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

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Impaired Preadipocyte Differentiation Into Adipocytes in Subcutaneous Abdominal Adipose of PCOS-Like Female Rhesus Monkeys

Endocrinology ◽

10.1210/en.2014-1050 ◽

2014 ◽

Vol 155 (7) ◽

pp. 2696-2703 ◽

Cited By ~ 33

Author(s):

Erica Keller ◽

Gregorio D. Chazenbalk ◽

Paul Aguilera ◽

Vanessa Madrigal ◽

Tristan Grogan ◽

...

Keyword(s):

Gene Expression ◽

Fatty Acid ◽

Free Fatty Acid ◽

Polycystic Ovary Syndrome ◽

Mrna Expression ◽

Rhesus Monkeys ◽

Polycystic Ovary ◽

Preadipocyte Differentiation ◽

Ovary Syndrome ◽

Female Rhesus

Metabolic characteristics of polycystic ovary syndrome women and polycystic ovary syndrome-like, prenatally androgenized (PA) female monkeys worsen with age, with altered adipogenesis of sc abdominal adipose potentially contributing to age-related adverse effects on metabolism. This study examines whether adipocyte morphology and gene expression in sc abdominal adipose differ between late reproductive-aged PA female rhesus monkeys compared with age-matched controls (C). Subcutaneous abdominal adipose of both groups was obtained for histological imaging and mRNA determination of zinc finger protein 423 (Zfp423) as a marker of adipose stem cell commitment to preadipocytes, and CCAAT/enhancer binding protein (C/EBP)α/peroxisome proliferator-activated receptor (PPAR)δ as well as C/EBPα/PPARγ as respective markers of early- and late-stage differentiation of preadipocytes to adipocytes. In all females combined, serum testosterone (T) levels positively correlated with fasting serum levels of total free fatty acid (r2 = 0.73, P < .002). PA females had a greater population of small adipocytes vs C (P < .001) in the presence of increased Zfp423 (P < .025 vs C females) and decreased C/EBPα (P < .003, vs C females) mRNA expression. Moreover, Zfp423 mRNA expression positively correlated with circulating total free fatty acid levels during iv glucose tolerance testing (P < .004, r2 = 0.66), whereas C/EBPα mRNA expression negatively correlated with serum T levels (P < .02, r2 = 0.43). Gene expression of PPARδ and PPARγ were comparable between groups (P = .723 and P = .18, respectively). Early-to-mid gestational T excess in female rhesus monkeys impairs adult preadipocyte differentiation to adipocytes in sc abdominal adipose and may constrain the ability of this adipose depot to safely store fat with age.

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Controversies in the diagnosis of polycystic ovary syndrome

Therapeutic Advances in Reproductive Health ◽

10.1177/2633494120913032 ◽

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.

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A Study on Physical and Physiological Impact of Polycystic Ovary Syndrome

International Journal of Pharmaceutical Sciences Review and Research ◽

10.47583/ijpsrr.2021.v69i02.022 ◽

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.

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Polycystic Ovary Syndrome, Obesity and Reproductive Implications

Women s Health ◽

10.2217/whe.09.39 ◽

2009 ◽

Vol 5 (5) ◽

pp. 529-542 ◽

Cited By ~ 24

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.

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Phenotype and Metabolic Disorders in Polycystic Ovary Syndrome

ISRN Endocrinology ◽

10.5402/2012/569862 ◽

2012 ◽

Vol 2012 ◽

pp. 1-7 ◽

Cited By ~ 23

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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Granulosa Cell Survival and Proliferation Are Altered in Polycystic Ovary Syndrome

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/jc.2007-1650 ◽

2008 ◽

Vol 93 (3) ◽

pp. 881-887 ◽

Cited By ~ 99

Author(s):

M. Das ◽

O. Djahanbakhch ◽

B. Hacihanefioglu ◽

E. Saridogan ◽

M. Ikram ◽

...

Keyword(s):

Gene Expression ◽

Polycystic Ovary Syndrome ◽

Cell Survival ◽

Granulosa Cell ◽

Granulosa Cells ◽

Polycystic Ovary ◽

Reproductive Age ◽

Ovary Syndrome ◽

Survival Factor ◽

Effector Caspase

Abstract Context: Polycystic ovary syndrome (PCOS) represents the most common endocrine abnormality in women of reproductive age. The cause of PCOS remains largely unknown, but studies suggest an intrinsic ovarian abnormality. Objective: The objective of the study was to test our hypothesis that differences in granulosa cell proliferation and apoptosis may underlie abnormalities that affect follicular development. Design: Granulosa cells were prepared from follicular fluid aspirated from 4- to 8-mm follicles of unstimulated ovaries during routine laparoscopy or laparotomy from women with anovulatory PCOS and those with regular ovulatory cycles. Setting: The study was conducted at a university hospital. Patients: Fourteen women with anovulatory PCOS and nine women with regular ovulatory cycles participated in the study. Main Outcome Measures: Immunocytochemistry on granulosa cells to investigate apoptotic and proliferation rates, together with real-time RT-PCR to analyze gene expression profiles of apoptotic regulators, was measured. Results: Significantly lower apoptotic rates were found in granulosa cells from patients with PCOS, compared with women with regular ovulatory cycles (P = 0.004). Lower apoptotic rates were associated with decreased levels of the apoptotic effector caspase-3 (P = 0.001) and increased levels of the anti-apoptotic survival factor cellular inhibitor of apoptosis proteins-2 in the PCOS group that were coupled to higher proliferation rates (P = 0.032). Gene expression profiling confirmed the immunocytochemical findings. Conclusions: Our findings indicate that there are significant differences in the rate of cell death and proliferation in granulosa cell populations in PCOS patients. These are associated with decreased expression of apoptotic effectors and increased expression of a cell survival factor. These results provide new insights that may be useful in developing specific therapeutic intervention strategies in PCOS.

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Impact of SGLT-2 Inhibition on CardiometabolicAbnormalities in a Rat Model of Polycystic Ovary Syndrome

International Journal of Molecular Sciences ◽

10.3390/ijms22052576 ◽

2021 ◽

Vol 22 (5) ◽

pp. 2576

Author(s):

Jacob E. Pruett ◽

Edgar Torres Fernandez ◽

Steven Everman ◽

Ruth Vinson ◽

Kacey Davenport ◽

...

Keyword(s):

Polycystic Ovary Syndrome ◽

Angiotensin Converting Enzyme ◽

Polycystic Ovary ◽

Sglt2 Inhibitor ◽

Renin Angiotensin System ◽

Reproductive Age ◽

Converting Enzyme ◽

Sprague Dawley ◽

Ovary Syndrome ◽

Sglt2 Inhibition

Polycystic ovary syndrome (PCOS) is the most common endocrine disorder in reproductive-age women. PCOS is characterized by hyperandrogenism and ovulatory dysfunction. Women with PCOS have a high prevalence of obesity, insulin resistance (IR), increased blood pressure (BP), and activation of the renin angiotensin system (RAS). Effective evidence-based therapeutics to ameliorate the cardiometabolic complications in PCOS are lacking. The sodium-glucose cotransporter-2 (SGLT2) inhibitor Empagliflozin (EMPA) reduces BP and hyperglycemia in type 2 diabetes mellitus. We hypothesized that hyperandrogenemia upregulates renal SGLT2 expression and that EMPA ameliorates cardiometabolic complications in a hyperandrogenemic PCOS model. Four-week-old female Sprague Dawley rats were treated with dihydrotestosterone (DHT) for 90 days, and EMPA was co-administered for the last three weeks. DHT upregulated renal SGLT2, SGLT4, and GLUT2, but downregulated SGLT3 mRNA expression. EMPA decreased DHT-mediated increases in fat mass, plasma leptin, and BP, but failed to decrease plasma insulin, HbA1c, or albuminuria. EMPA decreased DHT-mediated increase in renal angiotensin converting enzyme (ACE), angiotensin converting enzyme 2 (ACE2), and angiotensin II type 1 receptor (AGT1R) mRNA and protein expression. In summary, SGLT2 inhibition proved beneficial in adiposity and BP reduction in a hyperandrogenemic PCOS model; however, additional therapies may be needed to improve IR and renal injury.

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Concentration of anti-Mullerian hormone in the blood as a result of electrical stimulation of polycystic ovaries in women with infertility

Heart Vessels and Transplantation ◽

10.24969/hvt.2019.151 ◽

2019 ◽

Vol 3 (Issue 4) ◽

Author(s):

Arystanbek O. Atykanov ◽

Nurgazy T. Dzhanuzakov

Keyword(s):

Electrical Stimulation ◽

Surgical Treatment ◽

Polycystic Ovary Syndrome ◽

Polycystic Ovary ◽

Reproductive Age ◽

Polycystic Ovaries ◽

Women Of Reproductive Age ◽

Ovary Syndrome ◽

Follicular Reserve ◽

Stimulation Of

This paper presents data on the effect of unilateral and bilateral electrical stimulation of the ovaries in 36 women of reproductive age with polycystic ovary syndrome and infertility on follicular reserve, estimated by the concentration of anti-Mullerian hormone in the blood serum. The results of surgical treatment showed that in the postoperative period in women, both with unilateral and bilateral ovarian cauterization, it does not lead to a critical decrease in the follicular reserve compared with indicators of healthy women.

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Luteolin alleviates polycystic ovary syndrome in rats by resolving insulin resistance and oxidative stress

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00034.2021 ◽

2021 ◽

Author(s):

Yue Huang ◽

Xiang Zhang

Keyword(s):

Insulin Resistance ◽

Polycystic Ovary Syndrome ◽

Polycystic Ovary ◽

Reproductive Age ◽

Sprague Dawley ◽

Ovary Syndrome ◽

Protein Levels ◽

Sprague Dawley Rats ◽

Ovarian Morphology ◽

Pcos Group

Polycystic ovary syndrome (PCOS) is an endocrine disorder characterized by elevated secretion of androgen, commonly associated with insulin resistance (IR), which could exacerbate patient with PCOS. Development of a safe and effective treatment in preventing and treating PCOS will be beneficial to women of reproductive age. Female Sprague-Dawley rats were randomly divided into 4 groups: sham group treated with vehicle (saline) or luteolin; letrozole and high fat diet induced PCOS group treated with vehicle or luteolin (25, 50, 100 mg/kg intraperitoneally). Ovary tissue and blood were collected for further analysis. Luteolin normalized estrus cycle and improved ovarian morphology, including reduced polycystic and alleviated the loss of oocytes and corpus luteum in PCOS rats. Serum follicle stimulating hormone, and estradiol were reduced while luteinizing hormone and testosterone were elevated in PCOS rats relative to that of sham, which were significantly normalized by luteolin. Notably, luteolin significantly inhibited IR and up-regulated protein levels of PI3K p85a and pAKT compared with PCOS rats treated with vehicle. In addition, the activities of antioxidants such as SOD, GPx, CAT and GSH were reduced in PCOS rats, which were significantly increased by luteolin. Protein and mRNA expressions of Nrf2 and downstream genes such as Hmox1 and Nqo1 were restored by luteolin in PCOS rats. Collectively, this study demonstrated that luteolin inhibited IR by prompting PI3K/AKT signaling pathway and enhanced antioxidative response through the restoration of Nrf2 pathway.

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

Archives of Biological Sciences ◽

10.2298/abs151214001n ◽

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.

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