Transcript Therapy of Anovulation

Lifestyle Therapy and Fertility in Women with PCOS
Infertility Treatment in PCOS
Richard S. Legro, M.D.
Penn State College of Medicine
Dept of Ob/Gyn
Hershey, PA

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
Infertile PCOS
Obese
Nonobese
Lifestyle therapy
Clomiphene
Clomiphene
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
Tang et al, Hum 143
Reprod 2006
Thompson et al, 104
2008
Karimzadeh et al, 343
2010
Treatments
Results
Metformin + lifestyle
vs
Placebo + Lifestyle for
6 months
No benefit of metformin on
menstrual frequency, slight
benefit to lifestyle
Diet + exercise vs.
Diet
Addition of exercise did not affect
reproductive and metabolic
abnormalities, only improvement
in body composition
CC vs Metformin vs
CC/Met vs Lifestyle
NS difference in pregnancy rates
between treatment arms, but
lifestyle best
*Lifestyle = 500 cal deficit/day,
increase physical activity by 15
minutes a day (unmonitored).
RCT of Lifestyle vs Medicine
in PCOS (?6 mos)
20
18
16
14
12
10
8
6
4
2
0
N = 343 women
Pregnancy Rate
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!!
CC
Met
CC + Met
Lifestyle
P = 0.56
Karimzedah, Fertil Steril, In Press
Change in BMI with Lifestyle
in PCOS (+/- metformin)
4
3
2
% change in 1
0
BMI -1
-2
-3
-4
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<0.01
P<0.01
NS
Hoeger et al JCEM 2008
High Dropout
in PCOS
Lifestyle
Studies
50% Dropout after
Randomization
Thomson, R. L. et al. J Clin Endocrinol Metab
2008;93:3373-3380
Weight loss (%) Over 20
Weeks by treatment group
% weight loss
0
-2
-4
-6
-8
Aer obic and
Resistance Tr aining
-10
-12
Diet
Diet/Aerobic
Diet/Combined
Thomson, R. L. et al. J Clin Endocrinol Metab 2008;93:3373-3380
Adults and Adolescents
Consented and Screened (n=215)
Randomized (n=136)
Exclusions (n=79)
Reasons for Exclusion:
1. Ineligible (n=25)
2. Withdrawn consent
(n=24)
3. Lost to follow-up
(n=30)
Metformin (n=66)
Dropout (n=34)
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)
Placebo (n=70)
Dropout (n=46)
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
Best Short Term and Long Term Weight Loss with a Low
Carbohydrate Diet
Shai I et al. N Engl J Med 2008;359:229-241
Methods to Encourage
Compliance
Diet and exercise logs
Weekly phone visit
Exchange records
2 week visits
Pedometer data
Heart monitor data
Educational modules
Supervised exercised
sessions
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
Mean heart
rate
Meharry
144 ± 44 bpm 146 ± 14bpm
No Change in Weight
between Treatment Groups
Change in Total Testosterone Levels
Between Treatment Arms
ng/dL
0
-2
-4
-6
*P = 0.003
-8
Metformin/Lifestyle
-10
-12
Placebo/Lifestyle
*
3 mos
6 mos
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)
Weight Changes among Subjects in the Swedish
Obesity Study over a 10-Year Period
Sjostrom, L. et al. N Engl J Med 2004
Unadjusted Cumulative Mortality After Bariatric
Surgery
Sjostrom L et al. N Engl J Med 2007;357:741-752
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
Clinical and
biochemical
characteristics of
the morbidly
obese PCOS
patients submitted
to bariatric
surgery, before
and after weight
loss
Escobar-Morreale, H. F. et al. JCEM 2005
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
OWLPCOS