pcos: dagli ormoni sessuali alle alterazioni metaboliche - moghetti paolo - pcos... · skeletal...

Endocrinologia, Diabetologia e Malattie del MetabolismoUniversità e Azienda Ospedaliera Universitaria Integrata

Verona

PCOS: dagli ormoni sessuali alle alterazioni metaboliche

Paolo Moghetti

L’INSULINORESISTENZA NELLE 3 ETÀ DELLA DONNA

Pisa, 16-17 Novembre 2017

Diapositiva preparata da PAOLO MOGHETTI e ceduta alla Società Italiana di Diabetologia.

Per ricevere la versione originale si prega di scrivere a [email protected]

Ai sensi dell’art. 3.3 del Regolamento applicativo dell’Accordo Stato-Regioni 05.11.2009, dichiaro che negli ultimi due anni ho avuto i seguenti rapporti

anche di finanziamento con i seguenti soggetti portatori di interessi commerciali in campo sanitario:

• Laborest• Movi• Novartis• Novo Nordisk

In fede, Paolo Moghetti



?



Frequency of insulin resistance and metabolic syndrome in 137 consecutive PCOS women

(Verona 3P Study; mean age 23 yr, BMI 28.5 kg/m2)

01020304050607080

Insulin resistance(clamp, WHO criteria)

%

Metabolic syndrome(IDF 2009 criteria)

(from Moghetti P et al, JCE&M 2013)



Frequency of alterations of the clinical elements included in the metabolic syndrome diagnosisamong PCOS women of the Verona 3P study

0

20

40

60

80

waist circumferenceHDL-Cblood pressuretriglyceridesglucose

%

(from Moghetti P et al, JCE&M 2013)



(Glintborg et al, Eur J Endocrinol 2015)

~2x~5x~4x

~8x• 19,199 women with PCOS,

included in the Danish National Patient Register

• 57,483 age-matched controls, randomly selected from the same register

~3x~3x

~3x



Tosi F, Moghetti P et al, J Clin Endocrinol Metab 2015

Relationship between insulin sensitivity and free testosterone levels in PCOS women



Deming regression of gold standard vs routine fT assay

Tosi F et al, J Clin Endocrinol Metab 2016

Misclassification of androgen excess by routine methods in ~30% of patients

Implications of inaccuracy in routine androgen assays in 204 women with PCOS of the Verona 3P Study



Implications of inaccuracy in routine androgen assays in women with PCOS

Comparison of true classic, false classic and true normoandrogenic PCOS women

Tosi F et al, J Clin Endocrinol Metab 2016



PCOS women recognized as hyperandrogenemic by gold standard methods, either without or with FT measurement

(Tosi F et al, J Clin Endocrinol Metab 2016)

AUC



R=0.612 p<0.001

G/I ratio QUICKI

0

4

8

12

16

20

0 2 4 6 8 10 12 14

Gutt index

M-clamp (mg/KgFFM x min-1)

0

4

8

12

16

20

-.4 -.3 -.2 -.1 0 .1 .2

Stumvoll0-120

R=0.631 p<0.001M-clamp (mg/KgFFM x min-1)

R=0.665 p<0.001

0

4

8

12

16

20

0 2 4 6 8 10 12 14

MATSUDA Index



HOMA IR

R=0.622 p<0.001

0

4

8

12

16

20

0 2 4 6 8 10 12 14 16 18

R=0.526 p<0.001

0

4

8

12

16

20

0 5 10 15 20 25 30 35 40 45


R=0.618 p<0.001M-clamp (mg/KgFFM x min-1)

0

4

8

12

16

20

.25 .28 .3 .32 .35 .38 .4 .43 .45 .47 ,5

Tosi, Bonora & Moghetti, Hum Reprod 2017

Relationships between insulin sensitivity measured by the glucose clamp and several surrogate indexes in 375 PCOS women



(Ezeh U et al, JCE&M 2013)

Comparison of PCOS women referred to a tertiary care clinic vs unselected PCOS and control women

identified at a pre-employment medical screening



Insulin sensitivity in PCOS vs control women subdivided according to BMI (< vs >27 kg/m2)

(Stepto NK et al, Hum Reprod 2013)

Mean BMI: 22 23 35 36

25th centile of lean controls



Fenotipi clinici della PCOS in base ai criteri di Rotterdam

Oligoanovulazione Iperandrogenismo

Morfologia policistica dell’ovaio

Fenotipo classico

Fenotipo ovulatorio

Fenotipo normoandrogenico



Divergences in insulin resistance between the PCOS phenotypes derived from Rotterdam diagnostic criteria

(Moghetti P et al, J Clin Endocrinol Metab 2013)

P<0.001 between PCOS phenotypes



In vivo aldo-keto reductase type 1C3 expression and androgen activation in sc adipose tissue microdialysates

O’Reilly MW et al, JCEM 2017

Testosterone



O’Reilly MW et al, JCEM 2017

Aldo-keto reductase type 1C3 may activate androgens in sc adipose tissue, inducing lipogenetic and anti-lipolytic effects



ControlsHyperandrogenic before treatment

Moghetti P et al, JCEM 1996

DOSE-RESPONSE CURVES FOR INSULIN-INDUCED GLUCOSE UPTAKE IN HEALTHY CONTROLS AND HYPERANDROGENIC WOMEN, BEFORE AND AFTER ANTIANDROGEN TREATMENT

p<0.01 vs hyperandrogenic

0

15

30

45

60

75

90

Plasma insulin (pmol/l)0 150 300 450 600 750 900

15

0

30

45

60

75

90G

luco

se u

ptak

e (µ

mol

/kg

FFM

· m

in)

Hyperandrogenic after treatment

p<0.01 vs before treatment



TriglyceridesCholesterol LDL HDL

EFFECTS OF FLUTAMIDE (500 mg/day) ON SERUM LIPIDS IN PCOS WOMEN

BasalAfter Flutamide**

**p<0.01Diamanti-Kandarakis E et al, JCEM 1998

0

1

2

3

4

5

mm

ol/l

**

**



Jensen JT et al, JCEM 2017

Estimated effects of estradiol, progesterone and presence of an active ovary (as a binary variable) during the natural

menstrual cycle in healthy women



Schiffer L et al, Eur J Endocrinol 2017

Estimated metabolic risk according to serum testosterone levels



Schiffer L et al, Eur J Endocrinol 2017

Differential effects of androgens on adipose tissue andskeletal muscle and implications for global metabolism



EFFETTI DI 12 SETTIMANE DI MODERATOIPERANDROGENISMO NEL RATTO OVARIECTOMIZZATO

OVX OVX +Testosterone

p

Testosteronemia (nmol/l) 0.4 ± 0.5 2.7 ± 0.5 0.001

Insulinemia (mU/l) 26 ± 2 31 ± 3 0.05

Uptake glucosio (mg/kg·min) 6.3 ± 0.7 1.0 ± 0.4 0.001

8 ± 1 22 ± 1 0.05Fibre musc. (soleus) tipo 2 (%)

Densità capillare nel muscolo(capillari/fibra)

5 ± 1 3 ± 1 0.05

(da Holmang et al, AmJ Physiol 1990)



VO2max

15

20

25

30

35

40

45

50

CONTROLLI PCOS

ml/k

g ·m

in

P=0.008

Fitness cardiorespiratoria in donne con PCOS e controlli normopeso

0.0590.245-0.491Massa grassa, Kg

0.1440.4560.692Sensibilità insulinica, mg/kg FFM · min

0.0175.910-15.325Testosterone libero, ng/dL

0.4410.244-0.192Età, anni

PStd. Err.b coeff.

Predittori di VO2max alla regressione multipla(R2 0.45, p=0.013)

Bacchi E et al, Clin Endocrinol 2015



Lipidomics of PCOS: serum lipids derived from arachidonic acid

Li S et al, J Clin Endocrinol Metab 2017

Lean CTObese CTLean PCOS

Obese PCOS



Take home messages

• Le alterazioni metaboliche sono un fenomeno molto frequente nelle donne con PCOS, ma eterogeneo all’interno dei diversi fenotipi della sindrome

• Il legame fra iperandrogenismo e insulinoresistenza è probabilmente bidirezionale, anche se restano molti aspetti da chiarire in questa associazione

• Non tutte le alterazioni metaboliche di queste pazienti sembrano ascrivibili alla presenza di insulinoresistenza, suggerendo un ruolo diretto degli androgeni

• Il ruolo delle alterazioni degli altri ormoni sessuali resta molto mal definitoDiapositiva preparata da PAOLO MOGHETTI e ceduta alla Società Italiana di Diabetologia.


pcos: dagli ormoni sessuali alle alterazioni metaboliche - moghetti paolo - pcos... · skeletal...

Documents