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GnRH Agonist and Antagonist
The two principal gonadotropins are luteinizing hormone (LH) and follicle stimulating hormone (FSH).
A third human gonadotropin is human chorionic gonadotropin (hCG), produced by the placenta during pregnancy.
GnRH Analogues / Agonists
GnRH – structure and function
What is GnRH?
- Decapeptide neuroendocrine hormone
- Induces both FSH and LH secretion by pituitary gonadotrope cells in orderly way
- Crucial for control of gonadal function and normal ovarian cyclicity
- Half life: 4 min
GnRH pulse generator
- GnRH molecules are transported from the hypothalamus to the anterior pituitary by the hypothalamic -hypophyseal portal system
- It is released rythymically in short bursts, known as the GnRH pulse generator.
- Pulsatile frequency varies from 71 minutes in late follicular phase to 216 minutes in late luteal phase.
Routes of administration
- After IV administration, plasma GnRH shows 2 phases of ½ lives, 2-8 minutes for fast and 15-16 minutes for slow phase
- Has to be administered parenterally as they are susceptible to gastrointestinal proteolysis.
- Subcutaneous- most common, high bio-availability (75-90%) and depot like effects result in prolonged absorption , blood concentrations remain high for many hours, hence effective as single dose.
- Depot formulations- continuous release, improved efficiency, more convenience to the patient.
- Specially for long term pituitary desensitization as in endometriosis, fibroids, and infertility
- 3.75 mg triptorelin or leuprolide I/M once a m
GnRH Agonist protocols
- Long protocols
- Short protocols
- Ultra-short protocols
- Ultra-long protocols
- Superior to short and ultra-short
- Can be used to plan timing of OPU, and administration of Hcg can be delayed without any detrimental effects on IVF outcome
- Higher no. of oocytes retrieved and higher pregnancy rates as compared to short and ultra-short protocols, although more ampoules of gonadotrophins were needed
- An unwanted side-effect is the induction of formation of functional cysts. Ovarian cyst formation was reduced when pre-treatment with OCP’s is done
- Higher pregnancy rates when compared to other protocols
- Mean desensitization phase with an agonist in the long protocol is about 3 weeks
- Not very good for poor responders and PCO’s
The Long Protocol
Overview of IVF cycles
- Pre-treatment with GnRH agonist started from luteal phase of previous cycle
- Controlled ovarian hyperstimulation started from 2nd day of treatment cycle withgonodotropins
- GnRH agonist continued at half-dose in treatment cyle
- Serial USG scans to monitor follicle recruitment and growthe
- Ovum pickup and fertilization
- ET after 48 h
- Follow-up with progesterone suppplentation
Advantages of GnRH Agonist
- Long-term treatment possible
- Depot formulations available.
- Depot formulations with long duration of action available (e.g. leuprolide SC implant)
- Relatively low cost.
Disadvantages of GnRH Agonist
- Flare-up risk of disease exacerbation in malignant tumors
- + antihormones
- + add-back therapy
- Longer treatment duration compared to antagonists (e.g. uterine fibroid
- It took nearly 10 years more (after analogues) to develop GnRH antagonists, with their ability to block pituitary function without any intrinsic effect, (the flare-up effect), and which could be used for clinical studies in the field of ovarian stimulation.
- Histamine release and allergic reactions were the initial problems in clinical use.
- Only two, cetrorelix and ganirelix have been commercially available
- Cetrorelix has 2 dosages (0.25mg, 3mg) hence 2 protocols – single dose and multiple dose.
- Ganirelix has only 1 dosage (0.25 mg) hence ganirelix can be used only in multiple dose protocols.
- The idea with the development of GnRH antagonists was to have an ovarian stimulation protocol available which is as close to the normal cycle as possible.
Other ways to use GnRH agonists, such as the short protocol, used the normal menstrual cycle; however these protocols have been less effective compared to the long protocol.
- The most convenient way for the patient is to start with spontaneous menstrual blleeding using the endogenous gonadotrophins as efficiently as possible and suppressing pituitary function as late as necessary.
- Hence, two dosage protocols- single-dose and multiple-dose were developed.
GnRH antagonist protocols
- The single-dose protocol
- The multiple-dose protocol
The multi-dose GnRH antagonist protocol
The multiple-dose GnRH antagonist protocol. Ovarian stimulation using gonadotropins starts on day 2 or 3 of the spontaneous menstrual cycle. In a fixed protocol the GnRH antagonist is administered for the first time on day 6 of gonadotropins. This is continued up to and including the day of hCG.
The single- dose antagonist Protocol
The single-dose GnRH antagonist protocol. Ovarian stimulation using gonadotropins starts on day 2 or 3 of the spontaneous menstrual cycle. In a fixed protocol the GnRH antagonist is administered in a single dose on day 7 of gonadotropins. A single injection of Cetrotide 3 mg lasts for 96 hours to prevent a premature LH surge. In case that hCG cannot be administered within this time frame additional dosage of Cetrotide 0.25 mg should be given daily.
GnRH antagonist protocol vs. GnRH agonist long protocol
The main results were-
1. a significantly lower risk of OHSS, (which can be confirmed for cetrorelix alone,for ganirelix the risk seems not to be reduced compared to the GnRH long protocol)
2. a significantly lower pregnancy rate for all studies
How can the lower risk of OHSS be explained?
- The number of retrieved oocytes was significantly lower by about 2 ( Al-inany and Aboulgar)
- The estradiol levels on the day of hCG were lower (with a difference of 570pg/ml to 650 pg/ml)
- The development of less small follicles as compared to GnRH agonist long protocol (Ludwig et al)
Why is there a difference regarding pregnancy rates?
- Early suppression of endogenous LH and thereby detrimental effects on follicular growth and the endometrium
Down regulation – Why the need for DR
- To bring down the basal hormone levels
Antagonist regimes in IVF
- Fixed day regimen- day 6 of cycle- irrespective of size of follicle
- When follicle is 14 mm in size till follicle is mature(18 or 19 mm)
- Give in morning on day of hcg
- Time interval between hcg and antagonist should not be more than 12 hours
- There is severe suppression of LH when we give antagonist, but threshold level of LH is required , hence if we can add recombinant LH (inj leuverin) for better results
- Another regime (rarely used) is – start antagonist along with stimulation (but requires very high doses of gonadotrophins)
Advantages of GnRH Antagonist
- Immediate suppression
- Rapid recovery from suppression
- Shorter treatment periods (e.g single-shot for certain IVF patients)
Disadvantages of GnRH Antagonist
- Markedly higher doses required for sustained complete suppression
- Probably markedly higher Cost for long-term treatment (e.g 3 mg CET ~ 390 Euro ~ 29,000 INR)