NEW DRUG CLASSES

New drug classes

Gonadotropin-releasing-hormone-receptor antagonists

Judith A F Huirne, Cornelis B Lambalk

Pulsatile gonadotropin-releasing hormone (GnRH) stimulates the pituitary secretion of both luteinising hormone (LH)
and follicle-stimulating hormone (FSH) and thus controls the hormonal and reproductive function of the gonads.
Blockade of GnRH effects may be wanted for a variety of reasons—eg, to prevent untimely luteinisation during
assisted reproduction or in the treatment of sex-hormone-dependent disorders. Selective blockade of LH/FSH
secretion and subsequent chemical castration have previously been achieved by desensitising the pituitary to
continuously administered GnRH or by giving long-acting GnRH agonists. Only recently have GnRH-receptor
antagonists, that immediately block GnRH’s effects, been developed for clinical use with acceptable
pharmacokinetic, safety, and commercial profiles. In assisted reproduction, these compounds seem to be as effective
as established therapy but with shorter treatment times, less use of gonadotropic hormones, improved patient
acceptance, and fewer follicles and oocytes. All current indications for GnRH-agonist desensitisation may prove to be
indications for a GnRH antagonist, including endometriosis, leiomyoma, and breast cancer in women, benign prostatic
hypertrophy and prostatic carcinoma in men, and central precocious puberty in children. However, the best clinical
evidence so far has been in assisted reproduction and prostate cancer.

The hormone gonadorelin, also known as gonadotropin-
releasing hormone or luteinising-hormone-releasing
hormone (GnRH, LHRH), induces both follicle-
stimulating hormone and LH secretion by the pituitary
gonadotrope cells in a orderly way which is crucial for the
control of gonadal function and normal ovarian cyclicity.
One logical consequence of the discovery of the aminoacid
sequence of GnRH in 1967 was the development of
synthetic agonists and antagonists. It was noted that
sustained stimulation of the pituitary with GnRH itself or
with a GnRH agonist caused desensitisation, by post-
receptor mechanisms that are still not well understood.1
The result, not immediately but after some time, was a
chemical hypophysectomy which was thought to be the
indication for GnRH antagonists. At first it seemed that the
development of clinically safe agents would be simple to
achieve by changing just one or two aminoacids but it was
to take almost 30 years of trial and error with three or more
replacements, including sometimes the use of unnatural
aminoacids, before antagonists with acceptable
pharmacokinetic, safety, and commercial profiles were
developed. Today these GnRH-antagonists are at an
advanced stage of clinical development.
In this review of the most commonly used GnRH
antagonists we have made use of some information that has
so far been presented only in abstracts so some statements
may need modification when the data are published in full.
Physiological principles
GnRH
GnRH is a decapeptide (panel 1) that was isolated and
characterised by the groups of A V Schally and
R C L Guillemin, the 1977 Nobel laureates. GnRH type I
is the classic reproductive neuroendocrine factor.2 It is
synthesised in the cytoplasm of the diencephalon of the
Lancet 2001; 358: 1793–803
Division of Reproductive Medicine, Department of Obstetrics and
Gynaecology, Vrije Universiteit Medical Centre, PO Box 7057,
1007MB Amsterdam, Netherlands (J A F Huirne MD, C B Lambalk MD)
Correspondence to: Dr Cornelis B Lambalk
(e-mail cb.lambalk@azvu.nl)
brain and packaged into granules in the Golgi apparatus
and then transported by the axons to the neuronal
terminal, where it is released in a pulsatile fashion into the
capillaries of the pituitary-portal circulation. GnRH
mRNA has been found in the pituitary3 and in
extrapituitary tissue, including the placenta, ovary,
myometrium, endometrium, and prostate and blood
mononuclear cells, indicating an autocrine/paracrine
role.4-6 The genes for human GnRH types I and II lie on
chromosome 8 (8p11.2-p21)7 and chromosome 20
(20p13),8 respectively.
GnRH receptor
The GnRH receptor (GnRH-r)9 (figure 1) is a member of a
family of receptors known as the rhodopsin-like G-protein-
coupled receptor family,10 which also includes the
thyrotropin-releasing hormone receptor. Most vertebrates
have at least two types of GnRH receptor.9 The gene for
GnRH type I receptor lies on chromosome 4 (4q21.2),11
and the type II receptor is thought to be on chromosome
1q.12 Cloning of a type II GnRH receptor in the marmoset
showed that only 41% is identical to the type I receptor and
that, unlike the type I receptor, it has a carboxyl-terminal
tail, which is important for rapid desensitisation.12 In
human beings, controversial data have been obtained for
extrapituitary expression of mRNA for GnRH-r in ovary,
breast, endometrium, myometrium, placenta, prostate, and
testis and in the various cancers of these tissues and their
associated cell lines. Variable presence of the different
GnRH-r transcripts13 and different distribution of type I
and type II receptors could have a role. The type II
receptor in mammals is more widely distributed than the
type I receptor. It is expressed throughout the brain,
including the pituitary and areas associated with sexual
arousal, and also in diverse non-neural and reproductive
tissues, suggesting various functions.12
GnRH signal transduction
GnRH binds to specific receptors on the gonadotrope
cells in the anterior pituitary. In gonadotropes, GnRH
receptor activation, after coupling to Gq s11 protein, leads
to the generation of several second messengers, among
which are diacylglycerol and inositol-4,5-triphosphate.

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NEW DRUG CLASSES

Panel 1: Structural formulae of native GnRH and third-generation GnRH-antagonists

Name Aminoacid found at position:
1 2 3 4 5 6 7 8 9 10
GnRH-I pGlu His Trp Ser Tyr Gly Leu Arg Pro Gly-NH2
GnRH-II 1 2 3 4 His 6 Trp Tyr 9 10
Abarelix D-Ala D-Phe D-Ala 4 5 D-Asp 7 Lys(iPr) 9 D-Ala
Antarelix D-Nal D-Phe D-Pal 4 Phe D-Hcit 7 Lys(iPr) 9 D-Ala
Cetrorelix D-Nal D-Phe D-Pal 4 5 D-Cit 7 8 9 D-Ala
Ganirelix D-Nal D-Phe D-Pal 4 5 D-hArg 7 hArg 9 D-Ala
Iturelix D-Nal D-Phe D-Pal 4 NicLys D-NicLys 7 Lys(iPr) 9 D-Ala
Nal-Glu D-Nal D-Phe D-Pal 4 D-Glu D-Glu 7 8 9 D-Ala

The former leads to activation of protein kinase C and the post-receptor signalling is involved, true receptor loss
latter to the production of cyclic AMP and release of (down-regulation) having only an initial role.1
calcium ions from intracellular pools.14,15 Both events A clear dichotomy of GnRH and competitive antagonist
result in secretion and synthesis of LH and FSH. GnRH (in which antagonist blocks agonist-induced effects and
II selectively binds to the type II receptor and signalling is vice versa) has not been shown in any human extrapituitary
distinctly different from that in the type I receptor.12 The tissue that expresses the receptor.16 Why agonists and
FSH and LH releasing potency of mammalian GnRH I antagonists sometimes exert similar effects is not clear. If
and GnRH II, tested in Soay rams, showed that the FSH the effects seen with an antagonist result from direct
to LH ratio was higher after treatment with GnRH II than blockade of the receptor while a similar effect with the
with GnRH I.12 These two GnRHs and GnRH receptor agonist is achieved via desensitisation, one would expect
systems, along with different signalling pathways, provide antagonist effects to be mitigated by an agonist, but this
the potential for differential FSH and LH secretion.12 does not usually happen. On the other hand, more recent
The natural GnRH signal from the hypothalamus to data show that GnRH antagonist abolishes a dose-
the pituitary is episodic (every 1-4 h) and this ensures LH dependent antiproliferative effect of a GnRH agonist on
and FSH secretion. However, upon continuous human ovarian epithelial cells and in human granulosa-
stimulation with GnRH, via a long-acting agonist, there is luteal cells.4 The antagonist reverses GnRH induced
first a period of hypersecretion quickly followed by activation of mitogen activated protein (MAP) kinase
pituitary desensitisation and arrest of gonadotropin which is known to regulate cell growth and
secretion. This mechanism is still not clear except that differentiation.4,17

1·15 (15)

G Q M L P I S N N I A S C H N Q N Q E P S
N A S N A M NH2
L
P H L G F T H C S L N R
T A S V M L
I Q S F
Y A D V
L W G M S T Q C E S
Q E R K W Q S 7·32(302)
T F H W P D
2·65 V I
L T L L Y L Q A D F P V
S G (102) I C
N W K V Q Y N F Y W W H F N
K I R M G P G
2·51 SL A F F F I G F F
V
T (26) D L V L 3·32 V S T F L V L F
V T P K (121) S Y A
M V L F S C L Y P F L
F F I L L I W
L 2·50 S M 5·50 F I 6·50 T W N P
F T E
4·50 A
L (87) Y A (223) I P (282) C V C F
L S L N L
A F P (164) L G V L T D
A T A L M S F I F S P L
F M M Q G M L T A 7·50 I Y
N 1·50 T L
A S V V V I C F A (320) G Y
F (53) H I K S N V F
L L K L S L 3·50 A K T M S L
K L L L D R I I K L
(139) N
Q K S L F T T
W K A S L K
T Q I T T R L
K M K R
R
R P V A
K 3·58
L A L L
S (145) Q H R
E 3·58
D P
K L (147)
G K K P I
H
E L Q L N Q S K N N

Figure 1: Schematic representation of human GnRH-r

Receptor composed of single polypeptide chain, with seven hydrophobic transmembrane domains, extracellular amino terminus, and intracellular carboxy
terminus. Known glycosylation site is marked, and certain key functional residues are numbered.

1794 THE LANCET • Vol 358 • November 24, 2001

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In in-vitro studies with cell lines of various tumour
types, antiproliferative activity was shown by both
types of analogue. In a cell line of a human kidney
embryo antiproliferative effects of agonist and
antagonist occurred only when expression of a high
affinity GnRH-r was induced, which strongly suggests
direct, specific, receptor-mediated effects.16 GnRH-r
stimulation of MAP kinases (MAPKs) in granulosa-
luteal cells of human beings confirmed the receptor
mediation; additional studies showed that cellular
responses (proliferation, hormone or peptide secretion)
to MAPK stimulation are tissue specific and duration
dependent.17 GnRH analogues may interfere with the
signal transduction of growth factor receptors and
related oncogene products associated with tyrosine-
kinase activity.15 So far, most studies have been done
on the assumption that there was only the GnRH type I
receptor. Cloning of the type II GnRH receptor
provides the opportunity to study the different affinity
and potency of analogues to the different types of
receptor and their signalling pathways and cellular
reactions. Differential expression of the GnRH type I
and type II receptors could have a role in the paradox
of similar effects of both GnRH agonists and
antagonists on proliferation in specific tumour cell
lines. Certain mammalian GnRH type I antagonists
behave as agonists on GnRH type II receptors.12 The
antiproliferative effects of GnRH analogues on cell
lines of these tumours are consistent with the activation
of MAPK p38␣ by the type II receptor, which is known
to be antiproliferative.18
LHRH antagonists
Unlike the agonists, GnRH antagonists do not induce
an initial stimulation of gonadotropin release, but cause
an immediate and rapid, reversible suppression of
gonadotropin secretion. The principal mechanism of
action of GnRH antagonists is competitive receptor
occupancy of GnRH-r (figure 2).
Structural modifications
The effects of a single aminoacid substitution may alter
affinity and agonist activity via modification of a side-
chain that interacts with the binding pocket and/or by
altering the conformation of the peptide. Whether a
ligand functions as agonist or antagonist is species
dependent and is determined by the structure of the
second extracellular loop of the GnRH-r.19
The structural features of GnRH antagonists are
reviewed elsewhere.20,21 The weak first-generation drugs
were hydrophilic and contained replacements for His at
position 2 and for Trp at position 3. Inhibitory activity
increased after incorporation of a D-aminoacid at
position 6 but increased histamine-releasing activity
resulted in anaphylactic reactions to the second-
generation antagonists such as detirelix.22 In the third
Panel 2: GnRH antagonists launched or under investigation
Name Manufacturer
Abarelix Praecis (Amgen)
Sanofi-Synthelabo
Antarelix Asta Medica
Cetrorelix (Cetrotide) Asta Medica/Serono
Ganirelix acetate
(Orgalutran, Antagon) Organon
Iturelix (Antide) Serono
SC=subcutaneous, IM=intramuscular.
THE LANCET • Vol 358 • November 24, 2001
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NEW DRUG CLASSES
GnRH neuron
Competitive receptor
blocking
GnRH
GnRH GnRH antagonist
FSH No intrinsic
LH activity
LH FSH
Figure 2: Working mechanism of GnRH antagonists
generation the undesirable risk of oedema was
eliminated by replacing the D-Arg at position 6 by
neutral D-ureidoalkyl aminoacids, to produce
compounds such as cetrorelix, iturelix, azaline B,
ganirelix, abarelix, and antarelix23–29 (panels 1 and 2).
Pharmacokinetics
The pharmacokinetic properties with regard to
maximum antagonist administration (Cmax) are linear
following single or multiple doses.30–32 The predominant
clearance is metabolic and hepatic.33 Absorption is the
time-limiting step for elimination. Plasma protein
binding averages 80% and the plasma half-life of a non-
depot antagonist varies from 5 to 30 h after single
subcutaneous administration of clinical doses and is
increased after multiple dose administration (panel 3).
Abarelix for injectable suspension allows single
intramuscular administration every 28 days in patients
with prostatic cancer.34–36
Pharmacodynamics
6 h (range 4–24 h) after administration of a GnRH-
antagonist plasma LH concentrations will have fallen by
70% (range 52–91%) and plasma FSH by 30% (range
23–61%). The size and duration of this suppression are
dose dependent.37,38 Complete reversal is achieved in
24–72 h. Comparable suppression is seen after
subcutaneous and intramuscular administration39 but
the intranasal route requires higher dosages.40 In women
with regular menstrual cycles, the LH suppressive effect
is greatest at the time of ovulation.41 Any residual
gonadotropin in the serum after administration of an
antagonist in maximally suppressive doses suggests
either incomplete blockade of pituitary receptors or, and
more probably, non-GnRH-dependent gonadotropin
secretion. The percentage decline in LH secretion
achieved by GnRH-antagonists is consistently higher
than the decline in FSH secretion,33,42–45 indicating the
existence of some additional, non-GnRH-dependent
control mechanism.
Route Status
IM Phase III, prostate cancer
Phase II, endometriosis
SC Phase I, prostate cancer
SC Approved IVF. Phase II, benign prostatic hyperplasia,
uterine myoma, prostate and ovarian cancer
SC Approved, female infertility
SC Phase II, IVF
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Panel 3: Pharmacokinetic indices following single and multiple dose administrations of GnRH antagonists
in (pre)clinical studies*
Compound M/F Dose (mg) Tmax Cmax T1/2 Refs
(h) (ng/mL) (h)
Single dose
Abarelix-depot Both 30–120 NA 7·5–38 >240 Wong118
Cetrorelix M 10 NA NA 20 Behre119
F 0·25 1·0 5·0 5·0 Duijkers31
F 1·0 1·0 21·2 9·4 Duijkers31
F 3·0 1·5 28·5 62·8 Erb120
Ganirelix F 0·25 1·1 14·8 12·8 Oberye32
Multiple dose†
Cetrorelix F 0·25 1·0 6·4 20·6 Duijkers31
F 1·0 1·0 21·1 77·4 Duijkers31
Ganirelix F 0·25 1·1 11·2 16·2 Oberye32
*Results of phase I studies, which studied recommended dose as applied in phase III trials, and published in peer-reviewed journals. †After multiple dosing (daily): Tmax=time of
maximum plasma concentration at steady state, Cmax=maximum plasma concentration at steady state, T1/2=terminal half-life.

Safety and tolerability Hernandez57 has hypothesised that GnRH antagonists

The third-generation antagonists have low histamine-
releasing potency, and iturelix and azaline-B have lower
histamine-releasing potencies than GnRH itself though
neither agent is currently under clinical
development.23,26,46 Toxicological studies have confirmed
the safety of the third-generation drugs. There is no
evidence for irreversible drug-related atrophy of the
target organs or for mutagenic/clastogenic potential.
Influence on the early embryonic development of rats
could not be demonstrated.30,47,48 Over 2000 patients
have now been treated with ganirelix, cetrorelix, or
abarelix, without evidence of anaphylactic reactions.49–53
Adverse effects of antagonists are largely the same as
those with agonists, and are attributable to hypo-
oestrogenism in women and hypoandrogenism in males,
including hot flushes, mood changes, headache, and
decreased libido. Prolonged exposure could lead to loss
of bone-mineral density to the same extent as the 2-8%
after 6 months seen with agonists. One common side-
effect is a local reaction at the injection site (redness and
pain), which usually resolves within an hour.52,53 Local
skin reactions seem to be less common with antagonists
than they are with agonists. No significant changes in
serum chemistry or haematological indices have been
noted.48,54 Clinical experience to date indicates that
GnRH antagonists are safe and well tolerated.
Extrapituitary effects
The safety of GnRH analogues in respect of structures
such as the ovary, oocyte, and granulosa cell and the
embryo has become a matter of debate since the
discovery of extrapituitary human GnRH-receptors. The
many paradoxical results in studies of ovarian
steroidogenesis may be caused by factors such as the
type, dose, and regimen of the analogues used, the
patient’s ovarian status, the ovarian cell types used and
the hormonal pretreatment of those cells, and the type
of in-vitro stimulation, besides methodological
differences in the experiments and physiological
variation in receptor abundance and type.12, 55–57
So far, intrinsic direct effects of GnRH antagonists on
human ovarian steroidogenesis or cAMP production in
vitro have not been demonstrated.58–60 An important,
recent finding is the expression of GnRH and GnRH-r
in the mouse embryo.61 Incubation of the murine
embryos with a GnRH agonist enhanced preimplan-
tation embryonic development whereas an GnRH
antagonist completely blocked this development.61 The
blockade could be reversed by a GnRH agonist.
interact with the mitotic programming of cells involved
in folliculogenesis, blastomere formation, and
endometrium development. Moreover, there is
evidence that GnRH (and agonists) increase the
cleavage rate of bovine oocytes, an effect that is
abolished by addition of a GnRH antagonist.62 Although
inhibition of sperm-binding to the zona pellucida was
inhibited by GnRH antagonists in vitro,63 lower
fertilisation rates were not found in phase III studies of
antagonists.50–53,64 The lower implantation rates seen with
higher doses of antagonists in in-vitro fertilisation
(IVF)65 are probably related to impaired endometrial
receptiveness rather than a direct embryonic effect
because cryopreserved embryos from these cycles
yielded normal pregnancy rates.66 Follicular growth was
also not influenced by the daily dose of GnRH
antagonist.67
Despite the reassurance to date, the safety GnRH
analogues in respect of human embryo development
remains a priority. So far no increased risk of birth
defects or pregnancy wastage in pregnancies exposed to
daily low-dose GnRH antagonist therapy in the first
weeks of gestation have been recorded.68
Therapeutic applications
On pharmacological grounds the primary indications for
GnRH antagonists will be in any situation in which
chemical gonadotropic hypophysectomy is required
(figure 3):
(1) Immediate blockade of the effect of gonadotropic
hormones –eg, in IVF to prevent the normal midcycle
rise in LH.
(2) Indirectly, to block gonadal sex-hormone secretion
via blockade of pituitary gonadotropin secretion. An
antagonist can, theoretically, be given to patients with a
sex-hormone-dependent disease such as benign
prostatic hypertrophy and prostate carcinoma,
leiomyoma and endometriosis, or precocious puberty.
(3) The treatment of cancer, based on evidence that
GnRH antagonists exert direct negative effects on
growth of certain malignant tumours.
The only two registered GnRH antagonists for IVF
are cetrorelix (Cetrotide; Serono International) and
ganirelix (Orgalutran, Antagon; Organon). Both are
approved only for use during IVF.
Prevention of premature LH surge in IVF
Placebo-controlled studies of GnRH agonists revealed
that in about 20% of women there was a premature LH

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 NEW DRUG CLASSES

Level Effects Agonist

hCG
Days 21–24 of the
GnRH neuron preceeding cycle
Hypothalamic FSH
desensitisation GnRH agonist
GnRH GnRH antagonist
Day 2 or 3 Day 6
Antagonist of menses of FSH hCG or GnRH
Selective chemical
Pituitary Pituitary
hypophysectomy
Multiple dose FSH
GnRH antagonist

LH and FSH LH and FSH Day 7 or 8

Chemical of FSH
Gonadal
castration Day 2 or 3 GnRH
ovary testis
of menses antagonist hCG or GnRH
Single dose
Oestrogens Androgens
FSH

Figure 3: Effects of GnRH antagonists Figure 4: GnRH analogue treatment regimens in in-vitro
Schematic representation of effects on different levels of hypothalamic- fertilisation
pituitary-gonadal axis. Schematic representation of most commonly used regimen in phase III
trials.

increase that led to cancellation of the IVF cycle.69,70
Preventing this untimely physiological change would
clearly be beneficial. Moreover, the IVF harvest is bigger
with more embryos, allowing better selection so that, on
average, the outcome in terms of pregnancy rates is
better.71 It takes time for a state of desensitisation to be
reached and, to start with, LH secretion actually
increases (flare-up). In an IVF setting, treatment with a
GnRH agonist usually begins in the midluteal phase of
the menstrual cycle preceding the IVF treatment cycle;
this is the so-called long protocol (figure 4). With an
antagonist, immediate blockade of pituitary gonadotropin
secretion when premature luteinisation during IVF
stimulation is imminent seemed an obvious approach.
Several studies of dose and treatment schedules have
been done,65,72,73 and two general approaches have
emerged. The first is a single subcutaneous injection of a
large dose on about the eighth day of stimulation with
gonadotropins (figure 4). The alternative is five or six
daily injections of a small dose from about day 6 of
stimulation until the day that hCG for final oocyte
maturation is given (figure 4, panel 4).
Panel 4 summarises suggested daily dosages based on
extensive dose-finding reports.65,72–74 The next step was to
establish whether a GnRH antagonist is at least as
effective as a GnRH agonist as the established reference
medication. So far, four such studies of repeated
antagonist injections have been reported50–53 and one with
a single-dose regimen64 (panel 5).
With repeated injections (panel 6), a consistent finding
is that duration of treatment with gonadotropins is
shortened by 1-2 days. With an antagonist slightly fewer
follicles are seen at the time of hCG injection so the
number of recovered oocytes tends to be lower. A likely
explanation is that an agonist suppresses the natural cycle
follicular recruitment initiated by the intercycle FSH
rise50–53 so that longer treatment with gonadotropins is
required, which allows more follicles to enter the growing
phase. No significant difference was found with respect
to percentages of metaphase II oocytes, fertilisation rates,
and number of good quality embryos.52,53
Pregnancy rates were high in both groups in all
four studies but in every one the rate was lower in
the antagonist group. A meta-analysis of the five
randomised trials (panel 5), shows an overall
significantly lower rate of pregnancy of 5%. This
meta-analysis unfortunately included the study that
compared a single-dose analogue regimen with different
gonadotropin starting dose as an additional variable.75
There is some concern that this may be a consequence
of the currently advised treatment regimen. It has been
suggested that the larger numbers of oocytes and
embryos with agonists allow better selection,71 although
the numbers of good quality embryos do not seem to be
different. A direct adverse effect on the embryo cannot
yet be ruled out but is not likely. There are many
reports of pregnancies inadvertently exposed to a GnRH
agonist without any adverse effect.56 In IVF treatment
the risk of embryonic exposure to an antagonist is
minimal. Cetrorelix plasma and follicular fluid levels fell
significantly after hCG administration, and at minimally
effective doses cetrorelix was not detectable during
ovum retrieval and embryo transfer.76 Nevertheless, only
long-term follow-up of the children born after IVF
procedures in which these new drugs have been used
can be conclusive. Follow-up of neonatal outcome after
pregnancies established in large phase II/III trials (474
pregnancies after ganirelix, 134 after a long agonist
protocol,77 and 227 children after centrorelix68) did not
show any negative effect.
No major side-effects have been reported. Minor side-
effects were limited to pain and redness at the injection
site. This happened with both types of analogue but was
less common with the antagonist.52,53 The smaller number
of injections and the reduction in the duration of IVF
treatment are welcomed by patients and this could be the
Panel 4: Prevention of premature LH surge; minimal
effective dose of GnRH antagonists in patients
undergoing in-vitro fertilisation
Compound Dose LH-surge Refs
Cetrorelix 3 mg single dose 0/34 Olivennes72
Cetrorelix 0·25 mg/day 0/30 Albano73
Ganirelix 0·25 mg/day 1/69 Ganirelix group65
Iturelix 0·5mg/day 0/32 Serono74
Single subcutaneous injection on stimulation day (SD) 8 or until oestradiol level
肁400 pg/mL.72 Multiple injections at one per day subcutaneous, from stimulation
day 6 or 7 up to hCG administration day.65,73,74 LH-surge defined as LH >10 IU/L
after first antagonist injection.

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NEW DRUG CLASSES

Panel 5: GnRH antagonist versus GnRH agonists: treatment schedules of phase III trials in in-vitro fertilisation
Antagonist group Agonist group
Drug dose FSH dose Drug Dose (mg) FSH dose No Refs
(mg) (units/day) (units/day)
Multiple dosing regimen
Cetrorelix 0·25 150 HMG Buserelin 0·6 150 HMG 293 Albano50
Ganirelix 0·25 150 rFSH Buserelin 0·6–1·2 150 rFSH 701 EUR Orgalutran study51
Ganirelix 0·25 150 rFSH Triptorelin 0·1 150 rFSH 337 EME Orgalutran study52
Ganirelix 0·25 225 rFSH Leuprolide 1–0·5 225 rFSH 297 Nam Ganirelix study53
Single dose regimen
Cetrorelix 3·0 150 HMG Triptorelin 3·75 225 HMG 154 Olivennes64
Multiple antagonist dosing one subcutaneous injection daily from stimulation day 6,7 or 8 up to HCG day; single dosing one subcutaneous injection on stimulation day 7 or if
oestradiol 500 pg/mL or follicle >14 mm. For agonists multiple dosing with daily subcutaneous or intranasal (buserelin) administration, starting midluteal phase of menstrual cycle
preceding ovarian stimulation cycle (long protocol). Single dosing regimen is one triptorelin depot injection during preceding luteal phase.

most important reason why GnRH antagonists will find a Other indications: female reproductive
therapeutic role in IVF clinics. So far, however, no large system
and moreover no blinded comparisons of GnRH agonists On theoretical grounds, many future indications are
and antagonists with pregnancy outcome as the endpoint feasible for GnRH antagonistic compounds (panel 7).
have been done. A further advantage of antagonists is
that less FSH is needed. Ovarian hyperstimulation syndrome
Antagonist blockade allows immediate reversal of Currently, ovarian hyperstimulation syndrome is
pituitary gonadotropin secretion. This means that in IVF managed by electrolyte and fluid administration, rest,
ovulatory ripening can be triggered via endogenous paracentesis, and, in severe forms, respiratory support.
gonadotropins by using a GnRH agonist.78,79 One The patient may benefit from immediate blockade of
advantage could be prevention of ovarian endogenous LH secretion. High doses of a GnRH
hyperstimulation syndrome, which is thought to result at antagonist may be used for this purpose.84
least in part from the prolonged LH effect of hCG.80
Finally, the use of GnRH antagonist blockade of Polycystic ovary syndrome
premature luteinisation can be used in IVF with very low Polycystic ovary syndrome (PCOS) is characterised by
or without any hormonal stimulation,81 lower risk of oligomenorrhoea, hyperandrogenism, and cystic
overstimulation, and simplification of the procedure.82 appearance of the ovaries. Raised LH levels are thought
A possible disadvantage of an antagonist in IVF is its to be responsible for the high androgen levels that
narrow therapeutic range with the currently advised adversely affect the development of follicles.
doses for repeated injections. Patient compliance needs Theoretically, blockade of endogenous LH secretion by
to be high because there is a risk of premature LH an antagonist combined with ovulation induction could
secretion if an injection is missed. result in improved follicular development. The abnormal
Another disadvantage is the unpredictable timing of LH secretion is thought to result from an abnormal
the start of the IVF procedure, which begins with the endogenous GnRH signal from the hypothalamus.85
administration of FSH on day 3 of the woman’s cycle Studies in monkeys showed that blockade of the
and so depends on how regular her menstruation is. This endogenous GnRH signal can be competed with by
problem may be solved by pretreatment with an oral exogenously administered pulsatile GnRH which restored
contraceptive.83 gonadotropin secretion and ovulation.86 So far the same

Panel 6: In-vitro fertilisation results in trials comparing repeated dose GnRH agonist and GnRH antagonist
Albano50 EUR Orgalutran Study51 EME Orgalutran Study52 NAM Ganirelix Study53
Cetrorelix Buserelin Ganirelix Buserelin Ganirelix Triptorelin Ganirelix Leuprolide
Patients (ITT) 188 85 463 237 226 109 198 99
LH surge (% ITT) 1·6 1·2 2·8 1·3 0·4 0 1·0 0
Days analogue (median, ITT) 5·7* 26·6* 5 26 5 26 4 22
Days FSH (median) 10·6* 11·4* 9 10 9 11 8 10
Total FSH (median, IU) 1770* 1920* 1500 1800 1350 1800 1800 2025
Follicles >10 mm hCG day (mean, ITT) 10·1* 12·3* 10·7 11·8 10·1 10·7 12·3 13·9
E2 on hCG day (median, pg/mL) 1625* 2082* 1190 1700 1090 1370 2001 2768
Oocytes (mean ITT) 7·4 9·6 8·7 9·7 7·9 9·6 11·6 14·1
Fertilisation rate (%) 53·6 52·9 62·1 62·1 64 64·9 62·4 61·9
Embryos (mean no, ITT) 4·0 4·1 6·0 7·1 4·0 4·7 6·9 8·2
Embryos transferred (mean no) 2·2 2·2 2·2 2·2 2·4 2·6 2·9 2·8
Implantation rate (IR) NA NA 15·7 21·8 22·9 22·9 21·1 26·1
Vital PR/ITT (%) 22·3 25·9 21·8 28·3 32·3 36·0 35·4 38·4
Ongoing PR/ITT (%) 18·1† 22·4† 20·3 25·7 31·0 33·9 30·8 36·4
OHSS (% ITT) 1·1 5·9 2·4 5·9 1·8 0·9 6·1 2·0
ITT=intent-to-treat group, is the number of patients who received at least one dose of LHRH analogue or FSH. E2=oestradiol. OHSS=ovarian hyperstimulation syndrome.
* Mean, calculated for the patients who reached the day of HCG. Fertilisation rate=% 2PN oocytes per number of oocytes incubated, IR=number of sacs/transferred embryo (patients
with embryo transfer). Vital pregnancy=intrauterine pregnancy with proof of at least one vital fetus as assessed by ultrasound scan 5–6 weeks after embryo transfer. Ongoing
pregnancy was defined as an intrauterine pregnancy with proof of at least one vital fetus as assessed by ultrasound at 12–16 weeks after transfer. † number of deliveries

1798 THE LANCET • Vol 358 • November 24, 2001

For personal use. Only reproduce with permission from The Lancet Publishing Group.

Panel 7: Other indications (being explored or
future) for GnRH antagonists
Female reproductive system
Ovarian hyperstimulation syndrome
Polycystic ovary syndrome
Endometriosis
Leiomyoma
Ovarian cancer
Endometrial cancer
Breast cancer
Mammography
Male reproductive system
Benign prostate hypertrophy
Prostate cancer
Male contraception
Paediatrics
Precocious puberty
Delay of puberty in children with small stature
Miscellaneous
Pituitary adenoma
Gonadal protection during radiation or chemotherapy
Paraphilias
Direct antitumour effects
Drug targeting
combination in PCOS patients normalised gonadotropin
secretion but failed to induce ovulation.87
Endometriosis
With endometriosis, an oestrogen-dependent disorder,
treatment with a GnRH antagonist is likely to be just as
effective as treatment with a GnRH agonist. Phase III
trials comparing abarelix with leuprolide are underway.88
Leiomyoma
Treatment of leiomyoma with GnRH antagonists, by
daily injections or by depot injections, results in shrinkage
of the leiomyoma by 30–50% within 4–8 weeks.89,90 The
avoidance of the flare-up in gonadotropin secretion seen
with the GnRH agonist may explain the rapid reduction
in fibroid size. Autocrine/paracrine effects mediated via
myometrial GnRH receptors may also be involved.
Endometrial ablation
Among other future benign gynaecological indications are
prevention of endometrial proliferation – eg, with difficult
dysfunctional bleeding and as pretreatment before
hysteroscopic surgery.91
Gynaecological cancers
The original rationale for a GnRH agonist in the
treatment of ovarian cancer was to block the endogenous
LH and FSH secretion which were thought to stimulate
tumour growth. However, a role for gonadotropins in
ovarian epithelial cancer remains controversial. Clinical
studies have recorded objective responses (9% to 26%)
with GnRH agonists, and there is evidence for a direct
antiproliferative effects of GnRH analogues.92 A role for
GnRH antagonists has yet to be established but studies
are underway.93
Favourable effects of GnRH agonists in patients with
recurrent endometrial cancer have been reported.94 These
favourable effects could be related to reduction in
oestrogen output but direct inhibitory effects are likely
also. GnRH agonists and antagonists inhibit proliferation
in endometrial cancer cell lines,95 but no clinical data on
the effects of antagonists are available.
THE LANCET • Vol 358 • November 24, 2001
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NEW DRUG CLASSES
Treatment with GnRH agonists of patients with
advanced metastatic breast cancer has been shown to
be effective and safe though in clinical practice
antioestrogenic therapy by tamoxifen prevails. Human
breast cancer does express the GnRH receptor
with moderately high-affinity binding, inducing
inhibition of cell proliferation in cultured cell lines.96,97
Although some studies with agonists show inhibition,
others found no effect.98 Unfortunately, at the moment
there are no reports or studies underway with regard
to the clinical application of GnRH antagonists in breast
cancer.
Mammography
Injection of a GnRH antagonist before screening
mammography, to achieve an antioestrogenic effect on
the breast, could permit better resolution.91
Other indications: male reproductive system
Benign prostatic hypertrophy
In one clinical study injections of cetrorelix (5 mg twice
daily for 2 days and then 1 mg twice daily for 2 months)
resulted in a rapid 27% reduction in prostate volume and
a 53% reduction of symptoms with improvement in
quality of life.99 During follow-up urinary symptoms
usually improved and sexual function was enhanced.
However, phase III comparative studies have yet to
be done.
Prostate cancer
GnRH agonists have advantages over orchidectomy and
oestrogens and were first-choice drugs, mostly initially
combined with antiandrogens, in the hormonal
treatment of prostate cancer.36 However, the initial
androgen surge as result of the LH flare may cause
significant complications such as ureteric obstruction
and severe pain from bone metastasis. This effect does
not occur with GnRH antagonists.36,100–104 With cetrorelix
1–2 mg per day after an initial loading of 10 mg over 2–5
days, castrate testosterone values are sustained with
reductions in prostate specific antigen (PSA), regression
of metastases, and rapid improvement of disseminated
prostate cancer.100 Immediate and sustained suppression
of tumour is achieved, with a rapid decline in prostate
volume compared with conventional treatments.101
Abarelix-depot 100 mg by intramuscular injection every
28 days with an additional injection on day 15 causes
rapid and profound reduction in androgen,
gonadotropin and PSA in men with various stages of
prostate cancer, superior by comparison with the GnRH
agonists up to 29 days36,100–105 and comparable during 85
to 169 days.104,105 An additional advantage of GnRH
antagonists by comparison with GnRH agonists is the
long-term (up to 169 days) suppression of FSH,27,104
since FSH has been implicated as a potential growth
factor for prostate cancer.106 At 12 weeks the overall
response to abarelix-depot is 74% (9% complete
response, 22% partial, 43% stable disease),102 median
PSA and testosterone levels declined with 90% of
baseline, cancer pain was reduced and narcotic use
declined with improvement of urinary complaints.107 A
New Drug Application has been submitted to the US
Food and Drug Administration, and has been filed for
approval in Europe for its use in prostatic cancer.
Male contraception
Weekly 200 mg testosterone injections cause reversible
oligozoospermia in 98% of men, and resulting pregnancy
rates are lower than those for the oral contraceptive for
1799
NEW DRUG CLASSES
women.108 However, reported side-effects are weight
gain, oily skin, and acne and if the dose is lowered
contraceptive efficacy declines. Azoospermia can be
achieved with lower dosages (25 mg weekly) if combined
with a GnRH antagonist.109 Low sperm counts can be
achieved with an initial combination of a daily sub-
cutaneous antagonist (Nal Glu) and weekly low-dose
testosterone followed by low-dose testosterone alone.108
The newly developed long-acting GnRH antagonist
preparations could bring us one step closer to the goal of
a satisfactory male hormonal contraceptive.
Other indications
Puberty disorders
GnRH agonists are the established treatment of
central precocious puberty. They act via desensitisation
of the pituitary to prematurely released endogenous
GnRH. There are no clinical data on GnRH antagonists
in this context, though animal experiments are en-
couraging.110Another future indication may be the
delay of normal puberty in children with short stature
but so far this has only been tested with a GnRH
agonist.111
Miscellaneous
Among other possible indications are the use of GnRH
antagonists in the hormonal treatment of pituitary
gonadotropin producing tumours,112,113 and the protection
of the gonads in a similar way as agonists may act
during radiation or chemotherapy.114,115 Finally, GnRH
antagonists may be useful as pharmacological agents in
treatment of hypersexuality and paraphilias.116
Future prospects
Current GnRH antagonists seem to be safe and effective
additions to the hormonal armamentarium for several
conditions though published clinical evidence so far is
mainly in IVF and prostate cancer. The hope remains that
all current indications for GnRH agonist therapy will also
become applications for GnRH antagonists. With respect
to direct anti-tumour effects we do not yet know whether
agonists or antagonists will prevail. More studies, looking
at tissue-specific distribution of GnRH receptor types,
their analogue affinity, potency, and specific signalling
pathway activation are needed. In all situations sound
comparative studies, and publication of them, are
essential. Expected long-term developments include non-
peptide orally active GnRH antagonists20,117 and targeted
drug administration for some cancers.21 Finally, licensed
GnRH antagonists are ideal research tools for further
exploration of the pathophysiology of the human
reproductive system.
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