Obtaining multi-follicular growth is the goal of
ovarian stimulation for assisted reproductive technologies
(ART). One of the most severe complications
of ovarian stimulation is ovarian hyper stimulation
syndrome (OHSS), which occurs in 1-10%
PCOS is the most common disorder that causes
chronic anovulation in the infertile population
with persistently elevated estrogen and luteinising
hormone (LH) levels (
The use of gonadotropin during controlled ovarian
hyperstimulation of PCOS patients is a major
challenge. There have been some controversies regarding
the use of preparations with LH activity in
PCOS women. The use of FSH-only products rather
than human menopausal gonadotropin (hMG) in
PCOS, where endogenous LH is already elevated,
is expected to have theoretical advantage and has
been advocated in this group of women (
Therefore, the aim of this study was to compare urinary hMG with rFSH in PCOS patients for clinical outcomes and OHSS rates in IVF treatment cycles.
This prospective randomized controlled trial was
conducted between January 2008-December 2008
in Zekai Tahir Burak Women’s Health Education
and Research Hospital. The study was approved
by the hospital Ethics Committee. The protocol
was explained to the patients before they entered
the study and informed consent was obtained from
each couple. PCOS was diagnosed according to the
revised Rotterdam criteria by the European Society
for Human Reproduction/American Society of
Reproductive Medicine (ASRM) as the presence
of oligo-and/or anovulation and sonographically
confirmed polycstic ovaries (
For luteal support, vaginal progesterone gel
(Crinone 8%, Merk Serono, Germany) at a dose of
90 mg/day was given from the time of oocyte retrieval
until clinical pregnancy (9-10 weeks of gestation) or negative serum β-hCG test (13-15 days after
embryo transfer). Clinical pregnancy was defined
as the presence of a gestational sac with accompanying
fetal heart beat as observed by ultrasound.
OHSS was diagnosed and classified as described by
the Practice Committee of the ASRM (
For patients, we determined the cycle characteristics of serum peak E2 levels; endometrial thickness on the day of hCG injection; duration of stimulation; total dose of gonadotropins used; number of follicles ≥14 mm and 10-14 mm; number of retrieved, MII and fertilized oocytes; number of top quality and transferred embryos; as well as clinical pregnancy and take home baby rates per cycle, the need for coasting, and the incidence of OHSS.
Statistical analysis of the data was performed using SPSS for Windows v. 11.5 statistical package program (SPSS, Chicago, IL). The Shapiro- Wilk test was used to test for normal distribution of continuous data. If the normality assumption for the comparison of means between two groups was satisfied, we used the student’s t-test for the comparisons of means. Alternatively, if there was evidence of non-normality, the Mann- Whitney test was used. Comparisons between proportions were performed with Pearson’s chisquare or Fisher’s exact tests. All reported p-values were two-tailed and statistical significance was set at 0.05.
We included 84 women with PCOS treated in the IVF unit of a tertiary referral hospital in this study, of which four women were lost to follow-up. Thus, 80 women completed the study, 38 patients in the hMG group and 42 patients in the rFSH group.
Patients’ characteristics revealed no significant
differences between the groups for age, body mass
index and baseline hormone levels, which confirmed
the appropriate randomization (
Patient characteristics in the treatment groups
|Variable||hMG (n=38)||rFSH (n=42)||P value|
|25.85 ± 3.92||25.98 ± 3.92||0.883|
|25.85 ± 4.90||25.08 ± 4.38||0.527|
|5.63 ± 2.41||6.31 ± 1.58||0.087|
|5.86 ± 2.41||6.41 ± 4.54||0.556|
Values are given as mean ± SD and p< 0.05 is considered significant.
Cycle characteristics and outcomes of patients in the treatment groups
|hMG (n=38)||rFSH (n=42)||P value|
|11.46 ± 1.90a||10.36 ± 1.58||0.025*|
|1716.06 ± 511.52||1429.50 ± 340.54||0.57|
|2880.23 ± 1284.22||3779.52 ± 1487.70||0.02*|
|5.92 ± 2.72||6.24 ± 3.85||0.75|
|9.35 ± 3.61||12.69 ± 3.98||0.001*|
|10.54 ± 2.03||11.45 ± 1.85||0.06|
|9.54 ± 4.31||13.60 ± 5.56||0.002*|
|7.65 ± 3.39||11.20 ± 5.06||0.003*|
|81.24 (40-100)b||82.13 (37.5-100)||0.80|
|4.46 ± 2.62||6.07 ± 3.55||0.70|
|1.29 (0- 3)||1.48 (0-3)||0.48|
|3 (1-4)||3 (1-4)||0.25|
|0 (0.0%)||5 (11.9%)c||0.14|
a; Mean ± SD , b; Median (range), c; Number (percentage) and *; p< 0.05 is considered significant.
The mean duration of gonadotropin stimulation was significantly longer in the hMG group (11.46 ± 1.90 vs. 10.36 ± 1.58 days, p=0.025). There was no significant difference in total dose of gonadotropins between the groups. The mean mature follicle (≥14 mm) count was similar, but the mean intermediatesized follicle (10-14 mm) count was significantly lower in the hMG group (9.35 ± 3.61) compared to the rFSH group (12.69 ± 3.98, p=0.001). The mean peak E2 level was significantly lower in hMG group (2880.23 ± 1284.22 pg/mL) compared to the rFSH group (3779.52 ± 1487.70 pg/mL, p=0.02). Also, the mean number of oocytes retrieved were significantly lower in the hMG group (9.54 ± 4.31) compared to the rFSH group (13.60 ± 5.56, p=0.002). MII oocytes were significantly lower in the hMG group (7.65 ± 3.39) compared to the rFSH group (11.20 ± 5.06, p=0.003). There were no significant differences between groups with regards to endometrial thickness, percentage of MII oocytes, number of fertilized oocytes, fertilization rates, top quality embryo counts, and the number of transferred embryos.
Coasting requirement was significantly lower in the
hMG group (19.2% vs. 48.9%, p=0.013). The need
for coasting longer than three days was not required
for any patient. OHSS rate was 11.9% (5 patients)
in the rFSH group, whereas no patient developed
OHSS in the hMG group, but this was not significant
(p=0.14). All hyperstimulation cases were mild.
Moderate or severe OHSS was not observed in either
group. The clinical pregnancy and take home baby
rates were similar in both groups (
The occurrence of small-sized preovulatory
ovarian follicles is directly related to FSH stimulation
and leads to ovulation induction complications.
The small/medium-sized follicles are mostly
responsible for high serum E2 concentrations and
vasoactive compounds leading to OHSS (
Platteau et al. (
Although the number of oocytes retrieved and
the number of MII oocytes were lower in the hMG
group, the percentage of MII oocytes, fertilization
rate, number of top quality embryos and number
of embryos transferred were comparable between
the two groups in our study. It has been considered
that quality is more important than quantity;
the success criterion has changed from obtaining
many oocytes to obtaining an adequate cohort of
top-quality embryos. In a study by Andersen et al.
In recent years, rFSH has increasingly been
used in ovulation induction and IVF treatments. A
number of studies have evaluated the effectiveness
of rFSH and hMG in IVF cycles (
To the best of our knowledge, this is the first prospective design study evaluating PCOS patients in IVF treatment with the outcome measures of pregnancy and OHSS rates. The main limitation of our study is its size. Ovulation induction with rFSH is common in PCOS women. Since women with PCOS already have elevated endogen LH levels, the use of hMG is not preferred in our clinics as with other IVF centers. For this reason, this study has been conducted with a restricted patient population. As no data on this issue are currently available, this study may be considered a feasibility study.
Based on the current study, ovarian stimulation performed with hMG in PCOS patients treated with a long GnRH agonist protocol results in the same clinical pregnancy and take baby home rates compared to ovarian stimulation with rFSH. However, for the consideration of other important factors such as the need of coasting and safety in particular, hMG has major advantages over rFSH. This results warrant further evaluation in a larger prospective series.