FOLLICLE SIZE MATTERS Further evidence that the time has come to individualize the timing of ovulation triggers and egg retrieval in IVF
By Norbert Gleicher, MD, Medical Director and Chief Scientist at The Center for Human Reproduction in New York City. He can be contacted though The Reproductive Times or directly at either ngleicher@thechr.com or ngleicher@rockefeller.edu. This article was originally written for The CHR VOICE, where it will appear in the January-February 2025 double issue.
This Breaking News posting informs on a just-published important paper by a consortium of British investigators from several universities which offers further evidence that the longstanding IVF practice of triggering all cycles at ca. 18-22mm lead follicle sizes has come to an end. Our Center already reached this conclusion ten years ago, based on molecular studies of follicles in older women above age 43. This study now expands this concept to practically all IVF with the difficult-to-reject conclusion that trigger timing in IVF cycles, going forward, must be individualized for all patients.
There are not too many clinical practices left in IVF that have remained unchanged from the earliest days of the procedure. One of those is the worldwide practice of triggering IVF cycles at lead follicle sizes of 18-22mm on average. Moreover, if deviations occur, they usually occur upwards to larger sizes, rather than downwards to earlier retrievals at smaller sizes. The latter fact is likely driven by the earliest stages of IVF, when IVF cycles were still stimulated with clomiphene citrate, and best trigger sizes were considered to be approximately 22-24mm.
The switch to 18-22 mm occurred only with the introduction of gonadotropin stimulation to IVF in 1981 by the first IVF clinics in the U.S. (1) and Australia (2).
Howard Jones, MD and his wife Georgeanna Jones, MD, who established the U.S.’s first IVF program in Norfolk in 1980 and werethe first to introduce gonadotropin stimulation to IVF (Photo source: PBS)
And that trigger range has since 1981 become a dogma of IVF practice all around the world, only challenged by investigators at our clinic in NYC, the Center for Human Reproduction (CHR, founded in Chicago in 1981), when we in molecular studies of older patients above age 43 discovered that follicles luteinize progressively earlier as women age (3, 4) and, therefore, concluded that with advancing female age egg retrievals—and, therefore, ovulation triggers—had to be administered earlier and earlier. And it is now indeed the 10-year anniversary of the radical step we took at the CHR in 2015 to age-adjust the timing of ovulation triggers in first IVF cycles to the age (and functional ovarian reserve, representing ovarian age) of patients in a process we have named Highly Individualized Egg Retrieval (HIER).
This step has been central to the CHR’s success in treating older patients, with women above 43—and especially above age 45—routinely being triggered at lead follicle sizes as small as 10-12mm. This step was also crucial in discovering additional age-dependent changes in folliculogenesis which had not been known before (5) (more on that below).
This lengthy introduction is necessary to understand the importance of a recently published paper by a consortium of British investigators in Nature Communications, which—with the use of artificial intelligence (A.I.)—demonstrated that best follicle sizes are not the same for everybody (6).
In a multi-center study, the investigators used data from 19,082 women (before any fertility treatments) from 11 European IVF centers and harnessed explainable A.I. to identify follicle sizes that contributed most to relevant clinical IVF outcomes. And especially considering our 10-year experience with HIER, their results were interesting because what they discovered was that follicle sizes at retrieval mattered. Specifically, intermediate-size follicles were—for example—most important in determining the number of mature oocytes subsequently retrieved. Maximizing these mid-size follicles by end of ovarian stimulation also led to an improved live birth rate. Unsurprisingly they also found that larger follicle sizes, especially those over 18mm, were, based on premature progesterone elevations, obviously—as we had reported in older women (3) —associated with premature luteinization. Also, unsurprising and previously reported by us in older women, (3,4) the diagnosis of premature luteinization negatively impacted live birth rates in fresh embryo transfer cycles.
Unfortunately, the investigators in this study only differentiated between patients under and above age 35, thereby not really allowing for the detailed age associations we reported with increasingly declining best follicle sizes at ovulation trigger in older infertility patients. Even though their data, therefore, do not directly confirm the CHR’s HIER data in older women, they nevertheless appear to support them. For example, that best oocytes—regarding maturity as well as quality—are not necessarily in the biggest follicles became obvious years ago in older patients. Some very tiny follicles at times produced perfectly mature metaphase 2(M2) oocytes, while bigger ones in the same cycle cohort might yield still immature M1 or even more immature germinal vesicle (GV) eggs. The CHR’s investigators are, therefore, currently attempting to identify markers on follicles during vaginal ultrasound examinations that may help in identifying mature follicles even at very small sizes.
Moreover, CHR’s practice of HIER more recently, as alluded to above, allowed its investigators to discover yet another previously unknown physiologic phenomenon of human oocytes that breached yet another dogma in reproductive medicine. The three major maturity grades of oocytes M2, M1, and GV, since the establishment of IVF have been considered fixed in their respective clinical potentials: Mature M2 oocytes have been widely considered the overreaching goal of all IVF cycles, while the most immature GV oocytes in most IVF clinics to this day are mostly automatically discarded because maturation attempts in vitro have in general been very unsuccessful.
Because the CHR serves a unique, very poor-prognosis patient population, in which every fertilizable oocyte is disproportionally valuable, we have been performing so-called rescue in vitro maturation (rIVM) on all immature oocytes retrieved for over 10 years (7) In this process, we started to suspect that the clinical efficiency of M2, M1, and GV oocytes to produce good quality embryos did not appear to remain stable with advancing female age. A formal prospective study then very recently confirmed this observation (5).5 It demonstrated that mature M2 oocytes lost significant ability to produce good-quality embryos with advancing female age, while very immature GV oocytes greatly improved in their ability, further supporting the hypothesis that evolution favors increasingly earlier retrievals as women age.
That this hypothesis is likely correct can be also deducted from the observation that practically all fertility-related biological processes are controlled by inhibition. Luteinization and ovulation of follicles are good examples: As women age, inhibitory controls progressively weaken, resulting in above-noted earlier and earlier premature luteinization and premature progesterone rises and, ultimately, in shorter and shorter menstrual periods. In IVF cycles, this development is reflected in their shortening length with advancing female age. Another observation pointing at disinhibition as a sign of follicular stress is the well-known observation that follicle growth increases with premature luteinization based on increases in progesterone levels (8).
In other words, premature luteinization elicits a stress response in the affected follicle, resulting in increasing disinhibition, with the follicle demonstrating a growth spurt. Follicles at similar sizes in the same follicle cohort, therefore, may be under different stress levels. Here discussed paper by Hanassab et al., therefore, reaffirms by demonstrating the importance of early rises in progesterone at all ages the importance of premature luteinization in harming egg quality at all ages.
The single most important message this paper offers, however, is that the dogma of a uniform 18-22mm trigger sizes of leading follicles in all IVF cycles should be considered a bygone. Individualization of trigger and, therefore, retrieval timing is not only important in older women but affects oocytes and, therefore, embryo quality at all ages.
References:
1. Jones et al. Fertil Steril, 1982, 38 (1) 14–21
2. Trounson et al., Science 1981;212(4495):681-682)
3. Wu et al., J Endocrinol 2015;226(3): 167-180
4. Wu et al., J. Ov Res 2018;11:23
5. Nicholas et a., iScience 2023;26:107308
6. Hanassab et al., Nat Commun 2025;16:296
7. Lee et al., Endocrine 2016;52:165-171
8. Cortés-Vasquez et al., JBRA Assist Reprod 2022;26(3):531-537