One upon a time (months ago), I wrote a post on gonadotropin-releasing hormone (GnRH) agonists but I don’t think anyone really saw it. I guess it’s the name. Gonadotropin-releasing hormone agonist does sound kind of strange.
How about Lupron, Synarel, and Zoladex? Yeah, still a little funny sounding but better. Lupron, Synarel, and Zoladex all belong to the class of drugs known as (everybody chime in)… gonadotropin-releasing hormone agonists (GnRH agonists).
What does that mean?
An agonist is simply something that acts like something else. In this case, Lupron, Synarel, and Zoladex act like GnRH (the natural thing in your body). Let’s look at GnRH for a moment. This is the normal chain of events in your body:
- GnRH is a decapeptide (10 amino acids) synthesized and secreted by the hypothalamus (in your brain).
- GnRH travels to the anterior pituitary (the anterior lobe of the pituitary gland located at the base of your brain) and binds to its specific receptor.
- The binding of GnRH to its receptor results in the synthesis and secretion of luteinizing hormone (LH) and follicle-stimulating hormone (FSH).
- LH and FSH travel to the ovary.
- In the ovary, LH (in conjunction with FSH) increases the production of estrogen.
- Elevated levels of estrogen in the blood inhibit the secretion of GnRH, LH, and FSH (negative feedback loop).
What’s a negative feedback loop?
Think in terms of the furnace in your house. From Control of Endocrine Activity:
When the furnace produces enough heat to elevate temperature above the set point of the thermostat, the thermostat is triggered and shuts off the furnace (heat is feeding back negatively on the source of heat). When temperature drops back below the set point, negative feedback is gone, and the furnace comes back on.
So normally in your body, GnRH causes the release of LH and FSH. LH and FSH cause estrogen production. High estrogen inhibits GnRH, LH, and FSH. Got it.
Well then, what the heck is a GnRH agonist?
Let’s look at the amino acid structures first.
Here is GnRH that is in your body naturally:
*D-Nal = D-3-(2-naphthyl)-alanine
See how they’re actually quite similar? Just a couple of amino acids are changed. These changes cause Lupron, Synarel, and Zoladex (GnRH agonists) to bind to the GnRH receptor in the anterior pituitary better than your naturally occurring GnRH. The substitutions also inhibit rapid degradation (the agonists stay around a little longer).
GnRH agonists bind to the receptors so well that…
- This initially causes an increase in secretion of LH and FSH.
- This stimulates estrogen production causing a temporary increase in estrogen during the first 2 weeks of treatment.
- Because the GnRH agonist is bound to the receptor already, you don’t get the LH and FSH secretion caused by receptor binding.
- Low or no LH/FSH eventually leads to low or no estrogen production.
Side effects: The result is prolonged suppression (hypogonadism). Decreased estrogen may lead to hot flashes and sweats, headaches, depression, diminished libido, generalized pain, vaginal dryness, and breast atrophy.
The lower your estrogen level falls, the more therapeutic benefit you will receive (periods stopping completely and/or fibroid shrinkage). Also remember that the lower your estrogen level falls, the higher your risk of side effects and the longer it will take for your estrogen level to rise post-treatment. It really is risk vs. benefit. Gonadotropin-releasing hormone agonists are good but not perfect. Estrogen production is not a light switch. Taking a drug will not just easily shut it off in every individual. Think more in terms of a dimmer switch. Remember that bell curve I discussed a few posts back? Most patients fall under the bell.
Why does it take so long for the side effects to go away?
It can take several weeks for the GnRH agonist to “clear” your body. Think about a monthly shot for example. A therapeutic level of the drug will be in your body for at least a month after your last injection. Once the GnRH agonist is gone, it will still take some time before your estrogen level rises. Remember that you have to return to your normal pattern. Your natural GnRH has to be produced and secreted. It binds to the receptor and LH/FSH is produced and secreted. LH and FSH both travel to the ovary and increase estrogen production. Just like much in life, it’s a process.