A trial comparing a modified letrozole protocol with a conventional GnRH antagonist protocol found no significant difference in cumulative live birth rates: 24.5% versus 22.6%.
Stimulation was shorter and gonadotropin use lower with letrozole, but fewer mature eggs and usable embryos were obtained, highlighting the need for individualized treatment.
Reduced ovarian function can create considerable difficulties for women undergoing IVF. Follicles may not grow sufficiently despite stimulation injections, and even a difficult egg retrieval may not produce embryos for transfer.
Increasing injection doses or adding another medication may be considered in such circumstances. More medication, however, does not necessarily mean more eggs or a higher chance of pregnancy.
How much difference can a change in stimulation approach make? Researchers in China reported a randomized trial comparing two protocols in 318 women with ovarian aging or diminished ovarian reserve.
Adding letrozole shortened ovarian stimulation
The researchers assigned 318 participants to two groups of 159. One received a modified protocol combining letrozole with gonadotropin injections; the other received a GnRH antagonist protocol widely used in IVF.
Letrozole inhibits estrogen synthesis and can modify the hormonal environment involved in follicle growth. The trial examined whether adding it to stimulation injections changed egg retrieval, pregnancy and birth outcomes.
Mean stimulation duration was 6.6 days with the letrozole protocol, compared with 9.4 days with the conventional protocol—a difference of approximately 2.8 days. Mean total gonadotropin use was also lower: 2,006 IU versus 2,653 IU.
However, the mean number of mature eggs retrieved was 2.4 with letrozole and 3.1 with the conventional protocol. The numbers of embryos usable for transfer or freezing were 2.0 and 2.7, respectively. Less medication and shorter stimulation did not translate into more eggs or embryos.
No significant live birth difference; a pregnancy finding in a subgroup
For IVF, the most important outcome is ultimately a live birth, rather than the number of eggs retrieved. Cumulative live birth rates using embryos obtained from one stimulation were 24.5% in the letrozole group and 22.6% in the conventional group. The difference was not statistically significant.
Cumulative clinical pregnancy rates were also similar, at 32.1% and 34.0%, respectively. Adding letrozole did not clearly improve pregnancy or live birth outcomes across the overall trial population.
An interesting difference appeared in a subgroup. Among women younger than 40 with diminished ovarian reserve who received a fresh transfer of two day-3 embryos, the clinical pregnancy rate was 65.8% with letrozole and 36.4% with the conventional protocol.
This was a subgroup analysis of patients meeting specific conditions. It should not be interpreted as evidence that the letrozole protocol benefits every woman with reduced ovarian function or that it improves live birth rates.
Choosing a treatment strategy matters more than simply increasing medication
The study highlights the need to consider both medication burden and stimulation approach in women with impaired ovarian function. The letrozole protocol used fewer gonadotropins over a shorter period, but did not demonstrate superior overall cumulative live birth outcomes.
There were important limitations. Recruitment ended at 318 participants, below the planned sample size, partly because of the COVID-19 pandemic. The limited sample also means that the two treatments cannot be declared equivalent. Further research is needed to investigate the pregnancy difference observed in the subgroup.
Women with reduced ovarian reserve do not all require the same treatment. Age, ovarian reserve, responses in previous cycles, and the characteristics of retrieved eggs and embryos can all influence the appropriate stimulation strategy.
The practical message is that simply increasing injections is not necessarily the best answer to reduced ovarian function. Selecting a suitable approach matters more than medication quantity alone. Any change in treatment or use of letrozole should be discussed with the treating fertility specialist.
Source: “Modified letrozole vs GnRH antagonist protocols in ovarian aging women for IVF: an open-label, multicenter, randomized controlled trial,” by researchers including Guangdong Provincial People's Hospital and Sun Yat-sen University, China. Published in Nature Communications on March 20, 2026. DOI: 10.1038/s41467-026-70964-5.
Related reading: Why AMH and antral follicle count need to be interpreted together when predicting egg yield.
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