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Razvoj medicinskih nauka baziran je na istraživanju koje krajnjoj instanci delimično mora da se obavi na ljudima. Biomedicinsko istraživanje na ljudima.

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Presentation on theme: "Razvoj medicinskih nauka baziran je na istraživanju koje krajnjoj instanci delimično mora da se obavi na ljudima. Biomedicinsko istraživanje na ljudima."— Presentation transcript:

1 Razvoj medicinskih nauka baziran je na istraživanju koje krajnjoj instanci delimično mora da se obavi na ljudima. Biomedicinsko istraživanje na ljudima deli se na: istraživanje čiji je cilj poboljšanje dijagnostičkih i terapijskih postupaka istraživanje sa isključivo naučnim ciljem, bez direktne dobrobiti za dijagnostiku odnosno terapiju subjekta istraživanja. Cilj biomedicinskog istraživanja na ljudima jeste poboljšanje postojećih dijagnostičkih, terapijskih i profilaktičkih metoda, kao i rasvetljenje etiologije i patofiziologije oboljenja.

2 Vrste kliničkih istraživanja Opservaciona Intervenciona Vrste kliničkih istraživanja

3 Razjašnjavanje etiologije i patogeneze Procena i optimizacija dijagnostike Procena efikasnosti terapije Vrste kliničkih istraživanja

4 –Kontrolnu grupu –Eksperimentalne metode –Cilj istraživanja (primarni, sekundarni) –Istraživače uključene u studiju –Eksperimentalnu grupu Šta je najbitnije definisati pre otpočinjanja istraživanja?

5 Odabrati odgovarajuću grupu ispitanika Kriterijumi za uključenje u studiju

6 Slučajevi koji ne mogu da se procene (ergotest kod ispitanika bez noge) Ne-uključenje iz bezbednosnih razloga (trudnoća) Motivisanost bolesnika (non compliat) Kriterijumi koje sprečavaju uključenje (ekskluzioni)

7 Paralelne grupe Ukršteni tip (jedan pacijent) Eksperimentalni dizajn

8 Konsultacija eksperta i definisanje metoda se radi pre otpočinjanja studije! Analiza podataka:

9 J Steroid Biochem Dec;31(6): Androgen levels during sequential insulin euglycemic clamp studies in patients with polycystic ovary disease. Micic D, Popovic V, Nesovic M, Sumarac M, Dragasevic M, Kendereski A, Markovic D, Djordjevic P, Manojlovic D, Micic J. Clinic for Endocrinology, Diabetes and Diseases of Metabolism, University Clinical Center, Yugoslavia. It is postulated that insulin may play a role in the regulation of ovarian androgen production. In order to test the possible interrelation between serum insulin levels and androgen production, sequential euglycemic insulin clamp (Mode 9:1 on Biostator, insulin infusion rate: 0.1; 0.2 and 0.4 U/kg b. wt/h, each rate for 90 min, BC = 80 mg/dl) was done in 6 patients with polycystic ovary disease and normal glucose tolerance. Insulin, C-Peptide, testosterone and dehydroepiandrosterone-sulphate were measured in 0, 70, 80, 90, 160, 170, 180, 250, 260 and 270 min. Significant suppression of C-Peptide levels were achieved (0 min vs 270 min = vs nmol/l; P less than 0.05). Basal insulin as well as the mean plateau for each insulin infusion rate were as follows: ; ; and microU/l. There was significant testosterone increase at the end of insulin infusion (0 vs 270 min = vs nmol/l; P less than 0.05). There were no significant changes in dehydroepiandrosterone-sulphate levels during clamp studies (0 vs 270 min = vs ng/ml; P greater than 0.05). It is concluded that acute insulin infusion under the condition of sequential euglycemic clamp could increase androgen production in the ovaries of patients with PCO. Micic DPopovic VNesovic MSumarac MDragasevic M Kendereski AMarkovic DDjordjevic PManojlovic DMicic J

10 It is postulated that insulin may play a role in the regulation of ovarian androgen production. Teorijske postavke

11 Le virilisme pilaire et son association a l’insufficance glycolitique (diabete des femmes a barb) Achard C., Thiers J. Bull Acad Natl Med 1921; 86: 51-64

12 Correlation of hyperandrogenism with hyperinsulinism in polycystic ovarian disease Burgen G.A., Givens R.J., Kitabchi A.E., J. Clin. Endocrinol. Metab. 1980; 50:

13 Revised 2003 consensus on diagnostic criteria of PCOS Fauser B., Human Reproduction 19: 41-47, 2004.

14 Salehi M. et al., Metabolism 2004; 53: Theories of the Pathogenesis of PCOS

15 How common is it ? Common endocrine disorder in pre- menopausal women: 5-20 % Hoeger K, Obstet Gynecol Clin North Am 2001; 28: % of PCOS women are overweight Gambineri A et al., Int J Obes Relat Metab Disord 2002; 26:

16 The role of Obesity in PCOS Enhancement of hyperinsulinemia The role of leptin The enzymatic activity of adipose tissue in relation to steroid hormone metabolism

17 Syndrome X Resistance to insulin stimulated glucose uptake Glucose intolerance Hyperinsulinaemia Increased very-low density lipoprotein triglycerides Decreased high-density lipoprotein cholesterol Hypertension

18 Fauser B., Human Reproduction 19: 41-47, Criteria for the Metabolic Syndrome in PCOS

19 MARKERS OF THE RISK OF CORONARY HEART DISEASE HYPERINSULINEMIC WOMEN WITH POLYCYSTIC OVARY SYNDROME MAY REPRESENT THE FEMALE COMPONENT OF REAVEN’S SYNDROME X Jacobs H.S.: Polycystic Ovary Syndrome: the present position Gynecol Endocrinol 1996;10:

20 Health consequences of PCOS Syndrome X: Elevated VLDL triglycerides Decreased HDL cholesterol Hypertension Insulin resistance Hyperinsulinemia Glucose intolerance Syndrome XX:PCOS Endometrial cancer Breast cancer (?) Kazer R.R., Seminars in Reproductive Endocrinology, 1997; 15:

21 Zaključci hipoteze Sy PCO “ DUAL DEFECT “ (Poretsky & Piper, 1994) Dva nezavisna genetička defekta:Dva nezavisna genetička defekta: Povećanje LH sekrecijePovećanje LH sekrecije Insulinska rezistencijaInsulinska rezistencija Razvoj Sy PCO je rezultat: Sinergističkog delovanja povišenih LH nivoa i hiperinsulinemije na jajnik.Razvoj Sy PCO je rezultat: Sinergističkog delovanja povišenih LH nivoa i hiperinsulinemije na jajnik.

22

23 Periferna insulinska rezistencija Serumski insulin Serumski IGFBP-1 Slobodni IGF-1 Povisena sekrecija LH Folikularni IGFBPs Izostanak FSH efekta Povecano stvaranje androgena u teki Defektna folikularna maturacija Aciklicno stvaranje estrogena HIPERANDROGENIZAMANOVULACIJA PATOFIZIOLOGIJA Sy PCO

24 Tscichorozidou T et al.., Clin Endocrinol 60: 1-17, 2004 PATHWAYS LEADING TO ANDROGEN EXCESS IN PCOS

25 The aim of the study was to test the possible interrelation between serum insulin levels and androgen production. Definisanje ciljeva

26 Insulin Effects Related to Ovarian Function Salehi M. et al., Metabolism 2004; 53:

27 Dve karakteristike Sy PCO Hiperinsulinemijska insulinska rezistencijaHiperinsulinemijska insulinska rezistencija Povećana aktivnost ovarijalnog citohroma P450c17 Povećana aktivnost ovarijalnog citohroma P450c17  Hiperinsulinemija stimuliše ovaj enzim:Hiperinsulinemija stimuliše ovaj enzim: direktnodirektno indirektno, povećavajući sekreciju gonadotropinaindirektno, povećavajući sekreciju gonadotropina Urodjena abnormalnost ?Urodjena abnormalnost ?

28 Insulin and Cytochrome P450c17  Cytochrome P450c17  : key enzyme in the biosynthesis of ovarian androgens Bifunctional enzime : - 17  -hydroxylase - 17, 20-lyase Many women with PCOS: increased ovarian cytohrome P450c17  activity Hallmark: exaggerated serum 17  - hydroxyprogesterone response to stimulation by GnRH agonist ( nafarelin; buserelin; leuprolide )

29 Hipofiza Ćelija teke HOLESTEROL PREGNENOLON 17 a  HIDROKSIPROGESTERON ANDROSTENEDION TESTOSTERON INSULIN LH + + ? PROGESTERON 17  hidroksilaza 17, 20 - liaza { P450c17  17  reduktaza STIMULACIJA OVARIJALNOG STVARANJA ANDROGENA INSULINOM

30 Postulated role for insulin-sensitising agents Harborne L et al., Lancet 2003; 361:

31 dehydroepiandrosterone-sulphat (nadbubreg vs. ovarijum) PCOS vs. zdrave zene Značaj kontrolne grupe

32 “PCOS gen hipoteza” Insulin nije dovoljno visok u normalnih žena ili insulin ne reguliše ovarijalne androgene pod fiziološkim uslovimaInsulin nije dovoljno visok u normalnih žena ili insulin ne reguliše ovarijalne androgene pod fiziološkim uslovima Atraktivno objašnjenje je da normalne žene nemaju genetsku predispoziciju za stimulatorno delovanje insulina na ovarijalne androgeneAtraktivno objašnjenje je da normalne žene nemaju genetsku predispoziciju za stimulatorno delovanje insulina na ovarijalne androgene Nestler JE: Insulin resistance effects on sex hormones and ovulation in the Polycystic Ovary Syndrome, U: Contemporary Endocrinology: Insulin Resistance, 1999:

33 Definisanje eksperiementa Sequential euglycemic insulin clamp (Mode 9:1 on Biostator, insulin infusion rate: 0.1; 0.2 and 0.4 U/kg b. wt/h, each rate for 90 min,) was done in 6 patients with polycystic ovary disease and normal glucose tolerance. Insulin, C-Peptide, testosterone and dehydroepiandrosterone-sulphate were measured in 0, 70, 80, 90, 160, 170, 180, 250, 260 and 270 min. Sigurnost za pacijenta BC = 80 mg/dl Eksperiementalni protokol

34 TESTOSTERONE (nmol/l) t (min) Insulin (U/kg/h) Micić D. et al.; J Steroid Biochem 1988; 31:

35 It is concluded that acute insulin infusion under the condition of sequential euglycemic clamp could increase androgen production in the ovaries of patients with PCO. Zakljucak

36 2 Phenotypes Low LH- High Insulin High LH- Low Insulin Barbieri R., 1988

37 Minimal model - IVGTT Plasma glucose (mg/dl) Plasma insulin (mU/l) M. Sumarac-Dumanovic,, Insulin secretion and action in PCOS, PhD thesis, Belgrade, 2000

38 Insulin sensitivity in patients with PCOS and in controls controlsPCOS Si P < 0.05 BMI p < 0.05 IN-BMI + IN-WHR + M. Sumarac-Dumanovic,, Insulin secretion and action in PCOS, PhD thesis, Belgrade, 2000

39 Korelacija testosterona i insulinske senzitivnsti (Si) u SyPCO Testosteron (nmol/l) SI gojazne SyPCO negojazne SyPCO Sve SyPCO r= -0,258, p<0,05


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