Infertility Treatment in PCOS

Richard S. Legro, M.D.

Penn State College of Medicine

Dept of Ob/Gyn

Hershey, PA

USA

Lifestyle Therapy and Fertility in Women with PCOS

AUTHORS' CONCLUSIONS: No RCTs were located that assessed the effects of preconception advice on the chance of a live birth or other fertility outcomes in people who perceived that they may be infertile and were investigating the possibility of medical treatment to address subfertility.

There ıs no evidence based schema

Hum Reprod. 2008 Mar;23(3):462-77 and Fertil Steril. 2008 Mar;89(3):505-22

First Line Treatment Options

Clomiphene

Lifestyle therapy

Obese

Clomiphene

Nonobese

Infertile PCOS

Hum Reprod. 2008 Mar;23(3):462-77 and Fertil Steril. 2008 Mar;89(3):505-22

Rausch et al, JCEM, 2009

Can we achieve meaningful weight loss which will improve

fertility outcomes?

Limitations of Lifestyle Therapy in Infertility

Dose? Is there an ideal rate of weight loss or activity

increase Duration?

How long should the intervention be instituted Timing?

Is the intervention before or during infertility treatment?

Patient Compliance (buy in) Will patients be able to follow our instructions

N = 13 (study completers)

RCTs of Lifestyle Intevention in PCOS (N ≥ 100)

Study N Treatments Results

Tang et al, Hum Reprod 2006

143 Metformin + lifestyle vs

Placebo + Lifestyle for 6 months

No benefit of metformin on menstrual frequency, slight benefit to lifestyle

*Lifestyle = 500 cal deficit/day, increase physical activity by 15 minutes a day (unmonitored).

Thompson et al, 2008

104 Diet + exercise vs. Diet

Addition of exercise did not affect reproductive and metabolic abnormalities, only improvement in body composition

Karimzadeh et al, 2010

343 CC vs Metformin vs CC/Met vs Lifestyle

NS difference in pregnancy rates between treatment arms, but lifestyle best

RCT of Lifestyle vs Medicine in PCOS (?6 mos)

02468

101214161820

CC Met CC + Met Lifestyle

Pregnancy RateN = 343 women

Lifestyle: 500 Kcal daily diet deficit, 3-5x week exercise x 30 mins, had to lose 5% of body weight to be in the study!!

P = 0.56

Karimzedah, Fertil Steril, In Press

Change in BMI with Lifestyle in PCOS (+/-

metformin)

-4-3-2-101234

% change in BMI

Met Placebo

Tang et al, Hum Reprod 2006

Metformin, Lifestyle Modification or OC treatment

in PCOS Pilot trial of 43 obese adolescents with PCOS

randomized to metformin, placebo, lifestyle modification or oral contraceptive for 6 months

Lifestyle Modification: Combined group start, parent/adolescent 24 class educational session, 500 cal/d deficit, 30 mins/d moderate to intense activity, unmonitored)

9 dropped out ( 3 of 11 in lifestyle)

Hoeger, et al JCEM 2008

Weight changes by group

Hoeger, et al JCEM 2008

Combination therapy for obese PCOS adolescents

Follow Up Trial of 36 obese adolescents treated with oral contraceptive (ethinyl estradiol + drosperinone) with metformin or placebo

4 dropped out over the 6 month trial. All received lifestyle modification program as before

(parent/adolescent educational program, 500 cal/d deficit/30 mins/d exercise- now monitored, flexible enrollment, email/web support)

Hoeger et al JCEM 2008

Reduction in Weight over 24 weeks

P<0.01P<0.01

NS

Hoeger et al JCEM 2008

Thomson, R. L. et al. J Clin Endocrinol Metab 2008;93:3373-3380

High Dropout in

PCOS Lifestyle Studies

50% Dropout after Randomization

Weight loss (%) Over 20 Weeks by treatment group

-12

-10

-8

-6

-4

-2

0

Diet Diet/Aerobic Diet/Combined

% weight loss

Aerobic and Resistance Training

Thomson, R. L. et al. J Clin Endocrinol Metab 2008;93:3373-3380

Adults and AdolescentsConsented and Screened (n=215)

Exclusions (n=79) Randomized (n=136)

Reasons for Exclusion:1. Ineligible (n=25)2. Withdrawn consent

(n=24)3. Lost to follow-up (n=30)

Metformin (n=66) Placebo (n=70)

Dropout (n=34) Dropout (n=46)

Reasons for Dropout:1. Medication side effects (n=6)2. Lost interest/unable to comply

(n=4)3. Personal constraints/health issues

(n=8)4. Lost to follow-up (n=16)

Reasons for Dropout:1. Lost interest/unable to comply

(n=10)2. Personal constraints/health issues

(n=13)3. Pregnancy (n=4)4. Lost to follow-up (n=19)

Penn State College of Medicine/ Meharry Medical College

Demographics

Penn State Rural Primarily Caucasian Located in Hershey

PA

Meharry Urban Diverse Located in Nashville

TN

Lifestyle Intervention

Dietary Lose 7% of body

weight in 6 mos and maintain.

Hypocaloric diet

Exercise Supervised

– 1 session/week

Unsupervised– 1500-2000 kcal/wk

Monitor Submaximal VO2 Max monthly

Shai I et al. N Engl J Med 2008;359:229-241

Best Short Term and Long Term Weight Loss with a Low Carbohydrate Diet

Methods to Encourage Compliance

Diet and exercise logs Weekly phone visit

Exchange records 2 week visits

Pedometer data

Heart monitor data

Supervised exercised sessions

Educational modules

Compliance with Unsupervised Exercise

Visit Mean # Sessions/week

1 mos 3.0

2 mos 2.9

3 mos 2.3

Mean exercise time/session

38 ± 22 minutes

Mean Exercise Monitored Heart Rates

PSU Meharry

Mean heart rate

144 ± 44 bpm 146 ± 14bpm

No Change in Weight between Treatment

Groups

Change in Total Testosterone Levels Between Treatment

Arms

-12

-10

-8

-6

-4

-2

0

3 mos 6 mos

Metformin/Lifestyle

Placebo/Lifestyle

*

*P = 0.003

ng/dL

No Difference in Ovulation Rates between Treatment

Groups

Summary: Lessons Learned

External Validity Many will not even attempt a lifestyle intervention Most who do will drop out Severely obese patients may be poor candidates for

such programs There will be hurdles to implementing these programs

in our current medical system Best Case Scenario

Modest Effects, ? Improved outcomes

The common resources of the lancet, a garden, a kitchen, fresh air, cool

water and exercise will be sufficient to cure all diseases that are at

present under the power of medicine

Benjamin Rush (1745-1813)

Sjostrom, L. et al. N Engl J Med 2004

Weight Changes among Subjects in the Swedish Obesity Study over a 10-Year Period

Sjostrom L et al. N Engl J Med 2007;357:741-752

Unadjusted Cumulative Mortality After Bariatric Surgery

NIH consensus: Indications for Bariatric Surgery

BMI > 40 BMI > 35 with serious medical

comorbidities Is PCOS and/or infertility a serious medical

comorbidity

Malcolm, NEJM, 2009

Reproductive Health in Women undergoing Bariatric

Surgery

1,538 females having bariatric surgery (NIH-LABS Consortium).

PCOS had been diagnosed in 13.1% of subjects. Women who were obese by 18 years old were more likely

to report PCOS and infertility and less likely to have ever been pregnant, compared with women who became obese later in life.

Future pregnancy was important to 30.3% of women younger than 45 years, and overall to 51.4%.

Gosman et al, Fertil Steril, 2009

Escobar-Morreale, H. F. et al. JCEM 2005

Clinical and biochemical

characteristics of the morbidly obese PCOS

patients submitted to bariatric

surgery, before and after weight

loss

Conclusion: Rates of many adverse maternal and neonatal outcomes may be lower in women who become pregnant after having had bariatric surgery compared with rates in pregnant women who are obese; however, further data are needed from rigorously designed studies.

Can we achieve meaningful weight loss which will improve

fertility outcomes?

Only with bariatric surgery!

Funding/Collaborators Supported by NIH grants, K08 and K24 grant, The National Cooperative Program

for Infertility Research U54 HD 34449, U10 38992, Reproductive Medicine Network, 1R01HD056510 and A General Clinical Research Center grant MO1 RR 10732 to Penn State

Northwestern Andrea Dunaif, M.D.

Virginia Commonwealth Jerry Strauss, M.D.,Ph.D., John Nestler, M.D.

University of Pennsylvania Christos Coutifaris, M.D., Ph.D. Rich Spielman, Ph.D. Anuja Dokras, M.D., Ph.D.

Penn State- Jan McAllister, Ph.D. Larry Demers, Ph.D. Bill Dodson, M.D. Rich Zaino, M.D. Peter Lee, M.D., Ph.D. Alex Vgontzas, M.D. Allen Kunselman Jami Ober Kelly Stamets Rawa Patsy Emily George Sandra Eyer

RMN Principal Investigators

Reproductive Medicine Network PPCOS Investigators

OCP vs Weight Loss for Pregnancy in Polycystic Ovary

Syndrome

OWL-PCOS