scholarly journals Pregnancy Protects Hyperandrogenemic Female Rats From Postmenopausal Hypertension

Hypertension ◽  
2020 ◽  
Vol 76 (3) ◽  
pp. 943-952
Author(s):  
Noha M. Shawky ◽  
Chetan N. Patil ◽  
Carolina Dalmasso ◽  
Rodrigo O. Maranon ◽  
Damian G. Romero ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Blood Pressure ◽  
Polycystic Ovary Syndrome ◽  
Polycystic Ovary ◽  
Reproductive Age ◽  
Female Rats ◽  
Ovary Syndrome ◽  
Uncomplicated Pregnancy ◽  
Age Related ◽  
Endothelin B

Polycystic ovary syndrome, the most common endocrine disorder in women of reproductive age, is characterized by hyperandrogenemia, obesity, insulin resistance, and elevated blood pressure. However, few studies have focused on the consequences of pregnancy on postmenopausal cardiovascular disease and hypertension in polycystic ovary syndrome women. In hyperandrogenemic female (HAF) rats, the hypothesis was tested that previous pregnancy protects against age-related hypertension. Rats were implanted with dihydrotestosterone (7.5 mg/90 days, beginning at 4 weeks and continued throughout life) or placebo pellets (controls), became pregnant at 10 to 15 weeks, and pups were weaned at postnatal day 21. Dams and virgins were then aged to 10 months (still estrous cycling) or 16 months (postcycling). Although numbers of offspring per litter were similar for HAF and control dams, birth weights were lower in HAF offspring. At 10 months of age, there were no differences in blood pressure, proteinuria, nitrate/nitrite excretion, or body composition in previously pregnant HAF versus virgin HAF. However, by 16 months of age, despite no differences in dihydrotestosterone, fat mass/or lean mass/body weight, previously pregnant HAF had significantly lower blood pressure and proteinuria, higher nitrate/nitrite excretion, with increased intrarenal mRNA expression of endothelin B receptor and eNOS (endothelial nitric oxide synthase), and decreased ACE (angiotensin-converting enzyme), AT1aR (angiotensin 1a receptor), and endothelin A receptor than virgin HAF. Thus, pregnancy protects HAF rats against age-related hypertension, and the mechanism(s) may be due to differential regulation of the nitric oxide, endothelin, and renin-angiotensin systems. These data suggest that polycystic ovary syndrome women who have experienced uncomplicated pregnancy may be protected from postmenopausal hypertension.

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 Naloxone Breeding Effectiveness in Rat Suffering from Nitric Oxide-induced Polycystic Ovary Syndrome

2015 ◽  
Vol 6 (2) ◽  
pp. 67-72
Author(s):  
Manizheh Karami ◽  
Fatemeh Lakzaei ◽  
MohammadReza Jalali Nadoushan
Keyword(s):  
Nitric Oxide ◽  
Polycystic Ovary Syndrome ◽  
Wistar Rats ◽  
Polycystic Ovary ◽  
Treated Group ◽  
Female Rats ◽  
Control Group ◽  
Ovary Syndrome ◽  
Crown Rump Length ◽  
Female Wistar Rats

ABSTRACT Background and objective Polycystic ovary syndrome (PCOS) can be induced in Wistar rats by over production of nitric oxide (NO). This study evaluated the efficacy of naloxone on the breeding characteristics of rats suffering from nitric oxide induced PCOS. Materials and methods Twenty-four female Wistar rats(200–250 gm) were kept as virgin under standard conditions. They were divided into four groups (n = 6). One group of the animals received L-arginine (50 mg/kg) intraperitoneally (i.p.) for 9 days/once a day. Another group was administered naloxone hydrochloride (0.4 mg/kg, i.p.) prior to injection of L-arginine. The third group was injected solely naloxone. Control group received saline solution (1 ml/kg, i.p.). After the treatments, all female rats were coupled with the intact males. They were then separated by observation of vaginal plaques; it was considered as day 0 of pregnancy. Eventually, they were operated on days 18 to 19 of the gestation to collect the animals’ ovaries. The samples were studied for pathological evidence. The fetal number and weight along with the fetal crown-rump length (CRL) were measured. Results The ovaries obtained from the L-arginine treated group had large cysts with thickened granulosa cell layer in contrast to those of the control or naloxone treated rats (p < 0.0001). The number of fetus though showed a decrease in the L-arginine treated rats (3 ± 1), but the fetal weight or fetal CRL did not change (p > 0.05). Conclusion This study may clearly illustrate the polycystic characteristics in the L-arginine treated group. It may particularly display the breeding efficacy of naloxone in rats with PCOS. How to cite this article Karami M, Lakzaei F, Nadoushan MRJ. Naloxone Breeding Effectiveness in Rat Suffering from Nitric Oxide-induced Polycystic Ovary Syndrome. Int J Infertil Fetal Med 2015;6(2):67-72.

Abstract 246: Role Of Cytochrome P450 4a2 In Mediating The Elevated Blood Pressure In A Rat Model Of Polycystic Ovary Syndrome

Hypertension ◽  
2014 ◽  
Vol 64 (suppl_1) ◽  
Author(s):  
Rodrigo O Maranon ◽  
Chetan N Patil ◽  
Carolina Dalmasso ◽  
Richard Roman ◽  
Jane F Reckelhoff
Keyword(s):  
Blood Pressure ◽  
Cytochrome P450 ◽  
Polycystic Ovary Syndrome ◽  
Polycystic Ovary ◽  
Female Rats ◽  
Elevated Blood Pressure ◽  
Elevated Blood ◽  
Renal Vasculature ◽  
Ovary Syndrome

Women with polycystic ovary syndrome (PCOS) often have elevated blood pressure (BP). PCOS is characterized in part by increases in androgens, and androgens can increase cytochrome P450 (CYP) 4A isoforms and 20-HETE synthesis. We have found that CYP4A2 expression is increased in renal vasculature of hyperandrogenemic female rats, a model of PCOS. In the present study we tested the hypothesis that androgen increase would not cause elevated BP in CYP4A2 -/- rats compared with wild type SS.Bn5 rats. CYP4A2 -/- and SS.Bn5 rats (n=6-8/grp) were treated from 4 wks of age with dihydrotestosterone pellets (DHT 7.5 mg/90 d) or placebo pellets until 14 wks, and then telemetry transmitters were implanted. After 2 wks, mean arterial pressure (MAP) was measured for 10 days. DHT increased MAP and decreased HR in SS.Bn5 compared with placebo controls (placebo: 104±2 vs. DHT: 126±6 mmHg, p<0.001). In contrast, while placebo-treated CYP4A2 -/- rats had higher MAP than WT, DHT did not increase BP in CYP4A2 -/- rats (Placebo: 120±1 vs. DHT: 118±1 mmHg, p=NS). These data suggest that CYP4A2 may be necessary for DHT to increase BP in our model of PCOS. However, by what mechanism(s) CYP4A2 -/- rats have higher MAP than SS.Bn5 WT remains to be determined. Supported by NIH R01HL66072, P01HL05971 and AHA 14POST18640015.

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.

Abstract 245: Role Of Melanocortin-4-receptor In The Blood Pressure Regulation In Female Hyperandrogenemic Rats, A Model Of Polycystic Ovary Syndrome

Hypertension ◽  
2014 ◽  
Vol 64 (suppl_1) ◽  
Author(s):  
Rodrigo O Maranon ◽  
Roberta Lima ◽  
Jussara M do Carmo ◽  
Alexander Da Silva ◽  
John E Hall ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Body Weight ◽  
Food Intake ◽  
Polycystic Ovary Syndrome ◽  
Polycystic Ovary ◽  
Female Rats ◽  
Sprague Dawley ◽  
Ovary Syndrome ◽  
Melanocortin 4 Receptor ◽  
Ad Libitum

Women with polycystic ovary syndrome (PCOS) are characterized by hyperandrogenemia, hirsutism, infertility, and enlarged cystic ovaries. Obesity and hypertension are also frequently found in women with PCOS, although the mechanisms responsible for the elevated blood pressure (BP) are unclear. Thus we tested the hypothesis that the melanocortin-4 receptor (MC4R), known to contribute to obesity hypertension in males, contributes to the elevated BP in hyperandrogenemic female rats, a model of PCOS. Female Sprague Dawley rats (4 wks) were implanted with dihydrotestosterone (DHT; 7.5mg/90 days sc) or placebo pellets (PL) (n=5/grp) and aged to 12 wks. Body weight and food intake (whether rats were pair fed or had ad libitum access) were measured daily. Two wks following implantation of radiotelemetry transmitters and intracerebroventricular cannulae, baseline mean arterial pressure (MAP) was measured for 5 days; then rats received MC3/4R antagonist, SHU-9119 (SHU; 1 nmol/h ICV) or vehicle for 7 days and MAP was recorded. DHT-treated rats had higher body weight and MAP than PL rats (BW: PL: 266.0±8.7; DHT: 348.5±10.4 g, p<0.01; MAP: PL rats: 102±5; DHT: 114±5 mmHg, p<0.05). SHU significantly increased food intake and body weights in both placebo (PL) and DHT-treated rats fed ad libitum (PL: 379.2±28.5; DHT: 451/3±7.3 g, p<0.01 DHT vs PL; 0.01 SHU vs control), but had no effect on MAP compared to controls (PL: 104±5; HAF rats: 114±5 mmHg; p<0.05, HAF vs PL; p=NS, SHU vs controls). However, in other rats, when pair fed with little increase in body weight (PL: 253.7±2.0, SHU: 261.0±0.6, p<0.05; DHT: 306.7±2.6, SHU: 316.7±1.5 g, p<0.05), SHU decreased MAP in DHT treated rats but not placebo controls (PL rats: 102±1, SHU: 103±2 mmHg; p=NS; DHT rats: 110±1 vs. SHU: 97±1 mmHg; p<0.001). Thus MC4R antagonist reduces MAP in DHT-treated rats only when food intake and body weight are controlled. These data suggest that activation of MC4R contributes to elevated BP in our model of PCOS and may also contribute to the elevated BP in women with PCOS. Supported by NIH R01HL66072, P01HL05971 and AHA 14POST18640015.

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.

Hypertension in Polycystic Ovary Syndrome: Novel Insights

2020 ◽  
Vol 16 (1) ◽  
pp. 55-60 ◽  
Author(s):  
Djuro Macut ◽  
Violeta Mladenović ◽  
Jelica Bjekić-Macut ◽  
Sarantis Livadas ◽  
Olivera Stanojlović ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Blood Pressure ◽  
Endothelial Dysfunction ◽  
Polycystic Ovary Syndrome ◽  
Polycystic Ovary ◽  
Ppar Gamma ◽  
Reproductive Age ◽  
Angiotensin Ii Receptor ◽  
Ovary Syndrome ◽  
Increased Risk

Polycystic ovary syndrome (PCOS) is a common endocrine disease in women during reproductive age. It was shown that PCOS women are with high risk for dyslipidemia, glucose intolerance, type 2 diabetes and metabolic syndrome. These factors are considered to represent traditional risk factors for the occurrence of cardiovascular disease. Observed increased risk for hypertension in PCOS women seems to be associated with insulin resistance and hyperinsulinemia. Both conditions interfere with the endothelium-dependent vasodilatation mechanisms causing vascular muscle wall hypertrophy. Obesity and insulin resistance are considered key factors for the alteration of blood pressure in PCOS women. Higher cardiovascular risk is implicated in PCOS with aging and its consequent association with both systolic and diastolic blood pressure. The elements of renin-angiotensin-aldosterone system (RAAS) have an impact on endothelial dysfunction as a marker of cardiovascular damage that could be modified is women with PCOS. Androgens and components of RAAS are involved in the process of atherogenesis in PCOS women. Therefore, it is hypothesized that spironolactone treatment could ameliorate endothelial dysfunction in PCOS women. Recently it was shown that telmisartan, angiotensin II receptor antagonist poses insulinsensitizing capacity to activate PPAR gamma and mediate favorable metabolic and reproductive effects in hypertensive PCOS women.

Age-related hormonal and metabolic alterations in women with polycystic ovary syndrome (PCOS)

2013 ◽  
Author(s):  
Pekka Pinola ◽  
Eszter Vanky ◽  
Inger Sundstrom-Poromaa ◽  
Elisabeth Stener-Victorin ◽  
Johanna Puurunen ◽  
...  
Keyword(s):  
Polycystic Ovary Syndrome ◽  
Polycystic Ovary ◽  
Ovary Syndrome ◽  
Metabolic Alterations ◽  
Age Related

IMPACT OF POLYCYSTIC OVARY SYNDROME ON QUALITY OF LIFE OF WOMEN IN EARLY REPRODUCTIVE AGE

2018 ◽  
Vol 14 (66) ◽  
pp. 087
Author(s):  
L. V. Pakharenko ◽  
I. T. Kyshakevych ◽  
V. D. Vorobii
Keyword(s):  
Quality Of Life ◽  
Polycystic Ovary Syndrome ◽  
Polycystic Ovary ◽  
Reproductive Age ◽  
Ovary Syndrome
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