Angiotensin II Type 2 Receptor Stimulation Improves Fatty Acid Ovarian Uptake and Hyperandrogenemia in an Obese Rat Model of Polycystic Ovary Syndrome

Abstract Polycystic ovary syndrome (PCOS) is mainly defined by hyperandrogenism but is also characterized by insulin resistance (IR). Studies showed that overexposure of nonadipose tissues to nonesterified fatty acids (NEFA) may explain both IR and hyperandrogenism. Recent studies indicate that treatment with an angiotensin II type 2 receptor (AT2R)-selective agonist improves diet-induced IR. We thus hypothesized that PCOS hyperandrogenism is triggered by ovarian NEFA overexposure and is improved after treatment with an AT2R agonist. Experiments were conducted in 12-week-old female JCR:LA-cp/cp rats, which are characterized by visceral obesity, IR, hyperandrogenism, and polycystic ovaries. Control JCR:LA +/? rats have a normal phenotype. Rats were treated for 8 days with saline or the selective AT2R agonist C21/M24 and then assessed for: 1) fasting testosterone, NEFA, and insulin levels; and 2) an iv 14(R,S)-[18F]fluoro-6-thia-heptadecanoic acid test to determine NEFA ovarian tissue uptake (Km). Compared with controls, saline-treated PCOS/cp rats displayed higher insulin (100 vs 5.6 μU/mL), testosterone (0.12 vs 0.04 nmol/L), NEFA (0.98 vs 0.48 mmol/L), and Km (20.7 vs 12.9 nmol/g·min) (all P < .0001). In PCOS/cp rats, C21/M24 did not significantly improve insulin or NEFA but normalized testosterone (P = .004) and Km (P = .009), which were strongly correlated together in all PCOS/cp rats (ρ = 0.74, P = .009). In conclusion, in an obese PCOS rat model, ovarian NEFA uptake and testosterone levels are strongly associated and are both significantly reduced after short-term C21/M24 therapy. These findings provide new information on the role of NEFA in PCOS hyperandrogenemia and suggest a potential role for AT2R agonists in the treatment of PCOS.

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Polycystic Ovary Syndrome, Insulin Resistance, and Obesity: Navigating the Pathophysiologic Labyrinth

International Journal of Reproductive Medicine ◽

10.1155/2014/719050 ◽

2014 ◽

Vol 2014 ◽

pp. 1-17 ◽

Cited By ~ 60

Author(s):

Joselyn Rojas ◽

Mervin Chávez ◽

Luis Olivar ◽

Milagros Rojas ◽

Jessenia Morillo ◽

...

Keyword(s):

Insulin Resistance ◽

Polycystic Ovary Syndrome ◽

Polycystic Ovary ◽

Ovarian Tissue ◽

Ovary Syndrome ◽

Main Culprit ◽

Exact Etiology

Polycystic ovary syndrome (PCOS) is a highly prevalent endocrine-metabolic disorder that implies various severe consequences to female health, including alarming rates of infertility. Although its exact etiology remains elusive, it is known to feature several hormonal disturbances, including hyperandrogenemia, insulin resistance (IR), and hyperinsulinemia. Insulin appears to disrupt all components of the hypothalamus-hypophysis-ovary axis, and ovarian tissue insulin resistance results in impaired metabolic signaling but intact mitogenic and steroidogenic activity, favoring hyperandrogenemia, which appears to be the main culprit of the clinical picture in PCOS. In turn, androgens may lead back to IR by increasing levels of free fatty acids and modifying muscle tissue composition and functionality, perpetuating this IR-hyperinsulinemia-hyperandrogenemia cycle. Nonobese women with PCOS showcase several differential features, with unique biochemical and hormonal profiles. Nevertheless, lean and obese patients have chronic inflammation mediating the long term cardiometabolic complications and comorbidities observed in women with PCOS, including dyslipidemia, metabolic syndrome, type 2 diabetes mellitus, and cardiovascular disease. Given these severe implications, it is important to thoroughly understand the pathophysiologic interconnections underlying PCOS, in order to provide superior therapeutic strategies and warrant improved quality of life to women with this syndrome.

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Role of Lipotoxicity and Contribution of the Renin-Angiotensin System in the Development of Polycystic Ovary Syndrome

International Journal of Endocrinology ◽

10.1155/2018/4315413 ◽

2018 ◽

Vol 2018 ◽

pp. 1-13 ◽

Cited By ~ 2

Author(s):

Alexandre Connolly ◽

Samuel Leblanc ◽

Jean-Patrice Baillargeon

Keyword(s):

Insulin Resistance ◽

Polycystic Ovary Syndrome ◽

Rat Model ◽

Polycystic Ovary ◽

Renin Angiotensin System ◽

Ovary Syndrome ◽

Nonesterified Fatty Acids ◽

Insulin Resistant ◽

Cellular Dysfunction

Polycystic ovary syndrome (PCOS) is a common and significant condition associated with hyperandrogenism, infertility, low quality of life, and metabolic comorbidities. One possible explanation of PCOS development is cellular dysfunction induced by nonesterified fatty acids (NEFAs), that is, lipotoxicity, which could explain both the hyperandrogenemia and insulin resistance that characterize women with PCOS. The literature suggests that androgen biosynthesis may be induced by overexposure of androgen-secreting tissues to NEFA and/or defective NEFA metabolism, leading to lipotoxic effects. Indeed, lipotoxicity could trigger androgenic hyperresponsiveness to insulin, LH, and ACTH. In most PCOS women, lipotoxicity also causes insulin resistance, inducing compensatory hyperinsulinemia, and may thus further increase hyperandrogenemia. Many approaches aimed at insulin sensitization also reduce lipotoxicity and have been shown to treat PCOS hyperandrogenemia. Furthermore, our group and others found that angiotensin II type 2 receptor (AT2R) activation is able to improve lipotoxicity. We provided evidence, using C21/M24, that AT2R activation improves adipocytes’ size and insulin sensitivity in an insulin-resistant rat model, as well as androgen levels in a PCOS obese rat model. Taken together, these findings point toward the important role of lipotoxicity in PCOS development and of the RAS system as a new target for the treatment of PCOS.

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Activation of Angiotensin II mediated hypertension in a rat model of Polycystic Ovary Syndrome.

The FASEB Journal ◽

10.1096/fasebj.24.1_supplement.1041.14 ◽

2010 ◽

Vol 24 (S1) ◽

Author(s):

Licy Lorena Yanes ◽

Deborah Davis ◽

Damian G Romero ◽

Jane F Reckelhoff

Keyword(s):

Angiotensin Ii ◽

Polycystic Ovary Syndrome ◽

Rat Model ◽

Polycystic Ovary ◽

Ovary Syndrome

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Polycystic Ovary Syndrome as an Endogenous Alcoholic Polycystic Ovary Syndrome

10.1101/143495 ◽

2017 ◽

Author(s):

IC. Medeiros ◽

JG. Lima

Keyword(s):

Polycystic Ovary Syndrome ◽

Polycystic Ovary ◽

Ovarian Tissue ◽

Blood Alcohol Concentration ◽

Public Health Problem ◽

Alcohol Concentration ◽

Reproductive Age ◽

Polycystic Ovaries ◽

Ovary Syndrome ◽

Nonalcoholic Fatty Liver

ABSTRACTPolycystic ovary syndrome (PCOS) is a growing worldwide public health problem that affects millions of women in their reproductive age. Despite being a very common disorder among women, there are still gaps regarding knowledge of disease mechanisms. In this respect, it was recently reported that acetaldehyde (ACD) is endogenously formed during normal ovarian steroidogenesis. The researchers demonstrated that in physiological concentrations ACD caused no detrimental effect on ovarian tissue. Contrariwise, in supraphysiological levels, ACD impairs granulosa cell differentiation, reduces ovulation, and decreases oocyte quality. Gut microbiota of patients with nonalcoholic fatty liver disease (NAFLD) produces significant quantities of endogenous ethanol (EE) and ACD. Because PCOS is closely linked to NAFLD, an ethanol-producing disorder, we hypothesize that it can be an endogenous alcoholic polycystic ovary syndrome (EAPCOS). The main findings of this study were that (i) the odds ratio of having polycystic ovaries is 30-fold greater in alcohol-exposed women than among unexposed controls; (ii) NAFLD/PCOS patients produce gonadotoxic quantities of EE; (iii) NAFLD/PCOS and alcoholic hepatitis individuals share similar liver expression levels of genes regulating high-km ethanol-metabolizing enzymes; (iv) NAFLD/PCOS and alcohol-tolerant drinkers share similar high-capacity to metabolize ethanol in the gut-liver axis; and (v) low blood alcohol concentration (BAC) in NAFLD/PCOS and alcohol-tolerant individuals stem from extensive alcohol degradation in gut-liver axis and significant fecal loss of ethanol. In summary, we provide mechanistic insights supporting the hypothesis that PCOS can be indeed an EAPCOS.

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Diagnostic difficulty in polycystic ovary syndrome due to an LH-beta-subunit variant

Acta Endocrinologica ◽

10.1530/eje.0.1400235 ◽

1999 ◽

pp. 235-238 ◽

Cited By ~ 4

Author(s):

H Kurioka ◽

K Takahashi ◽

M Irikoma ◽

M Okada ◽

T Ozaki ◽

...

Keyword(s):

Polycystic Ovary Syndrome ◽

Polycystic Ovary ◽

Ovarian Tissue ◽

Point Mutations ◽

Beta Subunit ◽

Variant Form ◽

Wild Type ◽

Polycystic Ovaries ◽

Ovary Syndrome ◽

Laparoscopic Biopsy

We initially failed to confirm a case of polycystic ovary syndrome (PCOS) because underestimation of LH concentrations due to a variant form of this hormone resulted in a misleadingly low LH/FSH ratio. A 26-year-old woman presented to our hospital with infertility. Given the presence of bilateral polycystic ovaries, oligomenorrhea and hirsutism. PCOS was suspected, but a normal LH/FSH ratio as measured by RIA led to diagnostic problems. When we remeasured LH and FSH using a chemical luminescence enzyme immunoassay (CLEIA), the ratio of the LH concentration measured by RIA to that measured by CLEIA was 0.29, and the ratio of LH to FSH measured by CLEIA was 3.3 compared with 0.81 measured by RIA. We then diagnosed PCOS. The point mutations Trp8 to Arg8 and Ile15 to Thr15 in the LH subunit were detected in the corresponding gene. The patient's LH status represented variant and wild-type LH equally. She was therefore diagnosed as heterozygous for the mutant LH-beta. Histologic assessment of ovarian tissue after laparoscopic biopsy was compatible with a polycystic ovary.

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