scholarly journals Chronic Excess of Non-Aromatizable Androgens From Puberty Does Not Drive a Neuroendocrine Phenotype Observed in Other Preclinical Rodent Models of PCOS

2021 ◽  
Vol 5 (Supplement_1) ◽  
pp. A533-A534
Author(s):  
Chris Coyle ◽  
Amy Ruddenklau ◽  
Mel Prescott ◽  
Kirsty A Walters ◽  
Rebecca Elaine Campbell
Keyword(s):  
Chronic Exposure ◽  
Fluorescent Protein ◽  
Polycystic Ovary ◽  
Prenatal Development ◽  
Reproductive Age ◽  
Androgen Excess ◽  
Gabaergic Innervation ◽  
Lh Pulsatility ◽  
Gnrh Neurons ◽  
The Brain

Abstract Polycystic ovary syndrome (PCOS) is the most common form of anovulatory infertility in women of reproductive age, characterised by androgen excess, polycystic appearance of the ovary and irregular menstruation. PCOS is also frequently associated with metabolic abnormalities, including increased adiposity and insulin resistance. The origins of PCOS are unknown, however recent findings in animal models strongly implicate androgen signalling in the brain in the development of PCOS pathophysiology. Exposure to androgen excess, either acutely during prenatal development or chronically from a peripubertal timepoint, can drive the development of PCOS-like features in adulthood. Prenatally androgenized (PNA) mice exhibit the cardinal reproductive features of PCOS and increased luteinizing hormone (LH) pulse frequency. This phenotype is associated with increased GABAergic innervation of gonadotropin-releasing hormone (GnRH) neurons, postulated to drive elevated GnRH/LH release and downstream effects. Chronic exposure to di-hydrotestosterone (DHT) from 3 weeks of age drives both reproductive and metabolic PCOS-like features that are ameliorated by selective AR loss from the brain. Here, we aimed to determine whether chronic exposure to DHT drives a similar increase in LH pulsatility and elevated GABAergic innervation to GnRH neurons as seen following prenatal exposure to androgen excess. GnRH-green fluorescent protein (GFP) female mice received either DHT or blank capsules for 90 days from postnatal day (PND) 21 (N = 6-7/group). Serial tail tip blood sampling was used to measure pulsatile LH and fixed brains were collected and immunolabelled for vesicular GABA transporter (VGAT) to assess putative GABAergic terminals associated with GFP-labelled GnRH neurons. Chronic androgen excess from the peripubertal period resulted in acyclicity and increased body weight as expected. However, LH pulsatility was not different between DHT-treated females and controls. Similarly, the density of VGAT appositions to GnRH neurons was not different between groups. Therefore, the programmed changes in the GnRH neuronal network and hyperactive LH secretion that result from prenatal androgen excess are not affected by chronic DHT exposure initiated at 3 weeks of age. These findings suggest that unique central mechanisms are involved in the reproductive impairments driven by exposure to androgen excess at different developmental stages.

scholarly journals Androgen Receptor Blocker Improves the Cardiometabolic Profile in a Rat Model of Polycystic Ovary Syndrome, but at What Cost?

2021 ◽  
Vol 5 (Supplement_1) ◽  
pp. A803-A804
Author(s):  
Jacob E Pruett ◽  
Steven Everman ◽  
Edgar David Torres Fernandez ◽  
Kacey Davenport ◽  
Damian G Romero ◽  
...  
Keyword(s):  
Polycystic Ovary Syndrome ◽  
Polycystic Ovary ◽  
Reproductive Age ◽  
Female Rats ◽  
Chow Diet ◽  
Model Assessment ◽  
Androgen Excess ◽  
Ovary Syndrome ◽  
Glutamyl Transferase ◽  
Cardiometabolic Profile

Abstract Introduction: Polycystic ovary syndrome (PCOS) is the most common endocrine disorder in women of reproductive age. PCOS is characterized by androgen excess and ovulatory dysfunction high prevalence of cardiovascular risk factors such as increased blood pressure (BP), insulin resistance (IR), and obesity. We have demonstrated previously that exposing prepubertal female rats to dihydrotestosterone (DHT) leads to increase in food intake (FI), body weight (BW), BP, and IR. We tested the hypothesis that administration of the AR blocker bicalutamide (BICA) would decrease BP, IR, and obesity in PCOS model. As there are previous reports of severe hepatotoxicity with the AR blocker flutamide, we also examined BICA effects in the liver. Methods: Four-week old female Sprague Dawley rats implanted with DHT pellets (7.5mg/90 days) or placebo (PBO) were randomized to standard chow diet with or without the AR blocker bicalutamide (BICA) at a dose of 250 mg/kg/day throughout the study (n=10/group). BW and FI were measured weekly. BP and heart rate (HR) were measured by radiotelemetry. Fasting plasma was collected for IR (Homeostatic model assessment for IR, HOMA-IR). At euthanasia, the liver was collected, as well as plasma for gamma glutamyl transferase (GGT), alanine transaminase (ALT), and aspartate transaminase (AST) quantification. Results: PCOS rats had increased BW, FI, IR, and BP compared to PBO. BICA treatment had no impact on BW (285.3 ± 7.0 vs 270 ± 8.2 g, P=0.2) as well as FI and HR in PCOS. However, in PCOS, BICA decreased HOMA-IR (5.10 ± 0.40 vs 3.33 ± 0.31, P<0.05) and BP (115.4 ± 0.7 vs 105.3 ± 0.2 mmHg, P<0.01). Compared to PBO, PCOS+BICA rats had similar IR (3.83 ± 0.28 vs 3.33 ± 0.31, P=0.7) and BP (107.4 ± 0.8 vs 105.3 ± 0.2 mmHg, P=0.9). In addition, the liver weight to tibia length ratio was drastically increased by BICA in PCOS (222.9 ± 9.5 vs 360.4 ± 16.9 mg/mm, P<0.0001) as well as GGT (0.88 ± 0.88 vs 11.67 ± 0.58 U/L, P<0.0001), though it decreased AST (60.2 ± 6.9 vs 42.4 ± 1.9 U/L, P<0.05) and had no impact on ALT. Conclusion: In summary, in a model of PCOS, BICA treatment abolished IR and BP, independent of FI, BW and HR. Prompt treatment with an AR blocker can normalize increased IR and BP triggered by androgen excess in females. Further studies need to be done to fully understand the effect of BICA in the liver in PCOS. The beneficial effect of AR blockers as a therapeutic option to improve the cardiometabolic profile in PCOS may be hampered by its liver toxicity.

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 SAT-018 Androgen Actions in Adipose Tissue and the Brain Are Key Mediators in the Development of Polycystic Ovary Syndrome

2020 ◽  
Vol 4 (Supplement_1) ◽  
Author(s):  
Madeleine J Cox ◽  
Melissa C Edwards ◽  
Ali Aflatounian ◽  
Valentina Rodriguez Paris ◽  
William L Ledger ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
Polycystic Ovary Syndrome ◽  
Mouse Model ◽  
Hepatic Steatosis ◽  
Polycystic Ovary ◽  
Reproductive Traits ◽  
Reproductive Age ◽  
Ovary Syndrome ◽  
Adipocyte Hypertrophy ◽  
The Brain

Abstract Polycystic ovary syndrome (PCOS) is a complex disorder characterised by endocrine, reproductive and metabolic abnormalities. Despite PCOS being the most common endocrinopathy affecting women of reproductive age, its etiology is poorly understood so there is no cure and symptom-oriented treatment is suboptimal. Elucidation of the underlying mechanisms involved in the pathogenesis of PCOS would pave the way for the development of new interventions for PCOS. Hyperandrogenism is the most consistent feature observed in PCOS patients, and recently aberrant neuroendocrine signalling and adipose tissue function have been proposed as playing a pathogenic role in the development of experimental PCOS. To investigate the role of adipose tissue and the brain as potential key sites for androgen receptor (AR)-mediated development of PCOS, we combined an adipocyte and brain-specific ARKO knockout (AdBARKO) mouse model with a dihydrotestosterone (DHT)-induced mouse model of PCOS. Wildtype (WT) and AdBARKO prepubertal mice were implanted with a blank or DHT implant and examined after 12 weeks. In WT control females, DHT exposure induced the PCOS reproductive traits of cycle irregularity, ovulatory dysfunction and reduced follicle health. In contrast, these reproductive features of PCOS were absent in DHT-treated AdBARKO females. The PCOS metabolic characteristics of increased adiposity, adipocyte hypertrophy and hepatic steatosis were induced by DHT in WT females. Despite DHT treatment, AdBARKO females displayed normal white adipose tissue weight, and adipocyte hypertrophy and hepatic steatosis were not evident. However, as with WT mice, DHT treatment induced increased fasting glucose levels in AdBARKO females. These results demonstrate that adipose tissue and the brain are key loci for androgen-mediated actions involved in the developmental origins of PCOS. These findings support targeting adipocyte and neuroendocrine AR-driven pathways in the future development of novel therapeutic strategies for PCOS.

Androgen Action in Adipose Tissue and the Brain are Key Mediators in the Development of PCOS Traits in a Mouse Model

Endocrinology ◽  
2020 ◽  
Vol 161 (7) ◽  
Author(s):  
Madeleine J Cox ◽  
Melissa C Edwards ◽  
Valentina Rodriguez Paris ◽  
Ali Aflatounian ◽  
William L Ledger ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
Mouse Model ◽  
Polycystic Ovary ◽  
Liver Steatosis ◽  
Symptomatic Treatment ◽  
Reproductive Age ◽  
Glucose Levels ◽  
Brown Adipose ◽  
Adipocyte Hypertrophy ◽  
The Brain

Abstract Polycystic ovary syndrome (PCOS) is a complex disorder characterized by endocrine, reproductive, and metabolic abnormalities. Despite PCOS being the most common endocrinopathy affecting women of reproductive age, the etiology of PCOS is poorly understood, so there is no cure and symptomatic treatment is suboptimal. Hyperandrogenism is the most consistent feature observed in PCOS patients, and recently aberrant neuroendocrine signaling and adipose tissue function have been proposed as playing a role in the development of PCOS. To investigate the role of adipose tissue and the brain as key sites for androgen receptor (AR)-mediated development of PCOS, we combined a white and brown adipose and brain-specific AR knockout (AdBARKO) mouse model with a dihydrotestosterone (DHT)-induced mouse model of PCOS. As expected, in wildtype (WT) control females, DHT exposure induced the reproductive PCOS traits of cycle irregularity, ovulatory dysfunction, and reduced follicle health, whereas in AdBARKO females, DHT did not produce the reproductive features of PCOS. The metabolic PCOS characteristics of increased adiposity, adipocyte hypertrophy, and hepatic steatosis induced by DHT in WT females were not evident in DHT-treated AdBARKO females, which displayed normal white adipose tissue weight and no adipocyte hypertrophy or liver steatosis. Dihydrotestosterone treatment induced increased fasting glucose levels in both WT and AdBARKO females. These findings demonstrate that adipose tissue and the brain are key loci of androgen-mediated actions involved in the developmental origins of PCOS. These data support targeting adipocyte and neuroendocrine AR-driven pathways in the future development of novel therapeutic strategies for PCOS.

scholarly journals Adipose tissue dysfunction, adipokines, and low-grade chronic inflammation in polycystic ovary syndrome

Reproduction ◽  
2015 ◽  
Vol 149 (5) ◽  
pp. R219-R227 ◽  
Author(s):  
Poli Mara Spritzer ◽  
Sheila B Lecke ◽  
Fabíola Satler ◽  
Debora M Morsch
Keyword(s):  
Adipose Tissue ◽  
Polycystic Ovary Syndrome ◽  
Polycystic Ovary ◽  
Lifestyle Changes ◽  
Reproductive Age ◽  
Sufficient Evidence ◽  
Low Grade ◽  
Androgen Excess ◽  
Ovary Syndrome ◽  
Increased Risk

Polycystic ovary syndrome (PCOS), a complex condition that affects women of reproductive age, is characterized by ovulatory dysfunction and androgen excess. Women with PCOS present higher prevalence of obesity, central adiposity, and dyslipidemia, and face increased risk of type 2 diabetes. PCOS is closely linked to functional derangements in adipose tissue. Adipocytes seem to be prone to hypertrophy when exposed to androgen excess, as experienced by women with PCOS, and both adipose tissue hypertrophy and hyperandrogenism are related to insulin resistance. Hypertrophic adipocytes are more susceptible to inflammation, apoptosis, fibrosis, and release of free fatty acids. Disturbed secretion of adipokines may also impact the pathophysiology of PCOS through their influence on metabolism and on sex steroid secretion. Chronic low-grade inflammation in PCOS is also related to hyperandrogenism and to the hypertrophy of adipocytes, causing compression phenomena in the stromal vessels, leading to adipose tissue hypoperfusion and altered secretion of cytokines. Lifestyle changes are the first-line intervention for reducing metabolic risks in PCOS and the addition of an insulin-sensitizing drug might be required. Nevertheless, there is not sufficient evidence in favor of any specific pharmacologic therapies to directly oppose inflammation. Further studies are warranted to identify an adipokine that could serve as an indirect marker of adipocyte production in PCOS, representing a reliable sign of metabolic alteration in this syndrome.

scholarly journals Controversies in the diagnosis of polycystic ovary syndrome

2020 ◽  
Vol 14 ◽  
pp. 263349412091303
Author(s):  
Preetham Rao ◽  
Priya Bhide
Keyword(s):  
Polycystic Ovary Syndrome ◽  
Polycystic Ovary ◽  
Antral Follicle ◽  
Antral Follicle Count ◽  
Reproductive Age ◽  
Polycystic Ovaries ◽  
Women Of Reproductive Age ◽  
Androgen Excess ◽  
Ovary Syndrome ◽  
Ultrasound Features

Polycystic ovary syndrome is a common endocrinological condition which is found to be prevalent in 5–10% of women of reproductive age. Historically, a combination of anovulation and androgen excess was considered a hallmark in the diagnosis of polycystic ovary syndrome. Addition of ultrasound features of polycystic ovary syndrome has improved the detection of variation in the polycystic ovary syndrome phenotype. Despite the widespread use of consensus diagnostic criteria, there remain several unresolved controversies in the diagnosis of polycystic ovary syndrome. Difficulty arises in methods of assessment and types of androgens to be measured to detect biochemical hyperandrogenism, setting a cut-off value for the diagnosis of clinical hyperandrogenism, setting an ultrasound threshold of antral follicle count to diagnose polycystic ovaries and also diagnosing this condition in adolescence where there is no clear definition for ‘irregular cycles’. This article looks at various controversies in the diagnosis of polycystic ovary syndrome.

scholarly journals Neuroendocrine Impairments of Polycystic Ovary Syndrome

Endocrinology ◽  
2019 ◽  
Vol 160 (10) ◽  
pp. 2230-2242 ◽  
Author(s):  
Amy Ruddenklau ◽  
Rebecca E Campbell
Keyword(s):  
Polycystic Ovary Syndrome ◽  
Neuronal Network ◽  
Negative Feedback ◽  
Polycystic Ovary ◽  
Steroid Hormone ◽  
Unknown Etiology ◽  
Androgen Excess ◽  
Ovary Syndrome ◽  
The Brain

Abstract Polycystic ovary syndrome (PCOS) is a prevalent and distressing disorder of largely unknown etiology. Although PCOS defined by ovarian dysfunction, accumulating evidence supports a critical role for the brain in the ontogeny and pathophysiology of PCOS. A critical pathological feature of PCOS is impaired gonadal steroid hormone negative feedback to the GnRH neuronal network in the brain that regulates fertility. This impairment is associated with androgen excess, a cardinal feature of PCOS. Impaired steroid hormone feedback to GnRH neurons is thought to drive hyperactivity of the neuroendocrine axis controlling fertility, leading to a vicious cycle of androgen excess and reproductive dysfunction. Decades of clinical research have been unable to uncover the mechanisms underlying this impairment, because of the extreme difficulty in studying the brain in humans. It is only recently, with the development of preclinical models of PCOS, that we have begun to unravel the role of the brain in the development and progression of PCOS. Here, we provide a succinct overview of what is known about alterations in the steroid hormone–sensitive GnRH neuronal network that may underlie the neuroendocrine defects in clinical PCOS, with a particular focus on those that may contribute to impaired progesterone negative feedback, and the likely role of androgens in driving this impairment.

scholarly journals Developmental androgen excess disrupts reproduction and energy homeostasis in adult male mice

2013 ◽  
Vol 219 (3) ◽  
pp. 259-268 ◽  
Author(s):  
Kazunari Nohara ◽  
Suhuan Liu ◽  
Matthew S Meyers ◽  
Aurélie Waget ◽  
Mathieu Ferron ◽  
...  
Keyword(s):  
Adult Male ◽  
Energy Homeostasis ◽  
Polycystic Ovary ◽  
Hypogonadotropic Hypogonadism ◽  
Serum Testosterone ◽  
Reproductive Age ◽  
Male Mice ◽  
Androgen Excess ◽  
Ovary Syndrome ◽  
Subcutaneous White Adipose Tissue

Polycystic ovary syndrome is a common endocrine disorder in females of reproductive age and is believed to have a developmental origin in which gestational androgenization programs reproductive and metabolic abnormalities in offspring. During gestation, both male and female fetuses are exposed to potential androgen excess. In this study, we determined the consequences of developmental androgenization in male mice exposed to neonatal testosterone (NTM). Adult NTM displayed hypogonadotropic hypogonadism with decreased serum testosterone and gonadotropin concentrations. Hypothalamic KiSS1 neurons are believed to be critical to the onset of puberty and are the target of leptin. Adult NTM exhibited lower hypothalamicKiss1expression and a failure of leptin to upregulateKiss1expression. NTM displayed an early reduction in lean mass, decreased locomotor activity, and decreased energy expenditure. They displayed a delayed increase in subcutaneous white adipose tissue amounts. Thus, excessive neonatal androgenization disrupts reproduction and energy homeostasis and predisposes to hypogonadism and obesity in adult male mice.

scholarly journals The Role of Microglia in the Polycystic Ovary Syndrome (PCOS)-Like Brain

2021 ◽  
Vol 5 (Supplement_1) ◽  
pp. A556-A556
Author(s):  
Aisha Sati ◽  
Melanie Prescott ◽  
Christine Louise Jasoni ◽  
Elodie Desroziers ◽  
Rebecca Elaine Campbell
Keyword(s):  
Polycystic Ovary Syndrome ◽  
Mouse Model ◽  
Polycystic Ovary ◽  
Disease Onset ◽  
Reproductive Age ◽  
Specific Marker ◽  
Ovary Syndrome ◽  
Time Specific ◽  
The Brain ◽  
Amoeboid Microglia

Abstract Polycystic ovary syndrome (PCOS) is the most common cause of anovulatory infertility, affecting roughly 1 in 8 women of reproductive age. Accumulating evidence from animal models suggests that the brain plays a key role in the development and maintenance of PCOS. In a well-characterised prenatally androgenised (PNA) mouse model of PCOS, aberrant neuronal wiring associated with PCOS deficits in adulthood are detected as early as postnatal day (P) 25, prior to disease onset. However, the mechanisms by which prenatal androgen exposure alters brain wiring remains unknown. Microglia, the immune cells of the brain, are active sculptors of neuronal wiring across development, mediating both the formation and removal of neuronal inputs. Therefore, microglia may play an important role in driving the abnormal neuronal wiring that leads to PCOS-like features in the PNA brain. Here, to assess whether microglia are altered in the brain of PNA mice, microglia number and morphology-associated activation states were quantified in two hypothalamic regions implicated in fertility regulation. Microglia were identified by immunolabelling for the microglia-specific marker, Iba-1, across developmental timepoints, including embryonic day 17.5, P0, P25, P40 and P60 (n = 7–14/group). At P0, PNA mice had significantly fewer “activated” amoeboid microglia compared to controls (P < 0.05). Later in development at P25, PNA mice exhibited significantly fewer “sculpting” microglia (P < 0.001), whereas at P60, PNA mice possessed a greater number of “activated” amoeboid microglia relative to controls (P < 0.01). This study demonstrates time-specific changes in the number and morphology of microglia in a mouse model of PCOS and suggests a role for microglia in driving the brain wiring abnormalities associated with PCOS. These findings support the need for future functional experiments to determine the relative importance of microglia function in shaping the PCOS-like brain and associated reproductive dysfunction.

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