17
1 Alterazioni endocrino-metaboliche e riflessi sulla funzione ovarica e fertilita’ Antonio Lanzone Dipartimento per la Tutela della Salute della Donna e della Vita Nascente Università Cattolica del Sacro Cuore, Roma Criteri classificativi di sindrome metabolica Essah et al, JEI 2006 (almeno due) - obesità addominale - dislipidemia - ipertensione - alterazioni omeostasi glicoinsulinemica Sindrome metabolica Kahn’s categories of Insulin Resistance Kahn Type Insulin Receptor Defect Cause or associated Disease Hyper- androgenism A Defect intrinsic to insulin receptor resulting in a decreased function or decreased receptor number Genetic or obesity Often severe; virilization and ovarian stromal hyperthecosis common B Antibodies to insulin receptor Autoimmune, collagen vascular disease Mild to moderate C Receptor or post-receptor defect Obesity Moderate Kahn CR et al. N. Engl. J. Med. 1976

LANZONE s.metabolica e alterazioni ciclo - ccgm.itccgm.it/wp-content/uploads/lanzone-s.pdf · PCOS e controlli in base al peso corporeo 0 5000 10000 15000 20000 25000 I U / m l

  • Upload
    buihanh

  • View
    215

  • Download
    0

Embed Size (px)

Citation preview

1

Alterazioni endocrino-metaboliche e riflessi sulla funzione ovarica e

fertilita’Antonio Lanzone

Dipartimento per la Tutela della Salute della Donna e della Vita NascenteUniversità Cattolica del Sacro Cuore, Roma

Criteri classificativi di sindrome metabolica

Essah et al, JEI 2006

(almeno due)

- obesità addominale

- dislipidemia

- ipertensione

- alterazioni omeostasi glicoinsulinemica

Sindrome metabolica Kahn’s categories of InsulinResistance

KahnType

Insulin ReceptorDefect

Cause orassociated Disease

Hyper-androgenism

A Defect intrinsic toinsulin receptorresulting in adecreased functionor decreasedreceptor number

Genetic or obesity Often severe;virilization andovarian stromalhyperthecosiscommon

B Antibodies to insulinreceptor

Autoimmune,collagen vasculardisease

Mild to moderate

C Receptor orpost-receptor defect

Obesity Moderate

Kahn CR et al. N. Engl. J. Med. 1976

2

PCOS throughout life cycleClinical presentation and health

problemsOligomenorrhea Infertility Impaired glucose

tolerance

Irregular menses Hirsutism Type 2 diabetes

Hirsutism Obesity Dyslipidemia

Overweight Impaired glucose Cardiovasculartolerance diseases

Hypertension

Adolescence Adulthood Postmenopause

Obesity and PCOS

Prevalence: 50-70 %(including overweight) Phenotpe: abdominal < peripheral

NB: many “normal weight” women haveabdominal fatness

The abdominal phenotype is associated to the metabolic syndrome

Prevalenza dell’ iperinsulinemiain pz PCOS

Non obese n. 54 (42%)Obese n. 73 (58%)

Normoinsulinemiche60%

Iperinsulinemiche40%

Normoinsulinemiche28%

Iperinsulinemiche72%

Casistica UCSC

Risposta insulinemica all’OGTT in pazienti PCOS e controlli in base al peso corporeo

0

5000

10000

15000

20000

25000

IU

/ml/2

40’

IBW<120%;IBW>120% Lanzone et al Hum Reprod 1991

P < 0.01

P < 0.05

CTR PCOS

P < 0.001P < 0.02

3

Meccanismi responsabili del fenotipo “obesità-PCOS”

Dieta lipidi; fibre

Fattori

Genetici

Fattori intrauterini

↑PredispozionePCOS

Fenotipo “obesità-PCOS”

Obesità(soprattutto addominale)

androgeni

SHBG

Estrogeni

ß-endorphins

insulina/insulino resistenza

HPA

PCOS

Sindromemetabolica

Insulino-resistenza

50-80%43-47% 76-80%

Sovrapposizione tra caratteristiche della sindrome metabolica, della PCOS e insulinoresistenza

Modified from Essah et al, JEI 2006

The prevalence of the metabolic syndrome in women with PCOS is approximately 43-47%, a rate

2-fold higher than that for women in the general

population.

Essah et al, J Endocrinol Invest, 2006

0

10

20

30

40

50

60

70

<19 20-29 30-39 40-49 50-59 60-69

PCOS Controlli

Età

Prev

alen

za %

Prevalenza della sindrome metabolica in pazienti con PCOS e controlli in relazione all’età

*

*

*

* : P< 0.001 vs ctrl(Apridonidze et al, JCEM 2005)

4

Prevalenza della SM in donne U.S.A. con PCOS (n=106) e controlli stratificate per età e BMI

14.643.414.41.1Controlli (%)

53.161.840.023.1PCOS (%)

30-39 aa (n= 49)

5.927.58.30.8Controlli (%)

44.858.616.70PCOS (%)

20-29aa (n=29)

>3025-30<25

TotaleBMIGruppo d’età

(Apridonidze et al, JCEM 2005)

Prevalenza delle singole anomalie della SM tra 106 pazienti con PCOS

0 (0)9 (4)3.8 (4)Iperglicemia a digiuno

23 (14)74 (34)45 (48)Ipertensione

49 (29)91 (42)68 (71)↓ HDL

8 (5)70 (32)35 (37)Ipertrigliceridemia

29 (48)91 (42)67 (71)Alto BMI(Circ vita > 88cm)

No SM (n=60)

SM (n=46)

Totale (n=106)

Prevalenza [% (n)]Fattori della SM

(Apridonidze et al, JCEM 2005)

Dyslipidemia is the most common metabolic abnormality in PCOS:

prevalence 70%

LDL-C

HDL-C

Tryglycerides

Talbott J Clin Epid 1998Nobroson Clin Endocrinol 1990Conway Clin Endocrinl 1992Holte Clin Endocrinol 1994Raykowa J Clin End Metab 1997

Presence in obese and non-obese patiens

PCOS and dyslipidemiaStudy Population Findings evidence

Wild 1985

Slowinska-Srzednicka1991

Wild 1992

Talbott 1992

29 PCOS vs 30 ctr

49 lean and obese PCOS

47 hirsute vs 15 ctr

206 PCOS

TriglyceridesHDL-c

HDL2apolipoproteinB

Triglycerides, VLDL-c apolipoprotein C-AHDL-c

Triglyceridestotal HDL total cholesterol LDL levels

III

III

III

III

5

• I test d’insulino resistenza non sono necessari per fare diagnosi di PCOS nè per selezionare il trattamento

• Donne obese con PCOS dovrebbero essere sottoposte a test di screening per la sindrome metabolica incluso l’OGTT

• Sono necessari ulteriori studi nelle pazienti non obese con PCOS per valutare l’utilità dell’impiego di questi test,anche se essi potrebbero essere tenuti in considerazione in presenza di fattori di rischio addizionali quali la familiarità per diabete

Consensus Rotterdam (2003): aspetti metabolici Percentage frequency of menstrual

irregularities in women with PCOS

64051%28%19%Amenorrhea

54729%52%47%Oligomenorrhoea

N° of cases

Goldzieheret alN = 1079

FranksN = 300

Balen etal N=1741

(Modified from Hart 2004)

Approccio razionale al trattamento delle alterazioni mestruali nella PCOS

Individuazione di disturbi concomitanti: Alterazioni metaboliche (obesità,

dislipidemia, iperinsulinemia ed insulino-resistenza).

Iperandrogenismo (markers biochimici, acne, irsutismo, alopecia)

Approccio globale ai sintomi di PCOS. Prevenzione delle sequele a medio e lungo termine.

Categorie di pazienti PCOS con alterazioni del ciclo mestruale

1. Paziente senza alterazioni metaboliche nésegni di iperandrogenismo.

2. Paziente senza alterazioni metaboliche consegni di iperandrogenismo.

3. Paziente con alterazioni metaboliche, con o senza segni di iperandrogenismo.

6

Differenti distribuzioni del grasso corporeo sono associate a differenti

“endocrine environments” Diversa produzione e metabolismo

SHBG diverso Diversa produzione di androgeni Diversa insulino resistenza Diversa produzione di insulina

Diversa % di alterazioni del ciclo mestruale

Metabolismo degli androgeni ed estrogeni in 29 donne con upper body vs

lower body obesità

T - DHT - A4 elevati in tutti e due i gruppiT > in upper body obeseNessuna differenza per A4E2 > in upper body obeseAromatizzazione periferica A4→E1 > in

lower body obeseSHBG < in upper body obese

Kirschner, JCEM 1990

Caratteristiche cliniche e ormonali delle pazienti PCOS con e senza SM

0.00136.526.24SHBG (nmol/L)

0.0021.071.61T libero (ng/dl)

NS60.172.1T (ng/dl)

NS94.591.217OHP (ng/dl)

0.040.390.36Frequenza mestruale (cicli/mese)

NS29.131.0Età (aa)

0.00133.739.3BMI (kg/m2)

PNo SM (n=60)SM (n =46)Variabili

(Apridonidze et al, JCEM 2005)

Relazione tra insulino-resistenza e patterns mestruali nelle PCOS

PCO-Oligom. (n= 53)

PCO-Reg cicl. (n= 19)

Controlli (n= 31)

BMI (Kg/m2) 28.5 ± 0.8 29.5 ± 1.1 31.8 ± 1.5*

Glicemia basale(nmol/L) 4.8 ± 0.1 4.8 ± 0.1 4.8 ± 0.1

Insulina basale (mU/L) 9.3 ± 5.1 7.4 ± 4.3 6 ± 3.7*

Sensibilità insulinica

(µmol/L min) 147 ± 9.2 182 ± 12.5** 185 ± 7.4**

* p<0.05 Vs PCO-Oligomenorroiche

** p<0.01 Vs PCO-Oligomenorroiche

Robinson et al., Clin End 1993

7

Hyperinsulinemia effect

o ovarian androgen

o adrenal androgen

o LH secretion

o ovaric LH-Rc

o SHBG

Obesity

PCOS associated• ↑ incidence menstrualirregularities•↑ incidence infertility

Not PCOS associated

Independently of PCOS, obesity is associated with

↑ Testosterone concentration ↑ Insulin concentration ↓ SHBG concentration

Anthropometric characteristics of obese non-PCOSwomen with and without regular menstrual cycles

0.006137.8 10.3123.1 14.0122.64 13.66Hip Circ.(cm)

0.00631.1 10.118.6 8.515.7 9.8Basal insulin(U/dl)

0.001119.4 12.6107.1 12.7101.25 13.14Waist Circ.(cm)

<0.000146.3 6.640.4 6.837.17 6.04BMI (KG/m2)

0.001116.6 15.2101.2 18.994.18 16.44Weight (kg)

0.12528.7 7.429.6 5.630.5 6.5Age (y)

PAmenorrhea(n=14)

Oligomenorrhea(n=22)

Regular cycle(n=84)

Castillo-Martinez, Nutrition 2003

8

Correlation between obesity degreeand abnormal menstrual cycle

Obesity I-II grade ( 110%- 150% IBW)

Obesity IV-V grade ( > 175% IBW)

19%

54% P < 0.01

Castillo-Martinez, Nutrition 2003

Effetto dell’obesità sulla pulsatilità dell’LH nelle 24h in donne PCOS e controlli

Controlli normopeso

PCOS normopeso

Controlli obesi

PCOS obese

LH medio 10.4 ± 0.6 31.5 ± 4.1* 10.7 ± 0.7 20.8 ± 1.5*§

Ampiezza 5.0 ± 0.5 13.3 ± 2.8* 5.3 ± 0.49 6.4 ± 0.7§

No./24 h 15.9 ± 0.6 21.9 ± 1.4* 15.9 ± 1.15 23.9 ± 1.6*

Morales et al., JCEM 1996

* p<0.001 Vs gruppo di controllo corrispondente

§ p<0.01 Vs verso il gruppo normopeso corrispondente

LH response to GnRH in lean and obese PCOS and control women

Morales et al., JCEM 1996

0

5000

10000

15000

20000

LC LPCOS OC OPCOS

LH A

UC

(IU

/L x

120

’) *

* p<0.001 Vs corresponding control group§ p<0.001 Vs corresponding lean group

L= LeanO= ObeseC= Controls

Risposta dell’FSH e dell’LH al GnRH (100 µg) in 110 PCOS in base a BMI e secrezione insulinica

0

1

2

3

4

5

N-L H-L N-O H-O0

5

10

15

N-L H-L N-O H-OFSH

AU

C (m

IU/m

l x12

0’x

10-2

)

LH

AU

C (m

IU/m

l x12

0’x

10-3

) *

* p <0.05 vs N-LN-L = Normo-Lean H-L= Hyper-LeanN-O = Normo-Obese I-O= Hyper-Obese

Ciampelli et al., Metabolism 1999

9

LH

Obesity Pancreas

Insulin

Insulin and LH

Insulin resistanceLeptin (?)Neuropeptide Y (?)

Correlazione tra insulinemia a digiuno e livelli androgenici

Burghen 1980

Chang 1992

Pasquali 1982-86

Shoupe 1984

Stuart 1986

Smith 1987

14

20

14

19

33

17

FI & Δ4

0.64 (P<0.01)

0.52 (P<0.02)

0.64 (P<0.01)

-

0.52 (P<0.005)

0.57 (P<0.02)

FI & T

0.71 (P<0.01)

0.59 (P<0.01)

0.46 (P<0.05)

0.34 (P<0.05)

0.56 (P<0.001)

0.76 (P<0.001)

0

15

30

45

0

0,2

0,4

0,6

0,8

Testosterone e SHBG in PCOS in base a BMI e secrezione insulinica

*

* p<0.05 Vs PCO-NL # p<0.05 Vs PCO-HL Ciampelli, Metabolism 1999

Testosterone (ng/ml) SHBG (nmol/L)

*#

PCO-NL

PCO-HL

PCO-NO

PCO-HO02468

17-OH-P 17-OH-P A A

Basale Post ACTH

Increzione degli ormoni steroidei nelle PCOS normo e iperinsulinemiche dopo bolo di ACTH

Iperins IperinsNormoins Normoins

Lanzone et al Hum Reprod 1994

*

*P <0.05 § P< 0.02

§

nmol

/L

10

Selective insulin resistance

Hyperinsulinemia

Ovarian steroidogenesis

Adrenal steroidogenesis

LH secretion

Obesity -Obesity +

+

SHBGsecretion

Importanza dei criteri diagnostici

nell’individuare una popolazione femminile a

rischio…

Consensus Rotterdam (2003)Presenza di almeno due dei tre elementi

dopo esclusione di altre patologie:

• Oligomenorrea e/o anovulatorietà

• Segni clinici e/o biochimici di iperandrogenismo

• Ecostruttura policistica dell’ovaio

FAI value in the 348 PCOS patientsaccording to Rotterdam Consensus criteria

(Belosi et al; Hum Repr, 2006)

All 3 criteria present

Hyperandrogenism+Anovulation or US PCO

Anovulation + US PCO

9.72 ± 7.15*

5.78 ± 3.51

3.78 ± 1.44

FAI

* P <0.05

11

Presenza di:- Iperandrogenismo (irsutismo e/o livelli

elevati di testosterone libero)Associati ad almeno uno dei seguenti aspetti:- Oligo-anovulazione- Ovaie policistiche (come nei criteri di

Rotterdam)Dopo l’esclusione di altre patologie

SINDROME DELL’OVAIO POLICISTICO:

AES PCOS Phenotype Task Force Report

J Clin Endocrinolo Metab, 2006

Prevalence of PCOS in femalepopulation at fertile age

American’s criteria 4-9%US prevalence of polycystic

ovaries 17-33%

Criteria for Polycystic ovariesdefinition by Rotterdam Consensus

The polycystic ovary contains12 or more follicles measuring

2-9 mm in diameterand /or

increased ovarian volume (>10cm3)

Ultrasound criteria(Adams)

> 10 discrete follicles of 2 - 8 mm diameter, peripherally arrayed

Enlarged, hyperechogenic, centralstroma, occupying more than 25% of the ovarian volume

Lancet, 1985

12

Criticism to criteria of Adams

No quantification of stroma volume

PCOS vs PCO (absence of clinical symptomatology)

PCOS MFO ControlM

ean

strom

a /a

rea

ratio

0

1

0.2

0.4

0.6

0.8

Stroma /Area Ratio evaluationin the studied groups

Cut-off S/A= 0.34

Fulghesu, Fertil Steril 2001

Belosi, C. et al. Hum. Reprod. 2006

Patient's population according to different criteria for polycystic ovary syndrome (PCOS) diagnosis used

<0.055.80 ± 3.033.80 ± 2.23M (mg/kg/min)a

<0.0510361.30 ± 6060.6615809.78 ± 11731.00AUC insulin (µUI/ml x 240)

<0.058.49 ± 4.7213.79 ± 20.16Fast insulin (µUI/ml)

<0.054.76 ± 3.029.60 ± 7.04FAI

<0.0545.07 ± 17.8033.03 ± 17.72SHBG (nmol/l)

<0.051881.88 ± 780.662099.47 ± 813.64DHEAS (ng/ml)

NS1.25 ± 0.671.40 ± 0.6817-OHP (ng/ml)

NS2.30 ± 1.032.85 ± 1.08Androstenedione (ng/ml)

<0.050.52 ± 0.210.70 ± 0.28Testosterone (ng/ml)

NS8.23 ± 5.748.71 ± 5.12LH (mUI/ml)

<0.056.07 ± 2.335.36 ± 1.70FSH (mUI/ml)

<0.050.75 ± 0.060.81 ± 0.07WHR

<0.0524.90 ± 4.7526.86 ± 6.11BMI (kg/m2)

<0.0564.90 ± 14.0070.83 ± 17.75Weight (kg)

NS27.53 ± 6.6526.38 ± 5.76Age (years)

P-value

PCOS-Rotterdam(n°= 72)

PCOS-Rotterdam/NIH(n°= 273)

Belosi, C. et al. Hum. Reprod. 2006

13

Anthropometrical and hormonal characteristics of the polycystic ovary syndrome (PCOS)-Rotterdam/NIH and PCOS-Rotterdam groups

13 (18.1)*98 (35.9)↑ Testosterone +androstenedione (%)

3 (4.2)*75 (27.4)↑FAI + testosterone +androstenedione (%)

4 (5.5)*84 (30.1)↑FAI + androstenedione (%)

9 (12.5)*134 (49.1)↑FAI + testosterone (%)

15 (20.8)*119 (43.5)Androstenedione ≥ 3.0 ng/ml (%)

29 (40.3)*178 (65.2)Testosterone ≥ 0.6 ng/ml (%)

11 (15.3)*174 (63.7)FAI ≥ 7 (%)

0*17 (8.5)Altered OGTTa

23 (31.9)110 (40.3)BMI ≥27

PCOS-Rotterdam/ (n = 72)

PCOS-Rotterdam/NIH (n = 273)

FAI, free androgen index; OGTT, oral glucose tolerance test. PCOS-Rotterdam/NIH: patients defined as affected by PCOS according to both NIH and ESHRE/ASRM criteria. PCOS-Rotterdam: patients defined affected by PCOS according to only ESHRE/ASRM criteria. The threshold values were defined as mean plus 2 SD of the control population. a Calculated on 199 of 273 PCOS-Rotterdam/NIH patients and on 49 of 72 PCOS-Rotterdam patients. * P < 0.005 Group I versus Group II. Belosi, C. et al. Hum. Reprod. 2006

Clinical, echographic and hormonal parameters of the polycystic ovary syndrome (PCOS)-Rotterdam group according to stroma evaluation

8.28 ± 1.28*,**14.32 ± 2.99*16.04 ± 4.18Ovarian total volume (ml)

0.27 ± 0.05*0.28 ± 0.06*0.41 ± 0.05Ovarian stroma/area ratio

5.62 ± 1.80*5.87 ± 3.43M (mg/kg/min)a

1413.21 ± 692.951013.79 ± 351.67*1402.72 ± 376.02AUC Pep C

9048.29 ± 4471.819775.58 ± 6896.1010701.39 ± 5612.19AUC I (µUI/ml x 240!)0.87 ± 0.47*,**1.17 ± 0.581.51 ± 0.93LH/FSH

5.05 ± 2.63*,**6.88 ± 4.24*9.61 ± 6.77LH (mUI/ml)

0.82 ± 0.30*,**1.14 ± 0.531.37 ± 0.7717-OHP (ng/ml)2.03 ± 0.702.21 ± 0.932.39 ± 1.14Androstenedione (ng/ml)

0.39 ± 0.15*,**0.50 ± 0.160.55 ± 0.26Testosterone (ng/ml)

3.48 ± 1.74*4.09 ± 1.86*5.56 ± 3.67FAI21.80 ± 3.30*,**24.04 ± 4.9425.89 ± 4.38BMI (kg/m2)

57.88 ± 9.64*,**64.71 ± 14.6165.18 ± 13.35Weight0.73 ± 0.070.74 ± 0.050.76 ± 0.06WHR

24.81 ± 5.6327.00 ± 6.0728.21 ± 7.38Age (years)

No-PCOS (n = 27)PCOS-Rotterdam No-PCOS UCSC (n = 37)

PCOS-Rotterdam/UCSC (n = 35)

a Calculated on 18 of 35 PCOS-Rotterdam/UCSC and on 8 of 37 PCOS-Rotterdam/No-PCOS UCSC. * P < 0.05 versus PCOS-Rotterdam/UCSC. ** P < 0.05 versus PCOS-Rotterdam/No-PCOS UCSC. Belosi, C. et al. Hum. Reprod. 2006

1 (3.7)*3 (8.1)10 (28.5)T 0.6 ng/ml & A 3.0 ng/ml

003 (8.5)FAI 7 &T 0.6 ng/ml & A 3.0 ng/ml

004 (11.4)FAI 7 &A 3.0 ng/ml

04 (10.8)5 (14.3)FAI 7 &T 0.6 ng/ml

04 (10.8)11 (31.4)A 3.0 ng/ml

012 (32.4)17 (48.5)T 0.6 ng/ml

04 (10.8)7 (20)FAI 7

000Altered OGTT

000Three clinical signs

0*3 (8.1)*19 (54.3)Two clinical signs

27 (100)*34 (91.9)*16 (45.7)One clinical sign

6 (22.2)3 (8.1)*10 (28.5)Acne (%)

3 (11.1)*7 (18.9)*15 (42.8)Hirsutism (%)

18 (66.6)28 (75.6)29 (82.8)Oligomenorrhoea/amenorrhoea (%)

No-PCOS, n = 27 (%)

PCOS-Rotterdam/No-PCOS UCSC, n = 37 (%)

PCOS-Rotterdam/ UCSC, n = 35 (%)

FAI: free androgen index; OGTT, oral glucose tolerance test. PCOS-Rotterdam/UCSC: patients defined as affected by PCOS according to ESHRE/ASRM criteria and according to UCSC criteria but not according to NIH criteria. PCOS-Rotterdam/No-PCOS UCSC: patients defined as affected by PCOS according to ESHRE/ASRM criteria but not according to UCSC criteria and NIH criteria. No-PCOS: patients defined as not affected by PCOS according to all three classifications. * P < 0.05 versus PCOS-Rotterdam/UCSC.

Distribution of clinical and hormonal characteristics of the polycystic ovary syndrome (PCOS) Rotterdam group according the stroma evaluation

Belosi, C. et al. Hum. Reprod. 2006

PCOS

273/375345/375

NIH Rotterdam Consensus

311/375

Adams + S/A

- 72 (19.9%)

- 34 (10.0%)

14

Belosi, C. et al. Hum. Reprod. 2006

Summary of clinical and biochemical characteristics for different diagnostic subgroups of polycystic ovary syndrome (PCOS)

“PCOS is the leading cause of type 2 diabetes in

premenopausal women”

Richard Legro, 1999

In the general population glucosetolerance worsens with age

WorseningInsulin

resistance

Progressive - cells

dysfunction

IGT and Diabetes

The prevalence of IGT in women with PCOS is

increased of 40%Ehrmann DA, Diabetes care, 1999; Legro, J Clin EndocrinolMetab, 1999

IGT as a risk factorfor Diabetes type II

Conversion rate = 1 - 5 % year in generalpopulation

15

# PCOS patients have a 2-5 foldincrease risk of diabetes

Dalghren Int J Gynaecol Obstet 1994Retrospective studies: Wild ClinEndocrinol 2000

Cibula Hum Reprod 2000

Prospective case/control study:

# 11.9 % of women over 30ys withPCOS has been diagnosed diabetes

type 2 vs 1.4 % of control

Talbott, Obstet Gynecol Clin North Am 2001

PCOS and risk for abnormaltolerance/diabetes mellitus (DB)

Dalghren 1992

Ehrman 1999

Legro 1999

Cibula 2000

33 PCOS,wedge resection

122 PCOS

254 PCOS 14-44y

28 selected patients withovarian wedge resectioncompared with 752 ctr

Greater prevalenceof DB

IGT 35%- NIDDM 19%

DB 7,5%- IGT 10.3%

Prevalence of DB was 4 times higher

Study Population Findings evidence

III

IV

II,IV

IV

Wildt, 2002

Diabete mellito di tipo 2 e PCOS

Legro, 1999 254 PCOS vs 80 controlli (obese, età media 30)31% ITG e 7.5%NIDDM vs 14% e 0%

Holte, 1995 Rischio di diabete NIIDM nelle PCOS 7 vv> rispetto alla popolazione generale

Ciampelli, 1999 110 pazienti PCOS 15,5 % di IGT / NIIDM nelle obese IR

Ehrmann, 1999 122 PCOS obese, età media 27 35% ITG e 10%NIDDM correlazione con BMI e familiarità

Elting, 2001 346 PCOS BMI medio24.4, età media 39 2.3% NIDDM (x 4 popolaz. generale)correlazione con BMI ed età

Norman, 2001 67 PCOS BMI medio 29, età media 39 accelerata conversione da normoglicemia

a IGT/NIDDM in follow up di 6 annicorrelazione con BMI

Diabete mellito di tipo 2 e PCOS

16

Insulin-resistance prevalence in non-diabeticwomen with recurrent miscarriages

0

10

20

30

Controls Recurrent miscarriages

%

(La Tasha et al, Fertil Steril2002)

metformin control P

total patients 65 31

All women 8.8% 41.9% <0.001

EPL+ women 11.1% 58.3% 0.002

EPL- women 6.3% 31.6% 0.04

Polycystic ovary syndrome

Jakubowicz et al,JCEM,2002

*

*women with hystory ofmiscarriage

Early pregnancy loss(EPL) rate

POSSIBLE BENEFICIAL EFFECTS OF METFORMIN ON ENDOMETRIAL

VASCULARIZATION- Increase of uterine vascularization(Jakubovicz et al 2001)

- Increase of circulating concentrations of glycodelin (inhibition of the endometrial immune response to the embryo) (Jakubovicz et al 2002)

- Increase of circulating levels of IGFBP-1 (promotion of embryo implantation)

(Jakubovicz et al 2002)

- Reduction of PAI-1 circulating levels(Velazquez et al 1997, etc...) Lanzone A, Hum Reprod,

1996

PCOS 46%

Popolazione generale 1-5%

Incidenza delle alterazioni dell’omeostasi glicemica in gravidanza

17

Pregestational and gestational metabolicstudy in PCOS patients according to

insulin secretion

Lanzone A, Hum Reprod, 1996

Hyperinsulinemic(7 pts.)

Normoinsulinemic(8 pts.)

p value

% IBW 115.0 ± 21.28 114.9 ± 16.9 NSPregestational AUC-I

(pmol/L x 240’) 130924 ± 31545 64924 ± 19060 0.05Gestational AUC-I

(pmol/L x 240’) 238242 ± 44408 217829 ± 36009 NSPercentage increase 189.5 ± 53.0 378.3 ± 190.7 0.05Absolute difference 107318 ± 57839 152904 ± 42223 NS

IGT-GD 7/7 0/8 0.05

Continuing metformin throughout pregnancy in womenwith polycystic ovary syndrome appears to safely reduce first-trimester spontaneous abortion: a pilot study

(Glueck et al., Fertil Steril 2001)

Not receveing metformin

27%

73%

Live birth

First trimester spontaneousabortion

Receveing metformin

60%10%

30%

Live birthFirst trimester spontaneous abortionOngoing > 13 weeks

Conclusioni

La sindrome metabolica e la sindrome dell’ovaio policistico condividono diverse aspetti fisiopatologici.

L’insulinoresistenza e l’iperinsulinemia rappresentano l’anello di congiunzione tra tali condizioni.

Ancora discusse le relazioni tra SM e alterazioni mestruali; tuttavia modifiche dello stile di vita e trattamenti migliorativi della SM hanno effetti benefici sui disturbi del ciclo e sugli eventi ovulatori.