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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