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 The Role of the Brain in the Pathogenesis and Physiology of Polycystic Ovary Syndrome (PCOS)

2019 ◽  
Vol 7 (8) ◽  
pp. 84 ◽  
Author(s):  
Coutinho ◽  
Kauffman
Keyword(s):  
Animal Models ◽  
Polycystic Ovary Syndrome ◽  
Neural Circuit ◽  
Polycystic Ovary ◽  
Pulse Frequency ◽  
Reproductive Age ◽  
Neuron Activity ◽  
Ovary Syndrome ◽  
Gnrh Neurons ◽  
Reproductive Endocrine

Polycystic ovary syndrome (PCOS) is a common reproductive endocrine disorder, affecting at least 10% of women of reproductive age. PCOS is typically characterized by the presence of at least two of the three cardinal features of hyperandrogenemia (high circulating androgen levels), oligo- or anovulation, and cystic ovaries. Hyperandrogenemia increases the severity of the condition and is driven by increased luteinizing hormone (LH) pulse secretion from the pituitary. Indeed, PCOS women display both elevated mean LH levels, as well as an elevated frequency of LH pulsatile secretion. The abnormally high LH pulse frequency, reflective of a hyperactive gonadotropin-releasing hormone (GnRH) neural circuit, suggests a neuroendocrine basis to either the etiology or phenotype of PCOS. Several studies in preclinical animal models of PCOS have demonstrated alterations in GnRH neurons and their upstream afferent neuronal circuits. Some rodent PCOS models have demonstrated an increase in GnRH neuron activity that correlates with an increase in stimulatory GABAergic innervation and postsynaptic currents onto GnRH neurons. Additional studies have identified robust increases in hypothalamic levels of kisspeptin, another potent stimulator of GnRH neurons. This review outlines the different brain and neuroendocrine changes in the reproductive axis observed in PCOS animal models, discusses how they might contribute to either the etiology or adult phenotype of PCOS, and considers parallel findings in PCOS women.

scholarly journals Androgens Increase Gonadotropin-Releasing Hormone Neuron Firing Activity in Females and Interfere with Progesterone Negative Feedback

Endocrinology ◽  
2006 ◽  
Vol 147 (3) ◽  
pp. 1474-1479 ◽  
Author(s):  
Justyna Pielecka ◽  
Samuel D. Quaynor ◽  
Suzanne M. Moenter
Keyword(s):  
Animal Models ◽  
Firing Rate ◽  
Negative Feedback ◽  
Brain Slices ◽  
Neuron Activity ◽  
Gnrh Neuron ◽  
Firing Activity ◽  
Neuron Firing ◽  
Gnrh Neurons ◽  
Gaba Transmission

GnRH neurons are the central regulators of fertility, and their activity is modulated by steroid feedback. In women with hyperandrogenemic infertility and in animal models of these disorders, elevated androgen levels interfere with progesterone (P) negative feedback. Our previous work showed that steroids altered the frequency and amplitude of γ-aminobutyric acid (GABA) transmission to GnRH neurons. Specifically, P inhibited GABA transmission, which can excite GnRH neurons, whereas dihydrotestosterone (DHT) increased GABA transmission. In this study the GnRH neuron firing rate was examined in the same animal models. Adult (>2 months) female mice were ovariectomized and treated for 8–12 d with implants containing estradiol (E), E and P, E and DHT, or E, P, and DHT. Targeted extracellular recordings were used to examine the long-term firing activity of green fluorescent protein-identified GnRH neurons in brain slices from these mice. In comparing E alone to E plus P animals, P increased the percentage of time that GnRH neurons were quiescent and reduced the area under the curve of the firing rate and the instantaneous firing frequency, suggesting that P provides additional negative feedback over E alone. The addition of DHT markedly increased GnRH neuron activity in both the presence and absence of P. DHT also altered the firing pattern of GnRH neurons, such that peaks in the firing rate detected by the Cluster8 algorithm were approximately doubled in frequency and amplitude. These data support and extend our previous findings and are consistent with the hypothesis that the changes in GABAergic transmission observed in these animal models impact upon the activity of GnRH neurons, and central androgen action probably stimulates GnRH release.

Metformin Treatment Ameliorates Liver Injury Indicating Fatty Liver Polycystic Ovary Syndrome

2015 ◽  
Vol 53 (01) ◽  
Author(s):  
S Tan ◽  
N Vollmar ◽  
S Benson ◽  
LP Bechmann ◽  
G Gerken ◽  
...  
Keyword(s):  
Liver Injury ◽  
Polycystic Ovary Syndrome ◽  
Fatty Liver ◽  
Polycystic Ovary ◽  
Metformin Treatment ◽  
Ovary Syndrome

scholarly journals Metformin Improves Glucose Effectiveness, Not Insulin Sensitivity: Predicting Treatment Response in Women With Polycystic Ovary Syndrome in an Open-Label, Interventional Study

2014 ◽  
Vol 99 (5) ◽  
pp. 1870-1878 ◽  
Author(s):  
Cindy T. Pau ◽  
Candace Keefe ◽  
Jessica Duran ◽  
Corrine K. Welt
Keyword(s):  
Insulin Sensitivity ◽  
Glucose Tolerance Test ◽  
Polycystic Ovary ◽  
Tolerance Test ◽  
Metformin Treatment ◽  
Open Label ◽  
Ovary Syndrome ◽  
Glucose Effectiveness ◽  
Glucose Levels ◽  
Lower Baseline

Context: Although metformin is widely used to improve insulin resistance in women with polycystic ovary syndrome (PCOS), its mechanism of action is complex, with inconsistent effects on insulin sensitivity and variability in treatment response. Objective: The aim of the study was to delineate the effect of metformin on glucose and insulin parameters, determine additional treatment outcomes, and predict patients with PCOS who will respond to treatment. Design and Setting: We conducted an open-label, interventional study at an academic medical center. Subjects: Women with PCOS (n = 36) diagnosed by the National Institutes of Health criteria participated in the study. Interventions: Subjects underwent fasting blood sampling, an IV glucose tolerance test, dual-energy x-ray absorptiometry scan, transvaginal ultrasound, and measurement of human chorionic gonadotropin-stimulated androgen levels before and after 12 weeks of treatment with metformin extended release 1500 mg/d. Interval visits were performed to monitor anthropometric measurements and menstrual cycle parameters. Main Outcome Measures: Changes in glucose and insulin parameters, androgen levels, anthropometric measurements, and ovulatory menstrual cycles were evaluated. Results: Insulin sensitivity did not change despite weight loss. Glucose effectiveness (P = .002) and the acute insulin response to glucose (P = .002) increased, and basal glucose levels (P = .001) decreased after metformin treatment. T levels also decreased. Women with improved ovulatory function (61%) had lower baseline T levels and lower baseline and stimulated T and androstenedione levels after metformin treatment (all P < .05). Conclusions: Using an IV glucose tolerance test, which distinguishes improvements in glucose effectiveness and insulin sensitivity, metformin does not improve insulin sensitivity in women with PCOS but does improve glucose effectiveness. The improvement in glucose effectiveness may be partially mediated by decreased glucose levels. T levels also decreased with metformin treatment. Ovulation during metformin treatment was associated with lower baseline T levels and greater T and androstenedione decreases during treatment, but not with insulin or LH levels. Thus, the action of metformin in PCOS primarily affects glucose levels and steroidogenesis, which may be mediated by mechanisms that affect both pathways, such as inhibition of mitochondrial complex I.

scholarly journals Metformin treatment before and during IVF or ICSI in women with polycystic ovary syndrome

2014 ◽  
Author(s):  
Leopoldo O Tso ◽  
Michael F Costello ◽  
Luiz Eduardo T Albuquerque ◽  
Régis B Andriolo ◽  
Cristiane R Macedo
Keyword(s):  
Polycystic Ovary Syndrome ◽  
Polycystic Ovary ◽  
Metformin Treatment ◽  
Ovary Syndrome

Effect of metformin treatment on ovarian stromal blood flow in women with polycystic ovary syndrome

2019 ◽  
Vol 32 (4) ◽  
pp. 1371
Author(s):  
HusseinM A Esmaeel ◽  
MehanyM Abd EL-Sattar ◽  
OsamaA EL-Kelany ◽  
Alaa EL-DinF EL-Halaby
Keyword(s):  
Blood Flow ◽  
Polycystic Ovary Syndrome ◽  
Polycystic Ovary ◽  
Metformin Treatment ◽  
Ovary Syndrome

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 SUN-022 Metformin-Fish Oil Adjunct Therapy Improves apoB-Remnant Lipoprotein and Triglyceride Levels in Women with Polycystic Ovary Syndrome

2020 ◽  
Vol 4 (Supplement_1) ◽  
Author(s):  
Ethan Proctor ◽  
Olivia Weaver ◽  
Mahua Ghosh ◽  
Katerina Maximova ◽  
Spencer Proctor ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Cardiovascular Disease ◽  
Polycystic Ovary ◽  
Lipoprotein Metabolism ◽  
Atherogenic Dyslipidemia ◽  
Metformin Treatment ◽  
Ovary Syndrome ◽  
Adjunct Therapy ◽  
Remnant Lipoprotein ◽  
Fasting Plasma

Abstract Background: Polycystic ovary syndrome (PCOS) is highly associated with the metabolic syndrome (MetS): obesity, insulin resistance and atherogenic dyslipidemia. Women with PCOS-MetS are at higher risk of developing ischemic cardiovascular disease (CVD) and Type-2 Diabetes. First-line intervention in PCOS-MetS includes targeting diet and lifestyle, and metformin is commonly prescribed to treat insulin resistance, however these interventions have shown limited effectiveness to improve dyslipidemia. At present there are limited safe and efficious options to target atherogenic dyslipidemia in young women with PCOS. Fish oil (FO) and Icosapentyl ethyl supplementation have been shown to reduce fasting TG, apoB and to improve ischemic CVD outcomes. The efficacy of FO or as an adjunct therapy to metformin to improve ApoB-remnant lipemia in PCOS-MetS is unknown. The aim of this pilot study was to determine the effect of metformin, FO and FO-metformin combination treatment on fasting and non-fasting plasma TG and apoB-remnant lipoprotein metabolism in patients with PCOS-MetS. Methods: Participants diagnosed with PCOS aged 18-30yrs received dietary counselling and were randomly assigned to receive FO (n=8), metformin (n=7) or FO-metformin (n=12) treatment for 12 wks. Plasma lipids (TG and cholesterol), ApoB48 and ApoB100 lipoprotein metabolism were assessed in the fasting and non-fasting state using a standardized high-fat meal test. Results: At baseline, the fasting plasma TG, ApoB48 and ApoB100 was 238.0 ± 21.0 mg/dL, 9.00 ± 1.12 ug/ml and 290 ± 18.00 mg/dL. FO and FO-metformin decreased fasting plasma TG by 10% and 30% compared to the metformin treatment group (7%). Fasting ApoB48 was reduced 45%, 16% and 19% in FO-metformin, FO and metformin treatment groups, respectively. Non-fasting plasma TG and apoB48 lipoprotein area under the curve were reduced by 30% in the FO-metformin treatment group. Conclusion: These pilot findings demonstrate FO-metformin adjunct therapy may have greater efficacy to improve atherogenic apoB-dyslipidemia compared to metformin or FO alone in high-risk patients with PCOS-MetS. A larger clinical trial is warranted to determine the long term effects of FO-metformin intervention on apoB-dyslipidemia and atherosclerotic cardiovascular disease indices.

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