- Area: Science
- Program: Chemistry
- Type of Writing: Science (writing about science for professional or non-science readers)
- Course Level: 1000
- English Speaking Nativeness: Native
- Year: 2017
- Paper ID: S.C.S.1.N.2.5
Chemistry in My Life – In-Vitro Fertilization
Technically speaking, In-vitro fertilization is “an assisted reproductive technology (ART) commonly referred to as IVF. IVF is the process of fertilization by extracting eggs, retrieving a sperm sample, and then manually combining an egg and sperm in a laboratory dish (“In Vitro Fertilization (IVF): Side Effects and Risks” 2017)”. However, if you ask the couples who seek this and other assisted reproductive technologies, IVF is really so much more than that. For many, it is what they believe will help them finally complete their little family after so many years of trying naturally. For some, they are carriers of a genetic defect they do not wish to risk passing down to their children. For others, it is their only hope of having any children at all.
The history of assisted reproductive technologies began in the middle of the 19th century when J. Marion Sims, the chief doctor of the Women’s Hospital in New York, began to perform both gynecological surgeries and artificial insemination in an effort to help his patients achieve pregnancy (PBS “Test-Tube Babies” 2014). Fast forward to 1944, some 90 years later, scientists John Rock and Miriam Menkin successfully fertilize four ova in their lab after over a hundred failed attempts (PBS “Test-Tube Babies” 2014). Later on, in 1975, two British scientists, physiologist Robert Edwards and gynecologist Patrick Steptoe, have the first documented successful IVF pregnancy but the resulting pregnancy is ectopic (PBS “Test-Tube Babies” 2014), which means it implanted somewhere besides the uterus, and the baby is lost. Finally, in late 1977, Britain gets everything right and John and Lesley Brown get pregnant with their daughter thanks to the help of Steptoe and his IVF methods (PBS “Test-Tube Babies” 2014). Since then, IVF has only gained in popularity and now there are more than 5 million “test-tube babies” living in the world (Gallagher 2012).
My husband and I decided to do IVF because we have been unsuccessful on our own for so long. We do have a wonderful and amazing 5-year old son that we conceived naturally, and my husband does have a 10-year old son from his prior marriage, so we knew that we are both capable of reproduction. However, my husband is a little bit older than me and male fertility, which remains mostly in-tact throughout their lives, can begin to decline once a man hits about 40 years old. I, on the other hand, am 32 and likely have scaring or a blockage in my tubes due to a chlamydia infection that went unnoticed and untreated for months when I was 19 years old. According to the CDC, chlamydia is sexually transmitted bacterial infection that can put women at an increased risk of ectopic pregnancy and infertility later in life, well after the infection has been cured (CDC 2016). It is because of this fact that I believe chlamydia is what caused my ectopic pregnancy in late 2010, roughly 4 months before my husband and I successfully conceived our son in early 2011.
We first called Utah Fertility Center in the middle of 2015, but we were put off at the potential cost of the whole thing, which could top $20,000 if we decided to do genetic testing on the embryos. We decided to wait and save up money and continue to keep trying naturally. If not for my husband’s extremely low sperm count, we would have considered opting for intrauterine insemination (IUI), which is basically just the clinic using a catheter to place washed sperm in the uterus so that it doesn’t have so far to travel. While IUI is substantially cheaper than IVF ($1,000 vs $20,000) and is also much less invasive, the pregnancy and live birth rates that result are less encouraging.
We got our break in early 2016 when the clinic called to follow up and let us know that they were participating in a nationwide study on the connection between two different ovarian stimulation medications, Gonal-F and Menopur, and the quality of the embryos produced. The best thing about this was the cost, which would be $4,000 for everything. This included the medications, monitoring, procedures, and genetic testing (including gender) on all the embryos. We got the soonest appointment we could and began the process to determine our eligibility for the study. The criteria, which I met, were explained to me as follows: being between 21 and 35 years old; have a body mass index (BMI) between 18-30kg/m2; have a regular menstrual cycle of 21 to 45 days; have a history of infertility and desire pregnancy; have a good ovarian reserve with an Anti-Mullerian Hormone (AMH) level ≥5 (ng/mL); and do not have a history of endometriosis stage III-IV, recurrent miscarriage, and previous poor response to a controlled ovarian stimulation cycle (HRC Fertility 2016).
I also had to endure what they call a “water ultrasound”. It is performed by the nurse practitioner and it is used to diagnose any abnormalities with the uterus. It involves inserting a small catheter through the cervix and into the uterus so that a small amount of saline can be injected in. The procedure is quick but not painless. I experienced what I would consider a moderate amount of pain during the procedure, and then cramping for about the following four hours.
It took a few days to get my AMH test result back, but once it did the study coordinator from Utah Fertility Center called to tell me we had been officially accepted into the study. This was an enormous relief. She told me I should call them back on Day 1 of my next menstrual cycle so that they could get me started on birth control. I took the birth control for about 18 days and then was instructed to stop so that my next menstrual cycle would start. This is done so that the doctor has more control over the timing of all the events in my cycle. Once I began menstruating, they did my trans-vaginal baseline ultrasound and assigned me my stimulation medication.
This is also the point at which I learned that I would not be able to discuss very much with the study coordinator or the clinical staff who would be guiding me through the next month of this process. Due to the nature of this study, I was cautioned not to share too much information about symptoms or medication side effects otherwise I risked being ejected from it. While my husband and I were saving over $15,000 by participating, we were missing out on the comfort of in-depth feedback and personalized care that comes with being a non-study client of the fertility clinic. I would still be able to share my concerns with my doctor, but I would not be able to talk about much of anything with the nurses and other medical staff who I would be spending the most time with. The prospect of this made me really nervous. I trusted (and still trust) my doctor, but I would only be seeing her once or twice during the course of the study.
The medication chosen for me was Gonal-F, which happened to come in a convenient readily injectable “pen”. Due to my age and ovarian reserve, my reproductive endocrinologist (RE) chose to put me on the lowest dose allowed for the study. There is a moderate risk of ovarian hyper-stimulation with these drugs, so she was trying to help me minimize my risk. Using it was easy once I got the hang of selecting the correct dosage. The needle was very short and it was not uncomfortable to inject the medication into my abdomen. However, I do remember feeling a slight nervous hot flash the first few times I had to inject it, but that subsided once my brain got used to the idea of using the medication. I was told later that, had I been assigned the other medication, Menopur, I would have had to mix up my own medication prior to injection. Naturally, I was relieved to have been assigned the easier option.
According to the non-profit Canadian cheminformatics website DrugBank, Gonal-F is, “a human follicle stimulating hormone (FSH) preparation of recombinant DNA origin, which consists of two non-covalently linked, non-identical glycoproteins designated as the alpha- and beta- subunits. The alpha- and beta- subunits have 92 and 111 amino acids (“Follitropin beta” 2005).” And, during my research for this paper I learned that it is produced from genetically engineered Chinese hamster cell lines (“Follitropin beta” 2005). The picture on the left is a rendering of Gonal-F’s protein structure. The protein chemical formula for Gonal-F is C975H1513N267O304S26 (“Follitropin beta” 2005).
Menopur, on the other hand, “contains follicle stimulating hormone (FSH) and luteinizing hormone (LH) purified from the urine of postmenopausal women (“Menotropins” 2005).” It’s protein chemical formula is C1014H1609N287O294S27 (“Menotropins” 2005). Despite their structural differences, both Menopor and Gonal-F are classified as carboxylic acids and they have the same melting point, which is 55ºC (“Menotropins” 2005).
During the course of my ovarian stimulation, I had many more transvaginal ultrasounds and blood draws. The ultrasounds were to monitor how large my ovary follicles were growing and how many were nearing maturation for retrieval. I was informed before beginning the study that they would be taking over 8oz of my blood for the testing required for the study, and that turned out to be true. It didn’t take long for my arms to get sore. Also, I was required to drive to their Pleasant Grove office for each ultrasound and blood draw. I live in Holladay and was taking classes at the Taylorsville campus of Salt Lake Community College, so this was more than just a minor inconvenience.
I responded very well to the low doses of Gonal-F and, fortunately, experienced only mild side-effects. After a week and a half of stimulation medication, they gave me the instructions on administering a human chorionic gonadotropin (HCG) shot, which absolutely has to be given precisely 36 hours before oocyte (egg) retrieval. HCG is a protein produced by the placenta after implantation and has a protein chemical formula of C1105H1770N318O336S26 (“Chorionic Gonadotropin (Recombinant)” 2005). Also, HCG is classified as a peptide and targets both luteinizing hormone receptors and G-Protein coupled receptors (“Chorionic Gonadotropin (Recombinant)” 2005).
The next step for me was the oocyte retrieval. My husband and I had to wake up around 5:00 AM the morning of the procedure so that we could make it to the Pleasant Grove clinic by 6:15 AM. Because the retrieval is done under general anesthesia, I was not able to eat anything after midnight the night before. If I had to guess (I don’t really remember), I’d say I was probably unpleasant on the drive down due to the combination of sleepiness, hunger, and nerves.
Once we arrived at the clinic, we waited for what seemed like an eternity before we were called back into the procedure room. I was asked to undress from the waist down and put a hospital gown on over my shirt. A nurse started my IV and got me comfortably situated in the stirrups and then took my husband back out into the waiting room. I asked what they would be giving me to sedate me and I was told Propofol. Propofol is a Benzenoid, which means it contains a benzene ring, has a chemical formula of C12H18O, and is also known as 2,6-Diisopropylphenol (“Propofol” 2005). After my brief conversation with nurse, the anesthesiologist arrived and the next thing I remember is him walking me from the procedure room to the recovery room. I also vaguely recall seeing blood running down between my legs and I remember I was confused by it. I realized then that no one had told me how exactly the doctor was going to retrieve the eggs. I assume partial responsibility because I never asked and I never looked it up. It did not occur to me that my RE would be using a long needle to go through the walls of my vagina in order to remove the eggs. The method for the procedure wouldn’t have had any influence on my willingness to go through with it all, but I do regret not being better informed prior to the experience.
My husband was brought in immediately after I got to the recovery room and he helped me get cleaned up and dressed while we waited for the doctor to tell us how many oocytes were retrieved. Everyone, doctor included, was surprised that we got a total of 23 oocytes. This number was much higher than we had planned and we were very excited.
During the weeks leading up to the egg retrieval, my husband had given two sperm samples, so the next step for all of our genetic material was intracytoplasmic sperm injection or ICSI. According to the Human Fertilization & Embryology Authority, “ICSI differs from conventional in vitro fertilization (IVF) in that the embryologist selects a single sperm to be injected directly into an egg, instead of fertilization taking place in a dish where many sperm are placed near an egg (HFEA.GOV.UK)”. Basically, they put the sperm through an obstacle course of sorts and choose only the strongest to be injected into the oocyte. After injecting all the eggs, they sit in an incubator to mature for five days until they are ready to be either transferred into the uterus or cryogenically preserved.
Only 18 of our eggs fertilized successfully and then after that only 11 made it to Day 5 of maturation. We did get genetic testing done on all the Day 5 embryos, but we were not going to find out if an abnormal embryo was transferred until after the results came back, which would be about a week after the embryo transfer procedure was completed. The transfer itself was very quick and totally painless. It involved only a thin uterine catheter and that went in easy due to how relaxed I was (I was given a single valium to take prior to the transfer to help me calm my nerves). Upon returning home, I laid in bed for the better part of two days, per my RE’s instructions. After those two days were up, we just needed to wait.
The following week we got back our genetic testing results and found out they had transferred a genetically normal male embryo. Out of the rest of the embryos, we had two that were abnormal and two that came back as “Nonconcurrent”. My RE explained nonconcurrent meant they simply did not get enough material to test, thus could not give a definitive answer. I don’t know if that means they’d be willing to transfer them in the future if we wanted them to, or if I should just consider them abnormal.
After one more week, which seemed like the longest 7 days of my life, we found out that our cycle was unsuccessful. My serum HCG level, which is used to detect and track pregnancy progression, was at 2 mIU/ml. We were devastated but decided to jump right back into another IVF cycle. This time would be markedly different, though, because cycles that use thawed (previously frozen) embryos require even more injectable medications than “fresh” cycles. Frozen cycles require a combination of estrogen and progesterone injections in the days leading up to the embryo transfer and those shots, plus a nightly vaginal progesterone suppository, continue until the end of the 10th week of pregnancy.
The cost of the frozen cycle was $2,700 and, because I was no longer in the study, it came with all the medical advice and feedback I could hope for. I no longer needed to watch what I said to anyone. It was seriously such a relief to be able to discuss everything with the medical staff and my doctor.
The process for the cycle started the same way my previous cycle did – with Ortho Tri Cyclin, also known as Ethinyl Estradiol, to help regulate my cycle more efficiently before starting on my medications. Ethinyl Estradiol is a lipid and has the chemical formula C20H24O2 (“Ethinyl Estradiol” 2005). On the sixth day of my cycle, they started me on my estradiol valerate injections, which only needed to be administered twice a week – on Tuesday’s and Friday’s. These injections would be very different from the injections I did during my ovarian stimulation cycle because they needed to be administered in my lower back/upper buttocks area. I had the nurse from the clinic draw big circles around the desired injection locations on each side so that I didn’t put inject it in an undesirable location. My husband redrew these Sharpie marker circles many times throughout following weeks.
Estradiol comes in many forms and, through the research of this paper, I have learned that the particular type of estradiol I was injecting is a salt form of the original estradiol, (8R,9S,13S,14S,17S)-13-methyl-6,7,8,9,11,12,14,15,16,17-decahydrocyclopenta[a]phenanthrene-3,17-diol (“Estradiol”). The form I was injecting is identified by it’s IUPAC name is [(8R,9S,13S,14S,17S)-3-hydroxy-13-methyl-6,7,8,9,11,12,14,15,16,17-decahydrocyclopenta[a]phenanthren-17-yl] pentanoate (“Estradiol Valerate”), and only has an extra pentanoate ion attached to the original structure.
Next up for injections was the progesterone-in-oil, which is time consuming to type out repeatedly so it is generally shortened to simply “PIO”. These were, by far, the most uncomfortable injections involved in the whole process. Not only were they uncomfortable, but they were to be required once a day, every day, until the pregnancy reached the end of the 10th week. With the estradiol the needles were smaller, the liquid not very viscous, and each injection was only 0.15mL. The PIO, on the other hand, was very viscous, given in full 1mL doses, and done through an uncomfortable large needle. The medical staff compared the consistency of room temperature PIO to warm peanut butter. The injections left my backside so sore that it hurt to walk. After over a week in pain, I spent some time online reading tips from other IVF patients and discovered that massaging my back with a hot heating pad after each injection could greatly alleviate the pain and would help rid my back of the uncomfortable lumps forming at each injection site.
Progesterone, which has the chemical formula C21H30O2 (“Progesterone”), is arguably the most important hormone involved in pregnancy. It is a steroid and it is secreted by both the corpus luteum and the placenta. It is needed for implantation of the embryo, pregnancy retention, and it also aids in development of mammary tissue, which is needed to produce breastmilk (“Progesterone”). It’s IUPAC name is (8S,9S,10R,13S,14S,17S)-17-acetyl-10,13-dimethyl-1,2,6,7,8,9,11,12,14,15,16,17-dodecahydrocyclopenta[a]phenanthren-3-one. My doctor explained to me that the reason why so much progesterone was needed throughout the process was that it has a very short half-life and the pregnancy will not develop without it. With a frozen cycle, the body does not produce progesterone because it is not producing an egg to be fertilized, so a nearly constant stream of lipid-bound injectable progesterone is required.
The embryo transfer process was the same for me as it was with the previous cycle, only this time I needed vaginal progesterone suppositories every night before bed. These are chemically the same as regular progesterone, but they are compounded into a creamy mixture that forms into an easily inserted capsule.
Fast forward two weeks later and I got the call informing me that this cycle was also unsuccessful. My RE had us schedule a time to come in and discuss our options. In her words, there was no logical reason why this cycle would have failed given my age and the quality of the embryo. We went in and decided that we would take a break for one natural menstrual cycle before trying on last time. We also decided that we would do an endometrial biopsy and add an application, or “wash”, of Neupogen to my uterus before our next embryo transfer.
Neupogen, or filgrastim, was originally marketed to treat neutropenia caused by chemotherapy, but in my case was used to potentially replace a chemical that is sometimes not properly produced in the uterus. My RE explained that it was basically just an amino acid and that there is very little research on how it relates to pregnancy but that it has been known to act as a way to get embryos to “stick” and implant. The protein structure of filgrastim is amazingly complex (see image at right), it has many visible alpha-helices and beta-sheets. Filgrastim has the protein chemical formula C845H1343N223O243S9, and consists of 175 amino acid residues (“Filgrastim” 2005). This medicine is not cheap, either. The pharmacy charged us almost $300 for a little 300mcg vial.
During our time off, my body had a hard time trying to get back into a normal menstrual pattern so I ended up with a frustrating 55-day cycle. At day 44, I spoke with my doctor and she prescribed me a 10-day course of medroxyprogesterone in an effort to “reset” my cycle. It worked well, and I started my period one day after ending the medication. Medroxyprogesterone is a man-made variant of regular human progesterone and is also known as 17α-hydroxy-6α-methylprogesterone acetate (“Medroxyprogesterone acetate” 2005). It has the chemical formula C24H34O4 (“Medroxyprogesterone acetate” 2005), which is very similar to that of regular progesterone.
We got our endometrial biopsy done, which was far more painful than I could ever had imagined, and got our Neupogen “wash” in the week leading up to our 3rd embryo transfer. Aside from those two extra things, the protocol was exactly the same as our 2nd transfer. And, just like our 2nd transfer, it was also unsuccessful. At that point, we decided to give it a very long (if not permanent) break.
The effects of these medications on my body is still an issue. While I only weigh about 2lbs more than I did prior to treatment, my body fat is distributed differently and none of my pre-IVF pants (save the leggings/athletic/athleisure pants) still fit me. My thighs got bigger and my waistline now carries so much more padding that I can no longer even zip or button my pre-IVF jeans. During this process I subjected my body to seven medications that I would not otherwise have used.
For all of our cycles, we did a single embryo transfer. With our first cycle, it was part of the study protocol, but with the two additional cycles, we opted due to my aversion to having twins. Not only are twin pregnancies typically more difficult than singleton pregnancies, but it’s been found that there is a higher risk of autism in the twins (or triplets, etc) when they are born via IVF.
I would like to say that I have not endured many lasting effects of IVF on my mental health, but I do still feel a twinge of jealousy when I see women who are pregnant or who are carrying around their new babies. I also know that there are so many other out there who struggle with infertility like myself, but that doesn’t really make it much easier for me.
I was happy to write this paper because infertility is a painful, sensitive subject for many but I think that knowing you’re not alone can sometimes ease the burden. My husband and I have since decided that we will try two more times using the help of assisted reproductive technologies. This fall, providing my husband’s sperm count has improved enough, we will first try IUI. If that doesn’t work or if we are unable due to low sperm count, I have agreed to do one more frozen embryo transfer. This time, however, we will do our next two best embryos. I run the risk of a twin pregnancy, but I will also have far greater chances of even just a singleton pregnancy. I think I am at a point in my fertility journey that I am prepared to accept whatever may happen and am looking forward to moving on with my life, no matter what that may mean.
KEYWORDS: infertility, medications
“Chlamydia – CDC Fact Sheet.” Centers for Disease Control and Prevention, Centers for Disease Control and Prevention, 19 May 2016, www.cdc.gov/std/chlamydia/stdfact-chlamydia.htm. Accessed 1 Apr. 2017.
“Chorionic Gonadotropin (Recombinant).” Chorionic Gonadotropin, DrugBank, 13 June 2005, www.drugbank.ca/drugs/DB00097. Accessed 1 Apr. 2017.
“Estradiol.” National Center for Biotechnology Information. PubChem Compound Database, U.S. National Library of Medicine, pubchem.ncbi.nlm.nih.gov/compound/5757. Accessed 1 Apr. 2017.
“Estradiol Valerate.” National Center for Biotechnology Information. PubChem Compound Database, U.S. National Library of Medicine, pubchem.ncbi.nlm.nih.gov/compound/13791. Accessed 1 Apr. 2017.
“Ethinyl Estradiol.” Ethinyl Estradiol, DrugBank, 13 June 2005, www.drugbank.ca/drugs/DB00977. Accessed 1 Apr. 2017.
“Filgrastim.” Filgrastim, DrugBank, 13 June 2005, www.drugbank.ca/drugs/DB00099. Accessed 1 Apr. 2017.
“Follitropin beta.” Follitropin Beta, DrugBank, 13 June 2005, www.drugbank.ca/drugs/DB00066. Accessed 1 Apr. 2017.
Gallagher, James. “Five millionth ‘Test tube baby’.” BBC News, BBC, 2 July 2012, www.bbc.com/news/health-18649582. Accessed 1 Apr. 2017.
“In Vitro Fertilization (IVF): Side Effects and Risks.” American Pregnancy Association, 12 Mar. 2017, americanpregnancy.org/infertility/in-vitro-fertilization/. Accessed 1 Apr. 2017.
“Medroxyprogesterone acetate.” Medroxyprogesterone acetate, DrugBank, 13 June 2005, www.drugbank.ca/drugs/DB00603. Accessed 1 Apr. 2017.
“Menotropins.” Menotropins, DrugBank, 13 June 2005, www.drugbank.ca/drugs/DB00032. Accessed 1 Apr. 2017.
“Progesterone.” National Center for Biotechnology Information. PubChem Compound Database, U.S. National Library of Medicine, pubchem.ncbi.nlm.nih.gov/compound/5994. Accessed 1 Apr. 2017.
“Propofol.” Propofol, DrugBank, 13 June 2005, www.drugbank.ca/drugs/DB00818. Accessed 1 Apr. 2017.
“Test-Tube Babies.” American Experience, Public Broadcasting Service, www.pbs.org/wgbh/americanexperience/features/timeline/babies/. Accessed 1 Apr. 2017.
“The Megaset-HR study is currently seeking patients to participate in a fertility research study designed to compare two medications used for controlled ovarian stimulation (COS), in in vitro fertilization (IVF) cycles.” MEGASET-HR Study, www.havingbabies.com/Megaset-Study/. Accessed 1 Apr. 2017.