General Infertility News
Infertility for whom?
In their Clinical Practice articles The New England Journal of Medicine starts with a clinical case and then asks the authors of the article to offer evidence supporting various strategies for diagnosis and treatment, followed by - if they exist - formal guidelines. In one recent issue of The Journal, the clinical problem was a couple (the woman at age 36) presenting, despite regular intercourse, after one year of failed attempts at pregnancy. The authors were Nanette Santoro, MD, past Chair of Ob/Gyn at the University of Colorado, and now a member of Shady Grove – Colorado, and Alex J. Polotsky, MD, from Shady Grove – Colorado (1), and they did an excellent job in discussing a basic infertility work-up for a couple with primary infertility, followed by treatment options.
What we thought was missing was a purpose for the article: For fertility specialists, the article was absolutely non-contributory and for the general gynecologist, it may have offered a refresher function at a sufficiently primitive level. But considering current referral habits, the length of this article could really have been shortened to only one sentence: Considering the female’s age of 36 years and the couple’s desire for three children, they should be referred to a fertility clinic ASAP!
Reference
1. Santoro N, Polotsky AJ. N Engl J Med 2025;392(11):1111-1119
The difference between fertility and fecundity rates
Legacy as well as social media were buzzing recently after age-specific “fertility” trends were published by the CDC for the years 1990-2023 (1). The emphasis of our comment here today is on the word “fertility” because the CDC should do a little better in explaining the terminology of “fertility” which is the natural ability to reproduce. The “fertility rate,” moreover, is the average number of children an average woman gives birth to. This term, however, must be distinguished from the term “fecundity,” which refers to a woman’s inherent biological potential to reproduce by producing offspring.
When the CDC report then suggests a “steep decline” in fertility among U.S women under age 30 (2), this should not be misunderstood as these young women – suddenly – becoming infertile. They just don’t want to get pregnant as young as women used to get pregnant, - an observation increasingly prevalent not only in the U.S. but also in Europe and Asia.
References
1. Driscoll AK, Hamilton BE. Nat Vital Stat Rep 2025;74(3):1-9; March 6, 2025
2. Thomson D. Healthday, March 17, 2025. https://www.healthday.com/health-news/pregnancy/steep-decline-in-fertility-among-us-women-younger-than-30
And here we go again with AMH values to define PCOS
It is truly amazing what colleagues waste their time on without giving it thought or, at least studying the literature first. And it is even more amazing that they can get their paper published, - in this case in the American Journal of Obstetrics and Gynecology (AJOG), which apparently has only very limited REI expertise on board to control its peer review.
Here Iranian investigators claim to report on a meta-analysis of not less than 202 observational studies (can you imagine the time it took to go through 202 papers?) to reach the overwhelmingly old conclusion that AMH values are predictive of polycystic ovary syndrome (PCOS) (1). No kidding!
But, once again – and we as well as others have been screaming into the wind that AMH levels are of, course, age dependent and that, therefore, AMH studies must be age-adjusted – all of this work was done without age adjustments and, therefore, is completely wasted. And we, of course know why that is: because – even if they had wanted, they would not have been able to translate those 202 study populations into one cohesive study group because almost all AMH studies on PCOS in the literature (and also in other than PCOS frameworks) lack age-adjustments. What misery and definitely not a paper worth much more discussion.
Reference
Barghi et al., Am J Obstet Gynecol 2025;232(2):164-187.e31
A study of various treatments in women with low functional ovarian reserve (LFOR)
This time, it is not Iranian colleagues but, rather, our mostly Italian colleagues (n=15), including Laura Rienzi, PhD, and Filippo Maria Ubaldi, MD, whom we jokingly call the European IVF Mafia (Laura Rienzi has published 193 papers per PubMed between 2000 and 2025). The European IVF Mafia recently published yet another meta-analysis, this time, though, at least of randomized trials. But that alone—unfortunately—did not make it a much better paper than the above-criticized Iranian paper. To the contrary, in many aspects, the paper is even more absurd.
The authors want us to seriously believe that (note!)—after duplication removal—titles and abstracts of 4,806 articles were scrutinized, and among those, 124 were assessed for eligibility in their full text. Furthermore, only 38 were selected for final data analysis—not of one treatment in women with low functional ovarian reserve (LFOR), but for 13 different treatments (it must be their lucky number!).
Those treatments were specifically (in parentheses, number of patients studied): dehydroepiandrosterone (DHEA, n=1,336); testosterone (n=418); high vs. low dose gonadotropin stimulation (n=957); delayed start protocols with GnRH-antagonists (N=398); letrozole (n=612); clomiphene citrate (1,113); growth hormone (311); luteal phase stimulation (n=570); dual trigger (n=139); dual stimulation (168); luteinizing hormone (979); estradiol pretreatment (552); and corifollitropin alfa (n=561) (1).
And what did they study? The primary outcome was live birth rate or ongoing pregnancies. Secondary outcomes were oocyte numbers, M2 oocytes, clinical pregnancies, and miscarriages.
What did they report to have discovered? Among all 13 interventions, testosterone supplementation was found associated with higher live birth/ongoing pregnancy rates (4 studies for a total of only 368 patients with at least 13—and likely more—variables). In patient groupings between 300 and 400, testosterone, DHEA, and delayed start protocols significantly improved oocyte numbers, while women with lower dose gonadotropins (surprise, surprise!) retrieved smaller egg numbers than women with higher dose gonadotropins (905 patients studied). No other differences were found (again, what a surprise!).
Reading this paper, unbelievably accepted and published by Fertility and Sterility, it is difficult to even decide where to start the criticism. Of course, no statistical adjustments were done for age, with all fertility treatments, of course, being age-dependent. The authors included by design at least 13 variables; where were the adjustments for those? How and for how long were the various treatments given, etc. It is simply unbelievable that this paper was even submitted in the first place; it is even much more amazing that this paper went through peer review, and it is, finally, unconscionable that this paper was accepted and published by the main journal of the ASRM. We wonder whether it was first rejected by Human Reproduction?
As proponents of androgen supplementation in a to this practice sometimes-hostile world, we actually should be happy that women with LFOR with testosterone and DHEA supplementation demonstrated significant improvements in pregnancy outcomes and egg numbers. But considering the shamefully inadequacy of the study design of this paper, it is not even worthwhile pointing out that the variability of patients likely washed out even more significant findings.
If there was a special award for the worst paper among worst papers, this manuscript would have earned this award with honors.
Reference
1. Conforti et al., Fertil Steril 2025; 123(3):457-476.