Transcript OBESITY AND POLYCYSTIC OVARY SYNDROME

Razvoj medicinskih nauka baziran je na istraživanju
koje krajnjoj instanci delimično mora da se obavi na
ljudima.
Cilj biomedicinskog istraživanja na ljudima jeste
poboljšanje postojećih dijagnostičkih, terapijskih
i profilaktičkih metoda, kao i rasvetljenje
etiologije i patofiziologije oboljenja.
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.
Vrstekliničkih
kliničkih istraživanja
Vrste
istraživanja
• Opservaciona
• Intervenciona
Vrste kliničkih istraživanja
• Razjašnjavanje etiologije i
patogeneze
• Procena i optimizacija
dijagnostike
• Procena efikasnosti terapije
Šta je najbitnije definisati pre
otpočinjanja istraživanja?
–
–
–
–
–
Kontrolnu grupu
Eksperimentalne metode
Cilj istraživanja (primarni, sekundarni)
Istraživače uključene u studiju
Eksperimentalnu grupu
Odabrati odgovarajuću grupu
ispitanika
Kriterijumi za uključenje u studiju
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)
Eksperimentalni dizajn
• Paralelne grupe
• Ukršteni tip (jedan
pacijent)
Analiza podataka:
Konsultacija eksperta i
definisanje metoda se radi
pre otpočinjanja studije!
•
•
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.
Teorijske postavke
• It is postulated that insulin
may play a role in the
regulation of ovarian androgen
production.
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
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
Revised 2003 consensus on diagnostic criteria of PCOS
Fauser B., Human Reproduction 19: 41-47, 2004.
Theories of the Pathogenesis of PCOS
Salehi M. et al., Metabolism 2004; 53: 358-376
How common is it ?
• Common endocrine disorder in premenopausal women: 5-20 %
Hoeger K, Obstet Gynecol Clin North Am 2001; 28: 85-97
• 50 % of PCOS women are overweight
Gambineri A et al., Int J Obes Relat Metab Disord 2002;
26:883-896
The role of Obesity in PCOS
•Enhancement of hyperinsulinemia
•The role of leptin
•tissue
The enzymatic activity of adipose
in relation to steroid hormone
metabolism
Syndrome X
•Resistance to insulin stimulated glucose uptake
•Glucose intolerance
•Hyperinsulinaemia
•Increased very-low density lipoprotein triglycerides
•Decreased high-density lipoprotein cholesterol
•Hypertension
Criteria for the Metabolic Syndrome in PCOS
Fauser B., Human Reproduction 19: 41-47, 2004.
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;10:427-433.
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.
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.
HIPOFIZA
LH
Insulin
JAJNIK
NADBUBREG
Mišić
Androgeni
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
PATOFIZIOLOGIJA Sy PCO
ANOVULACIJA
PATHWAYS LEADING TO ANDROGEN EXCESS IN PCOS
Tscichorozidou T et al.., Clin Endocrinol 60: 1-17, 2004
Definisanje ciljeva
• The aim of the study was to
test the possible interrelation
between serum insulin levels
and androgen production.
Insulin Effects Related to Ovarian Function
Salehi M. et al., Metabolism 2004; 53: 358-376
Dve karakteristike Sy PCO
• Hiperinsulinemijska insulinska rezistencija
• Povećana aktivnost ovarijalnog citohroma
P450c17
• Hiperinsulinemija stimuliše ovaj enzim:
• direktno
• indirektno, povećavajući sekreciju
gonadotropina
• Urodjena abnormalnost ?
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 )
Hipofiza
LH
+
Ćelija teke
+?
HOLESTEROL
PREGNENOLON
P450c17
PROGESTERON
{
17  hidroksilaza
17 a HIDROKSIPROGESTERON
17, 20 - liaza
+?
INSULIN
ANDROSTENEDION
17breduktaza
TESTOSTERON
STIMULACIJA OVARIJALNOG STVARANJA ANDROGENA INSULINOM
Postulated role for insulin-sensitising agents
Harborne L et al.,
Lancet
2003; 361:
1894-1901
Značaj kontrolne grupe
• dehydroepiandrosterone-sulphat
(nadbubreg vs. ovarijum)
• PCOS vs. zdrave zene
“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: 347365.
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
Micić D. et al.; J Steroid Biochem 1988; 31:995-999.
10
TESTOSTERONE (nmol/l)
9
8
7
6
5
4
3
2
1
0.1
Insulin (U/kg/h)
0.4
0.2
0
0
70 80 90
160 170 180
250 260 270
t (min)
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.
2 Phenotypes
Low LHHigh Insulin
High LHLow Insulin
Barbieri R.,
1988
Minimal model - IVGTT
450
Controls
PCOS
250
200
150
100
50
0
-20
0
20
40
60
80 100 120 140 160 180 200
time (min)
400
(mU/l)(mU/l)
insulin
Plasma
Plasma
insulin
Plamsa
(mg/dl)
glucoseglucose
Plasma
(mg/dl)
300
Controls
PCOS
350
300
250
200
150
100
50
0
-50
-20 0
20 40 60 80 100 120 140 160 180 200
time (min)
M. Sumarac-Dumanovic,, Insulin secretion and action in PCOS, PhD thesis, Belgrade, 2000
Insulin sensitivity in patients with
PCOS and in controls
10
P < 0.05
BMI p < 0.05
IN-BMI +
IN-WHR +
Si
8
6
4
2
0
controls
PCOS
M. Sumarac-Dumanovic,, Insulin secretion and action in PCOS, PhD thesis, Belgrade, 2000
Korelacija testosterona i insulinske
senzitivnsti (Si) u SyPCO
10
8
6
SI
4
gojazne SyPCO
2
negojazne SyPCO
Sve SyPCO
0
r= -0,258, p<0,05
0
2
4
6
8
Testosteron (nmol/l)
10
12