OBESITY AND POLYCYSTIC OVARY SYNDROME

1

• Razvoj medicinskih nauka baziran je na
  istraživanju koje krajnjoj instanci delimicno
  mora da se obavi na ljudima.
• Biomedicinsko istraživanje na ljudima deli se na
• istraživanje ciji je cilj poboljšanje
  dijagnostickih
• i terapijskih postupaka
• istraživanje sa iskljucivo naucnim ciljem, bez
• direktne dobrobiti za dijagnostiku odnosno
  terapiju
• subjekta istraživanja.

Cilj biomedicinskog istraživanja na ljudima
jeste poboljšanje postojecih dijagnostickih,
terapijskih i profilaktickih metoda, kao i
rasvetljenje etiologije i patofiziologije
oboljenja.
2
Vrste klinickih istraživanja
Vrste klinickih istraživanja

• Opservaciona
• Intervenciona

3
Vrste klinickih istraživanja

• Razjašnjavanje etiologije i patogeneze
• Procena i optimizacija dijagnostike
• Procena efikasnosti terapije

4
Šta je najbitnije definisati pre otpocinjanja
istraživanja?

• Kontrolnu grupu
• Eksperimentalne metode
• Cilj istraživanja (primarni, sekundarni)
• Istraživace ukljucene u studiju
• Eksperimentalnu grupu

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Odabrati odgovarajucu grupu ispitanika
Kriterijumi za ukljucenje u studiju
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Kriterijumi koje sprecavaju ukljucenje
(ekskluzioni)

• Slucajevi koji ne mogu da se procene (ergotest
  kod ispitanika bez noge)
• Ne-ukljucenje iz bezbednosnih razloga (trudnoca)
• Motivisanost bolesnika (non compliat)

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Eksperimentalni dizajn

• Paralelne grupe
• Ukršteni tip (jedan pacijent)

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Konsultacija eksperta i definisanje metoda se
radi pre otpocinjanja studije!
Analiza podataka
9

• J Steroid Biochem. 1988 Dec31(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 91 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 linsufficance 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
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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
  26883-896

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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

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Criteria for the Metabolic Syndrome in PCOS
Fauser B., Human Reproduction 19 41-47, 2004.
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MARKERS OF THE RISK OF CORONARY HEART DISEASE

• HYPERINSULINEMIC WOMEN WITH POLYCYSTIC OVARY
  SYNDROME MAY REPRESENT THE FEMALE COMPONENT OF
  REAVENS SYNDROME X
• Jacobs H.S. Polycystic Ovary Syndrome the
  present positionGynecol Endocrinol
  199610427-433.

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Health consequences of PCOS

• Syndrome X Elevated VLDL triglycerides Decre
  ased HDL cholesterol Hypertension Insulin
  resistance Hyperinsulinemia Glucose
  intolerance
• Syndrome XXPCOS Endometrial cancer Breast
  cancer (?)Kazer R.R., Seminars in Reproductive
  Endocrinology, 1997 15193-194.

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Zakljucci hipoteze Sy PCO DUAL DEFECT
(Poretsky Piper, 1994)

• Dva nezavisna geneticka defekta
• Povecanje LH sekrecije
• Insulinska rezistencija
• Razvoj Sy PCO je rezultatSinergistickog
  delovanja povišenih LH nivoa i hiperinsulinemije
  na jajnik.

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

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

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Insulin Effects Related to Ovarian Function
Salehi M. et al., Metabolism 2004 53 358-376
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Dve karakteristike Sy PCO

• Hiperinsulinemijska insulinska rezistencija
• Povecana aktivnost ovarijalnog citohroma
  P450c17??
• Hiperinsulinemija stimuliše ovaj enzim
• direktno
• indirektno, povecavajuci sekreciju gonadotropina
• Urodjena abnormalnost ?

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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-hydroxyprogestero
  ne response to stimulation by GnRH agonist (
  nafarelin buserelin leuprolide )

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Hipofiza
LH

Celija teke
?
HOLESTEROL
PREGNENOLON
PROGESTERON
?

17 a hidroksilaza
INSULIN
P450c17a
17 a HIDROKSIPROGESTERON
17, 20 - liaza
ANDROSTENEDION
17b reduktaza
TESTOSTERON
STIMULACIJA OVARIJALNOG STVARANJA ANDROGENA
INSULINOM
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Postulated role for insulin-sensitising agents
Harborne L et al., Lancet 2003 361 1894-1901
31
Znacaj kontrolne grupe

• dehydroepiandrosterone-sulphat (nadbubreg vs.
  ovarijum)
• PCOS vs. zdrave zene

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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.

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Eksperiementalni protokol

• Definisanje eksperiementa
• Sequential euglycemic insulin clamp (Mode 91 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

34
Micic D. et al. J Steroid Biochem 1988
31995-999.
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)
35
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.

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
10
P lt 0.05 BMI p lt 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
39
Korelacija testosterona i insulinske senzitivnsti
(Si) u SyPCO
10
8
6
SI
4
gojazne SyPCO
2
negojazne SyPCO
Sve SyPCO
r -0,258, plt0,05
0
12
10
8
6
4
2
0
Testosteron (nmol/l)