Role of inositol in Reproductive Function

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1 Role of inositol in Reproductive Function Dr. Mirudhubashini Govindarajan, FRCSC Clinical Director Womens Center Coimbatore HYPE OR HOPE????

2 Inositol an Introduction Inositol has 10 types of isomers Myo inositol Muco inositol D Chiro inositol L Chiro inositol D Chiro Inositol and Scyllo inosit Myo Inositol are known to have proven effects in PCOS by facilitating Insulin s ol action Neo inosit ol Allo inosit ol Epi inosit ol Cis inosit? inactive molecule ol Current Evidence - significant

Myoinositol - the most common isomer (90%) D-chiro inositol (10%) Myoinositol converted

3 INOSITOLS Some basic facts Sugar alcohols belonging to Vitamin B family Highest concentration of Myo-Inositol in fruits, beans, corns, and nuts. Myoinositol - the most common isomer (90%) D-chiro inositol (10%) Myoinositol converted to DCI in some cells by epimerase Varying MI / DCI ratio in different tissues International Journal of Endocrinology,Vol 2016

4 Inositol - Functions Glucose metabolism Insulin signal transduction Fat metabolism Breakdown of fats and reducing blood cholesterol Intracellular functions calcium (Ca 2+ ) concentration control

5 Myoinositol Myoinositol plays an important role as the structural basis for a number of secondary messengers in Human Cell.

6 Role of Inositol Glucose metabolism Secondary Messenger International Journal of Endocrinology,Vol 2016

7 MI/DCI role in glucose uptake

8 Inositols Secondary Messenger to INSULIN, FSH and TSH

9 INOSITOLS Cell level functions Inositols are secondary messengers for cell signaling pathways such as Insulin Signal transduction Calcium trafficking Lipid metabolism Cytoskeletal protein assembly Cell growth and differentiation Oocyte maturation

10 MI/DCI physiological role Pivotal role as secondary messengers of insulin Tissue specific intra cellular levels and functions DCI MI High levels in liver, muscle and fat cells Mediates glycogen synthesis Aids in glycogen storage High in heart/brain cells which require increased glucose consumption Mediates glucose uptake at cell level Crucial in ovarian function

11 D-Chiroinositol Myoinositol

12 Myoinositol Positive effect on reproductive axis Secondary messenger for FSH Facilitates ovarian function Improves oocyte quality Improves metabolic parameters Govindrajan C et al. World Journal of Pharmacy and Pharmaceutical Sciences.2015;4(6):

13 Unfer V et al. Gynecol Endocrinol. Chiu 2012Jul;28(7): TT et al. Hum Reprod Jun;17(6): Myoinositol

14 MI Oocyte quality Increases calcium levels intracellular fluid Better quality oocyte

16 MI - oocyte quality Specific role in follicular maturation Enhances intracellular ca oscillation Facilitates meiotic division Progress of germinal vesicle to mature oocyte MI deficiency leads to poor oocyte quality MI replacement improves ovulation Eur Rev med Pharmacol Sci. 2007; 11:

17 MI deficiency Chiu TT et al. Hum Reprod Jun;17(6): Heimark D et al. Endocr J. 2014;61(2):111 7

18 D Chiroinositol crucial secondary messenger in insulin signal transduction as InositolPhosphoGlycans (DCI IPG) leading to control of insulin resistance DC I

19 DCI deficiency DeFronzo RA. Diabetes Care Mar;14(3): Karrer Voegeli S et al. Medicine (Baltimore) Jan;88(1):32 45

20 Larner J et al. Mol Med Nov Dec;16(11 12): Epimerase enzyme Epimerase is an insulin dependent enzyme Converts Myoinositol into D Chiro Inositol EPIMERA SE

21 Ovarian Paradox Epimerase is an insulin dependent enzyme Why is epimerase activity different in metabolic and reproductive organs? Skeletal muscles, liver and adipose tissue Become insulin resistant Reduced activity of Epimerase Reduced conversion of MI to DCI leading to DCI deficiency Ovary Does not become insulin resistant Increased activity of Epimerase Increased conversion of MI to DCI leading to MI deficiency

22 Inositols and PCOS

23 PCOS- Pathophysiology Insulin Resistance ( IR ) and compensatory hyperinsulinemia Hyperandrogenism / Excess androgen Inositol deficiency 23

25 Increased Insulin levels Ovary Adrenal Endometrium Liver Adipose tissue/muscle

26 Hyperinsulinemia Hyperinsulinemia Stimulation of theca cells Hepatic effect Increased production of androgens Decreased SHBG Hyperandrogenemia

28 Hyper insulinemia Ovarian effect IGF receptor activation Increased LH Stromal cells Leutinisation of theca cells Ovarian androgen Disruption of follicular maturation

29 Hyper insulinemia Adrenal effects Serine Phosphorilation Androgens DHS DAHS

30 Effects on Liver SHBG IGFBP Free testosterone Free estradiol

31 Role of androgens PCOS - Follicular recruitment Excessive recruitment of early antral follicles

32 Human Reproduction,

33 Morphology of polycystic ovary

34 Morphology of polycystic ovary

35 MI/DCI at ovarian level DCI paradox Insulin dependent epimerase activity Increased conversion of MI -> DCI IN PCOS MI decreases, DCI Increases MI involved in FSH signaling DCI responsible for insulin mediated testosterone over production Poor oocyte quality PCOS - ionisitols and changing Ovarian functions

36 MI:DCI in ovary Follicular fluid

37 PCOS DCI Paradox Dysovulation Hyperinsulinemia - M1/DCI imbalance Dysregulation of intra ovarian androgen metabolism Local hyper androgenism androgens promote excess follicle recruitment Excess antral follicles increase AMH levels AMH inhibits FSH induced aromatase activity Anovulation

38 MI vital for fertility High concentration of MYO-INOSITOL in the follicular fluid is a marker of good quality oocyte Human Reproduction vol 17 : 2002

39 Gynecological Endocrinology, 2012; 28(7):

40 MI role in oocyte maturation MI normalizes the LH/FSH ratio Triggers calcium ion oscillation in endoplasmic reticulum Helps in oocyte maturation.

41 MI role in Male Fertility Spermatogenesis Capacitation Chemotaxis Acrosomal Reaction Calcium ion oscillation Depends on Myoinositol

42 MI vital for fertility The concentration of MYOINOSITOL in the Seminiferous tubules fluid is higher than the levels found in the seminal plasma European Review for Medical and Pharmacological Sciences 2011.

43 Capacitation Mature spermatozoa - held immotile within the epididymis. Spermatozoa are motile after ejaculation, but unable to fertilize an oocyte. Spermatozoa gain fertilization ability only after shedding glycoprotein in the female reproductive tract with Ca 2+ ion oscillation. BioMed Research International, 2014

44 Chemotaxis Travel guide With calcium ion oscillation, sperm is directed towards ovum by chemo attractant.

45 Acrosomal reaction

46 R Myo & Ca2+ +

48 MI role in fertilization

50 120 Insulin Gynecological Endocrinology 2007, Vol. 23, No. 12, Pages

51 Androgen SHBG Gynecological Endocrinology 2007, Vol. 23, No. 12, Pages

52 Gynecological Endocrinology, 2012; 28(7):

53 Metformin Vs MI / DCI Metformin Has been first line of treatment for insulin resistance in PCOS Normalizes I.R at Systemic level Non I.R. PCOS use of metformin debatable Improves I.R in only 50% of PCOS

54 M I / DCI MI - Safer at ovarian and non-ovarian level DCI - Beneficial effect mainly limited to nonovarian tissue MI / DCI safer than metformin; less side effects; effective in PCOS with or without IR

56 Thank you

57 Hyper insulinemia & macro vessels Endothelial dysfunction Impaired vasodilatation Increased macro vascular disease Circ: 2001 March, University of Indiana

58 Long term Cardiovascular effects Direct atherogenic action of insulin Direct relationship between insulin level& BP Adverse lipoprotein changes Impaired fibrinolysis Increased PAI - I

59 Long term Cardiovascular effects Increased risk of MI Age fold increase Age fold increase

60 PCOS-Diabetes Mellitus Increased risk of NIDDM 15% in post menopausal PCOS 5% in control population Increased diabetes in pregnancy Abnormal GTT 32% Gestational Diabetes 13% Dahlgren et al 1992 Urman et al 1997

61 Hyper insulinemia Obesity Android obesity(central body fat) Abdominal wall and mesenteric location Waist - hip ratio >0.85 Waist circumference >100 cm in men > 90 cm in women

62 Anovulation of PCOS : generated by androgen excess

63 Insulin resistance / hyperandrogenemia PCOS systemic manifestations hyperinsulinemia directly stimulates Testosterone production by ovarian thecal cells Promotes hyperandrogenic states Leading to Hirsutism Acne Alopecia Higher waist to hip ratio Detrimental effects on follicular growth (anovulation) Menstrual disturbances Diamanti Kandarakis E et al. Endocr Rev Dec;33(6):

64 Hyperandrogenemia PCOS - Long term sequelae

65 Hyper insulinemia Adipose tissue/muscle effects Trigycerides Cholesterol LDH HDL

Myoinositol Pharmacology and Mode of action. Dr.Nalini Mahajan Director Mother & Child Hospital.Delhi President FPSI

Myoinositol Pharmacology and Mode of action Dr.Nalini Mahajan Director Mother & Child Hospital.Delhi President FPSI Inositol Inositol is a 6-carbon ring compound with a hydroxyl group attached to each