GnRH Antagonists: What They are and How They Work

Gonadotropin-releasing hormone (GnRH) antagonists play a crucial role in In Vitro Fertilization (IVF) by preventing premature ovulation, allowing as many eggs to reach maturity as possible, and allowing for precise control over the timing of egg retrieval.  

These medications work by inhibiting the release of luteinizing hormone (LH), ensuring eggs mature properly before retrieval.  

This article explains the mechanisms, benefits, and applications of GnRH antagonists in IVF protocols.  

What are GnRH Antagonists?  

GnRH antagonists are a category of medications that bind to gonadotropin-releasing hormone receptors in the pituitary gland. They effectively block endogenous (or natural) GnRH molecules from binding and triggering the release of gonadotropins from the pituitary gland.

Common GnRH Antagonists 

Many GnRH Antagonists have been developed.  

The two most common GnRH Antagonists available in the United States are Antagon (ganirelix acetate, commonly referred to as ganirelix) and Cetrotide (cetrorelix). 

How GnRH Antagonists Work 

Under normal circumstances, GnRH molecules bind GnRH receptors and trigger the release of FSH and LH into the circulatory system. In females, these FSH and LH stimulate the ovaries to make estrogen and progesterone. 

When GnRH Antagonists are administered, they bind to the same GnRH receptors in the pituitary gland, effectively blocking endogenous GnRH molecules from triggering the release of FSH and LH. This effectively prevents the ovaries from producing estrogen and progesterone and the surge in LH that triggers eggs to be released from the ovaries.

Why Antagonists Are Important in IVF, Egg Freezing, and other Fertility Treatments 

GnRH medications effectively inhibit the release of LH from the brain, thus preventing the surge in LH that causes eggs to be released from the ovary. 

 This is important because follicles and eggs develop at different rates. Preventing ovulation allows slower-maturing eggs to mature prior to egg retrieval, which is critical for the success of IVF. In general, more mature eggs at retrieval = more embryos available for embryo transfer = higher chance of a successful pregnancy.  

How are antagonists administered in IVF? 

GnRH Antagonists are typically administered as subcutaneous injections. 

The process is generally simple and can be done at home after proper instruction from a healthcare provider. 

The recommended injection site is usually a few inches below the navel. Because the injection is required daily, most doctors recommend alternating sides of the abdomen to avoid soreness. 

When Are Antagonists Taken During IVF? 

GnRH Antagonists are typically started around the 6th day of ovarian stimulation, that is, after 6 days of FSH (and LH) injections, but may vary based on how the patient’s body is responding to the FSH (and LH) medications. 

The Antagonist Protocol 

The antagonist protocol is a general term describing a class of medication protocols used in IVF, Egg Freezing, and other fertility treatments using gonadotropin stimulation. 

The antagonist protocol may also be called the short protocol or, due to its popularity, the standard protocol. 

An antagonist protocol generally follows the below structure: 

• FSH (and LH) is the first medication to be administered and is generally taken every day for approximately 9 days 

• GnRH Antagonist is started around day 6 of stimulation and continued for approximately 4 days 

• Both FSH and GnRH are stopped and Lupron and or hCG are administered for 1-2 days to finalize egg maturation and “trigger ovulation”. This is called the “Trigger Shot.” Do note that the eggs must be retrieved before ovulation. 

• The egg retrieval takes place 36 hours after the administration of the first trigger shot. 

• The day after the egg retrieval, estrogen and progesterone are started to prepare for a fresh transfer. If no fresh transfer is planned, no medications are typically taken until the start of the planned Frozen Embryo Transfer (FET) cycle. 

GnRH antagonists in IVF are administered as subcutaneous injections for two to six days, typically starting around the sixth day of an IVF cycle.

Side Effects of GnRH Antagonists 

GnRH antagonist injections often cause bruising or redness at the injection site. Other common side effects include:

• Itching, redness, and swelling at the injection site 

• Nausea 

• Headache 

• Hot flashes 

• Night sweats 

Some patients may develop ovarian hyperstimulation syndrome (OHSS). OHSS causes body swelling, particularly in the ovaries, and can lead to kidney issues and blood clots.  

Although OHSS is a serious complication, it has become less common with newer IVF medications.

During your cycle, your fertility specialist will monitor you to ensure you are not developing signs of OHSS and make adjustments to your protocol accordingly.  

GnRH Antagonists in IVF: The Takeaway 

GnRH antagonists are an important component of the most common IVF protocols. They are used to prevent premature ovulation, thereby allowing more eggs to mature before the egg retrieval.

Overall, GnRH antagonists enhance the chances of successful fertilization and pregnancy while minimizing complications like ovarian hyperstimulation syndrome (OHSS).