Gnrh Antagonist_frank Quinn

Dr Frank Quinn Clinical Director IVF Australia

Overview • • • •

• •

Introduction GnRH agonists and antagonist Mode of Action Antagonist vs Agonist efficacy GnRH antagonist protocols ♦

Multiple and single dose antagonists

♦

Fixed versus flexible start

♦

Cycle Programming

GnRH antagonists and Poor Responders Summary

Native GnRH and its Analogues pyro Glu

His

Trp

Ser

Tyr

Gly

Leu

Arg

Pro

Gly NH2

Chemically modify native GnRH to form:

Agonists

- initial stimulatory phase followed by suppression

Antagonists - immediate suppression

GnRH Agonist vs Antagonists: effect on LH levels 30

LH (IU/L)

25 20 Agonist Antagonist

15 10 5 0 -6

0

6

12 18 24 30 36 42 48 Hours

GnRH

1

2

3

4

5

6

7

8

9

10

pyro Glu

His

Trp

Ser

Tyr

Gly

Leu

Arg

Pro

Gly NH2

Leu

Arg

Pro

D-Ala

Arg

Pro

D-Ala

D-4Aph Leu (Et2)

L-4Aph (Et2) Pro

D-Ala

D-Cit

Arg

First-Generation

Nal-Arg

AcD- D-4F D-Trp Nal Phe

Ser

Tyr

D-Arg

Second-Generation

Nal-Glu

AcD- D-4Ci D-Pal Phe Nal

Ser

Arg

D-Glu (AA)

Leu

Third-Generation

Ganirelix Cetrorelix

AcDNal

D-4Ci D-Pal Phe

AcD- D-4Ci D-Pal Nal Phe

Ser

Ser

Tyr

Tyr

Leu

Pro

D-Ala

The GnRH antagonists available: cetrorelix and ganirelix 2 REGIMENS

• Multiple dose (0.25mg/day) ♦

cetrorelix, ganirelix

• Single dose (3mg) ♦

cetrorelix

PROTOCOLS

• !!!

Comparison of the long agonist and the antagonist protocols

more physiologic no hormonal antagonist no cyst withdrawal multiple dose protocol formation

antagonist administration

gonadotropin administration

less gonadotropins flare up pituitary effect suppression gonadotropin administration

agonist long protocol

longer treatment

agonist administration

pre-treatment cycle

treatment cycle

GnRH antagonists vs agonists Advantages and Questions? DEMONSTRATED

QUESTIONS

• Shorter treatment

• Outcome same as

• Less Injections • Less OHSS • Less FSH

Agonists?

• Best protocol? • Cycle

Programming?

• More patient friendly • Need for LH?

Is the outcome the same for GnRH antagonist and GnRH agonist protocols?

Antagonists vs Agonists in ART

GnRH ant protocol used more in older patients and following initial treatment failure BUT: in young patients with tubal infertility

•

A literature search identified 22 RCTs comparing GnRH antagonists and GnRH agonists that involved 3176 subjects. ♦

•

Dramatic reduction in the duration of analogue treatment ♦

•

–17.88 days; 95% CI, –20.41 to –15.36)

Significantly reduced duration of FSH stimulation was present in the antagonist group. ♦

•

Where live birth was not reported, an effort was made to contact the corresponding authors to retrieve the missing information.

–3.04 ampoules; 95% CI, –6.27 to +0.19).

Significantly less oocytes were retrieved in the antagonist group. ♦

–1.19 COCs; 95% CI, –1.82 to –0.56).

•

No significant difference was present in the probability of live birth between the two GnRH analogues ♦

•

Significantly lower OHSS requiring hospitalisation in the antagonist group ♦

•

[odds ratio (OR), 0.86; 95% confidence intervals (CI), 0.72 to 1.02].

OR, 0.46; 95% CI, 0.26 to 0.82;

In conclusion, the probability of live birth after ovarian stimulation for IVF does not depend on the type of analogue used for pituitary suppression.

•

6 trials fulfilled the inclusion criteria. There was no difference between GnRH-ant and GnRHa (long and flareup protocols) with respect to ♦

cycle cancellation rate, number of mature oocytes and clinical pregnancy rate per cycle initiated, per oocyte retrieval and per embryo transfer.

•

In the two trials that had used GnRH-ant versus long GnRHa, a significantly higher number of retrieved oocytes was observed in the GnRH-ant protocols [P = 0.018; WMD: 1.12 (0.18, 2.05)].

•

In the four trials that had used GnRH-ant versus flare-up protocols, a significantly higher number of retrieved oocytes (P = 0.032; WMD: −0.51, 95% CI −0.99, −0.04) was observed in the GnRHa protocols. Franco et al RBM online 2006

•

•

Poor Responders: 8 studies, with 575 patients treated with GnRHa or antagonist for ovarian stimulation in RCT. ♦

Long agonist protocol in poor responders is associated with significantly fewer oocytes retrieved compared with GnRH-ant protocol (OR 0.41, 95% CI: 0.0–0.83, P = 0.05)

♦

likelihood of clinical pregnancy higher after antagonist use; however, this did not reach statistical significance (OR 1.28, 95% CI: 0.84–1.96; P = 0.25;

PCOS: Four studies identified with 305 patients. ♦

duration of stimulation shorter using GnRH-ant (OR -0.86, 95% CI -1.14 to -0.59, P < 0.01),

♦

non-significant lower consumption of gonadotropins

♦

No significant difference in number of oocytes retrieved or likelihood of clinical pregnancy

Griesinger et al RBM online 2006

hCG 3 foll 17mm diam Day 6 FSH stim

Day 2 menses

GnRH ant R-hFSH

Vag P4 Papanikolaou et al NEJM 2006

Age

Single Blastocyst Single Cleavage stage embryo 30.4±3.6 30.5±3.2

FSH used (IUs)

1704±574

1699±515

Oocytes

12.5±7.1

13.9±8.1

Implantation rate %

38.7

27.4

% Clinical Preg

34.3

24.0

% Live Birth Rate

33.1

22.2 Papanikolaou et al NEJM 2006

Which is the best Antagonist protocol? •

Fixed daily ♦

•

Fixed single dose ♦

•

Day 7 FSH

Flexible daily/single dose ♦

•

Day 1 or 6 FSH

Follicle 14 or 15 mm

OC pre-treatment ♦

4-5 day interval before starting FSH

Administration of GnRH antagonist according to follicle size (flexible protocol) vs a fixed day of stimulation

•

No significant difference in clinical pregnancy rate between fixed and flexible protocols

•

Reduction in IU’s FSH with Flexible Protocol

•

No difference in oocytes recovered

•

Pregnancy/cycle 21.8 vs 31.1% in flexible vs fixed 0.25mg antag protocol arm In absence of foll ≥ 15mm on stim day 6 ongoing preg rate lower Patients receiving GnRH-ant on FSH day 8 or later had lower pregnancy rates

• •

Conclusion: Slow responders have lower pregnancy potential

Flexible vs Fixed Day Administration of GnRH antagonists

•

General Rule: To reduce risk of premature luteinisation in flexible protocol start GnRH antagonist no later than follicle size 14 mm

•

If > 6 follicles 11-13 mm diameter start GnRH antagonist (Kim et al 2005)

GnRH antagonist and Cycle Programming with Oral Contraceptive / oral E2

Cycle programming in Cetrorelix protocols using oral contraceptives 18 to 28 days

5 days

oral contraceptive pill

GnRH ant 0.25mg

- 30µg ethinylestradiol - 150 µg desogestrel

FSH

sunday

friday

last pill stimulation start Fischl et al 2001, Obruca, et al. Human Reprod 2001;16(Suppl 1):89

Cycle Programming in Cetrorelix Multiple Dose Protocol Using OCs With OCs

Without OCs

75

75

Ampoules of FSH*

22.1 ± 6.5

20.1 ± 4.7

Days of FSH*

11.4 ± 2.7

10.6 ± 2.0

Mean number of oocytes

5.8

6.3

Mean number of embryos transferred

2.5

2.3

39.7%

41.2%

0/68

6/66

Patients (n)

Clinical pregnancies/ET No. weekend OPUs

Obruca, Fischl etetalal. 2001, Human Obruca, Reprod et al. 2001;16(Suppl Human Reprod 1):89 2001;16(Suppl 1):89

*Mean ± SD

•

425 patients randomised to receive OC pretreatment or not with r-hFSH starting day 2 (menses) or 5 days after stopping OC. GnRH antag started stim day 6

•

Ongoing pregnancy rates per started cycle in the nonOCP and OCP group were 27.5% and 22.9%, respectively [95% confidence interval (CI) of the difference: -3.7 to +12.8].

•

Pregnancy loss was significantly increased in the OCP (36.4%) compared with the non-OCP group (21.6%),(95% CI of the difference: -28.4 to -2.3). ♦

Due to oversuppressed LH levels?

• • •

Randomised controlled study in 185 patients from16 US centres

• •

FSH Dose adjustment from stim day 6

OC pill administered from day 1 of previous cycle R-hFSH (follitropin alfa multi dose) 225 IU started on 5th day after stop of OC pill

Single dose GnRH antagonist (cetrorelix) 3mg or daily GnRH antagonist 0.25 mg (ganirelix) administered when lead foll >=14mm ♦

If hCG not administered 4 days after 3mg Cetrorelix daily 0.25mg Cetrorelix initiated

•

250 mcg r-hCG (Ovidrel) admin when 1 foll >=18mm, 2 foll >= 16mm and E2 150 pg/ml per mature foll

•

Vaginal progesterone(Crinone) admin from day of or day after oocyte retrieval Fertil Steril 2005 84: 108 - 117

•

No difference in outcome characteristics between Single dose 3mg and multi dose 0.25 mg

•

Use of OCP programming and flexible dosing of GnRH antagonist associated with acceptable outcomes of 46% pregnancy rate per cycle

Wilcox et al Fertil Steril 2005 84: 108 - 117

•

Oral 17β E2 (4mg each pm) from day 20 to day 2 of next cycle

•

Multidose r-hFSH 225 IU from day 3

•

Lead follicle >13mm Cetrorelix 3mg admin

•

More synchronised follicle cohort, higher oocyte yield

Possible benefits of oral contraceptives in GnRH antagonist protocols • Cycle programming for optimal timing of oocyte pick-up

• Synchronise Follicle cohort ♦

Avoid rapid emergence of dominant follicle

• Can benefit poor responders ♦

Cheung et al 2004

Is it necessary to increase the FSH dose when starting the GnRH antagonist?

hCG R-hFSH GnRH ant

R-hFSH GnRH ant

Control

Step-up

Age

31.8

31.4

FSH used (IUs)

2,540 ± 567

2,662 ± 593

Oocytes

14.6 ± 7.5

16.7 ± 10.4

Embryos Replaced

2.1 ± 0.4

2.2 ± 0.5

Live Birth Rate

56.7%

60.0%

Can GnRH agonist be used to trigger final follicular maturation?

YES

Is the use of GnRH agonist to trigger final follicular maturation associated with similar pregnancy rates as hCG?

•

No significant difference in number of oocytes retrieved (–0.94,–0.33–0.14), fertilization rate (0.15,–0.09–0.38)

•

No conclusion can be drawn as regards OHSS incidence after GnRH agonist triggering.

•

GnRH agonist administration is associated with a significantly reduced likelihood of achieving a clinical pregnancy (0.21, 0.05–0.84;P=0.03).

•

The odds of first trimester pregnancy loss is increased after GnRH agonist triggering.

What are the criteria for administering hCG in a GnRH antagonist Protocol?

Typical Follicle and E2 Patterns Following GnRH-a Down Regulation or GnRH-ant Administration Agonist 25

Plasma E2 (pg/ml)

Follicular Diameter

3000

20

E2

15

1000

5

0

0

*

2000

10

1 1

3

5

7

9

11

13

Leading follicle emerges earlier in in antag cycle Scott et al 2001

Antagonist

2

3

4

5

6

7

8

9

10 11 12 13 14

Cycle Day

E2 higher in early stim phase in antag cycle * Agonist > Antagonist

RBM online 2005

Higher (P > 0.02) pregnancy and implantation rate when hCG criteria when ≥ 3 foll 17mm (early hCG) vs late hCG group (hCG admin 2 days later)

Is there a need to add LH in a GnRH antagonist Protocol?

Is there a need to add LH in a GnRH antagonist Protocol? •

If rapid LH suppression has a detrimental effect would be most apparent in single dose 3mg cetrorelix protocol

•

Sauer et al 2004 in multicentre study using 3mg flexible protocol (+OCP) reported no benefit of LH supplementation (150 IU r-hLH dy 6 FSH) on MII oocytes or pregnancy rate vs no supplementation or GnRH agonist protocol

•

Cedrin et al 2004 in multicentre study using 3mg flexible protocol (+OCP) reported no benefit of LH supplementation (75 IU r-hLH dy antag) on oocytes or delivery rates

Women aged 32 yrs treated with Cetrotide 0.25mg from foll>= 14mm and randomised to receive 75 IU r-LH or no LH at same time No sig difference (except higher E2) in outcome parameters

Eur J Obstet Gyn 2006

Is there a need for luteal phase support a GnRH antagonist Protocol?

Is there a need for luteal phase support a GnRH antagonist Protocol? •

Due to immediate reversability of GnRH antagonist action – no need?

•

Controlled ovarian stimulation leads to short luteal phase (Jones et al 1981)

•

Inadequete luteal phase (Albano et al 1998)

•

Abnormal endometrial development (Kolibianakis et al 2003)

•

201 patients received rFSH / GnRH antagonist and randomized for luteal support from day 1 after oocyte retrieval to either ♦

600 mg of micronized progesterone vaginally (n = 100, progesterone group) or

♦

600 mg of micronized progesterone and 4 mg of E2 valerate orally (n = 101, progesterone/E2 group).

•

Twenty-six ongoing pregnancies were achieved in the progesterone (26%) and 30 in the progesterone/E2 group (29.7%). (Difference: 3.7 and 95%, CI: –15.8 to 8.6%).

•

In conclusion, the addition of E2 to progesterone in the luteal phase after stimulation with rFSH and GnRH antagonist does not appear to increase the probability of pregnancy.

GnRH antagonists in Poor Responder Patients

GnRH antagonists may be associated with - simpler stimulation protocols, - lower gonadotropin requirements, - reduced patient costs, - shorter downtimes between consecutive cycles. Greatest advantage of GnRH antagonists is the ability to assess ovarian reserves immediately prior to starting gonadotropin stimulation. The ability to respond to cycle-to-cycle variation in antral follicle counts may allow the optimization of oocyte yield and reduce cycle cancellation rates.

•

63 patients ave. 36 yrs received OCP pre-treatment

•

Long Luteal Agonist or Cetrotide fixed dose 0.25mg daily from day 6 FSH

• •

R-hFSH 300iu daily

•

More embryos transferred in Cetrotide group with a trend to higher pregnancy rate per cycle (16.1 vs 9.4%)

No differences in oocytes retrieved

Human Reprod 2005

Placido et al Fertil Steril 2006

•

300 IU r-hFSH (Gonal-f)

•

GnRH antag (Cetrotide) 0.25mg from foll size 14mm or short agonist protocol

•

150 IU r-LH from foll size 14mm

•

More mature and fertilized oocytes in GnRH antag group

The Use of GnRH Antagonists in Ovarian Stimulation Protocols: Summary

•

Single and multiple dose GnRH antagonist protocols are equally effective and patient friendly

• •

Antagonist protocols are as effective as Classic Long GnRH agonist Flexible administration of Antagonist (no later than follicle size 14mm) is effective

•

OC (or E2) programming improves cycle management and reduces LH secretion.

•

Supplemental LH in normogonadotrophic patients is not required Use of Antagonist in poor responders associated with more embryos for

An Ideal GnRH antagonist protocol today FIXED

FLEXIBLE

MENSES

PROGRAMMED GnRH ant 0.25mg hCG

5 Days

Leading follicle size 14mm FSH

OC 1

2

3

4

5

6

7

progesterone 8

9

10

11

12 13