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Updates on The 13^th world congress on In Vitro Fertilization, Assisted Reproduction and Genetics.

GnRH agonists versus GnRH antagonists

Historical background

The existence of elevated basal levels of LH were shown to have a poor correlation with the success of the IVF cycles. Premature LH surges which occured due to the positive feed back from the elevated E2 levels as a result of gonadotropin administration led to premature luteinization and eventually to cycle cancellation. The discovery that continous administration of GnRH analogs induced a state of pituitary desensitization provided a welcoming solution for that problem.

Types of GnRH analogs

There are 2 type of GnRH analogs which are GNRH agonists and GnRH antagonists. Although the antagonists were developed in the same time as the agonists, their use was not very popular due to the high incidence of histamines release after the injection of the first generations. This trend is changing dramatically with the development of the new generations (i.e. Cetrorelix) which are not associated with such histamine releasing effect.

When administered continuously, GnRH agonists (i.e Triptorelin acetate) initially stimulate the release of gonadotropins followed by prolonged suppression even after discontinuation due to store depletion. On the other hand, the administration of the GnRH antagonists competitively bind to the pituitary GnRH receptors leading to pituitary suppression without the initial stimulatory effect produced by the agonist group. 

GnRH stimulation protocols

There are 2 basic ways for the use of GnRH-agonist in ovarian stimulation protocols the Long protocol or else luteal protocol and the short protocol which is also called flare protocol.

The long protocol

Long protocols are more commonly used for most patients going through IVF. In general, pregnancy rates are thought to be better with the use of this type of stimulation. The GnRH-agonist is started about 7 days prior to the next expected menses, and the gonadotropines are started within the first 2-6 days after menses begins. GnRH agonist dose is reduced in half and given each day with gonadotropins until the hCG injection (ovulation trigger).

The short protocol

Short protocols were initially developed for poor (ovarian) responders. In this protocol GnRH agonist is started on cycle day 2 in the same menstrual cycle that we will retrieve the eggs - instead of starting it a week prior to the start of menses. We are trying to take advantage of an initial "flare-up" response of FSH and LH release from the woman's own pituitary gland that usually occurs in the first 3 days of GnRH agonist administration. Continuing GnRH agonist for more than 3 days temporarily suppresses the pituitary gland so that it has very low output of FSH and LH. The gonadotropines product is then started on the following day (day 3). The idea is that the GnRH agonist will stimulate release of a large amount of FSH (and LH) that will jump-start (flare-up) the follicles so that we might have a better ovarian stimulation with more mature follicles and more eggs to utilize with IVF.

GnRH antagonits

GnRH antagonist is usually started on (about) the sixth day of giving the FSH product that stimulates the development of follicles in the ovary. It is given subcutaneously once daily and is continued until HCG is given. There are other antagonists that can be used as a single shot, rather than as daily injections.

Advantages of GnRH antagonits

Use of GnRH antagonist results in less total number of shots being taken during the stimulation cycle than with the use of GnRH agonist.

Recent evidences suggest that GnRH antagonists are effective, safe and well tolerated alternatives to agonists for controlled ovarian hyperstimulation. According to a recent Study published in the European  Journal of Obstetrics and Gynecology Reproductive Biology 2005 ,there are no statistically significant differences between the agonist and the antagonist groups in terms of many outcome measures as:

·        Amount of rFSH required & Number of follicles equal to or more than15mm.

·        Estradiol level on hCG day & Endometrial thickness on oocyte retrival day.

·        Number of oocytes retrieved.

·        Fertilization rate & Clinical pregnancy rates per-attempt and per-transfer.(1)

Also, other studies (Fertility Sterility 2005), showed that there is a favorable effect of GnRH antagonists in reducing the incidence of OHSS and the number of assisted fertilization cycles cancelled because of the risk of OHSS in high responder patients. As a consequence, GnRH antagonist plus gonadotrophin administration could also increase the percentage of oocyte retrievals and embryo transfers in this high risk group of patients.(2)

Conclusion

GnRH antagonist (Cetrotide) is currently being used successfully amongst Horus IVF center protocols, so far the results are very promising in terms of pregnancy rates and cost-effectiveness.

Cost of GnRH antagonist (Cetrotide) 5 injections:  (220 L.E X 5 =1000 L.E)

Cost of GnRH agonist 21 injections: (36 X 21= 756 L.E)

Luteal phase support

Progesterone production in ART cycles

Progesterone and Estradiol play central roles in the maintenance of human reproduction. Their levels peaks about 4 days after ovulation and continues on this level for a week, falling about 5 days before the menstrual cycle. Progesterone role is crucial when it comes endometrial receptivity, and during the luteal phase progesterone production is 40 fold the maximal E2 production.

In stimulated cycles, the luteal phase differs from the natural cycles as because:

• Progesterone is produces from multiple corpora lutea which is super- physiological

• The luteal phase may be shortened due to a sharper decline in the serum Estrogen and progesterone levels.

For these reasons luteal phase support was widely adopted specially with the use of GnRH analogs.

Importance of luteal phase support

In stimulated IVF cycles, steroid production after the first week of oocyte retrieval is usually well times and sufficient, so the importance of luteal phase support is to maintain such an adequate level of support and preventing the sharp decline of Progesterone levels

According to the guide lines of the national institute for clinical excellence 2004, all women who are undergoing in vitro fertilization treatment using gonadotrophin-releasing hormone analog for pituitary down-regulation should be receive luteal support using human either chorionic gonadotrophin or progesterone  to improve pregnancy rates.

Progesterone vs hCG

According to the most recent meta-analysis of randomized clinical trials published in Gynecol Obstet Invest 2005; the routine use of human chorionic gonadotrophin (hCG) for luteal support is not recommended because of the increased likelihood of ovarian hyperstimulation syndrome (OHSS), specially in patients with polycystic ovarian syndrome, even though hCG was superior progesterone as luteal phase support with respect to pregnancy rates.

Routes of Progesterone administration

Several routes of Progesterone delivery are commonly used including oral, intramuscular and trasvaginal.

Although the development of micronized formulation of natural progesterone has resulted in preparations with improved absorption and increased bioavailability, the systemic levels that can be achieved through these preparation is still too low for endometrial support when given through the oral route. This is probably related to the first hepatic pass and extensive metabolic degradation.

The intramuscular route significantly increase the bioavailability of progesterone which is usually above the physiological range when this route is used leading to "in phase" endometrial maturation. However, the intramuscular route has some drawbacks, mostly local i.e. marked inflammation at the injection site.

According to the world health organization report of current practices and controvercies in assisted reproduction 2002, the vaginal route (whether in the form of tablets, suppositories, creams, or gel) offers several important advantages over  the intramuscular and the oral formulations due to many reasons:

1. It avoids the first hepatic pass and ensures sustained plasma progesterone concentration.

2. Using the new sustained release formulations, lower doses applied once daily or even once every other day was shown to de as effective as the intramuscular route.

3. Even though serum progesterone is less than normal, mid luteal endometrial biopsies of women using the vaginal route is mostly in phase due what is known by "the first uterine pass effect"

Accordingly, it is recommended that either the vaginal forms or less favorably the intramuscular forms should be used in luteal phase support.

Preimplantation Genetic Diagnosis

Current practice:

The current practice for prevention of chromosomal abnormalities involves prenatal screening (in the form of chorionic villous sampling, amniocentesis and cordocentesis) and termination of pregnancy, a procedure that is not universally acceptable and is psychologically traumatic to the couples.  Preimplantation genetic diagnosis (PGD) is one of the practical options available for couples at-risk, to avoid the birth of children with genetic and chromosomal abnormalities. Despite its novelty, PGD has already become an alternative to traditional prenatal diagnosis, allowing establishing only unaffected pregnancies and avoiding the risk for pregnancy termination.

Indications of PGD

PGD is done for a variety of clinical settings including:

• Single gene defect.

• Balanced translocation carriers.

• Advanced maternal age.

• Recurrent implantation failure.

• Recurrent pregnancy loss.

The burden of chromosomal abnormalities

Chromosomal abnormalities are thought to be responsible for implantation failure and account for the majority of pre- and post- implantation embryo wastage in humans. Among chromosomal abnormalities in normally developing embryos, aneuploidy is the most frequent which results from maternal meiotic errors and preferentially occur during the first meiotic division.

Many recent studies published lately in Reproductive Biomedicine Online Fertility Sterility 2005 showed that at least one half of oocytes and preimplantation embryos specially from women aged 35 years and older are aneuploid and have to be avoided from transfer during in vitro fertilization (IVF).

Role of PGD in improving IVF outcomes

The accumulated experience of thousands of PGD cycles for poor prognosis in vitro fertilization (IVF) patients e.g. repeated IVF failure, advanced maternal age, or recurrent spontaneous abortion, provides strong evidence of the improvement of clinical outcome. In a multi-center report published in Fertility Sterility 2004, it was shown that PGD for aneuploidy screening doubled the implantation rate in some groups when compared with their matched controls and also reduced the incidence of spontaneous abortions (up to fourfold in couples carrying translocations).

This makes of practical relevance to inform couples at-risk about availability of PGD option, so they make their own choice in avoiding the birth of affected offspring and having healthy children of their own.

Techniques used in PGD

According to the American Society for Reproductive Medicine report ( ASRM 2003), he following are the most commonly employed techniques in PGD.

• PGD for single gene defect is usually done by Polymerase chain reaction(PCR) or more recently multiplex PCR through blastomere analysis  obtained by day 3 biopsy.

• PGD for aneuploidy screening (PGD-AS), is performed either by blastomere analysis as mentioned before or the analysis of the first and second polar bodies following their extrusion from oocytes. Two effective techniques are available for cytogenetic screening for aneuploidy, which are:

  1. Fluorescence In-Situ Hybridization (FISH) which is the most widely used method as it is fast and reliable, enabling the detection of up to 10 chromosomes within a working day. Still, it can’t detect all chromosomal abnormalities except for those tested by the available probes.

  2. Comparative genomic hybridization(CGH) (which provides a full karyotype). Recent studies suggest that it is more effective than FISH for identifying chromosomally normal embryos, as it was able to identify many chromosomal abnormalities that would have been missed (about 33%)  if those cells had been analyzed by FISH.

Safety of PGD   

The fact that more than 1,000 apparently healthy unaffected children have been born after PGD suggests its accuracy, reliability, and safety.

Future prospects

In view of these findings, PGD should become an integral part of assisted reproductive techniques to increase the chance of success and to substitute the current practice of selection of embryos for transfer using morphological parameters. This is specially important as it was shown that morphology may not be a reliable predictor of genotype or the developmental potential. Also with the current tendency of limiting the number of transferred embryos to avoid complications due to multiple pregnancies, PGD is gaining much support these days.

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