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.

My colorful protocol

Today, C and I went in for our IVF medications “teach class”. I’m not sure why they need to add the word ‘teach’ in there. Are there classes that don’t involve any teaching that they need to distinguish this one from? Are they distinguishing this class from a “learn class”? (Our legal counsel informs us that we can’t promise that you’ll learn anything, but by God, we’ll teach you!) Actually, maybe I can use this…I think I’m going to rename all my courses “teach classes” to spare myself any responsibility for my students actually learning anything…

Anywho, it turns out IVF is a hell of a lot more work than medicated IUI. (Once again, I can hear all the seasoned IFers in unison…No shit!) The list of medications that I have to take is long and expensive, and I can see why my insurance drew the line after IUI…

It also seems like my protocol is a little unusual, so I thought I’d share the details of it here:

First, my calendar for May:

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And my calendar for June:

calendar a

Here’s my limited understanding of what everything is for:

  • Zithromax – to ensure that C & I are infection-free prior to beginning the cycle
  • Estradiol – to help me recruit more eggs and to prevent any new cysts from forming (which would force me to delay the cycle)
  • Testosterone (gel & patch) – to try and recruit a few more eggs (In explaining this one Dr. Y was careful to say “in theory” several times, leading me to think that this claim has not been proven…)
  • Aspirin – to improve blood flow to my uterus
  • Menopur – to stimulate multiple follicles to grow
  • Clomid – to stimulate multiple follicles to grow
  • Dexamethasone – to help with implantation
  • Growth hormone – to help the eggs develop/mature fully (to achieve better egg quality)
  • Ganirelix – to prevent premature ovulation (We don’t want those eggs to drop; we want Dr. Y to suction them out with a needle instead…)
  • Follistim (FSH) – same general idea as (and one of the ingredients of) Menopur; I think this serves as a little boost to get the eggs ready to go for retrieval the next day
  • hCG – stimulates ovulation; I’m guessing this finishes getting the eggs ready to drop, but that we’ll time it so that I go in for retrieval before they actually drop
  • Doxycycline – antibiotic prophylactic to prevent infection from the retrieval
  • Prednisone – not sure what the purpose of this steroid is…maybe prevent inflammation?

Has anybody else used testosterone in their cycles? From the mysterious way that Dr. Y talked about it, I get the idea that it’s not part of the typical IVF protocol.

I think another unusual (weird?) thing is that I’m using pretty low doses of stims (especially considering the fact that I’ve got diminished ovarian reserve): 100 mg of Clomid and 150 IU of Menopur per day…that’s less than half the daily dose of Menopur that I used for IUI. Dr. Y says that they’ve found that success rates with the low stim protocol are comparable to those with high stim, but at much lower cost.

Lastly, you may have noticed that the calendar above doesn’t include an embryo transfer. Dr. Y insisted that an important feature of this protocol – and one that he recommends for old lady patients (and patients with old lady ovaries, like me) is that it does NOT involve a fresh embryo transfer following retrieval. Instead, the plan is to flash freeze (vitrify) my embryos and store them for a full cycle while my body purges itself of the colorful drug cocktail listed above. In particular, the Clomid is supposed to make for a somewhat hostile uterine environment. According to Dr. Y, for older women, postponing the transfer for a month actually gives higher pregnancy rates.

My read of the clinic stats seems to validate Dr. Y’s claim: In 2011, the % of FETs resulting in clinical pregnancy was 58.3% for 38-40 year-olds, compared to 56.3% for fresh transfers for the same age group – despite transferring more embryos on average for the fresh transfers (2.1 per transfer versus 1.8). For younger women, the fresh transfer is definitely better, so the only question is whether this 34-year-old with diminished ovarian reserve will behave more like the average infertile 38-40 year-old, or like the average infertile <37 year-old…

I guess we’ll see! Anyway, I trust Dr. Y and am perfectly happy to go with his professional judgment. (Of course, my trust for Dr. Y’s judgment didn’t prevent me from trying to mine the SART data to answer this question, but it turns out that my clinic didn’t treat enough <37 year-olds with DOR to give meaningful data…)

The punch line of this is that assuming my sonogram in two weeks looks good (crossing my fingers for lots of follicles and no more cyst!), I’ll be moving ahead with the egg retrieval in mid-June, and assuming we get any good embryos (fingers crossed yet again), I’ll take a uterus-cleansing drug holiday in July followed by a frozen embryo transfer in August!

Trigger shot

I had my estradiol and follicles checked today. Two looked like they could drop any minute, so the nurse practitioner – D. – administered the hCG trigger shot while I was there. (Poor C. didn’t get to “stick me” after all!)

For all the data monkeys (like me) out there, here’s a summary of my test results:

Estradiol (E2):

  • baseline estradiol (taken during infertility workup 1/26) = 25 pg/mL
  • estradiol on 4/17 (after 4 days of injections) = 281 pg/mL
  • estradiol today (4/19, after 6 days of injections) = 572 pg/mL

According to this FAQ (http://www.fertilityplus.com/faq/iui.html), the target is 200-600 pg/mL per big follicle; since I only have two big follicles, I think this means I’m good.

Follicle size & count:

  • On Wednesday (4/17) I had three visible follicles, measuring 14.5 mm, 13 mm, and 11 mm.
  • Today (4/19) the same follicles measured 18.5 mm, 16.6 mm, and 11.5 mm. Below is a picture of my biggest follicle, viewed on ultrasound. (The follicle is the black oval just left of center with the dotted cross through it). 18.5 millimeters sounded huge to me, so I posed a penny (also 18.5 mm in diameter) in the photo for reference!

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According to that same FAQ above, it looks like 16-18 mm is a good range for Menopur-stimulated follicles, which is consistent with what nurse D. said. She expects that the smaller one will probably not release, so we’re looking at two follicles this cycle.

Things are slightly less than ideal. For our best chances of pregnancy, our target would have been 3-4 big follicles (to increase the odds of at least one ‘good’ egg taking). But 2 is better than 1, and better than 5+ (in which case we would’ve had to cancel the cycle or risk a multiple pregnancy). In addition, it would have been better to inseminate 36 hours after the trigger shot, but since the clinic is closed on Sunday, 24 hours will have to do! Nurse D. pointed out that it’s better to inseminate early than late, since the sperm can “wait for the egg”, while the egg can’t do the same. (I’m sure there’s a sexist joke to be made there…) She also suggested BDing on Sunday to be sure…

So I’ll be back tomorrow for the insemination. Wish me luck!

Looking good!

So today I had a blood estradiol (E2) test, and ultrasound to see how I’m responding to the Menopur, and all looks good. 🙂

The annoying part is that they only do the estradiol test at the hospital lab across town, and only from 7-7:30 am. So I had to wake up at 5:30 this morning to get ready and drive east to the hospital, and then drive back west in rush-hour traffic to teach my 8:30 class. Fortunately, the infertility clinic is on this side of town, so making it to my 10:30 ultrasound appointment was no problem.

Anyway, the result is that I have two decent-sized follicles, and one smaller one. This is good news, since our target is 2-3 follicles for IUI. Based on the size of the follicles and on my estradiol (281 pg/mL), the nurse practitioner recommended upping my dose of Menopur from 300 IU to 375 IU per injection, and repeating the blood draw (5:30 am wakeup – Boo!) and ultrasound on Friday. Depending on those results, we may do the insemination as early as Saturday!

Injections

After three days of injections, I can honestly say that they’re not that bad. C. seems genuinely impressed at how comfortable I’ve become with it. He also seems to enjoy making references to “sticking me” whenever he can…

So, what is it that I’m sticking myself with each evening?

So far, it’s been Menopur, a combination of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) purified from the urine of postmenopausal women. (Since menopause may not be that far off for me, I’ve got it on my ‘to do’ list to find out how to donate my pee to the cause!) Anyway, the idea here is that both LH and FSH work together to stimulate my ovaries to develop pre-eggs (“follicles”). At the right dose, we can hopefully get my ovaries to prep 2 or 3 eggs. They’ll be monitoring me closely by ultrasound to see if that’s what is happening.

Then, when they give me the go-ahead, C. will inject me with a megadose of (generic) human chorionic gonadotropin (hCG) to trigger my ovaries to drop all the mature eggs at once. That way, when we do IUI (intrauterine insemination, aka the turkey baster), the chances are better of getting at least one “good” egg, and a successful pregnancy. (Of course, this also increases the chance of twins, but at this point, twins sounds a lot better than childlessness, so we’re not going to let that stop us!)

hormones 2

Structurally, FSH, LH, and hCG are all related. They are all dimeric glycoproteins (composed of two separate protein pieces, each with sugars attached). One of the protein pieces (the “alpha subunit”) is the same for all three hormones. What differentiates them from one another is the other protein piece (the “beta subunit”).

The beta subunits of hCG and LH are highly similar, and both proteins bind the same receptor. Here are some fun facts that result from this similarity:

  • I don’t feel too bad about the fact that I couldn’t find an image of LH for the figure above. Just put your nose up to the screen and cross your eyes to see two of the hCG structures – that’s pretty much what LH should look like anyway!
  • When C. gives me the trigger injection of hCG, we’ll be technically using hCG as a stand-in for LH, since LH is what normally triggers ovulation. Unfortunately, I can’t seem to find a good explanation why hCG is preferred for this use…
  • You can use an ovulation predictor kit (OPK, which measures the natural LH surge that triggers ovulation) as a poor-man’s home pregnancy test (HPT). The hCG produced by a fertilized egg is similar enough to LH to get a positive test. Don’t believe me? See: http://tracysue.wordpress.com/2012/04/25/experiments/
  • A corollary of that last fact: after getting my trigger injection of hCG, I would test positive on an HPT. I haven’t decided yet if the thrill of seeing a false positive test is worth the expense of the test, but if I do, I’ll post the test (and freak out any sporadic readers…mua-ha-HA)!

And this brings me to why everyone should prefer OChem over biochem. Small molecule drugs (like aspirin, tetracyline and Clomid – the realm of organic chemists) can often be taken in pill form, while protein drugs (like insulin, Menopur and hCG) pretty much never can. This is because the delicate three-dimensional shape of proteins doesn’t hold up well in the stomach (amid all that hydrochloric acid and digestive enzymes), and because their size (~30,000 amu for FSH, LH, and hCG, versus 405 amu for Clomid) makes it hard for them to get absorbed through the intestine and into the bloodstream. On the other hand, Clomid doesn’t work nearly as well as Menopur and hCG do, so perhaps I should wait to condemn the biochemists…

Anyway, tomorrow I’ve got an estradiol blood test and ultrasound to see whether the injections are working. Stay tuned…

One-woman pharmacy

I went to pick up my drugs for medicated IUI yesterday. Annoyingly, the Kaiser pharmacy at the infertility clinic was out of Menopur – the clinic’s most-prescribed infertility drug – and I had to drive across town to the hospital pharmacy…only to find that they were out of needles?!

On the plus side, my insurance is evidently pretty good, and I got over $2K-worth of prescription drugs, syringes, and needles for $32! I wasn’t as lucky with the supplements Dr. L. recommended (including Coenzyme Q10, omega-3 fatty acids, and baby aspirin). Even with a buy-one-get-one-free sale at CVS, these cost me $134!

Here’s the loot:

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For the chemistry of these, I’ll start with the easy stuff (i.e. the small molecules)… Here are structures of the supplements Dr. L. recommended:

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Aspirin is the acetate of salicylic acid – a natural product from the bark of the willow tree. Coenzyme Q10 is a quinone (hence the Q), and an antioxidant. (The quinone part of CoQ10 is shown in blue above.) Omega-3 fatty acids are a class of fatty acids that contain multiple double bonds with the first double bond starting at carbon-3 (counting from the ‘omega’ end, or the left side on the structures above). Omega-3s are made by plants. People can get them by eating plants (especially the seeds), by eating fish (who in turn get them from eating algae and plankton…), or (in my case), by taking fish oil supplements.

Dr. L didn’t go into detail about the rationale, but said that she recommends these supplements to “maximize the quality” of my remaining eggs. From reading the labels, it looks like all are supposed to promote circulation, which I guess is a good thing for eggs. (Did I mention I’m not a biologist?) There’s also something psychologically satisfying about taking a bunch of pills…feels like I am doing something.

I’ll save the chemical structures of Menopur for another day, since it’s more biochemistry (yawn!); this post is already too long; and I’m hungry!

Wish me luck for my first Menopur injection tonight!

IUI cycle start

So despite C.’s valiant effort, we are definitely not pregnant. 😦

I suspected as much this morning, and it was confirmed during my ‘Menopur Teach Class’ (a required class for informed consent before medicated IUI).

Anyway, as I mentioned before, I needed to schedule a ‘baseline ultrasound’ during the first 3 days of my cycle if I wanted to do IUI this cycle. Since C. and I were already at the infertility clinic for the class, the staff at the clinic was very accommodating and got me in this afternoon for the ultrasound, and for the one-on-one session to teach us how to prep and administer the shots.

Because of the short notice, a different RE at the clinic – Dr. L. – performed the ultrasound. Upon entering her exam room and taking stock of the decor, C. and I appreciated what we assume is Dr. L’s subtle sense of humor:ImageUnfortunately, the decor was the highlight of the visit. Not that we didn’t like Dr. L – we did! But the ultrasound revealed even fewer antral follicles than last time – only 3. And Dr. L. was less equivocal than Dr. Y. Among other things, she said that I would probably hit menopause before age 40. 😦

But the ultrasound did not reveal any ovarian or uterine cysts, which was good news for moving ahead with medicated IUI, and we had our one-on-one meeting with the nurse. Starting on Saturday, I’ll be giving myself subcutaneous injections of Menopur every night, and when the doctor says it’s time, a one-time intramuscular HCG ‘trigger’ injection, which I very much hope C. will give me. I’m strangely proud to say that I gave my first shot today (just saline solution for practice), and it wasn’t so bad. C. (who loves to tease me for my fear of needles) was especially impressed!