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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
N°
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.