What is a short IVF protocol with GnRH antagonists?

By (gynecologist), (gynecologist), (embryologist) and (psychologist).
Last Update: 03/17/2022

GnRH antagonists are drugs used in assisted reproduction treatments to control ovarian function and prevent spontaneous ovulation. They are the most commonly used GnRH agonists in short ovarian stimulation protocols. We can find them with different chemical compositions and commercial names, but their function is the same, whether they are used in artificial insemination or in vitro fertilization (IVF) treatments.

What are GnRH antagonists?

GnRH antagonists are drugs belonging to the group of gonadotropin-releasing hormone (GnRH) analogs, which are used for ovarian stimulation in assisted reproduction treatments (artificial insemination, in vitro fertilization, and ICSI). Thanks to them, we can control ovarian function.

The purpose of these hormones is to prevent the LH peak, which would cause premature follicular ovulation and luteinization. In this way, we can control the time at which it occurs so that it does not occur prematurely.

If there were a spontaneous ovulation, it would not be possible to retrieve the eggs in the follicular puncture or to perform artificial insemination on an optimal day for fertilization to occur.

In addition, the LH peak would also affect endometrial receptivity. Therefore, in women who require endometrial preparation, either for frozen embryo transfer or for ovodonation treatments, GnRH analogs are also administered.

It should be noted that their use is not exclusive to assisted reproduction patients: they are also indicated, for example, in the treatment of endometriosis and hormone-dependent tumors, such as breast or prostate cancer.

Effects: how does it work?

Once a GnRH antagonist is administered, it binds to the GnRH receptors and blocksthem. In this way, it prevents GnRH from binding to its receptors by competitive blockade. These receptors are located on the surface of the gonadotroph cells of the pituitary gland.

Blocking GnRH receptors, in turn, inhibits the synthesis of gonadotrophins (FSH and LH) by the pituitary gland. These hormones exert their function in the ovary: they are involved in the regulation of the menstrual cycle. Therefore, GnRH antagonists slow down ovarian activity and inhibit the menstrual cycle.

Unlike GnRH agonists, their action is immediate and they do not produce a flare-up effect, which causes FSH and LH secretion to increase at the beginning of agonist administration.

The immediacy of their action and the absence of flare-up effect mean that, compared to protocols with GnRH agonists, it is necessary to inject fewer doses of antagonists to achieve the same pituitary suppression. Therefore, it simplifies ovarian stimulation and makes it less uncomfortable for the patient: we go from approximately one month of hormonal treatment to 10-12 days.

Advantages: simplification of treatments

The benefits of using this drug in ovarian stimulation treatments are as follows:

  • It produces immediate suppression of serum LH levels and prevents premature ovulation. Because their effect is so rapid, they can be administered at the time when there is an obvious risk of the LH peak occurring, as they take hours to achieve pituitary inhibition. In the case of agonists, they need 7-10 days to achieve this effect.
  • The duration of the ovulation stimulation treatment is shorter, thus reducing discomfort for patients: fewer injections are necessary and they have to visit the clinic less often for check-ups during ovarian stimulation.
  • It is usually well tolerated by the woman, with few side effects, as the stimulation is not very aggressive because it allows lower doses of FSHto be administered. The fact that fewer hormones are needed also makes the treatment cheaper.
  • It decreases the frequency of ovarian hyperstimulation syndrome (OHSS) because it allows GnRH agonists to be used to induce ovulation instead of hCG, which increases the risk of OHSS. Therefore, these protocols are especially indicated in patients with an elevated risk of OHSS: young women, such as donors, or with polycystic ovary syndrome.
  • It does not cause follicular cysts because it does not have the flare-up effect that occurs after administration of GnRH agonists.

For all these reasons, short protocols with GnRH antagonists are increasingly used among assisted reproduction specialists. The GnRH antagonists most commonly used in these treatments are Cetrotide (cetrorelix) and Orgalutran (ganirelix).

Disadvantages

The use of GnRH antagonists presents few disadvantages since, being a stimulation that is not too aggressive, it is tolerated by most women with practically no contraindications.

The only problem is that, in many studies, the pregnancy rate has been found to be slightly lower (between 3% and 5% lower) than that obtained in ovarian stimulation protocols using GnRH analogs. This is due to the effect that antagonists have on endometrial receptivity.

In addition, if oral contraceptives or estrogens are not administered prior to initiating antagonist therapy, it can make follicular growth asynchronous, which also negatively affects success rates because fewer eggs are retrieved per cycle.

FAQs from users

How do GnRH antagonists affect endometrial receptivity?

By Jon Ander Agirregoikoa M.D. (gynecologist).

The comparison of protocols with GnRH agonists and antagonists and their relationship to the impact on endometrial receptivity remain controversial. However, some studies have provided evidence that both GnRH agonists and antagonists slightly affect endometrial receptivity compared to natural cycles.

In contrast, other studies have suggested that antagonist protocols have a strong impact on the expression of related genes in human endometrial receptivity, as well as that agonists cause delay in this process.

For ovarian stimulation, is it sufficient to inject GnRH antagonists?

By Rebeca Reus BSc, MSc (embryologist).

No. GnRH antagonists only serve to control endogenous hormone levels. It is necessary to stimulate follicular growth by administration of gonadotropins and induce ovulation by hCG or GnRH agonists.

Is luteal phase support chosen in cycles with agonists?

By Carolina González Arboleya M. D. (gynecologist).

Dr. Carolina Arboleya answers the question:

Normally, when we do cycles with agonists, we do opt for luteal phase support, to put intravaginal progesterone to give that luteal phase support ras the puncture to the patient.

How many days does ovarian stimulation with GnRH antagonists last?

By Rebeca Reus BSc, MSc (embryologist).

With the use of GnRH antagonists, the duration of ovarian stimulation is approximately 10-12 days. It will depend on the exact protocol used and the woman's response to hormonal treatment.

If you want to know more about the drugs used in ovarian stimulation treatments, you will find more information in this article: Medications used in controlled ovarian stimulation.

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References

Authors and contributors

 Carolina González Arboleya
Carolina González Arboleya
M. D.
Gynecologist
Dr. Carolina González has a degree in Medicine and Surgery from the University of Santiago de Compostela. Currently, Dr. González is doing a Master in Assisted Reproduction by the Technological University TECH and another one in Aesthetic, regenerative and anti-aging medicine by the Complutense University of Madrid. More information about Carolina González Arboleya
Member number: 282875780
 Jon Ander  Agirregoikoa
Jon Ander Agirregoikoa
M.D.
gynecologist
Graduated in medicine from the "Pays Basque" University, with a specialization in obstetrics and gynaecology. He has several years of experience in the field of assisted human reproduction and is co-director and co-founder of the ART clinics. He also combines his medical activity with teaching at the "Pays Basque" University. More information about Jon Ander Agirregoikoa
License: 014809788
 Rebeca Reus
Rebeca Reus
BSc, MSc
Embryologist
Degree in Human Biology (Biochemistry) from the Pompeu Fabra University (UPF). Official Master's Degree in Clinical Analysis Laboratory from the UPF and Master’s Degree about the Theoretical Basis and Laboratory Procedures in Assisted Reproduction from the University of Valencia (UV). More information about Rebeca Reus
Adapted into english by:
 Cristina  Algarra Goosman
Cristina Algarra Goosman
B.Sc., M.Sc.
Psychologist
Graduated in Psychology by the University of Valencia (UV) and specialized in Clinical Psychology by the European University Center and specific training in Infertility: Legal, Medical and Psychosocial Aspects by University of Valencia (UV) and ADEIT.
More information about Cristina Algarra Goosman
Member number: CV16874

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