GENERAL ASPECTS OF IN VITRO FERTILIZATION
Progesterone support in FET cycles
We usually are not big fans of the Inklings articles in Fertility & Sterility, which now accompany most published papers. Often written by one of the reviewers, they, for several good reasons, represent a very questionable and relatively new practice at many journals, mostly instituted to improve the journal's impact factors since editorial comments and review articles are much more frequently cited than original papers (some more fastidious opinions describe their purpose more as dumbing-down articles).
But there are exceptions, and one such exception was recently an Inkling article by French colleague Dominique de Ziegler, MD (et al.) (1), who, after his retirement as chairman of an OB/GYN university department in Paris, has become a very visible international member of the editorial juggernaut Fertility & Sterility (which has the by far largest editorial board of any journal we are aware of). He and the CHR's Norbert Gleicher, MD – on a side note – as young physician-scientists in the mid-1970s occupied adjacent laboratories on the 20th floor of the Annenberg Research Building at New York's Mount Sinai Medical Center.
The article attracted our interest for several reasons: (i) First, the Inkling article had no connection whatsoever, as is usually customary, to any article in the same issue of Fertility & Sterility. In other words, it was, indeed, an "inkling" article (we for some time have been wondering why Fertility & Sterility named its commentaries "inklings," – clearly not a very authoritative term for a commentary) because it – kind of out of the blue – addressed the question why frozen embryo transfer (FET) results are poorer with vaginal than intramuscular progesterone? (ii) We were not certain whether the premise that vaginal progesterone causes poorer FET outcomes is correct (and we still are not certain of that because we believe that the difference may lie in the age of the patients, with older women benefitting from I.M. progesterone). And (iii) we found it laudable that de Ziegler used his obviously privileged access to the journal to offer an interesting reconsideration of an earlier publication of which he, himself, had been a co-author, which tried to explain this finding with a "first uterine pass effect" (2).
But reason (iv) was the real hook because de Ziegler directed the attention of readers to the fact that, among all of its endocrine functions, progesterone also functions as an immune suppressor and potentially participates in immune tolerance toward the fetal semi-allograft in pregnancy (3). And everybody who knows the CHR, of course, knows that we love reproductive immunology! Whether vaginal progesterone, indeed, lowers FET cycle outcomes in comparison to I.M. progesterone, therefore, for the CHR is less important than the acknowledgment that reproductive success may have something to do with the female immune system. Too many REIs to this day still deny this indisputable fact!
References
De Ziegler D, et al., Fertil Steril 2025 (6): 989-990
Bulleti et al., Hum Reprod 1997; 12:1073-1079
Motomura et al., J Steroid Biochem Mol Biol 2023;229:106254
Assisted reproduction in couples (females as well as males) with advancing parental age
However, the Ethics Committee of the ASRM recently published an updated guideline paper on extending assisted reproductive treatments (ART) – of course, mostly in vitro fertilization (IVF) – to couples of advanced paternal and maternal age (1). We are here reprinting the six key points:
Risks associated with reproduction at an advanced reproductive age (ARA) fall into three broad categories: risks to offspring associated with the use of gametes from older individuals, increasing health risks of gestating at an older age, and risks from having older parents who may have a limited number of expected healthy life years available for parenting. These age-related risks occur on a continuum and can be difficult to quantify. More precise estimates regarding healthy life years can be obtained using actuarial tables.
Clinics should have written policies regarding inclusion and exclusion criteria as they relate to parental age to ensure consistency in assessments and to reduce the risk of bias. Clinics may base age policy on the predicted number of healthy life years available for parenting or the risk of parental death before the offspring reaches the age of 18.
Those gestating at an ARA face increased medical risks, and careful counseling is warranted, potentially in conjunction with maternal-fetal medicine specialists.
Clinics should strongly consider having a policy that declines the transfer of an embryo to the uterus of a person at such age as a program may individually determine the need for a review of the relevant medical literature.
Prospective patients of ARA should be counseled about the potential negative impact of their age on the success of fertility treatments using autologous gametes and on the increased medical risks to the resultant offspring, including the fact that many of these risks are poorly characterized due to limited data.
Prospective patients of ARA should be counseled regarding short- and long-term parenting and child-rearing issues specific to their age and health. The age and health of the partner, if present, should also be considered in this discussion.
One more important point: Many IVF clinics have strict age cut-offs (usually primarily for women and more rarely for males). For most women, the cut-off for an IVF cycle with their own (autologous) eggs is usually somewhere between 42 and 43 years, when they are advised that their only "realistic" chance of pregnancy is with third-party egg donations. This is also reflected in national U.S. IVF data, which demonstrate only relatively few cycles after female age 42 and – most certainly – after age 43.
Some clinics also have combined cut-offs. We, for example, were recently informed by a couple that they were denied a frozen embryo transfer of their embryo because, combined, they exceeded 100 years. That, of course, makes absolutely no sense!
The CHR, out of principle, does not have age-dependent cut-offs for any reason, and here is why: First, having rigid cut-offs for women but not for men is, of course, inherently unfair. But, even more importantly, such cut-offs make little sense since some older women may have young-behaving ovaries while some younger women may have older-behaving ovaries. Similarly, some older women may be healthy and perfectly capable of withstanding the stresses of pregnancy. In comparison, some younger women may have severe medical problems, which may be life-threatening should they conceive.
In other words, because humans are just too variable, rigid age-dependent cut-offs for fertility services should never be used, and certainly not when it comes to making fertility services available. Except in very rare circumstances, whether women or couples are given access to fertility services should not be at the whim of a provider, but, of course, after appropriate informed consent, should ultimately be the patients' decision.
Providers can – and should – make recommendations, but should never mandate and/or withhold reasonable fertility treatments unless such services can unquestionably be assumed to be futile, and that is only very rarely the case. Many patients do not achieve mental peace until they conceive themselves or, at a minimum, convince themselves that they have given it all to conceive. And while such an effort may seem irrational to observers at times, to the patient, it may be essential.
References
Ethics Committee of the American Society for Reproductive Medicine. Fertil Steril 2025;123(6):999-1004