Insulin sensitizers in PCOS syndrome

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1 Insulin sensitizers in PCOS syndrome Chiara Riviello,MD Specialista in Ginecologia e Ostetricia Specialista in Medicina Legale Medico Agopuntore dottoressa@chiarariviello.it Milan, 2015/10/16

2 Who are we talking about?

3 1.

4 2.

5 3. Regular period

6 Definition: the conciliating RotterdAMH classification Dewailly et al., Human Reprod 2011

7 Other signs or symptoms Acanthosis Nigricans

8 Other signs or symptoms Insulin resistance Central Obesity: AC >80 cm

9 Other signs or symptoms Alopecia

10 Other signs or symptoms Acne

14 INSULIN TECA GRANULOSA Insulin + LH increase of Androgen Follicular atresia

15 PCOS TREATMENT Lifestyle Medication

16 Exercise

17 PCOS and Nutrition J Pediatr Adolesc Gynecol Jan 7. Effect of Dietary Weight Loss on Menstrual Regularity in Obese Young Adult Women with Polycystic Ovary Syndrome. Marzouk TM, Sayed Ahmed WA INTERVENTIONS: Women in the intervention group (n = 30) were subject to an intensive dietary educational program with instructions to follow a conventional energy restricted diet, whereas women in the control group were instructed to follow the same healthy diet of the first group without calorie restriction. Dietary weight loss in adolescent women with PCOS resulted in significant improvement in menstrual regularity, BMI, waist circumference, and hirsutism score.

18 PCOS and Nutrition

19 PCOS and Medication Want a baby Ovulation induction:clomiphene citrate Insulin sensitizer as single agent Insulin sensitizer + clomiphene Gonadotropin therapy, FSH Gonadotropins + insulin Don t want a baby OC Antiandrogen metformin

INOSITOL Considered a member of the vitamin B complex, is present in many animal tissues, with the highest levels in heart and brain Sourses: nuts, seeds,

22 INOSITOL Considered a member of the vitamin B complex, is present in many animal tissues, with the highest levels in heart and brain Sourses: nuts, seeds, beans, whole grains, cantaloupe, and citrus fruits Involved in the enzymatic chain of the glucose metabolism Cellular functions of the nervous system metabolism

Inositol and the transmission of the insulin signal Inositol acts as an intracellular insulin mediator as inositolofosfoglicani (ipgs) 1 The main inositol stereoisomers are myo-inositol (MYO) and

23 Inositol and the transmission of the insulin signal Inositol acts as an intracellular insulin mediator as inositolofosfoglicani (ipgs) 1 The main inositol stereoisomers are myo-inositol (MYO) and d-chiro-inositol (DCI) 1 In plasma, the phisiological concentration of MYO and DCI has ratio 40:1 2 1 Isabella R. e Raffone E. : Does ovary need d-chiro-inositol? - Journal of Ovarian Research Nordio M. e Proietti E.: The combined therapy with myo-inositol and D-Chiro-inositol reduces the risk of metabolic disease in PCOS overweight patients compared to myo-inositol supplementation alone -Eur Rev Med Pharmacol Sci 2012; 16:

Myo/D-Chiro-Inositol Ratio 6 1 2 5 4 3 activity + epimerase - activity 6 1 2 5 4 3 Myo-inositolo D-chiro-inositolo IN TISSUE, EPIMERASE BALANCES THE RATIO BETWEEN MYO AND D-CHIRO1 INSULIN RESISTENCE

24 Myo/D-Chiro-Inositol Ratio activity + epimerase - activity Myo-inositolo D-chiro-inositolo IN TISSUE, EPIMERASE BALANCES THE RATIO BETWEEN MYO AND D-CHIRO1 INSULIN RESISTENCE MODIFIES EPIMERASE ACTIVITY IN A DIFFEREN WAY IN DIFFERENT TISSUE 2 2 Nordio M. e Proietti E.: The combined therapy with myo-inositol and D-Chiro-inositol reduces the risk of metabolic disease in PCOS overweight patients compared to myo-inositol supplementation alone -Eur Rev Med Pharmacol Sci 2012; 16:

Physiological actions of Myo and D-Chiro-inositol Myo-inositolo Cellular glucose uptake 1 Oocyte quality and maturity 1 D-chiro-inositolo Glucose to glycogen conversion (intracellular storage) 1 No

25 Physiological actions of Myo and D-Chiro-inositol Myo-inositolo Cellular glucose uptake 1 Oocyte quality and maturity 1 D-chiro-inositolo Glucose to glycogen conversion (intracellular storage) 1 No activity on ovarian function 2 PRINCIPAL ACTION AT OVARIAN LEVEL PRINCIPAL ACTION IN STORAGE TISSUE 1 Isabella R. e Raffone E. : Does ovary need d-chiro-inositol? - Journal of Ovarian Research Carlomagno G. et al.: The D-chiro-inositol paradox in the ovary - Fertil Steril 2011; 95:

26 Myo/D-Chiro inositol ratio in pathological conditions (PCOS and insulin-resistence) MYO DCI OH epimerase OH OVARY Reduction cellular glucose uptake 2 Reduction oocyte quality and maturity 2 + No action on ovarian function 3 LIVER AND GLYCOGEN STORAGE TISSUE Increase of cellular glucose uptake 2 - Reduction in glucose to glycogen conversion 2 1 Adattato da Larner J et al.: D-chiro-Inositol-Its functional role in insulin action and its deficit in insulin resistence Int Jnl Experimental Diab Res Isabella R. e Raffone E. : Does ovary need d-chiro-inositol? - Journal of Ovarian Research Carlomagno G. et al.: The D-chiro-inositol paradox in the ovary - Fertil Steril 2011; 95:

27 Aim of specific supplementation in overweight PCOS patients MYO DCI OH OH OVARY LIVER AND GLYCOGEN STORAGE TISSUE Restore cellular glucose uptake Improve oocyte quality and maturity + Restore glucose to glycogen storage, avoiding the worsening of the hyper-insulinemic condition

28 Chiu T.Y et al.: Follicular Fluid and serum concentrations of myo-inositol in patients undergoing IVF: relationship with oocyte quality Human Reproduction 2002; 17 (6): OVARY Myo-inositol and Oocytes Quality Design of the clinical trial : prospective, observational 53 patients (IVF): follicular fluid samples end serum group A group B follicular fluid with mature and fertilized oocytes follicular fluid with immature and not fertilized oocytes Myo-inositol concentration in follicular fluid and serum 7 Mean Myo-inositol concentration in the Follicular Fluid was significantly higher in the group with mature and fertilized oocytes 7

29 Myo-inositol and Oocytes Quality Relationship between estradiol and myo-inositol in follicular fluid Relationship between stages of embryo development and myo-inositol levels in follicular fluid High Myo-inositol levels in human follicular fluid affect follicular maturity and represent a marker of the good oocyte quality Chiu T.Y et al.: Follicular Fluid and serum concentrations of myo-inositol in patients undergoing IVF: relationship with oocyte quality Human Reproduction 2002; 17 (6):

30 OVARY D-chiro-inositol and Oocytes Quality Randomised, controlled trial versus placebo -54 euglycemic PCOS patients, enrolled for ICSI -pretreated for 8 monthes before r-fsh administration divided into 5 treatment groups at increased doses of D-Chiro-inositol (DCI) and placebo PLACEBO A (DCI 300 mg) B (DCI 600mg) C (DCI 1200mg) D (DCI 2400mg) No. Oocytes IU rfsh administered * ** 17β-E2 (pg/ml) levels at hcg * administration Stimulation Days * ** ** N of cancelled cycles *, P < 0.05 vs placebo, **, P < 0.01 vs placebo Isabella R. e Raffone E. : Does ovary need d-chiro-inositol? - Journal of Ovarian Research 2012

OVARY D-chiro-inositol and Oocytes Quality DCI effects (300,600,2400 mg) on immature oocytes number, on 1

Di ovociti immaturi Embrioni di grado I N.

vs placebo ( n=10-11 per gruppo) * P< 0,01 vs placebo,**p<0,001 vs placebo ( n=10-11 per gruppo)

31 OVARY D-chiro-inositol and Oocytes Quality DCI effects (300,600,2400 mg) on immature oocytes number, on 1 degree embryos number, on Metafase II (MII) oocytes number. Data are indicated as mean ± SD No. Di ovociti immaturi Embrioni di grado I N. Ovociti in MII * P< 0,05 vs placebo,**p<0,001 VS placebo ( n=10-11 per gruppo) * P< 0,01 vs placebo,**p<0,001 vs placebo ( n=10-11 per gruppo) * P< 0,01 vs placebo,**p<0,001 vs placebo ( n=10-11 per gruppo) D-CHIRO-INOSITOL ADMINISTRATION REDUCES OOCYTES QUALITY, AS WELL AS OVARIAN RESPONSE, DECLINES AT INCREASED DCI LEVELS Isabella R. e Raffone E. : Does ovary need d-chiro-inositol? - Journal of Ovarian Research 2012

STORAGE TISSUE (LIVER) D-chiro-inositol and Insulin-Resistence Control D-Chiro inositol ORAL ADMINISTRATION OF D-CHIRO-INOSITOLO IMPROVES THE GLYCEMIC CONTROL IN

32 STORAGE TISSUE (LIVER) D-chiro-inositol and Insulin-Resistence Control D-Chiro inositol ORAL ADMINISTRATION OF D-CHIRO-INOSITOLO IMPROVES THE GLYCEMIC CONTROL IN INSULIN-RESISTENT PRIMATES Ortmeyer HK et al.: Effects of D-chiro-inositol added to a meal on plasma glucose and insulin in hyperinsulinemic rhesus monkeys Obes Res 1995: S4:605S-608S.

33 STORAGE TUSSUE (LIVER) D-chiro-inositol and e Insulin-Resistence D-CHIRO-INOSITOL ADMINISTRATION IN HYPERINSULINEMIC AND OBESE PCOS WOMEN, REDUCED INSULINIC ANSWER TO ORAL ADMINISTERED GLUCOSE, PROBABLY BECAUSE OF AN IMPROVEMENT OF PERIPHERAL INSULINEMIA Nestler J.E. et al. : Ovulatory and Metabolic effects of D-Chiro-inositol in the Polycystic Ovary Syndrome - The New England

34 THE RIGHT COMBINATION OF MYO AND D-CHIRO INOSITOL FOR OVERWEIGHT PCOS WOMEN We can get two combined goals 1 : - Improve ovarian function (MYO) - Reduce peripheric hyper-insulinemia (DCI) We can give the right supplementation of the two stereoisomers in the correct physiological ratio 40:1 MYO/DCI di 1 1 Nor dio M. e Proietti E.: The combined therapy with myo-inositol and D-Chiro-inositol reduces the risk of metabolic disease in PCOS overweight patients compared to myo-inositol supplementation alone -Eur Rev Med Pharmacol Sci 2012; 2 16: Carlomagno G. et al: Myo-inositol in a new pharmaceutical form: a step forward to a broader clinical use -Expert Opin Drug Deliv 2012; 9:

MYO AND D-CHIRO-INOSITOLO COMBINED IN THE PHYSIOLOGICAL RATIO (40:1) SYNERGIC ACTION MYO + D-CHIRO RANDOMIZED CLINICAL TRIAL RESULTS: 50 overweight PCOS women (BMI>27) 2 g myo-inositol POWDER Twice

35 MYO AND D-CHIRO-INOSITOLO COMBINED IN THE PHYSIOLOGICAL RATIO (40:1) SYNERGIC ACTION MYO + D-CHIRO RANDOMIZED CLINICAL TRIAL RESULTS: 50 overweight PCOS women (BMI>27) 2 g myo-inositol POWDER Twice daily for 6 months 550 mg myo-inositol + 13,8 mg D-chiro-inositol SOFT GEL CAPSULES METABOLIC AND HORMONAL PARAMETERS EVALUATION: T0, 3 months (T1), 6 months (T2) Nor dio M. e Proietti E.: The combined therapy with myo-inositol and D-Chiro-inositol reduces the risk of metabolic disease in PCOS overweight patients compared to myo-inositol supplementation alone -Eur Rev Med Pharmacol Sci 2012; 16:575-

36 CONCLUSIONS The positive effect of MYO and DCI on ovarian function and on storage tissue respectively has been well documented A supplementation of MYO and DCI in the physiological ratio can be considered as a new way to treat PCO disorders

37 Thank you!!

Inositols for PCOS : An Update. Mark H. Ratner, MD Shady Grove Reproductive Science Center Rockville, Maryland

Inositols for PCOS : An Update Mark H. Ratner, MD Shady Grove Reproductive Science Center Rockville, Maryland Overview Understanding the role of insulin in PCOS The relationship between inositols and insulin