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L’insulino-resistenza nelle 3 età della donna

Renato Pasquali

Alma Mater Studiorum, Bologna

PCOS: il presente e il futuro

Clinical Endocrinology TrustEuropean Society for Endocrinology Prize & Lecture 2017 Lisbon, Portugal

Title: New perspectives on the definition and management of the Polycystic Ovary Syndrome

Diapositiva preparata da RENATO PASQUALI e ceduta alla Società Italiana di Diabetologia.

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

Conflitto di interessi

Renato Pasqualidichiara di aver non aver ricevuto negli ultimi

due anni compensi o finanziamenti Aziende Farmaceutiche e/o Diagnostiche



PCOS: from phenotypes to definitionA phenotype-biological approach

Issues of interest: The strenghts & drawbacks of different diagnostic criteria

(NIH Evidence-based Methodology Workshop on PCOS, 2012)

New perspectives in the definition of hyperandrogenemiain women with PCOS

Hyperandrogenemia & hirsutism: are they synonimous? The concept of “secondary PCOS” revisited Is it possible to think that the different phenotypes of

PCOS may involve different pathophysiologicalmechanisms and therefore different therapies?



Prevalence of hyperandrogenemia & hirsutism in PCOS (data available until 2007 )

Ferriman & Purdie, 1983 280 82.14%Conway et al., 1989 556 22.3 57.55%Kiddy et al., 1990 263 49.0Rajkhowa et al., 1995 153 80.4Balen et al., 1995 1741 28.9 66.23%Norman et al., 1995 122 84.4Falsetti & Eleftheriou, 1996 240 38.3Khoury et al., 1996 112 17.9Talbott et al., 1998 244 43.0Alborzi et al., 2001 371 80.9Williamson et al., 2001 162 90.7Amer et al., 2002 161 32.9Orio et al., 2003 100 33.0 100.00%Azziz et al., 2004 873 72.2Chang et al., 2005 316 38.6 68.4 70.89%Hahn et al., 2005 200 81.0 38.0 64.50%Legro et al., 2006 626 60.8 80.67%Diamanti-Kandarakis, 2007 634 84.4 69.55%

Total 6281 49.8% 60.6% 74.7%

Study Total N° % with >T % with >FT % hirsutism

Azziz R et al. Fertility & Sterility, 2009



Stener-Victorin E, et al. JCEM. 2010

Sensitivity & specificity of sex steroid markers for PCOS

Levels of E1 and FT in PCOS women & controls

Proposed decision thresholds for the diagnosis of PCOS

ROC curves for the detection ofPCOS using E1 and FT.

AUCROC was 0.93 for E1, 0.91 forFT, and 0.94 for E1+FT.

Estrone (E1) Free testosterone

These data support an relevant role of androgen metabolism and SHBG (not only testosterone!)



O’Reilly MW et al J Clin Endocrinol Metab. 2014

How to define hyperandrogenemia in PCOS: a strong correlation between T and ∆4A

Relationship of serum T and A with stratification of PCOS subgroups:(i) normal D4A+normal T) (n=10),(ii) high D4A+normal T) (n=20), (iii) High D4A + high T) (n=56). (iv) No pts were identified with NA/HT

P<0.001



An androgen profile is a cardinal feature of PCOSParameters Controls

(n=143)OA/PCOm

(=43)HA/OA (n=65)

HA/OA/PCOm (n=48)

P for trend (PCOS)

Testosterone, ng/mL

0.26±0.08 0.28±0.08 0.32±0.13b

0.41±0.18c <0.001

∆4A ng/mL 0.82±0.34 1.44±0.41c 1.79±0.74c

2.05±0.67c <0-001

FAI 0.68±0.45 1.06±0.87b 1.22±0.71c

1.55±0.78c <0.001

DHEA (ng/mL) 7.39±4.83 6.22±4.39 8.79±5.86 7.64±3.50 0.044

Accuracy (PCOS women vs ctrs): 91.1%; (P<0.001) for ∆4A, & 75.0% (P<0.001) for FAI. ∆4A showed high sensitivity, while FAI showed high specificity . The accuracy of both reached to 94.4% and 85.0% in the

classic phenotype. The combination of hirsutism, high-T, high-A, and high-FAI categorized phenotypes into 8 hyperandrogenic subgroups, with divergent steroid profile and metabolic pattern.

Pasquali R et al, JCEM 2016



11-o

xyge

nate

d an

drog

en

path

way

11-Oxygenated C19 steroids (adrenal origin) are the

predominant androgens in PCOS

• Serum concentrations of ( ) classic and ( ) 11-oxygenated steroids in PCOS women and healthy age-matched controls.

• Serum levels of the 11-oxygenated androgens 11OHA4, 11OHT, 11KA4, and 11KT were all significantly higher in the PCOS cohort.

11β-hydroxyandrostenedione (11βOHA4) is a major product of adrenal steroidogenesis, with a

downstream conversion generating 11-ketotestosterone and 11-keto-5α-DHT, wich bind

and activate the ARs

Clas

sic st

eroi

ds11

-oxy

gena

ted

ster

oids

O’Reilly MW et al. J Clin Endocrinol Metab. 2016



Prospettiva 1: Un profilo degli androgeni è più opportuno della singola misurazione del T totale ed è plausibile ritenere che gli steroidi surrenalici debbano essere opportunamente inclusi (valutazione mediante LC-MS/MS)



The OD-PCOm phenotype revisited: (phenotype 1) hyperandrogenic ------- (phenotype 2) non-hyperandrogenic

Phenotypes

High A

High FAI

Normal A/normal

FAI(B)

Normal A/high

FAI(A)

High A/norma

l FAI(A)

High A/high

FAI

OA + PCOm

14 33%)

13 (30%)

16 (37%)

13 (30%)

14 (33%) 0%

Frequency of the combination of high A & high FAI

(A) Women presenting with the OD+PCOm phenotype may have variable androgen excess (therefore they can be defined as TRUE PCOS) ( );

(B) The non-hyperandrogenemic OD+PCOm phenotype could represent a PCOS-like phenotype or a mild variant? ( )

phenotype 1 Phenotype 2



Prospettiva 1: Un profilo degli androgeni è più opportuno della singola misurazione del T totale ed è plausibile ritenere che gli steroidi surrenalici debbano essere opportunamente inclusi(valutazione mediante LC-MS/MS)Prospettiva 2:E’ presumibile che un adeguato profilo steroideo possa dimostrare più compiutamente che il fenotipo OD+PCOm sia, di fatto, iperandrogenico



Correlations between hirsutism (mFG score) with T, ∆4A, T/∆4A ratio and FAI in women with PCOS

r=0.113 p=0.16

(r=0.071 p=0.38)

r=0.221 P=0.005

r=0.179 p=0.036

Blood androgen excess does not explain hirsutism per se!

Pasquali R et al.JCEM, 2016



The skin as a steroidogenic extra-glandular organ: steroidogenic pathways

The potential intrinsic role of the skin in the development of hirsutism1. >> activity of local 5α-reductase 1-2 may favor the production of DHT 2. Potential alteration in the AR function ?

Slominsky A et al J Steroid Biochem Mol Biol. 2013

The skin cells express crucial genes of steroidogenesis &

active enzymes, and can favor a de novo steroidogenesis from

cholesterol.This could play a specific role

in the development of hirsutism in a subgroup of pts and in determining systemic

effectsThe hypothesis requires further research



Prospettiva 1: Un profilo degli androgeni è più opportuno della singola misurazione del T totale ed è plausibile ritenere che gli steroidi surrenalici debbano essere opportunamente inclusi(valutazione mediante LC-MS/MS) Prospettiva 2:E’ presumibile che un adeguato profilo steroideo possa dimostrare più compiutamente che il fenotipo OD+PCOm sia, di fatto, iperandrogenico Prospettiva 3: L’irsutismo ed iperandrogenemia dovrebbero essere valutati separatamente nella PCOS (irsutismo non sinonimo di iperandrogenemia)



PCOS secondary to obesity: does it exists ? Conceptual and pathophysiological aspects

• PCOS is a “syndrome”, therefore it implies different phenotypes with different pathophysiology

• There is epidemiological evidence that obesity is very common in adolescent girls

• Adolescent obesity per se may be associated with androgen excess of ovarian and adrenal origin

• Treatment of adolescent obesity may restore normal weight & normalize androgen levels

• In most adult obese-PCOS women the PCOS phenotype may totally disappear after weight loss (lifestyle/bariatry)

• The concept of secondary PCOS to obesity may identify a specific phenotype, with a specific pathophysiology



Prevalence of Childhood in U.S.Ogden CL, et al JAMA. 2014.

Prevalence of high BMI by selected cut-off for youth aged 2-19 years race/hispanic origin, US 2011-12.

All race 2-19 y 2-5 y 6-11 yAll 31.8 22.8 34.2Boys 32.0 23.9 33.2

Girls 31.6 21.7 35.2

BMI for age ≥85° ptle of the Growth charts

Perioperative outcomes of adolescents undergoing bariatric surgery: the Teen-Longitudinal Assessment of Bariatric Surgery study.

Inge TH et al. JAMA Pediatr. 2014Baseline comorbidities

No. (%)Sleep apnea 137 56.6Joint pain 110 45.6Hypertension 109 45.0Back pain 109 45.2Fatty liver disease 89 36.9

PCOS, females only 38 20.9Chronic kidney dis. 43 19.2Diabetes mellitus 33 13.6



Obesity is associated with hyperandrogenemia in women already across puberty

McCartney et al., JCEM 2007

During adolescence, obesity per se favors testosterone excessPt

s with

ele

vate

d (T

anne

r sta

ge-

spec

ific)

free

T)



Hyperandrogenemia in obese peri-pubertal girls: correlates and potential etiological determinants

Knudsen KL et al. Obesity (Silver Spring), 2010

LH and fasting insulin are significant and independent predictors of free T levels in obese girls. The data suggest a possible causative role for both LH excess and obesity-associated

hyperinsulinemia in the development of HA in some obese girls and a predisposition to the development of PCOS

Parameters Early puberty(n=28)

Mid puberty(n=20)

Late puberty(n=44)

Age (yrs) 9.5±1.5 11.8±1.3 14.9±1.7

BMI (kg/m2) 31.4±5.2 32.4±4.9 37.3±5.8

Tanner stage 1 (6), 2 (26) All 3 All 4/5

Hirsutism 4% 10% 59%

Testo (pmol/mL) 61±48 123±75 161±81

SHBG (nmol/ml) 27±15 19±13 19±10

LH (IU/L) 0,6±1,1 2,4±2,5 5,7±2.9

Insulin (pmol/L) 157±124 227±120 166±90

> Testo / < SHBG



Higher BMI is associated with androgen excess &PCOS in late adolescent women (aged 16-19 years)

EPIDEMIOLOGICAL SURVEY ON ITALIAN HIGH-SCHOOL STUDENTS

Gambineri A. et al. JCE&M 2013

316 declined further participation 104 excluded for OCPs

21 excluded for chronic diseases

2052 were offered participation

546 declined participation37 crucial items not compiled

1469 were included in the 1st self reporting analysis

431 declined further participation 203 excluded for OCPs

835 were included in the 2nd analysis

394 included in the 3rd analysis

Variables PCOS OR (95%CI)

PValue

BMI (SD) 1.42 (1.09-1.84) 0.009Waist, 1cm

incr0.91 (0.83-

1.00)0.060

Polytomous logistic regression model

NormalIsolated menstrual irregolaritiesIsolated clinical HAIsolated biochemical HAClinical + biochemical HAPCOS

4,3%

60,9 %

10%17% 7%13%



The concept of “secondary PCOS to obesity”A mechanistic perspective

Early androgenexcess• Overactivation of the HPG axis

• Hyper-leptinemia•11β-HSD activation in the expanded VAT leading to > deactivation of cortisol & increased ACTH drive, leading in turn to increased adrenal androgen production.

• Other factors…………

Insulin resistance (VAT/SAT, muscle, liver)

Reduced whole body insulin sensitivity

Obesity (early onset? during adolescence)

Development of the PCOS phenotype in during adolescence or during early adulthood age



Insulin sensitivity is reduced and insulin levels are increased in the plycysticovary syndrome.

Obesity contributes an additional dominant component to insulin resistance in PCOS

Morales, JCEM, 1996

Independent effect of obesity on insulin sensitivity in PCOS

6

4

2

0

b

ca,c

800

600

400

200

0

24h Insulin (pmol/L)Insulin sensitivity

d

c,d

LC LPCOS OC OPCOS LC LPCOS OC OPCOS



Mechanisms linking severe insulin-resistant states, overproduction of androgen & PCOS

Pasquali R et al. Eur J Endocrinol 2016



Major findings:Weight loss by long-term lifestyle intervention discovered 3

different patters of response:1. persistence of the PCOS phenotype (15.4%)2. partial recovery from the PCOS phenotype

(47.7%) (ovulation occurred in 35% of women)3. complete recovery from the PCOS phenotype

(36.9%) (ovulation occurred in all women)

Abdominal fatness (WHR) and particularly ∆4-androstenedionelevels (p<0.001) significantly predicted the outcome

Heterogeneity in the responsiveness to long-term lifestyle intervention and predictive factorsin 65 obese patients with

PCOS

Pasquali R et al, Eur J Endocrinol 2010



Baseline After Baseline After

0100200300400500600700

( ) Baseline After Baseline After

Baseline After Baseline After

p<0.001

p<0.001

p<0.001

p=0.002

p=NS

p=0.023

N° of ovarian folliclesOvarian volume (mL)

PCOm Normal Fully Recovered () vs. Still PCOS ()

Efficacy of weight loss in obese PCOS women: the fully recovered group (24/65 pts)

Pasquali R et al, Eur J Endocrinol 2010

○ Normal-weight at the end of the treatment ● Still overweight or obese at the end of the treatmentDiapositiva preparata da RENATO PASQUALI e ceduta alla Società Italiana di Diabetologia.


BMI decreased from 46.3 to 34.2 at 12m follow-up and study

endpoint

The impact of bariatric surgery on PCOS: a systematic review and meta-analysis (2130 PCOS pts) (Study endpoints (14±28 moths)

Study endpoints (14±28 moths)

Skubleny D et al, Obes Surg. 2016

The incidence of PCOS decreased from 45.6% to 6.8 (p<0.001) Irregular menses decreased from 56.2% to 7.7 % (P<

0.001) Hirsutism declined from 67.0 % to 38.6 % (P= 0.03) Infertility declined from 18.2 % to 4.3 % (P<0.001)



Prospettiva 1: Un profilo degli androgeni è più opportuno della singola misurazione del T totale ed è plausibile ritenere che gli steroidi surrenalici debbano essere opportunamente inclusi (valutazione mediante LC-MS/MS) Prospettiva 2:E’ presumibile che un adeguato profilo steroideo possa dimostrare più compiutamente che il fenotipo OD+PCOm sia, di fatto, iperandrogenico Prospettiva 3: L’irsutismo ed iperandrogenemia dovrebbero essere valutati separatamente nella PCOS (irsutismo non sinonimo di iperandrogenemia) Prospettiva 4: E’ presumibile che esista un fenotipo di PCOS secondario all’obesitàDiapositiva preparata da RENATO PASQUALI e ceduta alla Società Italiana di Diabetologia.


Population of PCOS (n=821)referred to the Endocrinology Unit (Bologna), 2004-2014

Insulin distribution at baseline

792757

63027

130

181

348

426480496

481

575

0

200

400

600

800

1000

Fasting insulin (µU/mL)

0102030405060708090

100

0 200 400 600 800 1000 1200

Peak insulin on OGTT (µU/mL)

0

200

400

600

800

1000

0 200 400 600 800 1000 1200

Cut off:

21 µU/mL

Cut off:

209 µU/mL

LMNA

PPARG CGL (Hypo Leptin)

PLIN1

27 130

181

348 426 481

480630

496

575

757792

0

20

40

60

80

100

Pasquali R, et al Eur J Endocrinol, 2016)

Genes identifiedAmong 1200 pts with PCOS included in the data-base we have extracted 97 patients with SSIR. Eighteen of these patients

(18.6%) had a lipodystrophic phenotype (representing 1.5% of the entire cohort).



Severe insulin resistant states presenting with a PCOS phenotype

Insulin Receptoropathy

PPARg mutation LMNA (1) mutations

PPARg mutation PLIN 1 mutation (partial lypodistrophy)Mutaz

MYBPC3Generalized lipodystroph

y



Prospettiva 1: Un profilo degli androgeni è più opportuno della singola misurazione del T totale ed è plausibile ritenere che gli steroidi surrenalici debbano essere opportunamente inclusi (valutazione mediante LC-MS/MS)

Prospettiva 2:E’ presumibile che un adeguato profilo steroideo possa dimostrare che il fenotipo OD+PCOm sia, di fatto, iperandrogenico

Prospettiva 3: L’irsutismo ed iperandrogenemia dovrebbero essere valutati separatamente nella PCOS (irsutismo non sinonimo di iperandrogenemia)

Prospettiva 4: E’ presumibile che esista un fenotipo di PCOS secondario all’obesità

Prospettiva 5: E’ assolutamente necessario, in presenza di livelli marcatamente elevati di insulina (a digiuno e/o glucosio-stimolata), pensare/escludere una SSIR (valutare possibile presenza di lipodistrofia!)



Heterogeneity of PCOS: a constellation of different phenotypes (according to the concept of “syndrome”)

Classic hyperandrogenic(HA) phenotype [androgenexcess, hirsutism, ovarian dysfuntion, PCOm, IR] (Overweight/obesityworsens the phenotype )

“Secondary PCOS” to obesity ?

Isolated hirsutism (a skinproblem?)

PCOS secondary to:• other endocrinopaties• drugs

Most of the women with the OD-PCOm phenotype may have HA (>∆4A/FT). The OD-PCOm non HA phenotype as a mild variant?

Clinical implications: a phenotype-oriented treatment

Severe insulin resistant states and the PCOS phenotype



pcos: diabetologia. il presente e il futuro - sid italia - pasquali renato - pcos... · il presente...

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