Peter Kovacs, MD, PhD
Flexible GnRH Antagonist Protocol Versus GnRH Agonist Long
Protocol in Patients With Polycystic Ovary Syndrome Treated for IVF: A
Prospective Randomised Controlled Trial (RCT)
Laines TG, Sfontouris IA,
Zorzovilis IZ, et al
Hum Reprod. 2010;25:683-689
Hum Reprod. 2010;25:683-689
Background
Polycystic ovary syndrome
(PCOS) is the most common endocrine abnormality in reproductive-aged women and
accounts for most ovulatory infertility. The diagnosis of PCOS is made on the
basis of irregular menstrual cycles, hyperandrogenism, and polycystic ovaries.
Various treatments are available for the management of PCOS; the choice
primarily depends on the problem for which the patient seeks help. PCOS is
often associated with infertility as a result of ovulatory irregularity.
Because about half of the patients are obese, lifestyle changes are often part
of the treatment. Despite the obvious ovulatory defect, couples need to undergo
a proper infertility workup before treatment can be offered. If the only
problem is oligo- or anovulation, then the treatment has to correct this. In
addition to lifestyle changes, both medical (clomiphene citrate, aromatase
inhibitors, insulin sensitizing agents, gonadotropins) and surgical (ovarian
drilling) options can be explored.
If the cause of infertility is
more complex, ovarian stimulation alone may not be sufficient, and a more
sophisticated approach may be needed. Some of these patients will require in
vitro fertilization (IVF) to manage their infertility. Stimulation of the
patient who has PCOS for IVF may be challenging. Most patients have a robust
response to gonadotropin stimulation and are at significant risk for
hyperstimulation. Besides careful drug dose selection, one can use several stimulation
protocols, and various management options exist for treatment (coasting,
elective cryopreservation, cycle cancellation) in addition to avoiding ovarian
hyperstimulation syndrome (OHSS). This study compared 2 stimulation protocols
that are often used for the hyperresponder patient.
Study Summary
Patients diagnosed with PCOS in
whom IVF was needed were randomly assigned to gonadotropin-releasing hormone
(GnRH) agonist long stimulation or to a GnRH antagonist protocol (110 patients
in each group). Baseline characteristics (age, hormone levels, body mass index,
order of treatment cycle, indication for IVF) were well balanced. In the
antagonist group, the duration of stimulation was shorter, less medication was
used, and the peak estradiol level was lower. Clinical and ongoing pregnancy
rates were similar (agonist: 50.9% vs antagonist: 47.3%). Mild hyperstimulation
(not requiring treatment or monitoring) was more common in the antagonist
group, and moderate OHSS (requiring outpatient monitoring/management) was more
common in the agonist group (60% vs 40%). Cycle cancellation rates were
similar.
Viewpoint
OHSS is the most severe
complication of gonadotropin stimulation. On the basis of severity of the
symptoms and laboratory value deteriorations, OHSS is classified as mild,
moderate, or severe. In general, severe OHSS complicates 1%-2% of IVF cycles.
The best treatment approach starts with the identification of patients at risk.
Women with polycystic ovaries and/or PCOS are at high risk for OHSS.[1,2] Once the patient is identified, an
appropriate stimulation protocol can be selected. This means not only an
appropriate gonadotropin dose but also a stimulation protocol with low risk for
OHSS (step-up, step-down, dual suppression with oral contraceptives and GnRH
agonist, GnRH antagonist, etc.).[3]Close
monitoring is important; if needed, the dose of the gonadotropin can be reduced
or even withheld. One has to be ready for cycle cancellation or elective
cryopreservation to avoid OHSS.
Previously it was shown that
the antagonist protocol is associated with fewer cases of OHSS.[4]Antagonist
use is associated with profound luteinizing hormone suppression and decreased
stimulation of smaller follicles from midcycle. The benefit may be a
consequence of fewer small follicles, but the possibility of a difference in
vasoactive substance production between the 2 approaches cannot be ruled out.
In addition, the antagonist protocol allows the use of a GnRH agonist to
trigger ovulation.[5]This
approach has been shown to be associated with a significant reduction in OHSS
risk. This current study confirms the lower risk for OHSS with antagonist use.
It has to be pointed out that
the rate of moderate OHSS was very high in this study (60% vs 40%). The mean
number of eggs was also very high (27 vs 28). One wonders how the patients were
managed or monitored during stimulation. Despite the young age of the patients
and the low order of the treatment cycle, an average of 3 embryos were
transferred. This is no longer the international standard in this age group.
The high number of embryos transferred may explain the high pregnancy rates.
The proportion of multiple gestations is not reported, but one can assume that
this, too, was high and could partially explain the high OHSS incidence.
In summary, we can conclude
that in PCOS patients who undergo stimulation for IVF, the GnRH antagonist
protocol is associated with comparable pregnancy outcome but a lower risk for
OHSS when compared with the long protocol.