No follicle left behind

Last weekend, C & I went out with some local infertility survivor friends. (They conceived their daughter on their second IVF attempt). I was so excited to see them and ask for their advice and provider recommendations. They’ve been understandably busy with their little bundle of joy, and we hadn’t seen them since deciding to undergo IVF.

Early in our dinner, I was reminded of how different this journey is for each of us, when I started explaining my protocol to this friend and she interrupted me to offer some well-meaning advice,

“You just need to forget about all those stats and research and just believe that this is going to work!”

Um. Yeah.

C suppressed a laugh, and I quickly explained that, in fact, the only way I was going to make it through this was to read and research everything I could, because I like learning about stuff (especially stuff that, you know, matters this much…), because it gives me something I can do, and because by doing it I can regain some feeling of control.

To her credit, she quickly relented, “I forget. You’re such a scientist!” Yes, yes I am.

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So, after asking for your book suggestions and reading your comments (Thank you SO MUCH for those by the way!), I got inspired to make the leap from nonfiction books on infertility (which were too general to answer specific questions about my IVF protocol or my diminished ovarian reserve) to the primary medical literature. It’s a far cry from my area of expertise, but I’m doing my best to find answers to some of my most pressing questions… But before I continue with what I think I know, let me offer an important disclaimer:

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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Now that I’ve got that out of the way, let’s talk about Estrace! I’m currently on day 16 of Estrace supplements. I take two tabs (4 mg total) each evening (and thanks to you bloggy friends, I make sure to silently thank Dr. Y each time for instructing me to take them orally. No smurf sex for me, thank you!)

As I’ve mentioned several times by now, Estrace is just estradiol (E2) – the most potent of the female sex hormones. So, why take estradiol?

Here’s what I think I know about E2:

1) Estradiol serves a similar purpose to that of birth control pills in traditional IVF cycles. That is, it suppresses pituitary signaling to keep levels of follicle stimulating hormone (FSH) and luteinizing hormone (LH) low. The idea here is to shut down ‘business as usual’, so that Dr. Y can take control of my hormones with the stims when he is ready.

I was confused by this at first, since in a lot of the hormone signaling diagrams that I got from Dr. Google, estrogens (including estradiol) are shown stimulating the pathway leading to FSH and LH (a so-called positive feedback effect). But upon further study, I learned that moderate levels of estrogens inhibit production of FSH and LH (a negative feedback effect), while high levels of estrogens (such as occur when there are a couple of big lead follicles spitting out estradiol) stimulate FSH and LH production. Endocrinology is weird (and cool…and confusing, but mostly weird).

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Here’s some data I collected with a fertility monitor stick that corroborates this claim:

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To fully appreciate the significance of this blank stick, you might check out this post about how the CBFM works. In brief, the absence of an LH line (left) shows that no LH is being detected, while the faint E2 line (right) shows the presence of ‘moderate’ circulating E2 levels… (In case you’re wondering, the monitor read ‘high’ fertility due to the estradiol; it doesn’t realize that I’m in the middle of an IVF cycle and won’t be ovulating normally this month…)

But why not just use BCPs like everybody else?

Apparently, it is thought that in some people,  the classic ‘long Lupron’ protocol with BCPs might lead to less responsive ovaries, suppressed ovarian function, and/or decreased egg yields. From what I can tell, this may be a particular concern for members of the DOR club (like me), who need all the ovarian function we can muster…

2) Estradiol helps make lots of EWCM. I can vouch for this side effect of the Estrace pills. However, this is irrelevant to my cycle, since we’re doing IVF. No sperm needs to travel through my cervix this month (via my sperm-friendly EWCM).

3) Estradiol helps to prep the uterine lining for implantation. (Progesterone plays a major role in this, but apparently E2 can help out.) This is also irrelevant for me right now, since we’ll be freezing any embryos and doing a frozen embryo transfer in August. (I’m interested to see if Estrace is part of my protocol for getting ready for the embryo transfer, though. If so, I’ll assume this is the reason.)

4) The most interesting – and from what I can tell, least certain – effect of estradiol is that it in theory (C does a great impression of Dr. Y gesturing with both hands as he tilts his head to the side and says “in theory,…”)

Anyway, in theory, estradiol promotes the gradual, coordinated growth of follicles, which hopefully will yield more, high quality embryos. We don’t want one or two show-off follicles running ahead of the pack. It’s sort of a “No follicle left behind” situation.

Here’s hoping it works!

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.

Roid Monkey

So, on Monday I started rubbing Androgel on my upper arm each morning…and taking two Estrace (orally…phew!) each night. This is the hormone priming step of my IVF protocol. Add these to the Pulmicort inhaler that I use to keep my asthma under control and the progesterone that my corpus luteum is dutifully excreting, and you’ve got quite a steroid soup warming in my innards… I keep checking in the mirror for facial hair, bacne, or increased muscle mass. Aside from my pesky chin hair (excuse me while I find my tweezers…erm…got it!) I haven’t noticed anything.

ImageA sampling of roids in my system. You can read about progesterone, and what makes a steroid a steroid, here.

 

Speaking of progesterone, I’ve relapsed into another of my pre-IUI TTC habits, namely, charting. I keep track of each morning’s BBT (basal body temp) measurement, my CBFM (ClearBlue Fertilility Monitor) reading, any eggwhite sightings, and sexual encounters on a little paper chart on my nightstand. Recording it on the paper chart has a certain old-school charm about it, but can be a bit tricky to analyze and doesn’t quite satisfy my appetite for data.

Enter FertilityFriend. I type in my data to this website and it uses an algorithm that incorporates the data from my temperature, cervical fluid, fertility monitor, and OPK (when I use it) to determine when I ovulated. Actually, there’s a ridiculous amount of other data I could enter, but even a data junkie like me has to draw the line somewhere…

charts aMy paper chart for this month (left), and the FertilityFriend version, with est. ovulation shown as a red vertical line (right).

If you spring for the VIP membership (or if you are a new member, in which case you get a free ‘teaser’ VIP membership), the website will evaluate how well you timed intercourse. C and I apparently did ‘Good’ this month

ImageAnother feature of the VIP membership is that it will overlay up to 7 charts and show you the average BBT pattern. I’m not sure what this would be useful for, but it looks pretty cool:

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The average line (in blue) eliminates some of the noise of individual monthly charts to reveal a general trend of low temps pre-ovulation, followed by progesterone-elevated temps post-ovulation, which drop off just before the next cycle start (bonus benefit of charting – no surprise visits from AF!)

 

And this brings me to my newest dilemma: when to pick up my meds. Obviously, I already have some of them (including the Androgel and Estrace), but there are still ~$1K-worth of meds that Kaiser pharmacy doesn’t carry, which I have to pick up. If it weren’t for traffic, I would have picked them up the day Dr. Y prescribed them. But now that there is a chance – however miniscule – that I might be pregnant, I can’t bring myself to shell out that $1K until I’m sure I’ll need it…

So it’s one more thing on my ‘to do’ list. If FertilityFriend is right about my ovulation date, and if I follow my usual luteal phase of 11 days, then AF should arrive on Monday, and I can swing by the pharmacy after that, with plenty of time before I need those particular stims… On the other hand, maybe I should wait longer – until my baseline ultrasound (next Thursday) to make sure there are any follicles to stimulate with those drugs…yes, I think that makes more sense.

It’s a plan! And thank you, bloggy friends, for inspiring me to think this through, and patiently reading while I do. 🙂 Yet another perk of blogging…it forces me to think before shelling out C’s hard-earned money!

 

p.s. Welcome ICLW visitors! You can read my TTC resume here, but in brief: I’m a 34-year-old chemistry professor with diminished ovarian reserve, who has been TTC for about 15 months, including one missed miscarriage at 9 weeks. After 1 unsuccessful round of IUI, we are moving ahead with our first IVF next month. I use this blog as a form of therapy, and as a repository for interesting chemistry (and biology) that I learn along the way!

Old habits die hard

As you may recall from my last post, the current plan is IVF homework this month; stims and ER next month; detox in July; and FET in August. Not wanting to waste a single egg (what if it’s my only good one left?!), I naturally asked Dr. Y for permission to try ‘the old-fashioned way’ this month. Ever the gentleman, Dr. Y refrained from sharing his thoughts (Why not just enjoy the break? Don’t you realize how low your chance of success is?), and he politely said that would be fine.

So I pulled my BBT thermometer, pen, and a blank chart out of the nightstand drawer, and dug around in the bathroom cupboard for my ClearBlue Fertility Monitor and a stash of test sticks. (Okay, so I may have used the phrase ‘the old-fashioned way’ a tad liberally…) I had skipped all this during our IUI cycle thinking it would be a relief not to have to trouble myself with the morning routine, but I actually ended up regretting it. Throughout the cycle I found myself missing all that precious data! I wanted answers:

  • Would the Menopur injections cause a ‘peak’ reading on the monitor?
  • What about the hCG trigger shot?
  • How long after the trigger shot did my BBT rise?
  • Did the progesterone suppositories cause a higher BBT than usual?

I don’t know! And that bugs me a little bit.

Anyway, I’m back to collecting my precious data this month (and probably will through IVF too, because, why not?!)

And to everyone who wondered how the ClearBlue Fertility Monitor works, the rest of this post is for you. (Wait, nobody is wondering that? In that case, read this hilarious post by Stupid Stork instead…)

Still here?

So, the ClearBlue Fertility Monitor…

Like OPKs, the ClearBlue Fertility Monitor (or CBFM for short) monitors the levels of hormone in my urine. While OPKs detect luteinizing hormone (LH) that surges 24-48 hours prior to ovulation, CBFM detects both LH and estradiol (E2). E2 rises a bit sooner, and a bit more gradually than LH, which means the CBFM can give me more advance warning before ovulation. (This makes it easier to have some semblance of romance in this whole TTC thing. I can say ‘It’s been awhile since we’ve gone out; let’s make Wednesday a date night,” instead of “Wake up! Sexytime! Now! NOW!”)

Each morning starting on CD6, I POAS, cap the little stick, and snap it into the appropriate slot on the monitor. The monitor waits 3 minutes for the stick to develop and then shines a little red light on the stick ‘reading’ the result. For the scientists reading this, I assume the monitor works like a visible absorbance spectrophotometer; I’m looking forward to taking it apart to investigate once I’m sure I don’t need it anymore…

Anyway, after reading the stick, the monitor displays one of three possibilities:

  • Low: low E2 and LH levels. You can have sex today for fun or romance, but you can’t in good conscience use TTC as an excuse.
  • High: high E2 but low LH levels. You can use TTC as a pretty good excuse to have sex today.
  • Peak: LH surge. Ovulation is imminent. Sex today is pretty much required.

The sticks (which you have to purchase separately) look a lot like OPK sticks. But there’s no ‘control’ line – just one line for E2 and one for LH. And the color changes (particularly the E2 color change) are definitely more subtle than for OPKs – hence the need for the monitor to read the result.

I tried, unsuccessfully, to figure out the chemistry (or biochemistry) behind how CBFM works. I imagine that the LH line works using antibodies in a way similar to what I described in this post about how HPTs work, but I don’t know for sure. The mechanism for detecting E2 has to be somewhat different since (a) it’s not a protein hormone, and (b) the E2 line gets lighter as E2 levels increase, instead of darker.

Anyway, here’s a figure showing my monitor & corresponding test sticks for each possible fertility reading:

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Note the cute little egg symbol on the display for ‘peak’ fertility.

I color coded the hormone labels in the figure above to match this diagram I found on the interwebs showing how the menstrual hormones rise and fall at varying stages in a cycle. Note the gradual estradiol rise (blue), peaking a day or two before the LH surge (green):

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Incidentally, while doing a Google image search for LH and estradiol levels, I found the coffee mug above right, which I would want…except that I don’t think I’m gutsy enough to use it in public. They also sell a hat…

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!

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:

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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/