Couples are
often puzzled when they face infertility as well as modifiable morbidity (overweight
and obesity) limiting the chances of successful conception and healthy
pregnancy thereof. It’s a
tough choice to opt between starting the infertility treatment or correcting
the underlying morbidity.
Obesity is
associated with delayed conception, increased pregnancy loss, higher rates of
preeclampsia and preterm labor and metabolic syndrome leading to perinatal and
neonatal morbidity and mortality.
Expert
opinion have always advocated that obese women with PCOS delay infertility
therapy and pursue lifestyle modification, but has lacked high quality evidence
in support of the claim. There are no data on the optimum weight loss as well
as duration of preconception treatment.
Dr. Richard S. Legro, MD, from Penn State College of Medicine,
Hershey, Pennsylvania, and colleagues recently published
their study findings in online edition of the Journal of
Clinical Endocrinology and Metabolism.
“We found
that pretreatment lifestyle modification for weight loss, with or without
concurrent OC therapy, was associated with a significant improvement in the
rate of ovulation and an even greater increase in live birth rate than
immediate fertility treatment with clomiphene. Further, ovulation and live
birth rates were nearly identical between pretreatment with oral contraceptives
vs immediate treatment with clomiphene, suggesting that there is little
fertility benefit to pretreatment with hormonal suppression, alone or in
combination with lifestyle modification” opined the researchers.
Two very good
trials recently were concurrently conducted to demonstrate significant benefits
of lifestyle modification on ovulation and live births rate in obese women with
PCOS. The trials are The Treatment of
Hyperandrogenism vs. Insulin Resistance in Infertile PCOS Women or OWL PCOS
study and The Pregnancy in Polycystic Ovary Syndrome II or PPCOS II study.
Both the
trials were multicentric conducted concurrently by the researchers.
The OWL PCOS
was a randomized open labeled two site study constituting 149 women, diagnosed
with PCOS by Modified Rotterdam criteria. The women were assigned to 3 groups
to receive either 16-week Preconception treatment with continuous oral
contraception, lifestyle modification or combination of both before going to receive
4 cycles of clomiphene and timed intercourse.
The PPCOS II study was double blind, with 750
women receiving either 5 cycles of ovulation induction with
letrozole or clomiphene citrate and timed intercourse. No study participants received
any life style modification earlier.
A secondary post
hoc analysis was done by combining data from both the studies. An intentional similar
design, with same inclusion/exclusion criteria’s and use of clomiphene for ovulation
induction made it feasible to combine the data from the two trials.
The researchers
extracted the data for all women in the PPCOS II study in the clomiphene arm
who met the BMI criteria of the OWL PCOS study. So, they had data on 187 women
from the PPCOS II study and 142 women from the OWL PCOS study.
The primary
outcome was live birth, while predetermined secondary outcomes were conception,
ovulation and pregnancy loss rates.
It was seen
that earlier lifestyle modification leading to weight loss, irrespective of hormonal
treatment with OCP resulted in significant improvement in ovulation rate and
greater increase in live birth rates as compared to starting immediate
clomiphene treatment.
In those
patients who only received clomiphene the ovulation rate was 44.7% (277/619),
and the live birth rate was 10.2% (19/187) while patients who underwent weight loss
before fertility treatment the ovulation rate was 62.0% (80/129), and the live
birth rate was 25.0% (12/48).
Patients who
underwent lifestyle modification (In the OWL PCOS study, as well as patients in
the Combined group of the OWL PCOS study) had 2.5-fold increase in live births.
Patients in the Lifestyle modification and Combined groups also had a 1.4-fold
increase in cumulative ovulation rate (P .003 and P .001, respectively)
compared to treatment with only clomiphene in PPCOS II.
Use of OCP
before starting clomiphene did not have any significant effect on ovulation or
live birth rates.
Comparing
the results at the end of first cycle, only patients who lost weight in OWL
PCOS had a significantly improved chance of pregnancy and live birth in the
first ovulation induction cycle compared to the first ovulation induction cycle
in direct clomiphene group. The study also demonstrated that improving the
quality of ovulation is as important as improving the rate of ovulation to achieve
a higher live birth rate.
"Our
research holds significant implications for current practice, and supports the
concept of delaying fertility treatment to pursue lifestyle modification in
overweight/obese women with PCOS. It provides momentum to test this concept
more completely and prospectively in properly designed and adequately powered
multicenter studies to generate Level I evidence for the practice," the
authors explain.
"Future
studies may also want to utilize other ovulation induction agents in the
infertility treatment phase such as low dose gonadotropin or letrozole, which
tend to have greater success rates combined with comparable rates of multiple
pregnancy and congenital anomalies as clomiphene," the authors conclude.
Disclosure Statement: Dr. Legro
reports consulting fees from Euro screen, Astra Zeneca, Clarus Therapeutics,
Takeda, Kindex and research funding from Ferring and Astra Zeneca. Dr. Estes
and Dr. Schlaff reports research funding from AbbVie. Dr. Dokras reports
consulting fees from JDS Therapeutics. Mr. Kunselman reports ownership of Merck
stock. Dr. Sarwer reports consulting fees from BAROnova, EnteroMedics, and
Ethicon. The other investigators report no disclosures.
References:
http://press.endocrine.org/doi/pdf/10.1210/jc.2016-1659
