Phosphodiesterase 4 inhibitor plus metformin is superior to metformin alone for the treatment of polycystic ovary syndrome: A rat model study

Tohma,Yusuf  Aytac; Onalan,Gogsen; Tepeoglu,Merih; Bayraktar,Nilufer; Colak,Eser; Ozcimen,Emel  Ebru; Zeyneloglu,Hulusi   Bulent

doi:10.3892/etm.2019.7428

Phosphodiesterase 4 inhibitor plus metformin is superior to metformin alone for the treatment of polycystic ovary syndrome: A rat model study

Authors:
- Yusuf Aytac Tohma
- Gogsen Onalan
- Merih Tepeoglu
- Nilufer Bayraktar
- Eser Colak
- Emel Ebru Ozcimen
- Hulusi Bulent Zeyneloglu
View Affiliations

Affiliations: Department of Obstetrics and Gynecology, Başkent University School of Medicine, 06490 Ankara, Turkey, Department of Pathology, Başkent University School of Medicine, 06490 Ankara, Turkey, Department of Biochemistry, Başkent University School of Medicine, 06490 Ankara, Turkey, Department of Obstetrics and Gynecology, Başkent University School of Medicine, 42080 Konya, Turkey
Published online on: March 22, 2019 https://doi.org/10.3892/etm.2019.7428
Pages: 4013-4022
Copyright: © Tohma et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

The role of metformin in the management of polycystic ovary syndrome (PCOS) and PCOS‑related obesity remains controversial. Recent research on the treatment of PCOS‑related obesity investigated novel therapeutic agents with the potential to work synergistically with metformin. The aim of the present study was to determine the synergistic effect of a phosphodiesterase 4 inhibitor (PDE4i) and metformin on weight and hormonal changes in a rat model of PCOS. A total of 40 female Sprague‑Dawley rats were randomly divided into 4 groups (n=10/group): Sham; PCOS control (no medication after PCOS induction with dehydroepiandrosterone); metformin (300 mg/kg/day p.o. after PCOS induction); and metformin + PDE4i (300 mg/kg/day p.o. metformin + 0.5 mg/kg/day p.o. PDE4i after PCOS induction). The body weight was measured every 7 days, from day 1 to day 49. Vaginal smears were performed and examined daily via light microscopy for determination of the stage of each rat's estrous cycle. At the end of 21st day and at the end of the study, blood samples were collected from rats and the testosterone and insulin levels were measured. Immunohistochemical staining was performed to quantify phosphorylated cyclic AMP response element‑binding protein expression in all groups. At the end of the study, the median body weight differed significantly among the groups (χ2=30.581, P<0.001), being the highest in the PCOS control group and the lowest in the metformin + PDE4i group. At the end of the study, the median testosterone level differed significantly among the groups (χ2=27.057, P<0.001), being the highest in the PCOS control group and the lowest in the metformin + PDE4i group. The cycle was restored to normal at the end of the study in all the rats in the metformin and metformin + PDE4i groups, whereas an irregular cycle persisted in all the rats in the PCOS control group. In conclusion, PDE4i + metformin was superior to metformin alone in reducing weight gain and decreasing the testosterone levels in a rat model of PCOS.

View Figures

View References

1	Stein IF and Leventhal ML: Amenorrhea associated with bilateral polycystic ovaries. Am J Obstet Gynecol. 29:181–191. 1935. View Article : Google Scholar
2	Carmina E, Napoli N, Longo RA, Rini GB and Lobo RA: Metabolic syndrome in polycystic ovary syndrome (PCOS): Lower prevalence in southern Italy than in the USA and the influence of criteria for the diagnosis of PCOS. Eur J Endocrinol. 154:141–145. 2006. View Article : Google Scholar : PubMed/NCBI
3	Broekmans FJ, Knauff EA, Valkenburg O, Laven JS, Eijkemans MJ and Fauser BC: PCOS according to the Rotterdam consensus criteria: Change in prevalence among WHO-II anovulation and association with metabolic factors. BJOG. 113:1210–1217. 2006. View Article : Google Scholar : PubMed/NCBI
4	Anagnostis P, Tarlatzis BC and Kauffman RP: Polycystic ovarian syndrome (PCOS): Long-term metabolic consequences. Metabolism. 86:33–43. 2018. View Article : Google Scholar : PubMed/NCBI
5	Li Q, Du J, Feng R, Xu Y, Wang H, Sang Q, Xing Q, Zhao X, Jin L, He L and Wang L: A possible new mechanism in the pathophysiology of polycystic ovary syndrome (PCOS): The discovery that leukocyte telomere length is strongly associated with PCOS. J Clin Endocrinol Metab. 99:E234–E240. 2014. View Article : Google Scholar : PubMed/NCBI
6	Alanbay I, Ercan CM, Sakinci M, Coksuer H, Ozturk M and Tapan S: A macrophage activation marker chitotriosidase in women with PCOS: Does low-grade chronic inflammation in PCOS relate to PCOS itself or obesity? Arch Gynecol Obstet. 286:1065–1071. 2012. View Article : Google Scholar : PubMed/NCBI
7	Ortega I, Villanueva JA, Wong DH, Cress AB, Sokalska A, Stanley SD and Duleba AJ: Resveratrol potentiates effects of simvastatin on inhibition of rat ovarian theca-interstitial cells steroidogenesis. J Ovarian Res. 7:212014. View Article : Google Scholar : PubMed/NCBI
8	Noroozzadeh M, Behboudi-Gandevani S, Zadeh-Vakili A and Ramezani Tehrani F: Hormone-induced rat model of polycystic ovary syndrome: A systematic review. Life Sci. 191:259–272. 2017. View Article : Google Scholar : PubMed/NCBI
9	Bingham J, Sudarsanam S and Srinivasan S: Profiling human phosphodiesterase genes and splice isoforms. Biochem Biophys Res Commun. 350:25–32. 2006. View Article : Google Scholar : PubMed/NCBI
10	Vezzosi D and Bertherat J: Phosphodiesterases in endocrine physiology and disease. Eur J Endocrinol. 165:177–188. 2011. View Article : Google Scholar : PubMed/NCBI
11	Calverley PM, Rabe KF, Goehring UM, Kristiansen S, Fabbri LM and Martinez FJ; M2-124 and M2-125 study groups, . Roflumilast in symptomatic chronic obstructive pulmonary disease: Two randomised clinical trials. Lancet. 374:685–694. 2009. View Article : Google Scholar : PubMed/NCBI
12	Tsai LC and Beavo JA: The roles of cyclic nucleotide phosphodiesterases (PDEs) in steroidogenesis. Curr Opin Pharmacol. 11:670–675. 2011. View Article : Google Scholar : PubMed/NCBI
13	Wouters EF, Bredenbröker D, Teichmann P, Brose M, Rabe KF, Fabbri LM and Göke B: Effect of the phosphodiesterase 4 inhibitor roflumilast on glucose metabolism in patients with treatment-naive, newly diagnosed type 2 diabetes mellitus. J Clin Endocrinol Metab. 97:E1720–E1725. 2012. View Article : Google Scholar : PubMed/NCBI
14	Jensterle M, Kocjan T and Janez A: Phosphodiesterase 4 inhibition as a potential new therapeutic target in obese women with polycystic ovary syndrome. J Clin Endocrinol Metab. 99:E1476–E1481. 2014. View Article : Google Scholar : PubMed/NCBI
15	Jin P and Xie Y: Treatment strategies for women with polycystic ovary syndrome. Gynecol Endocrinol. 34:272–277. 2018. View Article : Google Scholar : PubMed/NCBI
16	Jensterle M, Salamun V, Kocjan T, Vrtacnik Bokal E and Janez A: Short term monotherapy with GLP-1 receptor agonist liraglutide or PDE 4 inhibitor roflumilast is superior to metformin in weight loss in obese PCOS women: A pilot randomized study. J Ovarian Res. 8:322015. View Article : Google Scholar : PubMed/NCBI
17	Anderson E, Lee MT and Lee GY: Cystogenesis of the ovarian antral follicle of the rat: Ultrastructural changes and hormonal profile following the administration of dehydroepiandrosterone. Anat Rec. 234:359–382. 1992. View Article : Google Scholar : PubMed/NCBI
18	Mannerås L, Cajander S, Holmäng A, Seleskovic Z, Lystig T, Lönn M and Stener-Victorin E: A new rat model exhibiting both ovarian and metabolic characteristics of polycystic ovary syndrome. Endocrinology. 148:3781–3791. 2007. View Article : Google Scholar : PubMed/NCBI
19	Wu XY, Li ZL, Wu CY, Liu YM, Lin H, Wang SH and Xiao WF: Endocrine traits of polycystic ovary syndrome in prenatally androgenized female Sprague-Dawley rats. Endocr J. 57:201–209. 2010. View Article : Google Scholar : PubMed/NCBI
20	Sander V, Luchetti CG, Solano ME, Elia E, Di Girolamo G, Gonzalez C and Motta AB: Role of the N, N′-dimethylbiguanide metformin in the treatment of female prepuberal BALB/c mice hyperandrogenized with dehydroepiandrosterone. Reproduction. 131:591–602. 2006. View Article : Google Scholar : PubMed/NCBI
21	Reagan-Shaw S, Nihal M and Ahmad N: Dose translation from animal to human studies revisited. FASEB J. 22:659–661. 2008. View Article : Google Scholar : PubMed/NCBI
22	Marcondes FK, Bianchi FJ and Tanno AP: Determination of the estrous cycle phases of rats: Some helpful considerations. Braz J Biol. 62:609–614. 2002. View Article : Google Scholar : PubMed/NCBI
23	Wang H and Edens NK: mRNA expression and antilipolytic role of phosphodiesterase 4 in rat adipocytes in vitro. J Lipid Res. 48:1099–1107. 2007. View Article : Google Scholar : PubMed/NCBI
24	Miao ZL, Guo L, Wang YX, Cui R, Yang N, Huang MQ, Qin WB, Chen J, Li HM, Wang ZN and Wei XC: The intervention effect of Rosiglitozone in ovarian fibrosis of PCOS rats. Biomed Environ Sci. 25:46–52. 2012.PubMed/NCBI
25	Liu W, Liu W, Fu Y, Wang Y and Zhang Y: Bak Foong pills combined with metformin in the treatment of a polycystic ovarian syndrome rat model. Oncol Lett. 10:1819–1825. 2015. View Article : Google Scholar : PubMed/NCBI
26	Chang H, Jung WY, Kang Y, Lee H, Kim A and Kim BH: Expression of ROR1, pAkt, and pCREB in gastric adenocarcinoma. Ann Diagn Pathol. 19:330–334. 2015. View Article : Google Scholar : PubMed/NCBI
27	Lafontan M and Berlan M: Fat cell adrenergic receptors and the control of white and brown fat cell function. J Lipid Res. 34:1057–1091. 1993.PubMed/NCBI
28	Doseyici S, Mehmetoglu I, Toker A, Yerlikaya FH and Erbay E: The effects of forskolin and rolipram on cAMP, cGMP and free fatty acid levels in diet induced obesity. Biotech Histochem. 89:388–392. 2014. View Article : Google Scholar : PubMed/NCBI
29	Snyder PB, Esselstyn JM, Loughney K, Wolda SL and Florio VA: The role of cyclic nucleotide phosphodiesterases in the regulation of adipocyte lipolysis. J Lipid Res. 46:494–503. 2005. View Article : Google Scholar : PubMed/NCBI
30	Nakamura J, Okamura N and Kawakami Y: Augmentation of lipolysis in adipocytes from fed rats, but not from starved rats, by inhibition of rolipram-sensitive phosphodiesterase 4. Arch Biochem Biophys. 425:106–114. 2004. View Article : Google Scholar : PubMed/NCBI
31	Zhang R, Maratos-Flier E and Flier JS: Reduced adiposity and high-fat diet-induced adipose inflammation in mice deficient for phosphodiesterase 4B. Endocrinology. 150:3076–3082. 2009. View Article : Google Scholar : PubMed/NCBI
32	Ong WK, Gribble FM, Reimann F, Lynch MJ, Houslay MD, Baillie GS, Furman BL and Pyne NJ: The role of the PDE4D cAMP phosphodiesterase in the regulation of glucagon-like peptide-1 release. Br J Pharmacol. 157:633–644. 2009. View Article : Google Scholar : PubMed/NCBI
33	Vollert S, Kaessner N, Heuser A, Hanauer G, Dieckmann A, Knaack D, Kley HP, Beume R and Weiss-Haljiti C: The glucose-lowering effects of the PDE4 inhibitors roflumilast and roflumilast-N-oxide in db/db mice. Diabetologia. 55:2779–2788. 2012. View Article : Google Scholar : PubMed/NCBI
34	Franks S, Stark J and Hardy K: Follicle dynamics and anovulation in polycystic ovary syndrome. Hum Reprod Update. 14:367–378. 2008. View Article : Google Scholar : PubMed/NCBI
35	Willis D and Franks S: Insulin action in human granulosa cells from normal and polycystic ovaries is mediated by the insulin receptor and not the type-I insulin-like growth factor receptor. J Clin Endocrinol Metab. 80:3788–3790. 1995. View Article : Google Scholar : PubMed/NCBI
36	Lebbe M and Woodruff TK: Involvement of androgens in ovarian health and disease. Mol Hum Reprod. 19:828–837. 2013. View Article : Google Scholar : PubMed/NCBI
37	Adashi EY, Hsueh AJ and Yen SS: Insulin enhancement of luteinizing hormone and follicle-stimulating hormone release by cultured pituitary cells. Endocrinology. 108:1441–1449. 1981. View Article : Google Scholar : PubMed/NCBI
38	Dumesic DA, Akopians AL, Madrigal VK, Ramirez E, Margolis DJ, Sarma MK, Thomas AM, Grogan TR, Haykal R, Schooler TA, et al: Hyperandrogenism accompanies increased intra-abdominal fat storage in normal weight polycystic ovary syndrome women. J Clin Endocrinol Metab. 101:4178–4188. 2016. View Article : Google Scholar : PubMed/NCBI
39	Tsafriri A, Chun SY, Zhang R, Hsueh AJ and Conti M: Oocyte maturation involves compartmentalization and opposing changes of cAMP levels in follicular somatic and germ cells: Studies using selective phosphodiesterase inhibitors. Dev Biol. 178:393–402. 1996. View Article : Google Scholar : PubMed/NCBI
40	Thomas RE, Armstrong DT and Gilchrist RB: Differential effects of specific phosphodiesterase isoenzyme inhibitors on bovine oocyte meiotic maturation. Dev Biol. 244:215–225. 2002. View Article : Google Scholar : PubMed/NCBI