REVIEWS AND COMMENTARY on recent literature in reproductive medicine and biology
The staff of THE REPRODUCTIVE TIMES here offers commentaries on recently published articles, primarily chosen for educational values—in the positive but also in the negative—for clinical purposes, and for their potential translational values to clinical medicine when addressing basic science in reproductive medicine and biology.
GnRH agonist vs. antagonist in ovarian stimulation
Most U.S. fertility centers, approximately 25 years ago after the first GnRH antagonist was approved in the U.S. for use in infertility, succumbed to the manufacturer’s marketing efforts and started using the antagonist in place of GnRH agonists. For some centers the results were, however, remarkably disappointing, as they experienced significant declines in pregnancy rates. Some IVF clinics, therefore, switched back to agonists and never returned to routine antagonist use. Most IVF clinics, however, to this date prefer the conveniences of GnRH antagonists over agonists.
Now, an international consortium of investigators have published an important study in Human Reproduction, basically fully reaffirming the nay-sayers from over 25 years ago (sometimes it may take a little too long; but ultimately in medicine the truth always prevails) (1). Administering randomized between antagonist and agonist during first stimulation cycles in a prospective, randomized multicenter trial of an obviously unselected patient population individualized follitropin delta dosages to patients, the study offered the following results: 437 women from IVF clinics in Austria, Denmark, Israel, Italy, The Netherlands, Norway, and Switzerland were randomized, 221 to agonist and 216 to antagonist. Mean age was 32.3 ± 4.3 years and mean AMH was 16,6 ± 7,8 pmol/L (2.3 ± 1.1 ng/mL). The study group, in other words, was relatively young and had relatively normal functional ovarian reserve.
Agonist patients produced significantly more oocytes (11.1 ±5.9 vs. 9.6 ±5.5; P=0.0185). Unsurprisingly, greater differences were observed in younger women under age 35 and with better AMH values above 15.0 pmol/L (2.1 ng/mL). Both groups had similar cycle cancellation rates, though trends favored agonists (2.0% vs 3.4% for cycle cancellations and 13.4% vs. 14.7% for fresh blastocyst transfer cancellations). The ongoing pregnancy rate was also higher with agonist (35.8% vs. 28,7%), though this difference did not reach significance (P=0.1002). The same applied to live birth rates (35.8% vs. 28.7%; P=0.1265).
In looking at these data it is important to recognize that neither pregnancy nor live birth rates represent cumulative rates. Having more eggs, however, usually means having more embryos, and more embryos usually mean higher cumulative than first-cycle numbers. In other words, the data of this study strongly suggest that cumulative pregnancy and live birth rates can be expected to further improve over the obvious—statistically non-significant—trends, in favor of agonists the study produced, probably reaching statistical significance. Moreover, these data were produced in relatively young women with relatively normal functional ovarian reserve. In poorer prognosis patients and with advancing age, here observed trends in favor of agonists over antagonists, therefore, can also be expected to strengthen.
Does this mean that the field will show an impact from this (in our opinion) very important study? We don’t think so! When antagonists first entered fertility practice, one of the principal arguments of antagonist proponents was the convenience and shorter time period of antagonist over agonist cycles for patients and providers (2). Those are, of course, important and appropriate considerations but only as long as IVF cycle outcomes are not adversely affected. Proponents of antagonist treatments, therefore, from the beginning claimed that there were no outcome differences between agonists and antagonists, even though already in 2002 a Cochrane review suggested outcome advantages for agonists (3). In other words, already then—somewhat surprisingly—the field chose convenience over outcomes. There is little reason to believe that now it will respond differently.
Reference
1. Lobo et al., Hum Reprod 2024;39(7):1481-1494
2. Albano et al., Hum Reprod 2000;15(3):526-531
3. Al-Inany H, Aboulghar M. Hum Reprod 2002;17(4):874-875
What aneuploidy does to preimplantation-stage embryos—does it explain self-correction? CAUTION, UNREVIEWED PREPRINT
We only rarely present unreviewed preprints, but we found a recent one by Belgian investigators, published by bioRxiv on September 14, 2024 (1), interesting enough to make an exception since it is highly relevant to a still somewhat controversial subject, the question of whether embryos at early stages can self-correct from chromosomal abnormalities.
That this may, indeed, be happening was first suggested in the mouse (2) and more recently in a paper by New York investigators (3). This preprint is the product of research the Belgian investigators initiated to potentially better understand this self-correction mechanism.
They now reported that aneuploidy triggers proteotoxic stress, autophagy, p53-signaling, and apoptosis independent from DNA damage. The consequence was lower total cell numbers in aneuploid embryos. Lower cell numbers in trophectoderm were attributable to apoptosis, while in the embryonic cell lineage (epiblast/primitive endoderm) aneuploid apparently impaired second lineage segregation and, especially, formation of the primitive endoderm.
Summarizing their findings, these authors thus claimed that aneuploidies in human preimplantation-stage embryos trigger autophagy and p53-mediated apoptosis and impairs the second lineage segregation, thereby leading to embryo arrest in many aneuploid embryos but, also, potentially contributing to the ability of embryos to self-correct in the embryonic cell lineage (fetus), while this ability is strongly diminished in the extraembryonic cell lineage (trophectoderm and placenta).
Reference
1. Regin et al., bioRxiv preprint. Doi: https://doi.org/10.1101/2022.08.31.506009, posted September 14, 2024
2. Bolton et al., Nat Commun 2016;7:1-12
3. Yang et al., Nat Cell Biol 2021;23:312-321
Ovarian aging—among other things—also reflects cancer risks
As a model for general aging, ovarian aging in recent years has become increasingly prominent in the medical literature. An international group of investigators have now, however, taken these studies a step further: After human genetic studies of common variants have informed well about biological mechanisms that govern ovarian aging, a consortium of international investigators now reported in Nature magazine analyses of rare protein-coding variants in 106,973 women from the UK Biobank study (1).
With approximately five-times larger effects than had been previously found four more common variants, specifically ETAA1, ZNF518A, PNPLA8, PALB2, and SAMHD1, the latter association reinforcing the link between ovarian aging and cancer susceptibility already previously reported (2). Damaging germline variants of SAMHD1 were furthermore associated with extended reproductive lifespan and increased all causes of cancer risk in women and men.
Protein-truncating variants in ZNF518A on the other hand, were associated with shorter reproductive lifespan (i.e., earlier menopause) by a whopping 5.61 year and with later menarche age by 0.56 years. The study also revealed that common genetic variants associated with earlier ovarian aging also associated with an increased rate of maternally derived de-novo mutations, though the authors were unable to replicate this result with another database.
An accompanying commentary by Anne Goriely summarized these findings as follows (3): “By mining large-population genetic data sets, the researchers identified the key factors controlling menopause timing, and revealed a close connection between reproductive longevity, cancer risk and new mutations in children.” She also concluded that “these findings could also provide avenues for developing treatments to delay ovarian aging,” though hopefully without increasing cancer risk.
References
1. Stankovic et al., Nature 2024;633:608-614
2. Ruth et al., Nature 2021;596:393-397
3. Goriely A. Nature 20224;633:530-531