Journal of Literature Pharmacy Sciences

Polikistik Over Sendromlu Kadınlarda Beta-3 Adrenerjik Reseptör ve Trp64Arg Polimorfizminin Rolünün Belirlenmesi: Sistematik Derleme
Determining the Role of Beta-3 Adrenergic Receptor and Trp64Arg Polymorphism in Women with Polycystic Ovary Syndrome: Systematic Review
Dilan AŞKIN ÖZEKa , Songül ÜNÜVARb
aFırat Üniversitesi Kovancılar Meslek Yüksekokulu, Eczane Hizmetleri Bölümü, Elazığ, Türkiye
bİnönü Üniversitesi Eczacılık Fakültesi, Farmasötik Toksikoloji AD, Malatya, Türkiye
J Lit Pharm Sci. 2024;13(2):99-107
doi: 10.5336/pharmsci.2024-101237
Article Language: TR
Full Text
ÖZET
Polikistik over sendromu (PKOS) üreme çağındaki kadınlarda yaygın görülen kısırlık ve gebelik komplikasyonları gibi önemli üreme bozukluklarına neden olan aynı zamanda insülin direnci, diyabet ve obezite gibi metabolik bozukluklar ve psikolojik sorunların eşlik ettiği heterojen bir hastalıktır. Hormonal dengesizlik, insülin direnci, obezite, inflamasyon ve genetik faktörler PKOS'un en önemli nedenleridir. PKOS'un nedenleri ve sonuçları arasında birbirini tetikleyen bir kısır döngü söz konusudur. Genetik faktörler, bu yaygın endokrin bozukluğun gelişiminde önemli rol oynar. Son zamanlarda PKOS'un etiyopatogenezinin araştırılmasında özellikle gen mutasyonları ve polimorfizmlerin etkisine odaklanılmıştır. Genetik özelliklerin belirlenmesiyle erken teşhis ve hedefe yönelik tedavilerin yapılması PKOS'un uzun vadeli komplikasyonlarının da azaltılmasına önemli bir katkı sağlayacaktır. PKOS'ta, sürekli gonadotropin ve beta adrenerjik reseptör (βAR) uyarımı nedeniyle yumurtalıklarda steroid üretimi artar. Ayrıca obezitede artan sempatik aktivite, adipoz dokuda katekolamin direnci ve β3-AR duyarsızlaşmasına neden olmaktadır. β3-AR duyarsızlaşması lipolizi azaltır ve yağ depolarını artırarak obezite ve inflamasyon gelişimine zemin hazırlamaktadır. Bu durum PKOS'ta görülen neden ve sonuçlar arasındaki kısır döngüye katkı sağlar. Glukoz, lipid, enerji metabolizması ve insülin direncinde önemli rolleri olan β3-AR'ye ait Trp64Arg gen polimorfizmi, β3-AR'nin fonksiyonlarını azaltır. Daha önce Trp64Arg polimorfizmi insülin direnci, diyabet, enerji metabolizmasının bozulması, kilo alımı, infertilite ve kan lipid düzeylerinde artış ile ilişkilendirilmiştir. Trp64Arg polimorfizminin PKOS için kötü prognozla ilişkili olabileceği düşünülmektedir. Bu derlemenin amacı, PKOS'lu kadınlarda β3-AR'nin Trp64Arg gen polimorfizminin rolünü belirlemeye yönelik literatür bilgileri sunmaktır.

Anahtar Kelimeler: Polikistik over sendromu; beta-3 adrenerjik reseptörler; Trp64Arg polimorfizmi; insülin direnci
ABSTRACT
Polycystic ovary syndrome (PCOS) is a heterogeneous disease that causes significant reproductive disorders such as infertility and pregnancy complications, which are common in women of reproductive age and are accompanied by metabolic disorders and psychological problems such as insulin resistance, diabetes, and obesity. Hormonal imbalances, insulin resistance, obesity, inflammation, and genetic factors are the most important causes of PCOS. There is a vicious circle between the causes and consequences of PCOS. Genetic factors play important roles in the development of this common endocrine disorder. Recently, research on the etiopathogenesis of PCOS has focused on the effects of genetic mutations and polymorphisms. Early diagnosis and targeted treatment by determining genetic characteristics will significantly contribute to reducing the long-term complications of PCOS. In PCOS, steroid production increases in the ovaries owing to continuous gonadotropin and beta-adrenergic receptor (β-AR) stimulation. In addition, increased sympathetic activity in obesity causes catecholamine resistance and β3-AR desensitization in the adipose tissue. β3-AR desensitization reduces lipolysis and increases fat stores, paving the way for the development of obesity and inflammation. This contributes to the vicious circle between the causes and effects of PCOS. The Trp64Arg gene polymorphism of β3-AR, which plays important roles in glucose and lipid metabolism, energy metabolism, and insulin resistance, reduces the function of β3-AR. The Trp64Arg polymorphism is associated with insulin resistance, diabetes, impaired energy metabolism, weight gain, infertility, and increased blood lipid levels. It is thought that the Trp64Arg polymorphism may be associated with poor prognosis in PCOS. This review aimed to provide literature information to determine the role of the Trp64Arg gene polymorphism in β3-AR in women with PCOS.

Keywords: Polycystic ovary syndrome; beta-3 adrenergic receptors; Trp64Arg polymorphism; insulin resistance
REFERENCES:
  1. Kabel AM. Polycystic ovarian syndrome: insights into pathogenesis, diagnosis, prognosis, pharmacological and non-pharmacological treatment. Pharm Bioprocess. 2016;4(1):7-12. [Link] 
  2. Rotterdam ESHRE/ASRM-Sponsored PCOS Consensus Workshop Group. Revised 2003 consensus on diagnostic criteria and long-term health risks related to polycystic ovary syndrome. Fertil Steril. 2004;81(1):19-25. [Crossref]  [PubMed] 
  3. Lizneva D, Suturina L, Walker W, Brakta S, Gavrilova-Jordan L, Azziz R. Criteria, prevalence, and phenotypes of polycystic ovary syndrome. Fertil Steril. 2016;106(1):6-15. [Crossref]  [PubMed] 
  4. Knochenhauer ES, Key TJ, Kahsar-Miller M, Waggoner W, Boots LR, Azziz R. Prevalence of the polycystic ovary syndrome in unselected black and white women of the southeastern United States: a prospective study. J Clin Endocrinol Metab. 1998;83(9):3078-82. [Crossref]  [PubMed] 
  5. Escobar-Morreale HF. Polycystic ovary syndrome: definition, aetiology, diagnosis and treatment. Nat Rev Endocrinol. 2018;14(5):270-84. [Crossref]  [PubMed] 
  6. Hoeger KM, Dokras A, Piltonen T. Update on PCOS: consequences, challenges, and guiding treatment. J Clin Endocrinol Metab. 2021;106(3):e1071-e83. [Crossref]  [PubMed] 
  7. Dumesic DA, Oberfield SE, Stener-Victorin E, Marshall JC, Laven JS, Legro RS. Scientific statement on the diagnostic criteria, epidemiology, pathophysiology, and molecular genetics of polycystic ovary syndrome. Endocr Rev. 2015;36(5):487-525. [Crossref]  [PubMed]  [PMC] 
  8. Burger HG. Androgen production in women. Fertil Steril. 2002;77 Suppl 4:S3-5. [Crossref]  [PubMed] 
  9. Rosenfield RL. Ovarian and adrenal function in polycystic ovary syndrome. Endocrinol Metab Clin North Am. 1999;28(2):265-93. [Crossref]  [PubMed] 
  10. Dumesic DA, Padmanabhan V, Abbott DH. Polycystic ovary syndrome and oocyte developmental competence. Obstet Gynecol Surv. 2008;63(1):39-48. [Crossref]  [PubMed]  [PMC] 
  11. Ferriman D, Gallwey JD. Clinical assessment of body hair growth in women. J Clin Endocrinol Metab. 1961;21:1440-7. [Crossref]  [PubMed] 
  12. Wild RA. Long-term health consequences of PCOS. Hum Reprod Update. 2002;8(3):231-41. [Crossref]  [PubMed] 
  13. Azziz R, Carmina E, Chen Z, Dunaif A, Laven JS, Legro RS, et al. Polycystic ovary syndrome. Nat Rev Dis Primers. 2016;2:16057. [Crossref]  [PubMed] 
  14. Brunetti A, Chiefari E, Foti D. Recent advances in the molecular genetics of type 2 diabetes mellitus. World J Diabetes. 2014;5(2):128-40. [Crossref]  [PubMed]  [PMC] 
  15. Al Wattar BH, Fisher M, Bevington L, Talaulikar V, Davies M, Conway G, et al. Clinical practice guidelines on the diagnosis and management of polycystic ovary syndrome: a systematic review and quality assessment study. J Clin Endocrinol Metab. 2021;106(8):2436-46. [Crossref]  [PubMed]  [PMC] 
  16. Thessaloniki ESHRE/ASRM-Sponsored PCOS Consensus Workshop Group. Consensus on infertility treatment related to polycystic ovary syndrome. Hum Reprod. 2008;23(3):462-77. Erratum in: Hum Reprod. 2008;23(6):1474. [Crossref]  [PubMed] 
  17. National Institutes of Health. Evidence-based methodology workshop on polycystic ovary syndrome, December 3-5, 2012. Available: [Link] 
  18. Pasquali R, Pelusi C, Genghini S, Cacciari M, Gambineri A. Obesity and reproductive disorders in women. Hum Reprod Update. 2003;9(4):359-72. [Crossref]  [PubMed] 
  19. Boomsma CM, Eijkemans MJ, Hughes EG, Visser GH, Fauser BC, Macklon NS. A meta-analysis of pregnancy outcomes in women with polycystic ovary syndrome. Hum Reprod Update. 2006;12(6):673-83. [Crossref]  [PubMed] 
  20. Gambineri A, Pelusi C, Vicennati V, Pagotto U, Pasquali R. Obesity and the polycystic ovary syndrome. Int J Obes Relat Metab Disord. 2002;26(7):883-96. [Crossref]  [PubMed] 
  21. Ehrmann DA. Obesity and glucose intolerance in androgen excess. In: Azziz R, Nestler JE, Dewailly D, eds. Androgen Excess Disorders in Women. 1st ed. Philadelphia: Lippincott-Raven; 1997. p.705-12.
  22. Reaven GM. The insulin resistance syndrome: definition and dietary approaches to treatment. Annu Rev Nutr. 2005;25:391-406. [Crossref]  [PubMed] 
  23. Imani B, Eijkemans MJ, te Velde ER, Habbema JD, Fauser BC. A nomogram to predict the probability of live birth after clomiphene citrate induction of ovulation in normogonadotropic oligoamenorrheic infertility. Fertil Steril. 2002;77(1):91-7. [Crossref]  [PubMed] 
  24. Legro RS, Barnhart HX, Schlaff WD, Carr BR, Diamond MP, Carson SA, et al; Cooperative Multicenter Reproductive Medicine Network. Clomiphene, metformin, or both for infertility in the polycystic ovary syndrome. N Engl J Med. 2007;356(6):551-66. [Crossref]  [PubMed] 
  25. Hugues JN, Cédrin-Durnerin I, Howles CM; FSH OI Study Group; Amram M, Angelini A, Balen A, Barbereau D, Birkhauser M, Boujenah A, et al. The use of a decremental dose regimen in patients treated with a chronic low-dose step-up protocol for WHO Group II anovulation: a prospective randomized multicentre study. Hum Reprod. 2006;21(11):2817-22. [Crossref]  [PubMed] 
  26. Balen A. Surgical treatment of polycystic ovary syndrome. Best Pract Res Clin Endocrinol Metab. 2006;20(2):271-80. [Crossref]  [PubMed] 
  27. Urman B, Fluker MR, Yuen BH, Fleige-Zahradka BG, Zouves CG, Moon YS. The outcome of in vitro fertilization and embryo transfer in women with polycystic ovary syndrome failing to conceive after ovulation induction with exogenous gonadotropins. Fertil Steril. 1992;57(6):1269-73. [Crossref]  [PubMed] 
  28. Hiam D, Moreno-Asso A, Teede HJ, Laven JSE, Stepto NK, Moran LJ, et al. The genetics of polycystic ovary syndrome: an overview of candidate gene systematic reviews and genome-wide association studies. J Clin Med. 2019;8(10):1606. [Crossref]  [PubMed]  [PMC] 
  29. Khan MJ, Ullah A, Basit S. Genetic basis of polycystic ovary syndrome (PCOS): current perspectives. Appl Clin Genet. 2019;12:249-60. [Crossref]  [PubMed]  [PMC] 
  30. Lansdown A, Rees DA. The sympathetic nervous system in polycystic ovary syndrome: a novel therapeutic target? Clin Endocrinol (Oxf). 2012;77(6):791-801. [Crossref]  [PubMed] 
  31. Alvarez GE, Beske SD, Ballard TP, Davy KP. Sympathetic neural activation in visceral obesity. Circulation. 2002;106(20):2533-6. [Crossref]  [PubMed] 
  32. Grassi G, Dell'Oro R, Facchini A, Quarti Trevano F, Bolla GB, Mancia G. Effect of central and peripheral body fat distribution on sympathetic and baroreflex function in obese normotensives. J Hypertens. 2004;22(12):2363-9. [Crossref]  [PubMed] 
  33. Song Y, Altarejos J, Goodarzi MO, Inoue H, Guo X, Berdeaux R, et al. CRTC3 links catecholamine signalling to energy balance. Nature. 2010;468(7326):933-9. [Crossref]  [PubMed]  [PMC] 
  34. Flaa A, Aksnes TA, Kjeldsen SE, Eide I, Rostrup M. Increased sympathetic reactivity may predict insulin resistance: an 18-year follow-up study. Metabolism. 2008;57(10):1422-7. [Crossref]  [PubMed] 
  35. Masuo K, Kawaguchi H, Mikami H, Ogihara T, Tuck ML. Serum uric acid and plasma norepinephrine concentrations predict subsequent weight gain and blood pressure elevation. Hypertension. 2003;42(4):474-80. [Crossref]  [PubMed] 
  36. Barria A, Leyton V, Ojeda SR, Lara HE. Ovarian steroidal response to gonadotropins and beta-adrenergic stimulation is enhanced in polycystic ovary syndrome: role of sympathetic innervation. Endocrinology. 1993;133(6):2696-703. [Crossref]  [PubMed] 
  37. Schlaich MP, Straznicky N, Grima M, Ika-Sari C, Dawood T, Mahfoud F, et al. Renal denervation: a potential new treatment modality for polycystic ovary syndrome? J Hypertens. 2011;29(5):991-6. [Crossref]  [PubMed] 
  38. Heider U, Pedal I, Spanel-Borowski K. Increase in nerve fibers and loss of mast cells in polycystic and postmenopausal ovaries. Fertil Steril. 2001;75(6):1141-7. [Crossref]  [PubMed] 
  39. Aurbach GD, Spiegel AM, Gardner JD. Beta-adrenergic receptors, cyclic AMP, and ion transport in the avian erythrocyte. Adv Cyclic Nucleotide Res. 1975;5:117-32. [PubMed] 
  40. Emorine LJ, Feve B, Pairault J, Briend-Sutren MM, Marullo S, Delavier-Klutchko C, et al. Structural basis for functional diversity of beta 1-, beta 2- and beta 3-adrenergic receptors. Biochem Pharmacol. 1991;41(6-7):853-9. [Crossref]  [PubMed] 
  41. Fève B, Elhadri K, Quignard-Boulangé A, Pairault J. Transcriptional down-regulation by insulin of the beta 3-adrenergic receptor expression in 3T3-F442A adipocytes: a mechanism for repressing the cAMP signaling pathway. Proc Natl Acad Sci U S A. 1994;91(12):5677-81. [Crossref]  [PubMed]  [PMC] 
  42. Hadri KE, Charon C, Pairault J, Hauguel-De Mouzon S, Quignard-Boulangé A, Fève B. Down-regulation of beta3-adrenergic receptor expression in rat adipose tissue during the fasted/fed transition: evidence for a role of insulin. Biochem J. 1997;323 ( Pt 2)(Pt 2):359-64. [Crossref]  [PubMed]  [PMC] 
  43. Coman OA, Păunescu H, Ghiţă I, Coman L, Bădărăru A, Fulga I. Beta 3 adrenergic receptors: molecular, histological, functional and pharmacological approaches. Rom J Morphol Embryol. 2009;50(2):169-79. [PubMed] 
  44. Susulic VS, Frederich RC, Lawitts J, Tozzo E, Kahn BB, Harper ME, et al. Targeted disruption of the beta 3-adrenergic receptor gene. J Biol Chem. 1995;270(49):29483-92. [Crossref]  [PubMed] 
  45. Valentine JM, Ahmadian M, Keinan O, Abu-Odeh M, Zhao P, Zhou X, et al. β3-Adrenergic receptor downregulation leads to adipocyte catecholamine resistance in obesity. J Clin Invest. 2022;132(2):e153357. [Crossref]  [PubMed]  [PMC] 
  46. Goldberg M, Gordon ES. Energy metabolism in human obesity. plasma free fatty acid, glucose, and glycerol response to epinephrine. JAMA. 1964;189:616-23. [Crossref]  [PubMed] 
  47. Lönnqvist F, Thörne A, Large V, Arner P. Sex differences in visceral fat lipolysis and metabolic complications of obesity. Arterioscler Thromb Vasc Biol. 1997;17(7):1472-80. [Crossref]  [PubMed] 
  48. Arner P, Hoffstedt J. Adrenoceptor genes in human obesity. J Intern Med. 1999;245(6):667-72. [Crossref]  [PubMed] 
  49. Masuo K, Katsuya T, Fu Y, Rakugi H, Ogihara T, Tuck ML. Beta2-adrenoceptor polymorphisms relate to insulin resistance and sympathetic overactivity as early markers of metabolic disease in nonobese, normotensive individuals. Am J Hypertens. 2005;18(7):1009-14. [Crossref]  [PubMed] 
  50. Widén E, Lehto M, Kanninen T, Walston J, Shuldiner AR, Groop LC. Association of a polymorphism in the beta 3-adrenergic-receptor gene with features of the insulin resistance syndrome in Finns. N Engl J Med. 1995;333(6):348-51. [Crossref]  [PubMed] 
  51. Kurabayashi T, Carey DG, Morrison NA. The beta 3-adrenergic receptor gene Trp64Arg mutation is overrepresented in obese women. Effects on weight, BMI, abdominal fat, blood pressure, and reproductive history in an elderly Australian population. Diabetes. 1996;45(10):1358-63. [Crossref]  [PubMed] 
  52. Thomas GN, Tomlinson B, Chan JC, Young RP, Critchley JA. The Trp64Arg polymorphism of the beta3-adrenergic receptor gene and obesity in Chinese subjects with components of the metabolic syndrome. Int J Obes Relat Metab Disord. 2000;24(5):545-51. [Crossref]  [PubMed] 
  53. Luo Z, Zhang T, Wang S, He Y, Ye Q, Cao W. The Trp64Arg polymorphism in β3 adrenergic receptor (ADRB3) gene is associated with adipokines and plasma lipids: a systematic review, meta-analysis, and meta-regression. Lipids Health Dis. 2020;19(1):99. [Crossref]  [PubMed]  [PMC] 
  54. Mitchell BD, Blangero J, Comuzzie AG, Almasy LA, Shuldiner AR, Silver K, et al. A paired sibling analysis of the beta-3 adrenergic receptor and obesity in Mexican Americans. J Clin Invest. 1998;101(3):584-7. [Crossref]  [PubMed]  [PMC] 
  55. Malik SG, Saraswati MR, Suastika K, Trimarsanto H, Oktavianthi S, Sudoyo H. Association of beta3-adrenergic receptor (ADRB3) Trp64Arg gene polymorphism with obesity and metabolic syndrome in the Balinese: a pilot study. BMC Res Notes. 2011;4:167. [Crossref]  [PubMed]  [PMC] 
  56. Liu J, Zhang B, Li M, Li C, Liu Y, Wang Z, et al. [Study on relationship between Trp64Arg polymorphism of β3-adrenergic receptor gene and obesity and blood lipids]. Zhonghua Yi Xue Za Zhi. 2015;95(20):1558-62. Chinese. [PubMed] 
  57. Kurokawa N, Young EH, Oka Y, Satoh H, Wareham NJ, Sandhu MS, et al. The ADRB3 Trp64Arg variant and BMI: a meta-analysis of 44 833 individuals. Int J Obes (Lond). 2008;32(8):1240-9. [Crossref]  [PubMed] 
  58. Wang HD, Zhang CS, Li MW, Lin Q, Zhang Q, Liu DF, et al. The Association of Trp64Arg polymorphism in the beta-adrenergic receptor with insulin resistance: meta-analysis. Front Endocrinol (Lausanne). 2021;12:708139. [Crossref]  [PubMed]  [PMC] 
  59. Kurabayashi T, Yahata T, Quan J, Tanaka K. Association of polymorphisms in the beta2 and beta3 adrenoceptor gene with polycystic ovary syndrome. J Reprod Med. 2006;51(5):389-93. [PubMed] 
  60. Zangeneh FZ, Shoushtari MS, Shojaee S, Aboutorabi E. Investigation Trp64Arg polymorphism of the beta 3-adrenergic receptor gene in nonobese women with polycystic ovarian syndrome. Int J Reprod Biomed. 2020;18(3):165-74. [PubMed]  [PMC] 
  61. Pérez-Bravo F, Echiburú B, Maliqueo M, Santos JL, Sir-Petermann T. Tryptophan 64 --> arginine polymorphism of beta-3-adrenergic receptor in Chilean women with polycystic ovary syndrome. Clin Endocrinol (Oxf). 2005;62(2):126-31. [Crossref]  [PubMed] 
  62. Abeer M, Samah AG. Polymorphism of beta 3-adrenergic receptor gene and glycogen synthetase gene in polycystic ovary syndrome. MJCU. 2007;75(4):243-7 Available: [Link] 
  63. Witchel SF, Fagerli J, Siegel J, Smith R, Mitwally MF, Lewy V, et al. No association between body mass index and beta(3)-adrenergic receptor variant (W64R) in children with premature pubarche and adolescent girls with hyperandrogenism. Fertil Steril. 2000;73(3):509-15. [Crossref]  [PubMed] 

.: Up To Date

Login



Contact


Ortadoğu Reklam Tanıtım Yayıncılık Turizm Eğitim İnşaat Sanayi ve Ticaret A.Ş.

.: Address

Turkocagi Caddesi No:30 06520 Balgat / ANKARA
Phone: +90 312 286 56 56
Fax: +90 312 220 04 70
E-mail: info@turkiyeklinikleri.com

.: Manuscript Editing Department

Phone: +90 312 286 56 56/ 2
E-mail: yaziisleri@turkiyeklinikleri.com

.: English Language Redaction

Phone: +90 312 286 56 56/ 145
E-mail: tkyayindestek@turkiyeklinikleri.com

.: Marketing Sales-Project Department

Phone: +90 312 286 56 56/ 142
E-mail: reklam@turkiyeklinikleri.com

.: Subscription and Public Relations Department

Phone: +90 312 286 56 56/ 118
E-mail: abone@turkiyeklinikleri.com

.: Customer Services

Phone: +90 312 286 56 56/ 118
E-mail: satisdestek@turkiyeklinikleri.com

1. TERMS OF USE

1.1. To use the web pages with http://www.turkiyeklinikleri.com domain name or the websites reached through the sub domain names attached to the domain name (They will be collectively referred as "SITE"), please read the conditions below. If you do not accept these terms, please cease to use the "SITE." "SITE" owner reserves the right to change the information on the website, forms, contents, the "SITE," "SITE" terms of use anytime they want.

1.2. The owner of the "SITE" is Ortadoğu Advertisement Presentation Publishing Tourism Education Architecture Industry and Trade Inc. (From now on it is going to be referred as "Turkiye Klinikleri", shortly) and it resides at Turkocagi cad. No:30, 06520 Balgat Ankara. The services in the "SITE" are provided by "Turkiye Klinikleri."

1.3. Anyone accessing the "SITE" with or without a fee whether they are a natural person or a legal identity is considered to agree these terms of use. In this contract hereby, "Turkiye Klinikleri" may change the stated terms anytime. These changes will be published in the "SITE" periodically and they will be valid when they are published. Any natural person or legal identity benefiting from and reaching to the "SITE" are considered to be agreed to any change on hereby contract terms done by "Turkiye Klinikleri."

1.4. The "Terms of Use" hereby is published in the website with the last change on March 30th 2014 and the "SITE" is activated by enabling the access to everyone. The "Terms of Use" hereby is also a part of the any "USER Contract" was and/or will be done with the users using "Turkiye Klinikleri" services with or without a fee an inseparable.

2. DEFINITIONS

2.1. "SITE": A website offering different kind of services and context with a certain frame determined by "Turkiye Klinikleri" and it is accessible on-line on http://www.turkiyeklinikleri.com domain name and/or subdomains connected to the domain name.

2.2. USER: A natural person or a legal identity accessing to the "SITE" through online settings.

2.3. LINK: A link enabling to access to another website through the "SITE", the files, the context or through another website to the "SITE", the files and the context.

2.4. CONTEXT: Any visual, literary and auditory images published in the "Turkiye Klinikleri", "SITE" and/or any website or any accessible information, file, picture, number/figures, price, etc.

2.5. "USER CONTRACT": An electronically signed contract between a natural or a legal identity benefiting from special services "Turkiye Klinikleri" will provide and "Turkiye Klinikleri".

3. SCOPE OF THE SERVICES

3.1. "Turkiye Klinikleri" is completely free to determine the scope and quality of the services via the "SITE".

3.2. To benefit the services of "Turkiye Klinikleri" "SITE", the "USER" must deliver the features that will be specified by "Turkiye Klinikleri". "Turkiye Klinikleri" may change this necessity any time single-sided.

3.3. Not for a limited number, the services "Turkiye Klinikleri" will provide through the "SITE" for a certain price or for free are;

- Providing scientific articles, books and informative publications for health industry.

- Providing structural, statistical and editorial support to article preparation stage for scientific journals.

4. GENERAL PROVISIONS

4.1. "Turkiye Klinikleri" is completely free to determine which of the services and contents provided in the "SITE" will be charged.

4.2. People benefiting from the services provided by "Turkiye Klinikleri" and using the website can use the "SITE" only according to the law and only for personal reasons. Users have the criminal and civil liability for every process and action they take in the "SITE". Every USER agrees, declares and undertakes that they will not proceed by any function or action infringement of rights of "Turkiye Klinikleri"s and/or other third parties', they are the exclusive right holder on usage, processing, storage, made public and revealing any written, visual or auditory information reported to Turkiye Klinikleri" and/or "SITE" to the third parties. "USER" agrees and undertakes that s/he will not duplicate, copy, distribute, process, the pictures, text, visual and auditory images, video clips, files, databases, catalogs and lists within the "SITE", s/he will not be using these actions or with other ways to compete with "Turkiye Klinikleri", directly or indirectly.

4.3. The services provided and the context published within the "SITE" by third parties is not under the responsibility of "Turkiye Klinikleri", institutions collaborated with "Turkiye Klinikleri", "Turkiye Klinikleri" employee and directors, "Turkiye Klinikleri" authorized salespeople. Commitment to accuracy and legality of the published information, context, visual and auditory images provided by any third party are under the full responsibility of the third party. "Turkiye Klinikleri" does not promise and guarantee the safety, accuracy and legality of the services and context provided by a third party.

4.4. "USER"s cannot act against "Turkiye Klinikleri", other "USER"s and third parties by using the "SITE". "Turkiye Klinikleri" has no direct and/or indirect responsibility for any damage a third party suffered or will suffer regarding "USER"s actions on the "SITE" against the rules of the hereby "Terms of Use" and the law.

4.5. "USER"s accept and undertake that the information and context they provided to the "SITE" are accurate and legal. "Turkiye Klinikleri" is not liable and responsible for promising and guaranteeing the verification of the information and context transmitted to "Turkiye Klinikleri" by the "USER"s, or uploaded, changed and provided through the "SITE" by them and whether these information are safe, accurate and legal.

4.6. "USER"s agree and undertake that they will not perform any action leading to unfair competition, weakening the personal and commercial credit of "Turkiye Klinikleri" and a third party,  encroaching and attacking on personal rights within the "SITE" in accordance with the Turkish Commercial Code Law.

4.7. "Turkiye Klinikleri" reserves the right to change the services and the context within the "SITE"  anytime. "Turkiye Klinikleri" may use this right without any notification and timelessly. "USER"s have to make the changes and/or corrections "Turkiye Klinikleri" required immediately. Any changes and/or corrections that are required by "Turkiye Klinikleri", may be made by "Turkiye Klinikleri" when needed. Any harm, criminal and civil liability resulted or will result from changes and/or corrections required by "Turkiye Klinikleri" and were not made on time by the "USER"s belongs completely to the users.

4.8. "Turkiye Klinikleri" may give links through the "SITE" to other websites and/or "CONTEXT"s and/or folders that are outside of their control and owned and run by third parties. These links are provided for ease of reference only and do not hold qualification for support the respective web SITE or the admin or declaration or guarantee for the information inside. "Turkiye Klinikleri" does not hold any responsibility over the web-sites connected through the links on the "SITE", folders and context, the services or products on the websites provided through these links or their context.

4.9. "Turkiye Klinikleri" may use the information provided to them by the "USERS" through the "SITE" in line with the terms of the "PRIVACY POLICY" and "USER CONTRACT". It may process the information or classify and save them on a database. "Turkiye Klinikleri" may also use the USER's or visitor's identity, address, e-mail address, phone number, IP number, which sections of the "SITE" they visited, domain type, browser type, date and time information to provide statistical evaluation and customized services.

5. PROPRIETARY RIGHTS

5.1. The information accessed through this "SITE" or provided by the users legally and all the elements (including but not limited to design, text, image, html code and other codes) of the "SITE" (all of them will be called as studies tied to "Turkiye Klinikleri"s copyrights) belongs to "Turkiye Klinikleri". Users do not have the right to resell, process, share, distribute, display or give someone permission to access or to use the "Turkiye Klinikleri" services, "Turkiye Klinikleri" information and the products under copyright protection by "Turkiye Klinikleri". Within hereby "Terms of Use" unless explicitly permitted by "Turkiye Klinikleri" nobody can reproduce, process, distribute or produce or prepare any study from those under "Turkiye Klinikleri" copyright protection.

5.2. Within hereby "Terms of Use", "Turkiye Klinikleri" reserves the rights for "Turkiye Klinikleri" services, "Turkiye Klinikleri" information, the products associated with "Turkiye Klinikleri" copyrights, "Turkiye Klinikleri" trademarks, "Turkiye Klinikleri" trade looks or its all rights for other entity and information it has through this website unless it is explicitly authorized by "Turkiye Klinikleri".

6. CHANGES IN THE TERMS OF USE

"Turkiye Klinikleri" in its sole discretion may change the hereby "Terms of Use" anytime announcing within the "SITE". The changed terms of the hereby "Terms of Use" will become valid when they are announced. Hereby "Terms of Use" cannot be changed by unilateral declarations of users.

7. FORCE MAJEURE

"Turkiye Klinikleri" is not responsible for executing late or never of this hereby "Terms of Use", privacy policy and "USER Contract" in any situation legally taken into account as force majeure. Being late or failure of performance or non-defaulting of this and similar cases like this will not be the case from the viewpoint of "Turkiye Klinikleri", and "Turkiye Klinikleri" will not have any damage liability for these situations. "Force majeure" term will be regarded as outside of the concerned party's reasonable control and any situation that "Turkiye Klinikleri" cannot prevent even though it shows due diligence. Also, force majeure situations include but not limited to natural disasters, rebellion, war, strike, communication problems, infrastructure and internet failure, power cut and bad weather conditions.

8. LAW AND AUTHORISATION TO FOLLOW

Turkish Law will be applied in practicing, interpreting the hereby "Terms of Use" and managing the emerging legal relationships within this "Terms of Use" in case of finding element of foreignness, except for the rules of Turkish conflict of laws. Ankara Courts and Enforcement Offices are entitled in any controversy happened or may happen due to hereby contract.

9. CLOSING AND AGREEMENT

Hereby "Terms of Use" come into force when announced in the "SITE" by "Turkiye Klinikleri". The users are regarded to agree to hereby contract terms by using the "SITE". "Turkiye Klinikleri" may change the contract terms and the changes will be come into force by specifying the version number and the date of change on time it is published in the "SITE".

 

30.03.2014

Privacy Policy

We recommend you to read the terms of use below before you visit our website. In case you agree these terms, following our rules will be to your favor. Please read our Terms of Use thoroughly.

www.turkiyeklinikleri.com website belongs to Ortadoğu Advertisement Presentation Publishing Tourism Education Architecture Industry and Trade Inc. and is designed in order to inform physicians in the field of health

www.turkiyeklinikleri.com cannot reach to user’s identity, address, service providers or other information. The users may send this information to the website through forms if they would like to. However, www.turkiyeklinikleri.com may collect your hardware and software information. The information consists of your IP address, browser type, operating system, domain name, access time, and related websites. www.turkiyeklinikleri.com cannot sell the provided user information (your name, e-mail address, home and work address, phone number) to the third parties, publish it publicly, or keep it in the website. Gathered information has a directing feature to be a source for the website’s visitor profile, reporting and promotion of the services.

www.turkiyeklinikleri.com uses the taken information:

-To enhance, improve and maintain the quality of the website

-To generate visitor’s profile and statistical data

-To determine the tendency of the visitors on using our website

-To send print publications/correspondences

-To send press releases or notifications through e-mail

-To generate a list for an event or competition

By using www.turkiyeklinikleri.com you are considered to agree that;

-Ortadoğu Advertisement Presentation Publishing Tourism Education Architecture Industry and Trade Inc. cannot be hold responsible for any user’s illegal and immoral behavior,

-Terms of use may change from time to time,

-It is not responsible for other websites’ contents it cannot control or the harms they may cause although it uses the connection they provided.

Ortadoğu Advertisement Presentation Publishing Tourism Education Architecture Industry and Trade Inc. may block the website to users in the following events:

-Information with wrong, incomplete, deceiving or immoral expressions is recorded to the website,

-Proclamation, advertisement, announcement, libelous expressions are used against natural person or legal identity,

-During various attacks to the website,

-Disruption of the website because of a virus.

Written, visual and audible materials of the website, including the code and the software are under protection by legal legislation.

Without the written consent of Ortadoğu Advertisement Presentation Publishing Tourism Education Architecture Industry and Trade Inc. the information on the website cannot be downloaded, changed, reproduced, copied, republished, posted or distributed.

All rights of the software and the design of the website belong to Ortadoğu Advertisement Presentation Publishing Tourism Education Architecture Industry and Trade Inc.

Ortadoğu Advertisement Presentation Publishing Tourism Education Architecture Industry and Trade Inc. will be pleased to hear your comments about our terms of use. Please share the subjects you think may enrich our website or if there is any problem regarding our website.

info@turkiyeklinikleri.com