Role of Activin in Follicular Development
Activin functions as a critical autocrine/paracrine regulator that promotes follicular growth and granulosa cell proliferation while preventing premature luteinization and follicular atresia throughout multiple stages of follicle development.
Primary Functions of Activin in Folliculogenesis
Promotion of Follicular Growth and Granulosa Cell Proliferation
- Activin-A directly stimulates granulosa cell proliferation, increasing both cell number and thymidine incorporation more than 2-fold in cultured granulosa-oocyte complexes 1
- Activin enhances follicular thymidine incorporation, demonstrating its role in promoting cell division during follicular development 2
- In the presence of FSH, activin-A induces reorganization of follicular structures from monolayer cultures, causing cells from primary follicles to develop into large follicle-like structures exceeding 1 mm in diameter with proper antral formation 1
Regulation of Follicular Activation and Preantral Development
- Activin-A treatment significantly increases preantral follicle numbers (P<0.0001) in cultured postnatal ovaries, demonstrating a stimulatory role in the primordial to primary and preantral stages 3
- Activin decreases the proportion of atretic follicles in both primary and preantral classes when administered alone, suggesting an inhibitory action on oocyte apoptosis 3
- Activin acts as a follicular growth signal in a paracrine manner, with specific receptors identified on granulosa cells (2.3 × 10⁴ receptors/cell) 2
Molecular Mechanisms and Gene Expression
Regulation of Follicular Gene Expression
- Activin-A upregulates expression of follistatin, FSH receptor, and activin βA and βB subunits in ovarian tissue, creating a coordinated regulatory network 3
- Activin directly induces both estrogen receptor alpha (ERα) and estrogen receptor beta (ERβ) gene expression in granulosa cells at the transcriptional level, with effects observable at 4,12, and 24 hours 4
- This induction of estrogen receptors by activin is mediated through Smad2 and Smad3 signaling pathways, as demonstrated by decreased ER expression in mice with impaired activin-Smad2 signaling 4
Prevention of Premature Luteinization
- Activin maintains the folliculogenic state by preventing premature luteinization during later stages of antral follicle development, either alone or in combination with FSH 5
- Activin promotes granulosa cell differentiation during preantral and early antral stages while maintaining follicular integrity 5
Interaction with FSH and Other Regulatory Factors
Synergistic and Antagonistic Effects
- The PI3K-PTEN-AKT-FOXO3 pathway plays a fundamental role in FSH stimulation of granulosa cell differentiation in antral follicles and oocyte maturation in preovulatory follicles 6
- When activin-A is combined with FSH, the proportion of atretic preantral oocytes increases, suggesting complex interactions between these hormones that may be context-dependent 3
- Activin has a negative paracrine action on LH-induced androgen production by theca cells, contrasting with inhibin's positive regulatory role 5
Modulation by Follistatin
- Follistatin neutralizes activin's actions through direct binding, modulating granulosa cell function in favor of luteinization or atresia 5
- The activin effect on granulosa cell proliferation can be completely inhibited by follistatin, an activin-binding protein 1
Clinical Relevance in Fertility Preservation
Role in Follicular Activation Protocols
- In vitro activation protocols targeting the PI3K-PTEN-AKT-FOXO3 pathway (which interacts with FSH-mediated activin signaling) are under development to increase the pool of viable activated follicles for in vitro growth procedures 6
- These pathways have demonstrated clinical success, with live births achieved after IVF and embryo transfer in women with primary ovarian insufficiency using follicle activation approaches 6
Important Caveats
- The effect of activin is highly dependent on the developmental stage of the follicle and the presence of other hormones, particularly FSH, which can modify activin's actions from protective to potentially detrimental 3
- While activin promotes follicular development when administered alone, its combination with FSH may increase atresia in certain follicular stages, highlighting the importance of precise hormonal balance 3
- Activin's role as both a growth promoter and potential atresia regulator depends on the specific follicular microenvironment and developmental context 2, 5