What Down-Regulation Means in IVF Treatment

Process Increases the Production of Viable Eggs

Doctor discussing with a couple during consultation.
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Down-regulation is a term that scientists use to describe the process of reducing or suppressing the body's response to specific stimuli. When used with regards to in vitro fertilization (IVF), down-regulation essentially "turns off" the ovaries to better control ovulation and egg maturation during treatment.

There are two types of drugs used for this purpose: GnRH agonists and GnRH antagonists. An agonist is a type of drug that stimulates a response, while an antagonist is a type that blocks a response. While the mechanisms of action for the two drugs differ, they both work by suppressing the body's production of various hormones that trigger egg development and ovulation. In this way, they down-regulate the physiological function of the ovaries.

Why Down-Regulation Is Used During IVF Treatment

Your ovaries contain thousands of follicles. Each follicle contains an immature egg or oocyte.

At the start of your cycle, luteinizing hormone (LH) and follicle stimulating hormone (FSH) trigger the maturation process in a group of competing follicles. As the follicles begin to grow in size, they will release other hormones to regulate the flow of LH and FSH—sometimes up, sometimes down—until ovulation finally occurs.

Ovulation usually involves only one egg. After that egg is released, all of other follicles in that group wither and die. With IVF, your doctor doesn't want this to happen. Instead, the aim would be to down-regulate that response so that:

  1. Multiple follicles are able to produce a viable, mature egg.
  2. The eggs remain in the follicles so that they can be easily harvested.

Long vs. Short IVF Protocol

You may have also heard the terms long and short protocol. These describe two different approaches to down-regulation. As the name implies, the difference between these two approaches is the length of time down-regulation is imposed on the body.

With the long protocol, down-regulation is started in the cycle before IVF treatment takes place. It may begin on day one or two of the cycle before, or it may not start until the mid-luteal phase, which is about one-week post ovulation (day 21). Medications known as gonadotropin-releasing hormone agonists are used during a long protocol down-regulation, the most common one being Lupron. (More on those medications below.) Birth control pills may also be taken the cycle or two before treatment as well. 

Long IVF protocols require more days of medication and more injections, which means the cycle tends to be more expensive. Also, because your hormones are being down-regulated over more days, you’re more likely to experience side effects over a longer period of time.

That said, for many women, the long IVF protocol offers the best chances for IVF success. This makes the additional days of treatment, side effects, and increased cost possibly more worthwhile.

In the short protocol, down-regulation is achieved quickly and usually doesn’t start until the start of the IVF cycle itself. The medications used for this are GnRH antagonists, like Antagon, Ganirelix, and Orgalutran. The short protocol may be better for women who are poor responders and might be better for women who are at higher risk of developing ovarian hyperstimulation syndrome (OHSS). Because you’re taking medications for a shorter period of time, this also means lower costs and fewer days of side effects.

On the other hand, the short protocol may lead to fewer follicles (and therefore fewer embryos). There are also some concerns that GnRH antagonists come with an increased risk of birth defects, though the risk is still relatively small. 

Drugs Used for Down-Regulation

There are a number of drugs used in IVF for downregulation, and they are broadly characterized as follows:

  • GnRH agonists include such drugs as Lupron (leuprolide), Synarel (nafarelin), and Zoladex (goserelin). GnRH agonists mimic the naturally occurring hormone known as gonadotropin-releasing hormone (GnRH). This is the hormone that triggers increased production of FSH and LH. By flooding the body with "fake" GnRH, the ovaries become increasingly overwhelmed and eventually shut down the production of LH and FSH after around three weeks.
  • GnRH antagonists include the drugs Antagon (ganirelix) and Cetrotide (cetrorelix). GnRH antagonists work by binding to the receptor on GnRH and blocking its ability to receive signals of any sort. By doing so, the production of FSH and LH are shut down almost immediately.

After taking the GnRH drugs for several days or weeks, an ultrasound would be used to confirm that the uterine lining is thin and the eggs are ready to be harvested. Fertility drugs would then be administered to stimulate the ovaries, after which the eggs would be harvested under local anesthesia.

Alternate Means of Down-Regulation

While down-regulation is an effective means of desensitizing the ovaries during IVF, it doesn't work well for all women.

This is especially true in women with low ovarian reserves (a significantly decreased number of eggs). Because there would be far fewer follicles to work with, GnRH drugs can something work too well. Rather than desensitizing the ovaries, they might end up canceling the cycle altogether.

For these women, there are alternate techniques fertility specialists will use to achieve down-regulation:

  • Starting birth control pills for a month prior to IVF and then skipping doses to temper the maturation and ovulation process
  • Giving GnRH drugs at lower does or for fewer days
  • Starting GnRH treatment much later than usual
  • Starting and then stopping the GnRH injections at different stages
  • Adding additional hormones to the treatment

During this time, the doctor will use blood tests and ultrasound to assess and better regulate the follicular development.

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