Original article 451

Significance of a common single nucleotide polymorphism in

exon 10 of the follicle-stimulating hormone (FSH) receptor
gene for the ovarian response to FSH: a pharmacogenetic
approach to controlled ovarian hyperstimulation
Hermann M. Behrea, Robert R. Grebc, Andrea Mempelc, Barbara Sonntagc,
Ludwig Kieselc, Petra Kaltwaerb, Ewald Seligerb, Friedrich Ropkeb,
Jorg Gromolld, Eberhard Nieschlagd and Manuela Simonid
The p.N680S sequence variation of the follicle-stimulating
hormone (FSH) receptor gene was previously shown to
influence the ovarian response to FSH in normo-ovulatory
women undergoing controlled ovarian hyperstimulation. In
this prospective, randomized, controlled study, we tested
whether the same daily dose of FSH results in lower levels
of oestradiol in women homozygous for the p.N680S
sequence variation, and whether the difference can be
overcome by higher FSH doses. Women undergoing
controlled ovarian hyperstimulation for in vitro fertilization
or intracytoplasmic sperm injection and homozygous for
the wild-type or for the p.N680S FSH receptor were
randomly assigned to group I (Ser/Ser, n = 24), receiving
an FSH dose of 150 U/day, or group II (Ser/Ser, n = 25),
receiving an FSH dose of 225 U/day. In group III (Asn/Asn,
n = 44), the FSH dose was 150 U/day. Age and basal FSH
levels were not different between groups. At ovulation
induction, total FSH doses were comparable in group I
(1631 96 U) and group III (1640 57 U) but significantly
higher in group II (2421 112 U) (P < 0.001). Peak oestradiol levels on the day of human chorionic gonadotrophin
(hCG) administration were significantly lower in group I
(5680 675 pmol/l) compared to group III
(8679 804 pmol/l) (P = 0.028). Increasing the FSH dose
from 150 to 225 U/day overcame the lower oestradiol

Introduction
Follicle-stimulating hormone (FSH) stimulates growth
and maturation of antral follicles and oestradiol production by granulosa cells and is widely used in assisted
reproduction. Assisted reproduction techniques (ART)
are indicated both for female and for male infertility and
require controlled ovarian hyperstimulation (COH) with
FSH to achieve maturation of multiple ovarian follicles
and oocytes, accompanied by high serum oestradiol levels.
It has long been known that the outcome of COH is
unpredictably variable between patients and the narrow
window between insufficient ovarian response and
development of a life-threatening ovarian hyperstimulation syndrome (OHSS) is a serious problem in individual
patients. As a result, although several ovarian stimulation
protocols have been developed in the last decades [1],
the FSH dosage for the individual patient is often chosen

response in women with Ser/Ser (group II,

7804 983 pmol/l). In women undergoing controlled ovarian hyperstimulation, the p.N680S sequence variation
results in lower oestradiol levels following FSH stimulation.
This lower FSH receptor sensitivity can be overcome by
higher FSH doses. Pharmacogenetics and Genomics
c 2005 Lippincott Williams & Wilkins.
15:451456
Pharmacogenetics and Genomics 2005, 15:451456
Keywords: FSH, FSH receptor, ovarian stimulation, ovary,
sequence variation, SNP
a

Andrology Unit, Department of Urology, bDepartment of Obstetrics and

Reproductive Medicine, University Hospital, Halle, cDepartment of Obstetrics
and Gynaecology and dInstitute of Reproductive Medicine of the
University, University Hospital, Munster, Germany.

Sponsorship: This study was supported by a research grant of the German

Research Foundation (DFG project SI 526/1).

Correspondence and requests for reprints to Professor Manuela Simoni,

Institute of Reproductive Medicine, Domagkstrasse 11, D-48149 Munster,
Germany.
Tel: + 49 251 8356 444; fax: + 49 251 835 6093;
e-mail: manuela.simoni@ukmuenster.de

Received 28 February 2005 Accepted 18 April 2005

empirically and adjusted during the cycle. The identification of parameters predicting the ovarian response to
FSH stimulation is an important issue still to be solved in
reproductive endocrinology [2].
The effects of endogenous or exogenous FSH on the
ovary can be modulated by mutations or polymorphisms
of the FSH receptor gene [3,4]. Homozygous, inactivating mutations of the FSH receptor gene result in
hypergonadotropic ovarian dysgenesis with primary ovarian failure [5]. Screening for mutations revealed the
presence of two common single nucleotide polymorphisms (SNP) in the coding region of the FSH receptor
gene [5]. In a partly retrospective study, we hypothesized
a role for one of these SNPs in determining ovarian
response to FSH [6]. This functionally important SNP
(NCBI refSNP ID: rs6166) is located in exon 10 of the

c 2005 Lippincott Williams & Wilkins

1744-6872

Copyright Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.

452 Pharmacogenetics and Genomics

2005, Vol 15 No 7

FSH receptor gene, where a G > A exchange at nucleotide position 2039 results in the occupation of codon 680
in the intracellular domain of the FSH receptor either by
asparagine (Asn) or serine (Ser) [4]. This polymorphism
is mostly in linkage dysequilibrium with a SNP at
nucleotide position 919, [919A > G; 2039G > A] (NCBI
refSNP ID: rs6165), resulting in two very common alleles
almost equally distributed (55% versus 45%) in Caucasians [4]. In our partly retrospective, non-randomized
study, the amount of FSH needed for COH to achieve
similar peak oestradiol levels was significantly lower in
homozygous women with Asn/Asn at codon 680 of the
FSH receptor gene compared to women with Ser/Ser or
Asn/Ser, indicating a lower ovarian sensitivity to FSH
in vivo of the p.N680S allele [6]. Similar results were
later obtained by other investigators [79].
This multicentre interventional study was performed to
test, in a prospective randomized controlled trial,
whether the ovarian response to FSH in COH differs
depending on the 2039G > A SNP. As a parameter of FSH
action, we chose serum oestradiol levels on the day of
ovulation induction by human chorionic gonadotrophin
(hCG). We analysed whether the same daily dose of FSH
given for COH results in lower levels of oestradiol in
women homozygous for the p.N680S allele compared to
women homozygous for the wild-type FSH receptor, and
whether a potential difference can be overcome by higher
exogenous FSH.

Patients and methods

Study design

The study protocol was approved by the Ethics

Committees of the Medical Faculties and State Medical
Boards of the Universities of Muenster and Halle,
Germany. Patient inclusion criteria for the study were:
(i) women undergoing in vitro fertilization (IVF) or
intracytoplasmic sperm injection (ICSI) therapy aged 18
39 years; (ii) normal menstrual cycle (2435 days cycle
duration); (iii) no ovarian pathology, including ovarian
cyst, ovarian endometriosis or polycystic ovary syndrome;
(iv) r 3 previous IVF or ICSI therapies; and (v) serum
FSH < 10 U/l on cycle day 3. In addition, only women
with FSH receptor genotype at codon 680 homozygous
Asn/Asn or Ser/Ser were considered. Exclusion of heterozygous women was decided to simplify the study design
and improve the power of this relatively small-scale,
proof-of-principle study. Consecutive, potentially eligible
patients from the ongoing assisted reproduction programs
of the womens hospitals of the Universities of Muenster
and Halle were informed about the study and provided
their informed consent to FSH receptor genotyping. FSH
receptor genotype was assessed in 381 consecutive
women. Of those, 175 women were heterozygous Asn/
Ser and were not further considered. Ninety-three of
206 women with homozygous FSH receptor Asn/Asn or

Ser/Ser, all of Caucasian origin, confirmed their consent to

participate in the study, were assigned to three treatment
groups, and completed the study protocol as described
below. The remaining 113 homozygous women were not
included because: (i) they were found to be ineligible
upon rechecking for the inclusion criteria; (ii) they
withdrew consent in the meantime for personal reasons;
or (iii) they opted for the routine stimulation protocol.
The study design was based on the hypothesis that the
same FSH dose would be less efficient in stimulating
oestradiol levels in Ser/Ser women compared to Asn/Asn
women, and that increasing the FSH dose in the Ser/Ser
women would result in a response similar to that obtained
in Asn/Asn women with a lower dose. The three
treatment groups (I, II, III) of the study were defined
considering that COH starts usually with an FSH dose of
150 U/day. Groups were assigned as follows. Both groups I
(n = 24) and II (n = 25) included women with the
homozygous Ser/Ser genotype, which were randomized
to be treated with a FSH dose of 150 U/day (group I) or
225 U/day (group II), respectively. Randomization was
performed by opening consecutively numbered sealed
envelopes containing group assignments, which were
determined previously based upon random numbers.
Group III (n = 44) included all women with the
homozygous Asn/Asn genotype. These women were all
treated with a FSH dose of 150 U/day. In all three groups,
the daily FSH dose was kept constant until ovulation
induction and dose adjustment was not allowed. IVF or
ICSI therapy was performed according to standard
protocols. Premature luteinization was prevented by
administration of gonadotrophin-releasing hormone
(GnRH) analogues. A follicle size of at least 17 mm
diameter, independent of oestradiol serum concentration,
was the criterion for hCG administration for ovulation
induction. There was no restriction to a specific
pharmaceutical preparation of FSH (urinary or recombinant) or GnRH analogues (agonist or antagonist) to
reflect best daily practice therapy.
Based on the results of our previous retrospective study
[6], the primary endpoint parameter of the study was the
serum concentration of oestradiol at the time of hCG
injection for ovulation induction. The power analysis for
the study and determination of the sample size was based
on this primary end point. The study was not powered to
detect differences in follicle or oocyte number, pregnancy
rates or adverse side-effects, such as severe OHSS.
Assessment of FSH receptor genotype

The FSH receptor genotype at position 680 in exon 10

was analysed by the Taqman allelic discrimination assay,
using the Taqman machine (ABI Prism 7000 sequence detection system, Applied Biosystems, Darmstadt,
Germany), as described previously [10].

Copyright Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.

Pharmcogenetics of FSH treatment Behre et al. 453

Serum FSH and oestradiol were measured by immunofluorimetric assay and by fluorimmunoassay, respectively,
using the Autodelfia system (Perkin Elmer, Freiburg,
Germany), as described previously [11]. The sensitivities
of the assays were 0.05 IU/l and 25 pmol/l for FSH and
oestradiol, respectively. Intra- and interassay coefficient
of variations were < 3% and < 7% for FSH and
oestradiol, respectively.

Fig. 1

3000

Results
Age (group I, n = 24: 32.7 0.7 years; group II, n = 25:
33.9 0.7 years; group III, n = 44: 32.7 0.6 years;
ANOVA: P = 0.39) and basal FSH levels on cycle day 3
(group I: 5.9 0.4 U/l; group II: 6.1 0.5 U/l; group III:
5.7 0.3 U/l; ANOVA: P = 0.72) were not different
between groups.
Total FSH doses for ovarian stimulation were comparable
in group I (1631 96 U) and group III (1640 57 U),
whereas FSH dose was significantly higher in group II
(2421 112 U) (ANOVA: P < 0.001) (Fig. 1, upper
panel), in the presence of no difference in the total
duration of FSH stimulation (Table 1). This confirms
that women in group II were indeed exposed to a 50%
higher amount of FSH compared to groups I and III.
Because the only parameter for deciding when to
discontinue FSH stimulation and proceed with ovulation
induction was follicular diameter, these data indicate
similar follicular development dynamics in the three
groups, independently of the total FSH dose applied.
The frequency distribution of women treated with

2000
1500
1000
500

Statistical analysis

0
Ser/Ser
150 U/day FSH

Ser/Ser
Asn/Asn
225 U/day FSH 150 U/day FSH

10 000
Oestradiol (pmol/l)

Statistical calculations were performed by SigmaStat for

Windows, version 2.03 (SPSS Inc., Chicago, Illinois,
USA). The results are shown as means SEM. All
variables were checked for normal distribution by the
KolmogorovSmirnov test and equal variance. For the
variables oestradiol serum concentration and duration of
FSH stimulation, analysis was performed on log-transformed data to achieve normal distribution. Differences
between groups were tested by one-way analysis of
variance (ANOVA). In the case of significant overall
differences, differences between the individual groups
were analysed by a posteriori StudentNewmanKeuls
(SNK) tests. Because no normal distribution by logtransformation could be achieved for the variables total
FSH stimulation dose and cumulative embryo score, the
respective analysis was performed by KruskalWallis oneway ANOVA with Dunns method. Differences in
frequency distribution of recombinant versus urinary
FSH and GnRH agonists versus antagonists, and differences in pregnancy rates between study groups, were
tested by the chi-square test. P < 0.05 (two-tailed) was
considered statistically significant.

2500
Total FSH dose (U)

Hormone analysis

8000

6000
4000
2000
0
Ser/Ser
150 U/day FSH
Group I

Ser/Ser
225 U/day FSH
Group II

Asn/Asn
150 U/day FSH
Group III

Total follicle-stimulating hormone (FSH) dose (mean SEM, upper

panel) and oestradiol levels (lower panel) in the three study groups.
Serum levels of oestradiol before ovulation induction were significantly
lower in women with the Ser/Ser allele variant (group I, n = 24)
compared to the Asn/Asn allele variant (group III, n = 44) of the FSH
receptor (lower panel: *significant difference between group I and III).
This difference in ovarian response could be overcome by increasing
the daily FSH dose from 150 U/day to 225 U/day (upper panel:
*significant higher total FSH dose) in women with the Ser/Ser allele
variant (group II, n = 25); lower panel: no significant difference between
group II and III.

recombinant versus urinary FSH and of women treated

with GnRH agonist versus antagonist was similar in the
three groups (P = NS, chi-squared) (Table 2).
Oestradiol levels on the day of hCG administration were
significantly different among the three groups (ANOVA:
P = 0.028). In particular, oestradiol levels were significantly lower in group I (5680 675 pmol/l) compared to
group III (8679 804 pmol/l) (SNK test: group I versus
III, P < 0.05; Fig. 1, lower panel). Increasing the FSH
stimulation dose from 150 to 225 U/day was able to
overcome the lower oestradiol response in women with
the Ser/Ser FSH receptor variant (group II,
7804 983 pmol/l) (SNK test: group II versus III,
P > 0.05) (Fig. 1, lower panel).
As shown in Table 1, no differences were seen between
the groups for number of follicles, retrieved oocytes,

Copyright Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.

454

Pharmacogenetics and Genomics 2005, Vol 15 No 7

Table 1 Baseline characteristics and results of controlled ovarian hyperstimulation depending on follicle-stimulating hormone (FSH)
stimulation dose and FSH receptor genotype in the three study groups
Group I: Ser/Ser; 150 U/day FSH
Age of the women (years)
Early follicular phase FSH (U/l)
Duration of FSH stimulation (days)
Ovarian follicles > 10 mm diameter
before hCG administration (n)
Retrieved oocytes (n)
Fertilization rate (%)
Cumulative embryo score
Clinical pregnancy rate

32.7 0.7
5.9 0.4
10.9 0.6
10.2 1.1

Group II: Ser/Ser; 225 U/day FSH

(25.138.6)
(2.09.4)
(621)
(125)

33.9 0.7
6.1 0.5
10.8 0.5
11.3 1.1

8.7 0.9 (017)

58.6 7.9 (0100)
26.5 2.9 (448)
5/24

(26.339.7)
(2.29.4)
(716)
(423)

11.0 1.1 (225)

62.2 5.2 (8100)
28.5 3.1 (464)
4/25

Group III: Asn/Asn; 150 U/day FSH

32.7 0.6
5.7 0.3
11.1 0.4
12.3 0.8

(25.539.3)
(2.69.9)
(718)
(329)

10.2 0.7 (122)

53.4 4.7 (0100)
29.2 2.8 (296)
10/44

P
0.39
0.72
0.82
0.30
0.25
0.52
0.79
0.80

Data are mean SEM (range) and proportions, respectively. hCG, Human chorionic gonadotrophin.

Table 2 Number of patients treated with recombinant versus urinary follicle-stimulating hormone (FSH) as well as gonadotrophinreleasing hormone (GnRH) agonist versus antagonist in each study group

Recombinant/urinary FSH
GnRH agonist/antagonist

Group I: Ser/Ser; 150 U/day FSH

Group II: Ser/Ser; 225 U/day FSH

Group III: Asn/Asn; 150 U/day FSH

22/2
19/5

23/2
19/6

37/7
39/5

0.51
0.35

fertilization rate, cumulative embryo score, and clinical

pregnancy rate. No woman experienced severe OHSS.

Discussion
This prospective interventional study is the first randomized controlled trial to demonstrate a differential
oestradiol response to FSH due to the SNP at nucleotide
position 2039 of the FSH receptor gene. We are able to
show that the same FSH dose for COH results in
significantly lower serum levels of oestradiol in women
homozygous for Ser/Ser at codon position 680 compared
to women homozygous for Asn/Asn. These results confirm
previous data obtained by us and by other groups in
retrospective, non-randomized, cross-sectional trials [6
9]. At odds with our previous study [6], day 3 serum
FSH levels were not different among the groups.
However, this is not surprising because women with
FSH levels >10 IU/l were excluded and the number of
subjects considered was much lower in the present study.
In addition, in a very recent study involving menstrual
cycle monitoring in women with normal, mono-ovulatory
cycles, we demonstrated that women homozygous for Ser
at codon 680 have significantly higher serum FSH levels
between the luteal-follicular transition up to ovulation
than women homozygous for Asn, in the presence of
similar serum oestradiol levels (Greb et al., unpublished
data). These data demonstrate convincingly that FSH is
less efficient in women with the p.N680S FSH receptor
sequence variation, at least in terms of oestradiol
production.
Despite differences in oestradiol levels, no significant
differences were detected in the number of follicles or
retrieved oocytes. In addition, fertilization rate, cumulative embryo score and pregnancy rate were similar in the
three groups. However, the present study was not

powered to address possible differences in these parameters, which were not the primary end point and require
much larger multicentre trials. In any case, our data
suggest that differences in oestradiol levels due to the
FSH receptor polymorphism do not appear to have major
effects on IVF/ICSI outcome, indicating that the two
main functions of FSH (i.e follicular development and
stimulation of oestradiol production) might be uncoupled
and/or involve different downstream pathways of the FSH
receptor. Oestradiol production depends on the availability of androgen substrate, which is luteinizing
hormone (LH)-dependent. FSH stimulates expression
of LH receptors [12]. It is tempting to speculate that the
p.N680S FSH receptor is less effective in inducing LH
receptor and/or aromatase expression, a hypothesis which
might be investigated in granulosa cells retrieved from
women undergoing COH.
In the present study, the decreased sensitivity of the
FSH receptor regarding oestradiol production could be
overcome by a 50% increase of the exogenous FSH dose.
This finding is of major clinical relevance because women
homozygous for Asn at codon 680 who are stimulated with
the same amount of FSH as women homozygous for Ser
will achieve significantly higher oestradiol levels, which
might affect adequate endometrial maturation in these
patients [13] or might even put them at greater risk for
OHSS, a potentially life-threatening condition. Although
FSH itself is not responsible for OHSS, the response to
gonadotropin stimulation (i.e. development of multiple
follicles and rapid increase of oestradiol levels) are wellknown risk factors [14]. A recent retrospective association
study demonstrated that the FSH receptor p.N680S
variant was significantly more represented in women
developing iatrogenic OHSS but that the wild-type allele
was significantly associated with the severity of OHSS

Copyright Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.

Pharmcogenetics of FSH treatment Behre et al. 455

[15]. Together with our data, these findings strongly

suggest that women with Asn at codon 680 undergoing
COH for IVF/ICSI are at risk of excessive stimulation
with FSH, which might result in severe iatrogenic OHSS.
Therefore, this FSH receptor SNP should be considered
before starting COH for IVF/ICSI.
The individual response to FSH stimulation in COH is
rather variable and many studies have attempted to
identify predictive factors of ovarian response that could
be useful in determining the gonadotropin stimulation
protocol and the FSH starting dose. Age and day 3 FSH
levels have been used as an indicator of ovarian response
in ART. In addition, antral follicle count and ovarian
volume are useful in predicting ovarian response to
hormone stimulation [16]. More recently, other factors,
such as serum inhibin B and antimullerian hormone
concentrations, have been considered [17]. Our data
suggest that the FSH receptor exon 10 SNP should be
considered as well, at least in women with normal ovarian
function. The available data of the literature support our
conclusion. One recent non-randomized study found
significantly lower oestradiol levels per retrieved oocyte
in women with the Ser/Ser variant treated by high hMG
doses in IVF cycles [7], corroborating our original finding
[6]. In another non-randomized study, the number of
poor responders to FSH stimulation in IVF/ICSI cycles
was significantly higher in women with the Ser/Ser
variant compared to the Asn/Asn and Asn/Ser variants [8].
Admittedly, our study has a number of limitations that
need to be considered. Among them, the relatively low
number of subjects, the exclusion of heterozygous
women, and the use of different FSH and GnRH analog
preparations should be mentioned. Knowing these limits,
we chose a primary end point (serum oestradiol level) for
which the study was sufficiently powered. Larger
numbers of patients can be achieved only with much
larger multicentre trials, in which heterozygous women
should be considered as well and a fixed protocol, based
on the same FSH and analog preparation, should be
applied. Such a trial could effectively analyse the ovarian
response in terms not only of oestradiol concentrations,
but also of follicular growth, number of oocytes retrieved,
pregnancy rate, number of live births and side-effects,
including severe OHSS.
Notwithstanding its drawbacks, this randomized, controlled study demonstrates a differential response of
serum oestradiol levels in women receiving FSH for
COH. These results are of immediate clinical relevance
for infertile women treated by ART. If treatment cycles
are primarily monitored by ultrasonography of ovarian
follicular development, comparable daily and total
exogenous FSH doses result in similar follicular growth
but in different oestradiol serum levels depending on the
FSH receptor allele variant at codon 680. Individual

patients with Asn/Asn at codon 680 achieving high levels

of oestradiol and potentially other ovarian factors could be
at increased risk for the severe OHSS. Conversely, if
treatment cycles are primarily monitored by serum levels
of oestradiol, these patients, with higher sensitivity for
oestradiol production, might have a decreased follicular
response and lower numbers of retrievable oocytes
because of lower exogenous FSH administration.
In conclusion, the present study has proven that a
common FSH receptor SNP influences ovarian response
to FSH in COH. In perspective, in women with normal
ovarian function undergoing ART, it might be possible to
define the optimal FSH starting dose based on the simple
determination of the FSH receptor genotype. This
should be investigated further in large prospective,
randomized, multicentre trials to determine whether
such a pharmacogenetic approach to ovarian stimulation
will prove advantageous both in terms of number of live
births and safety.

Acknowledgements
The skilful technical assistance of N. Terwort and the
language editing of S. Nieschlag are gratefully acknowledged.

References
1

Cohen J. A short review of ovarian stimulation in assisted reproductive

techniques. Reprod Biomed Online 2003; 6:361366.
2 Kligman I, Rosenwaks Z. Differentiating clinical profiles: predicting good
responders, poor responders, and hyperresponders. Fertil Steril 2001;
76:11851190.
3 Simoni M, Gromoll J, Nieschlag E. The follicle-stimulating hormone receptor:
biochemistry, molecular biology, physiology, and pathophysiology. Endocr
Rev 1997; 18:739773.
4 Simoni M, Nieschlag E, Gromoll J. Isoforms and single nucleotide
polymorphisms of the FSH receptor gene: implications for human
reproduction. Hum Reprod Update 2002; 8:413421.
5 Aittomaki K, Lucena JL, Pakarinen P, Sistonen P, Tapanainen J, Gromoll J,
et al. Mutation in the follicle-stimulating hormone receptor gene
causes hereditary hypergonadotropic ovarian failure. Cell 1995; 82:
959968.
6 Perez Mayorga M, Gromoll J, Behre HM, Gassner C, Nieschlag E, Simoni M.
Ovarian response to follicle-stimulating hormone (FSH) stimulation
depends on the FSH receptor genotype. J Clin Endocrinol Metab 2000;
85:33653369.
7 Sudo S, Kudo M, Wada S, Sato O, Hsueh AJ, Fujimoto S. Genetic and
functional analyses of polymorphisms in the human FSH receptor gene. Mol
Hum Reprod 2002; 8:893899.
8 de Castro F, Ruiz R, Montoro L, Perez-Hernandez D, Sanchez-Casas Padilla
E, Real LM, et al. Role of follicle-stimulating hormone receptor Ser680Asn
polymorphism in the efficacy of follicle-stimulating hormone. Fertil Steril
2003; 80:571576.
9 de Castro F, Moron FJ, Montoro L, Galan JJ, Hernandez DP, Padilla ES, et al.
Human controlled ovarian hyperstimulation outcome is a polygenic trait.
Pharmacogenetics 2004; 14:285293.
10 Ahda Y, Gromoll J, Wunsch A, Asatiani K, Zitzmann M, Nieschlag E, Simoni
M. FSH receptor gene haplotype distribution in normozoospermic and
azoospermic men. J Androl 2005, in press.
11 Simoni M, Gromoll J, Hoppner W, Kamischke A, Krafft T, Stahle D,
et al. Mutational analysis of the follicle-stimulating hormone (FSH)
receptor in normal and infertile men: identification and characterization of
two discrete FSH receptor isoforms. J Clin Endocrinol Metab 1999;
84:751755.
12 Zeleznik AJ. The physiology of follicle selection. Reprod Biol Endocrinol
2004; 2:31.

Copyright Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.

456

Pharmacogenetics and Genomics 2005, Vol 15 No 7

13 Kosmas IP, Kolibianakis EM, Devroey P. Association of estradiol levels on the

day of hCG administration and pregnancy achievement in IVF: a systematic
review. Hum Reprod 2004; 19:24462453.
14 Delvigne A, Rozenberg S. Related review of clinical course and treatment of
ovarian hyperstimulation syndrome (OHSS). Hum Reprod Update 2003;
9:7796.
15 Daelemans C, Smits G, de Maertelaer V, Costagliola S, Englert Y, Vassart G,
et al. Prediction of severity of symptoms in iatrogenic ovarian
hyperstimulation syndrome by follicle-stimulating hormone receptor

Ser680Asn polymorphism. J Clin Endocrinol Metab 2004; 89:

63106315.
16 Bancsi LF, Broekmans FJ, Eijkemans MJ, de Jong FH, Habbema JD, te Velde
ER. Predictors of poor ovarian response in in vitro fertilization: a prospective
study comparing basal markers of ovarian reserve. Fertil Steril 2002;
77:328336.
17 Muttukrishna S, Suharjono H, McGarrigle H, Sathanandan M. Inhibin B and
anti-Mullerian hormone: markers of ovarian response in IVF/ICSI patients?
BJOG 2004; 111:12481253.

Copyright Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.