Polycystic Ovary SyndromePolycystic Ovary Syndrome

PCOSPCOSPolycystic Ovary SyndromePolycystic Ovary Syndrome

PCOSPCOSZeev Blumenfeld, M.D.Zeev Blumenfeld, M.D.

Reproductive Endocrinology, Reproductive Endocrinology,

Rambam Health Care Campus, Faculty of Medicine,Rambam Health Care Campus, Faculty of Medicine,Technion- Israel Institute of Technology (IIT)Technion- Israel Institute of Technology (IIT)

Haifa, IsraelHaifa, Israel

Zeev Blumenfeld, M.D.Zeev Blumenfeld, M.D.

Reproductive Endocrinology, Reproductive Endocrinology, Rambam Health Care Campus, Faculty of Medicine,Rambam Health Care Campus, Faculty of Medicine,

Technion- Israel Institute of Technology (IIT)Technion- Israel Institute of Technology (IIT)Haifa, IsraelHaifa, Israel

PCOSPCOSPCOSPCOS•Irregular menses (oligo-Irregular menses (oligo-amenorrhea)amenorrhea)

•HirsutismHirsutism

•ObesityObesity

•AndrogenizationAndrogenization

•PCOPCO

•InfertilityInfertility

•Insulin ResistanceInsulin Resistance

RisksRisks

•Cardiovascular diseaseCardiovascular disease

•HypertensionHypertension

•Thromboembolic diseaseThromboembolic disease

•DiabetesDiabetes

•Endometrial Ca.Endometrial Ca.

•25-35% of obese PCOs will 25-35% of obese PCOs will have NIDDM or impaired have NIDDM or impaired G.T. by 30 years.G.T. by 30 years.

Prof Roy HomburgProf Roy Homburg

PCOSPCOSPCOSPCOS

PCOPCOPCOPCO

Prof Roy HomburgProf Roy Homburg

One in every One in every five womenfive womenhas polycystichas polycysticovaries.ovaries.

One in every One in every five womenfive womenhas polycystichas polycysticovaries.ovaries.

Prof Roy HomburgProf Roy Homburg

Fertil Steril & Hum Reprod, 2004Fertil Steril & Hum Reprod, 2004

PCOS Revised DefinitionPCOS Revised Definition

ESHRE / ASRM Criteria 2003ESHRE / ASRM Criteria 2003

AnovulationAnovulation HyperandrogenismHyperandrogenism

PCO morphology

PCO morphology

& Exclusion of related disorders& Exclusion of related disorders

PCOS Pathophysiology – “Vicious Cycle”PCOS Pathophysiology – “Vicious Cycle”PCOS Pathophysiology – “Vicious Cycle”PCOS Pathophysiology – “Vicious Cycle”

Stromal Stromal HyperthecosisHyperthecosis

AndrAndr

Acyclic Acyclic Peripheral Peripheral Conversion Conversion

of Aof AEE

Acyclic Acyclic Peripheral Peripheral Conversion Conversion

of Aof AEE

Increased Pituitary Increased Pituitary Sensitivity & Sensitivity &

Hypothalamic Hypothalamic PulsatilityPulsatility

LH /FSHLH /FSH

PCOS –פתופזיולוגיההפרשה לא תקינה של גונדוטרופינים

PCOS –פתופזיולוגיההפרשה לא תקינה של גונדוטרופינים

Two cell two gonadotropin theoryTwo cell two gonadotropin theory

PCOS- The Final Common Pathway?PCOS- The Final Common Pathway?PCOS- The Final Common Pathway?PCOS- The Final Common Pathway?

P.C.OP.C.O..P.C.OP.C.O..

Exagerrated Adrenarche?Exagerrated Adrenarche?Exagerrated Adrenarche?Exagerrated Adrenarche?

Inhibin B?Inhibin B? Inhibin B?Inhibin B?

Follistatin Follistatin gene?gene?Follistatin Follistatin gene?gene?

Thyroid DisordersThyroid DisordersThyroid DisordersThyroid Disorders

Serine Phosphorylation?Serine Phosphorylation?Serine Phosphorylation?Serine Phosphorylation?

Chromosome 2- Chromosome 2- Male baldness geneMale baldness geneChromosome 2- Chromosome 2- Male baldness geneMale baldness gene

LO-CAHLO-CAHLO-CAHLO-CAHVNTR- VNTR- Variable Variable Number Tandem RepeatNumber Tandem Repeat- - a promising candidatea promising candidate

VNTR- VNTR- Variable Variable Number Tandem RepeatNumber Tandem Repeat- - a promising candidatea promising candidate

Insulin Insulin genegeneInsulin Insulin genegene

CYP11a-CYP11a- P450 S.C.C. P450 S.C.C.CYP11a-CYP11a- P450 S.C.C. P450 S.C.C.

P450-17 P450-17 HyperactivityHyperactivityP450-17 P450-17 HyperactivityHyperactivity

-OH-ase-OH-ase-OH-ase-OH-ase

-17-20- lyase-17-20- lyase-17-20- lyase-17-20- lyaseFollistatin?Follistatin?Follistatin?Follistatin?

Activin?Activin?Activin?Activin?

Insulin in PCOSInsulin in PCOS(JCEM- editorial 2000;85:3520)(JCEM- editorial 2000;85:3520)

*““The actual role of insulin in PCOS is controversial” and The actual role of insulin in PCOS is controversial” and no consensus exists.no consensus exists.

*An increase in serine/threonine phosphorylation ofAn increase in serine/threonine phosphorylation of PP450-17450-17

17,20 lyase activity17,20 lyase activity ovarian ovarian

androgens.androgens.

*Increased serine phosphorylation of insulin receptor Increased serine phosphorylation of insulin receptor chain chain insulin resistance by inhibiting insulin resistance by inhibiting tyrosine phosphorylationtyrosine phosphorylation

Insulin in PCOSInsulin in PCOS(JCEM- editorial 2000;85:3520)(JCEM- editorial 2000;85:3520)

*““The actual role of insulin in PCOS is controversial” and The actual role of insulin in PCOS is controversial” and no consensus exists.no consensus exists.

*An increase in serine/threonine phosphorylation ofAn increase in serine/threonine phosphorylation of PP450-17450-17

17,20 lyase activity17,20 lyase activity ovarian ovarian

androgens.androgens.

*Increased serine phosphorylation of insulin receptor Increased serine phosphorylation of insulin receptor chain chain insulin resistance by inhibiting insulin resistance by inhibiting tyrosine phosphorylationtyrosine phosphorylation

Common molecular pathway?Common molecular pathway?Hyperactivity of a single serine kinaseHyperactivity of a single serine kinase

hyperandrogenism hyperandrogenism insulin resistanceinsulin resistance

CAH(21-ase)CAH(21-ase)

CAH(21-ase)CAH(21-ase)

HAIR-ANHAIR-AN

HA.IR.-ANHA.IR.-AN (Acanthosis Nigricans) (Acanthosis Nigricans)

Blumenfeld ZKupershmidt L

Kerner H *Offer A **Engel A **

Zila Shen Orr

Blumenfeld ZKupershmidt L

Kerner H *Offer A **Engel A **

Zila Shen Orr

Ovarian and adrenal venous catheterization for the

investigation of postmenopausal

virilization

Ovarian and adrenal venous catheterization for the

investigation of postmenopausal

virilization

TestoTesto 17OH17OH CortCort D-SD-S מיקום דגימה

מיקום דגימה

שעהשעה

מס. דגימהמס.

דגימה4.074.07 4.74.7 539539 1.7

31.7

3Rt. Common

IliacRt. Common

Iliac00 5949

 5949

 

150150 >75>75 437437 1.78

1.78

Lt.Ov.VeinLt.Ov.Vein 11:40

11:40

5950 

5950 

>52>52 >75>75 415415 1.68

1.68

Lt.Ov.VeinLt.Ov.Vein 11:45

11:45

5951 

5951 

4.64.6 6.36.3 427427 1.70

1.70

Lt. Renal VeinLt. Renal Vein 11:50

11:50

5952 

5952 

3.773.77 3.93.9 266266 1.52

1.52

Rt. Renal VeinRt. Renal Vein 12:00

12:00

5953 

5953 

3.863.86 7.17.1 800800 1.64

1.64

Lt. Adrenal Vein

Lt. Adrenal Vein

12:10

12:10

5954 

5954 

3.563.56 6.26.2 657657 1.72

1.72

Lt. Adrenal Vein

Lt. Adrenal Vein

12:13

12:13

5955 

5955 

3.953.95 3.43.4 315315 1.52

1.52

Rt. Ov. כניסה ל-Vein

.Rt. Ovכניסה ל-Vein

12:16

12:16

5956 

5956 

3.683.68 3.63.6 294294 1.68

1.68

I.V.C בגובה(הכליה הימנית(

I.V.C בגובה(הכליה הימנית(

12:20

12:20

59575957

40.7940.79 25.525.5 221221 1.32

1.32

Rt. Ov. VeinRt. Ov. Vein 12:32

12:32

5958 

5958 

אין דםאין דם אין דםאין דם אין דם אין דם אין דם

אין דם

IVC-Rt. Adrenal Vein

באזור הכניסה

.IVC-RtAdrenal Vein

באזור הכניסה

12:39

12:39

59595959

4.464.46 2.92.9 169169 1.74

1.74

IVC-Rt. Adrenal Vein

באזור הכניסה

.IVC-RtAdrenal Vein

באזור הכניסה

12:42

12:42

5960 

5960 

3.283.28 2.42.4 171171 1.22

1.22

גבוה, קרוב לעליה ימנית

IVC

גבוה, קרוב לעליה ימנית

IVC

12:45

12:45

59615961

Obese PCOSObese PCOS

HyperinsulinemiaHyperinsulinemia

IGF- BPIGF- BPII

IGF-IIGF-I

P450C17P450C17- activity- activity SHBGSHBG

Free AndrogensFree Androgens

Ovarian Ovarian androgen secretionandrogen secretion

LHLHaugmentationaugmentation

Insulin Effects in PCOSInsulin Effects in PCOS)JCEM- editorial 2000;85:3520()JCEM- editorial 2000;85:3520(

*Direct effect on Direct effect on ovarianovarian cytochrome cytochrome PP450 450 1717Androgen secretionAndrogen secretion

*Increases Increases ovarianovarian LH receptors LH receptors

*Stimulates LH release from Stimulates LH release from pituitarypituitary gonadotropes gonadotropes

*Augments Augments adrenaladrenal androgen synthesis androgen synthesis

*Decreases Decreases hepatichepatic SHBG production SHBG production

*Decreases Decreases in vitroin vitro IGF- BP IGF- BP11 IGF-1 IGF-1

Insulin Effects in PCOSInsulin Effects in PCOS)JCEM- editorial 2000;85:3520()JCEM- editorial 2000;85:3520(

*Direct effect on Direct effect on ovarianovarian cytochrome cytochrome PP450 450 1717Androgen secretionAndrogen secretion

*Increases Increases ovarianovarian LH receptors LH receptors

*Stimulates LH release from Stimulates LH release from pituitarypituitary gonadotropes gonadotropes

*Augments Augments adrenaladrenal androgen synthesis androgen synthesis

*Decreases Decreases hepatichepatic SHBG production SHBG production

*Decreases Decreases in vitroin vitro IGF- BP IGF- BP11 IGF-1 IGF-1

PCOS- Metabolic AbnormalityPCOS- Metabolic AbnormalityPCOS- Metabolic AbnormalityPCOS- Metabolic Abnormality

““Syndrome X”Syndrome X”““Syndrome X”Syndrome X”•DyslipidemiaDyslipidemia

•HypertensionHypertension

•Insulin ResistanceInsulin Resistance

•DyslipidemiaDyslipidemia

•HypertensionHypertension

•Insulin ResistanceInsulin Resistance ))Editorial- JCEM 2000;85:3520Editorial- JCEM 2000;85:3520(( ))Editorial- JCEM 2000;85:3520Editorial- JCEM 2000;85:3520((

Recently, the International Diabetes Federation (IDF) developed a simple clinical tool to define the metabolic syndrome:

Central Obesity, * DM, * Dyslipidemia, &

* Hypertension [Alberti et al; Lancet 2005; 366: 1059-1062].

Recently, the International Diabetes Federation (IDF) developed a simple clinical tool to define the metabolic syndrome:

Central Obesity, * DM, * Dyslipidemia, &

* Hypertension [Alberti et al; Lancet 2005; 366: 1059-1062].

Prof. Roy HomburgProf. Roy Homburg

DyslipidemiaDyslipidemiaHypertensionHypertensionInsulin Insulin ResistanceResistance

DyslipidemiaDyslipidemiaHypertensionHypertensionInsulin Insulin ResistanceResistance

The National Cholesterol Education Program Adult Treatment Panel )NCEPATP III( guidelines define the MBS as having three or more of the following abnormalities:

Waist circumference > 88 cm;

Fasting serum glucose > 110 mg/dl;

Fasting serum triglycerides > 150 mg/dl;

Serum HDL-C < 50 mg/dl; &

Blood pressure > 130/85mmHg.

The National Cholesterol Education Program Adult Treatment Panel )NCEPATP III( guidelines define the MBS as having three or more of the following abnormalities:

Waist circumference > 88 cm;

Fasting serum glucose > 110 mg/dl;

Fasting serum triglycerides > 150 mg/dl;

Serum HDL-C < 50 mg/dl; &

Blood pressure > 130/85mmHg.

Insulin resistanceInsulin resistance

HyperandrogenismHyperandrogenismObesity

Obesity

-cell dysfunction-cell dysfunction

HyperestrogenismHyperestrogenism

Genetic factorsGenetic factors

Acquired factorsAcquired factors

The Obesity-PCOS AssociationThe Obesity-PCOS Association

PCOSPCOS

Metabolic Syndrome Metabolic Syndrome

Abdominal obesity Insulin resistance ± glucose intolerance Atherogenic dyslipidemia Elevated blood pressure Proinflammatory state Prothrombotic state

Abdominal obesity Insulin resistance ± glucose intolerance Atherogenic dyslipidemia Elevated blood pressure Proinflammatory state Prothrombotic state

PCOS & Insulin Resistance

Therapeutic Endeavours(Endo. Rev. 1999; 20:535)

(1) Diet- weight reduction

(2) Insulin sensitizing agents: Metformin(Biguanide)

Troglitazone Rosiglitazone(thiazolidinedione)

Beta-3 adrenergic receptor agonists

Vanadate

D- chiro- Inositol (INS-1)

PCOS & Insulin Resistance

Therapeutic Endeavours(Endo. Rev. 1999; 20:535)

(1) Diet- weight reduction

(2) Insulin sensitizing agents: Metformin(Biguanide)

Troglitazone Rosiglitazone(thiazolidinedione)

Beta-3 adrenergic receptor agonists

Vanadate

D- chiro- Inositol (INS-1)

PCOSPCOSInsulin resistance

Hyperinsulinaemia

Hyperandrogenaemia

Menstrual Irregularity

Hirsutism

Acne

Weight loss

Exercise

Metformin

PCOS (n=117)Control (n=84)

36.8%

6.0%0%

5%

10%

15%

20%

25%

30%

35%

40%

45%

50%

High CRP Levels ( >5 mg/L) in PCOS & Controls

p<0.001

PCOS (n=117)Control (n=84)

36.8%

6.0%0%

5%

10%

15%

20%

25%

30%

35%

40%

45%

50%

High CRP Levels ( >5 mg/L) in PCOS & Controls

p<0.001

CRP<11<CRP<3

CRP>3CRP>5

22.8

%45

.2%

30.7

%29

.8%

46.5

%25

.0%

36.0

%6.

0%

0%

5%

10%

15%

20%

25%

30%

35%

40%

45%

50%

Distribution of CRP Levels (mg/L) in PCOS & Controlsp=0.0004

PCOS (n=114)

Control (n=84)

CRP<11<CRP<3

CRP>3CRP>5

22.8

%45

.2%

30.7

%29

.8%

46.5

%25

.0%

36.0

%6.

0%

0%

5%

10%

15%

20%

25%

30%

35%

40%

45%

50%

Distribution of CRP Levels (mg/L) in PCOS & Controlsp=0.0004

PCOS (n=114)

Control (n=84)

Treatment regimens directed towards lowering CRP levels (such as diet, smoking cessation, exercise, blood pressure control, low-dose aspirin, metformin, and possibly statins in the future) should probably be more aggressive for those PCOS women with increased CRP levels.

Treatment regimens directed towards lowering CRP levels (such as diet, smoking cessation, exercise, blood pressure control, low-dose aspirin, metformin, and possibly statins in the future) should probably be more aggressive for those PCOS women with increased CRP levels.

ConclusionConclusionConclusionConclusion

CRP – a marker of CVD CRP – a marker of CVD

Insulin resistanceHyperinsulinaemia

Hyperandrogenaemia

Menstrual Irregularity

Hirsutism

Acne

Weight loss

Exercise

Metformin