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Insulin Resistance & Rush Hour


PCOS Pregnancy Complications

§ Spontaneous Abortions• Increased in high BMI/PCOS patients

Wang et al. Hum Reprod 16:2606; 2001

§ Impaired Glucose ToleranceTurhan et al. Int J Gynaecol Obstet 81:163; 2003

§ Gestational DiabetesMikola et al. Hum Reprod 16:1537; 2001

Bjercke et al. Gynecol Obstet Invest 54:94; 2002

§ HypertensionWeerakiet et al. Gynecol Endocrinol 19:134; 2004

§ Small for Gestational AgeSir-Petermann et al., Hum Repro 20:2122; 2005


Effects of Obesity in Reproductive Development

Stage of Development

Proposedmechanism

Possibleeffects on reproduction

Evidence References

Oocyte AbnormalGnRHpulsatility, follicular development

Poor oocyte quality, impaired ovulation

Human IVF specimens, serum samples

Jain A, et al. 2007Robker RL, et al. 2009

Preimplanta-tion Embryo

Impaired embryonic metabolism

Impairedimplantation, miscarriage

Human IVF specimens

Metwally M, et al. 2007Carrell DT, et al. 2001

Implantation Abnormal endometrium

Impairedimplantation, miscarriage

Human endometrialbiopsies

Mozzanega B, et al. 2004


Obesity & Pregnancy Complications Adjusted odds ratios (OR)

Overweight Obese SevereObesity

GestationalDM

3.5 7.7 11.0

Preeclampsia 1.9 3.0 4.4Macrosomia 1.6 2.2 2.7Low Apgars 1.3 1.4 1.9Stillborn 1.4 1.6 1.9

Per Ovesen, et al. Obstet Gynecol, 2011


PCOS: Multi-Factorial Treatment Approach

§ Eating plan & supplements§ Physical activity§ Sleep hygiene§ Stress management§ Insulin-sensitizing medications

• Metformin• GLP-1 receptor agonists• Myoinositol:DCI

Grassi A. PCOS:The Dietitian’s Guide to PCOS. Luca Publishing, Haverford, PA 2013.

Cheang KI, Huszar JM, Best AM, Sharma S, Essah PA, Nestler JE. Long-term effect of metformin on metabolic parameters in the polycystic ovary syndrome. Diab Vasc Dis Res. 2009 Apr;6(2):110-9.

Elkind-Hirsch K, Marrioneaux O, Bhushan M, Vernor D, Bhushan R. Comparison of single and combined treatment with exenatide and metformin on menstrual cyclicity in overweight women with polycystic ovary syndrome. J Clin EndocrinolMetab. 2008 Jul;93(7):2670-8.

Copyright ® 2014 PCOS Nutrition Center


PCOS Exercise

§ Sugar intake 10x over past 100 years• As glycogen storage ↑ muscles become more insulin resistant, insulin

levels rise• Insulin = storage

§ Once glycogen storage maxed, FFA stored as TG

§ Peripheral muscle cells metabolize 80% of glucose• Stored as glycogen

§ High Intensity Interval Training• Utilized during endurance cardio > 60 – 70% target rate & resistance

training over 70% of weight maxLittle JP et al: Appl Physiol EPUB, 2011

§ Aerobic exercise• 3-4x/wk 20-30 min/session• Burns 100-200 kcal• 40% improvement in insulin sensitivity lasting 48 hrs.

DeFronzo RA, et al: Diabets 36:1379, 1987; Segal KR, et al: J Appl Physiol 71:2502, 1991


Burning Calories§ Muscle tissue is active tissue that burns

calories and fat is inactive tissue that stores calories.• 75 calories/day lb of muscle tissue.• 3 calories a day per lb of fat

§ Those trying to burn calories and lose body fat should increase muscle mass.


Strength Training Program

§ 2-3 sets at 75% of max. weight load§ Muscle failure ~ 50 seconds or 8-10

reps§ 2 min break between sets § 7 day rest after working each area§ Exercise large muscle groups first§ Add 5 lbs if reps > 15§ Moderate to slow speed

• A longer period of muscle tension• A higher level of muscle force• A lower level of momentum• A lower risk of tissue injury


PCOS Weight Loss

§ Frequency of obesity in women with anovulation and PCO: 30%-75%

Ehrmann. NEJM 325:1223; 2005

§ Six month weight-loss program for overweight anovulatory womenResults of the Treatment group: • Lost an average of 6.3 kg (13.9 lbs)• Decreased fasting insulin and testosterone levels• Increased SHBG concentrations• 92% resumed ovulation (12/13)• 85% became pregnant (11/13)

Clark et al. Hum Reprod 10:2705; 1995


PCOS Nutritional Supplements

§ Myoinositol D-Chiro 40:1§ NAC 600mg bid§ Cinnamon 600 mg bid§ Fish Oil 1,000 mg/day: § Vitamin D3§ Berberine§ Maitake Mushroom Extract§ Chlorogenic Acid§ Advocare Carbease: white kidney

bean extract, coffer bean extract

§ Garcinia Cambogia Ultra§ Irwin Natural 3-in 1 Carb

Blocker: chromium piccolinate, Fish Oil, white kidney bean extract, cinnamon, lipase, protease, black pepper extract

Hlebowicz J,et al. Amer J Clin Nutr. 85(6):1552, 2007Nestler J, et al. N Engl J Med. 340:1314, 1999

Oner G, et al. Eur J Obstet Gynecol Reprod Biol. 159(1):127, 2011 Fulghesu AM, et al. Fertil Steril. 77(6):1128 2002

Wehr E, et al. Eur J Endocrinol. 164(5):741, 2011


Inositols

§ Inositols and its derivatives are found in foods (fruits, beans, cereals,etc)

§ Inositol is incorporated into cell membranes as phosphotidyl-myo-inositol, which is a precursor of inositol triphosphate

§ Inositol triphosphate acts as a second messenger and regulates acitivities of hormones including FSH, TSH and insulin

§ Inositol derivates participate in calcium oscillations which is important for oocyte maturation


Inositol and Oocyte Biology§ Myoinositol (MI) is the most abundant isoform of inositol

in nature and plays a role in regulating gamete development, oocyte maturation, fertilization and early embryonic development and in the regulation of LH/FSH activity

§ Calcium fluctuations during the process of oocyte maturation, fertilization and embryogenesis is linked to bio-availability of MI

§ High concentrations of MI in both male and female reproductive system suggest that inositol concentration in physiological fluids may influence fertility.

§ Studies have shown that high concentrations of MI in follicular fluid is a marker of good quality oocytes.


MI and DCI in Glucose Metabolism

§ D-chiro-inositol (DCI) is synthetized by an enzyme that converts MI to DCI. This reaction is insulin dependent.

§ DCI is crucial for glycogen synthesis while MI increases glucose cellular uptake

§ MI seems to play a more important role in oocyte maturation

§ Evidence suggests that upsetting the MI/DCI ration may play a role in ovarian dysfunction


MI and DCI Clinical Trials

§ Artini, et al 2013: • RCT, 50 PCOS patients MI + FA vs FA alone• Duration: 12week prior to IVF• Results: Tx ↓ LH, PRL, Insulin, LH/FSH ratio; ↑ insulin sensitivity

§ More top quality oocytes§ Significantly higher clinical pregnancy rate

§ Brusco et al 2013:• RCT 149 PCOS patients MI+DCI+FA vs FA alone• Duration: 6 months• Results: Improved oocyte and embryo quality

§ Significant ↑ clinical pregnancy in Tx group• DCI rapidly reduces peripheral hyperinsulinemia while MI

improves ovulatory function


MI and DCI Clinical Trials

§ Minozzi, et al, 2013:• 20 obese women with PCOS• Duration: 6 months MI + DCI• Results: ↓ Total Cho, LDL, TG, FI, FG & HOMA

§ Nordio, et al, 2012:• 50 overweight women with PCOS• Duration: 6 months MI+DCI vs MI alone• Results: Combined group more effective @ 3mos; no difference @ 6

mos• “DCI rapidly reduces the peripheral resistance while MI mainly improves

ovluatory dysfunction

§ Colazingari, et al, 2013:• RCT 100 women planning IVF• MI + DCI vs DCI alone• Results: combined group had ↓ FSH dose, shorter stimulation, ↑ embryo

quality, and ↑ pregnancy rate


Myoinositol versus Metformin§ Raffone E, et al, 2010

• RCT 120 PCOS women• MET vs MI+FA• Results:

§ Metformin: – 50% restored ovulation 18% conceived– 42 pts received MET+ FSH 37.5 IU/day 26%

conceived§ Total pregnancy rate MET and MET+FSH: 36% § Myoinositol:

– 65% restored spontaneous ovulation 30% conceived

– 38 pts received MYO+FSH 29% conceived§ Total pregnancy rate MYO and MYO+FSH 48%


Inositol vs Metformin in PCOS

§ 128 women treated for 3 months• Group A: myoinositol+d-chiroinositol• Group B: metformin 1500mg

§ Significantly better restoration of menses, pregnancy and weight loss in Group A

18 |

05

101520253035404550

Menses Pregnancy

Inositol

Metformin

Hamid A, et al Evidence Based Women’s Health J. 5:3; 93-98, 2015.


Is obesity related to high fat diets?

“A substantial decline in the percentage of energy from fat during the last 2 decades has corresponded with a massive increase in the prevalence of obesity.Diets high in fat do not appear to be the primary cause of the high prevalence of excess body fat in our society, and reductions in fat will not be a solution.”

» Willet WC, et al: Am J Med 113S:47S, 2002


PCOS Dietary Recommendations

§ Avoid High Fructose Corn Syrup Sweeteners• ê appetite suppression ê Gherelin secretion• Calories stored as triglycerides and fat• Hepatoxicity similar to alcohol

§ Potential Benefit• D-chiro inositol• DHA/Fish Oils Essential Fatty Acid

Supplementation• Antioxidants• Resveratrol


GLP-1 Receptor Agonists & PCOS§ Prospective 12 week study. 40 obese women with PCOS,

pretreated with metformin randomized to one of three groups: • [1] metformin 1000 mg BID, [2] victoza 1.2 mg QD or [3]combined

metformin 1000 mg BID and Victoza 1.2 mg QD

§ Results: “Combined group of metformin and Victozasignificantly more weight loss, BMI and waist circumference decreases than other groups.”

Jensterle Sever etal. Eur J Endocrinol. 170(3): 451, 2014.

§ “Combination therapy was superior to Byetta or metformin monotherapy in improving menstrual cyclicity, ovulation rate, free androgen index, and insulin sensitivity and reducing weight and abdominal fat. Both Byetta arms were more effective in promoting weight loss than metformin alone.”

Elkind-Hirsch et al, J Clin Endocrinol Metab. 93(7):2670, 2008.


Reproductive Factors

§ Gonadotropin sensitivity§ Oocyte maturity§ Embryo development§ Delayed ovulation§ Implantation§ Proinflammatory state§ Miscarriage

• ↑ AMH / ↑ antral follicles ↓ adiponectin

• ↑ CRP• ↑ cytokines ? obesity

• ↑ TNF-α, IL-6, IFNɤ• ↑ testosterone

• ↓ HOXA-10• ∆ uterine & ovarian

blood flow• ↑ Sleep apnea

PCOS Observations

• >75% anovulatory women Franks et al. Int J Androl 29:278; 2006

• ↑ LH pulsatilityTaylor et al. J Clin Endocrinol Metab 82:2248; 1997

• 6-fold ↑ of primary growth follicles

Webber et al. Lancet 362:1017; 2003• Follicular arrest: impaired

selection of dominant follicle Jonard & Dewailly. Hum Reprod Update 10:107; 2004

• Circulating markers of oxidative stress are abnormal independent of obesity

Murri M, et al: Hum Reprod Update. 19(3):268, 2013


PCOS & TNF-a

§ TNF-a # in normal-weight women with PCOS Bivikli M, et al. Metab Syndr Relat Disord 4(2) 122, 2006

§ Insulin resistance is associated with #TNF-a, 60% # lipid accumulation in blastomeres, & 45% # apoptosis

Moley KH, et al. SGI abstract, 2008

§ TNF-a inhibits FSH induced follicle growth, E2 production & hCG induced ovulation in mice follicles

Kurachi H, et al: J Ovarian Res 6:69, 2013

§ TNF-a induces apoptosis in bovine pre-implantation embryos

Hansen PJ, et al. Reproduction 133(6) 1129, 2007


PCOS & TNF-a

§ Oocytes exposed to TNF-a during maturation developed fewer blastocysts & increased blastomere apoptosis >9 cell stage.

Hansen PJ, et al. Am J Reprod Immunol, 50(5) 380, 2003

§ Thiazolidinediones $ TNF-aMcVeigh GE, et al. Br J Pharmacol, 153(4), 2008

§ Dan-Shao Hua Xian & Resveratrol (grapes, peanuts) #transcription of PPAR-g and$TNF-a

Aggarwal BB, et al. Cell Cycle, 7(8), 2008Cheng ML Hepatobilliary Pancreeat Dis Int. 7(2), 179, 2008


PCOS & Adiponectin

§ Adiponectin produced by adipose tissue• Subcutaneous fat > visceral fat

§ Adiponectin ↓ with ↑ BMI§ Improves insulin sensitivity§ ↑ human granulosa cell estrogen & progesterone

production § Improves oocyte maturation and embryo development§ ↓ AdipoR in women with implantation failure§ Adipokines could be a link between reproduction &

energy metabolism partly explaining infertility related to obesity & PCOS.

J. Dupont, et al: Adipokines and the Female Reproductive Tract, Int J Endocrinol, 232454, 2014


Infertility Treatments

§ Low glycemic diet, strength training, supplements, insulin sensitizers • If BMI elevated, 5-10% weight loss• Insulin sensitizer as single agent• Supplements

§ NAC, Ovasitol, Cinnamon, Carb Blocker, Maitake Mushroom Extract, Chlorogenic Acid, Fish Oil, Low Dose Aspirin

§ Letrozole or clomiphene ± insulin sensitizer§ Gonadotropins + insulin sensitizer

• Birth control pretreatment• GnRH-agonist vs antagonist• Low dose treatment • Low dose hCG• Follicular reduction + oocyte cryopreservation

§ Ovarian surgery§ IVM, IVF

§ Ovulation rate• 61.7% vs 48.3% of cycles

§ Live births• 27.5% vs 19.1% L vs C• 44% more likely with L

§ No significant difference in preg loss rate

§ Twins 3.4% vs 7.4% NS§ Clomiphene ↑ hot flashes§ Letrozole ↑ fatigue &

dizzinessLegro RS, et al: NEJM 371(2):119 2014

Letrozole vs Clomiphene for Infertility in PCOS

• 750 women received letrozole or clomiphene for 5 cycles

• Rotterdam PCOS criteria

• 18-40 years old• Adequate sperm, ≥ 1

patent fallopian tube & nl uterine cavity


Metformin Who might benefit?

§ 8 or fewer menses per year§ Hirsutism or elevated androgens§ Acanthosis nigricans§ History of gestational diabetes§ PCO appearing ovaries§ Family history of diabetes§ Fasting insulin over 10 miu/ml; 2 hour over 50

miu/ml§ Hypoglycemic response on 2hr IGTT§ Metabolic Syndrome


PCOS GRS Metformin Protocol

• Metformin 500 mg qd wk 1; bid wk 2; tid wk 3; followed by metformin 850 mg bid

• Take with full glass of water/milk at middle of meal• Monitor BBT’s, u-hCG if 16 day temp rise seen• Re-evaluate @ 3 months

— Additional time— Supplements: NAC, Cinnamon,

Ovasitol— Increased metformin to 1000mg bid— Add GLP1 receptor agonist— Letrozole/clomiphene— Ovarian drilling— Low dose injectables with oocyte

cryopreservation— IVF

PCOS Metformin & Ovulation

61 PCOS women with BMI >28

26 women received - Placebo

35 women received - Metformin 1500 mg/day

1 14 28 35

Prog. >25 nmol/L

1 ovulated

14 ovulated

P<0.001

Nestler et al. N Engl J Med 1998


PCOS Metformin & Clomiphene

25 women received - Placebo

1 5 10 18

2 ovulated

P<0.001

Nestler et al. N Engl J Med 1998

21 women received - Metformin 1500 mg/day

19 ovulated

CC

50 mg


Metformin Improves Pregnancy Rates

§ OGTT offered to women with obesity, AN, GDM, FHX or CC failure

§ 51 had hyperinsulinemia• Group 1: Metformin alone (n=11), Met+CC (n=17),

Group 2: CC alone (n=23) for 7.5 months average• Ovulation (82% vs 78%)• Pregnancy rates (63% vs 36%, NS) • Pregnancy in women who ovulated appeared higher in

metformin patients (75% vs 44%, p=0.054)Lavoie HB, et al. Abstract P2-426 Endocrine Society, 2001


Pregnancies Following Metformin in PCOS

£Anovulatory patients (N=48) with PCOS• Metformin 500 mg b.i.d. 6 weeks, t.i.d. thereafter• Clomiphene added if anovulatory at 12 weeks• 31/48 (64.5%) resumed spontaneous menses• 16/31 (52%) conceived within the first six months• 3/16 (19%) had spontaneous abortions• 19/48 (40%) suffered gastrointestinal related side-

effects, including diarrhea, abdominal cramping, and nausea

Heard MJ, et al: Abstract 140, Society of Gynecologic Investigation, 2001


Glucophage XR vs Clomiphene

§ 626 infertile women with the polycystic ovary syndrome

§ Pregnancy rate• Clomiphene + placebo 22.5%• Extended release metformin plus placebo 7.2%• Clomiphene +metformin XR 26.8%

§ Multiples 6%, 0%, 3%§ Synergistic effect of diet and exercise ignored§ Equivalency of Glucophage XR and metformin not

provenLegro etal: N Engl J Med. 2007 Feb 8;356(6):551-66.


Metformin Reduces Pregnancy Loss in PCOS

§ Retrospective study of PCOS women who became pregnant• Group 1: received metformin during pregnancy

(n=101)• Group 2: control (n=31)

§ Early loss rate 12.9% vs 41.9% (p=0.001)§ Prior SPAB: 15.7% vs 58.3% (p=0.005)

Jakubowicz DJ, et al: abstract P2-427, Endocrine Society, 2001

PCOS Ovarian Drilling

• Spontaneous ovulation– 60-95%

• Pregnancy– 60-85%

• Requires surgery• Adhesions formation• 30% require ovulation

meds• Doesn’t work in

smokers


PCOS & IVF META-ANALYSIS

Objective: To compare conventional IVF outcomes of PCOS and non-PCOS patients

Materials and Methods: Meta-analysis of nine studies

• 458 PCOS (n=793 cycles)• 694 Control (n=1116 cycles)

Analysis Requirements:• Non-male factor control matches• 2003 PCOS criteria used• Patients within a study on same ovarian protocol

Heijnen et al. Human Reprod Update 12:13; 2006


§ Results:• PCOS patients demonstrated a reduced chance of oocyte retrieval

per started cycle• Significantly more oocytes per retrieval in PCOS group

§ N/S Results:• Chance of Embryo Transfer (ET) per oocyte retrieval• Number of oocytes fertilized• Clinical pregnancy rate per started cycle

§ Conclusions:• Increased cancellation rate and lower fertilization rate, but more

oocytes per retrieval with PCOS women using IVF• Similar pregnancy and live birth rates were achieved

Heijnen et al. Human Reprod Update 12:13; 2006

PCOS & IVF META-ANALYSIS


ICSI Clinical Study: Esinler et al.Objective: To determine the ET & ICSI outcomes of PCOS patients

Materials and Methods: Case-control study at an IVF Center; Ankara, Turkey

• 99 PCOS (n=109 cycles)• 58 PCO (n=58 cycles)• 210 Control (n=232 cycles)

Intervention: Controlled Ovarian Hyperstimulation (COH) & ICSI

Measurements: Oocyte number, fertilization rate, embryo quality, clinical pregnancy rate, implantation rate and OHSS

Esinler et al. Fert Steril 84:932; 2005


PCOS Stimulated Cycles

£ Patients are often hyperresponders• Reduced follicular vascularization in PCOS women

Jarvela et al. Fert Steril 82:1358; 2004• Hyperinsulinema can result in higher E2/androstendione ratios and

increased immature folliclesFulghesu et al. J Clin Endocrinol Metab 82:644; 1997

£ A major concern is Ovarian Hyperstimulation Syndrome (OHSS) £ How do you lower risk of OHSS?

• Insulin sensitizers• Lower gonadotropin doses• GnRH antagonist cycles• Coasting vs low dose hCG• Embryo cryo with ET in an unstimulated cycle• Oocyte vitrification• Hespan, Dostinex Delvigne & Roszenberg Hum Reprod Update 8:559; 2002


The Effect of Metformin on Pregnancy Outcome & Endometrial Receptivity

§ 120 PCOS patients enrolled for IVF/ICSI• Group A metformin 500mg TID; Group B placebo

§ Clinical pregnancy rate• Group A: 58.9%• Group B: 37.5% p<0.05

§ OHSS: 8.3% vs 21.7% p<0.05§ Receptivity markers

• HOXA10: 30.95 vs 0.58 p<0.05• ITGB3: 0.97 vs .0.42 p<0.05

J Zhai, ASRM Abracts 106:3 e260, Sept 2016


Effect of Metformin on IntrafollicularCytokines, Response & IVF Outcome

§ 24 infertile women with PCOS§ Randomized (A) metformin 500mg BID vs (B)

placebo with OCP 23 weeks prior to stimulation§ Results:

• Total FSH dose: 1403 vs 1896• # grade I or II embryos é in the metformin group p<0.002• FF TNFα ê, IL-6 ê, FF Adiponectin é

• Clinical pregnancy rate: 80% vs 18%• Embryo implantation é in metformin group p<0.02

Kang et al: P409 ASRM Abstracts. 106:3 supp, Sept 2016


Conclusions

§ Best pregnancy rates and outcomes when PCOS metabolic abnormalities have been corrected

§ Better pregnancy rates, implantation rates, lower miscarriage rates with metformin

§ Reduced OHSS with metformin§ Reduced gestational diabetes


Schedule an Appointment

§ Online PCOS TV: http://bit.ly/GRS_PCOS

§ Call 404-843-BABY

§ Visit www.IVF.com

§ Email us

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Meet Our Physicians

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Anne Brawner Namnoum, MD • Mark Perloe, MD • Desireé McCarthy-Keith, MD

Documents

PERLOE - Improving Fertility - PCOS Challengepcoschallenge.org/symposium/2016-atlanta...Grassi A. PCOS:The Dietitian’s Guide to PCOS. Luca Publishing, Haverford, PA 2013. Cheang