Down-Regulation and IVF Treatment

What Is Down-Regulation? And How Does It Work?

couple talking to their doctor about down regulation protocals for IVF
There are many different down-regulation protocals for IVF treatment.. skynesher / E+ / Getty Images

Quick definition:  in the simplest terms, down-regulation is the process of lowering a cell’s sensitivity to specific molecules and/or hormones.

Down-regulation as a part of IVF treatment is when your doctor “turns off” your ovaries, temporarily. This way, your doctor can better control ovulation and egg maturation during treatment.

Drugs used to down-regulate the ovaries include GnRH antagonists and GnRH agonists.

GnRH antagonists and GnRH agonists are also known together as GnRH analogues.

These drugs work in different ways, but they both eventually suppress your body’s production of FSH and LH. FSH and LH are hormones that trigger egg development and ovulation.

After taking the GnRH analogues for a period of days or weeks, ultrasound is used to confirm that the ovaries are not producing eggs and that the uterine lining is thin.

Next, fertility drugs meant to stimulate the ovaries are taken.

Why Down-Regulation Is Used During IVF Treatment

To fully understand, it would help if you have a basic understanding of female reproduction. Go read this article first, and then come back.

Your ovaries contain thousands of follicles. In each follicle is a potential oocyte, or egg.

Follicles go through a number of developmental phases, starting as microscopic primordial follicles, and then growing into as-big-as-a-grape graafian follicles.

Even though you ovulate just one egg (sometimes two) each cycle, many more follicles compete to be that one egg.

As many as 20 follicle may be “competing” to be The Follicle in any given cycle.

At the start of your cycle, hormonal signals stimulate that month’s group of follicles.

The follicles grow in size. As they grow, they release hormones.

These hormones (estrogen, inhibin) signal the glands in your brain to produce more or less of the egg stimulating hormones (FSH and LH).

This creates a feedback loop. Essentially, your ovaries tell your brain, “Send us more hormones!” or “Enough, enough, we’re good!”

This process occurs until one follicle wins (so to speak) and ovulation happens. All the non-winning follicles shut down and die.

When it comes to IVF, your doctor doesn’t want this natural process to occur. For two reasons...

  1. Your doctor doesn’t want only one follicle to win – for IVF, they need several follicles to win.
  2. Your doctor doesn’t want the eggs that are developing to ovulate on their own. If this happens, the eggs can’t be retrieved for IVF treatment. 

Down-regulation protocols “turn off” your body’s signaling for ovulation.  

But how will the eggs grow if the signaling is turned off?  

That’s where gonadotropins come in.

Gonadotropins (FSH, LH) are biochemically similar to the hormones you body produces to develop and trigger ovulation.

They stimulate the ovaries to develop many follicles (and eggs). 

Drugs Used for Down-Regulation

These are the most commonly used methods of down-regulation during IVF.

GnRH agonists: GnRH agonists include Lupron, Synarel, Suprecur, and Zoladex.

GnRH agonists mimic the body’s natural hormone GnRH. GnRH stands for gonadotropin releasing hormone. This hormone is what triggers FSH and LH hormonal levels to increase, which in turn stimulates the egg in your ovaries.

If given just before ovulation, GnRH agonist can actually be used to trigger ovulation.

However, during IVF treatment, they are started after ovulation in the cycle before IVF will start.

At first, the body responds by producing high levels of FSH and LH. This overwhelms the cells on the ovaries and pituitary gland.

In response, the receptor sites on the cells decrease and become desensitized.

This then leads the body to stop producing FSH and LH, creating a medically induced menopause-like state.

GnRH antagonists: these include the fertility drugs Antagon, Ganirelix, Orgalutran, and Cetrotide.

GnRH antagonists work differently than GnRH agonists.

While GnRH agonists act like the body’s natural GnRH, leading to an initial “flare” or increase in hormones, GnRH antagonists directly work against the GnRH in your body.

GnRH antagonists block cells from receiving signals from the GnRH present in your body.

So, in other words, your body becomes “deaf” to whatever GnRH hormones are in your system.

This in turn stops the production of GnRH stimulated hormones, like FSH and LH.

With GnRH agonists, it takes up to three weeks to get past the initial flare and then final down-regulation.

With GnRH antagonists, down-regulation occurs almost right away.

You take these drugs for fewer days than GnRH agonists, which means fewer injections and less time with uncomfortable side effects.

Possible Problems With Down-Regulation

One potential problem with down-regulation is it desensitizes the ovaries. That is the point, in order to gain control of the ovulation process.

However, for women with low ovarian reserves, down-regulation can work too well.

If this happens, the ovaries may not produce enough eggs for IVF treatment. If there aren’t enough developing follicles, the cycle may be canceled.

For these women, there are less aggressive methods to down-regulate the ovaries. The doctor stills “puts your ovaries to sleep” – but a little more gently.

It may mean...

  • skipping birth control pills (usually taken the month before an IVF cycle)
  • giving GnRH agonists or antagonists at lower does or for fewer days
  • starting a GnRH agonist or antagonist much later than is typically done
  • starting and then stopping the injectionsadding in additional hormones to the protocol

More on IVF treatment:

Sources:

Badawy A1, Wageah A, El Gharib M, Osman EE. “Strategies for Pituitary Down-regulation to Optimize IVF/ICSI Outcome in Poor Ovarian Responders.” J Reprod Infertil. 2012 Jul;13(3):124-30. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3719354/

Magon N1. “Gonadotropin releasing hormone agonists: Expanding vistas.” Indian J Endocrinol Metab. 2011 Oct;15(4):261-7. doi: 10.4103/2230-8210.85575. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3193774/

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