Best Practice & Research Clinical Endocrinology & Metabolism

Vol. 20, No. 4, pp. 561e576, 2006

doi:10.1016/j.beem.2006.09.003
available online at http://www.sciencedirect.com

Gonadotrophin resistance

Ilpo Huhtaniemi* MD, PhD

Professor of Reproductive Biology
Institute of Reproductive and Developmental Biology, Imperial College London, Hammersmith Campus,
Du Cane Road, London W12 0NN, UK

Maria Alevizaki MD, PhD

Associate Professor of Endocrinology
Endocrinology, Metabolism and Diabetes Unit, Evgenidion Hospital and Department of Medical
Therapeutics, Alexandra Hospital, Athens University School of Medicine, Athens, Greece

Gonadotrophin resistance is caused by inactivating mutations in receptors (Rs) of the two

gonadotrophins, i.e. luteinizing hormone (LH) and follicle-stimulating hormone (FSH), presenting
as hypergonadotrophic hypogonadism and infertility/subfertility in both sexes. These conditions
are extremely rare, but must be kept in mind upon differential diagnosis of disorders of sexual
maturation, hypogonadism and infertility. In 46,XY individuals inactivation of LHR causes a distur-
bance in male-type sexual differentiation that ranges from male pseudohermaphroditism
(complete lack of genital masculinization) to mild conditions such as cryptorchidism and
hypospadias, depending on completeness of the receptor inactivation. In women, the phenotype
is milder, presenting mainly as anovulatory amenorrhoea and hypo-oestrogenization. Inactivation
of FSHR causes in otherwise normally masculinized men small testis size and variably reduced
spermatogenesis, but not azoospermia or absolute infertility. In women the phenotype is
more severe, with primary or early secondary amenorrhoea, arrested follicular maturation
and anovulatory infertility. Incomplete forms with milder phenotype and partial responsiveness
to FSH have also been described. Although gonadotrophin resistance is a very rare condition, its
correct diagnosis is important for the selection of adequate treatment.

Key words: anovulation; follicle-stimulating hormone (FSH); follicle-stimulating hormone receptor

(FSHR); gonadotrophins; gonadotrophin receptors; hormone resistance; hypergonadotrophic
hypogonadism; infertility; luteinizing hormone (LH); luteinizing hormone receptor (LHR); male
pseudohermaphroditism; mutation; sexual differentiation; spermatogenesis; subfertility.

* Corresponding author. Tel.: þ44 20 75942104; Fax: þ44 20 75942184.

E-mail address: ilpo.huhtaniemi@imperial.ac.uk (I. Huhtaniemi).
1521-690X/$ - see front matter ª 2006 Elsevier Ltd. All rights reserved.
562 I. Huhtaniemi and M. Alevizaki

Hormone resistance is caused by inactivating mutations in hormone receptors or by

inactivation of the hormone’s signalling pathway(s). All known cases of gonadotrophin
resistance are caused by inactivating mutations in the luteinizing hormone (LH) or
follicle-stimulating hormone (FSH) receptor (R). Such mutations were first described
about 10 years ago1e3; they are extremely rare, but reports on new mutations are slowly
accumulating in the scientific literature.3e5 Specific mutations in the gonadotrophin sig-
nalling pathway, which would bring about similar phenotypes, have not been described.
Another possibility for similar phenotype(s) are inactivating mutations of the cognate
hormone subunit genes, either LHb or FSHb, and these cases are also extremely
rare.3,4 It is possible that such cases, especially when sporadic, may not be recognized,
and therefore their genetic basis remains obscure. It is therefore important that both
ligand and receptor mutations must be kept in mind when studying the pathogenesis
of hypergonadotrophic hypogonadism. In this chapter we will discuss the phenotypic,
pathogenetic, diagnostic and therapeutic aspects of gonadotrophin resistance due to
inactivating LHR and FSHR mutations. We contrast these cases with mutation in the
cognate hormone subunits, and also introduce the animal models for gonadotrophin
resistance and the clinical implications arising from their study.

NORMAL AND ABERRANT FUNCTIONS OF LHR AND FSHR

LHR and FSHR constitute together with the structurally homologous thyroid-stimulating
hormone receptor (TSHR) the subfamily of glycoprotein hormone receptors amongst
the large group of G-protein-coupled receptors (GPCRs). LHR binds both pituitary
LH and placental choriongonadotrophin (hCG) with similar affinity and functional
consequences, whereas FSHR is activated only by its single cognate ligand. The glycopro-
tein hormone receptors are characterized by a large extracellular domain (ECD; about
400 amino acid residues) and a rhodopsin-like transmembrane (TM) domain.3,6e8 While
the TMs of individual glycoprotein hormone receptors are interchangeable with high se-
quence homology (about 70%), the amino acid compositions of the ECDs are less similar
(about 40%), being responsible for specific ligand recognition and binding.9e11 Complete
crystallization data on glycoprotein hormone receptors are still missing. The structural
organization of the TM region with its 7-transmembrane serpentine structure has been
assigned using the structurally similar bovine rhodopsin as template12, and the crystal
structure of the partially deglycosylated complex of FSH and ECD of FSHR was very
recently published.13 The ECDs of the glycoprotein hormone receptors contain nine
leucine-rich repeats (LRR) flanked by N- and C-terminal cysteine-rich regions.6,8,10
The hormone apparently binds with its long axis perpendicular to the receptor’s concave
LRR tube in a hand-grip fashion, but it also has additional contact sites with the TM
region.6 Recent studies have emphasized the possibility of receptor dimers or higher-order
complexes as the functional units14e16, but detailed information about this phenomenon is
still missing. Proper signal transduction requires specific conformational alterations
following hormone binding, where structural integrity e in particular of the 7th transmem-
brane helix is important.3,4 Receptor inactivation, as the cause of hormone resistance, can
occur through multiple mechanisms that include decreased synthesis, aberrant intracellu-
lar processing, impaired or missing ligand binding, impaired or missing signal transduction,
inability to anchor to plasma membrane, inability to form dimers or multimers, formation
of dominant negative complexes with functional receptors, or increased degradation. Most
of these mechanisms are known to inactivate gonadotrophin receptor function in
mutations that have been detected in humans.
 Gonadotrophin resistance 563

LH RESISTANCE

The LHR gene resides on chromosome 2p21, and both alleles must be inactivated to
provide a phenotypic effect, which is possible through homozygous or compound
heterozygous loss-of-function mutations. In the female, LHR is expressed in ovarian
theca, mature granulosa and luteal cells, and LHR action is needed for stimulation
of theca-cell androgen production, to provide substrate for granulosa-cell oestrogen
synthesis, for the final stage of pre-ovulatory follicular maturation, for ovulation,
and for stimulation of progesterone production in corpus luteum. Although low levels
of LHR are also expressed in numerous extragonadal organs17, convincing evidence for
their physiological significance is missing.18 During pregnancy, hCG functions as an
agonist of pituitary LH, acting through the same receptor, and stimulates the hormone
production of corpus luteum of pregnancy. In addition, a fraction of hCG is transferred
to the fetal circulation, where it stimulates testosterone production by fetal testicular
Leydig cells.19 In the adult male, LHR is expressed in testicular Leydig cells, and LH
stimulation maintains their testosterone production. If LH action is inhibited by inac-
tivating LHb subunit or LHR mutations, all the LH/hCG-regulated functions presented
above can be expected to be impaired.
The first description of a typical case of LH resistance with complete male pseudo-
hermaphroditism was published in 197620, long before the genetic diagnosis of the
condition was possible. The subject was a 35-year-old 46,XY woman with high serum
LH, normal FSH, and very low testosterone. Her LH responded briskly to GnRH
stimulation but FSH only marginally, and her testosterone responded to adrenocorti-
cotrophic hormone (ACTH) but was completely unresponsive to hCG. Her external
genitalia were completely feminized, but internally she had two abdominal testes with
epididymides and vasa deferentia, but absent structures of Müllerian ductal origin
(upper part of vagina, cervix, uterus and oviducts). Microscopic examination of the re-
moved gonads proved them to be testes with presence of seminiferous tubules
containing normal Sertoli cells, occasional immature germ cells, but notably no mature
Leydig cells. The same phenotype, subsequently termed Leydig-cell hypoplasia or
Leydig-cell agenesis, was thereafter reported in several patients21e25, also in a familial
form.26e28 The lack of hCG responsiveness in all cases, and the absence of LH/hCG
binding in the removed testis tissue29e31, prompted the hypothesis that Leydig cells
fail to develop in these subjects due to non-functional LHR.
Before genetic diagnosis was possible, the lack of responsiveness to LH/hCG was
suggested to be due to loss-of-function mutation of the LHR gene or the signalling
cascade downstream of the receptor. After unravelling of the structure of LHR, the
first inactivating mutation of this gene was soon discovered: an A593P missense
mutation near the extracellular side of the plasma membrane (Figure 1).2 This homo-
zygous mutation was found in a 46,XY pseudohermaphrodite adult sibling, born from
consanguineous parents, who presented with female external genitalia, primary
amenorrhoea, and lack of breast development at the age of puberty. As expected,
the parents were non-symptomatic heterozygous carriers for the same mutation.
Cryptorchid testicular tissue of the subject showed hyalinized seminiferous tubules
with total lack of spermatogenesis, and immature-type Leydig cells in the interstitial
space. When the mutated receptor was expressed in vitro, it displayed low levels of
ligand binding and total lack of cAMP production in response to hCG.
The homozygous mutant sister of the above patient32 presented with a milder
phenotype. She had amenorrhoea with normal primary and secondary sex
564 I. Huhtaniemi and M. Alevizaki

insLLKLLLLLQ ->

-NH2

Cys133Arg Val144Peh

Phe194Val

Deletion of:
Exon 8 ->
Exon 10 ->
Cys343Ser
Glu354Lys

Trp491Stp
Ala593Pro

ΔLeu608/Val609

589insT->fs

Ser616Tyr
Tyr623Ser

Ile625Lys
Ile374Thr

Thr392Ile
Cys545Stp

Arg554Stp
Cys543Arg
-COOH

Figure 1. The currently known inactivating mutations in the human LHR gene. Ins, insertion;
fs, frameshift.3,4,88

characteristics, increased levels of LH and FSH, and low levels of oestradiol and pro-
gesterone unresponsive to hCG stimulation, in keeping with non-responsive LHR
function. Upon histological examination, the ovary of the proband showed all stages
of follicular development up to the antral stage, a well-developed theca cell layer,
but no preovulatory follicles or corpora lutea. One ovary had a large cyst, presumably
a remnant of a non-ovulated follicle. Clinical examination revealed a small uterus, a
normal-sized vagina with hyposecretory function and thin walls, and decreased bone
mass, all indicative of reduced oestrogen production. The initial case has subsequently
been confirmed by additional observations on similar cases, all detected as XX siblings
of 46,XY cases of complete male pseudohermaphroditism.33e35
Currently, a total of 20 inactivating LHR mutations have been identified, the
inactivation ranging from partial to complete (Figure 1). In complete inactivation all
LHR activity is lost, while in the partial mutations some receptor activation remains.
The hallmark of the above-described complete form of Leydig-cell hypoplasia and
 Gonadotrophin resistance 565

male pseudohermaphroditism is complete lack of development of secondary sex char-

acteristics, including absence of breast development at the age of puberty. The latter is
the clearest phenotypic difference between this condition and complete androgen
insensitivity syndrome (CAIS, testicular feminization) due to inactivating mutation of
the androgen receptor, where there is normal breast development. Individuals with
complete LHR inactivation have female external genitals, low testosterone and high
LH levels, normal FSH levels, a total lack of response to LH/hCG stimulation, and
no development of secondary male or female sex characteristics at puberty. There
are also milder forms of LHR inactivation where the receptor is only partially inacti-
vated.3,4 In these cases some testicular androgen production is maintained, and
consequently the male phenotype is partially induced, ranging from cryptorchidism
and micropenis36 to severe perineoscrotal hypospadias.34 In these cases the differential
diagnosis must be made with partial androgen insensitivity syndrome (PAIS) caused by
partial androgen receptor inactivation.
LHR expression begins already in utero, where it mediates the stimulatory effect of
hCG on fetal Leydig cells and results in testosterone and insulin-like factor 3 (INSL3)
production. In the male fetus, testosterone stabilizes the Wolffian ducts and induces
their differentiation into male accessory sex organs (prostate, seminal vesicle), and
INSL3 regulates the transabdominal phase of testicular descent.37,38 If LHR is inactive,
fetal testes do not produce the androgens needed for the above masculinization, with
the consequent male pseudohermaphroditism. However, the upper part of vagina,
cervix, uterus and oviducts are missing, because the fetal testes produce anti-Müllerian
hormone normally. Interestingly, these individuals do have epididymides, which is an
apparent sign of autonomous testosterone production and paracrine action on
Wolffian ductal structures close to the testis.2 Upon histological examination, the
testes of an individual with complete LHR mutation contain no mature Leydig cells,
and spermatogenesis is completely arrested.2,34 As with subjects with CAIS, XY
individuals with complete LHR inactivation are raised as females.
Genetic women with LHR mutation have a milder phenotype, with normal female
development of internal and external genitals and normal pubertal maturation, but
they have primary or secondary amenorrhoea, hypo-oestrogenism, high LH, normal
FSH, cystic ovaries, and osteopenia.32 Ovarian histology reveals all stages of follicular
development up to the antral stage, with a well-developed theca cell layer but conspic-
uously no pre-ovulatory follicles or corpora lutea. Non-ovulatory follicles may develop
into cysts. Upon clinical examination, these patients have a small uterus, a normal-sized
vagina with hyposecretory function and thin walls, and decreased bone mass, all
indicative of a hypo-oestrogenic status. The phenotype of the females with inactivating
LHR mutation is clearly in keeping with our knowledge about the role of LH in the
female, being essential for sufficient oestrogen production, ovulation and corpus
luteum function. Follicular development up to the antral stage is initially autonomous
and subsequently under FSH stimulation. Normal feminization at puberty in these
individuals indicates that this process in girls is dependent mainly on FSH.
In vitro studies on function of the mutated LHRs has shown clear correlation
between the phenotype and the extent of receptor inactivation.3,4 The inactivating
mutations are scattered throughout the receptor protein (Figure 1), in keeping with
the multiple functional and structural causes of GPCR inactivation (see above).
Most of the inactivating mutations are complete, meaning that both ligand binding
and signalling are totally abolished when a mutated receptor is transfected in cell lines
in vitro. In these cases also the phenotype in vivo is total, i.e. Leydig-cell hypoplasia and
male pseudohermaphroditism are present. The most likely cause for receptor
566 I. Huhtaniemi and M. Alevizaki

inactivation in these cases is sequestration of the mutated receptor protein inside the
cell during its synthesis, as has been demonstrated with some mutations.32,39 In con-
trast, some mutations in TM helices 6 and 7 (e.g. A593P and I625K) maintain significant
ligand binding but severely reduced signal transduction.3,32,40 However, signal trans-
duction in these cases is apparently not totally lost, because the phenotypes are partial
with variable degrees of undermasculinization. An interesting LHR mutation illustrating
the variable structure/function relationship is one where exon 10, comprising the
hinge region of the receptor, is deleted.41 The affected man had normal intrauterine
masculinization but failed to develop normally at puberty. It was found that the
mutated LHR could respond to hCG but not to pituitary LH, which explained the
man’s phenotype.

FSH RESISTANCE

FSHR is located next to LHR on chromosome 2p, and its inactivation causes pheno-
types in homozygous and compound heterozygous forms. Fewer inactivating FSHR
than LHR mutations have been described (Figure 2). The rarity of these cases may
be because the phenotypes caused by them are less clear, and probably less striking
clinically, than those caused by LHR inactivation. Alternatively, a selection mechanism

-NH2

Ile160Thr Ala189Val (Asn191Ile)

Asp224Val

Pro346Arg

Pro519Thr

Leu 601Val

Arg573Csy

Ala419Thr

-COOH

Figure 2. The currently known inactivating mutations in the human FSHR gene.3,4,88
 Gonadotrophin resistance 567

may operate against these mutations because of their strong detrimental effect on
fertility, precluding the inheritance of the faulty alleles. FSH action is essential for ovar-
ian follicular maturation, and by stimulating aromatase activity of granulosa cells it
maintains ovarian oestrogen production. It also induces LHR expression in mature
granulosa cells in synergistic fashion with oestrogen. In men, FSH regulates Sertoli
cell proliferation before and at puberty, and it participates in the regulation of
spermatogenesis by maintaining various aspects of Sertoli cell metabolism, thus making
the intratubular environment favourable for qualitatively and quantitatively normal
spermatogenesis. FSH action has also been suggested to be mandatory for the puber-
tal onset of spermatogenesis. Thus loss-of-function mutations of FSHR can be
expected to be found in connection with hypergonadotrophic hypogonadism associ-
ated with retarded follicular maturation and anovulatory infertility in women, and in
connection with small testicles and impaired spermatogenesis in normally masculinized
males. In line with these hypotheses, inactivating FSHR mutations were looked for in
cases such as premature ovarian failure, gonadal dysgenesis, resistant ovary syndrome,
hypergonadotrophic hypogonadism, polycystic ovary syndrome42e45, and granulosa
cell tumours46e48 in women. In men the candidate syndromes include absent, low
or aberrant sperm production with high FSH levels49 and idiopathic infertility.50
However, this search was unsuccessful in detecting FSHR mutations.
The first successful search for loss-of-function FSHR mutations was carried out by
taking advantage of the considerable enrichment in mutations of certain recessively
inherited disorders in Finland.51 A population-based study of hypergonadotrophic
hypogonadism in women revealed upon linkage analysis a locus at chromosome
2p21 that contained both the LHR and FSHR genes, located next to each other. On
the basis of phenotype inclusion criteria of the subjects, including high gonadotrophin
levels, primary or early-onset secondary amenorrhoea, absence of follicular matura-
tion, and absence of male pseudohermaphroditism in the families (a sign of LHR
inactivation), the FSHR gene was chosen as the candidate for further study. Sequencing
of the ten exons of FSHR revealed a homozygous A-to-G point mutation in codon 189
in exon 7 of the gene, inducing an amino acid alteration from alanine to valine.
Ala189 is the first amino acid in a perfectly conserved stretch of five amino acids in
the gonadotrophin receptors (AFNQT), where also inactivating LHR mutations have
been found.52 Valine in position 189 may interfere with the efficacy of glycosylation
and impair receptor trafficking and folding, limiting the access of the mutated protein
to the plasma membrane, where it has to reside in order to mediate the FSH signal. It
was subsequently shown that when over-expressed in vitro, only a very small propor-
tion of the mutated receptor was able to access the plasma membrane, where it could
bind FSH and mediate its signal. Instead, the mutated receptor was sequestered inside
the cell, explaining the inactivating nature of the single amino acid alteration. The
A189V mutation can therefore be considered physiologically totally inactivating. It is
curious that such a conserved mutation can so drastically affect the intracellular recep-
tor trafficking, but in this respect FSHR appears to be very sensitive to structural
alterations.53,54 Also another mutation, N191I, proven in vitro to be inactivating,
was found in heterozygous form in the same locus in a non-symptomatic woman of
German origin.55 This provides further evidence for functional significance of this
region for function of the glycoprotein hormone receptors.
A notable and pathognomonic feature of ovarian dysgenesis due to FSHR inactiva-
tion, and a sign to discriminate it from other cases of ovarian dysgenesis, is the pres-
ence of ovarian follicles in almost all cases with verified FSHR mutation56 This is
consistent with the knowledge that the early stages of primordial follicular recruitment
568 I. Huhtaniemi and M. Alevizaki

and early follicular growth are independent of gonadotrophin action. In contrast, total
absence of all stages of follicles was observed in cases where FSHR mutation could not
be detected. Thus, the FSHR mutation phenotype is distinct from the common form of
ovarian dysgenesis such as found in Turner syndrome with streak ovaries and absent
follicles.56
Two pairs of compound heterozygous FSHR mutations were described from France
in women with primary or secondary amenorrhoea, normal pubertal development,
and follicular development up to the antral stage.53,57 Two of the mutations, I160T
and D224V, located in the ECD of the receptor (Figure 2), caused near-complete
loss of FSHR binding. Confocal microscopy showed impaired targeting to the cell
membrane with both mutants, and cells expressing these receptors showed absent
or marginal cAMP response to FSH stimulation. The other two mutations, R573C
and L601V, residing in the TM region, caused less complete receptor inactivation,
mainly due to impaired signal transduction.
Recently another woman with normal secondary sex characteristics but primary
hypergonadotrophic hypogonadism was described from Finland.58 She was a compound
heterozygote for the originally detected A189V mutation and a novel A419T mutation
located in the second TM loop on FSHR. The mutated receptor displayed somewhat
reduced ligand binding capacity without altered affinity, but the cAMP signal was totally
lost. The new mutation is located in a highly conserved region, which indicates its
functional significance, apparently for signal transduction. Another inactivating FSHR
mutation detected recently is P346R in the extracellular part of exon 10, and it was
also detected in a hypergonadotrophic woman with delayed puberty and primary
amenorrhoea.59 This mutation totally abolished ligand binding, but whether it was
caused by sequestration of the receptor inside the cell or to genuine lack of ligand
binding to a normally exteriorized receptor protein was not studied. The last FSHR
loss-of-function mutation so far detected was found in a female presenting with hyper-
gonadotrophic ovarian failure, very low oestrogen and inhibin B levels, and total lack of
response to high dose of recombinant FSH.60 The subject had a homozygous P519T
mutation, located in a conserved motif in both gonadotrophin and TSH receptors in
the second extracellular loop of the TM region. Typical of the FSHR mutations, the
mutated protein was entrapped intracellularly and consequently unable to bind
hormone and evoke signalling. Histological analysis of ovarian biopsy confirmed the
findings which were similar to those found in the Finnish mutations on arrest of
follicular maturation beyond the primary stage.
The A189V mutation of FSHR seems to belong to the Finnish heritage of genetic
diseases, because despite multiple attempts it has not been detected in other
populations.42,61e64 It also still remains the only mutation that has been found in
familial as well as sporadic cases.
Five homozygous men with the A189V FSHR mutation were found in the Finnish
families carrying the mutation.65 This made it possible to assess the phenotype of
men with absent FSHR function. All men were found to be normally masculinized,
indicating normal Leydig cell function. The testosterone level of all men was normal,
their LH was normal or slightly elevated, FSH moderately elevated, inhibin B low,
and testis volumes slightly to severely reduced. All men produced a semen sample,
and their sperm counts ranged from normal to severe oligozoospermia, with low
volume and teratozoospermia in one man. Notably, none of the men was azoosper-
mic. These observations allowed the conclusion that FSH contributes to the quality
and quantity of spermatogenesis, but is not mandatory for this process per se. The
normal androgen production alone in the mutant men may be sufficient to maintain
 Gonadotrophin resistance 569

their spermatogenesis and fertility. Unlike what was previously suggested, FSH action
is not compulsory for the pubertal onset of spermatogenesis. These findings also
indicate that attempts to reduce spermatogenesis for contraceptive purposes by inhib-
iting FSH secretion or action may be futile.
Despite the paucity of inactivating FSHR mutations, there is good correlation
between the phenotype and the degree of receptor inactivation, as well as the site
of mutation and its functional consequences, as has been found with the larger number
of different loss-of-function mutations of LHR.3,4 All mutations in the extracellular
region, I160T, A189V, N191I, D224V, and P346R (Figure 2), drastically impair targeting
of the receptor protein to the plasma membrane, and therefore abolish both ligand
binding and signalling. In contrast, the three mutations in the TM region, A419T,
R573C and L601V, have minimal effects on ligand binding but impair to a variable
extent, but not totally, the signal transduction. The P519T mutation in extracellular
loop 2 of the TM region is the only exception, being devoid of signalling and ligand
binding. Therefore it seems that the location, rather than nature of the amino acid
alteration, determines the functional response. The mutations in the transmembrane
region, in addition, seem to cause only partial receptor inactivation. Hence, patients
with the milder forms of mutations may respond to high-dose FSH stimulation, as
has already been demonstrated57, whereas complete loss of function mutations are
totally unresponsive.66 Hence the molecular diagnosis of these rare patients may be
helpful in selecting the most rational and effective treatment for their infertility.

SIMILARITIES AND DIFFERENCES BETWEEN INACTIVATING

LH AND FSH RECEPTOR AND SUBUNIT MUTATIONS

Other mutations that induce almost identical phenotypes with inactivating LHR and
FSHR mutations are those affecting the LHb67e69 and FSHb70e74 subunits, respectively.
Loss-of-function mutations of glycoprotein hormone common a-subunit have not been
found, and they are unlikely to be found because of concomitant inactivation of hCG
which is apparently indispensable in the maintenance of gestation. Concerning diagnos-
tics, the apparent difference is that gonadotrophin levels in hormone subunit
mutations are low, in particular their bioactivity. However, depending on the mutation,
it is possible that the immunoreactive level of hormone is high if the mutation does not
affect synthesis and/or assembly of the dimeric hormone.68 Levels of the ligand
hormone are high in connection with receptor mutations. Sequencing and functional
analysis of the mutated gene provide the final proof for phenotypic effect of the
detected mutation.
Concerning therapeutic aspects, a clear difference between hormone and receptor
mutations is that the former can be treated with exogenous hormone, whereas the
latter, if receptor inactivation is complete, are totally resistant to treatment with
the ligand hormone. Finally, because the hormone protein is mutated, the immunolog-
ical system of a patient may recognize the exogenous hormone to be used for
treatment as foreign, and start producing antibodies against it, as has been reported
in the case of one FSHb mutation.75
Numerous cases of inactivating LHR mutations in men have been described, but
only three men with inactivating LHb mutation have been reported.67,68,76 The pheno-
type of the LHR mutations varies with severity of the receptor inactivation, but if we
consider complete receptor inactivation the phenotype is quite uniform, i.e. male
pseudohermaphroditism. However, the men with LHb mutation are normally
570 I. Huhtaniemi and M. Alevizaki

masculinized at birth but lack totally postnatal sexual differentiation. The reason for
the difference is that placental hCG is able to stimulate fetal testicular testosterone
production if LHb is inactivated, but when hCG is eliminated after birth, no trophic
stimulus is available for postnatal Leydig cells. With LHR mutation also the fetal testis
is devoid of the trophic stimulus, which blocks the normal intrauterine masculinization
driven by fetal testicular testosterone. This is a special feature of the human and at
variance with the rodent models used in experimental research (see below).
As concerns women, only inactivating LHR mutations are known, but none with
LHb inactivation has been described. New mutations, including larger families carrying
inactivating LHb mutations, have recently been detected, and it is apparently only
a matter of time before the first female with inactivating LHb mutation is described
(R. Gaillard, personal communication). It is apparent that the phenotype of such an
individual will be very similar or identical to that in LHR inactivation, because this
receptor appears in the ovary only after birth, for which reason missing LHb expres-
sion in the female fetus is unlikely to have phenotypic effect at birth.
Women with complete loss-of-function mutation in FSHR or FSHb have practically
identical phenotypes, with primary or early-onset secondary amenorrhoea, lack of
follicular maturation and anovulatory infertility. The women with hormone inactivation
can be treated with exogenous FSH70, but oocyte donation is the best means of treat-
ment for women suffering from receptor mutation.77 In theory, since these women
have in their ovaries a large pool of oocytes arrested in their maturation, in vitro
maturation of oocytes could be a possible treatment once these methods have
been sufficiently developed.
The situation in males represents a conundrum. The five men with inactivating FSHR
mutation show variable suppression of spermatogenesis, but none are azoospermic;
two of these men have even fathered two children each.65 In contrast, the three men
with inactivating FSHb mutation are all azoospermic.71,73,74 The reason for the discrep-
ancy may be in the selection criteria for the men. Two of the men with FSHb were
studied because of their azoospermia, whereas the FSHR mutation men were brothers
of the affected women, thus representing an unselected group of men with FSHR
mutation. The number of cases is clearly too small to allow definitive conclusions about
the difference or similarity of phenotypes of FSHb and FSHR inactivation in men.

ANIMAL MODELS

Genetically modified mice with knockout of LHR and FSHR have been produced, and
there are numerous detailed reports on their phenotypes.18,78e80 By and large, these
mutant mice provide accurate phenocopies of the relevant human mutations. Female
mice with LHR81,82 and LHb83 knockout have anovulatory infertility, as do women with
loss-of-function LHR mutations. Male mice with inactive LHR are normally masculinized
at birth, because in the mouse there is a plethora of paracrine factors that can maintain
fetal Leydig cell function in the absence of LH.84 There is apparently a large safety
margin in the need of testosterone for intrauterine masculinization, and even sup-
pressed levels of the hormone in the absence of LH stimulation are sufficient. Unlike
rodents, in humans hCG provides the backup stimulus for fetal Leydig-cell androgen
synthesis and masculinization in the absence of sufficient LH supply. It is curious
that such an important developmental event as intrauterine masculinization is under
so differential an endocrine control as hCG and non-gonadotrophic paracrine factors
in humans and mice.
 Gonadotrophin resistance 571

The phenotypes of FSHR85,86 and FSHb87 knockout mice are identical to those of
inactivating FSHR mutations in humans. The females have the expected phenotype
of hypergonadotrophic arrest of follicular maturation and anovulatory infertility. The
male mice have reduced testis size and impaired spermatogenesis but maintain their
fertility, which is a close phenocopy of men with similar mutation but at variance
with the azoospermic phenotype of men with FSHb inactivation. The mutant mice
provide further evidence that maybe the unexpected azoospermia in the three men
with inactivating FSHb mutation (see above) is not the correct phenotype. Additional
cases of men with FSHb mutation need to be detected to resolve this discrepancy.

Practice points

 the inactivating LHR and FSHR mutations are very rare, but have to be kept in mind
upon differential diagnostics of ambiguous genitalia, pubertal disturbances, hyper-
gonadotrophic hypogonadism and idiopathic infertility
 the location of the mutation, in ECD or TM domain, is usually indicative of
completeness of the inactivation, especially in the case of FSHR, and this may
have prognostic value in the selection of treatment; patients with incomplete
inactivation may respond to high-dose FSH treatment
 LHR inactivation and complete androgen insensitivity syndrome can be discrim-
inated by the lack of breast development at the age of puberty in the former,
and the presence of high circulating testosterone concentration in the latter
 ovaries of women with inactivating FSHR mutation contain numerous immature
follicles, which differentiates them from other causes of ovarian dysgenesis (e.g.
Turner syndrome)
 the phenotypes of inactivating gonadotrophin receptor and hormone subunit
mutations are very similar, and high hormone levels in the former and low
(less bioactive) levels in the latter augment the differential diagnostics; this is
important because the cases with hormone mutations are susceptible to
gonadotrophin therapy, whereas the receptor mutations are resistant (in cases
of complete inactivation)
 despite clear phenotypes, gonadotrophin receptor or hormone mutations are
rarely found in sporadic cases of hypergonadotrophic hypogonadism, apparently
because of the number of other genetic and non-genetic causes for similar
phenotypes

SUMMARY

Gonadotrophin resistance is caused by inactivating (or loss-of-function) mutations in LHR or

FSHR, presenting clinically as hypergonadotrophic hypogonadism and infertility/subfertility
in both sexes. These conditions are extremely rare, but they must be kept in
mind when doing the differential diagnostics of disorders of sexual differentiation
and maturation, hypogonadism and infertility. Inactivation of LHR results in 46,XY in-
dividuals in a disturbance in male-type sexual differentiation that ranges, depending
on completeness of the receptor inactivation, from male pseudohermaphroditism
(complete lack of genital masculinization) to mild forms such as cryptorchidism
and hypospadias. These individuals are raised as females, and they differ from
572 I. Huhtaniemi and M. Alevizaki

androgen insensitivity syndrome by the lack of breast development at the age of pu-
berty. The phenotype of genetic females is milder, presenting mainly as anovulatory
amenorrhoea and hypo-oestrogenization. Their anovulation is resistant to gonado-
trophin treatment. Inactivation of FSHR causes, in otherwise normally masculinized
men with normal Leydig-cell testosterone production, small testis size and variably
reduced spermatogenesis, but not azoospermia or absolute infertility. In women,
the phenotype is more severe, with primary or early secondary amenorrhoea, ar-
rested follicular maturation and anovulatory infertility. Complete FSHR inactivation
is resistant to gonadotrophin treatment. Incomplete forms with milder phenotype
(anovulation with secondary amenorrhoea) may be responsive to gonadotrophin
treatment. Mutations are rarely found in sporadic patients, because a similar pheno-
type can be caused by numerous other as yet unidentified mutations. Although go-
nadotrophin resistance is a very rare condition, its correct diagnosis is important for
the selection of adequate treatment.

REFERENCES

*1. Aittomaki K, Lucena JL, Pakarinen P et al. Mutation in the follicle-stimulating hormone receptor gene
causes hereditary hypergonadotropic ovarian failure. Cell 1995; 82(6): 959e968.
2. Kremer H, Kraaij R, Toledo SP et al. Male pseudohermaphroditism due to a homozygous missense
mutation of the luteinizing hormone receptor gene. Nature Genetics 1995; 9(2): 160e164.
*3. Themmen APN & Huhtaniemi IT. Mutations of gonadotropins and gonadotropin receptors: elucidating
the physiology and pathophysiology of pituitary-gonadal function. Endocrine Reviews 2000; 21(5):
551e583.
*4. Huhtaniemi IT & Themmen AP. Mutations in human gonadotropin and gonadotropin-receptor genes.
Endocrine 2005; 26(3): 207e217.
5. Alevizaki M & Huhtaniemi I. Structure-function repationships of glycoprotein horemones; lessons form
mutations and polymorphisms of the thyrotrophin and gonadotrophin subunit genes. Hormones 2002; 1:
224e232.
6. Ascoli M, Fanelli F & Segaloff DL. The lutropin/choriogonadotropin receptor, a 2002 perspective.
Endocrine Reviews 2002; 23(2): 141e174.
7. Dias JA & Van Roey P. Structural biology of human follitropin and its receptor. Archives of Medical
Research 2001; 32(6): 510e519.
8. Szkudlinski MW, Fremont V, Ronin C et al. Thyroid-stimulating hormone and thyroid-stimulating
hormone receptor structure-function relationships. Physiological Reviews 2002; 82(2): 473e502.
9. Braun T, Schofield PR & Sprengel R. Amino-terminal leucine-rich repeats in gonadotropin receptors
determine hormone selectivity. The EMBO Journal 1991; 10(7): 1885e1890.
10. Cornelis S, Uttenweiler-Joseph S, Panneels V et al. Purification and characterization of a soluble bioac-
tive amino-terminal extracellular domain of the human thyrotropin receptor. Biochemistry 2001; 40(33):
9860e9869.
11. Remy JJ, Nespoulous C, Grosclaude J et al. Purification and structural analysis of a soluble human cho-
rionogonadotropin hormone-receptor complex. The Journal of Biological Chemistry 2001; 276(3):
1681e1687.
12. Palczewski K, Kumasaka T, Hori T et al. Crystal structure of rhodopsin: A G protein-coupled receptor.
Science 2000; 289(5480): 739e745.
13. Fan QR & Hendrickson WA. Structure of human follicle-stimulating hormone in complex with its
receptor. Nature 2005; 433(7023): 269e277.
14. Ji I, Lee C, Song Y et al. Cis- and trans-activation of hormone receptors: the LH receptor. Molecular
Endocrinology 2002; 16(6): 1299e1308.
15. Osuga Y, Hayashi M, Kudo M et al. Co-expression of defective luteinizing hormone receptor fragments
partially reconstitutes ligand-induced signal generation. The Journal of Biological Chemistry 1997; 272(40):
25006e25012.
 Gonadotrophin resistance 573

16. Urizar E, Montanelli L, Loy T et al. Glycoprotein hormone receptors: link between receptor homodi-
merization and negative cooperativity. The EMBO Journal 2005; 24(11): 1954e1964.
*17. Filicori M, Fazleabas AT, Huhtaniemi I et al. Novel concepts of human chorionic gonadotropin: repro-
ductive system interactions and potential in the management of infertility. Fertility and Sterility 2005;
84(2): 275e284.
18. Pakarainen T, Zhang FP, Poutanen M et al. Fertility in luteinizing hormone receptor-knockout mice after
wild-type ovary transplantation demonstrates redundancy of extragonadal luteinizing hormone action.
The Journal of Clinical Investigation 2005; 115(7): 1862e1868.
19. Huhtaniemi I. Fetal testisea very special endocrine organ. European Journal of Endocrinology 1994;
130(1): 25e31.
20. Berthezene F, Forest MG, Grimaud JA et al. Leydig-cell agenesis: a cause of male pseudohermaphrodi-
tism. The New England Journal of Medicine 1976; 295(18): 969e972.
21. Brown DM, Markland C & Dehner LP. Leydig-cell hypoplasia: a cause of male pseudohermaphroditism.
The Journal of Clinical Endocrinology and Metabolism 1978; 46(1): 1e7.
22. Lee PA, Rock JA, Brown TR et al. Leydig cell hypofunction resulting in male pseudohermaphroditism.
Fertility and Sterility 1982; 37(5): 675e679.
23. Wu RH, Rosenfeld R & Fukushima D. Hypogonadism and Leydig-cell hypoplasia unresponsive to human
luteinizing hormone (hLH). The American Journal of the Medical Sciences 1984; 287(3): 23e25.
24. Eil C, Austin RM, Sesterhenn I et al. Leydig-cell hypoplasia causing male pseudohermaphroditism:
diagnosis 13 years after prepubertal castration. The Journal of Clinical Endocrinology and Metabolism
1984; 58(3): 441e448.
25. Arnhold IJ, Mendonca BB, Bloise W et al. Male pseudohermaphroditism resulting from Leydig-cell
hypoplasia. The Journal of Pediatrics 1985; 106(6): 1057.
26. Perez-Palacios G, Scaglia HE, Kofman-Alfaro S et al. Inherited male pseudohermaphroditism due to
gonadotrophin unresponsiveness. Acta Endocrinologica 1981; 98(1): 148e155.
27. el-Awady MK, Temtamy SA, Salam MA et al. Familial Leydig-cell hypoplasia as a cause of male
pseudohermaphroditism. Human Heredity 1987; 37(1): 36e40.
28. Saldanha PH, Arnhold IJ, Mendonca BB et al. A clinico-genetic investigation of Leydig-cell hypoplasia.
American Journal of Medical Genetics 1987; 26(2): 337e344.
29. Schwartz M, Imperato-McGinley J, Peterson RE et al. Male pseudohermaphroditism secondary to an
abnormality in Leydig cell differentiation. The Journal of Clinical Endocrinology and Metabolism 1981;
53(1): 123e127.
30. David R, Yoon DJ, Landin L et al. A syndrome of gonadotropin resistance possibly due to a luteinizing
hormone receptor defect. The Journal of Clinical Endocrinology and Metabolism 1984; 59(1): 156e160.
31. Martinez-Mora J, Saez JM, Toran N et al. Male pseudohermaphroditism due to Leydig cell agenesia and
absence of testicular LH receptors. Clinical Endocrinology 1991; 34(6): 485e491.
32. Toledo SP, Brunner HG, Kraaij R et al. An inactivating mutation of the luteinizing hormone receptor
causes amenorrhea in a 46,XX female. The Journal of Clinical Endocrinology and Metabolism 1996;
81(11): 3850e3854.
33. Stavrou SS, Zhu YS, Cai LQ et al. A novel mutation of the human luteinizing hormone receptor in 46XY
and 46XX sisters. The Journal of Clinical Endocrinology and Metabolism 1998; 83(6): 2091e2098.
34. Latronico AC, Anasti J, Arnhold IJ et al. Brief report: testicular and ovarian resistance to luteinizing
hormone caused by inactivating mutations of the luteinizing hormone-receptor gene. The New England
Journal of Medicine 1996; 334(8): 507e512.
35. Latronico AC, Chai Y, Arnhold IJ et al. A homozygous microdeletion in helix 7 of the luteinizing
hormone receptor associated with familial testicular and ovarian resistance is due to both decreased
cell surface expression and impaired effector activation by the cell surface receptor. Molecular
Endocrinology 1998; 12(3): 442e450.
36. Toledo SP, Arnhold IJ, Luthold W et al. Leydig-cell hypoplasia determining familial hypergonadotropic
hypogonadism. Progress in Clinical and Biological Research 1985; 200: 311e314.
*37. Nef S & Parada LF. Hormones in male sexual development. Genes and Development 2000; 14(24):
3075e3086.
38. Nef S, Verma-Kurvari S, Merenmies J et al. Testis determination requires insulin receptor family func-
tion in mice. Nature 2003; 426(6964): 291e295.
574 I. Huhtaniemi and M. Alevizaki

39. Martens JW, Lumbroso S, Verhoef-Post M et al. Mutant luteinizing hormone receptors in
a compound heterozygous patient with complete Leydig-cell hypoplasia: abnormal processing causes
signaling deficiency. The Journal of Clinical Endocrinology and Metabolism 2002; 87(6): 2506e2513.
40. Martens JW, Verhoef-Post M, Abelin N et al. A homozygous mutation in the luteinizing hormone
receptor causes partial Leydig-cell hypoplasia: correlation between receptor activity and phenotype.
Molecular Endocrinology 1998; 12(6): 775e784.
41. Gromoll J, Eiholzer U, Nieschlag E et al. Male hypogonadism caused by homozygous deletion of exon 10
of the luteinizing hormone (LH) receptor: differential action of human chorionic gonadotropin and LH.
The Journal of Clinical Endocrinology and Metabolism 2000; 85(6): 2281e2286.
42. da Fonte Kohek MB, Batista MC, Russell AJ et al. No evidence of the inactivating mutation (C566T) in
the follicle-stimulating hormone receptor gene in Brazilian women with premature ovarian failure.
Fertility and Sterility 1998; 70(3): 565e567.
43. Whitney EA, Layman LC, Chan PJ et al. The follicle-stimulating hormone receptor gene is polymorphic
in premature ovarian failure and normal controls. Fertility and Sterility 1995; 64(3): 518e524.
44. Conway GS, Conway E, Walker C et al. Mutation screening and isoform prevalence of the follicle
stimulating hormone receptor gene in women with premature ovarian failure, resistant ovary syn-
drome and polycystic ovary syndrome. Clinical Endocrinology 1999; 51(1): 97e99.
45. Liu JY, Gromoll J, Cedars MI et al. Identification of allelic variants in the follicle-stimulating hormone
receptor genes of females with or without hypergonadotropic amenorrhea. Fertility and Sterility 1998;
70(2): 326e331.
46. Kotlar T, Young RH, Albanese C et al. Absence of mutations in the FSH receptor in ovarian granulosa
cell tumors. The Journal of Clinical Endocrinology and Metabolism 1998; 83(8): 3001.
47. Fuller PJ, Verity K, Shen Y et al. No evidence of a role for mutations or polymorphisms of the follicle-
stimulating hormone receptor in ovarian granulosa cell tumors. The Journal of Clinical Endocrinology and
Metabolism 1998; 83(1): 274e279.
48. Ligtenberg MJ, Siers M, Themmen AP et al. Analysis of mutations in genes of the follicle-stimulating
hormone receptor signaling pathway in ovarian granulosa cell tumors. The Journal of Clinical Endocrinol-
ogy and Metabolism 1999; 84(6): 2233e2234.
49. Tuerlings JH, Ligtenberg MJ, Kremer JA et al. Screening male intracytoplasmic sperm injection candi-
dates for mutations of the follicle stimulating hormone receptor gene. Human Reproduction 1998;
13(8): 2098e2101.
50. Simoni M, Gromoll J, Hoppner W 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. The Journal of Clinical Endocrinology and Metabolism 1999; 84(2): 751e755.
51. Norio R. Finnish Disease Heritage I: characteristics, causes, background. Human Genetics 2003;
112(5-6): 441e456.
52. Gromoll J, Schulz A, Borta H et al. Homozygous mutation within the conserved Ala-Phe-Asn-Glu-Thr mo-
tif of exon 7 of the LH receptor causes male pseudohermaphroditism. European Journal of Endocrinology
2002; 147(5): 597e608.
53. Beau I, Touraine P, Meduri G et al. A novel phenotype related to partial loss of function mutations
of the follicle stimulating hormone receptor. The Journal of Clinical Investigation 1998; 102(7):
1352e1359.
54. Rannikko A, Pakarinen P, Manna PR et al. Functional characterization of the human FSH receptor with
an inactivating Ala189Val mutation. Molecular Human Reproduction 2002; 8(4): 311e317.
55. Gromoll J, Simoni M, Nordhoff V et al. Functional and clinical consequences of mutations in the FSH
receptor. Molecular and Cellular Endocrinology 1996; 125(1-2): 177e182.
*56. Aittomaki K, Herva R, Stenman UH et al. Clinical features of primary ovarian failure caused by a point
mutation in the follicle-stimulating hormone receptor gene. The Journal of Clinical Endocrinology and
Metabolism 1996; 81(10): 3722e3726.
57. Touraine P, Beau I, Gougeon A et al. New natural inactivating mutations of the follicle-stimulating
hormone receptor: correlations between receptor function and phenotype. Molecular Endocrinology
1999; 13(11): 1844e1854.
58. Doherty E, Pakarinen P, Tiitinen A et al. A Novel mutation in the FSH receptor inhibiting signal
transduction and causing primary ovarian failure. The Journal of Clinical Endocrinology and Metabolism
2002; 87(3): 1151e1155.
 Gonadotrophin resistance 575

59. Allen LA, Achermann JC, Pakarinen P et al. A novel loss of function mutation in exon 10 of the FSH
receptor gene causing hypergonadotrophic hypogonadism: clinical and molecular characteristics.
Human Reproduction 2003; 18(2): 251e256.
60. Meduri G, Touraine P, Beau I et al. Delayed puberty and primary amenorrhea associated with a novel
mutation of the human follicle-stimulating hormone receptor: clinical, histological, and molecular
studies. The Journal of Clinical Endocrinology and Metabolism 2003; 88(8): 3491e3498.
61. Jiang M, Aittomaki K, Nilsson C et al. The frequency of an inactivating point mutation (566Ce>T) of
the human follicle-stimulating hormone receptor gene in four populations using allele-specific hybrid-
ization and time-resolved fluorometry. The Journal of Clinical Endocrinology and Metabolism 1998;
83(12): 4338e4343.
62. Loutradis D, Patsoula E, Stefanidis K et al. Follicle-stimulating hormone receptor gene mutations are not
evident in Greek women with premature ovarian failure and poor responders. Gynecologic and Obstetric
Investigation 2006; 61(1): 56e60.
63. Ishikawa T, Fujisawa M & Tapanainen J. Screening of FSH receptor gene mutation (C566T) in azoosper-
mic men in Japan. Archives of Andrology 2006; 52(1): 15e19.
64. Layman LC, Amde S, Cohen DP et al. The Finnish follicle-stimulating hormone receptor gene mu-
tation is rare in North American women with 46,XX ovarian failure. Fertility and Sterility 1998;
69(2): 300e302.
*65. Tapanainen JS, Aittomaki K, Min J et al. Men homozygous for an inactivating mutation of the follicle-
stimulating hormone (FSH) receptor gene present variable suppression of spermatogenesis and fertility.
Nature Genetics 1997; 15(2): 205e206.
66. Vaskivuo TE, Aittomaki K, Anttonen M et al. Effects of follicle-stimulating hormone (FSH) and human
chorionic gonadotropin in individuals with an inactivating mutation of the FSH receptor. Fertility and
Sterility 2002; 78(1): 108e113.
67. Valdes-Socin H, Salvi R, Daly AF et al. Hypogonadism in a patient with a mutation in the luteinizing
hormone beta-subunit gene. The New England Journal of Medicine 2004; 351(25): 2619e2625.
*68. Weiss J, Axelrod L, Whitcomb RW et al. Hypogonadism caused by a single amino acid substitution in
the beta subunit of luteinizing hormone. The New England Journal of Medicine 1992; 326(3): 179e183.
69. Daly AF, Salvi R, Menage J-J, et al. Identification of a family harboring a novel LHbeta subunit mutation
associated with hypogonadism. The Endocrine Society, 88th Annual Meeting 2006: OR52eOR55.
70. Matthews CH, Borgato S, Beck-Peccoz P et al. Primary amenorrhoea and infertility due to a mutation in
the beta-subunit of follicle-stimulating hormone. Nature Genetics 1993; 5(1): 83e86.
71. Phillip M, Arbelle JE, Segev Y et al. Male hypogonadism due to a mutation in the gene for the beta-
subunit of follicle-stimulating hormone. The New England Journal of Medicine 1998; 338(24): 1729e1732.
72. Layman LC, Lee EJ, Peak DB et al. Delayed puberty and hypogonadism caused by mutations in the
follicle-stimulating hormone beta-subunit gene. The New England Journal of Medicine 1997; 337(9):
607e611.
73. Layman LC, Porto AL, Xie J et al. FSH beta gene mutations in a female with partial breast development
and a male sibling with normal puberty and azoospermia. The Journal of Clinical Endocrinology and
Metabolism 2002; 87(8): 3702e3707.
74. Lindstedt G, Nystrom E, Matthews C et al. Follitrophin (FSH) deficiency in an infertile male due to
FSHbeta gene mutation. A syndrome of normal puberty and virilization but underdeveloped testicles
with azoospermia, low FSH but high lutropin and normal serum testosterone concentrations. Clinical
Chemistry and Laboratory Medicine 1998; 36(8): 663e665.
75. Rabinowitz D, Benveniste R, Linder J et al. Isolated follicle-stimulating hormone deficiency revisited.
Ovulation and conception in presence of circulating antibody to follicle-stimulating hormone. The
New England Journal of Medicine 1979; 300(3): 126e128.
76. Daly AF, Salvi R, Menage J-J, et al. Identification of a family harboring a novel LHbeta subunit mutation
associated with hypogonadism. The Endocrine Society, 88th Annual Meeting 2006: OR52eOR55.
77. Hovatta O, Soderstrom-Anttila V, Foudila T et al. Pregnancies after oocyte donation in women with
ovarian failure caused by an inactivating mutation in the follicle stimulating hormone receptor. Human
Reproduction 2002; 17(1): 124e127.
78. Danilovich N & Sairam MR. Targeting gonadotropin receptor genes: reproductive biology, aging, and
related health implications. Endocrine 2005; 26(3): 219e226.
576 I. Huhtaniemi and M. Alevizaki

79. Rao CV & Lei ZM. Consequences of targeted inactivation of LH receptors. Molecular and Cellular
Endocrinology 2002; 187(1-2): 57e67.
80. Hirst RC, Abel MH, Wilkins V et al. Influence of mutations affecting gonadotropin production or
responsiveness on expression of inhibin subunit mRNA and protein in the mouse ovary. Reproduction
2004; 128(1): 43e52.
*81. Zhang FP, Poutanen M, Wilbertz J et al. Normal prenatal but arrested postnatal sexual development of
luteinizing hormone receptor knockout (LuRKO) mice. Molecular Endocrinology 2001; 15(1): 172e183.
82. Lei ZM, Mishra S, Zou W et al. Targeted disruption of luteinizing hormone/human chorionic gonado-
tropin receptor gene. Molecular Endocrinology 2001; 15(1): 184e200.
83. Ma X, Dong Y, Matzuk MM et al. Targeted disruption of luteinizing hormone beta-subunit leads to
hypogonadism, defects in gonadal steroidogenesis, and infertility. Proceedings of the National Academy
of Sciences of the USA 2004; 101(49): 17294e17299.
84. El-Gehani F, Zhang FP, Pakarinen P et al. Gonadotropin-independent regulation of steroidogenesis in the
fetal rat testis. Biology of Reproduction 1998; 58(1): 116e123.
85. Dierich A, Sairam MR, Monaco L et al. Impairing follicle-stimulating hormone (FSH) signaling in vivo:
targeted disruption of the FSH receptor leads to aberrant gametogenesis and hormonal imbalance.
Proceedings of the National Academy of Sciences of the USA 1998; 95(23): 13612e13617.
86. Abel MH, Wootton AN, Wilkins V et al. The effect of a null mutation in the follicle-stimulating hormone
receptor gene on mouse reproduction. Endocrinology 2000; 141(5): 1795e1803.
*87. Kumar TR, Wang Y, Lu N et al. Follicle stimulating hormone is required for ovarian follicle maturation
but not male fertility. Nature Genetics 1997; 15(2): 201e204.
88. Richter-Unruh A, Verhoef-Post M, Hiort O, et al. 46,XY disorder of sex development (46,XY DSD) due
to two new mutations of the luteinizing hormone receptor gene. The Endocrine Society, 88th Annual
Meeting 2006:P2e701.