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
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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
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PCOS throughout life cycleClinical presentation and health
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
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• 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).
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.
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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
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
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
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%)
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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
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# 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
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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
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Pregestational and gestational metabolicstudy in PCOS patients according to
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.