Spironolactone reversed hepato-ovarian triglyceride accumulation caused by letrozole-induced polycystic ovarian syndrome: tissue uric acid—a familiar foe
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Polycystic ovarian syndrome (PCOS) is a complex endocrine disease among women of reproductive age and is one of the main causes of infertility. Non-alcoholic fatty liver disease (NAFLD), the most prominent chronic liver disease in adults, is characterized by excess hepatic triglyceride (TG) accumulation. PCOS women have increased risk of NAFLD and uric acid has been documented to have a positive correlation with subclinical tissue damage and might be the link in the cystic. Spironolactone (SPL) is a mineralocorticoid receptor (MR) blocker that has been in wide clinical use for some decades. In this research, we investigated the effects of SPL on ovarian and hepatic tissue damage in experimental PCOS rats induced by letrozole (LET). A total of eighteen adult female Wistar rats were used for this study and the animals divided into 3 groups are treated with vehicle, LET (1 mg/kg), and LET+SPL (SPL; 0.25 mg/kg), p.o. once daily respectively for 21 uninterrupted days. Results showed that LET treatment induced features of PCOS characterized by increased plasma testosterone (T) and luteinizing hormone (LH) together with increased body weight. Abnormal ovarian and hepatic histomorphological changes were also observed with elevated uric acid (UA) and TG accumulation in both tissues respectively. Treatment with SPL however attenuated the elevated testosterone in the LET-induced PCOS model accompanied with a reversal in the observed ovarian and hepatic UA, TG accumulation, and altered histomorphological changes. Taken together, spironolactone reversed the PCOS-induced ovarian and hepatic tissue damage by suppressing tissue UA and TG accumulation.
KeywordsTriglyceride accumulation PCOS Spironolactone NAFLD Uric acid
The authors acknowledge the technical support of Dr. Oniyide and Mrs. Olaiya Oluranti of Department of Physiology, Afe Babalola University. Mr. Adebowale of Bridge Biotech is also appreciated for the laboratory analysis.
TOF was an undergraduate student under the supervision of OAA; OAA conceived and designed the experiments. OAA, TOF, and OSA conducted the experiments. OSM, ALO, and RDA contributed in statistical and data analyses. OAA and OSM both wrote the manuscript and OAA revised and edited the same. All authors read and approved the manuscript for publication.
Compliance with ethical standards
The investigation was conducted in accordance with the National Institute of Health Guide for the Care and Use of Laboratory Animals and was approved by the University ethical review committee, with protocol identification number NHREC29/10/2019, and every effort was made to minimize both the number of animals used and their sufferings.
Conflict of interest
The authors declare that they have no conflicts of interest.
- Adeyanju OA, Michael OS, Soladoye AO, Olatunji LA (2018) Blockade of mineralocorticoid receptor ameliorates oral contraceptive-induced insulin resistance by suppressing elevated uric acid and glycogen synthase kinase-3 instead of circulating mineralocorticoid. Arch Phyiol Biochem:1–10. https://doi.org/10.1080/13813455.2018.1509220
- Bos MJ, Koudstaal PJ, Hofman A, Witteman JC, Breteler MM (2006) Uric acid is a risk factor for myocardial infarction and stroke: the Rotterdam study. Stroke 37:1503–1507. https://doi.org/10.1161/01.STR.0000221716.55088.d4 CrossRefPubMedGoogle Scholar
- Council NR (2010) Guide for the care and use of laboratory animals. National Academies Press, WashingtonGoogle Scholar
- Desai P, Malhotra N, Shah D (2008) Principles and practice of obstetrics and gynecology for postgraduates, 3rd edn. Jaypee Brothers Medical Publishers Private Limited, New Delhi, pp 676–683Google Scholar
- Guerrero-Romero F, Simental-Mendia LE, Gonzalez-Ortiz M, Martinez-Abundis E, Ramos-Zavala MG, Hernandez-Gonzalez SO et al (2010) The product of triglycerides and glucose, a simple measure of insulin sensitivity. Comparison with the euglycemic-hyperinsulinemic clamp. J Clin Endocrinol Metab 95:3347–3351PubMedCrossRefGoogle Scholar
- Jahan S, Munir F, Razak S, Mehboob A, Ain QU, Ullah H, Afsar T, Shaheen G, Almajwal (2016) Ameliorative effects of rutin against metabolic, biochemical and hormonal disturbances in polycystic ovary syndrome in rats. J Ovar Res 9:86Google Scholar
- Johnson RJ, Kang DH, Feig D, Kivlighn S, Kanellis J, Watanabe S, Tuttle KR, Rodriguez-Iturbe B, Herrera-Acosta J, Mazzali M (2003) Is there a pathogenetic role for uric acid in hypertension and cardiovascular and renal disease? Hypertension 41:1183–1190. https://doi.org/10.1161/01.HYP.0000069700.62727.C5 CrossRefPubMedGoogle Scholar
- Kauffman AS, Thackray VG, Ryan GE, Tolson KP, Glidewell-Kenney CA, Semaan SJ, Poling MC, Iwata N, Breen KM, Duleba AJ et al (2015) A novel letrozole model recapitulates both the reproductive and metabolic phenotypes of polycystic ovary syndrome in female mice. Biol Reprod 93:69PubMedPubMedCentralCrossRefGoogle Scholar
- Kucukaydin Z, Duran C, Basaran M, Camlica F, Erdem SS, Basaran A, Kutlu O, Burnik FS, Elmas H, Gonen MS (2016) Plasma total oxidant and antioxidant status after oral glucose tolerance and mixed meal tests in patients with polycystic ovarysyndrome. J Endocrinol Investig 39:1139–1148CrossRefGoogle Scholar
- Lanaspa MA, Sanchez-Lozada LG, Choi YJ, Cicerchi C, Kanbay M, Roncal-Jimenez CA, Ishimoto T, Li N, Marek G, Duranay M, Schreiner G, Rodriguez-Iturbe B, Nakagawa T, Kang DH, Sautin YY, Johnson RJ (2012) Uric acid induces hepatic steatosis by generation of mitochondrial oxidative stress: potential role in fructose-dependent and -independent fatty liver. J Biol Chem 287:40732–40744PubMedPubMedCentralCrossRefGoogle Scholar
- Macut D, Simic T, Lissounov A, Pljesa-Ercegovac M, Bozic I, Djukic T, Bjekic-Macut J, Matic M, Petakov M, Suvakov S, Damjanovic S, Savic-Radojevic A (2011) Insulin resistance in non-obese women with polycystic ovary syndrome: relation to by-products of oxidative stress. Exp Clin Endocrinol Diabetes 119:451–455PubMedCrossRefGoogle Scholar
- Mumford SL, Dasharathy SS, Pollack AZ, Perkins NJ, Mattison DR, Cole SR, Wactawski-Wende J, Schisterman EF (2013) Serum uric acid in relation to endogenous reproductive hormones during the menstrual cycle: findings from the Bio Cycle study. Hum Reprod 28:1853–1862PubMedPubMedCentralCrossRefGoogle Scholar
- Mumford SL, Schisterman EF, Siega-Riz AM, Gaskins AJ, Steiner AZ, Daniels JL, Olshan AF, Hediger ML, Hovey K, Wactawski-Wende J, Trevisan M, Bloom MS (2011) Cholesterol, endocrine and metabolic disturbances in sporadic anovulatory women with regular menstruation. Hum Reprod 26:423–430PubMedCrossRefGoogle Scholar
- Orio F, Muscogiuri G, Nese C, Palomba S, Savastano S, Tafuri D, Colarieti G, La Sala G, Colao A, Yildiz BO (2016) Obesity, type 2 diabetes mellitus and cardiovascular disease risk: an upto date in the management of polycystic ovary syndrome. Eur J Obstet Gynecol Reprod Biol. https://doi.org/10.1016/j.ejogrb.2016.08.026 CrossRefGoogle Scholar
- Rojas J, Chávez M, Olivar L, Rojas M, Morillo J, Mejías J et al (2014) Polycystic ovary syndrome, insulin resistance, and obesity: navigating the pathophysiologic labyrinth. Int J Reprod Med:1–17Google Scholar
- Usman TO, Areola ED, Badmus OO, Kim I, Olatunji LA (2018) Sodium acetate and androgen receptor blockade improve gestational androgen excess-induced deteriorated glucose homeostasis and antioxidant defenses in rats: roles of adenosine deaminase and xanthine oxidase activities. J Nutr Biochem 62:65–75. https://doi.org/10.1016/j.jnutbio.2018.08.018 CrossRefPubMedGoogle Scholar