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Insulin Resistance & Rush Hour

Biochemical • Androgen

• FreeTestosterone

• DHEAS

• 17OH progesterone

• Anti-mullerian hormone

• LH

• 2 hr Insulin/Glucose

• HgbA1c

• PAI-1

• Lipids

• hs CRP

• TNFα , IL-6, adiponectin

PCOS Findings

Ultrasound • Necklace sign

• Ovarian volume

• Antral follicle count

• Doppler blood flow changes

Physical

• Obesity

• Hirsutism

• Acanthosis

• Abnormal menses

• Acne

• Waist to hip ratio


PCOS: Multi-Factorial Treatment Approach

Identify multidisciplinary team

Eating plan & supplements

Exercise plan

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 Endocrinol

Metab. 2008 Jul;93(7):2670-8.

Copyright ® 2014 PCOS Nutrition Center


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 women

Results 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 Dietary Goals

• Change your relationship

with meal time & food

• Consume more foods

• rich in complex

carbohydrates

• monounsaturated fat

• fiber

• with a ratio of omega-6 to

omega-3 fatty acids

• Reduce

– Total caloric intake

– Saturated fat

– Cholesterol


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

Carbease: white kidney bean extract,

coffee bean extract

Garcinia Cambogia Ultra

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, 2007

Nestler 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


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 max Little 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


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

12 |

0

5

10

15

20

25

30

35

40

45

50

Menses Pregnancy

Inositol

Metformin

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


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 Victoza significantly 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.

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 &

dizziness

Legro 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


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

proven

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

http://www.ncbi.nlm.nih.gov/entrez/utils/fref.fcgi?PrId=3051&itool=AbstractPlus-def&uid=17287476&db=pubmed&url=http://content.nejm.org/cgi/pmidlookup?view=short&pmid=17287476&promo=ONFLNS19


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 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 follicles

• Fulghesu 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

• Lupron trigger

• Coasting vs low dose hCG

• Embryo cryo with ET in an unstimulated cycle

• Hespan, Dostinex (cabergoline) at retrieval

Delvigne & Roszenberg Hum Reprod Update 8:559; 2002


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grs pcospcoschallenge.org/symposium/2015-atlanta-presentations/...ovulation rate •61.7% vs 48.3%...

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