Prof. FRANCESCO ORIO. Professore Associato di Endocrinologia Università Parthenope Napoli Responsabile Sezione Endocrinologia «CMSO» Salerno

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1 Prof. FRANCESCO ORIO Professore Associato di Endocrinologia Università Parthenope Napoli Responsabile Sezione Endocrinologia «CMSO» Salerno

2 PCOS: STORIA 1721 Vallisneri A: giovane rustica, maritata, modicamente pingue, et infeconda, con due ovaie più grandi del normale, come uova di colomba, bernoccolute, lucenti et biancastre 1935 Stein and Leventhal: Descrizione ginecologica ovaia sclerotiche ingrandite alla laparotomia in donne che presentavano anovulatorietà o irsutismo, o entrambi 1996 Homburg: Evoluzione da curiosità ginecologica ad endocrinopatia multisistemica

3 Stein-Leventhal Syndrome 1935 Amenorrea associata ad ovaia policistiche bilaterali Resezione Cuneiforme ripristinava normali mestruazioni Stein I.F. and Leventhal M.L. (1935). Am. J. Obstet. Gynecol. 29:

4 PREMESSE PCOS malattia endocrina più comune dell età fertile: colpisce il 5-10% delle donne in età riproduttiva 90% dei casi di irsutismo non è soltanto una malattia che influenza la fertilità ma attualmente è anche considerata una sindrome plurimetabolica FATTORE DI RISCHIO PER MALATTIA CARDIOVASCOLARE? INSULINO-RESISTENZA FATTORE DI RISCHIO { PER COMPLICANZE obesità diabete mellito non insulino-dipendente ipertensione dislipidemia

5 Quando sospettare la PCOS Mestruazioni irregolari o non frequenti Aumentati livelli di androgeni causa di irsutismo ed acne Obesità ed Insulino-resistenza Ovaia policistiche all ecografia Esclusione di altre patologie endocrine (tiroide, surrene, ovaio)

6 Principali sintomi clinici della PCOS Sintomo Frequenza (%) Irsutismo 70 Infertilità 70 Obesità 50 Oligomenorrea (intervallo tra 2 cicli > 35 giorni) 50 Amenorrea (assenza di cicli >6 mesi) 30 Emorragie uterine disfunzionali 25 Virilizzazione 20 Acne 20

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9 Different criteria for diagnosing PCOS

10 ALERT! IL 40% DELLE GIOVANI DONNE DI UNA REGIONE DEL SUD ITALIA PRESENTA L ASPETTO ECOGRAFICO DI OVAIA POLICISTICHE MA CIO NON SIGNIFICA CHE HANNO LA SINDROME DELL OVAIO POLICISTICO BE CAREFUL! VERY CAREFUL!

11 How PCOS May Present in Patients

12 Ehrmann DA New Engl J Med 2005; 352:

13 PCOS «Sindrome multifattoriale» ALTERAZIONI METABOLICHE: Iperandrogenismo, Clinico e biochimico INSULINO- RESISTENZA Iperinsulinemia e DM2 ALTERAZIONI FUNZIONALITA OVARICA: DISORDINI DEL CICLO MESTRUALE Oligo/anovulazione e infertilità RIDOTTA QUALITA OVOCITARIA

14 PCOS TREATMENT It should be directed to: Signs, Symptoms and Endocrine Abnormalities of each single patient

15 Health issues PCOS-related Cosmetics (irsutism, acne, androgenic alopecia) Fertility (anovulatory cycle) Insulin-resistance (metabolic syndrome, cardiovascular disease)

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20 OLIGO/ AMENORRHEA PCOS TREATMENT HIRSUTISM ES GUIDELINE INFERTILITY OC, METFORMIN CC, LOD, GONADOTROPIN, AI OVERWEIGHT / OBESITY LIFESTYLE INTERVENTION DIET / PHYSICAL EXERCISE SCREENING FOR CVR AND CVD IN PCOS AT MAJOR RISK

21 PCOS TREATMENT HIRSUTISM ES GUIDELINE OLIGO/ AMENORRHEA INFERTILITY OC, METFORMIN CC, LOD, GONADOTROPIN, AI OVERWEIGHT / OBESITY LIFESTYLE INTERVENTION DIET / PHYSICAL EXERCISE SCREENING FOR CVR AND CVD IN PCOS AT MAJOR RISK

22 Lifestyle modifications as nonpharmacological approach to infertile women with PCOS: why? Obesity 50% (40% to 77%) Hyperinsulinemia and insulin resistance 60% (50% to 75%)

23 Lifestyle modification programs

24 Obesity and reproduction Is it ethical to provide a fertility treatment to obese patients? UK guidelines for managing obese women with PCOS recommend weight loss, preferably to a BMI of less than 30, before starting drugs for ovarian stimulation National Institute for Clinical Excellence, 2004 Weight loss is essential for obese women who wish to conceive not only prior to receiving infertility treatments, but prior to exposing them to the risks of pregnancy given the high incidence of fetal risks associated with maternal obesity, such as isolated fetal anomalies, fetal deaths, preterm delivery and early neonatal death Nelson and Fleming, 2007 An aggressive approach to reduce weight, including pharmacological strategies and the use of contraception and high-dose folic acid should be always proposed for obese women before planning a pregnancy National Institute for Clinical Excellence, 2004

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26 Lifestyle modification or clomiphene citrate? Lifestyle modification may be used as the first line of ovulation induction in obese PCOS patients Karimzadeh & Javedani, Fertil Steril 2010

27 Types of diet interventions Moran et al., Fertil Steril 2009

28 Physical excercise Moran et al., Fertil Steril 2009

29 First-step treatment Obesity adversely affects reproduction and is associated with anovulation, pregnancy loss, and late-pregnancy complications Experience from other areas of medicine suggests lifestyle modifications as the first-line treatment of obesity in PCOS The ideal amount of weight loss is unknown, but a 5% decrease of body weight might be clinically meaningful Clomiphene citrate remains the treatment of first choice for induction of ovulation in most anovulatory women with PCOS Selection of patients for CC treatment should take into account body weight/bmi, female age, and the presence of other infertility factors The starting dose of CC should be 50 mg/day (for 5 days), and the recommended maximum dose is 150 mg/day

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31 Weight loss and ovulatory infertility A weight loss as little as 5% of the initial body weight exert beneficial effects on reproductive function. Norman et al., Hum Reprod Update 2004 Each 1-Kg increase in body weight is associated with 2.84 (95%CI ) day increase in time to pregnancy. Each 1-Kg decrement in body weight is associated with 5.50 (95%CI ) day decrease in time to pregnancy. Ramlau-Hansen et al., Hum Reprod 2007

32 Non-pharmacological treatment Diet: nutritional program High protein intake (>25%) Moderate carbohydrate intake (55%) Low fat intake (<30%) Low glycaemic index diet A LOW CALORIES INTAKE IS THE MOST IMPORTANT COMPONENT OF A DIET!!!

33 Non pharmacological treatment Diet: total daily energy expenditure Harris-Benedict equation 9,000 cal 1 kg A weight loss about the 5% of the initial body weight improves the reproductive function. A weight loss of the 5% in a women who has a initial weight of 100 kg 5 kg 45,000cal/60 days: 750 cal daily energy expenditure to loss 5kg in 2 months How long?? 45,000 cal

34 Non-pharmacological treatment Physical activity WALKING CYCLING Aerobic physical training Moderate intensity RUNNING SWIMMING Hainer et al., Diabetes Care 2008

35 Lifestyle modification programs? Authors Source Follow-up (months) Drop-out rate (%) Palomba et al. Hum Reprod 2008 Six 35.0 Stamets et al. Fertil Steril 2004 One 26.0 Clark et al. Hum Reprod 1998 Six 23.0 Clark et al. Hum Reprod 1995 Six 27.0 High drop-out rate!!!

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38 FUTURE PERSPECTIVES Non conventional treatment NUTRACEUTICS: INOSITOL (D-CHIRO-INOSITOL, MYO-INOSITOL) MEDITERRANENAN DIET VLCD?

39 EFFETTI SUL METABOLISMO -RIDUCE l insulino resistenza -RIDUCE iperandrogenismo -RISTABILISCE il bilancio ormonale -RIDUCE irsutismo e acne -RISTABILISCE il profilo metabolico

40 Non conventional treatment: MEDITERRANEAN DIET

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61 Protocollo eseguito in pazienti con Sindrome dell Ovaio Policistico (PCOS) 10 giorni: Riduzione graduale dei carboidrati 6 settimane: Chetosi 6 settimane: Transizione Pazienti (n = 13) Basale Dopo 12 Settimane p Età (a) BMI (Kg/m 2 ) Peso (Kg) Massa Grassa (Kg) HOMA Index

62 Pazienti (n = 13) Basale Dopo 12 Settimane p FSH (mui/ml) LH (mui/ml) Beta Estradiolo (pg/ml) Testosterone (ng/ml) SHBG (nmol/l) <0.001 FAI (Tx100/SHBG) Delta4 Androstenedione (ng/ml)

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67 POSSIBLE CONCLUSIONS VLCD could really represents a valid future tool and therapeutic alternative in OBESE PCOS WOMEN with OLIGO-ANOVULATION and METABOLIC issues

68 CONCLUSIONS 1) PCOS TREATMENT MUST BE PERSONALISED IN EACH PATIENT 2) IT DOES NOT EXIST ONLY ONE THERAPY FOR EVERY PATIENTS 3) ANY DIFFERENT PCOS PHENOTYPE NEEDS A DIFFERENT SPECIFIC AND TAILORED TREATMENT 4) IT IS WRONG THINK TO TREAT WITH ONE THERAPY EVERY SIGN AND SYMPTOM OF PCOS

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70 Patologia frequente CONCLUSIONI Patologia multifattoriale Patologia metabolica Patologia multisistemica MALATTIA SOCIALE E una patologia sottostimata, non ben diagnosticata con importanti complicanze a carico di più organi ed apparati

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73 World Top 10 Leaders in Polycystic Ovary Syndrome (PCOS)

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75 Consensus in Medicine ".the work of science has nothing whatever to do with consensus. Consensus is the business of politics. Science, on the contrary, requires only one investigator who happens to be right, which means that he or she has results that are verifiable by reference to the real world. In science consensus is irrelevant. What is relevant is reproducible results. The greatest scientists in history are great precisely because they broke with the consensus.. There is no such thing as consensus science. If it's consensus, it isn't science. If it's science, it isn't consensus. Period. Consensus is invoked only in situations where the science is not solid enough. Michael Crichton Aliens Cause Global Warming The Caltech Michelin Lecture, January 17, 2003

76 We can never, in science, know that we have discovered the truth although there is such a thing as truth, it is a regulative idea which we try to approach, but can never be sure of reaching Karl Popper

77 THANK YOU FOR YOUR KIND ATTENTION!

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80 Stamets, 2004

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82 Mavropoulos, 2005

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84 Galletly 2007

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86 Nikokavoura 2015

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88 Anti-obesity agents and bariatric surgery Moran et al., Fertil Steril 2009