GnRH ANTAGONIST IN

INFERTILITY
 Infertility
Infertility is defined as a failure to conceive within one or more
years of regular unprotected coitus
– Primary Infertility – patient’s who have never conceived
– Secondary Infertility – indicates previous pregnancy
but
failure to conceive subsequently’.

80% of couple conceive within 1st year

10% conceive by the end of 2nd year
10% remain infertile by end of 2nd year

Incidence - Worldwide: 8-10%, in India: 15-20%

 Infertility in India

• In India , 8 – 10 million couples estimated

to be childless
• Infertility affects 1 in 6 couples in India
• According to Recent Family Health Survey
data , 3.8 % of couples between 40 – 44
years are childless
• 24 % in lower socio- economic group and
31 % in higher classes are childless
BJOG 2009 ; 116 ( Suppl 1 ) : 77-83 , National Family Health Survey 1998- 99 , India
 Fertility Factors
• Healthy spermatozoa should be deposited high in vagina
• The spermatozoa should undergo changes (capacitation,
acrosome reaction) and acquire motility
• Motile spermatozoa should ascend through the cervix into the
uterine cavity and fallopian tubes
• There should be ovulation
• Fallopian tubes should be patent, and oocytes should be picked
up
by the fimbriated end of the tubes
• Spermatozoa should fertilize the oocytes at the ampulla of the
tube
• Embryo should reach the uterine cavity after 3-4 days of
fertilization
• Endometrium should be prepared for implantation
INFERTILITY IS NOT ALWAYS A
WOMAN'S PROBLEM
 Causes of Infertility

In only about one-third of cases is infertility due

to the woman (female factors).

In another one third of cases, infertility is due

to the man (male factors).

The remaining one third of cases are caused by

combined or unknown factors.
Causes of Infertility: Female factor
Ovulatory dysfunction
Cervical factors
Tubal factors
Endometriosis
Uterine factors – Fibroid uterus, Uterine
Synechiae, Congenital malformation of uterus
Vaginal factors – Vaginal Atresia, Septate
vagina
Immunological
Coital problem
Hormonal
Unexplained
Causes of Infertility: Male factor

Defective spermatogenesis
Abnormal Semen Parameters
Obstruction of the duct
Failure to deposit sperm high in the vagina
Idiopathic
Varicocele
Hormonal
Systemic causes
Immunological
 Treatment of Infertility
• Needs to be evidence – based
• UK – based RCOG and NICE have produced
exhaustive guidelines
• Expectant management – for infertile couples
with a good prognosis for spontaneous
pregnancy
• ART – valuable treatment option for selected
couples with a low probability of natural
conception

BJOG 2009 ; 116 ( Suppl 1 ) : 77-83

Treatment Options… Overcoming Infertility

Nearly 90% of all infertility cases, both male and

female factor, are overcome through treatment
Treatment options are:
 Ovulation Induction
 Medical & Surgical treatment of Male
 Laparoscopic & Hysteroscopic Surgery for
Female
 Intrauterine Insemination (IUI)
 Assisted Reproductive Technology (ART)
 Super Ovulation

• Controlled Ovarian hyperstimulation (super

ovulation)
– In ovulatory patient this is called
Ovarian Stimulation
– In Anovulatory patient it is called
Ovarian Induction
 Ovulation Induction in
Anovulatory Patient

AIM : To achieve mono –follicular or bi-

follicular response to the ovarian induction
thus preventing OHSS and high multiple
pregnancy.
– Calculate BMI (less than 30-32good progress)
– Weight loss
– Oral Metformin
– Correction of thyroid and prolactin disorder
Controlled Ovarian Hyperstimulation

THE RATIONALE
•  Number of oocytes available
(  chance of fertilization )
•  Steroid production
(  chance of implantation )

• Prevention of premature LH surge

• To time the insemination
• Increase the pregnancy rate
 Principles of COH

• Achieve Pregnancy in the shortest time

• Avoid OHSS
• Avoid Multiple Pregnancy
Ovarian Stimulation Protocols
 Clomiphene citrate
 Letrozole (Aromatase inhibitors)
 Clomiphene citrate +hMG/FSH
 Letrozole+hMG/FSH
 hMG/FSH alone or in combination

----------------------------------------------
GnRH agonists in combination with hMG and/or
FSH (long, short or ultra short protocol)

 GnRH antagonists in combination with hMG

and/or FSH (fixed or variable protocol)
Problems Encountered in COH

 Poor responders
 OHSS
 Premature LH surge
 Multiple Pregnancy
 Poor endometrial development
 Empty follicle syndrome
 Premature LH Surge
• Defined as a premature rise of LH > 10 IU / l
accompanied by a concomitant rise in progesterone
( > 1 µg / l – 3.2 Nm / l )
• Multifollicular recruitment during COH – sudden
increase in serum Estradiol levels ( E2 )
• Enough to induce a LH surge while follicular growth
is still in progress
• Seen in 20%(frydman) of cycles
• Detection- urinary or serum LH estimations
 Premature LH surge
• Premature LH surge causes premature luteinization of
granulosa cells and progesterone production which
causes adverse effects on endometrium
• May result in cycle cancellation
• Impairs pregnancy rates
• Poor oocyte quality
• Decreased fertilization and implantation rate
• May interfere with adequate timing of IUI
• Economic and psychological stress for the patients

The Infertility Manual .Kamini Rao . 3rd ed . 2009 . 415 -434

Gonadotropin-releasing hormone
(GnRH)

• GnRH is a decapeptide synthesized and released in pulsatile

manner by the arcuate nucleus in the hypothalamus
• Secreted as a 92-amino-acid precursor protein encoded in the
short arm of chromosome 8
• Reaches pituitary cells by ways of specialized portal system
• Regulates synthesis and release of pituitary gonadotropins
that in turn regulates steroidogenesis and gametogenesis
• Receptors- GnRH I & GnRH II (Most tissues of body)
• GnRH I & II receptors – found in several malignant tissues
and cell line
 GnRH Analogs
• Synthetic derivatives - modifications of the native
GnRH molecule
• Effects of modification
• Increase receptor affinity ( 100-200 times that of native
GnRH)
• Decrease degradation by circulating and tissue peptidases
• More stable and powerful compounds
• Continued rather than pulsatile secretion
• Daily administration results in biphasic response overtime
• Types
• Agonist

• Antagonist
 History of GnRH analogs
• 1971: The GnRH decapeptide was isolated and its structure
elucidated
• Extensive work performed in the late 1970’s and early 1980’s
demonstrated the utility of LHRH super-agonists
• In 1980, pulsatile low-dose GnRH1a was used in a
physiological manner to produce the first reported pregnancy
in a woman with hypogonadotrophic hypogonadism
• 1982: The first demonstration that GnRH agonists can be used
to eliminate premature luteinization and control ovarian
stimulation
• 1991: The first report suggesting use of the GnRH antagonist,
Nal-Glue, to prevent premature LH rise and progesterone in
controlled ovarian hyperstimulation treatment.
• First establish pregnancy using recombinant FSH and GnRH
antagonist 1998
Gonadotropin Releasing Hormone
Analogs
– Agonists initially enhance Gonadotropin
released from the pituitary; but with
continuing administration, cause down-
regulation of the pituitary and reduced LH &
FSH secretion
– Antagonists bind onto GnRH receptors and
completely suppress the pituitary hormone
secretion within a few hours

– Effects completely reversible after withdrawal

GnRH Analogs: Clinical Applications

– To reduce basal level of LH

– To prevent premature LH surge from 20 -2%
– To trigger ovulation
– Endometriosis suppression
 GnRH agonist Protocol
• Long protocol – GnRH agonist is started in the mid-luteal
phase (Day 21) of the previous cycle or 10 to 14 days before
the onset of period
• Short protocol
– GnRH agonist begins on the day 2 of the treatment cycle
and FSH/hMG starts on the day 3 of the cycle and
continued until a day prior to hCG administration
– It takes advantage of the >flare‑up effect =, namely, the
initial burst‑like FSH and LH release under the agonist
therapy
• Ultrashort protocol - GnRH agonist administration is
limited to day 1, 2, 3 of the cycle and FSH administration is
continued as in other protocol.
• Combining the use of agonists and gonadotropins in IVF
cycles give high pregnancy rates after IVF and ET
GnRH agonist: Mechanism of action

GnRHa administered

Pituitary GnRH receptors occupied and internalized

gland
Initial LH and FSH surge

Loss of available GnRH receptors

Decreased LH and FSH synthesis and release

Ovaries Suppression of follicular development

Decreased estradiol synthesis and release

 GnRH Antagonists
• First generation Antagonists (amino acid modification at
position 1,2, & 3)
– Strong lipophilic properties and thus making parenteral
administration impossible
– Strong affinity towards GnRH receptors on mast cells, (histamine
release)
• Second generation Antagonist (amino acid modification at
position 5 & 6)
– Histamine related side effects seen
• Next generation compound (amino acid modification at position
1,2,3,6, & 10)
– Without histamine relasing and lipophilic property
– Cetrorelix and Ganirelix
– Abarelix and Degarelix (used in cancer treatment)
 GnRH antagonists
• New class of drugs, the GnRH antagonists have
become commercially available
• Immediate and rapid inhibition of LH & FSH
suppression without flare-up
• Antagonist can either prevent or interrupt LH
surges
• Dramatic reduction in duration of treatment
• Lower number of gonadotropin used
GnRH antagonists: Mechanism of
action
Action Pituitary-ovarian axis suppression
without flare effect
Compete with GnRH for its receptors

Prevent synthesis and release of

LH/FSH
GnRH antagonist
GnRH antagonist
consensus model
consensus model Induce immediate and transient
hypogonadism
Suppress gonadal steroidogenesis
 Mechanism of action Contd
• The degree of gonadotropin suppression depends on the
dose of GnRH antagonist administered
• Administration of GnRH antagonist is only required during
a short period of stimulation, viz. when a premature LH
surge is likely to occur.
• Lower total dose of FSH is needed for stimulation, since
with the use of a GnRH antagonist, FSH levels are only
partly suppressed during the late follicular phase.
• Cessation of GnRH antagonist treatment ensures a rapid
and predictable recovery of the pituitary ‑gonadal axis
 Antagonist Vs Agonist
Cycle Day 6 Day of
Day 2-3 of FSH hCG

FSH
GnRH antagonist
Cycle down Day of
Day 21-24 regulation hCG
2-4 weeks

GnRH agonist
FSH
Comparision of Mechanism of Action

GnRH antagonist GnRH agonist

• Receptor blockage without • Receptor down‑regulation
receptor activation

• Competitive inhibition • Pituitary desensitization

• Immediate and • Initial flare‑up

dose‑dependent suppression

• Rapid reversibility
• Slow reversibility
Clinical use of GnRH antagonists
• COH in infertility (IVF, IUI)
• Gynecological disorders
– Fibroids
– Endometriosis
– PCOD
• Antitumour activity
– Prostrate cancer
– Benign Prostatic Hyperplasia (BPH)
• Gynecological cancers
• Precocious puberty
• Hormonal male contraception
 ???? GnRH Antagonists and
tumour
• GnRH receptors ( and GnRH antagonist
effect) demonstrated in human malignant
tumours, breast, ovary, endometrium and
prostate
• Inhibits the release of Insulin like growth
factor and cell growth
• Potential use in IVF, prior to chemotherapy
in women wishing to become pregnant in
the future.
 Single vs Multiple dose
GnRH antagonist protocols

• Multiple dose protocol

– 0.25 mg/day from Day 6 of stimulation till day of HCG
• Single dose protocol
– 3 mg on Day 7 of ovarian stimulation
– If delay in HCG, low daily dose of GnRH antagonist added 4
days after single dose
0.25 mg multiple dose protocol
ovulation
induction

oocyte embryo
gonadotropin administration pick up transfer
in an individualized dosage

1st day
of menstruation

1st day
luteal phase support
of gonado-
tropins

GnRH antagonist 0.25 mg administration

daily s.c. starting on day 6 of stimulation
 3 mg single dose protocol
ovulation
induction

oocyte embryo
gonadotropin administration pick up transfer
in an individualized dosage

1st day
of menstruation

1st day
luteal phase support
of gonado-
tropins

GnRH antagonist 3 mg administration

on day 7 of stimulation, lasting for 96 hours
 Single dose GnRH antagonist
protocol
• Advantage
– fewer injection
– 10% cycles additional dose of GnRH antagonist are
necessary
• Disadvantage
– Besides inhibiting premature LH surge, causes
excessive & potentially harmful suppression of
endogenous LH
• No significant difference in pregnancy rate in two
protocol
 Multiple dose GnRH antagonist
protocols – fixed vs flexible regimens
• GnRH antagonist administration on stimulation day 6
(fixed protocol) or when the leading follicle reached a
mean diameter of 14 mm (flexible protocol)
• Lower pregnancy rate in flexible compared to fixed
protocol
• Criteria on which initiation of GnRH antagonist is based
on as well as the 1st day on which patient should start
evaluation – have not been assessed so far
• Earlier initiation of GnRH antagonist needs to be further
explored
• Dose and timing of gonadotropin may have an impact on
optimal day of starting GnRH antagonist
Al-Inany et al, 2005
 Use of exogenous FSH in
GnRH antagonist cycles
• ↑ of starting dose of FSH
– No ↑ in pregnancy rate
• ↑ of gonadotropin dose at GnRH antagonist
initiation
– No ↑ in pregnancy rate
• Type of gonadotropin
– Not important
 Use of Antagonists in IUI
• Drawback of COS – frequent occurrence of premature
LH rises and luteinisation
• This may interfere with the adequate timing of IUI or
result in cycle cancellation , thus impairing the
pregnancy rate
• Multifollicular recruitment during COS can bring about a
sudden increase in serum estradiol levels that is enough
to induce an LH surge while follicular growth is still in
progress
• 24 % of IUI cycles suffer undesired premature
luteinization
• Addition of a GnRH antagonist suppresses the
occurrence of premature luteinization
 Cetrorelix: Description
Cetrorelix is a synthetic decapeptide with
GnRH antagonistic activity

Expert Opin Drug Metab Toxicol 2009 ; 5 ( 10 ) : 1323 – 36

Structural comparison of Cetrorelix with natural GnRH

• Cetrorelix It is a synthetic decapeptide possessing

high antagonistic activity to GnRH
• GnRH is a peptide composed of 10 amino acids with
crucial functions at positions 1, 2, 3, 6 and 10.
• The molecule has a 9‑fold higher receptor binding
affinity as compared to GnRH
 Mechanism of action
Cetrorelix competitively
inhibits GnRH receptors

Prevents stimulatory effects

of endogenous GnRH on
pituitary cells

Rapid suppression of LH,

FSH and sex hormone
levels
Cetrorelix – Pharmacokinetics
• Rapidly absorbed after s.c. administration
• Bioavailability – 85 %
• T max – 1-2 hrs
• 86 % plasma protein bound
• Plasma t1/2 – 20 hrs
• 2-4 % excreted in urine , 5-10 % in bile

Expert Opin Drug Metab Toxicol 2009 ; 5 ( 10 ) : 1323 – 36

 Adverse drug reactions
• Mild local site reactions like redness,
erythema, bruising, itching, swelling and
pruritis have been documented
• Nausea (1.3%)
• Elevation of liver enzymes (hepatotoxicity-
1 to 2%)
• Headache (1.1%)
• Ovarian hyperstimulation syndrome (3.5%)
 Dosage
• Cetrorelix may be administered s.c. once
daily (0.25mg) during the early to mid
follicular phase
• 0.25mg of Cetrorelix is administered on
either stimulation day 5 (morning or
evening) or day 6 (evening) and continued
daily until the day of hCG administration
 GnRH antagonists vs GnRH
agonists – results of four meta-
analyses of data on the use of
cetrorelix in COS.
 Meta-analysis 1
• Study
– Al-Inany and Aboulghar
• Objective
– To evaluate the efficacy of GnRH antagonists
compared with standard GnRH long agonist protocols
for COS
• Findings
– GnRH antagonist protocols are short and simple but
associated with a lower pregnancy rate compared
with long agonist protocols
– GnRH antagonist protocols may be improved further
by developing more flexible regimens that consider
individual patient characteristics
Cochrane Database of Systematic Reviews. 2001; 4: CD001750
 Meta-analysis 2
• Study
– Ludwig et al.
• Objective
– To evaluate if there is a reduction in the incidence of
OHSS and/or a reduction in pregnancy rates with
cetrorelix compared with long agonist protocols
• Findings
Compared with a long agonist protocol, cetrorelix is
associated with a:
– Significantly lower incidence of OHSS
– Similar pregnancy rate
Arch Gynecol Obstet.2001;265:175-82
 Meta-analysis 3
• Study
– Kolibianakis et al
• Objective
– To determine whether the choice of GnRH
analog for pituitary suppression during COS
affects live birth rate
• Findings
– GnRH agonists and antagonist protocols result
in similar live birth rates (per randomized
patient)
Hum Reprod Update. 2006;12: 651-71
 Meta-analysis 4
• Study
– Al-lnany et al.
• Objective
– To update the comparative evidence on the efficacy
of GnRH antagonists versus standard long agonist
protocols for COS
• Findings
– GnRH antagonist protocols are short and simple, and associated
with good clinical outcomes
– Compared with GnRH agonists, antagonists are associated with
a:
• Significant reduction in the incidence of OHSS
• Significantly lower consumption of gonadotropins
– The slightly lower pregnancy rates associated with GnRH
antagonist compared with long agonist protocols must be
discussed with patients prior to treatments.

Reprod Biomed Online.2007;14: 640-9

 Key points of all the four meta-
analysis
• GnRH antagonist protocols are short and
simple
• Cetrorelix is associated with a:
– Significantly lower incidence of OHSS
– Similar pregnancy rate
• GnRH agonists and antagonist protocols
result in similar live birth rates
• Associated with significantly lower
consumption of gonadotropins
 Cochrane review – GnRH
agonists vs Antagonists
• 27 RCTs compared GnRH antagonist with the
long protocol of GnRH agonist
• Clinical pregnancy rates were significantly lower
in the antagonist group ( OR = 0.84 )
• Ongoing pregnancy /Live birth rate – showed the
same significant lower pregnancy rate in the
antagonist group ( P=0.03 ; OR 0.82 )
• Statistically significant reduction in incidence of
severe OHSS with antagonist protocol

Cochrane Review 2009 ; 1-51

 LH supplementation in GnRH
antagonist cycle
• Low LH level after GnRH antagonist initiation
– Not associated with ↓ in pregnancy rate
• Addition of r-LH 75 IU at GnRH antagonist initiation
– Pregnancy rate not ↑ed
• LH supplementation is not indicated in all GnRH
antagonist cycles
• LH supplementation is recommended for those patients:
– Who do not show sufficient follicular growth on gonadotropin day
6 (follicle size 10-11mm)
– Who did not respond well in a previous cycle
– In older patients
 Criteria for HCG administration
• There is marked variation in the criteria
used for triggering final oocyte maturation
in IVF in both GnRH agonist and
antagonist cycles
• Timing for HCG administration might be
important for pregnancy rate
• Further studies are necessary to explore
optimal timing of HCG administration
Recommended use of GnRH antagonist co-
treatment during ovarian stimulation for IVF

• Currently, data are not in favour of a need to increase

the starting dose of gonadotropins or to increase
gonadotropin dose at antagonist initiation.
• Clinical evidence generated so far suggests that OCP
pretreatment can be used for planning IVF cycles.
• Addition of LH from initiation of stimulation or from
antagonist administration does not appear to be
necessary.
• Replacement of HCG by GnRH agonist for triggering
final oocyte maturation is associated with lower
probability of pregnancy.
 Recommended use of GnRH antagonists co-
treatment during ovarian stimulation for IVF (contd)

• The optimal timing for HCG administration needs to be

further explored.
• GnRH antagonist initiation on day 6 of stimulation
appears to be superior to flexible initiation by a follicle of
14–16 mm, although earlier GnRH antagonist
administration is worth further evaluation.
• The role of GnRH antagonists in ovarian stimulation for
IUI as well as their application in mild stimulation
protocols for IVF appears to be promising.
• Luteal phase supplementation is required following
GnRH antagonist co-treatment protocols.
 Advantages of antagonists
• Prevention of premature LH increase is easier and
takes less time (within few hours)
• Exogenous gonadotropins are reduced – stimulation
less costly
• Not associated with an acute stimulation of
gonadotropins
• Duration of ovarian stimulation protocols is shortened
• Initial stimulation by GnRH agonists can induce cyst
formation, which is avoided with GnRH antagonists
• No hot flushes are observed with GnRH antagonist
• Inadvert administration of GnRH analogue in early
pregnancy can be avoided
• Risk of OHSS can be substantially reduced
Disadvantages of GnRH antagonist

• Novel approach and knowledge

accumulation necessary for optimization
• Less felxible regarding cycle programme
• Minor reduction in pregnancy rate 3.3%
less than agonist
 GnRH antagonists in poor
responders
• Numerous strategies to improve ovarian stimulation in
poor responders have been proposed , including
increasing gonadotropin dosages , stopping the GnRH
agonist , the use of a microdose GnRH flare ,and the use
of a GnRH antagonist
• GnRH antagonists may offer some advantages over
other poor- responder protocols
Advantages :
– Simplicity
– Shorter duration of stimulation
– Reduced consumption of gonadotropins
– Reduced patient costs
– Ability to determine ovarian reserve immediately prior to
initiating gonadotropins
Fertility and Sterility Feb 2007 ; 87 (2 ) : 241-249
 GnRH antagonists in IUI to IVF
conversions
• Patients given antagonist had more follicles, oocytes
retrieved , more fertilized oocytes , and the fertilization rate
was 9.7 % higher

• GnRH antagonist use in ovulation – induction – IUI to IVF

conversions was associated with increased pregnancy
rates and improved intermediate cycle parameters

• Addition of a GnRH antagonist should be considered in

ovulation – induction – IUI to IVF conversions

Fertility and Sterility Jan 2010 ; 93 (2 ) : 605-608

 GnRH antagonists
CAN WE AVOID WEEKENDS?
• Weekend avoided in majority patients
• Length of the stimulation is longer
• The cumulative Gonadotropin dose is higher
• PR are more or comparable
• Useful alternative for medical centers in which a
gynaecologist on call is not available

Fertil Steril 2006 March ; 85 ( 3 ) : 573- 7

Results: 1) Pregnancy rates more ( 20 % ) in the Cetrorelix
group vs Controls ( 12.5 % )
2) No case of OHSS occurred

Fertil Steril 2006 March ; 85 ( 3 ) : 573- 7

 GnRH Agonist vs HCG for
triggering final oocyte maturation
• ↓ OHSS
• LH surge is not identical to that occuring in
natural cycle
• ↓ pregnancy rate

A comparison between various methods to

prevent OHSS is currently lacking
 Oral contraceptive pill pre-treatment in
ovarian stimulation with GnRH antagonist
• Programming in IVF cycles
• May result in improved synchronization of
recruitable cohort of ovarian follicles
• Disadvantage:
– ↑ gonadotropin requirement
– Longer duration of treatment
– Use of OC pill may be emotionally disturbing
• No effect of OC pill on pregnancy rate
 Summary
• GnRH antagonists are valuable pharmacologic tools
for controlled ovarian hyperstimulation
• They are an acceptable alternative to the use of
GnRH agonist in IVF cycles
• Multiple dose protocol should be preferred over
single high dose protocol
• There is general resistance in clinic to further
explore the use of GnRH antagonist because of the
reported lower Pregnancy rate. So counseling is
required for changing GnRH agonist to antagonist.
 Summary
• GnRH antagonist co-treatment results in shorter and
more cost-effective ovarian stimulation protocols.
Further studies are required for its optimization
• Possibility of a reduced incidence of OHSS with
GnRH antagonist deserves further evaluation
• Their utility in cancer treatment, endometriosis, BPH
and male contraception is still being explored but
these areas might benefit from the continued
development of depot formulations and oral GnRH
antagonists.
 Summary
• Use of GnRH antagonist should be viewed in the
context of a broader discussion regarding how to
assess IVF outcomes -
– healthy children
– term births
– chances for success in relation to side effects
– complications and cost
• Further development of GnRH antagonists and their
delivery systems will open a road field of clinical
applications for GnRH antagonists
• Suitable sustained delivery systems and GnRH
antagonists with sufficient oral bioavailability represent
the present and future of these important compounds