Nervous System Peptides May Contribute To Ovarian Failure

Sergio R. Ojeda, D.V.M. Division Head and Senior Scientist Division of Neuroscience Division of Neuroscience, OR National Primate Research Center/Oregon Health and Science University, Beaverton OR 97006 MedicalResearch.com Interview with:
Sergio R. Ojeda, D.V.M.
Division Head and Senior Scientist Division of Neuroscience
Division of Neuroscience, OR National Primate Research Center/Oregon Health and Science University,
Beaverton OR 97006

MedicalResearch: What are the main findings of the study?

Dr. Ojeda: The study shows that a receptor for two growth factors (brain-derived neurotrophic factor and neurotrophin 4/5 ) that are known to be important for development of the nervous system is also essential for maintaining oocyte integrity and survival in the mammalian ovary. Intriguingly, the full-length form of this receptor (known as NTRK2-FL) is not expressed in oocytes until the time of the first ovulation. At this time, the pre-ovulatory gonadotropin discharge stimulates granulosa cells of ovarian follicles to produce not only more BDNF, but also more of a peptide known as kisspeptin, to induce the formation of NTRK2-FL in oocytes. To date, kisspeptin was known to be only critical for the hypothalamic control of reproduction. To induce NTRK2-FL, BDNF binds to truncated NTRK2 receptors (NTRK2-T1), which are abundant in oocytes throughout prepubertal development. Kisspeptin, on the other hand, does so by activating its receptor KISS1R, also expressed in oocytes. Once present after the first ovulation, NTRK2-FL is able to activate a survival pathway in oocytes following gonadotropin stimulation, presumably at every cycle. In the absence of NTRK2-FL, oocytes die, follicular structure disintegrates and a condition of premature ovarian failure ensues.

MedicalResearch: Were any of the findings unexpected?

Dr. Ojeda: Two findings were unexpected;

1) That the presence of NTRK2-FL in oocytes is required for gonadotropins to support oocyte survival after puberty, but not before the first ovulation, and

2) That preovulatory levels of gonadotropins require the dual release of BDNF and kisspeptin from granulosa cells of antral follicles to induce the expression of NTRK2-FL in oocytes. These findings indicate that oocyte survival after puberty is maintained by recurrent preovulatory increases in pituitary gonadotrophin secretion, but that, surprisingly, this effect is mediated by the concerted action of a neurotrophic factor (BDNF) and a neuroendocrine peptide (kisspeptin).

MedicalResearch: What should clinicians and patients take away from your report?

Dr. Ojeda: That loss of ovarian function during adulthood may be caused not only by endocrine factors but also by loss of function of two peptides previously known to be only important for nervous system development and for the hypothalamic control of reproduction.

MedicalResearch: What recommendations do you have for future research as a result of this study?

Dr. Ojeda: It will be important to carry out studies to determine if common genetic variation affecting the genes encoding BDNF and its receptor NTRK2-FL, in addition to KISS1 (the gene encoding kisspeptin) and KISS1R (the gene encoding the kisspeptin receptor) are affected in patients with premature ovarian failure. If this proven to be the case, it will be important to find ways to treat the disorder by administering BDNF and kisspeptin agonists.

Citation:

Loss of Ntrk2/Kiss1r signaling in oocytes causes premature ovarian failure

Dorfman MD1, Garcia-Rudaz C, Alderman Z, Kerr B, Lomniczi A, Dissen GA, Castellano JM, Garcia-Galiano D, Gaytan F, Xu B, Tena-Sempere M, Ojeda SR.
Endocrinology. 2014 May 30:en20141111.