University of Kerbala
اسم الباحث : منتهى رحيم حسين
اسم المشرف : أ.م. مازن حامد عودة ، د. حميدة هادي عبد الواحد
الكلمات المفتاحية :
الكلية : كلية الصيدلة
الاختصاص : الادوية والسموم
سنة نشر البحث : 2020
تحميل الملف : اضغط هنا لتحميل البحث
Summary
Background; Polycystic ovary syndrome (PCOS) is the most common disorder of the ovary. It is characterized by hyperandrogenism, irregular ovulatory cycle and metabolic derangement including glucose intolerance with hyperinsulinemia. Manifestations of this syndrome are heterogeneous with several consensus definitions of the disorder have been produced to describe polycystic ovary syndrome, and various emphases on clinical or biochemical hyperandrogenism, polycystic ovaries and oligoanovulation.
Diagnosis of this syndrome has at least two of the following characteristics, clinical or biochemical hyperandrogenism, oligoanovulation and polycystic ovaries on ultrasound according to Rotterdam criteria. Several genes are involved in the pathogenesis of polycystic ovary syndrome, among them a single nucleotide polymorphism of serine threonine kinase11(STK11) gene and it has been suggested to be associated with this syndrome and response to metformin therapy.
Aims of the Study; To investigate the relation of the serine threonine kinase11 (STK11) gene polymorphism (rs741765 C\T) and (rs8111699 C\G) with the response to metformin therapy for a period of three months in a polycystic ovary syndrome treated patients in Kerbala province.
Materials, Patients and Methods; This an interventional a prospective study for two hundred thirty-five Iraqi women patients, who newly diagnosed with polycystic ovary syndrome based on Roterdam criteria by physician’s diagnosis during their visit to Gynecology and Obstetrics Teaching Hospital in Kerbala /Iraq. All women enrolled in this study were taken a metformin therapy (500mg) twice daily for three months. Women who were excluded from the study; those who had thyroid dysfunction, congenital adrenal hyperplasia and Cushing’s syndrome, or others on hypoglycemic drugs rather than metformin and those using one or more of medication that interfere with metformin action, consequently all should be excluded before making diagnosis of PCOS. Demographic parameters for all patients were reported, by the history-taking specifically for address, age, body mass index, blood pressure, presence of other diseases, smoking, menstrual regularity, hirsutism, martial state, number of children and times of abortion.
XXV
Blood samples were obtained from all patients. Venous blood (8ml) was withdrawn and (5ml) was placed in EDTA-tube for genetic study and for measuring fasting glucose and HbA1c; DNA extraction and polymerase chain reaction were done at the laboratory of postgraduate research in the College of Pharmacy/Kerbala University. Other (3ml) from each blood sample was placed in gel tube (EDTA-free) and serum was separated after centrifugation of blood at 3000 rpm for 10 minutes, then used for measurement of biomarkers markers.
Results; Serine-threonine kinase11(STK11) gene rs741765 and rs8111699 polymorphism were associated with metformin efficacy. Results were predicted by comparing the clinical, endocrinal and metabolic parameters among the three genotypes of each SNP; for rs741765, wild genotype (CC), heterozygous genotype(CT) and mutant genotype(TT). And for rs8111699 wild genotype (CC), heterozygous genotype (CG), mutant genotype (GG), so results revealed that the efficacy of metformin was increase with the presence of mutant alleles among the patients in both SNPs.
Present study revealed that STK11 rs8111699 SNP was associated with baseline insulin sensitivity in polycystic ovary syndrome patients and G allele carrying in the STK11 rs8111699 SNP can result in lower STK11 action and therefore lower efficiency of AMPK phosphorylation by STK11. Furthermore, the same G allele in the STK11 rs8111699 SNP like T allele in rs741765 both were associated with more metformin efficacy. Conclusion; Polymorphism in a serine threonine kinase11 (STK11) gene, a kinase gene which expressed in liver and implicated in metformin action is associated with response to metformin treated polycystic ovary syndrome patients in Kerbala province. Present study recorded that percentage of women who responded to treatment was increased with the number of (T) allele in rs741765 and (G) allele in rs8111699, nevertheless the same mutant (G) allele in rs8111699 SNP was reported to be associated with baseline insulin sensitivity.
Association of Genetic Polymorphism of STK11 Gen with Therapeutic Response of Metformin in Women with Polycystic Ovary Syndrome.
Summary
Background; Polycystic ovary syndrome (PCOS) is the most common disorder of the ovary. It is characterized by hyperandrogenism, irregular ovulatory cycle and metabolic derangement including glucose intolerance with hyperinsulinemia. Manifestations of this syndrome are heterogeneous with several consensus definitions of the disorder have been produced to describe polycystic ovary syndrome, and various emphases on clinical or biochemical hyperandrogenism, polycystic ovaries and oligoanovulation.
Diagnosis of this syndrome has at least two of the following characteristics, clinical or biochemical hyperandrogenism, oligoanovulation and polycystic ovaries on ultrasound according to Rotterdam criteria. Several genes are involved in the pathogenesis of polycystic ovary syndrome, among them a single nucleotide polymorphism of serine threonine kinase11(STK11) gene and it has been suggested to be associated with this syndrome and response to metformin therapy.
Aims of the Study; To investigate the relation of the serine threonine kinase11 (STK11) gene polymorphism (rs741765 C\T) and (rs8111699 C\G) with the response to metformin therapy for a period of three months in a polycystic ovary syndrome treated patients in Kerbala province.
Materials, Patients and Methods; This an interventional a prospective study for two hundred thirty-five Iraqi women patients, who newly diagnosed with polycystic ovary syndrome based on Roterdam criteria by physician’s diagnosis during their visit to Gynecology and Obstetrics Teaching Hospital in Kerbala /Iraq. All women enrolled in this study were taken a metformin therapy (500mg) twice daily for three months. Women who were excluded from the study; those who had thyroid dysfunction, congenital adrenal hyperplasia and Cushing’s syndrome, or others on hypoglycemic drugs rather than metformin and those using one or more of medication that interfere with metformin action, consequently all should be excluded before making diagnosis of PCOS. Demographic parameters for all patients were reported, by the history-taking specifically for address, age, body mass index, blood pressure, presence of other diseases, smoking, menstrual regularity, hirsutism, martial state, number of children and times of abortion.
XXV
Blood samples were obtained from all patients. Venous blood (8ml) was withdrawn and (5ml) was placed in EDTA-tube for genetic study and for measuring fasting glucose and HbA1c; DNA extraction and polymerase chain reaction were done at the laboratory of postgraduate research in the College of Pharmacy/Kerbala University. Other (3ml) from each blood sample was placed in gel tube (EDTA-free) and serum was separated after centrifugation of blood at 3000 rpm for 10 minutes, then used for measurement of biomarkers markers.
Results; Serine-threonine kinase11(STK11) gene rs741765 and rs8111699 polymorphism were associated with metformin efficacy. Results were predicted by comparing the clinical, endocrinal and metabolic parameters among the three genotypes of each SNP; for rs741765, wild genotype (CC), heterozygous genotype(CT) and mutant genotype(TT). And for rs8111699 wild genotype (CC), heterozygous genotype (CG), mutant genotype (GG), so results revealed that the efficacy of metformin was increase with the presence of mutant alleles among the patients in both SNPs.
Present study revealed that STK11 rs8111699 SNP was associated with baseline insulin sensitivity in polycystic ovary syndrome patients and G allele carrying in the STK11 rs8111699 SNP can result in lower STK11 action and therefore lower efficiency of AMPK phosphorylation by STK11. Furthermore, the same G allele in the STK11 rs8111699 SNP like T allele in rs741765 both were associated with more metformin efficacy. Conclusion; Polymorphism in a serine threonine kinase11 (STK11) gene, a kinase gene which expressed in liver and implicated in metformin action is associated with response to metformin treated polycystic ovary syndrome patients in Kerbala province. Present study recorded that percentage of women who responded to treatment was increased with the number of (T) allele in rs741765 and (G) allele in rs8111699, nevertheless the same mutant (G) allele in rs8111699 SNP was reported to be associated with baseline insulin sensitivity.
