Role of insulin sensitising drugs in management of PCOS

1. Dr ANTIMA RATHORE
FELLOW REPRODUCTIVE MEDICINE
INSTITUTE OF HUMAN
REPRODUCTION
1

2. Dermatologist
Disorder of
Hair Growth,
Acne
Fertility problem
Menstrual
dysfunctionGynecologist
Obesity problem
Risk of DM II
Risk of CVS
disorderInternist
General
practitioner
?
PREVALANCE:
5-10% IN 20-40 YR
FEMALES
2

3. Diagnosis Of PCOS
3

4. OTHER ETIOLOGIES
• Hypothyroidism
• Hyperprolactinemia
• Nonclassic Congenital Adrenal Hyperplasia
• Cushing’s syndrome
• Androgen-secreting Neoplasm
• Acromegaly
• Drugs-related (Androgens, Valproic Acid, Cyclosporine, etc)
4

5. Insulin Receptor
• Insulin receptor (IR)is a
transmembrane receptor encoded
by a single gene (INSR gene;
Chromosome 19), belonging to
the large class of tyrosine kinase
receptors
• It is activated by INSULIN,
Insulin Growth Factor 1 (IGF-I),
and Insulin Growth Factor 2
(IGF-II)
5

6. The main activity of the Insulin Receptors when
bound by an insulin molecule is, inducing glucose
uptake
6

7. Insulin Resistance (IR)
A decrease in insulin-dependent glucose transport at
the level of target tissues due to defects at both the insulin
receptor and/or postreceptor signaling
7

8. Some Historical Facts
1921
• Relation between Glucose intolerance &
hyperandrogenism by Archard and Thiers
• Bearded diabetic woman
1980
• PCOS & insulin resistance
8

9. Insulin Resistance (IR)
• 50-75 % 0f PCOS
• 1st diagnosed those diagnosed using NIH
• Obese > Lean
• More in young females
– Ample of pancreatic reserve
– Capable to generate a compensatory
hyperinsulinemia
9

10. Insulin Resistance (IR)
• Different from Obesity and DM Type II
• More in skeletal muscle
• Only obese PCOS – hepatic too
• Pancreatic beta cell dysfunction in those with risk of
Type II DM
• Severity of IR related to abdominal obesity even in
females with normal BMI
10

11. Insulin Resistance (IR)
• Upto 35% of PCOS women – Impaired Glucose Tolerance
• 7-10% - Type II DM
• Type II DM 6 fold more likely to have PCOS
• Not in all PCOS
• Rotterdam with normal cycle – metabolically normal
• May be modifying factor rather than causative
11

12. Insulin resistance and PCOS
12

13. Insulin resistance and PCOS
13

14. Insulin resistance (IR)
• IR has recently been associated with increased levels of
inflammatory mediators in the blood
• Now considered to be an inflammatory disorder
• Associated with an increased incidence of cardiovascular disease
and atherosclerosis
• Thus, a risk factor for miscarriages in PCOS
14

15. Pathophysiology of IR
• Two distinct pathways
phosphotidyl-inositol 3-kinase (PI-3K)pathway
– metabolic effects
Mitogen activated protien kinase (MAPK
pathway – proliferative actions
• Insulin binding to receptor – conformational changes – tyrosine
phosphorylation of receptor & protien substrate – which binds
and serially activate PI-3K and Akt
• Akt – translocation of glucose transporter 4 (GLUT 4) from
intracellular compartment to plasma membrane – increase
glucose uptake
15

16. 16

17. 17
PI-3K
pathway
MAPK
pathway

18. Pathophysiology of IR
• PSOC – selective increase in insulin activation of MAPK pathway And resistance in PI-3K pathway
• Defect early in the post-receptor signaling pathway
• Number and affinity of insulin receptors – not decreased
• Constitutive increase in phosphorylation of serine residues & decrease in insulin-stimulated
phosphorylation of tyrosine residues
• Serine phosphorylation of insulin receptor substrate prevents their binding to PI-3K and thereby
inhibits insulin signaling
• Serine phosphorylation can be induced by intracellular metabolites of free fatty acids
18

19. Pregnancy & hyperinsulinemia
• Premature granulosa cells luteinization
• Paracrine dysregulation of growth factor may disrupt
intrafollicular environment
• Alter granulosa cell – oocyte interaction and impair
cytoplasmic and/or nuclear maturation of oocyte
19

20. Diagnosis of IR
ASRM
• 75 gm OGTT
• 0 and 2 hr
• High risk
a. Hyperandrogenism with anovulation
b. Acanthosis Nigricans
c. Obesity – BMI >30kg/m2
Asian >25kg/m2
d. Family history of Type II DM & GDM
20

21. Management of IR
AIMS
• Improved Insulin Resistance
• Decrease Insulin Concentration
• Improve Hyperandrogenism, Metabolic
Alterations and Effects on fertility
21

22. Management of IR
• Lifestyle Modifications (1st choice –
ASRM; Level B)
• Insulin-Sensitising Agents
• by using antiandrogens
22

23. INSULIN SENSITISING AGENTS
• BIGUANIDES - METFORMIN
• THIOZOLIDINEDIONES – PIOGLITAZONE,
ROSIGLITAZONE
• INOSITOLS – MYOINOSITOL, D CHIRO INOSITOL
• N ACETYLCYSTIENE
23

24. METFORMIN
2007
European Society for Human Reproduction and Embryology
(ESHRE)
&
American Society for Reproductive Medicine
(ASRM)
Issued Guidelines In Thessaloniki
“The use of METFORMIN should be limited to patients with
impaired glucose tolerance and should be interrupted well
before the administration of clomiphene”
Thus restricting the use of metformin to a minority of patients with
PCOS
24

25. METFORMIN
• Biguanide
• Oral hypoglycemic
• Mechanism of action
- not entirely clear
- exerts its action post-insulin receptor
- Increase Glucose uptake by insulin sensitive cells
• Metformin does not induce hyperinsulinemia and
therefore does not cause hypoglycemia (i.e. has no action
on the pancreatic β-cells).
25

26. METFORMIN
ACTIONS
• Reduces Hepatic Gluconeogenesis
• Decrease intestinal absorption of glucose
• Improves Insulin Sensitivity - increase peripheral uptake and
use of glucose by the muscles and liver.
• Increases uterine vascularization and blood perfusion
• Reduces androgen & LH levels
• Causes weight loss in some patients
26

27. METFORMIN IN PCOS
Increase
•Ovulation
•Pregnancy rates
Reduce
• Fasting Insulin Levels
(more in non-obese)
• Serum Testosterone
Concentration (modest
effect)
No Effect
•Live birth rates (alone or with
CC)
•Rate of miscarriage
•Serum lipid profiles
•Incidence of twin pregnancy
Side Effects
• Gastrointestinal (most
common)
• Lactic Acidosis (rare, but
serious)
27
Cochrane Review 2012. Insulin-sensitising drugs (metformin, rosiglitazone, pioglitazone, D-chiro-inositol) for women
with polycystic ovary syndrome, oligo amenorrhoea and subfertility

28. Thiazolidinediones
Selective ligands of the nuclear transcription factor
Peroxisome Proliferator - Activated Receptor Υ (PPARΥ),
which is expressed most abundantly in adipose tissue, but
is also found in pancreatic beta cells, vascular endothelium
and macrophages
28

29. Thiazolidinediones
Two Mechanisms
Directly - ‘Fatty Acid Steal’ Hypothesis
Promote Fatty Acid Uptake And Storage In Adipose Tissue
↓
Increase Adipose-tissue Mass
↓
Spare Other Insulin Sensitive Tissues And Possibly
Pancreatic Beta Cells
(from the harmful metabolic effects of high concentrations
of free fatty acids)
29

30. Thiazolidinediones
Indirectly
• Increasing the expression of adiponectin
(an adipocytokine with an insulin sensitivity effect)
• Probably by decreasing action of enzymes involved in
androgen synthesis
• Enhances insulin action in the skeletal muscle, liver and
adipose tissue - decrease peripheral insulin resistance
30
Cochrane Review 2012. Insulin-sensitising drugs (metformin, rosiglitazone, pioglitazone, D-chiro-inositol) for women with
polycystic ovary syndrome, oligo amenorrhoea and subfertility

31. Thiazolidinediones
In PCOS
• Improve androgen levels
• Improves ovulation rate
• Enhances insulin sensitivity
• No weight reduction
31

32. Thiazolidinediones
• Troglitazone was the first drug of this class to be studied
• Withdrawn from the market in 2000 due to Hepatotoxicity
• Only few recent studies are available using Rosiglitazone
and Pioglitazone.
32

33. Rosiglitazone
• Improve insulin sensitivity
• Improve the ovulation rate
• Decrease androgen levels
• Improve menstrual pattern
• Increases BMI
33
Cochrane Review 2012. Insulin-sensitising drugs (metformin, rosiglitazone, pioglitazone, D-chiro-inositol) for women
with polycystic ovary syndrome, oligo amenorrhoea and subfertility

34. Pioglitazone
• Improved the menstrual pattern
• No effects
a. anthropometric outcomes
b. endocrine outcomes (testosterone,
c. SHBG or metabolic outcomes (fasting insulin)
Cochrane Review 2012. Insulin-sensitising drugs (metformin, rosiglitazone, pioglitazone, D-chiro-inositol) for
women with polycystic ovary syndrome, oligo amenorrhoea and subfertility
• FDA category C
• Bladder cancer (recent FDA advisory)
34

35. Inositols
• INOSITOLS - family of nine stereoisomers that belong to
the polyols family
• Vitamine B complex Family (Vit.B8)
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36. Inositols
• Most relevent – Myoinositol (MYO) & D-Chiro Inositol (DCI)
• Both inositols are incorporated intracellularly into inositolphosphoglycans
(IPGs) – second messanger for insulin
• MYO being 99% of inositol
• Its reduction is important in pathogenesis of PCOS
• MYO & DCI – key role in controlling glucose homeostasis
• MYO →DCI by Epimerase
• Epimerase activated by insulin
36

37. Inositols
• MYO –IPGs mediate glucose uptake at cellular level
• DCI-IPGs mediate glycogen synthesis
• Cells with high glucose consumption has high MYO-IPGs
(brain, heart)
• DCI – mainly in glucose storage cells (liver, muscle & fat)
37

38. Inositols
• Myoinositol found naturally in many foods items - fruits, nuts and beans
• Serum concentrations - high during fetal life
- later on falls
(periconceptional periods
polycystic ovarian syndrome)
• An important constituent of the follicular microenvironment
• Play a key role in the nuclear and cytoplasmic oocyte’s development
• Higher concentrations of myoinositol in human follicular fluid provide a
marker of good-quality oocytes
• Unfer et al. Effects of Inositol(s) in Women with PCOS: A Systematic Review of
Randomized Controlled Trials. International Journal of Endocrinology 2016.
38

39. Inositols
• Observation – DCI-IPGs concentration in muscle cells &
DCI in urine of T2DM pt are lower than normal, but DCI is
increased in follicular fluid of insulin-resistant patient
• IR doesn’t effect all the cells of the body
• Infact Ovary never become insulin resistance
39

40. Inositols
Insulin resistance derived hyperinsulinemia
↓
Increase in epimerase conversion activity
↓
Increase DCI concentration into the ovary
↓
Drastic decrease in MYO concentration intracellularly
↓
Altered ovarian function
40

41. MYO:DCI
• Normal woman 100:1
• PCOS 0.2:1
• Physiological 40:1
• Combination – More physiological
Faster normalisation of insulin and glucose
response to OGTT
• Reduce cardiovascular risk of overweight insulin resistance
PCOS pt – by improving lipid profile
41

42. Inositols
• MYO to women undergoing IVF – reduce amount of rFSH
used, improving oocyte and embryo quality as well as
implantation rate
Simi et al. Inositol and In Vitro Fertilization with Embryo Transfer.
International Journal of Endocrinology. 2017
• MYO supplementation to PCOS women – restore
Spontaneous ovulation and menstrual cycles
Increase progesterone level in luteal phase
Decrease total and free testosterone
42

43. Inositols
• DCI administration is associated with improvement in IR after 8
weeks of treatment
• Recovering ovulatory function
• Reducing androgen levels & plasma TG level
• Increase SHBG level
• However, Recent Studies Outlined That Use Of DCI Seems To
Be Detrimental To The Quality Of Oocytes And Ovarian
Response To FSH Stimulation, In Non Obese Non PCOS
Women
43

44. D-chiro-inositol
• Did not improve ovulation rate the inadequate number of
studies
• Did not have any effects on BMI, waist-hip ratio or blood
pressure.
• Did not have any effects on- testosterone
SHBG
fasting glucose
fasting insulin
lipids profile
44

45. ASRM/ESHRE
Metformin in anovulatory PCOS
• No benefit in fertility or live birth rates
• Use not recommended (level A)
• No effect on miscarriage risk when given before pregnancy
• No effect on decreasing pregnancy complication or fetal wieght
45
Consensus aspects of on women,s health aspects of PCOS: the Amsterdam ESHRE/ASRM - sponsored 3rd PCOS
consensus workshop group 2012

46. RCOG
2008
Metformin alone / with CC – no benefit in
ovulation induction in PCOS
Metformin therapy for the management of infertility in women with Polycstic Ovary
Syndrome. Scientific paper no. 13. 2008
46

47. COCHRANE 2012
• Insulin-sensitising drugs - metformin, rosiglitazone,
pioglitazone and D-chiro-inositol
• Either alone or in combination with drugs to induce
ovulation (for example clomiphene citrate)
• Does not increase the chance of having a live birth
• Cochrane Review 2012. Insulin-sensitising drugs (metformin, rosiglitazone,
pioglitazone, D-chiro-inositol) for women with polycystic ovary syndrome, oligo
amenorrhoea and subfertility
47

48. COCHRANE 2014
• Metformin before or dering IVF
• Increase Clinical Pregnancy Rate and decrease OHSS
• Doesn’t increase Live Birth Rate
48

49. Clinical practice guidelines
endocrine society
2013
Recommendation
• Metformin - For PCOS Plus T2DM And IGT - who fail life
style modification
• 2nd line for Menstual Irregularity for those who can’t
tolerate Hormonal Contraceptives
• Adjuvant for prevention of OHSS in females with PCOS
undergoing IVF
49

50. Clinical practice guidelines
endocrine society
2013
• Against the use of metformin
1st line treatment of –
Cutaneous manifestion
Prevention of pregnancy complication
Treatment of obesity
Hirsutism
• Against insulin sensitizers
Inositols – due to lack of benefits
Thiozolidinedione – safety concern
50

51. INDIAN PCOS SOCIETY
2015
• Metformin is not recommended as first-line therapy for the management of
menstrual irregularity (Grade A, EL 4)
• Due to limited evidence on use of metformin in adolescents without
established glucose intolerance- recommends against its use in adolescents
with PCOS
• Lifestyle modification is better than metformin in improving
hyperandrogenism, obesity and signs of IR
• Therefore, recommends lifestyle modification as first-line therapy followed by
metformin in adolescents and children
• Metformin should be initiated in children only after a wait-period of two years
post-menarche
• PCOS Guideline 2015. Management of Polycystic Ovary Syndrome in India.
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52. INDIAN PCOS SOCIETY
2015
• In women with PCOS, it is recommended not to use
metformin therapy only during pregnancy until specific
evidence on beneficial effects is demonstrated (Grade B,
EL 3)
• Due to insufficient evidence, alternative (acupuncture)
and complementary therapeutic options (e.g. myoinositol,
omega-3 fatty acids) are not recommended for the
management of hyperandrogenism (Grade B, EL 4)
• PCOS Guideline 2015. Management of Polycystic Ovary Syndrome in India.
52

53. N ACETYL CYSTEINE
• Acetylated variant of amino acid L-Cystiene
• Commonly used safe mucolytic drug
• Increases the cellular levels of antioxidant and reduces
glutathione at higher doses.
• Convert proinsulin to insulin
• Therefore, NAC has a potential to improve insulin receptor
activity in human erythrocytes and improve insulin secretion
in response to glucose
• Thakker et al. N-Acetylcysteine for Polycystic Ovary Syndrome: A Systematic Review and Meta-Analysis of Randomized
Controlled Clinical Trials. Obstetrics and Gynecology International. 2015
53

54. N ACETYL CYSTEINE
• Significant improvement in pregnancy and ovulation rate
in the studies with short-term outcomes compared to
placebo
• Limitations of existing studies such as poor quality, less
studies assessing live-birth rates
• Well-designed randomized-controlled trials should
conducted
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55. THANK
YOU
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