rs4944653 — PRSS23 PRSS23 Ovarian Serine Protease

PRSS23 — When a Follicle Culling Enzyme Receives Too Much Encouragement

Every menstrual cycle, hundreds of follicles begin to grow but only one (occasionally two) is selected to ovulate. The rest undergo programmed destruction — a process called follicular atresia¹¹ follicular atresia
the apoptotic elimination of follicles that fail the selection process; accelerated atresia reduces ovarian reserve and is implicated in PCOS, diminished ovarian reserve, and early menopause — and the rate at which this culling occurs determines how rapidly the ovarian reserve depletes over a woman's reproductive lifespan. PRSS23²² PRSS23
serine protease 23; a conserved trypsin- family endopeptidase expressed in granulosa cells, theca tissue, and atretic follicles; located at chromosome 11q14.2 is one of the enzymes that carries out this culling. The rs4944653-G variant, located approximately 50 kilobases downstream of the PRSS23 gene, tags a regulatory signal that amplifies PRSS23 activity — and the consequences show up in measurable changes in circulating FSH.

The Mechanism

PRSS23 is expressed primarily in granulosa cells of secondary and early antral follicles — the very cells responsible for producing estrogen and expressing FSH receptor (FSHR). A 2026 study in avian granulosa cells³³ A 2026 study in avian granulosa cells
Wang et al. PRSS23 Promotes Ovarian Follicular Atresia in Wuding Chickens by Coordinately Suppressing Steroidogenesis and PI3K/AKT/mTOR Survival Signaling. Genes (Basel), 2026 showed that PRSS23 overexpression simultaneously downregulates FSHR and the steroidogenic enzymes CYP19A1, StAR, and HSD3β1, while activating the mitochondrial apoptotic pathway (increasing BAX, decreasing BCL2) via PI3K/AKT/mTOR inhibition. The result is cell cycle arrest and granulosa cell death — the molecular signature of atresia.

Critically, PRSS23 expression is downregulated by gonadotropins near the time of ovulation, ⁴⁴ Wahlberg et al. Expression and localization of the serine proteases HtrA1, SP23, and SP35 in the mouse ovary. Endocrinology, 2008 suggesting FSH normally suppresses this atretic enzyme to protect dominant follicles. When the rs4944653-G allele increases PRSS23 expression in the follicular microenvironment, the pituitary must compensate by producing more FSH to overcome amplified atretic pressure — hence the higher serum FSH seen in G carriers.

The Evidence

The clearest human evidence comes from Tidwell et al. 2024⁵⁵ Tidwell et al. 2024
Phenotypes Associated With Polycystic Ovary Syndrome Risk Variants. J Endocr Soc, 2024, a study of 404 PCOS cases and 408 controls from the Utah PCOS cohort. The rs4944653-G allele showed a strict dose-response relationship with FSH levels: AA carriers averaged 9.0 ± 3.1 IU/L, AG carriers 9.5 ± 3.2 IU/L, and GG homozygotes 10.7 ± 4.6 IU/L. The association survived adjustment for both age (beta 0.040 ± 0.010, P<.001) and BMI (beta 0.041 ± 0.010, P<.001), confirming it is not mediated by obesity — a key distinction in a PCOS population.

The PRSS23 locus was also among the loci associated with gonadotropin levels in this study, alongside the well-established FSHB locus. The G allele is common: approximately 62% of women globally are GG homozygotes, and a further 33% are AG heterozygotes, meaning fewer than 5% of women carry the AA (lowest-FSH) genotype.

The broader PCOS genetic architecture was established by the Day et al. 2018 meta-analysis⁶⁶ Day et al. 2018 meta-analysis
Large-scale genome-wide meta-analysis of polycystic ovary syndrome suggests shared genetic architecture for different diagnosis criteria. PLoS Genetics, 2018, which identified 14 genome-wide significant loci across 10,074 cases and 103,164 European-ancestry controls. PRSS23-region variants sit within this PCOS risk landscape, providing the biological rationale for the FSH association: elevated FSH in the absence of ovarian failure may reflect a continuous push against increased follicular atresia at the granulosa cell level.

Practical Actions

For women with one or two copies of the G allele, the elevated FSH signal has two actionable implications. First, standard FSH thresholds used to assess ovarian reserve (the commonly used "normal < 10 IU/L" cut-off) may need to be contextualised genetically — a GG woman with FSH of 10.5 IU/L may be within her genotype-normal range rather than showing early diminished ovarian reserve. Second, women with GG genotype and PCOS should discuss whether their FSH level is primarily driven by genetic background or by PCOS- related gonadotropin dysregulation, as this distinction affects treatment decisions.

Anti-Müllerian hormone (AMH) — which reflects the number of remaining antral follicles and is not directly influenced by this PRSS23 variant — provides a complementary measure of ovarian reserve that is unconfounded by this genetic background FSH elevation.

Interactions

The rs4944653 PRSS23 variant acts through the FSH axis and thus interacts conceptually with variants in the FSHB gene (rs11031006, which directly encodes the FSH beta subunit) and with ovarian reserve variants such as HELQ rs12651246. A woman carrying both elevated- FSH PRSS23 genotype and a FSHB variant would be expected to show compounded gonadotropin dysregulation, though direct interaction studies have not yet been published.

The PCOS susceptibility locus ZBTB16 (rs1784692) and the PRSS23 locus both appear in the Tidwell et al. 2024 study, and while they affect different PCOS phenotypic features (ovarian morphology vs. FSH levels respectively), women carrying risk alleles at both loci may present with a more complete PCOS endocrine profile.