Apoptosis plays a crucial part in human ovarian function from fetal development to the end ofreproductive potential. Failures in the regulation of ovarian apoptosis are associated with manypathological conditions such as premature ovarian insufficiency, infertility and cancer. Thepurpose of the present study was to analyze the factors regulating cell survival in human fetal andadult ovaries.

The fetus is exposed to maternal- and placental-derived estrogens and insufficient estrogenaction has destructive effects on rodent ovarian development. We detected estrogen receptors andestrogen-converting enzymes in human fetal ovaries after primordial follicle formation, indicatingthat estrogens participate in human fetal ovarian development, especially after folliculogenesis

The WNT4 gene is crucial for female sexual differentiation, follicle formation and oocytesurvival. We detected WNT4 in follicular cells of fetal and adult human ovaries. In addition, Wnt4-knockout mice demonstrated a dramatic loss of oocytes before birth. However, no changes weredetected in protein expression patterns of common apoptosis-related proteins. The results supportthe possible role of WNT4 in human ovarian function and strengthen previous knowledge on theantiapoptotic role of Wnt4.

Apoptosis signaling is mediated by extracellular- and mitochondria-associated- pathways,ending in caspase cascade activation and fragmentation of cellular structures. In the present studywe analyzed the expression of several apoptosis-related factors and detected TRAIL, TNF, Bcl-XL, Bok and caspase-3 in human ovaries. In addition, TRAIL was found to be a potent and rapidinducer of human granulosa tumor cell (KGN) apoptosis. Lentiviral downregulation of Bok orBcl-XL protein expression in KGN cells also resulted in significant changes in cell vulnerabilityto apoptosis. The results show for the first time the spatiotemporal expression patterns of TRAIL,TNF, Bcl-XL, Bok and caspase-3 in human ovaries and suggest an important functional role ofTRAIL, Bok and Bcl-XL in regulation of human ovarian apoptosis.

The present study offers novel information on the expression and function of cell survivalfactors in human ovaries. These new findings open possibilities for future clinical research inattempts to understand and treat ovarian diseases caused by imbalanced regulatory pathways ofapoptosis.