Sir, We have read with great interest the recently published MHR article by Bernstein et al.(2023):‘Maternal age and gonadotrophin elevation cooperatively decrease viable ovulated oocytes and increase ootoxicity, chromosome, and spindle-misalignments: 2-Hit and FSH-ootoxicity mechanisms as new reproductive aging hypotheses’. First, we would like to congratulate the authors for their study that sheds further light on a crucial topic in reproductive medicine, ie the potential impact of excessive FSH signaling on oocyte developmental competence. However, while recognizing the relevance and soundness of the study by Bernstein et al., we believe that it is important to highlight for the readership additional published studies that are highly pertinent to the topic. More than 15 years ago, based on the association between increased basal FSH concentrations and aneuploidy incidence in both adolescents and women at advanced maternal age, Dursun et al.(2006) first proposed that increased gonadotropin levels could disrupt meiotic accuracy by compromising cytoskeleton dynamics. Recently, motivated by data indicating that increased serum and intrafollicular FSH levels are negatively associated with oocyte quality (Ciepiela et al., 2019; Buratini et al., 2021), we produced an extensive literature review articulating data from women and different animal models, strongly supporting the hypothesis that excessive FSH signaling in cumulus cells can be detrimental to oocyte homeostasis and mediate, at least in part, the effects of aging on oocyte developmental competence (Buratini et al., 2022). The previous paper by Dursun et al.(2006) was cited in our review. In addition, based principally on possibly neglected data generated by David Albertini’s group around 20 years ago, indicating that excessive FSH signaling can cause retraction of transzonal projections (TZP; Combelles et al., 2004), we further hypothesized that an FSH-induced decrease of cumulus–oocyte communication is a major underlying cause of important deleterious events often associated with oocyte aging such as increased oxidative stress, increased DNA damage and/or increased incidence of meiotic errors. Interestingly, a recent paper published by our group further supported this hypothesis, presenting evidence that oocyte-secreted factors suppress FSH signaling in cumulus cells by reducing FSH receptor expression, while increasing that of anti-Müllerian hormone, a potent paracrine inhibitor of FSH activity (Buratini et al., 2023). Hence, our recent data strongly indicate that the oocyte reduces FSH activity in cumulus cells, in an apparent effort to safeguard/maximize TZP-mediated cell-tocell communication and, consequently, the delivery of cumulusderived factors essential to meiotic accuracy and developmental competence.

In conclusion, we suggest that our work, and the previous work of others, reinforces the importance of the data presented in the recent paper by Bernstein et al.(2023). More importantly, taken together, the studies above provide a compelling argument for further investigation and more in-depth data interpretation in order to clarify the participation of increased FSH activity in the etiology of age-related subfertility. Therefore, we hope that this letter may serve to reinforce the importance of our converging hypotheses and hence motivate further research of this extremely relevant topic to the progress of reproductive biology and medicine.