1. PCOS’ TA METFORMIN KULLANIMI
16.
Ulusal Jinekoloji
ve Obstetrik Kongresi
PCOS’ TA METFORMIN KULLANIMI
Prof. Dr. Oya GÖKMEN
Mayıs 2018
Titanic Deluxe Hotel, Antalya

2. PCOS
- Polycystic Ovary Syndrome (PCOS) is one of the most common endocrinopathies.
- Affects 6% - 7% of reproductive age women.
Ref: Azziz R. et.al. : J Clin Endocrin . Metab 2004: 39

3. DIAGNOSIS OF PCOS ( Rotterdam’s Criteria )
Diagnosis of PCOS is made in the presence of at least two of the following three criteria, when congenital adrenal hyperplasia {CAH), androgen- screening tumors, or Cushing
syndrome have been excluded.
• Oligo - Ovulation or Anovulation
Clinical / biochemical evidence of hyperandrogenism
Polycystic ovarian on ultrasonography (>12 small antral follicle in an ovary)

4. Pathophysiology of PCOS
Obesity
Insulin
resistance
Polycystic
Ovarian Syndrome
Hyperinsulinemia
Ovary Thecal
Cell hyperplasia
Anovulation
Liver
↑ Insulin –like growth
Factor 1
Obesity
↓ sex hormone
Binding globulin
↓ Insulin-like
Growth factor 1
Binding protein
↑ Luteinizing hormone
Hyperandrogenemia

5. PCOS- Major Challenges in infertility management
- Hyperandrogenaemia
- Hyperinsulinemia
- Obesity
- Premature LH Surge

6. Why does PCOS lead to infertility?
Ovulation
Fertilization
Implantation
Fetal Viability
Poor Oocyte
Quality
Affects gestational
diabetes and
hypertension
Endometrial
receptivity
Hyperinsulinemia
Healthy Live born

7. THIRD LINE IVF FIRST LINE CLOMIPHENE CITRATE
ESHRE/ASRM-Sponsored PCOS Consensus Workshop
FIRST LINE CLOMIPHENE CITRATE
R E S I S T A N C E
SECOND LINE LOD / GONADOTROPINS
F A I L U R E
R E S I S T A N C E
THIRD LINE IVF
These INFERTILITY GUIDELINES FOLLOWED WORLD OVER
Group March 2007, Thessaloni ki, Greece. Human Re production 2008

8. Strategies to optimize fertility in PCOS women
- Weight loss
- Insulin Sensitizers
- Ovulation Induction
- Laparoscopic Ovarian
drilling
- Assisted Reproduction
Contd…..

9. Obesity
&
PCOS

10. Obesity & Infertility
- Follicular fluid insulin and androgen levels corelate
with BMI in obese infertile women even in absence of
PCOS. ↑ BMI →
↑ androgens
Premature follicular atresia
↓ follicular maturation
anovulation
Infertility
Contd…
Ref. Franks S, et.al. Hum Reprod Update 2008;14:367-78

11. Obesity & Infertility OBESITY ↑ Adipokines (leptin, TNF- ά, IL – 6)
→ antagonise effect of Insulin
→ Insulin Resistance
→ Negative effects on oocyte development, embryo
development, endometrial receptivity.
Contd…
Ref. Lisa J. Moran, et.al. Endocrinol Metab Clin N Am 40 (2011)

12. Hyperinsulinaemia & Hyperandrogenemia

13. Hyperinsulinemia
- Insulin Resistance (IR) is present in approx. 50% of women with PCOS.
- 90% of obese women with PCOS have IR
- IR exacerbates ovulation dysfunction.
Ref. William Hurd et.al. Fertil Steril, Vol96, Oct 2011

14. Insulin Sensitizers resistant PCOS is with insulin sensitizers.
- Mainstay of managing insulin
resistant PCOS is with insulin
sensitizers.
- Commonest drug used is
METFORMIN.
- Dose of 1500 –1700mg/day in
divided doses.
- Causes G.I. side effects

15. PPCOS trial (Pregnancy in PCOS Trial)
Study : 626 infertile women randomly assigned to
CC+Placebo
METFORMIN + placebo x 6 months
METFORMIN + Clomiphene
CONCLUSION
Clomiphene is superior to Metformin in achieving live birth in infertile women with PCOS though multiple birth is a complication
26.8%
22.5% 6%
7.2%
3.1% 0%
Ref : Lagro RS et al N. Engl J Med 2007 Feb

16. PPCOS trial (Pregnancy in PCOS Trial)
Ref : Lagro RS et al N. Engl J Med 2007 Feb

17. Insulin Sensitizers in PCOS
Conclusion :
- Metformin is an effective treatment for anovulation in women with PCOS
- Ovulation rates higher when combined with CC
- Reduces risk of OHSS by approximately 75%
- ↓ serum E2 levels
Contd…..
Ref : Lord J M, Flight HK et al. Cocherane syst Rev 2005:3

18. Ovulation Induction in PCOS- Best
Practices
Specific programs
For lifestyle
Modifications (at
least 6 months) in
Obese women
BMI
LOD
(in infertile PCOS pts when co-factors of sub fertility are suspected and/or diagnosed)
Clomiphene Citrate
METFORMIN
Gonadotropins
METFORMIN+CC
COS+TI / IUI
Gh + Gn Antagon + IUI
ARTs
METFORMIN+
Gonadotropins (?)
Palomba. Ovulation induction in PCOS. Fertil Steril 2006
PREGNANCY

19. WE SHOULD ALL AIM FOR OHSS FREE IVF PREGNANCY
INCIDENCE of OHSS
MILD – 33% Now Omitted in IVF Cycles
MODERATE – 3-6%
SEVERE – 2%
Critical – 0.1 – 0.2%
RISK FACTOR
WE SHOULD ALL AIM FOR OHSS FREE IVF PREGNANCY

20. METFORMIN AND OHSS
Two meta-analyses found that METFORMIN co­ administration in PCOS women undergoing IVF decreased the incidence of OHSS
The beneficial effect was observed in all RCTs regardless of duration and dosage of metformin
Number of oocytes collected and peak E2 levels were unaffected by METFORMIN
Costell o et al Hum. Rep. 21(6);
Moll et al Hum. Repro d . Upd ate 13(6);
Tsolo, Castello MF et al Meta analysis Metformin BJGO 2013

21. Diagnosis o f f It is Good to
It is Good to RULE OUT Diagnosis of following before start of IVF Treatment
It is Good to
Diagnosis o f f
BMI
Pre-Diabetes
Diabetes type II
Insulin Resistance
Metabolic Syndrome
Hypertension
Fatty Liver
Hyperlipidemia
Hypo-Thyroidism
Vitamin-D Deficiency
Ensure good general health of women to ensure safe pregnancy in case of success

22. Pre. IVF Considerations i
Pre. IVF Considerations in PCOS Patients
Pre. IVF Considerations i n
Weight Loss In Overweight Women
Structured weight loss
Place of Orlistat
Bariatric Surgery
METFORMIN
OCP Prior to IVF
Hysteroscopy & EB to R/0 TB

23. 60- 65 % of our patients are over weight or obese
OBESITY
% of our patients are over weight or obese
Over weight BMI > 24 Obese BMI > 27
Morbid Obesity is >32.5
Literature shows that patients of BMI > 29, they are likely to take longer to conceive. So it is good to lose weight by structured weight loss programme and not be allowed to do on t heir own
Bart. CJM, FAUSER Up TO Date 2017 March

24. Role of METFORMIN in IVF
ADVANTAGES
ESHRE and ASRM international workshops concluded that metformin should no longer be considered as a first - line medication in PCOS,anovulatory infertility and should be restricted to those women with demonstrable glucose intolerance.
Also use It in patients with BMI> 30
The use of METFORMIN to decrease Incidence of OHSS in
high responders
is known to be beneficial, so it should be started a month
or two prior to IVF
Robert L. Barbieri, David A Ehremann, Overview of PCOS Up TO Date 2017 March

25. DOES METFORMIN ALONE AS FIRST-LINE OVULATION INDUCTION THERAPY IMPROVE CLINICAL PREGNANCY AND LIVE-BIRTH RATES COMPARED WITH PLACEBO?
There is good evidence that METFORMIN alone vs placebo in­ creases the ovulation rate in women with PCOS. (Grade A)
There is insuffıcient evidence to suggest that METFORMIN alone increases pregnancy rates or live-birth rates compared with placebo . (Grade C)
PCOS guideline ASRM Fertility and Sterility Vol. 108, No:3 September 2017

26. DOES METFORMIN ALONE AS FIRST-LINE OVULATION INDUCTION THERAPY IMPROVE CLINICAL PREGNANCY AND LIVE-BIRTH RATES COMPARED WITH CC?
There is fair evidence from one large, well-designed RCT that METFORMIN alone is less effective than CC alone for the achievement of ovulation induction, clinical pregnancy, and live birth in women with PCOS. (Grade B)
PCOS guideline ASRM Fertility and Sterility Vol. 108 September 2017

27. DOES METFORMIN ALONE AS FIRST-LINE OVULATION INDUCTION THERAPY IMPROVE CLINICAL PREGNANCY AND LIVE-BIRTH RATES COMPARED WITH LETROZOLE ALONE?
There is insuffıcient evidence to suggest that METFORMIN alone increases pregnancy or live-birth rates compared with letrozole alone. (Grade C)
However, there is fair evidence based on one well-designed trial in support of letrozole for ovulation induction. (Grade B). Therefore, letrozole is a reasonable fırst-line agent for ovulation induction in PCOS patients.
PCOS guideline ASRM Fertility and Sterility Vol. 108 September 2017

28. WHEN USED IN COMBINATION WITH OTHER AGENTS AS FIRST-LINE THERAPY FOR OVULATION INDUCTION IN WOMEN WITH PCOS, DOES METFORMIN INCREASE PREGNANCY RATES AND LIVE-BIRTH RATES?
There is good evidence that METFORMIN in combination with CC improves ovulation and clinical pregnancy rates but does not improve live-birth rates compared with CC alone in women with PCOS. (Grade A)
There is fair evidence from one RCT that pre-treatment with METFORMIN for at least 3 months followed by the addition of another ovulation-inducing drug increases live-birth rate. (Grade B)
PCOS guideline ASRM Fertility and Sterility Vol. 108 September 2017

29. DOES THE COMBINATION OF METFORMIN AND CC OR OTHER OVULATION INDUCTION AGENTS IMPROVE OVULATION, CLINICAL PREGNANCY RATE, OR LIVE-BIRTH RATE IN THE SUBSET OF CC-RESISTANT PATIENTS WITH PCOS?
There is fair evidence that CC-METFORMIN improves ovula­tion and pregnancy rates compared with CC alone in CC­ resistant PCOS women. (Grade B).
However, more studies are needed to determine whether there may be subgroups of women (e.g., specifıc BMI, ethnicity, absence of insulin resistance, etc.) with PCOS and CC resistance for which CC-METFORMIN provides the most benefıt over CC alone.
PCOS guideline ASRM Fertility and Sterility Vol. 108 September 2017

30. Metformin versus Laparoscopic Ovarian Drilling (LOD)
There is fair evidence that overall pregnancy rates are not different with CC-METFORMIN, CC-LOD, or LOD alone in women with CC-resistant PCOS. (Grade B)
There is insuffıcient evidence regarding pregnancy rate or live-birth rate with the use of METFORMIN alone compared with LOD for ovulation induction in CC-resistant PCOS patients. (Grade C)
PCOS guideline ASRM Fertility and Sterility Vol. 108 September 2017

31. CC-Metformin versus Aromatase lnhibitors
• There is insuffıcient evidence to compare METFORMIN plus CC to aromatase inhibitors alone or METFORMIN plus aro­matase inhibitors for ovulation induction in CC-resistant women. (Grade C)
PCOS guideline ASRM Fertility and Sterility Vol. 108 September 2017

32. CC-Metformin versus Gonadotropins
There is insuffıcient or conflicting evidence regarding METFORMIN use combined with CC compared with gonado­tropins for ovulation induction in women with CC- resis­tant PCOS. (Grade C)
PCOS guideline ASRM Fertility and Sterility Vol. 108 September 2017

33. DOES PRE-PREGNANCY USE OF METFORMIN REDUCE THE RISK OF MISCARRIAGE IN NON-ASSISTED REPRODUCTIVE TECHNOLOGY (NON-ART) PREGNANCIES?
There is fair evidence that METFORMIN used while attempting pregnancy and stopped at the initiation of pregnancy does not affect the rate of miscarriage. (Grade B)
There is insufficient evidence to recommend METFORMIN during pregnancy to reduce the chance of miscarriage. (Grade C)
PCOS guideline ASRM Fertility and Sterility Vol. 108 September 2017

34. DOES METFORMIN AFFECT THE LIKELIHOOD OF MULTIPLE PREGNANCIES?
There is good evidence that METFORMIN alone does not increase the rate of multiple pregnancey. (Grade A )
Wlıile there is no evidence of an effect (either increase or decrease) on multiple pregnancy rates in cycles using com­ bination CC plus METFORMIN vs CC alone, there remains insuffıcient data on this matter due to lack of adequate power to detect a difference. (Grade C)
There is insufficient evidence of a reduced risk for multiple pregnancy with the addition of METFORMIN to FSH compared with FSH alone. (Grade C)
PCOS guideline ASRM Fertility and Sterility Vol. 108 September 2017

35. IS METFORMIN MORE EFFECTIVE IN LEAN OR OBESE PCOS PATIENTS?
There is insuffıcient good-quality evidence to determine if METFORMIN is more effective in non-obese or obese women with PCOS. (Grade C)
PCOS guideline ASRM Fertility and Sterility Vol. 108 September 2017

36. THANK YOU… TAKE HOME MESSAGES
PCOS guideline ASRM Fertility and Sterility Vol. 108 September 2017