Professore Associato di EndocrinologiaUniversità “Parthenope” Napoli

Responsabile Sezione Endocrinologia «CMSO» Salerno

Prof. FRANCESCO ORIO

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”

PCOS: STORIA

Stein-Leventhal Syndrome 1935

Amenorrea associataad ovaia policistiche

bilaterali

Resezione Cuneiformeripristinava normali

mestruazioni

Stein I.F. and Leventhal M.L. (1935). Am. J. Obstet. Gynecol. 29:181-189

• 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

• obesità• diabete mellito non insulino-dipendente

• ipertensione• dislipidemia

INSULINO-RESISTENZA

PREMESSEPCOS

FATTORE DI RISCHIO PERMALATTIA

CARDIOVASCOLARE ?

COMPLICANZE

FATTORE DI RISCHIO PER

{

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)

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

Different criteria for diagnosing PCOS

ALERT!IL 40% DELLE GIOVANI DONNE DI UNA REGIONE DEL SUD ITALIA

PRESENTA L’ASPETTO ECOGRAFICO DI OVAIA POLICISTICHEMA CIO’ NON SIGNIFICA CHE HANNO LA

SINDROME DELL’OVAIO POLICISTICO

BE CAREFUL! VERY CAREFUL!

How PCOS May Present in Patients

Ehrmann DA New Engl J Med 2005; 352:1223-1236

PCOS

«Sindrome multifattoriale»

Iperandrogenismo, Clinico e

biochimico

RIDOTTA QUALITA’

OVOCITARIA

DISORDINI DEL CICLO MESTRUALE

Oligo/anovulazione e infertilità

INSULINO-RESISTENZA

Iperinsulinemia e DM2

• ALTERAZIONI METABOLICHE:

• ALTERAZIONI FUNZIONALITA’ OVARICA:

PCOS TREATMENT

It should be directed to:Signs, Symptoms

and Endocrine Abnormalities of each single patient

Health issues PCOS-related

Cosmetics(irsutism, acne, androgenic alopecia)

Fertility(anovulatory cycle)

Insulin-resistance(metabolic syndrome, cardiovascular disease)

PCOS TREATMENTHIRSUTISM

INFERTILITYOLIGO/

AMENORRHEA

ES GUIDELINE

CC, LOD, GONADOTROPIN, AI

LIFESTYLE INTERVENTION

DIET / PHYSICAL EXERCISE

SCREENING FOR CVR AND CVD IN PCOS AT MAJOR RISK

OVERWEIGHT / OBESITYOC, METFORMIN

PCOS TREATMENTHIRSUTISM

INFERTILITYOLIGO/

AMENORRHEA

ES GUIDELINE

CC, LOD, GONADOTROPIN, AI

LIFESTYLE INTERVENTION

DIET / PHYSICAL EXERCISE

SCREENING FOR CVR AND CVD IN PCOS AT MAJOR RISK

OVERWEIGHT / OBESITYOC, METFORMIN

Lifestyle modifications as nonpharmacologicalapproach to infertile women with PCOS: why?

Obesity50% (40% to 77%)

Hyperinsulinemia and insulin resistance

60% (50% to 75%)

Lifestyle modification programs

Weight loss is essential for obese women who wish to conceivenot 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, suchas isolated fetal anomalies, fetal deaths, preterm delivery and early neonatal death

Obesity and reproductionIs it ethical to provide a fertility treatment to

obese patients?

An aggressive approach to reduce weight, includingpharmacological strategies and the use of contraception and high-dose folic acid should be always proposed for obese women before planning a pregnancy

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

Nelson and Fleming, 2007

National Institute for Clinical Excellence, 2004

Lifestyle modification or clomiphene citrate?

Karimzadeh & Javedani, Fertil Steril 2010

Lifestyle modification may be used as the first line of ovulation induction in obese PCOS patients

Moran et al., Fertil Steril 2009

Types of diet interventions

Physical excercise

Moran et al., Fertil Steril 2009

• 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 otherinfertility factors• The starting dose of CC should be 50 mg/day (for 5 days), and the recommendedmaximum dose is 150 mg/day

• 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

First-step treatment

Weight loss and ovulatory infertility

• A weight loss as little as 5% of the initial body weight exert beneficial effects on reproductivefunction.

Norman et al., Hum Reprod Update 2004

• Each 1-Kg increase in body weight is associated with 2.84 (95%CI 1.33-4.35) day increase in time to pregnancy.

• Each 1-Kg decrement in body weight is associatedwith 5.50 (95%CI 1.35-9.65) day decrease in time to pregnancy.

Ramlau-Hansen et al., Hum Reprod 2007

Non-pharmacological treatmentDiet: 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!!!

9,000 cal 1 kg

A weight loss about the 5% of the initial body weight improves the reproductive function.

5 kgA weight loss of the 5% in a women who

has a initial weight of 100 kg

How long??

Non pharmacological treatmentDiet: total daily energ y expenditure

Harris-Benedict equation

45,000 cal45,000cal/60 days: 750 cal daily

energy expenditure to loss 5kg in 2 months

Aerobic physical training

Moderate intensity

Hainer et al., Diabetes Care 2008

Non-pharmacological treatmentPhysical activity

WALKING CYCLING

RUNNING SWIMMING

High drop-out rate!!!

Authors Source Follow-up (months)

Drop-out rate (%)

Palomba et al. Hum Reprod 2008 Six 35.0Stamets et al. Fertil Steril 2004 One 26.0Clark et al. Hum Reprod 1998 Six 23.0Clark et al. Hum Reprod 1995 Six 27.0

Lifestyle modification programs?

FUTURE PERSPECTIVESNon conventional treatment

NUTRACEUTICS: INOSITOL (D-CHIRO-INOSITOL, MYO-INOSITOL)

MEDITERRANENAN DIET

VLCD ?

EFFETTI SUL METABOLISMO

-RIDUCE l’insulino resistenza-RIDUCE iperandrogenismo-RISTABILISCE il bilancioormonale-RIDUCE irsutismo e acne -RISTABILISCE il profilometabolico

Non conventional treatment: MEDITERRANEAN DIET

Protocollo eseguito in pazienti con Sindrome dell’Ovaio Policistico (PCOS)

Pazienti (n = 13)Basale Dopo 12 Settimane p

Età (a) 23.2 + 3.8 23.4+3.7 0.89

BMI (Kg/m2) 39.7 + 5.6 34.4 + 4.2 0.012

Peso (Kg) 103.3 + 14.9 89.0 + 12.4 0.014

Massa Grassa (Kg) 48.9 + 11 36.5 + 7.8 0.003

HOMA Index 4.7 + 1.6 3.1 + 0.7 0.003

10 giorni: Riduzione graduale dei carboidrati

6 settimane: Chetosi6 settimane: Transizione

Pazienti (n = 13)Basale Dopo 12 Settimane p

FSH (mUI/ml) 5.5+1.2 6.8+1.9 0.05

LH (mUI/ml) 10.1+3.1 8.5+4.3 0.287

17 Beta Estradiolo (pg/ml)

101.2 + 20.8 98.1 + 25.4 0.736

Testosterone (ng/ml)

0.7 + 0.4 0.5+0.3 0.162

SHBG (nmol/L) 234 + 14.9 89 + 12.4 <0.001

FAI (Tx100/SHBG) 1.1+0.6 0.7 + 0.5 0.07

Delta4 Androstenedione(ng/ml)

3.8 + 1.6 3.6 + 1.4 0.737

POSSIBLE CONCLUSIONS

VLCD could really represents a valid future tool and therapeutic alternative in

OBESE PCOS WOMEN with OLIGO-ANOVULATION and METABOLIC issues

CONCLUSIONS

1) PCOS TREATMENT MUST BE PERSONALISED IN EACH PATIENT

2) IT DOES NOT EXIST ONLY ONE THERAPY FOREVERY 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

CONCLUSIONI

Patologia multifattoriale

E’ una patologia sottostimata, non ben diagnosticatacon importanti complicanze a carico di

più organi ed apparati

Patologia frequente

Patologia metabolica

Patologia multisistemicaMALATTIA SOCIALE

World Top 10 Leaders in Polycystic Ovary Syndrome (PCOS)http://www.expertscape.com/leaders/polycystic-ovary-syndrome

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

“We can never, in science, know that wehave discovered the truth although there issuch a thing as truth, it is a regulative idea which we try to approach, but can never be

sure of reaching”

Karl Popper

THANK YOU FOR YOUR KIND ATTENTION !

Stamets, 2004

Mavropoulos, 2005

Galletly 2007

Nikokavoura 2015

Moran et al., Fertil Steril 2009

Anti-obesity agents and bariatric surgery