LITERATURE for the INFERTILITY CLINIC
In this section, we offer commentaries on a broad survey of recent articles in the English literature. Articles are mostly chosen for one of two reasons: their potential translational value for immediate clinical practice, or to help in determining in what direction clinical practice might evolve.
Do contraceptives affect outcomes of social (planned) oocyte cryopreservation cycles?
This is the question investigators from the Mount Sinai IVF program in NYC recently addressed in a paper in RBMOnline, (1) in which they compared young women undergoing social (sometimes called “planned”) egg-freezing who had used contraceptives before their cycles with women who had not used any contraceptives. Outcome criteria was number of obtained oocyte-cumulus complexes retrieved and mature MII oocytes that were cryopreserved in a cycle. And after adjustments for confounders, a multivariate analysis found no difference between study and control groups or individual contraceptives.
Though this study has several shortcomings, including its retrospective nature and mostly reliance on patient memory, the finding can be considered as reassuring, on a practical level suggesting that prior utilization of especially hormonal contraceptives does not seem to require a prolonged washout period.
Reference
1. Hernandez-Nieto et al., Reprod Biomed Online 2024(3):104105
Affecting oocyte and embryo quality in IVF
IMPROVING EMBRYO QUALITY DURING RESCUE IVM Though this study still must be considered to be preliminary since it was only published as an abstract at the annual ASRM meeting (1), it nevertheless deserves attention and follow-up. Investigators from Penn State University reported that in vitro maturation of immature oocytes (also frequently called “rescue” maturation) improves oocyte and embryo quality in older women (age 38 and older) if culture media are supplemented with nicotinamide mononucleotide (NMN) and this effect may be mitochondria-mediated, as mitochondria demonstrated improved morphology and function.
While in vitro maturation, normal fertilization, and cleavage of immature oocytes from older women at ages 38 and above were not enhanced, there were substantial improvements in effective embryos (53.3% vs. 29.4%), high-quality embryos (31.7% vs. 8.8%), blastocyst formation (31.2% vs. 6.2%), and high-quality blastocysts (70.0% vs. 23.5%) (all P < 0.05). Transmission electron microscopy revealed increases in number of mitochondria with intact inner and outer membranes and clear cristae (P < 0.05). Moreover, fluorescence signal quantification analysis demonstrated significantly higher Tetramethyl rhodamine ethyl ester (P < 0.05) and mitochondrial activity and membrane potential by MitoTracker (P < 0.05), and fluorescence intensities. Single-cell transcriptome analysis identified 277 significantly upregulated genes and 183 significantly downregulated genes in the supplemented group. Gene Ontology (GO) analysis of differentially expressed genes showed significant enrichment in mitochondrial-related terms such as "positive regulation of protein targeting to mitochondrion" and "mitochondrial matrix." Real-time quantitative PCR results confirmed the upregulation of oxidative phosphorylation genes (ATP6V1D, ATP5MC1, PPA1, NDUFC1, CYC1, NDUFA12, and NDUFB3) in IVM oocytes of the principal aged study group, validating the accuracy of the RNA-seq data.
Though numbers are small, the data are interesting, not the least because they make physiological sense. As the authors noted, declines in oocyte quality are a primary factor in reduced fertility in women of advanced maternal age. Older women have also been demonstrated to exhibit an increased prevalence of abnormal mitochondria and reduced nicotine amid adenine dinucleotide (NAD+) levels. Restoring and enhancing oocyte NAD+ levels could, therefore, be a promising intervention.
DOES HUMAN GROWTH HORMONE AFFECT IVF CYCLE OUTCOMES? The peer review process at Human Reproduction is usual quite good in comparison to most other medical journals in the fertility field. But this time, the journal really got a black eye for publishing one of the most ridiculous papers in some time. The heading of the paper already says it all: “Empirical use of growth hormone (GH) in IVF is useless: the largest randomized controlled trial” (2).
The study basically investigates whether supplementation with GH in a general population of infertile women in an antagonist IVF cycle improves outcomes. The absurdity of this study design is the same as in a hypothetical study of aspirin use which tests in a prospectively randomized study of a general population (i.e. a population that may or may not have a headache) whether aspirin, indeed, does improve headache. Simply idiotic!
A medical treatment can show effectiveness only if the target population is affected by the medical problem the treatment is supposed to take care of. In an IVF cycle this means that GH supplementation makes sense only if insulin growth factor-1 (IGF-1) levels are abnormally low because GH acts on small growing follicles during folliculogenesis synergistically with FSH through IGF-1. And since abnormally low IGF-1 levels in infertile women are very rare, this study—with great likelihood—treated in a large majority women with GH who did not need it. Who can then be surprised about the conclusion of the study that GH showed no effects!
We, indeed, in these pages have repeatedly pointed out that the persistent controversy regarding GH supplementation in IVF is likely exclusively due to the fact that the different studies with varying outcomes just reflect the different prevalence of abnormally low GH levels in study populations.
This article, however, also raises another important point, namely positive biases affecting the peer review processes assuming that every prospectively randomized study represents a pinnacle of evidence. And that is not only false but there is literature that demonstrate the dangers of poorly executed and/or interpreted clinic trials because their results are so overestimated (2). This paper has special gall trying to blow up its importance even further by claiming to be the biggest trial of GH use in IVF ever. In other words, this makes it the biggest screw-up on a GH hormone study in infertility ever. Not a great compliment!
Related, another recent paper is worth mentioning. Investigators from several countries attempted to determine how the IGF system participates in the midcycle surge in women (3). As noted above, IGF-1 signaling is well known to affect follicular function during especially small growing follicle stages, but also to a lesser degree beyond. How it is involved in the ovulatory peak which greatly affects granulosa cell function is still largely unknown. What this study now suggested is that downregulation of IGF signaling at that time is mediated by increases in the expression of the inhibitory protein, STC1, which then is instrumental in the sudden cessation in GC proliferation and onset of differentiation during the ovulatory peak.
References:
1. Mourad et al., Hum Reprod 2024; doi: 10.1093/humrep/deae251. Online ahead of print.
2. Kis D. Medthority. March 30, 2023. https://www.medthority.com/news/news-trends/clinical-trials/how-can-flaws-in-clinical-trial-design-conduct-and-reporting-impact-clinical-decision-making/
3. Bøtkjær et al., J Clin Endocrinol Metab 2024;110(1):e160-e167
DO ARTIFICIAL INTELLIGENCE (A.I.). AND TIME-LAPSE MONITORING IMPROVE IVF OUTCOMES?
So claims the industry that is selling A.I. products and closed incubation systems with time-lapse—which, of course, has commercial interests—and, unfortunately, so do some colleagues and institutions, which often spend fortunes on this equipment and software (1). But, as we have repeatedly noted in these pages, major recent studies on A.I. (2) and time-lapse (3) have demonstrated no outcome benefits for IVF cycles (while, of course, further increasing costs for already widely unaffordable IVF).
References
1. Singer T. Northwell Health. https://r1.marketing-pages.com/p/7N0G-6LW/q424-improving-ivf-outcomes-with-ai-and-time-lapse-monitoring-?dm_i=7M0G,6WXA,1E6J9V,U3J6,1
2. Kieslinger et al. Nat Med 2024;30:3059-3060
3. Bhide et al., Lancet 2024;404(10449):P256-265