Author: Jeb Kinnison

Mostly harmless purveyor of gently-used memes. My latest book: "Red Queen: The substrate Wars," available at: http://www.amazon.com/gp/product/B00QSP3JTU/ref=as_li_tl?ie=UTF8&camp=1789&creative=390957&creativeASIN=B00QSP3JTU&linkCode=as2&tag=jebkinn-20&linkId=L5XO3S3LGKGGDT4B. Also see, "Bad Boyfriends: Using Attachment Theory to Avoid Mr. (or Ms.) Wrong and Make You a Better Partner," is now on sale exclusively for Kindle (this will change soon.) Get it at: http://www.amazon.com/dp/B00IW6JYV0

IVF Journey: Genetic Screening of Parents and Embryos
Genetic testing of human samples

Genetic testing – (credit NIH)

[Continued from Remedies for Male Factor Infertility – Azoospermia]

The additional cost and unnatural nature of IVF has some benefits — both parents and embryos can be genetically tested in advance. If the parents have certain recessive genes, they can either use donor sperm or eggs to avoid offspring with significant defects, or roll the dice and check the resulting embryos for the issues they’d like to avoid. Most testing is motivated by a family history of genetic disease for one or both parents — it can be demonstrated that a certain inherited disease is not likely, or the opposite (in which case IVF

Our process involves both an egg donor and a separate gestational carrier (GC.) Both intended fathers and the egg donor were Counsyl tested; husband’s passed with no problems, while my genetic tests showed two fatal recessives and one “problematic” recessive (not fatal for years if ever, but weakening the adult.) Fortunately the egg donor’s test combined with ours showed no bad combinations.

The modern IVF process can freeze both sperm, eggs, and the embryos resulting from fertilization after 5-7 days; this reduces the difficulty of timing each element. Instead of rushing to inseminate fresh eggs with fresh sperm, the eggs and sperm can be frozen and thawed later for combination. The resulting embryos are typically cultured for 5-7 days and frozen as soon as they develop enough. In an echo of the quiet natural winnowing process, often only half or less of the eggs develop at all, and around a quarter look like good candidates for implantation.

The embryos are graded (letter grades!) A-D for development of the part of the cell mass that will be the child, and separately for the cells destined to form the placenta and accessories. This can be augmented by PGT-A (Preimplantation Genetic Testing for Aneuploidies) to determine which embryos are most likely to be viable. This is accomplished by taking out one or two cells from the less-critical part of the embryo and testing them. This is controversial because it is expensive, may possibly harm the embryo, and is not necessarily reliable because it’s not uncommon for cells in the embryo to have different genetic makeups (“mosaic.”) Nevertheless, choosing embryos that pass this test greatly improves the live birth rate for IVF. Desperate for offspring of their own, couples sometimes direct implantation of apparently unsound mosaic embryos, which can sometimes develop normally, but usually don’t.

Embryos that are missing entire chromosomes or major segments will either not make it to term or suffer serious defects that limit their lives. Since we are already intervening in the natural process and each attempt at pregnancy is very costly, using these tests to improve the odds is very much worth it.

While I was unable to produce viable spermatozoa, [husband’s] were fine and so we went forward with the egg donor and directed half the harvested eggs to be fertilized with his contribution.

Oct 18 2019

So they centrifuged my pathetic sample and found 4 live (if not terribly healthy) spermatozoa. Not really enough to work with!

Nov 21 2019

Egg donor at IVF doctor’ office in LA. Got an Amex charge notice, $16K, billed for the next few days until the extraction on the 23rd. 15 follicles ready, so harvest will likely be good (avg is around 10.) They will immediately fertilize half with Paul’s sample (frozen months ago) and freeze the rest of the eggs (waiting on my less-than-robust spermatozoa, which may have to be handled one-by-one.)

This first stage [husband’s] went well enough, though in hindsight we were both old enough to have benefitted from the Zymot sorting chip, which would have improved the health of the spermatozoa used for ICSI. Then we waited for reports from the culture lab to see how the little buggers did.

Nov 24 2019

Update: Got a report from the lab. Darwinian selection (which occurs silently in the normal process) underway. Of 9 oocytes, 2 rejected as immature. They thawed [husband’s] sample and selected sperm cells from a microscopic examination, then used ICSI to fertilize seven of the fresh eggs. Two of the remainder were discarded for not developing a healthy profile of pronuclei (PNs). Research has shown that the most healthy look is 2 normal-sized PNs, but other configurations (0, 1, 2.1 [one of the two is small]) have some chance of healthy development, so they are grown for more days in case they turn out fine (it turns out the male’s DNA can still be incorporated without the obvious signal of two PNs.) That leaves 5 growing. They weren’t specific about the 0N-1N-2N status of each. Kind of nerve-wracking.

Technology has improved a lot, but expect by a century from now that it will have progressed past “screening” to libraries of genetic material that can be recombined at will, and probably an artificial womb for gestation. Brave New Worldish. Costs will drop and it may eventually be seen as retrograde to have children the old-fashioned way. We’ve already seen lots of world-building where that cultural struggle is a theme.

BTW, any “super race” ideas (e..g., Star Trek’s Khan) will require a lot of arm-waving to explain how gene engineers can improve on the best/luckiest naturally born people. I don’t think (other than splicing out obviously damaging defects) anyone will be able to tailor the perfect combination of traits, and one thing we do know is that the natural diversity of talents contributes to the advantages of human teams….

Nov 28 2019

IVF update: the tech was rushed and so the report for Day 5 came in early. 3 embryos looked good enough for genetic testing (there was a differentiated clump of cells that will end up as the fetus and surrounding cells that end up as placenta, and it’s safe to remove one of those for the gene testing (shipped frozen to the lab.)) The 3 candidate embryos were then frozen. Testing comes back < 10 days. We haven’t heard from the surrogate wranglers about who might be available. I hope there’s more data to decide with. nov 30 2019 Day 7 report: the two zygotes not frozen didn’t develop and so were disposed of. 3 survivors were frozen Day 5, so that’s the choice for [husband's] kid. Kinda sad but as expected (the beyond-5-days embryos rarely develop enough). Was just reading about a PA bill that supposedly requires burial certificates for disposal of any fertilized egg. This is, of course, silly. Whether the bill actually says that is unclear, the usual amplification to get people outraged for clicks being in play. Dec 9 2019 Monday morning news: genetic tests done, 1 of the 3 embryos failed. Awww. I resent they don’t send us the report, but we can talk it over with the doctor if we schedule a Skype call. [later edit]: We got the genetic test results. Two euploid XYs (boys) and the aneuploid XY (female) who lacked the full complement of 16 chromosomes. Eek. The lottery odds favor us (only 16% chance neither XY will be carried to term) but still that worries me. [further note: I think they mean one Chromosome 16 is absent or incomplete, not 16 missing chromosomes.]

[Current state 2-1-2021: [husband’s] best embryo was implanted 7 months ago and is likely to be born to our surrogate in mid-April. We’re getting ready by buying all the equipment, clothes, diapers, etc.! We’ll get to mine later in the saga, which took much longer and had more issues with “Sperm DNA Fragmentation” (SDF) because I am older. Half of our first batch of eggs were fertilized with my sperm, and none survived culturing and screening.]

IVF Journey: Remedies for Male Factor Infertility – Azoospermia

[continued from Donor Eggs.]

Update: in real time, offspring #1 is at 32 weeks, with two months to do. He is reportedly very active during the day, but sleeps at night, which is very helpful so his gestational carrier (GC) can sleep. #2 is frozen in pre-launch until his GC is ready, probably next month.

Now for my part of the tale: my sperm tests came back stamped “azoospermia,” which is the condition of having no spermatozoa in your semen sample. This is rare for older men (who usually have at least a few feeble wrigglers), but is common for any man of any age who has been on testosterone replacement therapy for a length of time.

July 30 2019

The saga continues. World-class LA IVF doc refers me to either a Beverly Hills or Century City urologist-fertility specialist. They turn out to require an office visit starting with a $400 phone consult to come up with a treatment plan (and there are no promises you’ll get one.) Meanwhile, I find sources online, especially a comparative study of treatments. (These were funded in an effort to test use of testosterone itself as a male contraceptive; it does quite reliably induce temporary sterility, but they were doing baseline studies to see what (patentable, easier, more targeted) molecules they might find.)

So the treatment is: 1) Stop T, wait. Most men restart sperm production in a year. 2) Accelerate recovery using the same kind of hormonal manipulation used on egg donors. Notably, clomiphene citrate (cheap, easy to get) and injections of hCG (expensive, hard to get, subject of a silly diet craze as well.) I can find bootleg sources of both but it would sure be nice if our legitimate system wasn’t such a clusterfuck. Something like 80% of the men in studies recover in 2-3 months (but they were on average much younger.)

So I called the most prominent of three Eisenhower medical group urologists. No appt until Feb (7 months.) Not useful.

It’s amusing that all healthcare types think the patient is central and should have informed consent, but then make it an exercise in paying gatekeepers and wasting time no matter how informed the patient might be. I’ve had a few doctors with enough experience and intuition that they can quickly judge and decide matters. But much more commonly I can research the narrow subject of my rare condition and know as much or more about it than they do in a day or two. But thousands of dollars and hours of wasted time are the price of lost freedom. The rest of us must pay in time and $ so that stupid people can be protected from their mistakes.

BTW, there are websites where you can order up lab tests from Labcorp and Quest for cash prices. The full battery of STD and other blood tests the IVF doc wants costs about $450 cash there. Given only a few of these would be covered under our grossly expensive ACA-monopoly insurance policy, may just pay cash. I can’t get my primary care doc’s staff to do anything. Tomorrow I see my doctor and four tests that were supposed to be done for a 1/18 appt I had to cancel have never been set up so we won’t be able to discuss results as is their plan; Eisenhower is a nonprofit run by doctors and they are trying to make all patients over 40 come in three times a year and constantly undergo screening for bp and cholesterol, pushing everyone onto medications and keeping those office visits (and revenue) coming in. “Nonprofit” doesn’t mean no one is making money.

In hindsight, it was a mistake not to go to the Beverly Hills fertility specialist. My primary care doctor helpfully prescribed the hCG (available from a local compounding pharmacy — a few months later, the FDA forbid such compounding, and after that I had to use GoodRx coupons to get it from a regular pharmacy: both products start from encapsulated powder which has to be mixed with distilled water, so what the compounding pharmacist used to do, the patient now has to do. The injections are simple — subcutaneous (just under the skin, into a fat layer) and water-based so small-needle insulin syringes can be used. My doctor had me on 25 ml every other day, which seemed to be enough.

The full regimen I went on included more drugs (oral):

    Clomiphene, 50 mg / every other day – inhibits the feedback loop that suppresses natural testosterone. It’s a “selective estrogen receptor modulator (SERM)”

    Anastrazole, 1 mg /day – suppresses estrogen production via aromatase inhibition.

    hCG, .25 ml / every other day – chemically similar to luteinizing hormone, so shields testosterone and sperm production from negative feedback loops. Restored my levels of FSH (follicle-stimulating hormone) to normal in six months.

To cut to the chase, I ceased t-supplementation in early August and after failing to fertilize a single egg from the first batch, went to the Beverly Hills fertility guy (via Zoom, since the pandemic caused him to waive his usual requirement of examining new patients in person.) That world-renowned expert recommended what I was already taking, plus use of a Zymot sperm-sorting chip to select the best spermatozoa for ICSI (more about that in a later post.) We had to wait months for our egg donor’s second donation before trying again, but this time it worked — more than a year since I started rehab, we had four new frozen embryos (my children-to-be) that passed all screenings.

The graph showing my hormonal recovery:

FSH and T graph 5-13-20 showing recovery to normal levels

FSH and T recovery graph

IVF Journey — Donor Eggs
Egg production in the human ovary

Oocytes and egg production

[cont’d from How our IVF Journey Began]

While we waited for husband’s second attempt at providing sperm, we started looking for a good egg donor. It’s kind of the Wild West, with little regulation and some donor agencies placing ads in college newspaper to entice young woe=men with promises of large fees (as much as $100K!) for “suitable” donors — there is great demand for certified excellent donors, with advanced degrees, Ivy League schools, being Asian (much IVF business in LA serves Chinese clients, who want a baby with US citizenship but are wary of having a child who doesn’t appear “different.”) The LA IVF clinics do a thriving business with the Chinese who have their IVF babies born in LA for US citizenship. Not to mention the thousands of Chinese birthmothers who fly in for a few week stay to have their babies here. Few countries would allow a mother to fly in as a tourist to have their children with automatic citizenship; various moves to limit birth citizenship in the US to those who have a permanent tie to the US (legal residence, employment in the US, etc.) have been floated but are quickly shot down as “xenophobic.”

IVF was pioneered and perfected in several countries, but LA has become a world center for intended parents from around the world(from Vogue): How California Became the World’s Fertility Treatment Destination “For a growing number of women worldwide, the often emotional struggle to get pregnant is leading to Los Angeles. With its top-notch tech and liberal laws, is California changing the business of giving birth?” Yes, it did.

July 4 2019

Spent the morning looking through egg donor listings. One was trying to impress with her educational accomplishments but used an apostrophe wrong — “Not today, Satan!”
Most impressive so far — young lady who grew up in the Central Valley / Fresno area, first to go to college, now at UCLA grad school in neuroscience, statistics. No glamour shot with eye makeup like most, no desire to stay in touch, cites Steven Pinker as her fave author. Swoon!

That egg donor did not pass further screening. We were looking for someone as intelligent as we are, to give the children the best chance at good genetics for learning and accomplishment. The egg donor sites are full of heavily-made-up and processed young ladies who pick glamour shots to represent themselves; Instagram and the like have trained young women to strive for this look. It’s a bit offputting.

July 12 2019

There are apparently 500,000 frozen embryos waiting for disposition in the US. This article jumps off a celebrity court battle to make some ethical comments: [Sofia Vergara’s Embryos Join Father Nick Loeb In Suing Her To Let Them Live]

Some Hollywood women have their children by surrogacy to avoid career interruption (they are paid enough so I hiatus results in lost income and career damage.) But the Intended Parents [IP] are treated the same in Family Court, so such children are given child support from the wealthier partner. A situation with divorce followed by one parent disowning the embryos and another wanting them decanted gets into ugly territory.

Note also the egg freezing that young career women are advised to do if they want to have children in later life. Eggs begin to deteriorate after the age of 30, so women, correctly believing they will be viewed as less serious and reliable if they pause to have children, postpone becoming mothers for a more convenient time. By waiting until they are well-established to bear a child, they can avoid loss of career momentum before they have established themselves. You can have your cake and eat it too by freezing your eggs when they are most viable and bearing them much later — much less risky than waiting to 45 or 50 to try for natural children. Many older couples end up doing IVF because of male factor infertility or poor quality eggs.

July 17 2019

The IVF clinic had a notary on staff to help you notarize a flurry of legal documents via Skype. 75 pages of legal and disclosures, initial every paragraph, sign about 10 times.
Very Brave New World. Reminds me of Heinlein’s The Door Into Summer with the frozen lives and contracts at the cryosleep place. Was strange visiting westside LA and seeing all the street names Heinlein had borrowed for characters, like Sawtelle. I remember them all from when I was 12.
— quote —
We understand that under California law our unused cryopreserved embryos, eggs and sperm are our property, subject to disposition under California Probate Code §6400 et seq., and California Family Code §2010, and that we jointly have the right to exercise decisional control over the disposition of our frozen embryos, eggs and/or sperm. We further understand that this Agreement is required to be provided to all IVF patients by CFP pursuant to California Health and Safety Code §125315, and that the possible choices for disposition of our embryos are dictated by that statute. We also understand that the disposition choices for our frozen eggs and/or sperm, although not specifically referred to in California Health and Safety Code §125315, will be treated in the exact same manner as our frozen embryos. We further understand that the legal status of cryopreserved embryos, eggs and/or sperm, and the use, custody, and ownership of said embryos, eggs and/or sperm is complex and unsettled in the law. We are making the choices indicated herein to avoid the complexities and ambiguities inherent in the process, and to ensure that our joint written directives regarding the disposition of our unused cryopreserved embryos, eggs and/or sperm are followed.

There are also many contracts required for egg donor agencies and donors, gestational carriers and their agents, escrow companies (where intended parents deposit what is promised to carriers and donors so that they can proceed without worry someone won’t be able to pay as promised.)

July 22 2019

Another fresh new experience – went to an IVF clinic in Palm Springs to have a sperm count done. 11 AM is too early for this kind of thing, and a white room with a foot-thick selection of reading material (on top: Hustler. It’s still a thing?) is hardly romantic. We survived, though. Results to be faxed to LA doc tonight or tomorrow. BTW, I tried to schedule this through my official doctor, and it took them days and they only found a LabCorp place in Riverside, an hour drive each way. This place I found myself was $140 cash each and you got an appointment the next business day. I’m guessing the insurance route would have cost $300.

Other patients there for IVF were about half foreign. Not obvious where from, but not Chinese. One couple was speaking Italian.

We found a new egg donor candidate at one of the more mercenary agencies. She was 29, had an impressive background at a well-known B-level STEM college, and was in mid-career in the video game industry. She was motivated by a desire to help people without herself having to go on hiatus before she was secure, plus of course the fee for her egg donation. We had a Zoom call with new egg donor (who lives in another state.) She was extremely impressive on call, polished and intelligent. Looking like a great choice.

How our IVF Journey Began

I’ll try to use my personal journal to proceed in chronological order — we began knowing little about IVF, and research took some time.

I haven’t made much of it here, but my husband of 15 years is a guy, which I think, unless the PC terminology has changed recently, makes us a gay couple having children. Our new neighborhood of 60 or so houses has two other gay couples with children already in residence, so we’re not unusual. This street has many children already and more on the way since the schools are considered top-notch and we’re within easy commuting distance of San Diego’s high-tech employers.

The first reason we started to think about kids was the experience of raising two puppies. I haven’t had a pet since I was five, and the sense of taking care of and training a young animal is similar enough to raising children that I realized we would enjoy it (after the initial unpleasantness!). We had both had some desire for kids earlier in our lives, but the hurdles then seemed insurmountable and of course we were busy with work.

First entry from my personal journal, June 5, 2019:

I checked again to see if it’s too late for us to have a kid of our own. No *outright* reason not to, except the $150-200K to order up a donor egg, IVF, and surrogate mother, *and* I’d be feeble long before the child left for college. Not that upper class families shrunk from sending their kids to boarding school at 12. If you’re not independent enough by then, you soon will be. 🙂 Kid would get a nice trust fund and of course lots of attention. I can’t get anything done anyway, might as well nurture, no?

As of two years ago, we were both retired from normal full-time work, so it now seemed practical to handle the baby years. Half the stamina, but two people home most of the time!

I found some online sources, and a surrogacy agency supportive of gay couples (and run by two gay dads.) Near enough, in LA, so I talked to them and they referred us to a West LA IVF doctor to get started.

July 2 2019:

I was going to write something about our Skype meeting with the LA baby consultants coming up later, but running out of time. We’re far from designer babies, but the current crude technology and regulation does let you 1) seek out and pay a premium for the egg donor with rare characteristics (it’s a hoot that Ivy League Asian women are the gold standard for certain seekers and so get the highest payments), and 2) you can’t do gene tests of the eggs yet without damaging them, but you can test embryos by removing a few pre-placental cells early, seemingly doing no harm at that stage. By choosing those without gross abnormalities you can reduce miscarriages and select for sex. We might try for twins, actually, for that 1.5x the costs for 1 and the sibling experience….

[Husband] is onboard. Which suddenly changes our plans for later life. Sort of like a Hail Mary pass on your last down, I’m starting to downgrade my expectations for my own work to put effort into the fresh new entrants in the race. They, at least, won’t be crippled by a lack of early support.

We found out later that multi-embryo surrogacy (hoping to improve chances of having one, but often ending up with twins) is no longer considered wise; this is partly because the technology has improved so 50-60% of screened and well-timed implantations result in a healthy birth, just as high as for multi-embryo attempts which risk twins and complications. Our meticulous IVF doctor won’t do multis anymore. This became the consensus in the last five years or so. Other changes in the technology made it just as safe to freeze embryos after 5-7 days of development, which allows the implantation at the perfect time for success. So our process was 1) freeze sperm, 2) have the egg donor provide eggs, and 3) fertilize eggs with sperm via ICSI (which is now standard for late-in-life IVF — ICSI is “intracytoplasmic sperm injection,” where the lucky sperm is injected into the egg by a very fine needle.) The resulting zygotes are cultured and observed for 5-7 days, graded on an A-F scale for viability, and genetically tested to improve likelihood of a successful birth.

micorphoto of needle injecting egg with a spermatozoa]

Needle injecting a single spermatozoa into an egg.

In hindsight, the natural process for prime-aged young people is error-prone and hit-or-miss, resulting in early miscarriages and other bad things. Nature’s Way includes Nature’s Punishments. Typically the natural way is to try many times and succeed enough to keep the species going, and the winnowing process sifts out most”tries” — either the egg doesn’t get fertilized, or if fertilized doesn’t implant, or if implanted doesn’t develop properly, and is expelled via silent miscarriage before the mother is even aware of being pregnant, or develops long enough for underlying defects to cause a later miscarriage. The latter feel like tragic losses, but it’s part of the natural process and no one’s fault.

We had both done sperm tests. [Husband] did fine, I did not — my test report was stamped “azoospermia,” which means zero spermatozoa in the sample. Turns out my decade of testosterone supplementation (“exogenous testosterone”) was the cause; complex feedback loops shut down both endogenous production of T and sperm production, which made drug companies run studies of such sufferers hoping to find the male Pill. No such drugs were found, but the cause and recovery are thoroughly documented in medical journals.

So I was hoping I could catch up with time and treatment — younger men in the same boat can have fertility restored in 3-6 months, but as the doctor warned me, that doesn’t mean an old man can recover as quickly, or at all.

[Husband] went ahead and started the process by driving to LA to deposit his contribution.

Aug 8 2019:

Project stall: [Husband] drove all the way to West LA (2+ hours) to make a 10:30 AM appointment to give a sperm sample for freezing. Two hours later, he’s told “we need more than that, could you come back next week?” The legally-required FDA paperwork only lasts 7 days so you can’t wait longer or you have to pay for it again (several hundred dollars?) So he goes back Tuesday leaving here at 6 AM. At least the doc complimented him on his youthful motility.

Meanwhile, I’m just working on producing a gamete or two. Tap tap tap.

[to be continued: “How We Did It,” in installments.]