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Journal of cellular physiology2020; 235(10); 7580-7591; doi: 10.1002/jcp.29663

The endocannabinoid system modulates the ovarian physiology and its activation can improve in vitro oocyte maturation.

Abstract: The cannabinoid (CB) system has been involved in many aspects of reproduction and it is known that the systemic chronic use of exogenous CBs are deleterious to reproductive processes. Even so, it is not known what happens in relation to the physiology of the ovary when CB receptors are absent. The present study investigated the effect of the lack of CB1 and CB2 receptors in mice ovarian morphology, folliculogenesis, oocyte retrieval, and oocyte maturation and evaluated the use of Δ9-tetrahydrocannabinol (THC) on oocyte in vitro maturation (IVM) by comparing classical IVM and two-step IVM by analyzing the meiotic competence of the oocytes and their evolution toward embryos. Thus, when CB1 and CB2 receptors were missed, the ovary area and volume was significantly less and the action of the equine chorionic gonadotropin (eCG) hormone was diminished. In addition, the mutant genotypes had fewer ovarian follicles and they were less competent after eCG administration compared with wild-type mice, and this lack of CB receptors showed a mismatch of oocyte maturation. However, the in vitro use of THC showed improvements in oocytes IVM after a Pre-IVM step for 48 hr, as those oocytes reached a significantly higher polar body rate, a larger diameter and the best result on blastocysts rate was achieved when THC was used during the IVM step.
Publication Date: 2020-03-20 PubMed ID: 32198753DOI: 10.1002/jcp.29663Google Scholar: Lookup
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  • Journal Article
  • Research Support
  • Non-U.S. Gov't

Summary

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This research article investigates the role of cannabinoid receptors in mouse ovarian health and fertility, as well as the effect of Δ9-tetrahydrocannabinol (THC) on in vitro maturation of oocytes (egg cells).

Research methods and objectives

The researchers aimed to understand the role of cannabinoid receptors CB1 and CB2 in ovarian physiology. They studied mice that lacked these receptors and assessed various factors, such as ovarian morphology, folliculogenesis (the maturation of ovarian follicles), the number of oocytes retrieved, and their maturation. The researchers also tested the impact of THC, the main psychoactive compound in cannabis, on in vitro maturation of oocytes. They compared the traditional in vitro maturation method with a two-step method to evaluate the oocytes’ meiotic competence (ability to undergo cell division) and potential developmental progression to embryos.

Findings: Detrimental Effects of Cannabinoid Receptor Deficiency

The absence of CB1 and CB2 receptors in mice had several adverse effects on ovarian health and performance. Observations included:

  • Decreased ovary size in terms of both area and volume.
  • Diminished reaction to equine chorionic gonadotropin (eCG), a hormone used to stimulate follicle development in the ovaries.
  • Fewer ovarian follicles, especially after eCG administration.
  • Decreased competency of these follicles when compared to normal mice.
  • Discrepancy in oocyte maturation, suggesting that cannabinoid receptors play a role in this process.

Findings: Positive Influence of THC on In Vitro Maturation

The in vitro use of THC showed promise in enhancing oocyte maturation. The study revealed several benefits of using THC, especially before the actual in vitro maturation process (Pre-IVM step):

  • Oocytes that underwent a 48-hour Pre-IVM step with THC showed a significantly higher polar body rate (an indicator of successful cell division).
  • These oocytes also had a larger diameter, suggesting improved health and development.
  • The most successful blastocyst (early embryo) generation rate occurred when THC was used during the in vitro maturation process.

In conclusion, this study highlights the potential impact of the cannabinoid system on ovarian health and fertility, shedding light on possible avenues for enhancing in vitro oocyte maturation using THC. However, it also underscores the detrimental effects that might occur if the cannabinoid receptors are deficient or absent, emphasizing the complexity and importance of this system in reproductive health.

Cite This Article

APA
Totorikaguena L, Olabarrieta E, Lolicato F, Romero-Aguirregomezcorta J, Smitz J, Agirregoitia N, Agirregoitia E. (2020). The endocannabinoid system modulates the ovarian physiology and its activation can improve in vitro oocyte maturation. J Cell Physiol, 235(10), 7580-7591. https://doi.org/10.1002/jcp.29663

Publication

ISSN: 1097-4652
NlmUniqueID: 0050222
Country: United States
Language: English
Volume: 235
Issue: 10
Pages: 7580-7591

Researcher Affiliations

Totorikaguena, Lide
  • Department of Physiology, Faculty of Medicine and Nursing, UPV/EHU, Leioa, Bizkaia, Spain.
Olabarrieta, Estibaliz
  • Department of Physiology, Faculty of Medicine and Nursing, UPV/EHU, Leioa, Bizkaia, Spain.
Lolicato, Francesca
  • Laboratory of Follicular Biology (FOBI), UZ Brussel, Brussels, Belgium.
Romero-Aguirregomezcorta, Jon
  • Department of Physiology, Faculty of Medicine and Nursing, UPV/EHU, Leioa, Bizkaia, Spain.
Smitz, Johan
  • Laboratory of Follicular Biology (FOBI), UZ Brussel, Brussels, Belgium.
Agirregoitia, Naiara
  • Department of Physiology, Faculty of Medicine and Nursing, UPV/EHU, Leioa, Bizkaia, Spain.
Agirregoitia, Ekaitz
  • Department of Physiology, Faculty of Medicine and Nursing, UPV/EHU, Leioa, Bizkaia, Spain.

MeSH Terms

  • Animals
  • Blastocyst / metabolism
  • Blastocyst / physiology
  • Endocannabinoids / metabolism
  • Female
  • In Vitro Oocyte Maturation Techniques / methods
  • Meiosis / physiology
  • Mice
  • Mice, Inbred C57BL
  • Mice, Inbred CBA
  • Oocytes / metabolism
  • Oocytes / physiology
  • Oogenesis / physiology
  • Ovarian Follicle / metabolism
  • Ovarian Follicle / physiology
  • Receptors, Cannabinoid / metabolism

References

This article includes 46 references
  1. Adashi EY, Jones PBC, Hsueh AJW. Direct antigonadal activity of cannabinoids: Suppression of rat granulosa cell functions. American Journal of Physiology-Endocrinology and Metabolism 7(2), E177-E185.
  2. Agirregoitia E, Ibarra-Lecue I, Totorikaguena L, Mendoza R, Expósito A, Matorras R, Agirregoitia N. Dynamics of expression and localization of the cannabinoid system in granulosa cells during oocyte nuclear maturation. Fertility and Sterility 104(3), 753-760.
  3. Agirregoitia E, Totorikaguena L, Expósito A, Mendoza R, Matorras R, Agirregoitia N. Dynamic of expression and localization of cannabinoid-degrading enzymes FAAH and MGLL in relation to CB1 during meiotic maturation of human oocytes. Cell and Tissue Research 1-9.
    doi: 10.1007/s00441-016-2381-2google scholar: lookup
  4. Aiken CE, Tarry-Adkins JL, Ozanne SE. Suboptimal nutrition in utero causes DNA damage and accelerated aging of the female reproductive tract. FASEB Journal 27(10), 3959-3965.
    doi: 10.1096/fj.13-234484google scholar: lookup
  5. Ayalon D, Nir I, Cordova T, Bauminger S, Puder M, Naor Z, Lindner HR. Acute effect of delta1-tetrahydrocannabinol on the hypothalamo-pituitary-ovarian axis in the rat. Neuroendocrinology 23, 31-42.
  6. Bagavandoss P, Grimshaw S. Temporal and spatial distribution of the cannabinoid receptors (CB 1, CB2) and fatty acid amide hydroxylase in the rat ovary. Anatomical Record 293(8), 1425-1432.
    doi: 10.1002/ar.21181google scholar: lookup
  7. Brents LK. Marijuana, the endocannabinoid system and the female reproductive system. Yale Journal of Biology and Medicine 89(2), 175-191.
  8. Buckley NE, McCoy KL, Mezey É, Bonner T, Zimmer A, Felder CC, Zimmer A. Immunomodulation by cannabinoids is absent in mice deficient for the cannabinoid CB2 receptor. European Journal of Pharmacology 396(2-3), 141-149.
  9. Cacciola G, Chioccarelli T, Altucci L, Ledent C, Mason JI, Fasano S, Cobellis G. Low 17beta-estradiol levels in Cnr1 knock-out mice affect spermatid chromatin remodeling by interfering with chromatin reorganization. Biology of Reproduction 88(6), 152.
  10. Cecconi S, Rossi G, Oddi S, Di Nisio V, Maccarrone M. Role of major endocannabinoid-binding receptors during mouse oocyte maturation. International Journal of Molecular Sciences 20(12), 2866.
    doi: 10.3390/ijms20122866google scholar: lookup
  11. Chianese R, Ciaramella V, Fasano S, Pierantoni R, Meccariello R. Anandamide modulates the expression of GnRH-II and GnRHRs in frog, Rana esculenta, diencephalon. General and Comparative Endocrinology 173(3), 389-395.
  12. Correa F, Wolfson ML, Valchi P, Aisemberg J, Franchi AM. Endocannabinoid system and pregnancy. Reproduction 152(6), R191-R200.
    doi: 10.1530/rep-16-0167google scholar: lookup
  13. Coticchio G, Dal Canto M, Mignini Renzini M, Guglielmo MC, Brambillasca F, Turchi D, Fadini R. Oocyte maturation: Gamete-somatic cells interactions, meiotic resumption, cytoskeletal dynamics and cytoplasmic reorganization. Human Reproduction Update 21(4), 427-454.
    doi: 10.1093/humupd/dmv011google scholar: lookup
  14. De Domenico E, Todaro F, Rossi G, Dolci S, Geremia R, Rossi P, Grimaldi P. Overactive type 2 cannabinoid receptor induces meiosis in fetal gonads and impairs ovarian reserve. Cell Death and Disease 8(10):e3085.
    doi: 10.1038/cddis.2017.496google scholar: lookup
  15. El-Talatini MR, Taylor AH, Elson JC, Brown L, Davidson AC, Konje JC. Localisation and function of the endocannabinoid system in the human ovary. PLOS One 4(2):e4579.
  16. El-Talatini MR, Taylor AH, Konje JC. Fluctuation in anandamide levels from ovulation to early pregnancy in in-vitro fertilization-embryo transfer women, and its hormonal regulation. Human Reproduction 24(8), 1989-1998.
    doi: 10.1093/humrep/dep065google scholar: lookup
  17. ElSohly MA, Slade D. Chemical constituents of marijuana: The complex mixture of natural cannabinoids. Life Sciences 78(5), 539-548.
    doi: 10.1016/j.lfs.2005.09.011google scholar: lookup
  18. Galiègue S, Mary S, Marchand J, Dussossoy D, Carrière D, Carayon P, Casellas P. Expression of central and peripheral cannabinoid receptors in human immune tissues and leukocyte subpopulations. European Journal of Biochemistry 232(1), 54-61.
  19. Gammon CM, Freeman GM Jr, Xie W, Petersen SL, Wetsel WC, Petersen SL, Wetsel WC. Regulation of gonadotropin-releasing hormone secretion by cannabinoids. Endocrinology 146, 4491-4499.
  20. González-Fernández L, Sánchez-Calabuig MJ, Alves MG, Oliveira PF, Macedo S, Gutiérrez-Adán A, Macías-García B. Expanded equine cumulus-oocyte complexes exhibit higher meiotic competence and lower glucose consumption than compact cumulus-oocyte complexes. Reproduction, Fertility, and Development 30(2), 297-306.
    doi: 10.1071/rd16441google scholar: lookup
  21. Hinrichs K. In vitro production of equine embryos: State of the art. Reproduction in Domestic Animals 45(Suppl. 2), 3-8.
  22. Hinrichs K. The equine oocyte: Factors affecting meiotic and developmental competence. Molecular Reproduction and Development 77(8), 651-661.
    doi: 10.1002/mrd.21186google scholar: lookup
  23. Khatir H, Lonergan P, Mermillod P. Kinetics of nuclear maturation and protein profiles of oocytes from prepubertal and adult cattle during in vitro maturation. Theriogenology 50(6), 917-929.
  24. Lonergan P, Fair T. Maturation of oocytes in vitro. Annual Review of Animal Biosciences 4(1), 255-268.
  25. López-Cardona AP, Pérez-Cerezales S, Fernández-González R, Laguna-Barraza R, Pericuesta E, Agirregoitia N, Agirregoitia E. CB1 cannabinoid receptor drives oocyte maturation and embryo development via PI3K/Akt and MAPK pathways. FASEB Journal 31(8), 3372-3382.
    doi: 10.1096/fj.201601382rrgoogle scholar: lookup
  26. López-Cardona AP, Sánchez-Calabuig MJ, Beltran-Breña P, Agirregoitia N, Rizos D, Agirregoitia E, Gutierrez-Adán A. Exocannabinoids effect on in vitro bovine oocyte maturation via activation of AKT and ERK1/2. Reproduction 152(6), 603-612.
    doi: 10.1530/rep-16-0199google scholar: lookup
  27. Marsicano G, Wotjak CT, Azad SC, Bisogno T, Rammes G, Cascio MG, Lutz B. The endogenous cannabinoid system controls extinction of aversive memories. Nature 418(6897), 530-534.
    doi: 10.1038/nature00839google scholar: lookup
  28. Meccariello R, Franzoni MF, Chianese R, Cottone E, Scarpa D, Donna D, Fasano S. Interplay between the endocannabinoid system and GnRH-I in the forebrain of the anuran amphibian Rana esculenta. Endocrinology 149(5), 2149-2158.
    doi: 10.1210/en.2007-1357google scholar: lookup
  29. Mechoulam R, Gaoni Y. The absolute configuration of delta-1-tetrahydrocannabinol, the major active constituent of hashish. Tetrahedron Lettera 8(12), 1109-1111.
  30. Oláh M, Milloh H, Wenger T. The role of endocannabinoids in the regulation of luteinizing hormone and prolactin release. Differences between the effects of AEA and 2AG. Molecular and Cellular Endocrinology 286(1-2 Suppl. 1), 36-40.
    doi: 10.1016/j.mce.2008.01.005google scholar: lookup
  31. Peralta L, Agirregoitia E, Mendoza R, Expósito A, Casis L, Matorras R, Agirregoitia N. Expression and localization of cannabinoid receptors in human immature oocytes and unfertilized metaphase-II oocytes. Reproductive BioMedicine Online 23(3), 372-379.
  32. Romero S, Sanchez F, Lolicato F, Van Ranst H, Smitz J. Immature oocytes from unprimed juvenile mice become a valuable source for embryo production when using C-type natriuretic peptide as essential component of culture medium. Biology of Reproduction 95(3), 64.
  33. Sánchez F, Lolicato F, Romero S, De Vos M, Van Ranst H, Verheyen G, Smitz JEJ. An improved IVM method for cumulus-oocyte complexes from small follicles in polycystic ovary syndrome patients enhances oocyte competence and embryo yield. Human Reproduction 32(10), 2056-2068.
    doi: 10.1093/humrep/dex262google scholar: lookup
  34. Schuel H, Burkman LJ, Lippes J, Crickard K, Mahony MC, Giuffrida A, Makriyannis A. Evidence that anandamide-signaling regulates human sperm functions required for fertilization. Molecular Reproduction and Development 63(3), 376-387.
    doi: 10.1002/mrd.90021google scholar: lookup
  35. Scorticati C, Ferná Ndez-Solari J, De Laurentiis A, Mohn C, Prestifilippo JP, Lasaga M, Rettori V. The inhibitory effect of anandamide on luteinizing hormone-releasing hormone secretion is reversed by estrogen. Proceedings of the National Academy of Sciences 101(32), 11891-11896.
  36. Shi L, Zhang J, Lai Z, Tian Y, Fang L, Wu M, Wang S. Long-term moderate oxidative stress decreased ovarian reproductive function by reducing follicle quality and progesterone production. PLOS One 11(9), 1-18.
  37. Silva JRV, Van Den Hurk R, De Matos MHT, Dos Santos RR, Pessoa C, De Moraes MO, De Figueiredo JR. Influences of FSH and EGF on primordial follicles during in vitro culture of caprine ovarian cortical tissue. Theriogenology 61(9), 1691-1704.
  38. Smith CG, Besch NF, Smith RG, Besch PK. Effect of tetrahydrocannabinol on the hypothalamic-pituitary axis in the ovariectomized rhesus monkey. Fertility and Sterility 31(3), 335-339.
  39. Takeo T, Mukunoki A, Nakagata N. Ovulation of juvenile, mature, and aged female C57BL/6 mice following coadministration of inhibin antiserum and equine chorionic gonadotropin. Theriogenology 135, 1-6.
  40. Tilly JL. Ovarian follicle counts-Not as simple as 1, 2, 3. Reproductive Biology and Endocrinology 1, 1-4.
    doi: 10.1186/1477-7827-1-11google scholar: lookup
  41. Totorikaguena L, Olabarrieta E, López-Cardona AP, Agirregoitia N, Agirregoitia E. Tetrahydrocannabinol modulates in vitromaturation of oocytes and improves the blastocyst rates after in vitro fertilization. Cellular Physiology and Biochemistry 53(3), 439-452.
    doi: 10.33594/000000149google scholar: lookup
  42. Tyrey L. A-9-Tetrahydrocannabinol suppression of episodic luteinizing hormone secretion in the ovariectomized rat. Endocrinology 102(6), 1808-1814.
  43. Walker O, Holloway A, Raha S. The role of the endocannabinoid system in female reproductive tissues. Journal of Ovarian Research 12(Suppl. 1), 2-10.
    doi: 10.1186/s13048-018-0478-9google scholar: lookup
  44. Wang H, Guo Y, Wang D, Kingsley PJ, Marnett LJ, Das SK, Dey SK. Aberrant cannabinoid signaling impairs oviductal transport of embryos. Nature Medicine 10(10), 1074-1080.
    doi: 10.1038/nm1104google scholar: lookup
  45. Wenger T, Ledent C, Csernus V, Gerendai I. The central cannabinoid receptor inactivation suppresses endocrine reproductive functions. Biochemical and Biophysical Research Communications 284(2), 363-368.
    doi: 10.1006/bbrc.2001.4977google scholar: lookup
  46. Zhang M, Su YQ, Sugiura K, Xia G, Eppig JJ. Granulosa cell ligand NPPC and its receptor NPR2 maintain meiotic arrest in mouse oocytes. Science 330(6002), 366-369.
    doi: 10.1126/science.1193573google scholar: lookup

Citations

This article has been cited 5 times.
  1. Rossi G, Di Nisio V, Chiominto A, Cecconi S, Maccarrone M. Endocannabinoid System Components of the Female Mouse Reproductive Tract Are Modulated during Reproductive Aging. Int J Mol Sci 2023 Apr 19;24(8).
    doi: 10.3390/ijms24087542pubmed: 37108704google scholar: lookup
  2. Rava A, Trezza V. Emerging Roles of Endocannabinoids as Key Lipid Mediators for a Successful Pregnancy. Int J Mol Sci 2023 Mar 9;24(6).
    doi: 10.3390/ijms24065220pubmed: 36982295google scholar: lookup
  3. Taylor AH, Tortolani D, Ayakannu T, Konje JC, Maccarrone M. (Endo)Cannabinoids and Gynaecological Cancers. Cancers (Basel) 2020 Dec 25;13(1).
    doi: 10.3390/cancers13010037pubmed: 33375539google scholar: lookup
  4. Duval C, Wyse BA, Fuchs Weizman N, Kuznyetsova I, Madjunkova S, Librach CL. Cannabis impacts female fertility as evidenced by an in vitro investigation and a case-control study. Nat Commun 2025 Sep 9;16(1):8185.
    doi: 10.1038/s41467-025-63011-2pubmed: 40925892google scholar: lookup
  5. Mirzaie V, Eslaminejad T, Sheikhbahaei F, Vafaei S, Nabipour F, Behzadi M, Nematollahi-Mahani SN. The role of cannabinoid agonists and antagonists on folliculogenesis and evolutionary events in the mouse ovary. Iran J Basic Med Sci 2025;28(9):1171-1179.