Stims

Yesterday at 7:45 am I had my first IVF monitoring appointment. Since Kaiser doesn’t cover IVF, Dr. Y does all his IVF appointments in the early morning, across town from his main office. Lucky for me, this is only about 10 minutes from my house. (The Kaiser office is about 10 minutes from my work, so it’s been pretty convenient all-around.) I liked my new clinic. The waiting room looked much nicer than the Kaiser facility: lots of good magazines, friendly staff, and a beautiful aquarium. I sat and watched the fish eating their breakfast while C studied his iPhone.

And… my follies are growing, but slowly (which Dr. Y insisted isn’t necessarily a bad thing). The biggest one measured 8 mm. Estradiol level was 83. Dr. Y said to keep taking the same dose of Clomid & Menopur (and dexamethasone, although he didn’t mention that), and to come back on Saturday.

Oh, and we paid the first big bill: $10,115 “Global Fee” for IVF + ICSI. This amount covers all the monitoring appointments and labs, the egg retrieval, and the embryology part. The Global Fee does NOT cover meds, “Embryo Banking” (freezing and storing the embryos), or frozen embryo transfer, so a complete account of the full cost will have to wait.

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Given where I’m at in my cycle, it seems like my stims would be a good science topic for today, but first the usual:

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!

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So, stims…

My ovarian stimulation regimen is low-dose menopausal gonadotropins (Menopur, 150 IU), and clomiphene (Clomid, 100 mg). The goal is to get my ovaries to produce not one but several large, mature, healthy eggs. To understand how these drugs are supposed to accomplish this goal, it would probably help to provide some background. And I feel the need to point out, once again, that I am not an expert. (This blog is not called ‘the infertile endocrinologist’! But if you find a blog with that title, please let me know. I’d love to read it.) So anyway, here’s how I think it works:

Sex hormone signaling 101

Normally, when my body wants to produce estradiol (the most important of the estrogens), my brain sends a signal to my pituitary gland. The pituitary responds by sending a signal to my ovaries, which respond by doing a bunch of things, including making estradiol. The estradiol itself acts as a signal that travels around and tells various body parts to do things.

The carrier pigeons transmitting all these signals are hormones. So, more precisely, my brain produces a hormone called luteinizing hormone releasing hormone (LHRH, also known as gonadotropin-releasing hormone or GnRH), which travels to my pituitary and tells it to produce two more hormones: luteinizing hormone (LH) and follicle stimulating hormone (FSH). These hormones travel to my ovaries and stimulate them to do a bunch of things – like grow eggs and make estradiol…which itself helps to prep the uterine lining, and so on.

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Feedback

As the level of estradiol increases, it circulates through the bloodstream and some of it reaches my brain. Once there, the estradiol tells my brain to stop sending the signal to make more estradiol (in other words, to stop making LHRH). This is a natural “negative-feedback loop”.

Estrogen signaling under the influence

While I’m on my stims, the goal is to get lots of follicles to grow at once. This takes high levels of FSH in there, for an extended period of time. There are two main ways of doing this:

  1. Make more of my own FSH. This is what Clomid aims to accomplish. Clomid blocks estradiol from telling the brain to STOP making LHRH. In this case, two wrongs do make a right, and blocking a stop signal is effectively the same as telling the brain to GO! The brain makes LHRH, which stimulates the pituitary to make LH and FSH, which stimulates the ovaries to grow follicles. Nice.
  2. Add in FSH from the outside. This is what I’m doing when I inject Menopur into my belly each night. Technically, Menopur is a mixture of both FSH and LH, but I think FSH plays the bigger role in follicle development (at least, that’s what its name would lead me to believe…)

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The downside of Clomid is that it doesn’t just block estradiol from talking to my brain. It blocks estradiol from talking to anyone…including my ovaries and uterus (who it’s supposed to tell to start prepping the uterine lining for implantation and making lots of sperm-friendly eggwhite cervical mucus). Clomid steals the entire message from the estradiol carrier pigeon.

Enter my weird protocol. Since the Clomid will prevent my uterine lining from being ‘embie-proofed’ in time for transfer this month, we’ll flash freeze those little guys (hopefully lots of them!) and let them chill for a month. This should give me time to do some nesting and get everything nice and ready to welcome the little tykes!

Why such a low dose of Menopur?

It seems counterintuitive that I would be using a low dose of Menopur, since the conventional wisdom is that patients with diminished ovarian reserve are generally less responsive to stims, and should therefore need more stims… For reference, I used 300 – 375 IU (4 or 5 vials) per day for my IUI cycle…more than twice as much as I’m using for IVF. From what I can tell from my limited reading of the literature, it sounds like for DOR patients with few eggs that are available for stimulation, adding more stims doesn’t increase the number of eggs recruited…and might harm egg quality.

Why Clomid?

I haven’t been able to find a clear reason why Clomid is a good choice in my case. The best I can think is that maybe in poor responders using two strategies for increasing FSH levels will work better than just one? Obviously, the fact that we aren’t doing a fresh transfer is a large part of why Clomid becomes a viable option.

What I know for sure

Clomid plus low-dose Menopur is much cheaper than the high-stims alternative.

Aside from a small crop of pimples on my forehead (which I’m guessing is due to the dexamethasone), I haven’t noticed any side-effects so far. I’m grateful for this!

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That’s where we are for now! We’ll see how the follies are doing bright and early Saturday morning!

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One-woman pharmacy, Redux

Now that we have the green light for IVF, I finally trekked over to the pharmacy and picked up the rest of the drugs for my protocol. Here’s the loot this time:

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Between Dr. Y’s sketchy (in my favor) billing and two hefty manufacturer coupons, I got quite a discount. Even with the discount, though, the grand total was quite a bit more than for my IUI drugs:

 

List price

Covered by Kaiser?

Coupon?

My cost

Androgel ~$380

Yes

$20

Androderm ~$390

Yes

$20

Estrace ~$100

Yes

$10

Aspirin ~$5

No

$5

Menopur $750 for 10 vials

Yes

$20

Clomid ~$50

Yes

$20

Decadron ~$7

Yes

$10

Prednisone ~$5

Yes

$10

Vibra-Tabs ~$120

Yes

$10

Pregnyl $89

No

$89

Follistim $299

No

$300

$0

Antagon $354 for 3 syringes

No

$100

$254

Omnitrope $867

No

$867

Total $3416

I actually paid:

$1335

From a chemical standpoint, this list includes 8 small molecule drugs, 4 protein drugs, and one peptide (ganirelix) that is pushing the upper limit of what I’d usually call a small molecule. (I usually give 1000 atomic mass units as the cutoff; ganirelix has a molecular weight of 1570 amu…)

Here are the structures and modes of administration for my drugs:

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Notice anything?

The small molecules tend to have more appealing modes of entry (often pills). Protein and peptide drugs tend to involve needles, for reasons I explained in a previous post.

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I also found the biological source of many of these drugs interesting. (Note: If you’re using any of these drugs and are easily grossed out, or are philosophically opposed to Genetically Modified Organisms, you may not want to keep reading!)

Testosterone was originally discovered by painstaking isolation from bull testicles. The yield was paltry, though – just 20 milligrams from 40 pounds of testicles. (I’m trying not to think about how many bulls had to be emasculated to get 40 pounds of testicles…) Thankfully, nowadays testosterone – along with most other steroid drugs – is made semisynthetically from steroids isolated from plants (often soybeans or Mexican yams). In other words, chemists isolate a similar plant steroid and perform chemical reactions in a laboratory to convert it to the desired human hormone. Drug companies sometimes use the term ‘bioidentical’ to emphasize to non-chemists that hormones that are made semisynthetically are exactly the same – chemically and biologically – as the ones produced in your ovaries (or testicles…)

Menopur is a mixture of FSH and LH purified from the urine of postmenopausal women (hence its name; think Menopausal urine…) Historically this urine came from nuns living in convents in Italy, though I’m not sure if that’s still the case.

Pregnyl is also urine-derived, but presumably not from nuns… Pregnyl is purified hCG from the urine of pregnant women.

Follistim, on the other hand, is made from recombinant FSH (Follicle stimulating hormone) produced in Chinese hamster ovary (CHO) cells. This means that scientists copied a piece of human DNA – the blueprint that tells our cells how to make the FSH protein – and put it into the hamster cells. In effect, they hijacked the hamster cell’s protein factory and programmed it to produce large amounts of human FSH protein. (Don’t worry, the hamster cells now grow in Petri dishes; nobody is manufacturing protein in live hamsters…)

Omnitrope is also made from recombinant DNA technology, but in E. coli bacterial cells instead of hamster ovary cells. Unlike FSH (which is a challenging-to-make glycoprotein requiring sophisticated mammalian cell machinery), growth hormone is relatively easy to make. The human DNA ‘blueprint’ for growth hormone can be put into Escherichia coli cells and the bacteria cells produce the hormone for us.

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I think I’ll stop there. If you want to know more about the chemistry of these drugs, you might check out my previous posts about the structures of FSH, LH, hCG and Clomid; doxycycline; aspirin; testosterone and estradiol (in the context of my current IVF cycle, or of what makes them steroids); the role of estradiol in predicting ovulation with the Clearblue fertility monitor; how hCG is detected in home pregnancy tests; or the significance of FSH and estradiol for diagnosing infertility.

Hypothetical of a hypothetical

So we’re moving along with Plan D – completing our IVF homework. Here’s what I’ve accomplished in the last week:

  1. Repeated my day 3 bloodwork. This revealed virtually the same bad numbers as before. Actually, to be fair, they were a smidge better…but probably not statistically significant; FSH went from 13.7 to 13.5, E2 went from 24.6 to 27.2; AMH went from 0.17 to 0.22. More importantly, they didn’t get worse in the past 4 months, which I’ll take as good news. (Funny story about the blood draw: after so many IF-related blood draws, I decided that I was now a needle badass and would therefore watch as the phlebotomist drew my blood…naturally, that was the first time ever that someone missed the vein and had to stick me a second time! I did NOT watch the second stick. So much for being a badass.)
  2. Took blood pregnancy test. No surprises here. This test was a liability necessity before they’d do #4.
  3. Start Zithromax with C. Apparently they want to make sure neither of us has any infections prior to IVF (not sure why this isn’t required for IUI…) I’ll write about the chemistry of Zithromax below…
  4. Saline sonogram & mock transfer. Dr. Y filled my uterus with saltwater and observed it by ultrasound to make sure there were no obstructions that might pose a problem for an embryo. (Kind of like the HSG, except with saltwater in place of the dye and ultrasound instead of x-rays.) He also practiced inserting a catheter to get the ‘lay of the land’ for the real transfer. The whole thing was very anticlimactic. The most uncomfortable part was that I had to do it with a full bladder. (I have a very small bladder and practically live in the bathroom…) I would have asked C to take a picture of this, but it didn’t really look like anything. My HSG photo was much cooler.
  5. Sign & initial 9-page informed consent document. The first 6 1/2 pages of the thing discussed various aspects of the medical interventions involved. Yes, I understand that there may be side-effects of drugs, complications of surgery, that I may have multiples, and that the whole procedure may fail miserably…The unsettling part was the other 2 1/2 pages, which consisted of depressing hypothetical scenarios and our decisions about what we would want to do with our hypothetical embryos. For example, what should happen to our hypothetical embryos…
  • if we fail to pay our embryo storage bill?
  • if one of us dies?
  • if both of us dies?
  • if we are legally separated or get a divorce?
  • after I exceed my “normal reproductive life”? (defined as age 50; phew!)

C was no help at all, and I struggled with how seriously to take the whole thing. On the one hand, I was making a decision about what would happen to our precious embryos – C’s and my potential children (and the only that I might ever have). On the other hand, we were planning for a doomsday hypothetical of a hypothetical. Given my antral follicle count, we’ll be lucky to get one or two ‘good’ embryos to transfer. What are the chances that we’ll have ‘extras’ to store and worry about in the event of further hypothetical catastrophes? In the end, I tried my best to take the questions seriously…If we stop paying our bill or don’t use the hypothetical embryos by the time I’m 50, we’ll donate them to research; if one of us dies or we get divorced, they’ll be made available to the partner who wants them (probably only pertains to me, since if I die or we get divorced, C can make cheaper babies with his new wife!), and if we both die, they can be donated to another couple. Gosh I hope this post is the last time I have to think about such bummer scenarios!

 Still on our ‘To Do before IVF’ list:

  1. Submit C’s semen culture (after we finish the Zithromax course) to confirm no infection.
  2. Attend a ‘teach class’ with the nurse to learn how to do our new injections.
  3. Call the finance lady at the IVF clinic to work out arrangements for payment.
  4. Start taking estrogen (estrace) and testosterone gel.
  5. Do a blood draw (including a progesterone test, and others?) to confirm that my hormones are ‘turned off’ before officially beginning our cycle.

And finally, here’s your IF chemistry lesson for the day:

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Azithromycin (aka Zithromax) is a macrolide antibiotic. That just means that it contains a large (15-member, in the case of azithromycin) lactone ring (shown in blue). Actually, a lactone is defined as a cyclic ester, so “lactone ring” is redundant…kind of like “ATM machine”. Anyway, azithromycin is a synthetic analog of the natural product 🙂 erythromycin, produced by the soil bacterium Saccharopolyspora erythraea. Like erythromycin and other macrolide antibiotics, azithromycin has a sugar part (technically, two sugar parts, shown in green) that dangle off of the lactone ring.