Review TRENDS in Endocrinology and Metabolism
8 October 2005
Genetic complexity of FSH receptor
function
Jörg Gromoll and Manuela Simoni
Institute of Reproductive Medicine, Domagkstrasse 11, 48129 Münster, Germany
The interaction between follicle-stimulating hormone
(FSH) and the FSH receptor (FSHR) is essential for normal
oogenesis and spermatogenesis. Recently, single-nucleo-
tide polymorphisms (SNPs) have been assigned to the
FSHR gene. These give rise to different FSHR haplotypes
that modify the action of FSH. In women, FSH sensi-
tivities during the menstrual cycle and different cycle
lengths are observed, depending on the FSHR haplo-
type. Thus, SNPs of the FSHR determine the ovarian
response and should, therefore, be considered in con-
trolled ovarian hyperstimulation during assisted-repro-
duction techniques in women with normal ovarian
function. In men, the impact of the FSHR SNPs is
unclear. The genetic complexity of FSHR should be
considered when studying FSH action. These SNPs are
one of the first examples in which genetic changes
contribute to fine-tuning the endocrine regulation of
reproduction. A rational pharmacogenetic approach
that combines FSH dose according to the FSHR haplo-
type is envisaged.
Introduction
Follicle-stimulating hormone (FSH) is a key player in
human reproduction [1,2]. This pituitary gonadotropin
consists of two subunits, the a- and the b-subunits, and it
exerts its throphic and stimulatory effects on gameto-
genesis by binding to a specific receptor that is located
exclusively on the surface of Sertoli cells in the testis and
granulosa cells in the ovary (Box 1). The FSH receptor
(FSHR) is a G-protein-coupled receptor whose main
signal-transduction mechanism involves activation of
protein kinase A (PKA); however, PKB and PKC are
also involved [3–5].
Recently, the nature of the FSH–FSHR interaction has
been resolved by crystallizing FSH in a complex with the
extracellular domain of FSHR [6]. According to this, the
extracellular FSHR domain is shaped as a slightly curved
tube. An a-subunit and a b-subunit of FSH bind to the
inner, slightly concave face of the tube in a hand-clasp
fashion, and binding specificity is mediated by amino acids
in both subunits. Binding to the receptor involves con-
formational changes in the hormone, with the a-subunit-
loops adjusting their shape to reach optimal interaction.
The extracellular FSHR domain that is occupied by the
hormone forms dimers in the crystal, which indicates
Corresponding author: Gromoll, J. (Joerg.Gromoll@ukmuenster.de).
Available online 26 August 2005
www.sciencedirect.com 1043-2760/$ - see front matter Q 2005 Elsevier Ltd. All rights reserved. doi:10.1016/j.tem.2005.05.011
Vol.16 No.
that receptor dimerization might participate in signal
transduction.
The description of naturally occurring mutations of
the FSHR highlights the role of this gonadotropin in
male and female gonadal function (reviewed in [3,7–11])
and provides further evidence that spermatogenesis is
impaired and follicular maturation is halted by disruption
of FSH action. In addition, mutations that result in either
constitutive activation [12] or loss of binding specificity for
FSH, which result in human chorionic gonadotropin
(hCG)-induced ovarian hyperstimulation syndrome
[13–15], have been described (Box 1). However, studies
during the past decade demonstrate that mutations in
FSHR are rare. By contrast, mutation screening shows
that the FSHR gene contains several single-nucleotide
polymorphisms (SNPs), some of which are common and
might influence receptor activity. In this review we
summarize the current knowledge of the (patho)physio-
logical importance of SNPs in the FSHR gene.
SNPs
From sequencing the human genome and searching for
mutations in several pathophysiological conditions, it is
evident that genetic variations caused by SNPs are
frequent and occur in the hormones and receptors of the
hypothalamic–pituitary–gonadal axis [9,16]. In general,
the incidence of polymorphisms in a given gene ranges
Box 1. The FSH receptor
Gene: Chromosome 2 p21-p16; 10 exons spanning 54 kb (NCBI
database http://www.ncbi.nlm.nih.gov/entrez/; GeneID:2492; Locus
tag:HGNC:3969).
Protein family: G-protein-coupled receptor.
Structure: 678 amino acids; seven transmembrane domains; the
extracellular domain (359 amino acids) consists of 10 leucine-rich
repeats that form a horseshoe-shaped pocket for hormone binding.
Expression: Ovary, granulosa cells; testis, Sertoli cells.
Ligand: FSH.
Signal transduction pathway: PKA, PKB and PKC.
Pathophysiology of FSHR mutations: OMIM 136435
Male:
Activating mutation: sustained spermatogenesis without
gonadotropins
Inactivating mutations: hypospermatogenesis
Female:
Activating mutation: no activating mutations have been identified
Inactivating mutation: FSH-resistance syndrome, primary or second-
ary amenorrhoea with the presence of primordial follicles
Ligand-sensitive mutation: increased sensitivity to human
chorionic gonadotropin (hCG). Ovarian hyperstimulation syndrome
caused by hCG.
 Review TRENDS in Endocrinology and Metabolism Vol.16 No.8 October 2005 369

from 15 to 50% in the normal population. This indicates
that such genetic changes have no pronounced effects on
reproduction, otherwise evolution would have exerted
deleterious effects on them. Polymorphisms can affect
gene function by at least two mechanisms: by changing the
biochemical properties of the gene product directly; and
by acting at the transcriptional level to modify the activity
of the promoter. SNPs generate genetic diversity and
complexity within species [17]. It is possible that genetic
changes, such as SNPs, either singly or in combination,
modify and fine-tune endocrine-feedback systems and
hormone action. This results in variable inter-individual
reproductive performance that ranges from fully func-
tional gametogenesis to subfertility.
SNPs in FSHR
To date, the National Center for Biotechnology Infor-
mation (NCBI) SNP database (http://www.ncbi.nlm.nih.
gov/SNP/) indicates that there are 731 SNPs in the FSHR
gene. Only five of these are in the coding region (exons),
the rest are intronic. One SNP is located in the 5 0 untrans-
lated region of FSHR mRNA at position –29 (ss2189241).
The five SNPs in the coding region occur in exon 10,
at codons 307, 329, 524, 665 and 680, and four are
non-synonymous (result in amino acid substitution).
Although the Ala307Thr (rs6165) and the Ser680Asn
(rs6166) polymorphisms are well characterized with
respect to frequency and ethnic distribution (see below),
there is no information on the prevalence of the
Ala665Thr, Arg524Ser and the synonymous Thr329Thr
polymorphisms.
There are differences in the number of SNPs in the
FSHR genes of humans, mice and rats. Only 25 intronic
SNPs are described in mice and only four SNPs in exon 10
of rat FSHR. Although SNPs in mice and other species
might have received less attention than in humans,
this marked difference supports the view that genetic
polymorphisms spread late in evolution and are most
prevalent in humans [17].
The FSHR promoter
The promoter of the FSHR gene in humans, rats, mice and
sheep is in a class of promoters that lack conventional
TATA and CCAAT boxes and have multiple transcription
start sites. A core promoter region of human FSHR, which
displays the highest transcriptional activity but no cell
specificity, is assigned to a region between K225 and K1
relative to the translational start site [18–21]. To date, two
response elements have been identified within this core
promoter region. An E-box consensus sequence (CACATG),
which interacts with a family of basic helix–loop–helix
transcriptional factors such as USF, is required for full
promoter function [19,21–24]. Recently, it has been shown
that the sequence region covering the E-box might also be
the binding target for factors such as chicken ovalbumin
upstream promoter-transcription factors (COUP-TF) that
repress FSHR expression. Thus, the net regulation of the
FSHR gene might result from the relative availability of
repressors and activators in a given physiological state
[22]. The second element is an initiator element (Inr),
which has been identified covering the region of the
transcriptional start site, and is typical of housekeeping
genes (Figure 1) [21].
SNPs in the FSHR promoter
In accordance with the SNP database, a G/A SNP with a
heterozygosity rate of 0.6 occurs at position K29 within
the core promoter region of the FSHR. The A nucleotide
is conserved in chimpanzees and sheep, whereas G is
present in rats (Figure 1). This SNP is embedded in the
consensus sequence GG/AAA, which represents a putative
binding site for a c-E-twenty-six specific (c-ETS) tran-
scription factor. However, functional studies in COS-7
cells, and in granulosa- and Sertoli-cell lines, which

Initiation complex
USF USF

mRNA

–99
Exon 1
OligoA E-box
–257 bp Inr

–157 to –141 –124 to –119 –100 to –94 –29

Human An, n=13–17 CACATG Consensus A/G
Chimp AACAACA7 G T/C T/C A N T/A T/C T/C A
Ovine GAA6GA8GGA3 G A
Rat TA7 G G
TRENDS in Endocrinology & Metabolism

Figure 1. Schematic representation of the core promoter of human FSHR and the localization of polymorphisms. Indicated are the regulatory elements, including the E-box,
initiatior element region (Inr), the K29 SNP (yellow) and the variable oligoA stretch (yellow), and the transcription initiation complex with the corresponding transcriptional
start site. A sequence comparison of the human, chimpanzee, sheep and rat FSHR promoter for the SNPs and the regulatory elements within the core promoter region is
given in the bottom part of the figure. The chimpanzee nucleotide sequences were compiled from the chimpanzee genome database at the NCBI using the Pan troglodytes
chromosome 2A genomic contig NW_103405. The other sequences were obtained from GenBank: human FSHR accession No. X91738, ovine FSHR accession No. AF090438
and rat FSHR accession No. S81117.

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370 Review TRENDS in Endocrinology and Metabolism
measure activity of a luciferase reporter gene driven by
the core promoter region of FSHR (which contains this
SNP), reveal no significant differences in promoter
activity [25]. Therefore, in vitro data show no significant
effect of this SNP on gene transcription.
A detailed sequence comparison of the FSHR core
promoter region reveals another polymorphic region
covering an oligo A-stretch that is polymorphic in humans
(A11–17) and varies between species (Figure 1) [25].
However, neither the incidence of this polymorphism nor
functional data are available.
Recently, we have analyzed the effects of the SNP at
position K29 in 186 normozoospermic and 345 azo-
ospermic men. The genotype distribution is similar in
both groups, with the A–29 allele less frequent (25%) than
the G–29 allele (75%). In addition, this polymorphism does
not correlate with serum levels of FSH [25]. Therefore,
these in vivo data confirm the in vitro observation that the
SNP at position K29 is unlikely to influence FSH activity
directly when considered alone.
SNPs in exon 10 of FSHR
Exon 10 encodes the C-terminal end of the extracellular
domain, the entire transmembrane domain and the
intracellular domain of FSHR [3]. Although exon 10 is
fundamental for signal transduction, it is not necessary
for ligand binding. The transmembrane domain, however,
might contact hormone bound to the extracellular domain,
in particular to loops L1 and L3 of the a-subunit [6].
The two most common SNPs in the coding region of
FSHR occur at nucleotides 919 and 2039 in exon 10
(where 1 is the A of the ATG translation start codon),
which correspond to amino acid positions 307 and 680,
respectively, of the mature protein [26,27]. Residue 307 is
in the hinge region of the receptor. This region, which
is highly variable in the three glycoprotein hormone
receptors (FSHR, luteinizing hormone receptor and
thyroid-stimulating-hormone receptor), connects the
hormone-binding domain to the transmembrane domain.
The corresponding residue is not conserved in the
glycoprotein hormone receptors. Residue 680 is in the
intracellular, C-terminal domain in a region that also
varies between the three receptors. No roles have been
identified for residues 307 and 680.
The two polymorphisms in exon 10 are in linkage dis-
equilibrium and result in two major, almost equally
common, allelic variants in Caucasians: Thr307–Asn680
and Ala307–Ser680 [16,27], with the Ala307–Ser680
variant occurring in w40% of the population world-
wide. The other two combinations (Thr307–Ser680 and
Ala307–Asn680) are less common and constitute !5% of
FSHR alleles.
Effects of exon 10 SNPs on ovarian function
Controlled ovarian hyperstimulation
Studies in women with normal ovarian function demon-
strate that SNPs in exon 10 modulate FSHR function and
the ovarian response to FSH. This effect was observed first
in a partly retrospective, non-randomized study involving
women who were undergoing controlled ovarian hyper-
stimulation (COH) for assisted reproduction. It was shown
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Vol.16 No.8 October 2005
that the amount of FSH needed for COH to achieve similar
peak estradiol levels is significantly lower in women who
are homozygous for the Asn680 variant compared with
women who are either homozygous for Ser680 or are
heterozygous, indicating a lower ovarian sensitivity to
FSH in vivo of the Ser680 variant [28]. Similar results
have been obtained by others [29–31].
This observation has been corroborated recently in a
prospective interventional study in which a randomized,
controlled trial design showed a differential response of
estradiol to FSH because of the SNP at codon 680 of
FSHR. In this study, women undergoing COH were
administered the same dose of FSH but this resulted in
significantly lower serum levels of estradiol in Ser680/
Ser680 homozygote women compared with women with
Asn680/Asn680 homozygote women variant. This lower
response is overcome by increasing the FSH dose [32].
Despite differences in estradiol levels, no significant
differences were detected in either the number of follicles
or retrieved oocytes, fertilization rate, cumulative embryo
score and pregnancy rate. This indicates that, according to
the current protocols, some women might receive too much
FSH, thus putting them at risk of ovarian hyperstimula-
tion syndrome (OHSS), which depends indirectly on
excessive stimulation by FSH. Indeed, a recent, retro-
spective, association study has demonstrated that the
Ser680 variant occurs significantly more often in women
that develop iatrogenic OHSS but that the Asn680 variant
is associated with the severity of OHSS [33]. Therefore,
women with the Asn680 genotype that are undergoing
COH might be at risk for excessive stimulation with FSH,
which might increase the risk of severe iatrogenic OHSS.
Normal menstrual cycle
Generally, studies in women that are undergoing COH
indicate that ovarian FSH threshold is influenced by SNPs
in exon 10 of the FSHR. This concept is confirmed by a
recent study in which the menstrual cycle in women with
normal, mono-ovulatory cycles has been monitored.
During the luteo–follicular transition, serum levels of
estradiol, progesterone and inhibin A are significantly
lower, and FSH starts to rise earlier, in women who are
homozygous for the allele that encodes Ser680 compared
with women who are homozygous for Asn680. In addition,
FSH levels are significantly higher during the follicular
phase in this group (Figure 2), but no differences were
observed between groups in estradiol, inhibin B and growth
velocity of the dominant follicle, which shows that higher
concentrations of endogenous FSH are necessary to achieve
physiological ovulation in women who are homozygous for
Ser680. In addition, menstrual cycles are significantly
longer, with a difference of about three days in these
women. Thus, the Ser680/Ser680 genotype results in a
higher ovarian threshold for FSH, decreased negative feed-
back to the pituitary and a longer menstrual cycle [34].
Pathological ovarian function
Although clear in women with normal ovarian function,
the impact of this FSHR polymorphism in anovulation
and amenorrhea remains controversial. An association
between the Ser680 genotype and amenorrhea/anovulation
 Review TRENDS in Endocrinology and Metabolism
15 Menstruation
10
FSH (IU/L)
5 although the SNPs in exon 10 might have physiological
0 stimulation. In men, inhibin B responds indirectly to the
–25 –20 –15 –10 –5 0 effects of FSH on spermatogonial proliferation and, thus,
Day relative to midcycle LH peak
Asn/Asn Ser/Ser
TRENDS in Endocrinology & Metabolism
Figure 2. Menstrual-cycle-dependent serum levels of FSH referenced to the day of
the luteinizing hormone (LH) surge (0) in women with the Asn680/Asn680 (nZ12)
and the Ser680/Ser680 (nZ9) genotype from the luteo–follicular transition phase
(day K25) until ovulation (day 0). Results are meanGSEM. There is a statistically
significant difference between the two groups (Mann-Whitney-U test P!0.05) on
most days from day K18 until ovulation. (Reproduced from [34] with permission).
is described occasionally [29,35], whereas other studies
find no association between FSHR polymorphisms and
premature ovarian failure [36,37]. The Asn/Ser allele
variant is more common in Japanese women with poly-
cystic ovary syndrome than in normal controls [29]. No
difference was found in women with polycystic ovary
syndrome in the UK [36] and Singapore [38]. Similarly, no
association has been identified between FSHR polymorph-
isms and twinning [27,39]. In a non-randomized trial,
normogonadotropic anovulatory women who failed to
either ovulate or conceive after administration of clomi-
phene citrate have been treated with low-dose FSH to
induce ovulation [35]. No significant difference in the dose
of FSH needed for mono-follicular development was
detected between women with different allele variants of
the FSHR. Therefore, it appears that the effect of the
FSHR allele variants on the estradiol response is evident
only in women with normal ovarian function. However,
more extensive, prospective trials are necessary to inves-
tigate the precise physiological role of the allele variants
in women with pathologic ovarian function.
Effects of exon 10 SNPs on testicular function
In contrast to observations in women with normal ovarian
function, SNPs in exon 10 of the FSHR have no effect on
serum levels of FSH and other clinical parameters in men
with either normal or impaired spermatogenesis [26,40].
This sex-related difference is striking and might be caused
by the still unsolved role of FSH in spermatogenesis.
Studies in women indicate that inhibin A, which is not
present in men, is a major factor in the feedback control
of serum FSH, whereas inhibin B might function as a
marker of the number of developing follicles: higher
concentrations of inhibin B in women with the Ser680
variant of the FSHR do not suppress serum FSH, which is
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Vol.16 No.8 October 2005 371
higher in these women compared with those with the
Asn680 genotype [34]. These data indicate that inhibin A,
together with estradiol and progesterone in the luteal
phase, might be responsible for the difference in FSH
concentrations that correlates with the polymorphism in
exon 10 of the FSHR observed in women. These luteal
hormones are irrelevant for the feedback control of FSH
secretion in men and there are no differences in FSH
levels in men with different FSHR genotypes. Therefore,
effects in the testis, there is no good parameter to measure
this. Inhibin B is not a good marker because, unlike
estradiol in women, it does not respond directly to FSH
spermatogenesis. The total sperm count might be a better
parameter to discern functional differences that relate
to the SNPs in exon 10 in normal men, but this has not
been investigated.
Functional effects of FSHR SNPs in vitro
The molecular mechanism of the ‘resistance’ of Ser680-
FSHR to FSH is unclear. Studies in vitro following
transient transfection of COS7 and HEK cells show that
SNPs do not alter FSH binding and signal transduction
measured by cAMP and inositol (1,4,5)-triphosphate 3
[Ins(1,4,5)P3] stimulation [26,29]. FSH-dependent events
in granulosa cells, such as progesterone and estradiol
production, might be differentially regulated by poorly
understood mechanism(s) that either do not involve or
only partly involve cAMP production and PKA stimu-
lation. However, nuclear transcription factors such as
liver receptor homolog-1, and, possibly, steroidogenic
factor-1 and dosage-sensitive sex reversal-adrenal hypo-
plasia congenita critical region on the X-chromosome 1
(DAX-1) might be involved in the differential control of
estrogen and progesterone production by granulosa cells
[41]. No differences are seen when cAMP (the earliest
measurable effect of FSH stimulation in the signal-
transduction cascade) is measured after stimulation of
the two FSHR variants. Future studies, possibly in human
granulosa cells, are needed to ascertain if the two variants
activate different signal-transduction pathways down-
stream of cAMP/ Ins(1,4,5)P3 and/or whether quantitative
differences are observed. For example, the Ser680 (i.e. a
potential site of phosphorylation) is located in a region
that is important for receptor recycling [42]. Interestingly,
the C-terminal truncation of the human FSHR involving
the amino acid at position 680 results in rerouting of
the internalized receptor to lysosomes and increases
FSH-induced downregulation without affecting the pro-
duction of either cAMP or Ins(1,4,5)P3 [42]. It should be
considered that, in vivo, receptors are usually activated at
a low level of occupancy. If there is less Ser680 FSHR at
the cell surface, both promoter activity and intracellular
fate of the receptor protein might play a role in deter-
mining a quantitatively lower stimulation in response to
FSH, but this is difficult to address in vitro.
Alternatively, factors that are not related directly to
the FSHR polymorphism should also be considered. For
example, it is established that the development of ovarian
372 Review TRENDS in Endocrinology and Metabolism
follicles depends on members of the transforming growth
factor b superfamily [43], and that FSH and Sma and Mad
homolog 3 (Smad-3) interact in signaling downstream of
the FSHR in the mouse ovary [44]. In this respect, the
polymorphism at residue 680 of the FSHR might be a
marker of another, unrecognized factor in linkage dysequi-
librium that is responsible for the effect observed in vivo.
FSHR haplotypes
There are four common allelic combinations of
FSHR: A-29-A919-A2039 (A-Thr-Asn), G-29-A919-A2039
(G-Thr-Asn) A-29G919-G2039 (A-Ala-Ser) and G-29G919-
G2039 (G-Ala-Ser). Based on O600 subjects of both sexes
that we have screened, these four haplotypes account for
O99% of FSHR alleles in the Caucasian population.
Expression studies using the K29 SNP and a reporter
gene in vitro, identified no major changes in transcrip-
tional activity induced by this polymorphism [23]. How-
ever, this does not exclude the possibility that subtle
functional effects that are not evident in this system might
become relevant when considered in combination with
SNPs in exon 10 and/or following stimulation with FSH.
Interestingly, the two allelic variants A-Ala-Ser and
G-Thr-Asn showed a statistically significant different dis-
tribution between controls and men with non-obstructive
azoospermia [45]. Although these data await confirma-
tion, they indicate that the FSHR haplotype might be one
of many genetic factors that contributes to spermato-
genetic failure. The role of FSHR haplotypes in ovarian
function has not been investigated.
Perspectives
The Ala307Thr and Asn680Ser polymorphisms in the
FSHR represent the first example of a genetic marker that
might have important therapeutic implications for fertil-
ity treatment. Clinical studies show that SNPs in exon 10
of the FSHR determine the ovarian FSH threshold.
Therefore, these SNPs need to be considered in COH for
assisted reproduction techniques in women with normal
ovarian function. Future interventional, prospective
studies should be based on a pharmacogenetic approach
to ovarian stimulation that assesses the efficacy and safety
of patient-tailored stimulation protocols based on the
FSHR genotype. Finally, elucidation of the mechanism by
which different FSHR isoforms respond to different
isoforms of FSH might provide new therapeutic concepts
in reproductive endocrinology based on the genetic com-
plexity of FSHR function.
Acknowledgements
The authors work was supported by the German Research Foundation
(DFG-526/1–1). The language editing of S. Nieschlag, MA is gratefully
acknowledged.
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Disease models of autoimmunity

Look out for the November Special Issue of Trends in Immunology!

This issue will include clinical and scientific perspectives on whether, and how, disease models of autoimmunity have increased
our understanding of human autoimmune diseases. The authors are all experts in their field and selected articles within the issue
include:
Virtues and pitfalls of EAE for development of therapies for multiple sclerosis
Lawrence Steinman and Scott S. Zamvil
SLE: translating lessons from model systems to human disease
Ram Raj Singh
Of mice and men: use of animal models to identify possible interventions for the prevention of
autoimmune type 1 diabetes in humans
David V. Serreze and Yi-Guang Chen
NK cells: elusive players in autoimmunity
Sofia Johansson, Louise Berg, Håkan Hall and Petter Höglund

MHC II molecules in inflammatory diseases: interplay of qualities and quantities

Manuel A. Friese, E. Yvonne Jones and Lars Fugger

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