The Money Study

OK this it IT.. The Money Study. The Money Study is officially called “Pregnancy and Live Birth In Women With Pathogenic LHCGR Variants Using Their Own Oocytes.” This article was written by seventeen scientists doing advanced embryology work in China. It was published in December 2019.

This study followed three women who were ages 28, 38, and 32. All three had sought reproductive assistance and could produce a low quantity of oocytes, yet the quality of their eggs was also low and none could produce a good embryo. The women had grown up having infrequent menstrual periods, all three had cysts on their ovaries, and all three were diagnosed with having an abnormal genetic variation of a receptor called the luteinizing hormone /chorionic gonadotropin receptor, for short called “LHCGR.” This genetic mutation proves critical to fertility, because LHCGR is involved in many pathways, including ovulation, implantation, and early pregnancy. So far, there are ten mutations that we know for LHCGR in women. Until this money study, women with LHCGR mutations were thought to have zero chance of having their own baby. And that’s what makes this study so awesome - after the intervention, all three women made top quality embryos and two had babies!

Before going into how that happened, in this pharmacist’s opinion, it’s worth knowing more about the drugs that improved the quality of those oocytes, which in IVF land are known as the “trigger meds.” 

The first trigger med used in this study was human chorionic gonadotropin, which for short is known as hCG. Naturally produced in the body, hCG is important for creating and maintaining pregnancy in the early stages. There are two hCG products being used in the U.S. - one is Pregnyl, which is made from the urine of pregnant women  and the other is Ovidrel, which is made from hamster ovary cells. Studies have shown that both types of hCG are equally effective at helping oocytes to mature. hCG is typically given 36 hours before retrieval because that is TYPICALLY the best time to ensure that the eggs are ready (but not in the case in this study). 

Quick soapbox: In recent years, there has been buzz on the internet to buy homeopathic hCG for weight loss. In case you are tempted to substitute homeopathic hCG for a prescription of hCG from your clinic, please don’t do this because 1) hCG hasn’t been shown to work in weight loss and 2) this wouldn’t be the hCG you need to successfully trigger ovulation. 

Off the soapbox. Moving on. The second type of trigger med is the gonadotropin releasing hormone agonist called GNRHa. That will take awhile to say, so let’s call it the Grn-ha. There are many different GNRHas, including leuprolide (known by its brand name of Lupr   on in the U.S.), buserelin, and triptorelin. Triptorelin was the trigger med used in this money study. This class of drugs is considered safer than hCG for women who are at high risk of ovarian hyperstimulation, and sometimes for that reason it is given alone. If the risk for hyperstimulation is low, there can be an advantage to giving a GNRHa with HCG since they work in different ways to convince oocytes to mature - the the GRNHas tell the pituitary gland to release luteinizing hormone that act on the ovaries, while HCG works on the LHCGR receptor.  

Speaking of LHCGR receptor, let’s now return to the study. Here’s what happened. 

T = Triptorelin, hCG = human chorionic gonadotropin

During their first rounds of IVF, these women’s oocytes had responded very timidly and very slowly to normal trigger doses of hCG  to promote ovulation. One woman had also received a half dose of triptorelin with her first IVF cycle. Woman #1, who was 28, went through nine IVF cycles with just one viable embryo. She was game to keep trying, so for four more IVF cycles, she received a double trigger with meds PLUS the clinic waited longer to retrieve her eggs. Thus, she had higher levels of hormones engaging with her timid eggs, plus they were given more time to mature. After four cycles of delayed retrieval plus dual trigger, this 28 year old had four more high-quality embryos, two of which she used to create a healthy boy and a healthy girl. 

Woman #2, who was 38, wound up going through four cycles of double trigger with a prolonged time to retrieval of 42 hours. She had two mature oocytes that made two good-quality embryos. Unfortunately, she was unable to conceive after the transfer of the embryos failed. Woman #3, who was 32, wound up doing six IVF cycles. In her last three cycles, she received high doses of HCG (20,000 units) with triptorelin and the interval between hCG shots and egg retrieval time was extended for 50 hours. (That’s a long time compared to the typical 36 hours). Woman #3 wound up having three immature yet usable oocytes retrieved. They were nursed to maturity via in vitro maturation and after ICSI, she had two top-quality embryos. She used one of the embryos and delivered a healthy baby boy. 

The main takeaway was, here is a reason to hope! There is still SO MUCH we don’t know about how oocytes mature. Women with LHCGR mutations were previously thought to be completely infertile, and this study producing healthy babies throws a huge wrench in that assumption.

Resources

THE MONEY STUDY Lu, X et al. Pregnancy and Live Birth In Women With Pathogenic LHCGR Variants Using Their Own Oocytes. J Clin Endocrinol Metab. 2019 Dec 1;104(12):5877-5892. doi: 10.1210/jc.2019-01276.

Abbara, A et al. Novel Concepts for Inducing Final Oocyte Maturation in In Vitro Fertilization Treatment. Endocrine Reviews, Volume 39, Issue 5, October 2018, Pages 593–628, https://doi.org/10.1210/er.2017-00236

Depalo, R et al. GnRH agonist versus GnRH antagonist in in vitro fertilization and embryo transfer (IVF/ET). Reprod Biol Endocrinol. 2012 Apr 13;10:26. https://www.ncbi.nlm.nih.gov/pubmed/22500852

Eftekhar, M et al. The efficacy of recombinant versus urinary HCG in ART outcome. Iran J Reprod Med. 2012 Nov;10(6):543-8. https://www.ncbi.nlm.nih.gov/pubmed/25246924

Heidegger, H and Jeschke, U. Human Chorionic Gonadotropin (hCG)-An Endocrine, Regulator of Gestation and Cancer.Int J Mol Sci. 2018 May 17;19(5). pii: E1502. doi: 10.3390/ijms19051502.

Hershko, K and Shulman, A. hCG Triggering in ART: An Evolutionary Concept. Int J Mol Sci. 2017 May 17;18(5). pii: E1075. doi: 10.3390/ijms18051075.

Levran, D et al. Maturation arrest of human oocytes as a cause of infertility: case report. Hum Reprod. 2002 Jun;17(6):1604-9. https://www.ncbi.nlm.nih.gov/pubmed/12042285

Papaioannidou, P.G et al. In vitro maturation of germinal vesicle oocytes.  Fertility and Sterility, Volume 76, Issue 3, S231 https://doi.org/10.1016/S0015-0282(01)02689-9