scholarly journals 5α-dihydrotestosterone treatment induces metabolic changes associated with polycystic ovary syndrome without interfering with hypothalamic leptin and glucocorticoid signaling

2016 ◽  
Vol 68 (3) ◽  
pp. 473-481
Author(s):  
Marina Nikolic ◽  
Natasa Velickovic ◽  
Ana Djordjevic ◽  
Biljana Bursac ◽  
Djuro Macut ◽  
...  
Keyword(s):  
Polycystic Ovary Syndrome ◽  
Polycystic Ovary ◽  
Day Treatment ◽  
Reproductive Age ◽  
Female Rats ◽  
Leptin Resistance ◽  
Polycystic Ovaries ◽  
Metabolic Disturbances ◽  
Inflammatory Signaling ◽  
Ovary Syndrome

Polycystic ovary syndrome (PCOS) is the most common endocrinopathy in women of reproductive age. It is a heterogenous disorder, with hyperandrogenism, chronic anovulation and polycystic ovaries as basic characteristics, and associated metabolic syndrome features. Increased secretion of leptin and leptin resistance are common consequences of obesity. Leptin is a hormone with anorexigenic effects in the hypothalamus. Its function in the regulation of energy intake and consumption is antagonized by glucocorticoids. By modulating leptin signaling and inflammatory processes in the hypothalamus, glucocorticoids can contribute to the development of metabolic disturbances associated with central energy disbalance. The aim of the study was to examine the relationship between hypothalamic leptin, glucocorticoid and inflammatory signaling in the development of metabolic disturbances associated with PCOS. The study was conducted on an animal model of PCOS generated by a continual, 90-day treatment of female rats with 5?-dihydrotestosterone (DHT). The model exhibited all key reproductive and metabolic features of the syndrome. mRNA and/or protein levels of the key components of hypothalamic glucocorticoid, leptin and inflammatory pathways, presumably contributing to energy disbalance in DHT-treated female rats, were measured. The results indicated that DHT treatment led to the development of hyperphagia and hyperleptinemia as metabolic features associated with PCOS. However, these metabolic disturbances could not be ascribed to changes in hypothalamic leptin, glucocorticoid or inflammatory signaling pathways in DHT-treated rats.

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 Letrozole-Induced Polycystic Ovary Syndrome Attenuates Cystathionine-β Synthase Gene Expression in the Ovaries of Female Sprague Dawley Rats

2020 ◽  
Vol 4 (Supplement_2) ◽  
pp. 1244-1244
Author(s):  
Amanda Bries ◽  
Joe Webb ◽  
Brooke Vogel ◽  
Claudia Carrillo ◽  
Aileen Keating ◽  
...  
Keyword(s):  
Gene Expression ◽  
Polycystic Ovary Syndrome ◽  
Mrna Expression ◽  
Polycystic Ovary ◽  
Elevated Serum ◽  
Reproductive Age ◽  
Sprague Dawley ◽  
Polycystic Ovaries ◽  
Ovary Syndrome ◽  
Sd Rats

Abstract Objectives Polycystic ovary syndrome (PCOS) is an endocrine disorder that affects 10% of reproductive age women and leads to hyperandrogenism, abnormal menstrual cycles, and polycystic ovaries. Moreover, PCOS has been associated with elevated serum homocysteine; however, the characterization of one-carbon metabolism (OCM) in PCOS remains incomplete. The aim of our research was to examine OCM in a genetic and chemically-induced rodent model of PCOS: 1) viable yellow Agouti (Avy) mice; and 2) letrozole (Let)-induced Sprague Dawley (SD) rats. Methods Five wk old female Avy mice (N = 18), their lean controls (N = 18), and SD rats (N = 36) were acclimated for one wk. Following acclimation, the animals were placed on a modified standard AIN93G diet (energy, %: 50.4, carbohydrate; 17.3, protein; and 32.3, fat). Rats were randomly assigned to Let (1 g/kg BW) treatment or vehicle (carboxymethylcellulose) control that was administered via a subcutaneously implanted slow-release pellet every 30-d. For both models, 12 animals were randomly assigned to be euthanized during proestrus at one of the following ages: 8, 16 or 24 wk. Bodyweight and estrous cycles were measured daily. Ovaries were collected to assess gene expression of OCM. These data were analyzed using linear mixed models to determine the main effects of age and treatment at a significance level of P < 0.05. Results Letrozole significantly reduced the occurrence of proestrus and estrus stages (P = 0.0001 and P = 0.006, respectively). Additionally, Let-induced rats had increased BW compared to control rats, across all age groups (P < 0.0001). In contrast, Avy mice weighed less than their controls by 24 wk of age (P < 0.0001). Cystathionine-β synthase (CBS) mRNA expression was downregulated in the Let-induced vs. control rats at 16 (59%; P < 0.05) and 24 (77%; P < 0.01) wk of age. As expected, Cyp19A1, aromatase mRNA was downregulated in the Let-induced rats (P = 0.02). Interestingly, betaine-homocysteine s-methyltransferase (BHMT) mRNA increased as a function of age in Let-induced rats (P = 0.03). Conclusions These data demonstrate that Letrozole-induced PCOS temporally decreases ovarian CBS mRNA expression; whereas, BHMT mRNA is upregulated as a function of age. Funding Sources This work was supported by the National Institute of Child Health and Human Development.

scholarly journals Polycystic ovary syndrome: reviewing diagnosis and management of metabolic disturbances

2014 ◽  
Vol 58 (2) ◽  
pp. 182-187 ◽  
Author(s):  
Poli Mara Spritzer
Keyword(s):  
Polycystic Ovary Syndrome ◽  
Diagnostic Criteria ◽  
Polycystic Ovary ◽  
Pharmacological Therapy ◽  
Lifestyle Changes ◽  
Reproductive Age ◽  
Metabolic Dysfunction ◽  
Metabolic Disturbances ◽  
Ovary Syndrome ◽  
Individual Woman

Polycystic ovary syndrome (PCOS) is a common condition in women at reproductive age associated with reproductive and metabolic dysfunction. Proposed diagnosed criteria for PCOS include two out of three features: androgen excess, menstrual irregularity, and polycystic ovary appearance on ultrasound (PCO), after other causes of hyperandrogenism and dysovulation are excluded. Based on these diagnostic criteria, the most common phenotypes are the “classic PCOS” – hyperandrogenism and oligomenorrhea, with or without PCO; the “ovulatory phenotype” – hyperandrogenism and PCO in ovulatory women; and the “non-hyperandrogenic phenotype”, in which there is oligomenorrhea and PCO, without overt hyperandrogenism. The presence of obesity may exacerbate the metabolic and reproductive disorders associated with the syndrome. In addition, PCOS women present higher risk for type 2 diabetes and higher prevalence of cardiovascular risk factors that seems to be associated with the classic phenotype. The main interventions to minimize cardiovascular and metabolic risks in PCOS are lifestyle changes, pharmacological therapy, and bariatric surgery. Treatment with metformin has been shown to improve insulin sensitivity, lowering blood glucose and androgen levels. These effects are more potent when combined with lifestyle interventions. In conclusion, besides reproductive abnormalities, PCOS has been associated to metabolic comorbidities, most of them linked to obesity. Confounders, such as the lack of standard diagnostic criteria, heterogeneity of the clinical presentation, and presence of obesity, make management of PCOS difficult. Therefore, the approach to metabolic abnormalities should be tailored to the risks and treatment goals of each individual woman.

scholarly journals A New Rat Model Exhibiting Both Ovarian and Metabolic Characteristics of Polycystic Ovary Syndrome

Endocrinology ◽  
2007 ◽  
Vol 148 (8) ◽  
pp. 3781-3791 ◽  
Author(s):  
Louise Mannerås ◽  
Stefan Cajander ◽  
Agneta Holmäng ◽  
Zamira Seleskovic ◽  
Theodore Lystig ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Polycystic Ovary Syndrome ◽  
Structural Changes ◽  
Polycystic Ovary ◽  
Female Rats ◽  
Polycystic Ovaries ◽  
Ovary Syndrome ◽  
Continuous Administration ◽  
Metabolic Characteristics ◽  
Theca Interna

Polycystic ovary syndrome (PCOS) is a complex endocrine and metabolic disorder associated with ovulatory dysfunction, hyperandrogenism, abdominal obesity, and insulin resistance. However, its etiology is unclear, and its management is often unsatisfactory or requires a diversified approach. Here, we describe a new rat PCOS model, the first to exhibit both ovarian and metabolic characteristics of the syndrome. Female rats received the nonaromatizable androgen dihydrotestosterone (DHT) or the aromatase inhibitor letrozole by continuous administration, beginning before puberty, to activate androgen receptors. Adult DHT rats had irregular cycles, polycystic ovaries characterized by cysts formed from atretic follicles, and a diminished granulosa layer. They also displayed metabolic features, including increased body weight, increased body fat, and enlarged mesenteric adipocytes, as well as elevated leptin levels and insulin resistance. All letrozole rats were anovulatory and developed polycystic ovaries with structural changes strikingly similar to those in human PCOS. Our findings suggest that the formation of a “hyperplastic” theca interna reflects the inclusion of luteinized granulosa cells in the cyst wall rather than true hyperplasia. We conclude that the letrozole model is suitable for studies of the ovarian features of human PCOS, while the DHT model is suitable for studies of both ovarian and metabolic features of the 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 Diet-induced obesity exacerbates metabolic and behavioral effects of polycystic ovary syndrome in a rodent model

2015 ◽  
Vol 308 (12) ◽  
pp. E1076-E1084 ◽  
Author(s):  
Ilana B. Ressler ◽  
Bernadette E. Grayson ◽  
Yvonne M. Ulrich-Lai ◽  
Randy J. Seeley
Keyword(s):  
Insulin Resistance ◽  
Body Weight ◽  
Polycystic Ovary Syndrome ◽  
Polycystic Ovary ◽  
Forced Swim Test ◽  
Rodent Model ◽  
Reproductive Age ◽  
Female Rats ◽  
Ovary Syndrome ◽  
Stress Responsivity

Polycystic ovary syndrome (PCOS) is the most common endocrinopathy affecting women of reproductive age. Although a comorbidity of PCOS is obesity, many are lean. We hypothesized that increased saturated fat consumption and obesity would exacerbate metabolic and stress indices in a rodent model of PCOS. Female rats were implanted with the nonaromatizable androgen dihydrotestosterone (DHT) or placebo pellets prior to puberty. Half of each group was maintained ad libitum on either a high-fat diet (HFD; 40% butter fat calories) or nutrient-matched low-fat diet (LFD). Irrespective of diet, DHT-treated animals gained more body weight, had irregular cycles, and were glucose intolerant compared with controls on both diets. HFD/DHT animals had the highest levels of fat mass and insulin resistance. DHT animals demonstrated increased anxiety-related behavior in the elevated plus maze by decreased distance traveled and time in the open arms. HFD consumption increased immobility during the forced-swim test. DHT treatment suppressed diurnal corticosterone measurements in both diet groups. In parallel, DHT treatment significantly dampened stress responsivity to a mild stressor. Brains of DHT animals showed attenuated c-Fos activation in the ventromedial hypothalamus and arcuate nucleus; irrespective of DHT-treatment, however, all HFD animals had elevated hypothalamic paraventricular nucleus c-Fos activation. Whereas hyperandrogenism drives overall body weight gain, glucose intolerance, anxiety behaviors, and stress responsivity, HFD consumption exacerbates the effect of androgens on adiposity, insulin resistance, and depressive behaviors.

scholarly journals A Study on Physical and Physiological Impact of Polycystic Ovary Syndrome

2021 ◽  
Vol 69 (2) ◽  
Author(s):  
Sathish Kumar B.P ◽  
Dr. Sayantan Ghosh ◽  
Dr. Lipika Das ◽  
Dr. Aksa Merin Jose
Keyword(s):  
Menstrual Cycle ◽  
Polycystic Ovary Syndrome ◽  
Healthy Lifestyle ◽  
Polycystic Ovary ◽  
Reproductive Organs ◽  
Reproductive Age ◽  
Therapeutic Interventions ◽  
Polycystic Ovaries ◽  
Ovary Syndrome ◽  
Metabolic Complications

Polycystic ovary syndrome is a relatively common hormonal disorder that causes a number of different symptoms in women of reproductive age. In such conditions, enlarged ovaries containing multiple small cysts (polycystic ovaries), are found. Although most women with PCOS have polycystic ovaries, some affected women do not. Common to all women with PCOS is an irregularity in menstrual cycle and the presence of excess male hormones (androgen). It disrupts the functioning of the reproductive organs that produce progesterone and estrogen, the hormones that regulate the menstrual cycle. A prospective observational study was carried out in 125 inpatients, after taking written informed consent from patients those who met the study criteria. A total of 125 patients were enrolled in the study, it was observed that 17.74% have experienced moderate depression, 18.54% patients experienced major irregular menstrual period problem, 2-25% of the patients were dealing with body weight, and 6.45% patients were identified that the growth of visible hair on the upper lip as a major problem. It was also found that 8.87% of patients experienced major menstrual cramps and patients were found worried about PCOS and hence disturbing their quality of life. Various long-term complication and co morbidities have been associated with PCOS and early diagnosed and therapeutic interventions are needed. PCOS is a chronic disease with manifestations across the life span and represents a major health and economic burden. Management should focus on support, education, addressing physiological factors and strongly emphasizing healthy lifestyle with targeted medical therapy as required. Addressing hyperandrogenism is clinically important and monitoring for and managing longer-term metabolic complications including dyslipidemia, IGT, DM2, cardiovascular risk factors, is crucial. Overall, further research is needed in this complex condition.

scholarly journals Polycystic Ovary Syndrome, Obesity and Reproductive Implications

2009 ◽  
Vol 5 (5) ◽  
pp. 529-542 ◽  
Author(s):  
Angelica Lindén Hirschberg
Keyword(s):  
Polycystic Ovary Syndrome ◽  
Polycystic Ovary ◽  
Reproductive Function ◽  
Negative Influence ◽  
Reproductive Age ◽  
Polycystic Ovaries ◽  
Ovary Syndrome ◽  
Increased Risk ◽  
Important Challenge ◽  
Pharmacologic Treatments

Polycystic ovary syndrome (PCOS) is one of the most common causes of female infertility, affecting 5–10% of women of reproductive age. The syndrome is characterized by anovulation, hyperandrogenism and polycystic ovaries. Furthermore, PCOS is associated with insulin resistance and obesity, which is present in approximately 50% of women with PCOS. Reproductive function in women with PCOS is strongly dependent on bodyweight and metabolic status. Obesity is associated with an increased risk of infertility and may also have a negative influence on pregnancy outcome. Considering the worldwide epidemic of obesity, clinical problems relating to PCOS may worsen and increase in frequency. Lifestyle interventions resulting in weight loss comprise the most successful strategy to improve symptoms of PCOS. However, many patients fail to lose weight or may quickly regain weight. It is an important challenge to develop effective lifestyle programs and adjuvant pharmacologic treatments in order to improve reproductive and metabolic health among women with PCOS.

Cardiovascular Risk in Postmenopausal Women with Polycystic Ovary Syndrome

2019 ◽  
Vol 17 (6) ◽  
pp. 579-590 ◽  
Author(s):  
Eleni Armeni ◽  
Irene Lambrinoudaki
Keyword(s):  
Polycystic Ovary Syndrome ◽  
Polycystic Ovary ◽  
Clinical Manifestations ◽  
Reproductive Age ◽  
Metabolic Disturbances ◽  
Cvd Risk ◽  
Ovary Syndrome ◽  
Female Population ◽  
Previous Diagnosis ◽  
Aging Women

Polycystic ovary syndrome (PCOS) is one of the most common endocrinopathies affecting women of reproductive age. The hormonal alterations of PCOS have been linked with a higher risk of metabolic disturbances in young, reproductively active women. However, it remains to be clarified whether the presence of PCOS increases the risk of cardiovascular disease (CVD) later in life. Aging ameliorates the clinical manifestations of PCOS; hyperandrogenaemia and metabolic abnormalities, however, persist beyond the menopause. On the other hand, aging and menopause increase CVD risk in the general female population. The results of the limited available studies in aging women with a previous diagnosis of PCOS demonstrate early atherosclerosis. However, studies addressing clinical CVD outcomes in women with PCOS report inconsistent findings. A possible explanation for this heterogeneity is the difficulty in diagnosing PCOS after the menopausal transition, due to the absence of validated diagnostic criteria for this population. Larger prospective studies of women diagnosed during their reproductive years will shed more light on the longer-term CVD implications of PCOS.

scholarly journals Phenotype and Metabolic Disorders in Polycystic Ovary Syndrome

2012 ◽  
Vol 2012 ◽  
pp. 1-7 ◽  
Author(s):  
Olgierd Gluszak ◽  
Urszula Stopinska-Gluszak ◽  
Piotr Glinicki ◽  
Renata Kapuscinska ◽  
Hanna Snochowska ◽  
...  
Keyword(s):  
Polycystic Ovary Syndrome ◽  
Polycystic Ovary ◽  
Tolerance Test ◽  
Reproductive Age ◽  
Total Testosterone ◽  
Obese Women ◽  
Polycystic Ovaries ◽  
Ovary Syndrome ◽  
Female Population ◽  
Group A

The polycystic ovary syndrome (PCOS) is one of the most frequent endocrinopathies in women. Its incidence is assessed at 6–8% of the female population in the reproductive age. It is characterised by oligomenorrhea (Oligo), hyperandrogenism (HA), and the presence of polycystic ovaries (PCOs). Carbohydrate and lipid metabolism is being disturbed in many women with PCOS. The pathogenesis of PCOS is still unexplained. Following the main criteria of diagnosis (Rotterdam Consensus 2003), Dewailly, Welt and Pehlivanov divided the patients with PCOS into 4 phenotype groups: A, B, C, and D. In our studies of 93 patients with PCOS, we found (1) the most frequent appearance (60,2%) of the phenotype A [Oligo + HA + PCO]; (2) an increased androstenedione concentration in a group with HA (A, B, C); (3) an increased HOMA-β and insulin concentration after 30 min an oral 75 g glucose tolerance test (OGTT) in a group of obese women with BMI>30 kg/m2; (4) high levels of total testosterone, total cholesterol, and LDL cholesterol concentrations in a group A with classic phenotype of PCOS: Oligo + HA + PCO—increasing the risk of development of cardiovascular diseases, type 2 diabetes, or metabolic syndrome. The average androstenedione concentrations could be a good diagnostic and prognostic parameter.

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