Syndrome: A Systematic Review and Meta-Analysis

2019 ◽  
Vol 51 (01) ◽  
pp. 22-34 ◽  
Author(s):  
Mina Amiri ◽  
Fahimeh Tehrani ◽  
Razieh Bidhendi-Yarandi ◽  
Samira Behboudi-Gandevani ◽  
Fereidoun Azizi ◽  
...  
Keyword(s):  
Systematic Review ◽  
Polycystic Ovary Syndrome ◽  
Biochemical Markers ◽  
Polycystic Ovary ◽  
Meta Analysis ◽  
Metabolic Parameters ◽  
High Density Lipoproteins ◽  
Total Testosterone ◽  
Ovary Syndrome ◽  
Increased Risk

AbstractWhile several studies have documented an increased risk of metabolic disorders in patients with polycystic ovary syndrome (PCOS), associations between androgenic and metabolic parameters in these patients are unclear. We aimed to investigate the relationships between biochemical markers of hyperandrogenism (HA) and metabolic parameters in women with PCOS. In this systematic review and meta-analysis, a literature search was performed in the PubMed, Scopus, Google Scholar, ScienceDirect, and Web of Science from 2000 to 2018 for assessing androgenic and metabolic parameters in PCOS patients. To assess the relationships between androgenic and metabolic parameters, meta-regression analysis was used. A total number of 33 studies involving 9905 patients with PCOS were included in this analysis. The associations of total testosterone (tT) with metabolic parameters were not significant; after adjustment for age and BMI, we detected associations of this androgen with low-density lipoproteins cholesterol (LDL-C) (β=0.006; 95% CI: 0.002, 0.01), high-density lipoproteins cholesterol (HDL-C) (β=–0.009; 95% CI: –0.02, –0.001), and systolic blood pressure (SBP) (β=–0.01; 95% CI: –0.03, –0.00). We observed a positive significant association between free testosterone (fT) and fasting insulin (β=0.49; 95% CI: 0.05, 0.91); this association remained significant after adjustment for confounders. We also detected a reverse association between fT and HDL-C (β=–0.41; 95% CI: –0.70, –0.12). There was a positive significant association between A4 and TG (β=0.02; 95% CI: 0.00, 0.04) after adjustment for PCOS diagnosis criteria. We also found significant negative associations between A4, TC, and LDL-C. Dehydroepiandrosterone sulfate (DHEAS) had a positive association with LDL-C (β=0.02; 95% CI: 0.001, 0.03) and a reverse significant association with HDL-C (β=–0.03; 95% CI: –0.06, –0.001). This meta-analysis confirmed the associations of some androgenic and metabolic parameters, indicating that measurement of these parameters may be useful for predicting metabolic risk in PCOS patients.

scholarly journals Programming of growth, insulin resistance and vascular dysfunction in offspring of late gestation diabetic rats

2009 ◽  
Vol 117 (3) ◽  
pp. 129-138 ◽  
Author(s):  
Emily M. Segar ◽  
Andrew W. Norris ◽  
Jian-Rong Yao ◽  
Shanming Hu ◽  
Stacia L. Koppenhafer ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Vascular Function ◽  
Vascular Dysfunction ◽  
Diabetic Rats ◽  
Late Gestation ◽  
Group Differences ◽  
Pregnant Rats ◽  
Increased Risk ◽  
Specific Insulin ◽  
Diabetic Mothers

ODM (offspring of diabetic mothers) have an increased risk of developing metabolic and cardiovascular dysfunction; however, few studies have focused on the susceptibility to disease in offspring of mothers developing diabetes during pregnancy. We developed an animal model of late gestation diabetic pregnancy and characterized metabolic and vascular function in the offspring. Diabetes was induced by streptozotocin (50 mg/kg of body weight, intraperitoneally) in pregnant rats on gestational day 13 and was partially controlled by twice-daily injections of insulin. At 2 months of age, ODM had slightly better glucose tolerance than controls (P<0.05); however, by 6 months of age this trend had reversed. A euglycaemic–hyperinsulinamic clamp revealed insulin resistance in male ODM (P<0.05). In 6–8-month-old female ODM, aortas had significantly enhanced contractility in response to KCl, ET-1 (endothelin-1) and NA (noradrenaline). No differences in responses to ET-1 and NA were apparent with co-administration of L-NNA (NG-nitro-L-arginine). Relaxation in response to ACh (acetylcholine), but not SNP (sodium nitroprusside), was significantly impaired in female ODM. In contrast, males had no between-group differences in response to vasoconstrictors, whereas relaxation to SNP and ACh was greater in ODM compared with control animals. Thus the development of diabetes during pregnancy programmes gender-specific insulin resistance and vascular dysfunction in adult offspring.

Female Hyperandrogenism in Elite Sports and the Athletic Triad

2021 ◽  
Author(s):  
Angelica Lindén Hirschberg
Keyword(s):  
Female Athletes ◽  
Polycystic Ovary ◽  
Disorders Of Sex Development ◽  
Normal Female ◽  
Menstrual Disorders ◽  
Mineral Density ◽  
Energy Deficiency ◽  
Sex Development ◽  
Endocrine Disturbances ◽  
Increased Risk

AbstractEssential hyperandrogenism seems to be overrepresented in female elite athletes. This applies to mild forms such as polycystic ovary syndrome, as well as rare differences/disorders of sex development (DSD). The reason is likely a selection bias since there is increasing evidence that androgens are beneficial for athletic performance by potent anabolic effects on muscle mass and bone mass, and stimulation of erythropoiesis. XY DSD may cause a greatly increased production of testosterone in the male range, that is, 10 to 20 times higher than the normal female range. The established regulations concerning the eligibility of female athletes with severe hyperandrogenism to compete in the female classification remain controversial. The most common cause of menstrual disorders in female athletes, however, is probably an acquired functional hypothalamic disturbance due to energy deficiency in relation to energy expenditure, which could lead to low bone mineral density and increased risk of injury. This condition is particularly common in endurance and esthetic sports, where a lean body composition is considered an advantage for physical performance. It is important to carefully evaluate endocrine disturbances and menstrual disorders in athletes since the management should be specific according to the underlying cause.

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