Are STK11 polymorphisms a predictor of the response to metformin in polycystic ovarian syndrome?

Hamadneh,Jehan; Amarin,Zouhair; Alchalabi,Haifaa; Al-Bayyari,Nahla; Hamadneh,Shereen

doi:10.3892/br.2022.1553

Are STK11 polymorphisms a predictor of the response to metformin in polycystic ovarian syndrome?

Authors:
- Jehan Hamadneh
- Zouhair Amarin
- Haifaa Alchalabi
- Nahla Al-Bayyari
- Shereen Hamadneh
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Affiliations: Department of Obstetrics and Gynecology, Faculty of Medicine, Jordan University of Science and Technology, Irbid 22110, Jordan, Department of Nutrition and Food Technology, Al-Huson University College, Al-Balqa Applied University, Al-Salt 19117, Jordan, Department of Maternal and Child Health, Princess Salma Faculty of Nursing, Al al-Bayt University, Mafraq 25113, Jordan
Published online on: June 21, 2022 https://doi.org/10.3892/br.2022.1553
Article Number: 70

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Abstract

The aim of this study was to determine the frequencies of different genetic Serine threonine kinase 11 (STK11) variations in women with PCOS and to evaluate possible associations between the genetic polymorphisms of the STK11 gene and the response to metformin in women with polycystic ovary syndrome (PCOS). A prospective longitudinal cohort study of 57 women with PCOS was conducted. The anthropometric measurements, menstrual history, hirsutism, hair loss, acne, and biochemical parameters, in addition to gene testing for STK11 polymorphisms, were documented. Follow‑up was arranged after 6 menstrual cycles whilst on oral metformin therapy, (850 mg, twice daily). Of the 120 women who were interviewed, 88 women fulfilled the inclusion criteria and 57 women completed the study. The mean age, weight, height, and BMI were 23.8 years old, 72.1 kg, 159 cm, and 28.6 kg/m2 respectively. The frequencies of the genotypes of intron 1 of the STK11 gene were 26% CC, 44% CG, and 30% GG, and of intron 6 were 52% CC, 37% CT, and 11% TT genotype. There were statistically significant improvements following metformin therapy in menstrual frequency, blood loss, acne, ultrasound findings, and a decrease in BMI, acne, and hirsutism, but not in alopecia. Fasting insulin decreased significantly, but fasting blood sugar did not. There were no significant statistical differences in relation to the LH/FSH ratio, estradiol, FT, 17 OHP and length of menstruation. In relation to the SKT11 gene polymorphisms and metformin administration, there were variable and mostly insignificant differences in the results regarding menstrual regularity, amount of menstrual blood loss, acne, alopecia, ultrasound findings, and hirsutism score. There was a significant difference in relation to alopecia in the Intron 1 subgroups, and in relation to hirsutism score in the Intron 6 subgroups. It was concluded that polymorphisms in the STK11 gene in either Intron 1 or Intron 6 were not predictive of the response to metformin therapy at a dose of 850 mg twice daily, but may have some effect on alopecia and hirsutism.

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1	Dennett C and Simon J: The role of polycystic ovary syndrome in reproductive and metabolic health: Overview and approaches for treatment. Diabetes Spectr. 28:116–120. 2015.PubMed/NCBI View Article : Google Scholar
2	Wolf W, Wattick RA, Kinkade ON and Olfert MD: Geographical prevalence of polycystic ovary syndrome as determined by region and race/ethnicity. Int J Environ Res Public Health. 15(2589)2018.PubMed/NCBI View Article : Google Scholar
3	Barthelmess E and Naz R: Polycystic ovary syndrome: Current status and future perspective. Front Biosci (Elite Ed). 6:104–119. 2014.PubMed/NCBI View Article : Google Scholar
4	Talaei A, Adgi Z and Kelishadi M: Idiopathic hirsutism and insulin resistance. Int J Endocrin. 2013(593197)2013.PubMed/NCBI View Article : Google Scholar
5	Rasquin Leon LI and Mayrin JV: Polycystic ovarian disease. In: Stat Pearls [Internet]. Stat Pearls Publishing, Treasure Island, FL, 2020.
6	Dumitrescu R, Mehedintu C, Briceag I, Purcărea VL and Hudita D: Metformin-clinical pharmacology in PCOs. J Med Life. 8:187–192. 2015.PubMed/NCBI
7	Açbay O and Gündoğdu S: Can metformin reduce insulin resistance in polycystic ovary syndrome? Fertil Steril. 65:946–949. 1996.PubMed/NCBI
8	Mellott EN, Sharon EM and Hensley TL: Efficacy of metformin use to induce ovulation in women with polycystic ovarian syndrome. Obstet Gynecol Int J. 9:465–469. 2018.
9	Lord J, Flight I and Norman R: Metformin in polycystic ovary syndrome: Systematic review and meta-analysis. BMJ. 25:951–953. 2003.PubMed/NCBI View Article : Google Scholar
10	Foretz M, Guigas B and Viollet B: Understanding the glucoregulatory mechanisms of metformin in type 2 diabetes mellitus. Nat Rev Endocrinol. 15:569–589. 2019.PubMed/NCBI View Article : Google Scholar
11	Caudle KE, Gammal RS, Whirl-Carrillo M, Hoffman JM, Relling MV and Klein TE: Evidence and resources to implement pharmacogenetic knowledge for precision medicine. Am J Health Syst Pharm. 73:1977–1985. 2016.PubMed/NCBI View Article : Google Scholar
12	Hatoum D and McGowan E: Recent advances in the use of metformin: Can treating diabetes prevent breast cancer? Biomed Res Int. 2015(548436)2015.PubMed/NCBI View Article : Google Scholar
13	Guo Q, Liu Z, Jiang L, Liu M, Ma J, Yang C, Han L, Nan K and Liang X: Metformin inhibits growth of human non-small cell lung cancer cells via liver kinase B-1-independent activation of adenosine monophosphate-activated protein kinase. Mol Med Rep. 13:2590–2596. 2016.PubMed/NCBI View Article : Google Scholar
14	Stein B, Calzolari D, Hellberg K, Hu YS, He L, Hung CM, Toyama EQ, Ross DS, Lillemeier BF, Cantley LC, et al: Quantitative in vivo proteomics of metformin response in liver reveals AMPK-Dependent and -Independent signaling networks. Cell Rep. 29:3331–3348.e7. 2019.PubMed/NCBI View Article : Google Scholar
15	Goldenberg N and Glueck CJ: Is pharmacogenomics our future? Metformin, ovulation and polymorphism of the STK11 gene in polycystic ovary syndrome. Pharmacogenomics. 9:1163–1165. 2008.PubMed/NCBI View Article : Google Scholar
16	Legro RS, Barnhart HX, Schlaff WD, Carr BR, Diamond MP, Carson SA, Steinkampf MP, Coutifaris C, McGovern PG, Cataldo NA, et al: Ovulatory response to treatment of polycystic ovary syndrome is associated with a polymorphism in the STK11 gene. J Clin Endocrinol Metab. 93:792–800. 2008.PubMed/NCBI View Article : Google Scholar
17	Rotterdam ESHRE/ASRM-Sponsored PCOS consensus workshop group. Revised 2003 consensus on diagnostic criteria and long-term health risks related to polycystic ovary syndrome (PCOS). Hum Reprod. 19:41–47. 2004.PubMed/NCBI View Article : Google Scholar
18	Ferriman D and Gallwey JD: Clinical assessment of body hair growth in women. J Clin Endocrinol Metab. 21:1440–1447. 1961.PubMed/NCBI View Article : Google Scholar
19	Bridger T, MacDonald S, Baltzer F and Rodd C: Randomized placebo-controlled trial of metformin for adolescents with polycystic ovary syndrome. Arch Pediatr Adolesc Med. 160:241–246. 2006.PubMed/NCBI View Article : Google Scholar
20	Wang YW, He SJ, Feng X, Cheng J, Luo YT, Tian L and Huang Q: Metformin: A review of its potential indications. Drug Des Devel Ther. 11:2421–2429. 2017.PubMed/NCBI View Article : Google Scholar
21	Sam S and Ehrmann DA: Metformin therapy for the reproductive and metabolic consequences of polycystic ovary syndrome. Diabetologia. 60:1656–1661. 2017.PubMed/NCBI View Article : Google Scholar
22	Sharma S, Mathur DK, Paliwal V and Bhargava P: Efficacy of metformin in the treatment of acne in women with polycystic ovarian syndrome: A newer approach to acne therapy. J Clin Aesthet Dermatol. 12:34–38. 2019.PubMed/NCBI
23	Yang PK, Hsu CY, Chen MJ, Lai MY, Li ZR, Chen CH, Chen SU and Ho HN: The efficacy of 24-month metformin for improving menses, hormones, and metabolic profiles in polycystic ovary syndrome. J Clin Endocrinol Metab. 103:890–899. 2018.PubMed/NCBI View Article : Google Scholar
24	Harborne L, Fleming R, Lyall H, Sattar N and Norman J: Metformin or antiandrogen in the treatment of hirsutism in polycystic ovary syndrome. J Clin Endocrinol Metab. 88:4116–4123. 2003.PubMed/NCBI View Article : Google Scholar
25	Kelly CJ and Gordon D: The effect of metformin on hirsutism in polycystic ovary syndrome. Eur J Endocrinol. 147:217–221. 2002.PubMed/NCBI View Article : Google Scholar
26	Palomba S, Falbo A, Zullo F and Orio F Jr: Evidence-Based and potential benefits of metformin in the polycystic ovary syndrome: A comprehensive review. Endocr Rev. 30:1–50. 2009.PubMed/NCBI View Article : Google Scholar
27	Li Q, Li C, Li H, Zeng L, Kang Z, Mao Y, Tang X, Zheng P, He L, Luo F and Li Z: STK11 rs2075604 polymorphism is associated with metformin efficacy in Chinese type 2 diabetes mellitus. Int J Endocrinol. 2017(3402808)2017.PubMed/NCBI View Article : Google Scholar
28	Hussein MR, Ouda MH, Abdulwahid HH and Abo Al-Maali HM: Association of genetic polymorphism of LKB/STK11 with therapeutic response of metformin in women with polycystic ovary syndrome. Eur J Mol Clin Med. 7:539–552. 2021.
29	Goodman NF, Cobin RH, Futterweit W, Glueck JS, Legro RS and Carmina E: American Association of Clinical Endocrinologists (AACE); American College of Endocrinology (ACE); Androgen Excess and PCOS Society (AES). American Association of ClinicaL Endocrinologists, American College of Endocrinology, and Androgen Excess and PCOS Society Disease State ClinicaL Review: Guide to the best practices in the evaluation and treatment of polycystic ovary syndrome - part 1. Endocr Pract. 21:1291–300. 2015.PubMed/NCBI View Article : Google Scholar