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Cannabis and Cannabinoids in Reproduction and Fertility: Where We Stand

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Abstract

Although cannabis use is increasing in general population, their prevalence among young adults is remarkably high. In recent years, their medical use gained a renewed interest. However, it can underline the reputation of cannabis being a harmless drug. Between cannabinoids, uniquely found on the cannabis plant, Δ9-tetrahydrocannabinol (THC) is the well-studied compound. It is responsible for the psychoactive effects via central cannabinoid receptors. Nevertheless, cannabinoids interact with other chemical signalling systems such as the hypothalamic–pituitary–gonadal axis. THC indirectly decreases gonadotropin-releasing hormone (GnRH) secretion by the hypothalamus. The consequences are diverse, and several key hormones are affected. THC disturbs important reproductive events like folliculogenesis, ovulation and sperm maturation and function. Although generally accepted that cannabinoid consumption impacts male and female fertility, prevailing evidence remains largely on pre-clinical studies. Here, we introduce cannabinoids and the endocannabinoid system, and we review the most prominent clinical evidence about cannabis consumption in reproductive potential and teratogenicity.

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References

  1. Matsuda LA, Lolait SJ, Brownstein MJ, Young AC, Bonner TI. Structure of a cannabinoid receptor and functional expression of the cloned cDNA. Nature. 1990;346:561–4.

    Article  CAS  PubMed  Google Scholar 

  2. Munro S, Thomas KL, Abu-Shaar M. Molecular characterization of a peripheral receptor for cannabinoids. Nature. 1993;365:61–5.

    Article  CAS  PubMed  Google Scholar 

  3. Hua T, Vemuri K, Pu MC, Qu L, Han GW, Wu YR, Zhao SW, Shui WQ, Li SS, Korde A, Laprairie RB, Stahl EL, Ho JH, Zvonok N, Zhou H, Kufareva I, Wu BL, Zhao Q, Hanson MA, Bohn LM, Makriyannis A, Stevens RC, Liu ZJ. 2016. Crystal structure of the human cannabinoid receptor CB1. Cell, 167, 750-+.

  4. Hua T, Vemuri K, Nikas SP, Laprairie RB, Wu Y, Qu L, Pu M, Korde A, Jiang S, Ho JH, Han G. W, Ding K, Li X, Liu H, Hanson MA, Zhao S, Bohn LM, Makriyannis A, Stevens RC. Liu ZJ. 2017. Crystal structures of agonist-bound human cannabinoid receptor CB1. Nature, 547, 468-+.

  5. Li XT, Hua T, Vemuri K, Ho JH, Wu YR, Wu LJ, Popov P, Benchama O, Zvonok N, Locke K, Qu L, Han GW, Iyer MR, Cinar R, Coffey NJ., Wang JJ, Wu M, Katritch V, Zhao SW, Kunos G, Bohn LM, Makriyannis A, Stevens RC. Liu ZJ. 2019. Crystal structure of the human cannabinoid receptor CB2. Cell, 176, 459-+.

  6. Mackie K. 2005. Distribution of cannabinoid receptors in the central and peripheral nervous system. Handb Exp Pharmacol, 299-325.

  7. Chen DJ, Gao M, Gao FF, SU, Q. X. & Wu, J. Brain cannabinoid receptor 2: expression, function and modulation. Acta Pharmacol Sin. 2017;38:312–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Chung YC, Shin WH, Baek JY, Cho EJ, Baik HH, Kim SR, et al. CB2 receptor activation prevents glial-derived neurotoxic mediator production, BBB leakage and peripheral immune cell infiltration and rescues dopamine neurons in the MPTP model of Parkinson’s disease. Exp Mol Med. 2016;48:e205.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Van Sickle MD, Duncan M, Kingsley PJ, Mouihate A, Urbani P, Mackie K, et al. Identification and functional characterization of brainstem cannabinoid CB2 receptors. Science. 2005;310:329–32.

    Article  PubMed  CAS  Google Scholar 

  10. Dai E, Zhang L, Ye L, Wan S, Feng L, Qi Q, et al. Hepatic expression of cannabinoid receptors CB1 and CB2 correlate with fibrogenesis in patients with chronic hepatitis B. Int J Infect Dis. 2017;59:124–30.

    Article  CAS  PubMed  Google Scholar 

  11. Galiazzo G, Giancola F, Stanzani A, Fracassi F, Bernardini C, Forni M, et al. Localization of cannabinoid receptors CB1, CB2, GPR55, and PPARalpha in the canine gastrointestinal tract. Histochem Cell Biol. 2018;150:187–205.

    Article  CAS  PubMed  Google Scholar 

  12. Fonseca BM, Teixeira NA, Almada M, Taylor AH, Konje JC, Correia-Da-Silva, G. Modulation of the novel cannabinoid receptor-GPR55-during rat fetoplacental development. Placenta. 2011;32:462–9.

    Article  CAS  PubMed  Google Scholar 

  13. Devane WA, Hanus L, Breuer A, Pertwee RG, Stevenson LA, Griffin G, et al. Isolation and structure of a brain constituent that binds to the cannabinoid receptor. Science. 1992;258:1946–9.

    Article  CAS  PubMed  Google Scholar 

  14. Mechoulam R, Ben-Shabat S, Hanus L, Ligumsky M, Kaminski NE, Schatz AR, et al. Identification of an endogenous 2-monoglyceride, present in canine gut, that binds to cannabinoid receptors. Biochem Pharmacol. 1995;50:83–90.

    Article  CAS  PubMed  Google Scholar 

  15. Sugiura T, Kondo S, Sukagawa A, Nakane S, Shinoda A, Itoh K, et al. 2-Arachidonoylglycerol: a possible endogenous cannabinoid receptor ligand in brain. Biochem Biophys Res Commun. 1995;215:89–97.

    Article  CAS  PubMed  Google Scholar 

  16. Di Marzo V, DE Petrocellis L. Why do cannabinoid receptors have more than one endogenous ligand? Philos Trans R Soc Lond Ser B Biol Sci. 2012;367:3216–28.

    Article  CAS  Google Scholar 

  17. Bomar MG, Galande AK. Modulation of the cannabinoid receptors by hemopressin peptides. Life Sci. 2013;92:520–4.

    Article  CAS  PubMed  Google Scholar 

  18. Zygmunt PM, Petersson J, Andersson DA, Chuang H, Sorgard M, Di Marzo V, et al. Vanilloid receptors on sensory nerves mediate the vasodilator action of anandamide. Nature. 1999;400:452–7.

    Article  CAS  PubMed  Google Scholar 

  19. Spivak CE, Kim W, Liu QR, Lupica CR, Doyle ME. Blockade of beta-cell K(ATP) channels by the endocannabinoid, 2-arachidonoylglycerol. Biochem Biophys Res Commun. 2012;423:13–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Sigel E, Baur R, Racz I, Marazzi J, Smart TG, Zimmer A, et al. The major central endocannabinoid directly acts at Gaba(A) receptors. Proc Natl Acad Sci U S A. 2011;108:18150–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Matias I, Gonthier MP, Orlando P, Martiadis V, De Petrocellis L, Cervino C, et al. Regulation, function, and dysregulation of endocannabinoids in models of adipose and beta-pancreatic cells and in obesity and hyperglycemia. J Clin Endocrinol Metab. 2006;91:3171–80.

    Article  CAS  PubMed  Google Scholar 

  22. Fonseca BM, Costa MA, Almada M, Correia-Da-Silva G, Teixeira NA. Endogenous cannabinoids revisited: a biochemistry perspective. Prostaglandins Other Lipid Mediat. 2013b;102-103:13–30.

    Article  CAS  PubMed  Google Scholar 

  23. Murataeva N, Straiker A, Mackie K. Parsing the players: 2-arachidonoylglycerol synthesis and degradation in the CNS. Br J Pharmacol. 2014;171:1379–91.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Hillard CJ, Jarrahian A. The movement of N-arachidonoylethanolamine (anandamide) across cellular membranes. Chem Phys Lipids. 2000;108:123–34.

    Article  CAS  PubMed  Google Scholar 

  25. Kaczocha M, Glaser ST, Deutsch DG. Identification of intracellular carriers for the endocannabinoid anandamide. Proc Natl Acad Sci U S A. 2009;106:6375–80.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Ranganarayanan P, Thanigesan N, Ananth V, Jayaraman VK, Ramakrishnan V. Identification of glucose-binding pockets in human serum albumin using support vector machine and molecular dynamics simulations. IEEE/ACM Trans Comput Biol Bioinform. 2016;13:148–57.

    Article  CAS  PubMed  Google Scholar 

  27. Kopczynska B, Sulejczak D, Welniak-Kaminska M, Gietka A, Grieb P. Anandamide enhances expression of heat shock proteins Hsp70 and Hsp25 in rat lungs. Eur J Pharmacol. 2011;668:257–63.

    Article  CAS  PubMed  Google Scholar 

  28. Kaczocha M, Vivieca S, Sun J, Glaser ST, Deutsch DG. Fatty acid-binding proteins transport N-acylethanolamines to nuclear receptors and are targets of endocannabinoid transport inhibitors. J Biol Chem. 2012;287:3415–24.

    Article  CAS  PubMed  Google Scholar 

  29. Muccioli GG. Endocannabinoid biosynthesis and inactivation, from simple to complex. Drug Discov Today. 2010;15:474–83.

    Article  CAS  PubMed  Google Scholar 

  30. Kozak KR, Prusakiewicz JJ, Marnett LJ. Oxidative metabolism of endocannabinoids by COX-2. Curr Pharm Des. 2004;10:659–67.

    Article  CAS  PubMed  Google Scholar 

  31. Ueda N, Tsuboi K, Uyama T. N-acylethanolamine metabolism with special reference to N-acylethanolamine-hydrolyzing acid amidase (NAAA). Prog Lipid Res. 2010;49:299–315.

    Article  CAS  PubMed  Google Scholar 

  32. Blankman JL, Simon GM, Cravatt BF. A comprehensive profile of brain enzymes that hydrolyze the endocannabinoid 2-arachidonoylglycerol. Chem Biol. 2007;14:1347–56.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Maia J, Fonseca BM, Cunha SC, Braga J, Goncalves D, Teixeira N, Correia-Da-Silva G 2020. Impact of tetrahydrocannabinol on the endocannabinoid 2-arachidonoylglycerol metabolism: ABHD6 and ABHD12 as novel players in human placenta. Biochim Biophys Acta Mol Cell Biol Lipids, 1865, 158807.

  34. Howlett AC, Barth F, Bonner TI, Cabral G, Casellas P, Devane WA, et al. International Union of Pharmacology. XXVII. Classification of cannabinoid receptors. Pharmacol Rev. 2002;54:161–202.

    Article  CAS  PubMed  Google Scholar 

  35. Pertwee RG. Cannabinoid receptor ligands: clinical and neuropharmacological considerations, relevant to future drug discovery and development. Expert Opin Investig Drugs. 2000;9:1553–71.

    Article  CAS  PubMed  Google Scholar 

  36. Navarrete M, Araque A. Endocannabinoids mediate neuron-astrocyte communication. Neuron. 2008;57:883–93.

    Article  CAS  PubMed  Google Scholar 

  37. Glass M, Felder CC. Concurrent stimulation of cannabinoid CB1 and dopamine D2 receptors augments cAMP accumulation in striatal neurons: evidence for a Gs linkage to the CB1 receptor. J Neurosci. 1997;17:5327–33.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Felder CC, Joyce KE, Briley EM, Mansouri J, Mackie K, Blond O, et al. Comparison of the pharmacology and signal transduction of the human cannabinoid CB1 and CB2 receptors. Mol Pharmacol. 1995;48:443–50.

    CAS  PubMed  Google Scholar 

  39. Gomez Del Pulgar T, Velasco G, Guzman M. The CB1 cannabinoid receptor is coupled to the activation of protein kinase B/Akt. Biochem J. 2000;347:369–73.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Velasco G, Galve-Roperh I, Sanchez C, Blazquez C, Haro A, Guzman M. Cannabinoids and ceramide: two lipids acting hand-by-hand. Life Sci. 2005;77:1723–31.

    Article  CAS  PubMed  Google Scholar 

  41. Niehaus JL, Liu Y, Wallis KT, Egertova M, Bhartur SG, Mukhopadhyay S, et al. CB1 cannabinoid receptor activity is modulated by the cannabinoid receptor interacting protein CRIP 1a. Mol Pharmacol. 2007;72:1557–66.

    Article  CAS  PubMed  Google Scholar 

  42. Martini L, Waldhoer M, Pusch M, Kharazia V, Fong J, Lee JH, et al. Ligand-induced down-regulation of the cannabinoid 1 receptor is mediated by the G-protein-coupled receptor-associated sorting protein GASP1. FASEB J. 2007;21:802–11.

    Article  CAS  PubMed  Google Scholar 

  43. Jin WZ, Brown S, Roche JP, Hsieh C, Celver JP, Kovoor A, et al. Distinct domains of the CB1 cannabinoid receptor mediate desensitization and internalization. J Neurosci. 1999;19:3773–80.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Gaoni Y, Mechoulam R. Isolation, structure, and partial synthesis of an active constituent of Hashish. J Am Chem Soc. 1964;86:1646–7.

    Article  CAS  Google Scholar 

  45. Smith FL, Fujimori K, Lowe J, Welch SP. Characterization of delta9-tetrahydrocannabinol and anandamide antinociception in nonarthritic and arthritic rats. Pharmacol Biochem Behav. 1998;60:183–91.

    Article  CAS  PubMed  Google Scholar 

  46. Sofia RD, Solomon TA, Barry H, 3RD. Anticonvulsant activity of delta9-tetrahydrocannabinol compared with three other drugs. Eur J Pharmacol. 1976;35:7–16.

    Article  CAS  PubMed  Google Scholar 

  47. Croxford JL, Yamamura T. Cannabinoids and the immune system: potential for the treatment of inflammatory diseases? J Neuroimmunol. 2005;166:3–18.

    Article  CAS  PubMed  Google Scholar 

  48. Darmani NA. Delta(9)-tetrahydrocannabinol and synthetic cannabinoids prevent emesis produced by the cannabinoid CB(1) receptor antagonist/inverse agonist SR 141716A. Neuropsychopharmacology. 2001;24:198–203.

    Article  CAS  PubMed  Google Scholar 

  49. Mattes RD, Engelman K, Shaw LM, Elsohly MA. Cannabinoids and appetite stimulation. Pharmacol Biochem Behav. 1994;49:187–95.

    Article  CAS  PubMed  Google Scholar 

  50. Appendino G, Gibbons S, Giana A, Pagani A, Grassi G, Stavri M, et al. Antibacterial cannabinoids from Cannabis sativa: a structure-activity study. J Nat Prod. 2008;71:1427–30.

    Article  CAS  PubMed  Google Scholar 

  51. Van Klingeren B, Ten Ham M. Antibacterial activity of delta9-tetrahydrocannabinol and cannabidiol. Antonie Van Leeuwenhoek. 1976;42:9–12.

    Article  PubMed  Google Scholar 

  52. Burstein S, Levin E, Varanelli C. Prostaglandins and cannabis. II. Inhibition of biosynthesis by the naturally occurring cannabinoids. Biochem Pharmacol. 1973;22:2905–10.

    Article  CAS  PubMed  Google Scholar 

  53. Schaefer CF, Brackett DJ, Gunn CG, Dubowski KM. Decreased platelet aggregation following marihuana smoking in man. J Okla State Med Assoc. 1979;72:435–6.

    CAS  PubMed  Google Scholar 

  54. Kozela E, Juknat A, Kaushansky N, Rimmerman N, Ben-Nun A, Vogel Z. Cannabinoids decrease the th17 inflammatory autoimmune phenotype. J NeuroImmune Pharmacol. 2013;8:1265–76.

    Article  PubMed  Google Scholar 

  55. Garcia C, Palomo-Garo C, Garcia-Arencibia M, Ramos J, Pertwee R, Fernandez-Ruiz J. Symptom-relieving and neuroprotective effects of the phytocannabinoid delta(9)-THCV in animal models of Parkinson’s disease. Br J Pharmacol. 2011;163:1495–506.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Noonan J, Tanveer R, Klompas A, Gowran A, McKiernan J, Campbell VA. Endocannabinoids prevent beta-amyloid-mediated lysosomal destabilization in cultured neurons. J Biol Chem. 2010;285:38543–54.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Hacke ACM, Lima D, De Costa F, Deshmukh K, Li N, Chow AM, et al. Probing the antioxidant activity of delta(9)-tetrahydrocannabinol and cannabidiol in Cannabis sativa extracts. Analyst. 2019;144:4952–61.

    Article  CAS  PubMed  Google Scholar 

  58. Giudice ED, Rinaldi L, Passarotto M, Facchinetti F, D’arrigo A, Guiotto A, et al. Cannabidiol, unlike synthetic cannabinoids, triggers activation of RBL-2H3 mast cells. J Leukoc Biol. 2007;81:1512–22.

    Article  PubMed  CAS  Google Scholar 

  59. De Petrocellis L, Bisogno T, Maccarrone M, Davis JB, Finazzi-Agro A, Di Marzo V. The activity of anandamide at vanilloid VR1 receptors requires facilitated transport across the cell membrane and is limited by intracellular metabolism. J Biol Chem. 2001;276:12856–63.

    Article  PubMed  Google Scholar 

  60. Fonseca BM, Correia-Da-Silva G, Teixeira NA. Cannabinoid-induced cell death in endometrial cancer cells: involvement of TRPV1 receptors in apoptosis. J Physiol Biochem. 2018;74:261–72.

    Article  CAS  PubMed  Google Scholar 

  61. Blazquez C, Gonzalez-Feria L, Alvarez L, Haro A, Casanova ML, Guzman M. Cannabinoids inhibit the vascular endothelial growth factor pathway in gliomas. Cancer Res. 2004;64:5617–23.

    Article  CAS  PubMed  Google Scholar 

  62. Solinas M, Massi P, Cantelmo AR, Cattaneo MG, Cammarota R, Bartolini D, et al. Cannabidiol inhibits angiogenesis by multiple mechanisms. Br J Pharmacol. 2012;167:1218–31.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Volkow ND, Baler RD, Compton WM, Weiss SR. Adverse health effects of marijuana use. N Engl J Med. 2014;370:2219–27.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  64. Rabin RA, George TP. Cannabis and psychosis: understanding the smoke signals. Lancet Psychiatry. 2016;3:909–10.

    Article  PubMed  Google Scholar 

  65. Cohen K, Weizman A, Weinstein A. Modulatory effects of cannabinoids on brain neurotransmission. Eur J Neurosci. 2019;50:2322–45.

    Article  PubMed  Google Scholar 

  66. Ribeiro LI, Ind PW. Effect of cannabis smoking on lung function and respiratory symptoms: a structured literature review. NPJ Prim Care Respir Med. 2016;26:16071.

    Article  PubMed  PubMed Central  Google Scholar 

  67. Schmid K, Schonlebe J, Drexler H, Mueck-Weymann M. The effects of cannabis on heart rate variability and well-being in young men. Pharmacopsychiatry. 2010;43:147–50.

    Article  CAS  PubMed  Google Scholar 

  68. Tashkin Dp, Roth MD 2019. Pulmonary effects of inhaled cannabis smoke. Am J Drug Alcohol Abuse, 1-14.

  69. Payne KS, Mazur DJ, Hotaling JM, Pastuszak AW 2019. Cannabis and male fertility: a systematic review. J Urol, 101097JU0000000000000248.

  70. Fonseca BM, Correia-Da-Silva G, Almada M, Costa MA, Teixeira NA. The endocannabinoid system in the postimplantation period: a role during decidualization and placentation. Int J Endocrinol. 2013a;2013:510540.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Jordan T, Ngo B, Jones CA 2020. The use of cannabis and perceptions of its effect on fertility among infertility patients. Hum Reprod Open, 2020, hoz041.

  72. Metz TD, Silver RM, Mcmillin GA, Allshouse AA, Jensen TL, Mansfield C, et al. Prenatal marijuana use by self-report and umbilical cord sampling in a state with marijuana legalization. Obstet Gynecol. 2019;133:98–104.

    Article  PubMed  PubMed Central  Google Scholar 

  73. Wise LA, Wesselink AK, Hatch EE, Rothman KJ, Mikkelsen EM, Sorensen HT, et al. Marijuana use and fecundability in a North American preconception cohort study. J Epidemiol Community Health. 2018;72:208–15.

    Article  PubMed  Google Scholar 

  74. Luke S, Hutcheon J, Kendall T. Cannabis use in pregnancy in British Columbia and selected birth outcomes. J Obstet Gynaecol Can. 2019;41:1311–7.

    Article  PubMed  Google Scholar 

  75. Young-Wolff KC, Tucker LY, Alexeeff S, Armstrong MA, Conway A, Weisner C, et al. Trends in self-reported and biochemically tested marijuana use among pregnant females in California from 2009-2016. Jama-Journal of the American Medical Association. 2017;318:2490–1.

    Article  Google Scholar 

  76. Singh S, Filion KB, Abenhaim HA, Eisenberg MJ. Prevalence and outcomes of prenatal recreational cannabis use in high-income countries: a scoping review. Bjog-an International Journal of Obstetrics and Gynaecology. 2020;127:8–16.

    Article  CAS  PubMed  Google Scholar 

  77. Cecconi S, Rossi G, Castellucci A, D’andrea G, Maccarrone M. Endocannabinoid signaling in mammalian ovary. Eur J Obstet Gynecol Reprod Biol. 2014;178:6–11.

    Article  CAS  PubMed  Google Scholar 

  78. Resuehr D, Glore DR, Taylor HS, Bruner-Tran KL, Osteen KG. Progesterone-dependent regulation of endometrial cannabinoid receptor type 1 (CB1-R) expression is disrupted in women with endometriosis and in isolated stromal cells exposed to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). Fertil Steril. 2012;98:948–56 e1.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Liu X, Herbison AE. Dopamine regulation of gonadotropin-releasing hormone neuron excitability in male and female mice. Endocrinology. 2013;154:340–50.

    Article  CAS  PubMed  Google Scholar 

  80. Chakravarty I, Shah PG, Sheth AR, Ghosh JJ. Mode of action of delta-9-tetrahydrocannabinol on hypothalamo-pituitary function in adult female rats. J Reprod Fertil. 1979;57:113–5.

    Article  CAS  PubMed  Google Scholar 

  81. Mendelson JH, Mello NK, Ellingboe J, Skupny AS, Lex BW, Griffin M. Marihuana smoking suppresses luteinizing hormone in women. J Pharmacol Exp Ther. 1986;237:862–6.

    CAS  PubMed  Google Scholar 

  82. Mendelson JH, Mello NK, Ellingboe J. Acute effects of marihuana smoking on prolactin levels in human females. J Pharmacol Exp Ther. 1985;232:220–2.

    CAS  PubMed  Google Scholar 

  83. Brents LK. Marijuana, the endocannabinoid system and the female reproductive system. Yale J Biol Med. 2016;89:175–91.

    CAS  PubMed  PubMed Central  Google Scholar 

  84. Field E, Tyrey L. Delayed sexual-maturation during prepubertal cannabinoid treatment - importance of the timing of treatment. J Pharmacol Exp Ther. 1990;254:171–5.

    CAS  PubMed  Google Scholar 

  85. Neradugomma NK, Drafton K, Mor GG, Mao QC. Marijuana-derived cannabinoids inhibit uterine endometrial stromal cell decidualization and compromise trophoblast-endometrium cross-talk. Reprod Toxicol. 2019;87:100–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Gammon CM, Freeman GM Jr, Xie W, Petersen SL, Wetsel WC. Regulation of gonadotropin-releasing hormone secretion by cannabinoids. Endocrinology. 2005;146:4491–9.

    Article  CAS  PubMed  Google Scholar 

  87. Juan CC, Chen KH, Wang PH, Hwang JL, Seow KM. Endocannabinoid system activation may be associated with insulin resistance in women with polycystic ovary syndrome. Fertil Steril. 2015;104:200–6.

    Article  CAS  PubMed  Google Scholar 

  88. Cui N, Wang L, Wang W, Zhang J, Xu Y, Jiang L, et al. The correlation of anandamide with gonadotrophin and sex steroid hormones during the menstrual cycle. Iran J Basic Med Sci. 2017;20:1268–74.

    PubMed  PubMed Central  Google Scholar 

  89. Maia J, Almada M, Silva A, Correia-Da-Silva G, Teixeira N, Sa SI, et al. The endocannabinoid system expression in the female reproductive tract is modulated by estrogen. J Steroid Biochem Mol Biol. 2017;174:40–7.

    Article  CAS  PubMed  Google Scholar 

  90. Scotchie JG, Savaris RF, Martin CE, Young SL. Endocannabinoid regulation in human endometrium across the menstrual cycle. Reprod Sci. 2015;22:113–23.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Liu WM, Duan EK, Cao YJ. Effects of anandamide on embryo implantation in the mouse. Life Sci. 2002;71:1623–32.

    Article  CAS  PubMed  Google Scholar 

  92. Tanaka K, Mayne L, Khalil A, Baartz D, Eriksson L, Mortlock SA, et al. The role of the endocannabinoid system in aetiopathogenesis of endometriosis: a potential therapeutic target. Eur J Obstet Gynecol Reprod Biol. 2020;244:87–94.

    Article  CAS  PubMed  Google Scholar 

  93. Shen X, Duan H, Wang S, Gan L, Xu Q, Li JJ. 2019. Decreased expression of cannabinoid receptors in the eutopic and ectopic endometrium of patients with adenomyosis. Biomed Res Int, 2019, 5468954.

  94. almada m, Oliveira A, Amaral C., Fernandes Pa, Ramos MJ, Fonseca B, Correia-Da-Silva G, Teixeira N. 2019. Anandamide targets aromatase: a breakthrough on human decidualization. Biochimica Et Biophysica Acta-Molecular and Cell Biology of Lipids, 1864.

  95. Kasman AM, Thoma ME, McLain AC, Eisenberg ML. Association between use of marijuana and time to pregnancy in men and women: findings from the National Survey of Family Growth. Fertil Steril. 2018;109:866–71.

    Article  PubMed  Google Scholar 

  96. Sun AJ, Eisenberg ML. Association between marijuana use and sexual frequency in the United States: a population-based study. J Sex Med. 2017;14:1342–7.

    Article  PubMed  Google Scholar 

  97. Nassan FL, Arvizu M, Minguez-Alarcon L, Gaskins AJ, Williams PL, Petrozza JC, et al. Marijuana smoking and outcomes of infertility treatment with assisted reproductive technologies. Hum Reprod. 2019;34:1818–29.

    Article  PubMed  PubMed Central  Google Scholar 

  98. Blackard C, Tennes K 1984. Human Placental-Transfer of Cannabinoids. N Engl J Med, 311, 797

  99. Bertrand KA, Hanan NJ, Honerkamp-Smith G, Best BM, Chambers CD. Marijuana use by breastfeeding mothers and cannabinoid concentrations in breast milk. Pediatrics. 2018;142:e20181076.

    Article  PubMed  Google Scholar 

  100. Leemaqz SY, Dekker GA, Mccowan LM, Kenny LC, Myers JE, Simpson NAB, et al. Maternal marijuana use has independent effects on risk for spontaneous preterm birth but not other common late pregnancy complications. Reprod Toxicol. 2016;62:77–86.

    Article  CAS  PubMed  Google Scholar 

  101. Grzeskowiale LE, Grieger JA, Andraweera P, Knight E, Leemaqz S, Poston L, et al. The deleterious effects of cannabis during pregnancy on neonatal outcomes. Med J Aust. 2020;212:519–24.

    Article  Google Scholar 

  102. Gunn JKL, Rosales CB, Center KE, Nunez A, Gibson SJ, Christ C, et al. Prenatal exposure to cannabis and maternal and child health outcomes: a systematic review and meta-analysis. BMJ Open. 2016;6:e009986.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Conner SN, Bedell V, Lipsey K, Macones GA, Cahill AG, Tuuli MG. Maternal marijuana use and adverse neonatal outcomes: a systematic review and meta-analysis. Obstet Gynecol. 2016;128:713–23.

    Article  PubMed  Google Scholar 

  104. Corsi DJ, Donelle J, Sucha E, Hawken S, Hsu H, El-Chaar D, et al. Maternal cannabis use in pregnancy and child neurodevelopmental outcomes. Nat Med. 2020;26:1536–40.

    Article  CAS  PubMed  Google Scholar 

  105. Winiger Ea, Hewitt JK 2020. Prenatal cannabis exposure and sleep outcomes in children 9-10 years of age in the adolescent brain cognitive development (SM) study. Sleep Health.

  106. Lisdahl KM, TAMM L, Epstein JN, Jernigan T, Molina BSG, Hinshaw SP, et al. The impact of ADHD persistence, recent cannabis use, and age of regular cannabis use onset on subcortical volume and cortical thickness in young adults. Drug Alcohol Depend. 2016;161:135–46.

    Article  PubMed  PubMed Central  Google Scholar 

  107. Eidelman AI. Public health implications of recent breastfeeding research regarding cannabis use and risk of childhood obesity. Breastfeed Med. 2018;13:549–51.

    Article  PubMed  Google Scholar 

  108. Dinieri JA, Wang X, Szutorisz H, Spano SM, Kaur J, Casaccia P, et al. Maternal cannabis use alters ventral striatal dopamine D2 gene regulation in the offspring. Biol Psychiatry. 2011;70:763–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. CANADIAN TOBACCO, A. A. D. S. C. 2017. Available at: https://www.canada.ca/en/health-canada/services/canadian-tobacco-alcohol-drugs-survey/2017-summary.html (Accessed february 1, 2021).

  110. Lee MS, Lanes A, Ginsburg ES, Fox JH. Delta-9 THC can be detected and quantified in the semen of men who are chronic users of inhaled cannabis. J Assist Reprod Genet. 2020;37:1497–504.

    Article  PubMed  PubMed Central  Google Scholar 

  111. Kolodny RC, Masters WH, Kolodner RM, Toro G. Depression of plasma testosterone levels after chronic intensive marihuana use. N Engl J Med. 1974;290:872–4.

    Article  CAS  PubMed  Google Scholar 

  112. Fantus RJ, Lokeshwar SD, Kohn TP, Ramasamy R. The effect of tetrahydrocannabinol on testosterone among men in the United States: results from the National Health and Nutrition Examination Survey. World J Urol. 2020;38:3275–82.

    Article  CAS  PubMed  Google Scholar 

  113. Carroll K, Pottinger AM, Wynter S, Dacosta V. Marijuana use and its influence on sperm morphology and motility: identified risk for fertility among Jamaican men. Andrology. 2020;8:136–42.

    Article  CAS  PubMed  Google Scholar 

  114. Pizzol D, Demurtas J, Stubbs B, Soysal P, Mason C, Isik AT, et al. Relationship between cannabis use and erectile dysfunction: a systematic review and meta-analysis. American Journal of Mens Health. 2019;13:155798831989246.

    Article  Google Scholar 

  115. Amoako AA, Marczylo TH, Lam PM, Willets JM, Derry A, Elson J, et al. Quantitative analysis of anandamide and related acylethanolamides in human seminal plasma by ultra performance liquid chromatography tandem mass spectrometry. J Chromatogr B Anal Technol Biomed Life Sci. 2010;878:3231–7.

    Article  CAS  Google Scholar 

  116. Bari M, Battista N, Pirazzi V, Maccarrone M. The manifold actions of endocannabinoids on female and male reproductive events. Front Biosci (Landmark Ed). 2011;16:498–516.

    Article  CAS  Google Scholar 

  117. Aquila S, Guido C, Santoro A, Perrotta I, Laezza C, Bifulco M, et al. Human sperm anatomy: ultrastructural localization of the cannabinoid1 receptor and a potential role of anandamide in sperm survival and acrosome reaction. Anat Rec (Hoboken). 2010;293:298–309.

    Article  CAS  Google Scholar 

  118. Amoako AA, Marczylo TH, Marczylo EL, Elson J, Willets JM, Taylor AH, et al. Anandamide modulates human sperm motility: implications for men with asthenozoospermia and oligoasthenoteratozoospermia. Hum Reprod. 2013;28:2058–66.

    Article  CAS  PubMed  Google Scholar 

  119. Rossato M, Ion Popa F, Ferigo M, Clari G, Foresta C. Human sperm express cannabinoid receptor Cb1, the activation of which inhibits motility, acrosome reaction, and mitochondrial function. J Clin Endocrinol Metab. 2005;90:984–91.

    Article  CAS  PubMed  Google Scholar 

  120. Agirregoitia E, Carracedo A, Subiran N, Valdivia A, Agirregoitia N, Peralta L, et al. The CB(2) cannabinoid receptor regulates human sperm cell motility. Fertil Steril. 2010;93:1378–87.

    Article  CAS  PubMed  Google Scholar 

  121. Rossi G, Gasperi V, Paro R, Barsacchi D, Cecconi S, Maccarrone M. Follicle-stimulating hormone activates fatty acid amide hydrolase by protein kinase A and aromatase-dependent pathways in mouse primary Sertoli cells. Endocrinology. 2007;148:1431–9.

    Article  CAS  PubMed  Google Scholar 

  122. Zufferey F, Donze N, Rahban R, Senn A, Stettler E, Rudaz S, Nef S, Rossier MF 2020. Semen endocannabinoids are correlated to sperm quality in a cohort of 200 young Swiss men. Andrology.

  123. Murphy SK, Itchon-Ramos N, Visco Z, Huang Z, Grenier C, Schrott R, et al. Cannabinoid exposure and altered DNA methylation in rat and human sperm. Epigenetics. 2018;13:1208–21.

    Article  PubMed  PubMed Central  Google Scholar 

  124. Innocenzi E, De Domenico E, Ciccarone F, Zampieri M, Rossi G, Cicconi R, Bernardini R, Mattei M., Grimaldi P 2019. Paternal activation of CB2 cannabinoid receptor impairs placental and embryonic growth via an epigenetic mechanism. Scientific Reports, 9.

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Funding

This work was supported by the Applied Molecular Biosciences Unit - UCIBIO which is financed by national funds from Fundação para a Ciência e a Tecnologia (FCT) (UIDB/04378/2020); FEDER - Fundo Europeu de Desenvolvimento Regional funds through the COMPETE 2020 – Operacional Programme for Competitiveness and Internationalisation (POCI) and FCT in the framework of the project PTDC/MEC-OUT/28931/2017.

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B.M.F. conceived the idea and wrote the manuscript in consultation with I.R. All authors read and approved the final manuscript.

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Fonseca, B.M., Rebelo, I. Cannabis and Cannabinoids in Reproduction and Fertility: Where We Stand. Reprod. Sci. 29, 2429–2439 (2022). https://doi.org/10.1007/s43032-021-00588-1

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