Researchers in a 2023 study found that older women that are triggered earlier produce immature eggs that may be more competent than mature eggs after rescue IVM.
Egg retrievals are often optimized to obtain mature, or M2, eggs by triggering when the lead follicle reaches 18-22 mm. However, some labs have found that older women may benefit by triggering earlier, in what’s known as highly individualized egg retrieval, or HIER.
Nicholas et al. (2023) compared IVF outcomes of eggs obtained by HIER. This study took place at a single IVF center between 2021 and 2022.
Key information:
- Donor egg cycles, and cycles without any eggs retrieved, were excluded.
- DHEA was supplemented for 6-8 weeks in women with low androgen/SHBG levels until normalized.
- Dual triggers were given (hCG and Lupron).
- Ovulation was triggered based on the size of the lead follicle at different ages: <40: 18.4 ± 3.4 mm; 40-45: 16.8 ± 2.7 mm; >45: 14.4 ± 3.3 mm.
- Eggs that were mature on the day of retrieval were inseminated with ICSI, while M1 or GV eggs were inseminated the following day when they became M2 (ie. by rescue in vitro maturation or rescue IVM).
- Day 3 embryos were transferred. Transferrable day 3 embryos were those with 6-8 cells (from M2 eggs), or 2 cells (from M1/GV eggs that had rescue IVM — note that these eggs would have had ICSI the day after the M2 eggs, so by day 3 they have fewer cells). Transferrable day 3 embryos had “grades A, B or C for cell evenness” (symmetry) and “minimal fragmentation.” Check my complete guide to embryo grading and success rates for more info on cleavage embryo stage grading.
As a reminder, immature eggs come as two types: germinal vesicle (GV) or metaphase 1 (M1). Eggs mature starting from a GV, then to M1, then to M2. So a GV is less mature than an M1. An M2 egg is a mature egg. For more background on egg quality and maturity, check out my Complete guide to egg quality.
🔗 Original studies are referenced in this post or within the linked Remembryo posts.
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Earlier triggering by HIER results in the same proportion of M2, M1 and GV eggs
As indicated above, the researchers triggered ovulation when the lead follicle was smaller in older women:
- <40: 18.4 ± 3.4 mm
- 40-45: 16.8 ± 2.7 mm
- >45: 14.4 ± 3.3 mm
This had no difference on the proportion of mature (M2) and immature (M1, GV) eggs retrieved.
Immature eggs are more likely to produce transferable day 3 embryos with HIER in older women
Women of varying age were triggered at different lead follicle sizes as shown above, and the number of transferable embryos were recorded.
The data is shown below. Let’s focus on the M2 and GV eggs to start.
For the M2 eggs, you can see that M2 eggs from women <40 had a 63.8% chance to develop into transferable embryos, which decreased to 27.4% in women >45. This was statistically significant (p= 0.003).
For the GV eggs, you can see that GV eggs (that were matured overnight to M2 by rescue IVM) in women <40 had a 2.0% chance to develop into transferable embryos, which increased to 50.0% in women >45. This was statistically significant (p= 0.012).
There was no difference in the ability of M1 eggs (that were matured overnight by rescue IVM) to progress to transferable embryos (p= 0.754).
This shows that with advancing age, the chance of M2 eggs developing into transferable embryos decreases, while the chance of GV eggs developing into transferable embryos increases.
No changes in fertilization rates with HIER, although larger sample size needed
They also looked at rates for fertilization and abnormal fertilization (0PN, 1PN, 3PN, etc.). They found no difference in any of the groups.
However, they did note a non-statistically significant trend, where fertilization rates with GV eggs increased in women with advancing age (33.3% vs 70.6% vs 80.0%, p= 0.097). This was likely non-significant due to the small sample size, the researchers report.
Conclusions
This study found that triggering at a smaller lead follicle size with advancing age had no impact on the proportion of mature (M2), and immature (M1/GV) eggs retrieved.
They also found that with advancing age, the chance of M2 eggs developing into transferable embryos decreased, while the chance of GV eggs developing into transferable embryos increased. In other words, using an earlier trigger time for older women resulted in more transferable embryos (after rescue IVM).
The authors believe that the follicle’s metabolism may speed up with advancing age, however what causes quicker egg maturation specifically isn’t known. Note that “maturation” in this context likely refers to cytoplasmic maturation, which isn’t the same as nuclear maturation.
They point to a study by Fitzgerald et al. (1994), which found that older women have a smaller follicle diameter before ovulation compared to younger women (16.7 mm for women 37-45 vs 19.6 mm, 21.6 mm and 21.3 mm for women 21-25, 26-31 and 32-36, respectively; p< 0.001). In this way, HIER more closely mimics what’s seen in nature, the authors state.
The authors have been practicing HIER at their IVF clinic for years (at the Center for Human Reproduction in New York), and share their target lead follicle sizes by age and diagnosis:
“Like in most IVF centers, up to age 40, in women with normal functional ovarian reserve, the recommended size is 18-22 mm. If women at such young ages, however, suffer from [premature ovarian aging], they also become eligible for HIER. By age 43, the lead follicle size at trigger drops to 16 mm, and to 12–14 mm by age 45.”
Nicholas et al. (2023)
They comment that these target sizes may be adjusted based on additional factors, like the speed of follicle growth, E2 rise and P levels. They note it may be possible to trigger even earlier in older patients to avoid over-maturation of eggs.
On the topic of overmature eggs, the authors note that they “were surprised by the observation that despite at times very early retrievals at lead follicle sizes as small as 11-12 mm, many M2 oocytes were still over-matured and, therefore, did progressively worse in producing good quality transferable embryos with advancing female age.”
Obviously, this was a small study and needs to be repeated in a larger group and with pregnancy and live birth outcomes, as well as with proper controls (who receive or don’t receive HIER). It would also be nice to see a HIER study report on blastocyst development, rather than day 3 embryos.
Another point worth mentioning is that they found similar proportions of immature and mature eggs with age, so with this in mind how would it benefit older women if they’re not getting more immature eggs?
Often earlier triggers are considered to avoid over-maturation of eggs, which might be more common in older women. Other studies have shown that earlier triggers produce more immature eggs (here’s a couple I reviewed: here and here).
So it’s surprising that they didn’t find much of a difference in the proportions of GV/M1/M2. However, their average follicle size at 45+ was 14.4 ± 3.3 mm, which isn’t that small, and there were only 20 women in this group. It’s possible they didn’t see a difference because of the smaller sample size, and the relatively large follicle size in their early trigger group.
The overall message here is that GVs tend to produce more usable embryos than M2s in older patients. Generally, to get more GVs you would trigger earlier. Together this suggests that an earlier trigger might help in reducing the number of overmature eggs (they didn’t measure this) and might help in making more usable embryos (through rescue IVM of GVs).
Reference
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About Embryoman
Embryoman (Sean Lauber) is a former embryologist and the founder of Remembryo, an IVF research and fertility education website. After working in an IVF lab in the US, he returned to Canada and now focuses on making fertility research more accessible. He holds a Master’s in Immunology and launched Remembryo in 2018 to help patients and professionals make sense of IVF research. Sean shares weekly study updates on Facebook, Instagram, and Reddit regularly. He also answers questions on Reddit or in his private Facebook group.
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