TRANSLATIONAL BASIC SCIENCE & CLINICAL RESEARCH NEWS
The staff of The Reproductive Times here offers brief referenced notifications on interesting translational basic science & clinical research news with broad relevance to reproductive medicine and biology. Some of these news items may become subjects of more detailed reporting in The Reproductive Times on later occasions. The purpose of these relatively short notifications is to give readers the opportunity to get immediately more detailed information by looking up the listed references.
The Polycystic Ovary Syndrome (PCOS)
Comparing with different assays age-related AMH levels in PCOS patients with different phenotypes
This paper by Dutch investigators in the JCEM tackled at once two major diagnostic problems in women with PCOS: (i) The fact that different assays often produce quite divergent results and, (ii) that – once a patients have a PCOS diagnosis assigned – outcomes are usually no longer differentiated between the different PCOS phenotypes (1).
Importantly, the authors, therefore, developed assay-specific and age-specific AMH curves and – in doing so – correctly also rejected the still widely held false concept of universal cut-off values for the diagnosis of PCOS. They, moreover, also integrated polycystic ovarian morphology (PCOM) obtained by ultrasound into their models, another important acknowledgment of reality, since under still widely applied diagnostic criteria for PCOS, AMH levels and PCOM are still mostly excluded from diagnosing PCOS (as further discussed below, an in 2023 published new international PCOS guideline finally recommended the inclusion of PCOM in a PCOS diagnosis in adults only).
As with all clinical research, nothing is more important than the correct definition of studied patient populations, and indeed, we have made the point repeatedly in these pages that failure to do so in most PCOS studies is likely the principal reason why progress in PCOS research over the last 30 to 40 years has been so dismal.
The authors of this paper also correctly pointed out the importance of phenotype diagnoses, as non-fertility related differences in long-term patient prognosis, of course, differ significantly between phenotypes, with some being destined to develop metabolic syndrome in a high percentage, while phenotype D under Rotterdam criteria does not demonstrate this risk but carries a significant risk of developing a hyperactive immune system (autoimmunity, inflammation, allergies).
The authors are to be congratulated on an important paper, as only our Dutch colleagues can produce based on the unique collaboration model they have developed in the country for academic institutions.
And related, in another study – including again Dutch as well as Australian investigators – the authors investigated AMH as a diagnostic biomarker for PCOS and (as noted above) PCOM through a systematic review and meta-analysis (2). The study concluded that excessive AMH levels alone are insufficient for a PCOS diagnosis and are nonspecific for PCOM in adolescents. While acknowledging limitations of their study, the authors, however, in our opinion – in contrast to above noted study – reach all the wrong conclusions by claiming that “no international (???) cut-off value can be recommended for a PCOS and/or PCOM diagnosis.” Above-noted Dutch study, of course, very clearly demonstrated the opposite.
The authors of this study, however, nevertheless contributed a valuable message through their paper, even though it may not have been the message they wished to provide, and that message was to demonstrate once more the obscenity of so many published systematic reviews which include garbage-data from poorly performed studies, expecting that aggregated garbage will suddenly stop stinking. The old IBM dictum, “garbage in, garbage out” still holds. This paper reaffirmed this point and, therefore, is deserving of today’s “Worst Paper Award.”
Reference
1. Barbagallo et al., J Clin Endocrinol Metab 2024;109:2561-2570
2. Van der Ham et al., Fertil Steril 2024;122(4):727738” [“Worst Paper Award”}
The diagnostic accuracy of androgen levels in PCOS
And here is another still highly controversial subject regarding PCOS: the significance of androgen levels in a PCOS patient. This time an international group of investigators conducted yet another systemic review and meta-analysis in an attempt to assess different androgen levels in reaching a diagnosis of biochemical hyperandrogenism. Unfortunately, this systematic review and meta-analysis – for obviously the same reasons as already pointed out above in the preceding section – also did not do very well; and here is why:
More or less the same group of “experts,” in 2023 published briefly noted above “International PCOS Guidelines” which – among several recommendation – suggested the use of total testosterone (TT) and free testosterone (FT) as first-line laboratory tests for assessing biochemical hyper-androgenism (1). The only thing this paper could basically do, is to confirm this recommendation and spell out some technical advice regarding what testing methods should be used for androgens (which also are anything but new). The final “wider implications” the authors suggested for their paper were that “further studies should focus on establishing optimal normative cut-off values in large, unselected, and ethnically diverse cohorts of women.”
In other words, here we are served another completely useless study that offered no new insights and – on top of this – in its recommendations for future investigations got things completely wrong: While establishing optimal normative cut-off values for androgens is, of course, a laudable goal (maybe they should consult with our colleagues from the Netherlands on how to do this), such studies should not be performed in large, unselected, and ethnically diverse cohorts of women but in exactly the opposite, i.e.,- well-defined and highly homogenous patient groups, so that it becomes possible to design treatments targeted to these well-defined women. This article, therefore, just barely missed a “Worst Paper Award” designation.
Reference
1. Demis Bizuneh et al., Hum Reprod Update 2024; dmae028, https://doi.org/10.1093/humupd/dmae028
The association between obesity and PCOS
And in continuation of demonstrating why the progress in PCOS research has been so dismal, here is another paper by another group of PCOS “experts” which in fancy language describes their scientific effort as an “epidemiological study of observational data” alleging to investigate the association between obesity and PCOS. Including – in their literature review – 85,956 patients from 58 published studies, this paper concluded that “the prevalence of PCOS and obesity appear modestly associated, although their data cannot establish causality.” And then comes, of course, the usual gibberish: “This study also emphasizes the need to undertake only high-quality studies in assessing PCOS epidemiology (1).”
Really? And, if that is so, why was this study conducted and published in the first place without looking at PCOS phenotypes, when everybody knows that the D-phenotype under Rotterdam criteria is a “lean” PCOS phenotype, while the other three phenotypes are not? Where is, therefore, the differentiation?
It at times is truly astonishing how contradictory and absurd rationales for studies, data analyses, and conclusions can really be, while studies still make it through peer review in even reputable medical journals.
This paper is an excellent example and, therefore, unquestionably would also deserve a “Worst Paper Award.” But since we can choose only one paper per posting, this paper got lucky! The paper, however, with all the above already severely criticized papers on PCOS demonstrates well why the infertility field has made so little progress when it comes to PCOS over several decades: it all comes down to “expert opinions.”
Though frequently noted in the literature, it cannot be overemphasized that there exists, likely, no other diagnosis in fertility practice which is as heavily driven by “expert opinions.” Indeed, all historical classifications of phenotypes of PCOS, from Rotterdam, over NIH, or more recent “expert groupings” mostly out of Australia were based on a group of self-appointed “experts” who every few years find a reason to get together, only to come up with new definitions, rules, and classification of PCOS based on their “expert opinion,” but in the end are just another round of untested opinions. In contrast to politics, science cannot be done by ballot; yet – for some reason – “PCOS experts” honor us every few years with another “expert opinion” which never leads to any new understanding of PCOS but only reflects yet another round of reshuffling of cards.
Here presented recent PCOS publications demonstrate well why “expert opinions” is – deservingly – considered the lowest level of evidence. One really often wonders whether “expert opinion” should ever be considered as real evidence.
The performance of several prominent “experts” during the COVID-19 epidemic, for example, would have to be viewed not only as lacking any positive evidence but as causing unnecessary confusion and, indeed, harming the ability to develop clinically valuable evidence. And after COVID-19, there, likely, is no better example than PCOS that demonstrates how harmful “expert opinion” can be to scientific progress on a field.
Reference
1. Amiri et al., J Clin Endocrinol Metab 2024;109:2640-2657
In Vitro Fertilization (IVF)
Is pregnancy riskier with an “unrelated” embryo?
Three colleagues from the University of Chicago and Harvard University recently published an interesting though to a degree highly speculative paper in which they argued that when a woman gestates a genetically “unrelated” embryo (i.e., a 100% allogeneic embryo, while most pregnancies, involving the mother’s own eggs, are only semi-allogeneic, - i.e., 50%), the gestating woman’s immune system develops tolerance to the pregnancy less well than in a semi-allogeneic pregnancy. A 100% allogeneic pregnancy will arise if the mother uses third-party donor eggs or if a gestational carrier gestates a pregnancy from an unrelated couple (1).
Consequently, the authors claim that such allogeneic pregnancies are “riskier” and that patients (i.e., donor egg recipients and gestational carriers) must, therefore, be informed accordingly. While up to this point, their article makes sense (even though they do not offer any quantitation of the alleged risk), their paper then crosses over into Lalaland when they propose treating 100% allogeneic pregnancies like organ transplants in matching “donor” and “recipient.” That is, of course, total absurdity that can only be offered by clinically ignorant theoreticians who never took care of pregnancies conceived and delivered with donor oocytes and/or carried by gestational carriers.
This paper, however, does address a potentially very interesting model that – if properly investigated – could, likely, significantly contribute to our still very poor understanding of maternal tolerance toward the fetus.
Reference
1. McCoy et al., Early Hum Development 2024;196:106072
A new method of rescue in vitro maturation (rIVM) for immature oocytes
In a very interesting but still somewhat preliminary study, investigators from several U.S. organizations determined gene expression profiles of so-called ovarian support cells (OSCs) and – after stripping – cumulus-free oocytes in their bidirectional influences. They reported that rIVM with use of OSCs significantly improved MII formation rates in comparison to just media use with no effects on morphology or spindle assembly. rIVM oocytes also demonstrated a closer transcriptomic maturity signature to routine MII control oocytes. The authors concluded that rIVM with OSCs produces oocytes with improved nuclear maturity and suggested potentially enhanced cytoplasmic maturation in oocytes as well and they suggested furthermore that their results supported the existence of bidirectional crosstalk of cumulus-free oocytes and ovarian support cells (1).
If correct, these kind of studies may, indeed, become useful in improving rIVM. We, however, are skeptical because the CHR’s investigators several years ago compared in a small unpublished study cycle outcomes between stripped and unstripped oocytes and found no difference. This study, however, did not have the insights this study offered through gene expression profiles and we, therefore, are looking forward to follow-up studies from this group of authors.
Reference
1. Paulsen et al., J Assist Reprod Genet 2024;41:2021-2036
Does IVF cause more heart defects in offspring?
Swedish investigators now reported an increased risk for congenital heart defects in children conceived through IVF (1.84% vs. 1,15%; AOR 1.36; 95% CI 1.31-1.41) (1). Independent of conception method, the risk was – of course (because we are dealing with 2 or more instead of 1 potentially affected newborns) –higher in multiple pregnancies. Risks were similar between ICSI and IVF and fresh and frozen embryo transfers.
So, here we have once again (as in the single embryo transfer circumstance) an obviously statistically biased conclusion which, nevertheless led The New York Times to the headline, “Heart Defects Are Likelier from IVF” (2). And the error lies, of course, in the fact that the birth of two children creates more risk for the pregnancy than the birth of 1 child. A correct analysis, therefore, should have adjusted outcomes for number of birth and should not have the number of pregnancies as reference point. And, despite increasing utilization of elective single embryo transfer, IVF still produces more multiple births than spontaneous conception. The conclusion that IVF increases the risk of offspring for congenital abnormalities is, therefore, likely complete nonsense, even if The Times thinks otherwise.
References
1. Sargisian et al., Europ Heart J. 2024; ehae572, https://doi.org/10.1093/eurheartj/ehae572
2. Rosenbuth T. The New York Times . October 1, 2024. pA19
More evidence that blastocyst-stage transfer offers no benefit in cumulative life birth chances over cleavage stage
A national French study once again confirms what some investigators have by now claimed for almost 20 years: That blastocyst-stage embryo transfer improves cumulative life birth rates is a myth which, finally, must be acknowledged (1). In addition, as also claimed by some for many years, the study demonstrated that in IVF cycles which produce only small embryo numbers, cleavage-stage transfers, indeed, likely offer improved outcomes in comparison to blastocyst-stage transfers.
One more example in which a longstanding IVF practice contradicts “common wisdom” and, in the end, will be recognized as off the mark. How many hundreds of thousands of human embryos are every year unnecessarily routinely cultured to blastocyst-stage? And – even worse – how many thousands of women end up without embryo transfers in cycle because none of their embryos ever make it to blastocyst-stage, while day-3 cleavage-stage transfers may still give them a chance of pregnancy with their own autologous eggs!
Reference
1. Fauque et al., Reprod Biomed Online 2024;49(6):104384