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Ovulation requires the activation on proestrus of M1 muscarinic receptors in the left ovary

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Abstract

We analyzed the effects of chemically blocking type 1 muscarinic receptors (M1R) on either the left or right ovary on ovulation rate, number of ova shed and steroid hormones levels. M1R were unilaterally blocked in ovary with the M1R selective antagonist pirenzepine (PZP). PZP was delivered into the bursa ovarica of the left or right ovary of adult rats at 13:00 h on proestrus day. PZP treatment in the left but not in the right ovary blocked ovulation. PZP did not modify the number of ova shed, nor progesterone or 17β-estradiol serum levels. The surge of luteinizing hormone levels was diminished while that of follicle-stimulating hormone did not change in animals treated with PZP in the left ovary. Interestingly, treatment with either synthetic luteinizing hormone-releasing hormone or human chorionic gonadotropin 1 h after PZP administration in the left ovary restored ovulation in both ovaries. The presence of M1R protein in the theca cells of the ovarian follicles as well as in cells of the corpus luteum was detected on proestrus day. These results suggest that M1R activation in the left ovary is required for pre-ovulatory gonadotropin-releasing hormone (GnRH) secretion and ovulation. Furthermore, these results also suggest that M1R in the left ovary might be regulating ovulation asymmetrically through a stimulatory neural signal relayed to the hypothalamus via the vagus nerve to induce the GnRH secretion which then triggers ovulation.

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References

  1. H.W. Burden, M. Leonard, C.P. Smith, I.E. Lawrence Jr, The sensory innervations of the ovary: a horseradish peroxidase study in the rat. Anat. Rec. 207, 623–627 (1983)

    Article  CAS  PubMed  Google Scholar 

  2. I. Gerendai, I.E. Tóth, Z. Boldogköi, B. Halàsz, Recent findings on the organization of central nervous system structures involved in the innervations of endocrine glands and other organs; observations obtained by the transneuronal viral double-labeling technique. Endocrine 36, 179–188 (2009)

    Article  CAS  PubMed  Google Scholar 

  3. J. Calka, J.K. McDonald, S.R. Ojeda, The innervation of the immature rat ovary by calcitonin gene-related peptide. Biol. Reprod. 39, 1215–1223 (1988)

    Article  CAS  PubMed  Google Scholar 

  4. G.A. Dissen, S.R. Ojeda, Ovarian innervations, in Encyclopedia of Reproduction, ed. by E. Knobil, J.D. Neil (Academic Press, San Diego, 1999), pp. 583–589

    Google Scholar 

  5. R.F. Gilbert, P.C. Emson, J. Fahrenkrug, C.M. Lee, E. Penman, J. Wass, Axonal transport of neuropeptides in the cervical vagus nerve of the rat. J. Neurochem. 34, 108–113 (1980)

    Article  CAS  PubMed  Google Scholar 

  6. R. Chávez, S. Sánchez, A. Ulloa-Aguirre, R. Domínguez, Effects on oestrous cyclicity and ovulation of unilateral section of the vagus nerve performed on different days of the oestrous cycle in the rat. J. Endocrinol. 123, 441–444 (1989)

    Article  PubMed  Google Scholar 

  7. H.W. Burden, I.E. Lawrence Jr, T.M. Louis, C.A. Hodson, Effect of abdominal vagotomy on the estrous cycle of the rat and the induction of pseudopregnancy. Neuroendocrinology 33, 218–222 (1981)

    Article  CAS  PubMed  Google Scholar 

  8. H.W. Burden, I.E. Lawrence Jr, The effect of denervation on compensatory ovarian hypertrophy. Neuroendocrinology 23, 368–378 (1977)

    Article  CAS  PubMed  Google Scholar 

  9. S.R. Ojeda, S.S. White, L.I. Aguado, J.P. Advis, J.M. Andersen, Abdominal vagotomy delays the onset of puberty and inhibits ovarian function in the female rat. Neuroendocrinology 36, 261–267 (1983)

    Article  CAS  PubMed  Google Scholar 

  10. I.E. Lawrence Jr, H.W. Burden, T.M. Louis, Effect of abdominal vagotomy of the pregnant rat on LH and P4 concentrations and fetal resorption. J. Reprod. Fertil. 53, 131–136 (1978)

    Article  CAS  PubMed  Google Scholar 

  11. H.W. Burden, M.J. Leonard, C.A. Hodson, T.M. Louis, I.E. Lawrence Jr, Effect of abdominal vagotomy at proestrus on ovarian weight, ovarian antral follicles, and serum levels of gonadotropins, estradiol, and testosterone in the rat. Neuroendocrinology 42, 449–455 (1986)

    Article  CAS  PubMed  Google Scholar 

  12. R. Chávez, M.E. Cruz, R. Domínguez, Differences in ovulation rate of the right or left ovary in unilateral ovariectomized rats: effects of ipsi- and contralateral vagus nerves on the remaining ovary. J. Endocrinol. 113, 397–401 (1987)

    Article  PubMed  Google Scholar 

  13. M.E. Cruz, R. Chávez, R. Domínguez, Ovulation, follicular growth and ovarian reactivity to exogenous gonadotropins in adult rats with unilateral or bilateral sections of the vagi nerves. La Revista de Investigación Clínica 38, 167–171 (1986)

    CAS  Google Scholar 

  14. R.D. Peppler, G.S. Greenwald, Influence of unilateral ovariectomy on follicular development in cycling rats. Am. J. Anat. 127, 9–14 (1970)

    Article  CAS  PubMed  Google Scholar 

  15. R.D. Peppler, G.S. Greenwald, Effects of unilateral ovariectomy on ovulation and cycle length in 4- and 5-day cycling rats. Am. J. Anat. 127, 1–7 (1970)

    Article  CAS  PubMed  Google Scholar 

  16. S. Fritz, K.J. Föhr, S. Boddien, U. Berg, C. Brucker, A. Mayerhofer, Functional and molecular characterization of a muscarinic receptor type and evidence for expression of choline-acetyltransferase and vesicular acetylcholine transporter in human granulosa-luteal cells. J. Clin. Endocrinol. Metab. 84, 1744–1750 (1999)

    CAS  PubMed  Google Scholar 

  17. S. Fritz, L. Kunz, N. Dimitrijevic, R. Grünert, C. Heiss, A. Mayerhofer, Muscarinic receptors in human luteinized granulosa cells: activation blocks gap junctions and induces the transcription factor early growth response factor-1. J. Clin. Endocrinol. Metab. 87, 1362–1367 (2002)

    Article  CAS  PubMed  Google Scholar 

  18. A. Mayerhofer, N. Dimitrijevic, L. Kunz, The expression and biological role of the non-neuronal cholinergic system in the ovary. Life Sci. 72, 2039–2045 (2003)

    Article  CAS  PubMed  Google Scholar 

  19. S. Fritz, I. Wessler, R. Breitling, W. Rossmanith, S.R. Ojeda, G.A. Dissen, A. Amsterdam, A. Mayerhofer, Expression of muscarinic receptor types in the primate ovary and evidence for nonneuronal acetylcholine synthesis. J. Clin. Endocrinol. Metab. 86, 349–354 (2001)

    CAS  PubMed  Google Scholar 

  20. A. Mayerhofer, S. Fritz, Ovarian acetylcholine and muscarinic receptors: hints of a novel intrinsic ovarian regulatory system. Microsc. Res. Tech. 59, 503–508 (2002)

    Article  CAS  PubMed  Google Scholar 

  21. S. Batra, L.D. Popper, C.S. Iosif, Characterization of muscarinic cholinergic receptors in human ovaries, ovarian tumours and tumour cell lines. Eur. J. Cancer 29, 1302–1306 (1993)

    Article  Google Scholar 

  22. H. von der Kammer, M. Mayhaus, C. Albrecht, J. Enderich, M. Wegner, R.M. Nitsch, Muscarinic acetylcholine receptors activate expression of the EGR gene family of transcription factors. J. Biol. Chem. 273, 14538–14544 (1998)

    Article  PubMed  Google Scholar 

  23. S. Fritz, R. Grünert, D.M. Stocco, D.B. Hales, A. Mayerhofer, StAR protein is increased by muscarinic receptor activation in human luteinized granulosa cells. Mol. Cell. Endocrinol. 171, 49–51 (2001)

    Article  CAS  PubMed  Google Scholar 

  24. A. Mayerhofer, L. Kunz, A. Krieger, B. Proskocil, E. Spindel, A. Amsterdam, G.A. Dissen, S.R. Ojeda, I. Wessler, FSH regulates acetylcholine production by ovarian granulosa cells. Reprod. Biol. Endocrinol. 4, 37 (2006)

    Article  PubMed Central  PubMed  Google Scholar 

  25. J. Bódis, H.R. Tinneberg, F. Papenfuss, A. Török, P. Cledon, V. Hanf, H. Schwarz, Cholinergic stimulation of progesterone and estradiol secretion by human granulosa cells cultured in serum-free medium. Gynecol. Endocrinol. 7, 83–87 (1993)

    Article  PubMed  Google Scholar 

  26. L. Kornya, J. Bódis, M. Koppán, H.R. Tinneberg, A. Török, Modulatory effect of acetylcholine on gonadotropin-stimulated human granulosa cell steroid secretion. Gynecol. Obstet. Invest. 52, 104–107 (2001)

    Article  CAS  PubMed  Google Scholar 

  27. M.R. Luck, Cholinergic stimulation, through muscarinic receptors, of oxytocin and progesterone secretion from bovine granulosa cells undergoing spontaneous luteinization in serum-free culture. Endocrinology 126, 1256–1263 (1990)

    Article  CAS  PubMed  Google Scholar 

  28. I.E. Tóth, P. Banczerowski, Z. Boldogkoi, J.S. Tóth, A. Szabó, B. Halász, I. Gerendai, Cerebral neurons involved in the innervation of both the adrenal gland and the ovary: a double viral tracing study. Brain Res. Bull. 77, 306–311 (2008)

    Article  PubMed  Google Scholar 

  29. C. Morán, L. Morales, R.S. Razo, J. Apolonio, U. Quiroz, R. Chavira, R. Domínguez, Effects of sensorial denervation induced by capsaicin injection at birth or on day three of life, on puberty, induced ovulation and pregnancy. Life Sci. 73, 2113–2125 (2003)

    Article  PubMed  Google Scholar 

  30. R. Domínguez, M.E. Cruz, R. Chávez, Differences in the ovulatory ability between the right and left ovary are related to ovarian innervation, in Growth Factors and the Ovary, ed. by A.M. Hirshfiel (Plenum Press, New York, 1989), pp. 321–325

    Chapter  Google Scholar 

  31. R. Domínguez, L. Morales, M.E. Cruz, Ovarian asymmetry. Ann. Rev. Biomed. Sci. 5, 95–104 (2003)

    Google Scholar 

  32. A.I. Barco, A. Flores, R. Chavira, P. Damián-Matzumura, R. Domínguez, M.E. Cruz, Asymmetric effects of acute hemiovariectomy on steroid hormone secretion by the in situ ovary. Endocrine 21, 209–215 (2003)

    Article  CAS  PubMed  Google Scholar 

  33. A. Flores, G. Meléndez, M.T. Palafox, J. Rodríguez, A.I. Barco, R. Chavira, R. Domínguez, M.E. Cruz, The participation of the cholinergic system in regulating progesterone secretion through the ovarian-adrenal crosstalk varies along the estrous cycle. Endocrine 28, 145–152 (2005)

    Article  CAS  PubMed  Google Scholar 

  34. A. Flores, J.O. Rodríguez, M.T. Palafox, G. Meléndez, A.I. Barco, R. Chavira, M.E. Cruz, R. Domínguez, The acute asymmetric effects of hemiovariectomy on testosterone secretion vary along the estrous cycle. The participation of the cholinergic system. Reprod. Biol. Endocrinol. 4, 11 (2006)

    Article  PubMed Central  PubMed  Google Scholar 

  35. M.E. Cruz, A. Flores, M.T. Palafox, G. Meléndez, J.O. Rodríguez, R. Chavira, R. Domínguez, The role of the muscarinic system in regulating estradiol secretion varies during the estrous cycle: the hemiovariectomized rat model. Reprod. Biol. Endocrinol. 4, 43 (2006)

    Article  PubMed Central  PubMed  Google Scholar 

  36. C.V. Rao, L.A. Edgerton, Dissimilarity of corpora lutea within the same ovaries or those from right and left ovaries of pigs during the oestrous cycle. J. Reprod. Fertil. 70, 61–66 (1984)

    Article  CAS  PubMed  Google Scholar 

  37. R. Domínguez, M.E. Cruz, C. Morán, Differential effects of ovarian local anesthesia during proestrus, on the ovulation by the right or left ovary, normal and hemiovariectomized adult rat. J. Reprod. Fertil. 113, 185–190 (1998)

    Article  PubMed  Google Scholar 

  38. M.E. Cruz, L.P. Jaramillo, R. Domínguez, Asymmetric ovulatory response induced by unilateral implant of atropine in the anterior hypothalamus in the cyclic rat. J. Endocrinol. 123, 437–439 (1989)

    Article  CAS  PubMed  Google Scholar 

  39. M.E. Cruz, P.R. Arteaga, M.I. Huerta-Delgadillo, M.A. Sánchez, R. Domínguez, Differences on the acetylcholine concentration and binding and affinity parameters of the muscarinic receptors in the preoptic anterior hypothalamic area during the oestrous cycle of the rat. Med. Sci. Res. 25, 823–825 (1997)

    CAS  Google Scholar 

  40. A.E. Herbison, Physiology of the gonadotropin-releasing hormone neuronal network, in Knobil and Neill’s Physiology of Reproduction, ed. by Jimmy D. Neill (Academic Press, Oxford, 2006), pp. 1450–1454

    Google Scholar 

  41. R. Chávez, M.E. Cruz, R. Domínguez, Differences in ovulation rate of the right or left ovary in unilateral ovariectomized rats: effects of ipsi- and contralateral vagus nerves on the remaining ovary. J. Endocrinol. 113, 397–401 (1987)

    Article  PubMed  Google Scholar 

  42. I. Gerendai, M. Matta, Effect of unilateral vagotomy on serum gonadotropin concentration in rats with two testes and in hemicastrates. Endocrinol. Exp. 24, 325–332 (1990)

    CAS  PubMed  Google Scholar 

  43. G. Gabella, H.L. Pease, Number of axons in the abdominal vagus of the rat. Brain Res. 58, 465–469 (1973)

    Article  CAS  PubMed  Google Scholar 

  44. I.E. Tóth, O. Wiesel, Z. Boldogkoi, K. Bálint, Z. Tapaszti, I. Gerendai, Predominance of supraspinal innervation of the left ovary. Microsc. Res. Tech. 70, 710–718 (2007)

    Article  PubMed  Google Scholar 

  45. C. Morán, A. Franco, J.L. Morán, A. Handal, L. Morales, R. Domínguez, Neural activity between ovaries and the prevertebral celiac-superior mesenteric ganglia varies during the estrous cycle of the rat. Endocrine 26, 147–152 (2005)

    Article  PubMed  Google Scholar 

  46. A. Domínguez-González, P. Damian-Matsumura, C. Timossi, M.E. Cruz, R. Domínguez, Characterization of monoamine neural activity of the preoptic anterior hypothalamic area and medial basal hypothalamus during proestrus day, and its relation with gonadotrophin and sexual steroid hormone plasma levels. Med. Sci. Res. 26, 275–278 (1998)

    Google Scholar 

  47. J. Bódis, M. Koppán, L. Kornya, H.R. Tinneberg, A. Török, The effect of catecholamines, acetylcholine and histamine on progesterone release by human granulosa cells in a granulosa cell superfusion system. Gynecol. Endocrinol. 16, 259–264 (2002)

    Article  PubMed  Google Scholar 

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Acknowledgments

We thank to Miguel Martín Hernández Escobar for his assistance in performing the immunohistochemistry staining. This study was supported by a grant from Universidad Nacional Autónoma de México: DGAPA-PAPIIT (IN-220014).

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The authors declare that they do not have any conflict of interest.

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Cruz, M.E., Flores, A., Alvarado, B.E. et al. Ovulation requires the activation on proestrus of M1 muscarinic receptors in the left ovary. Endocrine 49, 809–819 (2015). https://doi.org/10.1007/s12020-014-0524-3

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