Antagonistic

The ultrasound today seemed to go fine. Lefty is at 17 mm, with Righty lagging behind… still measuring 11 mm. (Dr. Y also measured a third at 8 mm, but didn’t say anything about it.) C and I think that Dr. Y was disappointed with Righty’s slow growth, but felt sorry for us and refrained from saying anything… He recommended continuing stims + Antagon for a couple more days to give them more time to grow. He’d like Lefty to be at 20 mm for retrieval.

The next ultrasound will be Wednesday, with tentative retrieval on Friday – possibly later. Back when we started the cycle, Dr. Y said that it will be good if we can get a couple extra stim days prior to retrieval, so I’m going to stick with that and say this is a good thing…

*****

So, Antagon

I’m on day 3 of Antagon (aka ganirelix), which I inject into my belly every morning by way of a prefilled syringe with an annoyingly dull needle. (It doesn’t hurt that much, but it actually bounces off of my skin if I don’t shove it hard enough!) Aside from looking like a human pincushion, I haven’t observed any side-effects.

Despite my disappointing Saturday, I didn’t want to put off writing about Antagon for too much longer, since it is actually the drug that I find the most interesting, but first:

I am NOT an endocrinologist, or any kind of medical professional! This blog does NOT purport to offer medical advice, medical opinions, or recommendations. Please take this for what it is – the ramblings of an infertile woman trying to make sense of her complicated treatment protocol!

*****

Before explaining what Antagon does, it’s probably worth reviewing how this whole sex hormone signaling cascade is supposed to go normally.

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First, my brain sends a signal to my pituitary, which in turn sends a signal to my ovaries, which in turn make estrogen, grow eggs, and ovulate.

The ‘signal’ that my brain sends to my pituitary is carried by a peptide hormone called gonadotropin-releasing hormone (GnRH; also known as luteinizing hormone-releasing hormone or LHRH).

The ‘signal’ that my pituitary sends to my ovaries is carried by two proteins – our old friends FSH and LH. Normally, FSH stimulates one or two of the follicles to grow and develop into a single mature egg. LH (released in a surge) signals the ovaries to ‘drop’ the mature egg.

Of course, in the case of IVF, we don’t want to just have one mature egg, and we don’t want to have it get released before we are good and ready for it.

Here’s where Antagon comes in.

Image

As its name suggests, Antagon (aka ganirelix) is a GnRH antagonist, which means that it looks a lot like GnRH, but it doesn’t act like GnRH. You can see this if you look at the chemical structures of the two (below). Antagon is about the same size and shape as GnRH; it has similar atoms and functional groups (I highlighted the differences in red for your convenience). As a result, it can fit into the same tight spaces that GnRH can fit into – like the inside of the receptor protein ‘switch’ that GnRH normally turns on to make the pituitary send its signal…

Image

While Antagon looks like GnRH, it doesn’t act like GnRH. So when Antagon fits into the GnRH receptor protein, it doesn’t actually flip the switch ‘on’.

To pick another analogy, GnRH is the key that opens a lock on the pituitary gland. Antagon is like another key that fits into the same keyhole…but doesn’t open the lock. Having lots of Antagon around filling up keyholes makes it really hard for GnRH to actually turn any locks. (In biochemistry-speak, Antagon is a competitive inhibitor.) The effect is the same as if we had somehow removed all the GnRH from the system.

Without GnRH stimulating the pituitary gland, the pituitary gland doesn’t produce LH (or FSH, but we’re more concerned with LH at the moment), and we don’t get the surge, and ovulation is prevented (left panel, below).

Image

What about Lupron?

Interestingly, using a GnRH antagonist isn’t the only (or even the most popular) option for preventing ovulation.

The other, more common, method involves using a GnRH agonist (such as Lupron, aka leuprolide). A GnRH agonist both looks and acts like GnRH.

Lupron has a chemical structure that is even closer to that of GnRH. In fact, they differ by only one amino acid (in blue on the previous chemical structure drawing). Lupron also flips the GnRH receptor protein ‘on’…and keeps it on for longer than GnRH does.

But I thought we were trying to prevent GnRH from sending its signal?

The initial response of the agonist is to increase the GnRH signal – the opposite of what we want. But we’re counting on what happens next. All this signaling is very carefully regulated, so after a few days of having its GnRH switch frozen in the ‘on’ position, the pituitary figures out that something is wrong. It absorbs the GnRH receptors (the keyholes) from the cell surface, and all further signaling in the pathway gets shut down (above right).

It’s like the sirens go off, red lights start flashing, and the pituitary says “TERMINAL ERROR DETECTED. COMMENCE SYSTEM SHUTDOWN.

With the signal shut down, the pituitary doesn’t continue to make LH, and ovulation can be prevented until we’re ready for it.

What does DOR have to do with it?

Despite sounding more complicated, the agonist protocol is the more commonly-used option, or ‘plain Vanilla IVF’ if you prefer, and works well for the majority of IVF patients. However, some recent studies seem to suggest that using an antagonist might be better for poor responders (like people with diminished ovarian reserve). I think this is still pretty controversial, though.

I think the theory is that for DOR patients, the traditional agonist long protocol suppresses signaling for too long and gets in the way of recruiting the already-poorly-responsive eggs. For the agonist protocol to work, the agonist has to begin to be administered relatively early – before there are any follicles ready to drop (otherwise the initial burst of LH & FSH might trigger ovulation before the desired ‘System Shutdown’), so things are shut down for a relatively long period. By contrast, the antagonist can be administered later in the cycle, for just a few days.

*****

Whatever the reason, I’m gambling on the short, antagonist protocol. Odds are that I’m going to lose this poker hand, but dammit, I am not folding!

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19 Comments

  1. This is really interesting. I had a cancelled, poor response agonist cycle and did much better on an antagonist one with my DOR. Cool to see the science behind it!

    Reply
    • I’m very interested in learning more about people who have tried different protocols and had different responses. Mostly, I just want to have hope that there is the ‘right’ protocol out there that will get me some eggs!

      Reply
  2. Gosh your posts are just so good.
    I’m rooting for you!!! I think you have the makings of an excellent poker hand:-)

    Reply
  3. Thanks for the analogy of the keys and the lock. It makes it a lot easier to understand. I am like you, going to be on Ganirelix. My RE’s assistant told me to mix it in with the Menopur mixture rather than injecting it separately. I guess to prevent too many injections? I really love the explanations. It’s so relevant to what I am going to go through. Thanks!

    Reply
    • You’re welcome! And maybe your RE knows about the dull needles and this is their way of making sure you get to use a fresh one. 😉

      Reply
  4. I love reading these explanations. It feels like a fun science class. Also, dull needles?! Ouch.

    Reply
    • Yeah…I’m not sure saving me the ‘hassle’ of pulling the medicine up into a syringe is worth putting up with the needle they provide…

      Reply
  5. The problem is that you don’t know until you play the hand out, right? It all seems so frustrating. There should be a better algorithm!

    I appreciate the Kekulé diagrams, too. 🙂 My inner biochemist approves.

    Reply
  6. I hope that righty makes a move soon and catches up with lefty. Keeping my fingers crossed for you with egg retrieval. Good luck!

    Reply
  7. Good attitude, no folding! Keeping fingers crossed for you!!

    Reply
  8. Sooo interesting. You never know what those little follicles are going to do until they take them out on collection day. I am sending lots of wishes that the smaller one puts a growth spurt on. Two might be all you need.

    Good luck.

    Reply
  9. I’m still hopeful that a couple more eggies make their appearance for your retrieval. You never know. But I’ll say it again- it only takes one good egg, and one good sperm to complete the transaction. Hang in there!

    BTW- thank you for the endocrinology review… as a respiratory therapist, I certainly don’t use this stuff every day, but I did study it in school. I have to do continuing ed courses each year to maintain my license- I wonder if reading your blog would qualify as a course…

    Reply
  10. Stephanie

     /  June 19, 2013

    Good luck to you. For the record, I was on Generelix too and took an extra dosage the day of my HCG shot. I ended up ovulating 1 of my eggs so had 1 less during my retrieval. Quite disappointing… Apparently, its pretty rare to ovulate on these drugs but you may know more than me. 😉

    Reply
  11. Huh… so interesting! Had no idea that’s actually how Lupron worked, and why one has to start it so early on in the process. I guess the theory for DOR patients doing Ganirelix makes sense, but who knows really. Fingers crossed your second follie starts picking up the pace in time for retrieval!!

    Reply

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