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Vrste kliničkih istraživanja

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

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Vrste kliničkih istraživanja

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  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 Vrste kliničkih istraživanja • Opservaciona • Intervenciona

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

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

  5. Odabrati odgovarajuću grupu ispitanika Kriterijumi za uključenje u studiju

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

  7. Eksperimentalni dizajn • Paralelne grupe • Ukršteni tip (jedan pacijent)

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

  9. J Steroid Biochem. 1988 Dec;31(6):995-9. • 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 = 0.81 + 0.25 vs 0.15 + 0.20 nmol/l; P less than 0.05). Basal insulin as well as the mean plateau for each insulin infusion rate were as follows: 28 + 9; 248 + 119; 427 + 69 and 524 + 77 microU/l. There was significant testosterone increase at the end of insulin infusion (0 vs 270 min = 4.8 + 1.2 vs 8.1 + 1.7 nmol/l; P less than 0.05). There were no significant changes in dehydroepiandrosterone-sulphate levels during clamp studies (0 vs 270 min = 1055 + 133 vs 913 + 114 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.

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

  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: 113-116

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

  14. Theories of the Pathogenesis of PCOS Salehi M. et al., Metabolism 2004; 53: 358-376

  15. How common is it ? • Common endocrine disorder in pre-menopausal women: 5-20 %Hoeger K, Obstet Gynecol Clin North Am 2001; 28: 85-97 • 50 % of PCOS women are overweightGambineri A et al., Int J Obes Relat Metab Disord 2002; 26:883-896

  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. Criteria for the Metabolic Syndrome in PCOS Fauser B., Human Reproduction 19: 41-47, 2004.

  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 positionGynecol Endocrinol 1996;10:427-433.

  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; 15:193-194.

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

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

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

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

  25. Insulin Effects Related to Ovarian Function Salehi M. et al., Metabolism 2004; 53: 358-376

  26. Dve karakteristike Sy PCO • Hiperinsulinemijska insulinska rezistencija • Povećana aktivnost ovarijalnog citohroma P450c17 • Hiperinsulinemija stimuliše ovaj enzim: • direktno • indirektno, povećavajući sekreciju gonadotropina • Urodjena abnormalnost ?

  27. Insulin and Cytochrome P450c17a • Cytochrome P450c17a : key enzyme in the biosynthesis of ovarian androgens • Bifunctional enzime :- 17a-hydroxylase- 17, 20-lyase • Many women with PCOS: increased ovarian cytohrome P450c17a activity • Hallmark: exaggerated serum 17a-hydroxyprogesterone response to stimulation by GnRH agonist ( nafarelin; buserelin; leuprolide )

  28. Hipofiza LH + Ćelija teke + ? HOLESTEROL PREGNENOLON PROGESTERON + ? { 17 a hidroksilaza INSULIN P450c17a 17 aHIDROKSIPROGESTERON 17, 20 - liaza ANDROSTENEDION 17b reduktaza TESTOSTERON STIMULACIJA OVARIJALNOG STVARANJA ANDROGENA INSULINOM

  29. Postulated role for insulin-sensitising agents Harborne L et al., Lancet 2003; 361: 1894-1901

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

  31. “PCOS gen hipoteza” • Insulin 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 androgene Nestler JE: Insulin resistance effects on sex hormones and ovulation in the Polycystic Ovary Syndrome, U: Contemporary Endocrinology: Insulin Resistance, 1999: 347-365.

  32. Eksperiementalni protokol • 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

  33. 10 9 8 7 6 5 4 3 2 1 0 Micić D. et al.; J Steroid Biochem 1988; 31:995-999. TESTOSTERONE (nmol/l) Insulin (U/kg/h) 0.4 0.2 0.1 0 70 80 90 160 170 180 250 260 270 t (min)

  34. Zakljucak • 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.

  35. 2 Phenotypes Low LH- High Insulin High LH- Low Insulin Barbieri R., 1988

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

  37. Insulin sensitivity in patients with PCOS and in controls 10 P < 0.05 BMI p < 0.05 IN-BMI + IN-WHR + 8 Si 6 4 2 0 controls PCOS M. Sumarac-Dumanovic,, Insulin secretion and action in PCOS, PhD thesis, Belgrade, 2000

  38. Korelacija testosterona i insulinske senzitivnsti (Si) u SyPCO 10 8 6 SI 4 gojazne SyPCO 2 negojazne SyPCO Sve SyPCO r= -0,258, p<0,05 0 0 2 4 6 8 10 12 Testosteron (nmol/l)

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