In human in vitro fertilization, the main uncertainty factor impacting on success is oocyte quality, which largely depends on the follicular status at the time of collection. Decades of debate ensued to find the perfect stimulation protocol demonstrated the complexity of the ovarian response to exogenous gonadotropins and the dynamic nature of late folliculogenesis. Although several follicular markers, proteins, RNA from granulosa cells or microRNA, and follicular fluid metabolites have been associated with outcome, the possibility to influence them during stimulation remains elusive. The heterogeneity of the follicle's maturity following control ovarian stimulation is also an important factor to explain average poor oocyte quality still observed today. In this review, the analogy between the apple ripening on the tree and follicular development is presented to focus the attention on a biphasic process: growth and differentiation. The molecular analysis of the progressive follicular differentiation indicates two competing phenomena: growth and differentiation, where a delicate balance must operate from one to the other to ensure proper maturity at ovulation. As long as follicle-stimulating hormone (FSH) stimulates growth, follicles remain green, and it is only when FSH is replaced by luteinizing hormone that the ripening process begins, and “apples” become red. Both fruits, follicles and apples, depend on a perfect timing of events to generate offspring.

Summary Sentence

The importance of the final differentiation process during follicular dominance in relation to the resulting oocyte quality.

Graphical Abstract