GnRH Analogs – Indications & Use

Gonadotropin-releasing hormone (GnRH) is a hormone produced by the neurons of the hypothalamic arcuatus nucleus and then secreted into the portal circulation of the pituitary gland.

Its function is to regulate the production of gonadotropins (FSH and LH) by the pituitary gland, which is essential for the proper functioning of the male and female reproductive systems.

In recent years, numerous GnRH analogs have been synthesized for use as drugs in assisted reproduction treatments.

The different sections of this article have been assembled into the following table of contents.

Characteristics of GnRH

GnRH is a decapeptide, i.e. its structure is made up of 10 amino acids arranged in a linear sequence. Furthermore, since it is produced by neurons, GnRH is considered to be a neurohormone.

Other relevant characteristics of GnRH are the following:

• The gene that encodes the precursor of GnRH is located on the short arm of the chromosome 8.
• The secretion of GnRH is pulsatile, that is, it is released into the portal system by pulses of different amplitude and frequency.
• Its half-life is very short, about 2-4 minutes.
• GnRH cannot be detected in peripheral blood, so it cannot be quantified in a normal blood test.

Characteristics of GnRh

Mechanism of action

The peak of GnRH activity begins at puberty and continues throughout the reproductive life of both men and women.

GnRH has an endocrine function: it travels to the pituitary gland through the portal system, activates its receptor and stimulates the release of FSH and LH from the adenohypophysis.

These pituitary hormones then travel through the bloodstream and exert their function on a woman's ovaries or a man's testicles.

The pulsatile activity of GnRH can be seen interrupted or altered by different factors, which would affect the male and/or female reproductive function as the case may be. These factors are the following:

• A malfunctioning of the hypothalamus, whether due to dysfunction, trauma, or some type of tumor.
• Hyperprolactinemia: a high prolactin level decreases GnRH activity, which occurs mostly during pregnancy and breastfeeding.
• Patients with polycystic ovary syndrome (PCOS) and high insulin levels who have increased GnRH pulsation, which leads to disordered LH and FSH activity.
• Those affected by Kallmann's syndrome who have an absence of GnRH due to a congenital defect.

On the other hand, FSH and LH synthesis are also normally inhibited due to the negative feedback of androgens and estrogens on the pituitary gland.

GnRH Analogues

GnRH analogs are a type of molecule that has been artificially created by replacing some amino acids within the original GnRH molecule.

These new molecules imitate the shape of GnRH and also have a high affinity for its receptors in the pituitary gland.

Therefore, GnRH agonists can bind easily to the receptors and prevent the action of natural GnRH.

In short, the action of the GnRH analogues consists of blocking the normal function of GnRH and preventing the flow of FSH and LH from the pituitary gland to the gonads.

Operation of the GnRH analogs

This ability of the GnRH analogs has been used to create the drugs that are administered during assisted reproduction treatments, such as artificial insemination (AI) or in vitro fertilization (IVF).

These are drugs used during the ovarian stimulation phase to achieve a stop of the pituitary gland and keep the ovaries at rest. In this way, the number of developed follicles and the moment of ovulation are controlled.

Types

There are two types of GnRH analogues that act differently:

GnRH Agonists

have a longer half-life and great affinity for the GnRH receptor in the pituitary gland. After agonist-receptor binding, a sudden release of gonadotropins occurs, which is known as the flare-up effect. However, if GnRH agonists continue to be administered continuously, the receptors are eventually blocked and stop responding, so that FSH and LH secretion is suspended.

GnRH Antagonists

its inhibitory effect is more direct. Once the antagonist has joined the receptor, the latter is immediately blocked.

Nowadays, assisted reproduction professionals tend to schedule ovarian stimulation protocols with antagonists rather than agonists due to the multiple advantages it offers.

Effects

As we have already explained, the main effect of GnRH analogs on the female body is to block the release of gonadotropins by the adenohypophysis.

This action allows the synchronization of the cohort of follicles recruited by the ovary at the beginning of ovarian stimulation. In this way, homogeneous follicular growth can take place, reducing the variability of ovarian response to gonadotropins administered exogenously.

In summary, the use of GnRH analogs allows the gynecologist to have better control of the ovarian stimulation process in the patients, and to know which is the most appropriate moment to trigger ovulation and to program the artificial insemination or ovarian puncture according to the case.

Drugs with GnRH analoges

Depending on whether GnRH agonists or antagonists are used during the controlled ovarian stimulation phase, we will talk about long or short protocols, respectively.

This is because the agonists take longer to take effect, as we have already mentioned, while the antagonists have an immediate effect and will require fewer days of administration.

The commercial names of the agonists used in the long cycles and their active principles are as follows:

Synarel

This is a nasal spray containing nafarelin.

Procrin

the active ingredient is leuprorelin acetate and is administered subcutaneously.

Decapeptyl

Depending on the type of presentation, it is administered either subcutaneously or intramuscularly. It contains triptorelin as active ingredient.

GnRH analog drugs

As for the antagonists used in the short cycles, we find the following drugs:

Cetrotide

contains cetrorelix and injection is done subcutaneously

Orgalutran

its active ingredient is ganirelix and is administered subcutaneously.

If you are interested in obtaining more information about the drugs used in assisted reproduction, you can continue reading here: What Medication Are Used for Ovarian Stimulation?

FAQs from users

Why can't the GnRH hormone be detected in blood?

Gonadotropin-releasing hormone (GNRH) is a hormone released by neurons in the hypothalamus in a pulsatile form. It stimulates the release of gonadotropins (LH and FSH) by the adenohypophysis.

This hormone is rapidly metabolized and for this reason cannot be quantified in the blood.

Which GnRH analog drugs offer the best results?

There are several types of analogs, which differ by small variations of components of the molecule. These would be leuprorelin acetate, triptorelin, nafarelin, buserelin, and goserelin. There are several presentations (daily, monthly, quarterly ...), indicating at each time the most appropriate for the effect you want to achieve. Each type of analog also has its route of administration, which may be subcutaneous, intramuscular, or intranasal.

It has not been demonstrated that any of the agonists marketed is superior to another, although the subcutaneous route provides constant bioavailability and little variation between patients, while intranasal or inhalation absorption may be more variable.
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What effect do gonadotropin-releasing hormone agonists have?

The main effects produced by the use of analogs that are GnRH agonists are, on the one hand, the initial release of gonadotropins (flare-up effect) and then blocking the release of these gonadotropins, preventing the communication between the pituitary gland and the ovary so that there is no follicular development or ovulation.

All this occurs temporarily when the reserve of FSH and LH in the pituitary is empty. Normally, the total blockage of GnRH receptors occurs between 5-10 days after the first administration of the agonist.

What is the flare-up effect of GnRH analogs?

When the GnRH analog binds to its receptor, there is a massive release of the hormones FSH (follicle-stimulating hormone) and LH (luteinizing hormone). This is called the flare up effect.

This release of gonadotropins occurs endogenously, that is, the pituitary gland, located in the brain, synthesizes and releases these hormones into the bloodstream.

The flare-up effect occurs approximately in the first two days after the administration of a GnRH agonist. After this time, the pituitary gland becomes desensitized to the initial effect of the agonist, and gonadotropin synthesis is blocked.

How does a GnRH analog treatment for uterine myomatosis look like?

Although the most common treatment for removing fibroids is surgical, GnRH agonist analogs can also serve as drug treatment to reduce the size of these fibroids.

Due to their effects, GnRH agonists cause a state of hypogonadotropic hypogonadism with very low estradiol values in women. This can help reduce fibroids and possible associated symptoms such as bleeding.

However, these drugs have unwanted side effects, and, after stopping treatment, the fibroids may grow back. For this reason, GnRH agonists are only used where indicated and as a pre-surgical step to facilitate surgery.

Suggested for you

Hemos hablado de las gonadotropinas como hormonas que tienen un efecto sobre el aparato reproductor femenino y masculino. Si quieres entrar en detalle sobre estas hormonas, puedes seguir leyendo en los siguientes artículos:

What is the Role of Follicle Stimulating Hormone (FSH)?

What is the Luteinizing Hormone or LH?