Follicular atresia

Follicular atresia is the breakdown of the ovarian follicles, which consist of an oocyte surrounded by granulosa cells and internal and external theca cells. It occurs continually throughout a woman's life, as she is born with millions of follicles but will only ovulate around 400 times in her lifetime.[1][2] Typically around 20 follicles mature each month but only a single follicle is ovulated; the follicle from which the oocyte was released becomes the corpus luteum. The rest undergo follicular atresia.[3][4][5][6]

Mechanism

Atresia is a hormonally controlled apoptotic process[7] that depends dominantly on granulosa cell apoptosis. Follicular atresia is inhibited by follicle-stimulating hormone (FSH), which promotes follicle development.[8] Once the follicle has developed, it secretes estrogen, which in high levels decreases secretions of FSH.[9] Granulosa cell apoptosis is considered the underlying mechanism of follicular atresia, and has been associated with five ligand-receptor systems involved in cell death:[10][11][12][5] They are:

  • tumor necrosis factor alpha (TNF alpha) and receptors
  • Fas ligand and receptors[4]
  • TNF-related apoptosis-inducing ligand (TRAIL; also called APO-2) and receptors
  • APO-3 ligand and receptors
  • PFG-5 ligand and receptors

Granulosa cell apoptosis is promoted by tumor necrosis factor-alpha (TNFα), though the mechanism of TNFα is unclear.[13][14]

Fas antigen, a cell surface receptor protein that is expressed on granulosa cells, mediates signals that induce apoptosis by binding Fas ligand and therefore plays an important role in follicular atresia. Lack of a functional Fas ligand / Fas receptor system has been linked to abnormal follicle development, and greater numbers of secondary follicles as a result of the inability to induce apoptosis.[15]

TNF-related apoptosis-inducing ligand TRAIL activates Caspase 3 (CASP3), which in turn interacts with caspases 6, 7, 8, 9, and 10 to induce apoptosis in granulosa cells.[16]

In addition, two intracellular inhibitor proteins, cellular FLICE-like inhibitory protein short form (cFLIPS) and long form (cFLIPL), which were strongly expressed in granulosa cells, may act as anti-apoptotic factors.

It has been proposed that enhanced levels of Nitrogen oxide in rats can prevent atresia of the ovarian follicle, and depressed levels have the opposite effect.[17]

Undergoing follicular atresia is necessary in order for women to maintain a healthy reproductive system. The inability to regulate granulosa cell apoptosis and undergo follicular atresia has been linked to the development of some hormone-related cancers and chemo-resistance.[18]

See also

References
  1. [Faddy, M. J. "Follicle dynamics during ovarian ageing." Molecular and Cellular Endocrinology 163.1 (2000): 43-48.]
  2. [Hampson, Elizabeth, and Elizabeth A. Young. "Methodological issues in the study of hormone-behavior relations in humans: Understanding and monitoring the menstrual cycle." Sex differences in the brain. From genes to behavior (2008): 63-78.]
  3. Rolaki A, Drakakis P, Millingos S, Loutradis D, Makrigiannakis A (July 2005). "Novel trends in follicular development, atresia and corpus luteum regression: a role for apoptosis". Reprod. Biomed. Online. 11 (1): 93–103. doi:10.1016/S1472-6483(10)61304-1. PMID 16102296.
  4. Manabe N, Matsuda-Minehata F, Goto Y, et al. (July 2008). "Role of cell death ligand and receptor system on regulation of follicular atresia in pig ovaries". Reprod. Domest. Anim. 43. Suppl 2: 268–72. doi:10.1111/j.1439-0531.2008.01172.x. PMID 18638134.
  5. Manabe N, Goto Y, Matsuda-Minehata F, et al. (October 2004). "Regulation mechanism of selective atresia in porcine follicles: regulation of granulosa cell apoptosis during atresia". J. Reprod. Dev. 50 (5): 493–514. doi:10.1262/jrd.50.493. PMID 15514456.
  6. Hsueh AJ, Billig H, Tsafriri A (December 1994). "Ovarian follicle atresia: a hormonally controlled apoptotic process". Endocr. Rev. 15 (6): 707–24. doi:10.1210/edrv-15-6-707. PMID 7705278.
  7. Kaipia A, Hsueh AJ (1997). "Regulation of ovarian follicle atresia". Annu. Rev. Physiol. 59 (1): 349–63. doi:10.1146/annurev.physiol.59.1.349. PMID 9074768.
  8. [Kaipia, Antti, and Aaron JW Hsueh. "Regulation of ovarian follicle atresia." Annual Review of Physiology 59.1 (1997): 349-363.]
  9. Marshall JC, Case GD, Valk TW, Corley KP, Sauder SE, Kelch RP (1983). "Selective inhibition of follicle-stimulating hormone secretion by estradiol. Mechanism for modulation of gonadotropin responses to low dose pulses of gonadotropin-releasing hormone". Journal of Clinical Investigation. 71 (2): 248–257. doi:10.1172/JCI110765. PMC 436863. PMID 6401767.
  10. [Manabe, Noboru, et al. "Regulation mechanism of selective atresia in porcine follicles: regulation of granulosa cell apoptosis during atresia." The Journal of reproduction and development 50.5 (2004): 493.]
  11. Matsuda-Minehata F, Goto Y, Inoue N, Manabe N (October 2005). "Changes in expression of anti-apoptotic protein, cFLIP, in granulosa cells during follicular atresia in porcine ovaries". Mol. Reprod. Dev. 72 (2): 145–51. doi:10.1002/mrd.20349. PMID 16010689.
  12. Matsuda F, Inoue N, Goto Y, et al. (October 2008). "cFLIP regulates death receptor-mediated apoptosis in an ovarian granulosa cell line by inhibiting procaspase-8 cleavage". J. Reprod. Dev. 54 (5): 314–20. doi:10.1262/jrd.20051. PMID 18603835.
  13. [Sasson, Ravid, et al. "Induction of apoptosis in granulosa cells by TNFα and its attenuation by glucocorticoids involve modulation of Bcl-2." Biochemical and biophysical research communications 294.1 (2002): 51-59.]
  14. [Billig, Hakan, I. T. S. U. K. O. Furuta, and A. J. Hsueh. "Estrogens inhibit and androgens enhance ovarian granulosa cell apoptosis." Endocrinology 133.5 (1993): 2204-2212.]
  15. [Sakamaki, Kazuhiro, et al. "Involvement of Fas antigen in ovarian follicular atresia and luteolysis." Molecular reproduction and development 47.1 (1997): 11-18.]
  16. [Inoue, Naoko, et al. "Roles of tumor necrosis factor-related apoptosis-inducing ligand signaling pathway in granulosa cell apoptosis during atresia in pig ovaries." Journal of Reproduction and Development 49.4 (2003): 313-321.]
  17. Najati V, Ilkhanipour M, Salehi S, Sadeghi-Hashjin G (January 2008). "Role of nitric oxide on the generation of atretic follicles in the rat ovaries". Pak. J. Biol. Sci. 11 (2): 250–4. doi:10.3923/pjbs.2008.250.254. PMID 18817198.
  18. [Kim, J. H., et al. "Differential apoptotic activities of wild-type FOXL2 and the adult-type granulosa cell tumor-associated mutant FOXL2 (C134W)." Oncogene 30.14 (2010): 1653-1663.]
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