The doctor: What happens in the downregulation stage?

Do you know why one enters long protocol? And what exactly goes on in the body during downregulation? Doctor Marie Louise Wissing reviews the topic of downregulation to provide us with a better understanding of what goes on.

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Marie Louise Wissing

22. juli - 2022

Interview with Marie Louise Wissing, Aleris Hamlet Fertility

What exactly happens to the body in downregulation?

Downregulation entails giving a drug that slows down the body's own release of the follicle-stimulating hormones FSH and LH. Therefore, one's own egg development will stop during downregulation, and only start up again when FSH or LH is added from the outside. Downregulation takes at least 2 weeks before the desired effect is achieved.

The type of drug used for this purpose is called a GnRH agonist.

Facts: GnRH stands for Gonadotrophin-Releasing Hormone.

Put simply, when a woman is given a GnRH agonist medication, it empties the stock of LH and FSH - and no new LH and FSH is then produced. It is actually being shut down. So, in principle, a woman will first experience a proper flushing out of LH and FSH when the stock is being emptied - and then nothing at all. This is also the why downregulation takes place over a minimum of 2 weeks.

Why do you do it that way?

The purpose of emptying the store of FSH and LH is to control follicle development. Once you have emptied the stock and thus have no egg development, the doctor can initiate stimulation - that is, add LH and FSH and be in full control of the process.

In some women, egg maturation already starts in the previous cycle, and these women may experience fewer eggs than expected in the short protocol, because a few follicles have ‘jumped the gun’ in terms of growth before menstruation. Already by day 2-3 of the cycle, these follicles will have grown so far that they can prevent other follicles from maturing in the short protocol.

Should downregulation always be around a menstrual period?

In principle, you can start downregulation at any time, but generally we choose to start downregulation about a week before expected menstruation. This is done because at that time in the cycle there are typically the fewest follicles that can respond to the first flushing out of FSH and LH that comes just when the downregulation starts.

How do you check if the downregulation is successful?

We scan after the woman has been in downregulation for two weeks. We scan to check if the downregulation has worked as intended. If the downregulation has worked as it should, the endometrium will be thin and the follicles small. In some cases, women's follicles are very good at capturing the initial flush of LH and FSH that comes when starting the GnRH agonist. If this is the case, there will be a follicular maturation and the follicles will grow. It appears in the shape of one or more simple cysts on the scan. The cysts are follicles that have started their maturation process but have not burst. This is called ‘flare up’. If this happens, we continue downregulation for one more week and then scan again. You only achieve the desired effect of the downregulation when the “flare-up” is gone.

Why should one actually be 'downregulated'?

In a normal cycle, you have continuous hormone fluctuations and thus continuous follicles that mature. This is exactly what you want to slow down in the long protocol and with downregulation.

In some women, there is a tendency for their follicles already to start maturing in the cycle before. So when you scan them at the beginning of the cycle, they may already have some follicles that are quite large (10-11mm). If you have that growth pattern, if you are in short protocol, there is the risk of actually developing slightly fewer follicles than you would otherwise have done. Simply because the body has already decided which follicles are allowed to grow. It just made that decision it just made in the cycle before.

When that happens, you can actually get more eggs out by running long protocol. You can do this because you get slowed down for the false start the follicles make - just by starting downregulation. That way, all the follicles are the same size when we start giving hormones.

What are the symptoms of downregulation?

In fact, the symptoms of downregulation are exactly the same as menopause. They are what we call ‘oestrogen deficiency symptoms’, as oestrogen becomes very low during downregulation, because the follicles do not receive a signal to grow.

Fortunately, you are only in downregulation for a few weeks, so very few experience severe symptoms. Some women may suffer from headaches, hot flashes and sweating at the end of the downregulation. These are exactly the same symptoms as menopause. The women who most often experience the symptoms are those who are in downregulation for longer than the usual 2 weeks.

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