Evidence for <i>de novo</i> synthesis of corticosteroids in the human ovary

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Original abstract

Abstract STUDY QUESTION Does the human ovary possess the enzymatic machinery required for local corticosteroid synthesis during follicular development? SUMMARY ANSWER The human ovary exhibits dynamic corticosteroid metabolism during follicular development and expresses enzymes consistent with local corticosteroid synthesis. WHAT IS KNOWN ALREADY Cortisol is a systemic glucocorticoid that binds to the glucocorticoid receptor (NR3C1), which is expressed in ovarian tissues. While excess systemic cortisol impairs follicular development, a surge in local cortisol activity around ovulation appears necessary for limiting the impact of the inflammatory process taking place. The preovulatory upregulation of 11β-hydroxysteroid dehydrogenase type 1 (HSD11B1) suggests local conversion of cortisone to active cortisol. However, whether the ovary can synthesize corticosteroids de novo remains uncertain. STUDY DESIGN, SIZE, DURATION This observational study included samples from 34 women undergoing ovarian cryopreservation and samples from 50 women undergoing IVF/ICSI according to a standard antagonist protocol at a university hospital-affiliated fertility clinic in Denmark. PARTICIPANTS/MATERIALS, SETTING, METHODS Women donated follicular fluid (FF), plasma, and granulosa cells. Steroid concentrations in FF and plasma were quantified using LC-MS/MS. Granulosa cell mRNA expression of steroidogenic enzymes (CYP11B1, CYP11B2, CYP21A2, HSD11B1, HSD11B2) was assessed by RT-qPCR. In addition, immunofluorescence (IF) was used to localize CYP21A2 in preantral and small antral follicles. FF samples were stratified according to follicle size (2–18 mm) and ovulatory status. Hormone dynamics and FF/plasma ratio were evaluated using linear mixed-effects models and non-parametric tests. MAIN RESULTS AND THE ROLE OF CHANCE Intrafollicular cortisol levels increased with follicle size up to 8–10 mm, then declined until close to ovulation, where a sharp increase was observed (from &amp;lt;40 to ∼100 nM). In contrast, cortisone showed an inverse pattern, remaining elevated throughout the follicular phase but dropping sharply at ovulation. The cortisol/cortisone ratio shifted markedly at the time corresponding to ovulation. Cortisol precursors, particularly 11-deoxycortisol and 11-deoxycorticosterone, were substantially enriched in FF compared to plasma (FF/plasma ratios &amp;gt;10), suggesting local synthesis. This is supported by the expression of CYP21A2 and low-level CYP11B1 mRNA in GCs, and by IF localization of CYP21A2 in preantral and small antral follicles. In contrast, FF cortisol concentrations were consistently lower than in plasma (FF/plasma ratio &amp;lt;0.1), indicating active inactivation by HSD11B2, which was abundantly expressed. HSD11B1 expression was low but detectable in periovulatory follicles, consistent with local reactivation of cortisone to cortisol. Among mineralocorticoids, corticosterone was only detectable at ovulation, while aldosterone was undetectable. LIMITATIONS, REASONS FOR CAUTION We were unable to localize CYP11B1 at the protein level due to limitations in available antibodies. Additionally, FF and plasma samples were obtained from different individuals, precluding direct paired comparisons. Some variability in plasma sample collection timing throughout the day also limits conclusions regarding diurnal fluctuations. WIDER IMPLICATIONS OF THE FINDINGS These findings suggest that the human ovary possesses the capacity for partial corticosteroid synthesis, utilizing locally abundant precursors. Cortisol bioactivity appears to be temporally regulated through both inactivation and reactivation mechanisms, enabling a controlled, pro-resolving inflammatory response at ovulation. This mechanism may be essential for timely corpus luteum formation and maintenance of luteal phase integrity. Dysregulation of local cortisol dynamics may contribute to luteal phase insufficiency in a subset of women. The concept of a follicular “inflammatome” and its role in ovulatory success warrants further exploration. FUNDING This research was supported by the University Hospital of Copenhagen (Rigshospitalet), The University of Copenhagen, and Novo Nordisk Foundation grant number NNF21OC00700556, as well as founded by the Interreg ÔKS V through ReproUnion (www.reprounion.eu) and a grant from Region Zealand Research Foundation. The funders had no role in study design, collection of data, analyses, writing of the manuscript, or the decision to submit it for publication. DISCLOSURES During the preparation of this work, the author(s) used ChatGPT 4o for language assistance. After using this tool/service, the author(s) reviewed and edited the content as needed and take(s) full responsibility for the content of the published article. Furthermore, CYA has received consultant fees and honoraria for lectures from Ferring and IBSA. TRIAL REGISTRATION NUMBER N/A.

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