Cannabinoids, Oxidative Stress and Female Reproduction: Where do we stand?
Article Sidebar
Main Article Content
Abstract
Cannabis sativum has long been used globally for hallucination. However, detrimental effects on female reproduction have never been studied. The aim of the present paper is to evaluate cannabinoid-induced oxidative stress and reproductive containment in female mice. Fifteen adult female Parkes strain mice were randomly chosen from institutional animal houses (n = 5/group) with ad libitum access to water and food. Animals were grouped into control (vehicle-treated), treated with 6 mg of Cannabis/100 g of body weight, and 12 mg of Cannabis/100 g of body weight. After 15 days all animals were sacrificed and tissues were collected for histology, immunohistochemistry, and estimations of different parameters. Histology and immunohistochemistry (of Cannabinoid Receptor 1; CB1) were performed following standardized protocols. All parameters were estimated either by standard biochemical protocols or by kit following the manufacturer’s protocol. Stress parameters (Super Oxide Dismutase; SOD, Catalase, CAT; Malonaldehyde, MDA and Glutathione Peroxidase; GPx), apoptotic parameters of thecal cells (by Caspase-3 assay), serum level of Estrogen (E2), steroidogenic parameters (3β Hydroxy-steroid dehydrogenase; 3β HSD and 17β Hydroxy-steroid dehydrogenase; 17β HSD) and expression of CB1 were noted in ovary. Data were analyzed by One-way Analysis of Variance (One-way ANOVA) followed by Duncan’s Multiple Range post hoc Test. We found a significant (p < 0.05) decrease in steroidogenic parameters and a significant increase (p < 0.05) in free radical and apoptotic parameters and CB1 receptor expressions upon dose-dependent Cannabis treatment. We may conclude that chronic treatment of Cannabis causes reproductive containment in females which has never been addressed previously.
Article Details
Copyright (c) 2025 Ghosh S.
This work is licensed under a Creative Commons Attribution 4.0 International License.
Ashton CH, Moore PB, Gallagher P, Young AH. Cannabinoids in bipolar affective disorder: a review and discussion of their therapeutic potential. Psychopharmacol. 2005;9:293–300. Available from: https://doi.org/10.1177/0269881105051541
Aversa A, Rossi F, Francomano D, Bruzziches R, Bertone C, Santiemma V, et al. Early endothelial dysfunction as a marker of vasculogenic erectile dysfunction in young habitual Cannabis users. Int J Impot Res. 2008;20:566–73. Available from: https://doi.org/10.1038/ijir.2008.43
Battista N, Pasquariello N, Di Tommaso, Maccarrone M. Interplay between endocannabinoids, steroids and cytokines in the control of human reproduction. J Neuroendocrinol. 2008;20:82–9. Available from: https://doi.org/10.1111/j.1365-2826.2008.01684.x
Bayewitch M, Rhee MH, Avidor-Reiss T, Breuer A, Mechoulam R, Vogel Z. D9-Tetrahydrocannabinol antagonizes the peripheral cannabinoid receptor-mediated inhibition of adenylyl cyclase. J Biol Chem. 1996;271:9902–5. Available from: https://doi.org/10.1074/jbc.271.17.9902
Brown TT, Dobs AS. Endocrine effects of marijuana. J Clin Pharmacol. 2002;42:S90–6. Available from: https://doi.org/10.1002/j.1552-4604.2002.tb06008.x
Cacciola G, Chioccarelli T, Mackie K, Meccariello R, Ledent C, Fasano S, et al. Expression of type-1 cannabinoid receptor during rat postnatal testicular development: possible involvement in adult Leydig cell differentiation. Biol Reprod. 2008;79:758–65. Available from: https://doi.org/10.1095/biolreprod.108.070128
Cobellis G, Cacciola G, Scarpa D, et al. Endocannabinoid system in frog and rodent testis: type-1 cannabinoid receptor and fatty acid amide hydrolase activity in male germ cells. Biol Reprod. 2006;75:82–9. Available from: https://doi.org/10.1095/biolreprod.106.051730
Chakravarty I, Shah PG, Sheth AR, Ghosh JJ. Mode of action of delta-9-tetrahydrocannibinol on hypothalamo–pituitary function in adult female rats. J Reprod Fertil. 1979;57:113–5. Available from: https://doi.org/10.1530/jrf.0.0570113
Cravatt BF, Giang DK, Mayfield SP, Boger DL, Lerner RA, Gilula NB. Molecular characterization of an enzyme that degrades neuromodulatory fatty-acid amides. Nature. 1996;384:83–7. Available from: https://doi.org/10.1038/384083a0
Campbell VA. Tetrahydrocannabinol-induced apoptosis of cultured cortical neurones is associated with cytochrome c release and caspase-3 activation. Neuropharmacol. 2001;40:702–9. Available from: https://doi.org/10.1016/s0028-3908(00)00210-0
Dalterio S, Bartke A, Burstein S. Cannabinoids inhibit testosterone secretion by mouse testes in vitro. Science. 1977;196:1472–3. Available from: https://doi.org/10.1126/science.867048
Singh SK, Chakravarty S. Antispermatogenic and antifertility effects of 20,25-diazacholesterol dihydrochloride in mice. Reprod Toxicol. 2003;17:37–44. Available from: https://doi.org/10.1016/s0890-6238(02)00075-8
Devane WA, Hanus L, Breuer A. Isolation and structure of a brain constituent that binds to the cannabinoid receptor. Science. 1992;258:1946–9. Available from: https://doi.org/10.1126/science.1470919
Dhawan K, Kumar S, Sharma A. Reversal of cannabinoids (delta9-THC) by the benzoflavone moiety from methanol extract of Passiflora incarnata Linneaus in mice: a possible therapy for cannabinoid addiction. J Pharm Pharmacol. 2002;54:875–81. Available from: https://doi.org/10.1211/0022357021779069
Dixit VP, Lohiya NK. Effects of Cannabis extract on the response of accessory sex organs of adult male mice to testosterone. Ind J Physiol Pharmacol. 1975;19:98–100. Available from: https://pubmed.ncbi.nlm.nih.gov/1158438/
Dixit VP, Gupta CL, Agarwal M. Testicular degeneration and necrosis induced by chronic administration of Cannabis extract in dogs. Endokrinologie. 1977;69:299–305. Available from: https://pubmed.ncbi.nlm.nih.gov/913356/
EL-Gohary M, Eid MA. Effect of cannabinoid ingestion (in the form of bhang) on the immune system of high school and university students. Hum Exp Toxicol. 2004;23:149–56. Available from: https://doi.org/10.1191/0960327104ht426oa
Gammon CM, Freeman GM Jr, Xie W, et al. Regulation of gonadotropin-releasing hormone secretion by cannabinoids. Endocrinol. 2005;146:4491–9. Available from: https://doi.org/10.1210/en.2004-1672
Gaoni Y, Mechoulam R. Isolation, structure and partial synthesis of an active constituent of hashish. J Am Chem Soc. 1964;86:1646–7. Available from: https://www.scirp.org/reference/referencespapers?referenceid=3701878
Gye MC, Kang HH, Kang HJ. Expression of cannabinoid receptor 1 in mouse testes. Arch Androl. 2005;51:247–55. Available from: https://doi.org/10.1080/014850190898845
Hillig KW, Mahlberg PG. A chemotaxonomic analysis of cannabinoid variation in Cannabis (Cannabaceae). Am J Bot. 2004;91:966–75. Available from: https://doi.org/10.3732/ajb.91.6.966
Ghosh S, Haldar C. Histology and immunohistochemical localization of different receptors (MT1, MT2, AR, GR, ERα) in various organs (spleen, thymus, testis, ovary, uterus) of Indian goat C. hircus. Int J Res Stud Bio Sci. 2015;7:1–13. Available from: https://www.arcjournals.org/pdfs/ijrsb/v3-i7/8.pdf
Shivanandappa T, Venkatesh S. A colorimetric assay method for 3β-hydroxy-Δ⁵-steroid dehydrogenase. Anal Biochem. 1997;254:57–61. Available from: https://doi.org/10.1006/abio.1997.2406
Blomquist CH, Lindemann NJ, Hakanson EY. 17β-Hydroxysteroid and 20α-hydroxysteroid dehydrogenase activities of human placental microsomes: kinetic evidence for two enzymes differing in substrate specificity. Arch Biochem Biophys. 1985;239:206–15. Available from: https://doi.org/10.1016/0003-9861(85)90828-8
Das K, Samanta L, Chainy GBN. A modified spectrophotometric assay of superoxide dismutase using nitrite formation by superoxide radicals. Indian J Biochem Biophys. 2000;37:201–4. Available from: https://www.researchgate.net/publication/221704769_A_Modified_Spectrophotometric_Assay_of_Superoxide_Dismutase_Using_Nitrite_Formation_by_Superoxide_Radicals
Sinha AK. Colorimetric assay of catalase. Anal Biochem. 1972;47:389–94. Available from: https://doi.org/10.1016/0003-2697(72)90132-7
Ohkawa H, Ohishi N, Yagi K. Reaction of linoleic acid hydroperoxide with thiobarbituric acid. J Lipid Res. 1978;19:1053–7. Available from: https://pubmed.ncbi.nlm.nih.gov/103988/
Mantha SV, Prasad M, Kalra J, Prasad K. Antioxidant enzymes in hypercholesterolemia and effect of vitamin E in rabbits. Atherosclerosis. 1993;101:135–44. Available from: https://doi.org/10.1016/0021-9150(93)90110-g
Sharma S, Haldar C, Chaube SK. Effect of exogenous melatonin on X-ray induced cellular toxicity in lymphatic tissue of Indian tropical male squirrel, Funambulus pennanti. Int J Radiat Biol. 2008;84:363–74. Available from: https://doi.org/10.1080/09553000802029894
Ghosh S, Singh AK, Haldar C. Seasonal modulation of immunity by melatonin and gonadal steroids in a short day breeder goat Capra hircus. Theriogenol. 2013;82:1121–30. Available from: https://doi.org/10.1016/j.theriogenology.2014.07.035
Bruning JL, Knitz BL. Computational handbook of statistics. 2nd ed. Illinois: Scott, Foresman and Company; 1977. Available from: https://www.amazon.in/Computational-Handbook-Statistics-James-Bruning/dp/0673150143
Hall W, Solowij N. Adverse effects of Cannabis. Lancet. 1998;14:1611–6. Available from: https://doi.org/10.1016/s0140-6736(98)05021-1
Harmon J, Aliapoulios MA. Gynecomastia in marijuana users. N Engl J Med. 1972;287:936. Available from: https://doi.org/10.1056/nejm197211022871824
Jackson AL, Murphy LL. Role of hypothalamic-pituitary-adrenal axis in the suppression of luteinizing hormone release by Delta-9-THC. Neuroendocrinol. 1977;65:446–52. Available from: https://doi.org/10.1159/000127208
Lewis SE, Maccarrone M. Endocannabinoids, sperm biology and human fertility. Pharmacol Res. 2009;60:126–31. Available from: https://doi.org/10.1016/j.phrs.2009.02.009
Maccarrone M, Finazzi-Agro A. The endocannabinoid system, anandamide and the regulation of mammalian cell apoptosis. Cell Death Differ. 2003;10:946–55. Available from: https://doi.org/10.1038/sj.cdd.4401284
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. Available from: https://doi.org/10.1038/346561a0
Meccariello R, Franzoni MF, Chianese R, et al. Interplay between the endocannabinoid system and GnRH-I in the forebrain of the anuran amphibian Rana esculenta. Endocrinol. 2008;149:2149–58. Available from: https://doi.org/10.1210/en.2007-1357
Moore TH, Zammit S, Lingford-Hughes A, Barnes TR, Jones PB, Burke M, et al. Cannabis use and risk of psychotic or affective mental health outcomes: a systematic review. Lancet. 2007;370:319–28. Available from: https://doi.org/10.1016/s0140-6736(07)61162-3
Munro S, Thomas KL, Abu-Shaar M. Molecular characterization of a peripheral receptor for cannabinoids. Nature. 1993;365:61–5. Available from: https://doi.org/10.1038/365061a0
Murphy LL, Munoz RM, Adrian BA, Villanua M. Function of cannabinoid receptors in the neuroendocrine regulation of hormone secretion. Neurobiol Dis. 1998;5:432–46. Available from: https://doi.org/10.1006/nbdi.1998.0224
Pertwee RG. The therapeutic potential of drugs that target cannabinoid receptors or modulate the tissue levels or actions of endocannabinoids. AAPS J. 2005;7:554–25. Available from: https://doi.org/10.1208/aapsj070364
Pertwee RG, Ross RA, Craib SJ, Thomas A. Cannabidiol antagonizes cannabinoid receptor agonists and noradrenaline in the mouse vas deferens. Eur J Pharmacol. 2002;456:99–106. Available from: https://doi.org/10.1016/s0014-2999(02)02624-9