PCOS: il presente e il futuro

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1 L insulino-resistenza nelle 3 età della donna PCOS: il presente e il futuro Renato Pasquali Alma Mater Studiorum, Bologna Clinical Endocrinology Trust European Society for Endocrinology Prize & Lecture 2017 Lisbon, Portugal Title: New perspectives on the definition and management of the Polycystic Ovary Syndrome

2 Conflitto di interessi Renato Pasquali dichiara di aver non aver ricevuto negli ultimi due anni compensi o finanziamenti Aziende Farmaceutiche e/o Diagnostiche

3 PCOS: from phenotypes to definition A 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 hyperandrogenemia in 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 pathophysiological mechanisms and therefore different therapies?

4 Prevalence of hyperandrogenemia & hirsutism in PCOS (data available until 2007 ) Study Total N % with >T % with >FT % hirsutism Ferriman & Purdie, % Conway et al., % Kiddy et al., Rajkhowa et al., Balen et al., % Norman et al., Falsetti & Eleftheriou, Khoury et al., Talbott et al., Alborzi et al., Williamson et al., Amer et al., Orio et al., % Azziz et al., Chang et al., % Hahn et al., % Legro et al., % Diamanti-Kandarakis, % Total % 60.6% 74.7% Azziz R et al. Fertility & Sterility, 2009

5 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 Estrone (E1) Free testosterone ROC curves for the detection of PCOS using E1 and FT. AUC ROC was 0.93 for E1, 0.91 for FT, and 0.94 for E1+FT. These data support an relevant role of androgen metabolism and SHBG (not only testosterone!) Stener-Victorin E, et al. JCEM. 2010

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

7 Parameters An androgen profile is a cardinal feature of PCOS Testosterone, ng/ml Controls (n=143) OA/PCOm (=43) HA/OA (n=65) 0.26± ± ±0.13 4A ng/ml 0.82± ±0.41 c 1.79±0.74 c FAI 0.68± ±0.87 b 1.22±0.71 c b HA/OA/PC Om (n=48) P for trend (PCOS) 0.41±0.18 c < ±0.67 c < ±0.78 c <0.001 DHEA (ng/ml) 7.39± ± ± ± 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

8 11-Oxygenated C19 steroids (adrenal origin) are the predominant androgens in PCOS 11-oxygenated androgen pathway 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 Classic steroids 11-oxygenated steroids 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. O Reilly MW et al. J Clin Endocrinol Metab. 2016

9 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)

10 The OD-PCOm phenotype revisited: (phenotype 1) hyperandrogenic (phenotype 2) non-hyperandrogenic Phenotyp es OA + PCOm High A 14 33%) Frequency of the combination of high A & high FAI High FAI 13 (30%) Normal A/normal FAI (B) 16 (37%) Normal A/high FAI (A) 13 (30%) phenotype 1 Phenotype 2 High A/norma l FAI (A) High A/high FAI 14 (33%) 0% (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? ( )

11 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

12 Correlations between hirsutism (mfg score) with T, 4A, T/ 4A ratio and FAI in women with PCOS r=0.113 p=0.16 r=0.221 P=0.005 (r=0.071 p=0.38) r=0.179 p=0.036 Blood androgen excess does not explain hirsutism per se! Pasquali R et al.jcem, 2016

13 The skin as a steroidogenic extra-glandular organ: steroidogenic pathways 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 effects The hypothesis requires further research The potential intrinsic role of the skin in the development of hirsutism 1. >> 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

14 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)

15 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

16 Prevalence of Childhood in U.S. Ogden CL, et al JAMA Prevalence of high BMI by selected cut-off for youth aged 2-19 years race/hispanic origin, US Inge TH et al. JAMA Pediatr Perioperative outcomes of adolescents undergoing bariatric surgery: the Teen- Longitudinal Assessment of Bariatric Surgery study. BMI for age 85 ptle of the Growth charts All race 2-19 y 2-5 y 6-11 y All Boys Girls Baseline comorbidities No. (%) Sleep apnea Joint pain Hypertension Back pain Fatty liver disease PCOS, females only Chronic kidney dis Diabetes mellitus

17 Obesity is associated with hyperandrogenemia in women already across puberty Pts with elevated (Tanner stagespecific) free T) During adolescence, obesity per se favors testosterone excess McCartney et al., JCEM 2007

18 Hyperandrogenemia in obese peri-pubertal girls: correlates and potential etiological determinants > Testo / < SHBG Parameters Early puberty(n=28) Mid puberty (n=20) Late puberty (n=44) Age (yrs) 9.5± ± ±1.7 BMI (kg/m 2 ) 31.4± ± ±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± ± ±90 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 Knudsen KL et al. Obesity (Silver Spring), 2010

19 Higher BMI is associated with androgen excess &PCOS in late adolescent women (aged years) EPIDEMIOLOGICAL SURVEY ON ITALIAN HIGH-SCHOOL STUDENTS 2052 were offered participation Gambineri A. et al. JCE&M declined participation 37 crucial items not compiled 1469 were included in the 1 st self reporting analysis 431 declined further participation 203 excluded for OCPs 835 were included in the 2 nd analysis 316 declined further participation 104 excluded for OCPs 21 excluded for chronic diseases 394 included in the 3 rd analysis 60,9 % Variables PCOS OR (95%CI) P Value BMI (SD) 1.42 ( ) Waist, 1cm incr 10% 13% Normal Isolated menstrual irregolarities Isolated clinical HA Isolated biochemical HA Clinical + biochemical HA PCOS 17% 7% 0.91 ( ) Polytomous logistic regression model 4,3% 0.060

20 The concept of secondary PCOS to obesity A mechanistic perspective Insulin resistance (VAT/SAT, muscle, liver) Reduced whole body insulin sensitivity Obesity (early onset? during adolescence) 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 Early androgen excess Development of the PCOS phenotype in during adolescence or during early adulthood age

21 Independent effect of obesity on insulin sensitivity in PCOS Insulin sensitivity is reduced and insulin levels are increased in the plycysticovary syndrome. Obesity contributes an additional dominant component to insulin resistance in PCOS Insulin sensitivity b c a,c 24h Insulin (pmol/l) LC LPCOS OC OPCOS d LC LPCOS OC OPCOS c,d Morales, JCEM, 1996

22 Mechanisms linking severe insulin-resistant states, overproduction of androgen & PCOS Pasquali R et al. Eur J Endocrinol 2016

23 Heterogeneity in the responsiveness to long-term lifestyle intervention and predictive factorsin 65 obese patients with PCOS 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-androstenedione levels (p<0.001) significantly predicted the outcome Pasquali R et al, Eur J Endocrinol 2010

24 Efficacy of weight loss in obese PCOS women: the fully recovered group (24/65 pts) Baseline After Baseline After ( ) p<0.001 p< Baseline After Baseline After p=0.002 Baseline After Baseline After Normal-weight at the end of the treatment Still overweight or obese at the end of the treatment 0 p<0.001 p=ns p=0.023 PCOm Normal Fully Recovered ( ) vs. Still PCOS ( ) Ovarian volume (ml) N of ovarian follicles Pasquali R et al, Eur J Endocrinol 2010

25 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) 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) BMI decreased from 46.3 to 34.2 at 12m follow-up and study endpoint Skubleny D et al, Obes Surg. 2016

26 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 obesità

27 Population of PCOS (n=821)referred to the Endocrinology Unit (Bologna), Insulin distribution at baseline Among 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). Cut off: 21 µu/ml Cut off: 209 µu/ml Fasting insulin (µu/ml) Peak insulin on OGTT (µu/ml) Genes identified LMNA PPARG PLIN CGL (Hypo Leptin) Pasquali R, et al Eur J Endocrinol, 2016)

28 Severe insulin resistant states presenting with a PCOS phenotype Insulin PPARg mutation LMNA (1) mutations Receptoropathy PPARg mutation PLIN 1 mutation (partial lypodistrophy) Mutaz MYBPC3 Generalized lipodystroph y

29 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!)

30 Heterogeneity of PCOS: a constellation of different phenotypes (according to the concept of syndrome ) Classic hyperandrogenic (HA) phenotype [androgen excess, hirsutism, ovarian dysfuntion, PCOm, IR] (Overweight/obesity worsens the phenotype ) Most of the women with the OD- PCOm phenotype may have HA (> 4A/FT). The OD-PCOm non HA phenotype as a mild variant? Isolated hirsutism (a skin problem?) Severe insulin resistant states and the PCOS phenotype PCOS secondary to: other endocrinopaties drugs Secondary PCOS to obesity? Clinical implications: a phenotype-oriented treatment

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