Alterazioni endocrino-metaboliche e riflessi sulla funzione ovarica e fertilita Antonio Lanzone

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1 Alterazioni endocrino-metaboliche e riflessi sulla funzione ovarica e fertilita Antonio Lanzone Criteri classificativi di sindrome metabolica Dipartimento per la Tutela della Salute della Donna e della Vita Nascente Università Cattolica del Sacro Cuore, Roma Essah et al, JEI 26 Sindrome metabolica - obesità addominale - dislipidemia - ipertensione - alterazioni omeostasi glicoinsulinemica (almeno due) Kahn Type A B C Kahn s categories of Insulin Resistance Insulin Receptor Defect Defect intrinsic to insulin receptor resulting in a decreased function or decreased receptor number Antibodies to insulin receptor Receptor or post-receptor defect Cause or associated Disease Genetic or obesity Autoimmune, collagen vascular disease Obesity Hyperandrogenism Often severe; virilization and ovarian stromal hyperthecosis common Mild to moderate Moderate Kahn CR et al. N. Engl. J. Med

2 PCOS throughout life cycle Clinical presentation and health problems Oligomenorrhea Infertility Impaired glucose tolerance Irregular menses Hirsutism Type 2 diabetes Hirsutism Obesity Dyslipidemia Overweight Impaired glucose Cardiovascular tolerance diseases Hypertension Obesity and PCOS Prevalence: 5-7 %(including overweight) Phenotpe: abdominal < peripheral NB: many normal weight women have abdominal fatness The abdominal phenotype is associated to the metabolic syndrome Adolescence Adulthood Postmenopause Prevalenza dell iperinsulinemia in pz PCOS Non obese n. 54 (42%) Normoinsulinemiche 6% Iperinsulinemiche 4% Obese n. 73 (58%) Normoinsulinemiche 28% Iperinsulinemiche 72% Casistica UCSC Risposta insulinemica all OGTT in pazienti PCOS e controlli in base al peso corporeo IU/ml/ P <.1 P <.1 P <.2 P <.5 5 CTR PCOS IBW<12%; IBW>12% Lanzone et al Hum Reprod

3 Meccanismi responsabili del fenotipo obesità-pcos Sovrapposizione tra caratteristiche della sindrome metabolica, della PCOS e insulinoresistenza Dieta lipidi; fibre Obesità (soprattutto addominale) androgeni SHBG Estrogeni Predispozione PCOS Fattori Genetici Fattori intrauterini PCOS 5-8% 43-47% 76-8% Sindrome metabolica ß-endorphins insulina/insulino resistenza HPA Fenotipo obesità- PCOS Insulino-resistenza Modified from Essah et al, JEI 26 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, 26 Prevalenza della sindrome metabolica in pazienti con PCOS e controlli in relazione all età Prevalenza % * * : P<.1 vs ctrl * PCOS * Controlli < Età (Apridonidze et al, JCEM 25) 3

4 Prevalenza della SM in donne U.S.A. con PCOS (n=16) e controlli stratificate per età e BMI Gruppo d età 2-29aa (n=29) PCOS (%) Controlli (%) 3-39 aa (n= 49) PCOS (%) Controlli (%) < BMI > Totale (Apridonidze et al, JCEM 25) Prevalenza delle singole anomalie della SM tra 16 pazienti con PCOS Fattori della SM Alto BMI (Circ vita > 88cm) Ipertrigliceridemia HDL Ipertensione Iperglicemia a digiuno Totale (n=16) 67 (71) 35 (37) 68 (71) 45 (48) 3.8 (4) Prevalenza [% (n)] SM (n=46) 91 (42) 7 (32) 91 (42) 74 (34) 9 (4) No SM (n=6) 29 (48) 8 (5) 49 (29) 23 (14) () (Apridonidze et al, JCEM 25) Dyslipidemia is the most common metabolic abnormality in PCOS: LDL-C HDL-C prevalence 7% Presence in obese and non-obese patiens Tryglycerides Talbott J Clin Epid 1998 Nobroson Clin Endocrinol 199 Conway Clin Endocrinl 1992 Holte Clin Endocrinol 1994 Raykowa J Clin End Metab 1997 PCOS and dyslipidemia Study Population Findings evidence Wild 1985 Slowinska- Srzednicka 1991 Wild 1992 Talbott PCOS vs 3 ctr 49 lean and obese PCOS 47 hirsute vs 15 ctr 26 PCOS Triglycerides HDL-c HDL2 apolipoproteinb Triglycerides, VLDL-c apolipoprotein C-A HDL-c Triglycerides total HDL total cholesterol LDL levels III III III III 4

5 Consensus Rotterdam (23): aspetti metabolici 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 Percentage frequency of menstrual irregularities in women with PCOS Oligomenorrhoea Amenorrhea Balen et al N= % 19% Franks N = 3 52% 28% Goldzieher et al N = % 51% N of cases (Modified from Hart 24) Approccio razionale al trattamento delle alterazioni mestruali nella PCOS Individuazione di disturbi concomitanti: Alterazioni metaboliche (obesità, dislipidemia, iperinsulinemia ed insulinoresistenza). 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 né segni di iperandrogenismo. 2. Paziente senza alterazioni metaboliche con segni di iperandrogenismo. 3. Paziente con alterazioni metaboliche, con o senza segni di iperandrogenismo. 5

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 gruppi T > in upper body obese Nessuna differenza per A4 E2 > in upper body obese Aromatizzazione periferica A4 E1 > in lower body obese SHBG < in upper body obese Kirschner, JCEM 199 Caratteristiche cliniche e ormonali delle pazienti PCOS con e senza SM Relazione tra insulino-resistenza e patterns mestruali nelle PCOS Variabili BMI (kg/m 2 ) SM (n =46) 39.3 No SM (n=6) 33.7 P.1 PCO-Oligom. (n= 53) PCO-Reg cicl. (n= 19) Controlli (n= 31) Età (aa) NS BMI (Kg/m 2 ) 28.5 ± ± ± 1.5* Frequenza mestruale (cicli/mese) 17OHP (ng/dl) SHBG (nmol/l) T (ng/dl) T libero (ng/dl) NS NS (Apridonidze et al, JCEM 25) Glicemia basale(nmol/l) 4.8 ± ± ±.1 Insulina basale (mu/l) 9.3 ± ± ± 3.7* Sensibilità insulinica (µmol/l min) * p<.5 Vs PCO- Oligomenorroiche ** p<.1 Vs PCO- Oligomenorroiche 147 ± ± 12.5** 185 ± 7.4** Robinson et al., Clin End

7 Hyperinsulinemia effect Obesity o ovarian androgen o adrenal androgen o LH secretion o ovaric LH-Rc o SHBG Not PCOS associated PCOS associated incidence menstrual irregularities incidence infertility Independently of PCOS, obesity is associated with Testosterone concentration Insulin concentration SHBG concentration Anthropometric characteristics of obese non-pcos women with and without regular menstrual cycles Age (y) Weight (kg) BMI (KG/m 2 ) Waist Circ. (cm) Hip Circ. (cm) Basal insulin ( U/dl) Regular cycle (n=84) Oligomenorrhea (n=22) Amenorrhea (n=14) < Castillo-Martinez, Nutrition 23 P 7

8 Correlation between obesity degree and abnormal menstrual cycle Obesity I-II grade ( 11%- 15% IBW) 19% Obesity IV-V grade ( > 175% IBW) Effetto dell obesità sulla pulsatilità dell LH nelle 24h in donne PCOS e controlli Controlli normopeso PCOS normopeso Controlli obesi PCOS obese LH medio 1.4 ± ± 4.1* 1.7 ± ± 1.5* Ampiezza 5. ± ± 2.8* 5.3 ± ±.7 No./24 h 15.9 ± ± 1.4* 15.9 ± ± 1.6* 54% P <.1 Castillo-Martinez, Nutrition 23 * p<.1 Vs gruppo di controllo corrispondente p<.1 Vs verso il gruppo normopeso corrispondente Morales et al., JCEM 1996 LH AUC (IU/L x 12 ) LH response to GnRH in lean and obese PCOS and control women * p<.1 Vs corresponding control group p<.1 Vs corresponding lean group * * LC LPCOS OC OPCOS L= Lean O= Obese C= Controls Morales et al., JCEM 1996 Risposta dell FSH e dell LH al GnRH (1 µg) in 11 PCOS in base a BMI e secrezione insulinica FSH AUC (miu/ml x12 x 1-2 ) * p <.5 vs N-L N-L H-L N-O H-O 5 LH AUC (miu/ml x12 x 1-3 ) N-L = Normo-Lean N-O = Normo-Obese * N-L H-L N-O H-O H-L= Hyper-Lean I-O= Hyper-Obese Ciampelli et al., Metabolism

9 Obesity Insulin and LH Pancreas Correlazione tra insulinemia a digiuno e livelli androgenici N FI & Δ 4 FI & T Burghen (P<.1).71 (P<.1) Chang (P<.2).59 (P<.1) Pasquali (P<.1).46 (P<.5) Insulin resistance Leptin (?) Neuropeptide Y (?) LH Insulin Shoupe 1984 Stuart 1986 Smith (P<.5).57 (P<.2).34 (P<.5).56 (P<.1).76 (P<.1),8,6,4,2 Testosterone e SHBG in PCOS in base a BMI e secrezione insulinica Testosterone (ng/ml) * SHBG (nmol/l) * p<.5 Vs PCO-NL # p<.5 Vs PCO-HL Ciampelli, Metabolism 1999 *# PCO-NL PCO-HL PCO-NO PCO-HO Increzione degli ormoni steroidei nelle PCOS normo e iperinsulinemiche dopo bolo di ACTH nmol/l Basale Post ACTH 17-OH-P 17-OH-P A A Iperins *P <.5 P<.2 * Normoins Iperins Normoins Lanzone et al Hum Reprod

10 SHBG secretion Obesity + Selective insulin resistance Ovarian steroidogenesis + Hyperinsulinemia Adrenal steroidogenesis Obesity - LH secretion Importanza dei criteri diagnostici nell individuare una popolazione femminile a rischio Consensus Rotterdam (23) 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 patients according to Rotterdam Consensus criteria (Belosi et al; Hum Repr, 26) All 3 criteria present Hyperandrogenism +Anovulation or US PCO Anovulation + US PCO * P <.5 FAI 9.72 ± 7.15* 5.78 ± ±

11 SINDROME DELL OVAIO POLICISTICO: AES PCOS Phenotype Task Force Report 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 Prevalence of PCOS in female population at fertile age American s criteria 4-9% US prevalence of polycystic ovaries 17-33% J Clin Endocrinolo Metab, 26 Criteria for Polycystic ovaries definition by Rotterdam Consensus The polycystic ovary contains 12 or more follicles measuring 2-9 mm in diameter and /or increased ovarian volume (>1cm 3 ) Ultrasound criteria (Adams) > 1 discrete follicles of 2-8 mm diameter, peripherally arrayed Enlarged, hyperechogenic, central stroma, occupying more than 25% of the ovarian volume Lancet,

12 Criticism to criteria of Adams No quantification of stroma volume PCOS vs PCO (absence of clinical symptomatology) Mean stroma /area ratio Stroma /Area Ratio evaluation in the studied groups Cut-off S/A=.34 PCOS MFO Control Fulghesu, Fertil Steril 21 Patient's population according to different criteria for polycystic ovary syndrome (PCOS) diagnosis used Age (years) Weight (kg) BMI (kg/m 2 ) WHR FSH (mui/ml) LH (mui/ml) PCOS-Rotterdam/NIH (n = 273) ± ± ± ± ± ± 5.12 PCOS-Rotterdam (n = 72) ± ± ± ± ± ± 5.74 P- value NS <.5 <.5 <.5 <.5 NS Testosterone (ng/ml) Androstenedione (ng/ml) 17-OHP (ng/ml) DHEAS (ng/ml) SHBG (nmol/l) FAI.7 ± ± ± ± ± ± ± ± ± ± ± ± 3.2 <.5 NS NS <.5 <.5 <.5 Fast insulin (µui/ml) AUC insulin (µui/ml x 24) M (mg/kg/min) a ± ± ± ± ± ± 3.3 <.5 <.5 <.5 Belosi, C. et al. Hum. Reprod. 26 Belosi, C. et al. Hum. Reprod

13 Anthropometrical and hormonal characteristics of the polycystic ovary syndrome (PCOS)-Rotterdam/NIH and PCOS-Rotterdam groups BMI (4.3) 23 (31.9) Altered OGTT a 17 (8.5) * FAI 7 (%) Testosterone.6 ng/ml (%) Androstenedione 3. ng/ml (%) FAI + testosterone (%) FAI + androstenedione (%) FAI + testosterone +androstenedione (%) Testosterone +androstenedione (%) PCOS-Rotterdam/NIH (n = 273) 174 (63.7) 178 (65.2) 119 (43.5) 134 (49.1) 84 (3.1) 75 (27.4) 98 (35.9) PCOS-Rotterdam/ (n = 72) 11 (15.3) * 29 (4.3) * 15 (2.8) * 9 (12.5) * 4 (5.5) * 3 (4.2) * 13 (18.1) * 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 <.5 Group I versus Group II. Belosi, C. et al. Hum. Reprod. 26 Age (years) WHR Weight BMI (kg/m 2 ) FAI Clinical, echographic and hormonal parameters of the polycystic ovary syndrome (PCOS)-Rotterdam group according to stroma evaluation Testosterone (ng/ml) Androstenedione (ng/ml) 17-OHP (ng/ml) LH (mui/ml) LH/FSH AUC I (µui/ml x 24!) AUC Pep C ± ± * ± M (mg/kg/min) a 5.87 ± ± 1.8 * Ovarian total volume (ml) Ovarian stroma/area ratio PCOS-Rotterdam/UCSC (n = 35) ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± 1.86 *.5 ± ± ± ± 4.24 * 1.17 ± ± ± 2.99 *.28 ±.6 * a Calculated on 18 of 35 PCOS-Rotterdam/UCSC and on 8 of 37 PCOS-Rotterdam/No-PCOS UCSC. * P <.5 versus PCOS-Rotterdam/UCSC. ** P <.5 versus PCOS-Rotterdam/No-PCOS UCSC. PCOS-Rotterdam No- PCOS UCSC (n = 37) No-PCOS (n = 27) ± ± ± 9.64 *, ** 21.8 ± 3.3 *, ** 3.48 ± 1.74 *.39 ±.15 *, ** 2.3 ±.7.82 ±.3 *, ** 5.5 ± 2.63 *, **.87 ±.47 *, ** ± ± 1.28 *, **.27 ±.5 * Belosi, C. et al. Hum. Reprod. 26 Distribution of clinical and hormonal characteristics of the polycystic ovary syndrome (PCOS) Rotterdam group according the stroma evaluation PCOS-Rotterdam/ UCSC, n = 35 (%) PCOS-Rotterdam/No-PCOS UCSC, n = 37 (%) No-PCOS, n = 27 (%) PCOS Oligomenorrhoea/amenorrhoea (%) 29 (82.8) 28 (75.6) 18 (66.6) Hirsutism (%) Acne (%) One clinical sign Two clinical signs Three clinical signs Altered OGTT FAI 7 T.6 ng/ml A 3. ng/ml FAI 7 &T.6 ng/ml FAI 7 &A 3. ng/ml FAI 7 &T.6 ng/ml & A 3. ng/ml T.6 ng/ml & A 3. ng/ml 15 (42.8) 1 (28.5) 16 (45.7) 19 (54.3) 7 (2) 17 (48.5) 11 (31.4) 5 (14.3) 4 (11.4) 3 (8.5) 1 (28.5) 7 (18.9) * 3 (8.1) * 34 (91.9) * 3 (8.1) * 4 (1.8) 12 (32.4) 4 (1.8) 4 (1.8) 3 (8.1) 3 (11.1) * 6 (22.2) 27 (1) * * 1 (3.7) * NIH 273/ (19.9%) Rotterdam Consensus 345/375 Adams + S/A 311/ (1.%) 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 <.5 versus PCOS-Rotterdam/UCSC. Belosi, C. et al. Hum. Reprod

14 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 Belosi, C. et al. Hum. Reprod. 26 IGT and Diabetes In the general population glucose tolerance worsens with age Worsening Insulin resistance Progressive - cells dysfunction IGT as a risk factor for Diabetes type II Conversion rate = 1-5 % year in general population The prevalence of IGT in women with PCOS is increased of 4% Ehrmann DA, Diabetes care, 1999; Legro, J Clin Endocrinol Metab,

15 Dalghren Int J Gynaecol Obstet 1994 Retrospective studies: Wild ClinEndocrinol 2 Cibula Hum Reprod 2 # PCOS patients have a 2-5 fold increase risk of diabetes Prospective case/control study: Talbott, Obstet Gynecol Clin North Am 21 # 11.9 % of women over 3ys with PCOS has been diagnosed diabetes type 2 vs 1.4 % of control PCOS and risk for abnormal tolerance/diabetes mellitus (DB) Study Population Findings evidence Dalghren 1992 Ehrman 1999 Legro 1999 Cibula 2 33 PCOS, wedge resection 122 PCOS 254 PCOS 14-44y 28 selected patients with ovarian wedge resection compared with 752 ctr Greater prevalence of DB IGT 35%- NIDDM 19% DB 7,5%- IGT 1.3% Prevalence of DB was 4 times higher III IV II,IV IV Wildt, 22 Diabete mellito di tipo 2 e PCOS Diabete mellito di tipo 2 e PCOS Holte, 1995 Ciampelli, 1999 Legro, 1999 Rischio di diabete NIIDM nelle PCOS 7 vv> rispetto alla popolazione generale 11 pazienti PCOS 15,5 % di IGT / NIIDM nelle obese IR 254 PCOS vs 8 controlli (obese, età media 3) 31% ITG e 7.5%NIDDM vs 14% e % Ehrmann, PCOS obese, età media 27 35% ITG e 1%NIDDM correlazione con BMI e familiarità Elting, PCOS BMI medio24.4, età media % NIDDM (x 4 popolaz. generale) correlazione con BMI ed età Norman, PCOS BMI medio 29, età media 39 accelerata conversione da normoglicemia a IGT/NIDDM in follow up di 6 anni correlazione con BMI 15

16 Insulin-resistance prevalence in non-diabetic women with recurrent miscarriages 3 2 % 1 Polycystic ovary syndrome Early pregnancy loss(epl) rate metformin control P total patients All women 8.8% 41.9% <.1 * EPL+ women 11.1% 58.3%.2 Controls Recurrent miscarriages (La Tasha et al, Fertil Steril 22) EPL- women 6.3% 31.6%.4 *women with hystory of miscarriage Jakubowicz et al,jcem,22 POSSIBLE BENEFICIAL EFFECTS OF METFORMIN ON ENDOMETRIAL VASCULARIZATION - Increase of uterine vascularization (Jakubovicz et al 21) - Increase of circulating concentrations of glycodelin (inhibition of the endometrial immune response to the embryo) (Jakubovicz et al 22) - Increase of circulating levels of IGFBP-1 (promotion of embryo implantation) (Jakubovicz et al 22) - Reduction of PAI-1 circulating levels (Velazquez et al 1997, etc...) Incidenza delle alterazioni dell omeostasi glicemica in gravidanza PCOS 46% Popolazione generale 1-5% Lanzone A, Hum Reprod,

17 Pregestational and gestational metabolic study in PCOS patients according to insulin secretion HyperinsulinemicNormoinsulinemic p (7 pts.) (8 pts.) value % IBW 115. ± ± 16.9 NS Pregestational AUC-I (pmol/l x 24 ) ± ± Gestational AUC-I (pmol/l x 24 ) ± ± 369 NS Percentage increa se ± ± Absolute difference ± ± NS IGT-GD 7/7 /8.5 Lanzone A, Hum Reprod, 1996 Continuing metformin throughout pregnancy in women with polycystic ovary syndrome appears to safely reduce first-trimester spontaneous abortion: a pilot study 3% 1% Receveing metformin Live birth First trimester spontaneous abortion Ongoing > 13 weeks 6% Not receveing metformin 73% Live birth First trimester spontaneous abortion 27% (Glueck et al., Fertil Steril 21) 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. 17