Impact of female age on concentrations of reproductive hormones and oocyte-specific growth factors in follicular fluid from human small antral follicles
Authors: Wang N Friis , Mamsen L S , Cadenas J , Saritas G , Macklon K T , Fedder J , Ernst E , Johannsen M L , Kristensen S G , Kelsey T , Kumar A , Kalra B , Løssl K , Andersen C Yding 
Published: February 2025

Abstract

STUDY QUESTION
Does maternal age impact hormonal secretions from granulosa cells, theca cells, and the oocyte in human small antral follicles?

SUMMARY ANSWER
Major hormones secreted by granulosa and theca cells, as well as the oocyte-specific TGF-β members—GDF9, BMP15, and the GDF9/BMP15 heterodimer cumulin—maintain a consistent concentration within the follicular fluid of human small antral follicles, regardless of maternal age.

WHAT IS KNOWN ALREADY
It is well established that female fertility declines with increasing age. However, it is not known whether this decline is exclusively due to a reduction in oocyte quality and quantity or also involves a decline in the hormone-secreting capabilities of granulosa cells, theca cells, and the oocyte itself.

STUDY DESIGN, SIZE, DURATION
This is a retrospective study of follicular fluid obtained from human small antral follicles collected in connection with cryopreservation of ovarian tissue at the Laboratory of Reproductive Biology, University Hospital Copenhagen, Rigshospitalet, Denmark, between 2010 and 2020 as part of the hospital’s fertility preservation program.

PARTICIPANTS/MATERIALS, SETTING, METHODS
Follicular fluid samples from human small antral follicles measuring 3–13 mm in diameter from macroscopically normal ovaries of 381 patients aged 5–43 years were included in the study, provided that at least one of the following parameters was measured: AMH, Inhibin A, Inhibin B, oestradiol (E2), progesterone (P4), androstenedione, testosterone, and/or the oocyte-specific TGF-β members GDF9, BMP15, or cumulin.

MAIN RESULTS AND THE ROLE OF CHANCE
In a linear regression analysis adjusted for follicular volume, female age did not predict the follicular fluid concentrations of AMH, Inhibin B, Inhibin A, E2, androstenedione, testosterone, GDF9, BMP15, or cumulin. Although a significant association was observed between female age and follicular fluid P4 levels, the predictive value of age was poor, accounting for at most 5% of the variation in P4.

LIMITATIONS, REASONS FOR CAUTION
Hormonal levels may vary with the degree of atresia in each follicle; however, the health status of the small antral follicles in this study was not characterized. Additionally, we cannot exclude possible age-related differences in human follicles larger than 10 mm, as very few of these were included. Furthermore, we did not include women above the age of 43, despite the potential for more pronounced age-related effects in these patients.

WIDER IMPLICATIONS OF THE FINDINGS
Our results support the idea that the age-related decline in female fertility is primarily due to a reduction in oocyte quality and quantity, but further research is needed to confirm this.

STUDY FUNDING/COMPETING INTEREST(S)
No specific funding was obtained, and the authors have no conflicts of interest to declare in relation to this work.

TRIAL REGISTRATION NUMBER
N/A.