Well, fuck!

That’s what I said when I read my most recent email from Dr. Y’s nurse:

“YOU DAY 3 LAB WORK CAME BACK AND THE RESULTS SHOW AND ELEVATED FSH AND THE AMH IS LESS THATN 0.03. IT WOULD BE BEST IF YOU CAME IN AND HAD AN APPOINTMENT WITH DR Y. I WILL NOT HAVE ANY APPOINTMENTS UNTIL AFTER YOU RETURN FROM EUROPE. PLEASE CALL ME AT xxx-xxx–xxxx SO THAT WE CAN SCHEDULE AN APPOINTMENT”

Yes, she writes her emails all in caps like that, as if I needed any more reason to feel alarmed.

My AMH is less than 0.03. I didn’t know the test measured amounts that low.

In what feels like another lifetime, I once wrote a long post about what AMH (and FSH and estradiol) mean for fertility.

Here’s a summary of my results the four times I’ve taken these tests. Prior to yesterday, 0.17 ng/mL was the lowest AMH of anyone I know in real life (including my Resolve support group).

  1/26/13 5/4/13 4/24/15 10/8/16
estradiol (E2) 24.6 pg/mL 27.2 pg/mL 23 pg/mL 20 pg/mL
follicle stimulating hormone (FSH) 13.7 mIU/mL 13.5 mIU/mL 9.7 mIU/mL 17.7 mIU/mL
anti-Mullerian hormone (AMH) 0.17 ng/mL 0.22 ng/mL 0.31 ng/mL <0.03 ng/mL

 

I’m feeling pretty hopeless at the moment.

At least I get to go to Rome on Sunday.

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When to try again

And now we arrive at the last of our unpleasant decisions following Jane’s passing:

Decision 10: When to try again.

By way of background for those of you who are new to my blog: three years ago, after an early miscarriage followed by 6 months of unsuccessful trying on our own, I was diagnosed with diminished ovarian reserve. I’m a non-responder to stims, having produced only a single egg during medicated IUI, and IVF cycles. Miraculously, we conceived our first rainbow baby C. Samuel spontaneously in between IVF cycles. After C. Samuel was born, we decided to try for #2 via natural cycle IUI. On the sixth month of this, we conceived Jane Margaret.

Some conclusions from our adventures in infertility:

  • I have precious few good eggs left. (One of my doctors predicted that I would go through menopause before age 40…I’ll be 38 next month.)
  • I consistently ovulate one (and only one) egg per month, with or without stims.
  • When we’ve been lucky enough to have one of C’s supersperm catch a good egg, the babies that result are beautiful and perfect (though I can’t say the same for the resulting placentas).  😦

Contrast that with the following advice re: trying again after stillbirth:

  • The American Pregnancy Association recommends waiting several months up to a year to try again after a stillbirth.
  • Dr. R recommended waiting 3-6 months before trying again.
  • Dr. R mentioned a study suggesting that shorter time between pregnancies may be correlated with shorter umbilical cords (part of Jane’s perfect storm), though she acknowledged that the study wasn’t especially compelling.

Having discussed all of these considerations and more, C and I quickly agreed on a decision:

We want to try again as soon as possible! 

We both find the egg scarcity argument more compelling than the emotional self-care concerns. What if I ovulate my last good egg on one of the months that we’re “waiting to try”?!

As it happens, my own body forced a bit of a compromise, since it took 11 weeks for my period to come back after Jane’s passing. My bitchy Aunt Flo showed up on Friday, and on Saturday I got my blood drawn to repeat my CD3 (in this case CD2) bloodwork. Unlike last time, my FSH went in the wrong direction (up to 17.7 mIU/mL). :/

.

At least C. Samuel is optimistic. He busted this song out during a recent visit to Ong Ba’s (Grandma & Grandpa’s) house. Neither C nor I had ever heard it before.

 

The Rainbow Song lyrics:

Red orange yellow green blue purple,

red orange yellow green blue purple,

red orange yellow green blue purple,

makes the rainbow bright bright bright!

.

[Deep breath] Here we go again.

Can we possibly have enough luck left over for another miracle?

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.

*****

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!

*****

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.

Image

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…)

Image

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!

*****

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

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:

Image

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:

Image

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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.

*****

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.

*****

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.

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…

Test results

First, another update: I picked up C. in San Jose last weekend and flew home to San Diego with him yesterday. The flight was uneventful (a bit of turbulence, but smooth landing), but he was pretty tuckered out from the trip. Nice to have him home, though. The doggies and I missed him!

Back to the IF world. Now that I’m firmly in the two-week wait, I don’t actually have any news, but figured this would be a good time to fill in some of the holes in my earlier posts…starting with my pre-HSG test results.

I won’t share C.’s sperm test results, for the simple reason that I don’t have the values. (Due to HIPAA or whatever, I never got a copy of the results.) I will say (again) that I hear they were awesome. The best our IF nurse has seen, or so she claimed. C. is happy to believe her, and so am I.

So below are the results of my tests:

1) Antral follicle count. At my first visit with Dr. Y., he performed a transvaginal ultrasound and counted the number of antral follicles (maturing pre-eggs, visible under ultrasound). The idea here is that you can’t actually count the number of eggs a woman has left, so you assume that the number of partially-mature eggs your RE can see under ultrasound will give some indication of how many immature eggs (which your RE can’t see) are there. In general, more antral follicles = good, with ‘normal’ (in other words, ‘fertile’) levels being 16-30. My antral follicle count = 5.

The remaining three are all tests of blood hormone levels, determined from a blood draw on day 3 of my menstrual cycle. The structures of these hormones are shown below:

Image

Now, despite what my dad said in pretty much every Christmas letter throughout six years of grad school, I am not a biochemist. I’m an organic chemist, which means that I love to look at little chemical structures like the one of estradiol above. I start to get uncomfortable looking at any molecules bigger than about 1000 atomic mass units. Forget about proteins and nucleic acids! Both AMH and FSH (discussed in detail below) are protein hormones, which means that they are long chains of amino acids (AMH is composed of 560 amino acids; FSH is smaller*). If I tried to draw them using the same style of line drawing as estradiol, the drawings would be ridiculously large, indicipherable, or both. Instead, biochemists like to use other representations, such as the ribbon drawings above. The space-filling model is a compromise that makes me a little less uncomfortable, because I can at least see that there are carbons and hydrogens and oxygens, etc. Anyway, back to the tests:

2) Anti-Mullerian hormone (AMH). AMH is named for its role in preventing the ‘default’ development of female plumbing (“Mullerian ducts”…like uterus, vagina, and fallopian tubes) in male embryos. Its significance for infertility testing arises because AMH is released by egg-associated cells (“granulosa cells”) in the ovary, and – like antral follicles – is used as an indirect measurement of how many eggs are left. So, high AMH (>1 ng/mL) = good; low AMH = bad. My AMH = 0.17 ng/mL.

3) Follicle-stimulating hormone (FSH). As the name suggests, FSH stimulates the development of follicles (i.e. eggs) in the ovaries. My RE describes it as being like the gasoline that revs up the engine and gets your ovaries to develop and drop an egg. In young, nubile women, it doesn’t take much FSH (“gas”) to get the egg to drop. In women approaching menopause, you have to push the pedal to the floor to get enough gas for the egg to drop. In other words, low FSH (<9 mIU/mL) = good; high FSH = bad. My FSH = 13.7 mIU/mL.

4. Estradiol (a type of estrogen) is the main female sex hormone. In terms of predicting fertility, estradiol behaves a bit like FSH, in that your body may produce higher levels of estradiol (turning up the gas) as the number of remaining eggs decreases. Moreover, estradiol suppresses FSH production, so someone who has low FSH might actually still be in trouble if high levels of estradiol are ‘masking’ what would otherwise be high FSH. For this reason, REs like Dr. Y. typically order FSH and estradiol tests together… I can’t seem to find ‘normal’ values for estradiol, but since my high FSH levels already indicate very low fertility, I don’t think it matters! My estradiol = 24.6 pg/mL.

A side note about units:

As a scientist, I find it a little strange that every medical test seems to have its own units of measure. A cynical explanation is that perhaps physicians aren’t big fans of scientific notation, and prefer to choose a unit of measure for each test that gives normal ranges with values from 0.1-100 or so…even if it means learning dozens of different units. A more generous explanation is that maybe each of these molecules are being detected in different ways, and the units used might be determined by the detection method and sensitivity.

Regardless of the reason, here’s my guide to units for the tests above:

  • mIU/mL (milli-International Units per milliliter of blood). From what I can tell, the ‘International Unit’ is a biologist’s invention. (Is my bias showing?) It’s sort of like an ‘effective concentration’ that doesn’t translate to anything that a chemist would understand as concentration (like molarity, molalilty, normality, ppm, ppb, mg/mL, % by volume, etc.)
  • ng/mL (nanograms/milliliter of blood) For non-scientist types, a nanogram is one billionth of a gram.
  • pg/mL (picograms/milliliter of blood) A picogram is one trillionth of a gram, or one thousandth of a nanogram.

*For more about the structure of FSH, see: https://infertilechemist.wordpress.com/2013/04/16/injections/