**Background:** Autophagy is a highly conserved cellular process that degrades cytoplasmic components via autophagosome-lysosome fusion to maintain homeostasis. It is involved in energy production, clearance of damaged organelles, and protein quality control. Dysregulation of autophagy contributes to neurodegenerative diseases, cancer, diabetes, and reproductive disorders. This narrative review aims to provide guidance on interpreting autophagic experiments and to summarize the role of autophagy in female reproduction, including ovarian function, embryonic development, decidualization, placentation, and pregnancy complications.
**Methods:** This is a narrative review. The authors searched PubMed for papers related to 'Autophagy and Reproduction' and note that fewer than 50 papers existed before 2011, with over 100 published annually since 2013 and over 200 since 2017. The review synthesizes findings from in vitro studies, animal models (primarily conditional knockout mice), and human placental tissue analyses. Key experimental methods discussed include western blotting for LC3-II and p62, use of bafilomycin A1 (BAF) or chloroquine to assess autophagy flux, immunocytochemistry for LC3 puncta, and genetic manipulation (siRNA, CRISPR, conditional knockout) of autophagy-related genes such as Atg5, Atg7, Atg16L1, Becn1, FIP200, and TFEB.
**Key Results:** (1) Ovarian function: Systemic Atg5 knockout mice show normal follicular development but lack corpus luteum and have increased atretic follicles, indicating ovulation failure. Ovary-specific Becn1 conditional knockout mice show >75% Becn1 reduction, p62 accumulation in granulosa cells, and increased miscarriages due to failure of progesterone production from impaired lipid droplet storage. FSH induces progesterone production via BECN1-mediated lipid droplet degradation in porcine granulosa cells. WT1 transcription factor, whose degradation is mediated by p62 via Epg5, suppresses FSHR and aromatase when accumulated due to autophagy inhibition. NLRP3 inflammasome mRNA is significantly higher in granulosa cells from patients with diminished ovarian reserve; MCC950 (NLRP3 inhibitor) suppresses age-dependent follicular atresia and increases pregnancy rate in aged mice. (2) Embryonic development: Autophagy is activated within 4 hours of fertilization. Atg5-null embryos arrest at the four- to eight-cell stage. Aneuploid mosaic embryos are eliminated via p53-dependent cell death, which is augmented by BAF or Atg5 deletion. Deletion of upstream factors (Becn1, FIP200, AMBRA1) causes embryonic lethality, while deletion of downstream factors (Atg5, Atg7, Atg9a, Atg16L) results in fetal growth restriction but not lethality. LC3B and GABARAP knockout mice are born normally with normal weight. (3) Decidualization: Autophagy flux increases in human immortalized endometrial stromal cells (ESCs) during decidualization. Atg16L1 siRNA reduces decidualization markers IGFBP1 and prolactin. Uterine Atg16L1 conditional knockout shows complete failure of decidualization and reduced implantation rate. FIP200 conditional knockout uterus shows complete implantation failure due to failure of progesterone-dependent vascular permeability. In contrast, Atg7 conditional knockout in uterus shows normal fertility in 8-week-old mice. (4) Placentation: LC3 puncta are observed in extravillous trophoblast (EVT) cells at 7 weeks of gestation. Hypoxia (2% oxygen) activates autophagy in primary trophoblasts. Autophagy-suppressed EVT cells (ATG4B C74A mutant) show failure of invasion and vascular remodeling under hypoxia. Placenta-specific Atg7 conditional knockout mice exhibit inhibited placental growth with poor trophoblast invasion. During syncytialization, LC3-II increases but appears saturated in terminally syncytialized cells; TFEB downregulation and p62 accumulation suggest autophagy suppression. BAF inhibits syncytial fusion and hCG production. TFEB-deficient placentas fail to construct the labyrinth layer, causing embryonic lethality. (5) Pregnancy maintenance: In preeclamptic placentas, conflicting reports exist on LC3-II and p62 expression. Declines in ATG3, ATG101, ATG5-12 complex, LAMP1, LAMP2, and TFEB suggest autophagy inhibition. Excessive autophagy activation mediated by ceramide, CYP11A1, or PKCβ inhibition has also been reported. Hypoxia-reoxygenation decreases autophagosome and autolysosome numbers in trophoblasts. ER stress inducers inhibit autolysosome formation by reducing lysosome numbers. Hydrogen peroxide activates autophagy in trophoblast cell lines in a dose-dependent manner and increases phosphorylated-p62, which induces heme oxygenase-1 (HO-1) via the p62-NBR1-Nrf2 axis. BAF decreases HO-1 and NQO1 expression. NBR1 is required for Nrf2-mediated antioxidant response independent of macroautophagy.
**Clinical Implications:** Autophagy is essential for normal ovarian function, embryonic development, decidualization, and placentation. Dysregulated autophagy—whether excessive or insufficient—is associated with preeclampsia, fetal growth restriction, recurrent pregnancy loss, and infertility. The authors emphasize that in fixed human tissues, increased LC3-II can indicate either autophagy activation or inhibition (due to lysosomal impairment), and therefore must be interpreted cautiously alongside other markers (p62, ATG proteins, electron microscopy). The p62-NBR1-HO-1 axis may represent a macroautophagy-independent antioxidant defense mechanism in trophoblasts. The authors conclude that maintaining normal autophagic homeostasis, rather than simply activating or inhibiting autophagy, is necessary for reproductive health. Future research should focus on identifying specific post-translational modifications of ATG proteins and tissue-specific markers for the female reproductive tract.