Skip to main content
Springer Nature Link
Log in

Endocannabinoid Regulation in Human Endometrium Across the Menstrual Cycle

  • Original Article
  • Published:
Reproductive Sciences Aims and scope Submit manuscript

Abstract

Humans produce endogenous cannabinoids (endocannabinoids), a group of molecules that activate the same receptors as tetrahydrocannabinol. Endocannabinoids play important roles in reproduction in multiple species, but data in human endometrium are limited. Because endocannabinoids such as anandamide (AEA) and 2-arachidonoyl glycerol (2-AG) often act within tissues as paracrine factors, their effects can be modulated by changes in expression of locally produced synthetic and degradative/oxidative enzymes. The objective of this study was to localize and quantify expression of these key synthetic and degradative/oxidative enzymes for AEA and 2-AG in human endometrium throughout the menstrual cycle. Key synthetic enzymes include N-arachidonyl-phosphatidylethanolamine phospholipase-D (NAPE-PLD), diacylglycerol-lipase a (DAGL-α, and DAGL-β. Key degradative enzymes include fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL); cyclooxygenase 2 (COX2) is an oxidative enzyme. Endometrial samples were collected in 49 regularly cycling, normal women. Protein localization and expression were achieved by immunohistochemistry and messenger RNA (mRNA) expression by real-time reverse transcriptase polymerase chain reaction. No significant cycle-dependent mRNA expression was observed except that of COX2 (P = .002), which demonstrated maximum expression in the proliferative phase. During the secretory phase, NAPE-PLD protein had increased expression in luminal (P = .001), stromal (P = .007), and glandular (P = .04) epithelia, while FAAH had increased glandular (P = .009) and luminal (P = .01) expression. Increased expression in glandular epithelia was identified for MAGL (P = .03). The COX2 had increased luminal expression during the early secretory phase (P < .0001). In conclusion, maximal expression of degradatory/oxidative enzymes in the secretory phase may foster decreased endocannabinoid tone during implantation.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Subscribe and save

Springer+ Basic
$34.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or eBook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

Price includes VAT (Canada)

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Alexander A, Smith P, Rosengren R. Cannabinoids in the treatment of cancer. Cancer Lett. 2009;285(1):6–12.

    Article  CAS  PubMed  Google Scholar 

  2. Gaoni Y, Mechoulam R. Isolation, structure, and partial synthesis of an active constituent of hashish. J Am Chem Soc. 1964;86(8): 1646–1647.

    Article  CAS  Google Scholar 

  3. Mendelson J, Mello N, Ellingboe J, Skupny A, Lex B, Griffin M. Marihuana smoking suppresses luteinizing hormone in women. J Pharmacol Exp Ther. 1986;237(3):862–866.

    CAS  PubMed  Google Scholar 

  4. Gibson G, Baghurst P, Colley D. Maternal alcohol, tobacco and cannabis consumption and the outcome of pregnancy. Aust N Z J Obstet Gynaecol. 1983;23(1):15–19.

    Article  CAS  PubMed  Google Scholar 

  5. Frank D, Bauchner H, Parker S, et al. Neonatal body proportionality and body composition after in utero exposure to cocaine and marijuana. J Pediatr. 1990;117(4):622–626.

    Article  CAS  PubMed  Google Scholar 

  6. Sherwood R, Keating J, Kavvadia V, Greenough A, Peters T. Substance misuse in early pregnancy and relationship to fetal outcome. Eur J Pediatr. 1999;158(6):488–492.

    Article  CAS  PubMed  Google Scholar 

  7. Mouslech Z, Valla V. Endocannabinoid system: an overview of its potential in current medical practice. Neuro Endocrinol Lett. 2009;30(2):153–179.

    CAS  PubMed  Google Scholar 

  8. Natarajan V, Schmid P, Reddy P, Schmid H. Catabolism of n-acylethanolamine phospholipids by dog brain preparations. J Neurochem. 1984;42(6):1613–1619.

    Article  CAS  PubMed  Google Scholar 

  9. Cravatt B, Giang D, Mayfield S, Boger D, Lerner R, Gilula N. Molecular characterization of an enzyme that degrades neuromo-dulatory fatty-acid amides. Nature. 1996;384(6604):83–87.

    Article  CAS  PubMed  Google Scholar 

  10. Cravatt B, Lichtman A. The enzymatic inactivation of the fatty acid amide class of signaling lipids. Chem Phys Lipids. 2002; 121(1–2):135–148.

    Article  CAS  PubMed  Google Scholar 

  11. Pacher P, Kunos G. Modulating the endocannabinoid system in human health and disease-successes and failures. FEBS J. 2013;280(9):1918–1943.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Di Blasio AM, Vignali M, Gentilini D. The endocannabinoid pathway and the female reproductive organs. J Mol Endocrinol. 2013;50(1):R1–R9.

    Article  PubMed  CAS  Google Scholar 

  13. Sun X, Dey S. Cannabinoid/endocannabinoid signaling impact on early pregnancy events. Curr Top Behav Neurosci. 2009; 1: 255–273.

    Article  CAS  PubMed  Google Scholar 

  14. Wang H, Xie H, Sun X, et al. Differential regulation of endocannabinoid synthesis and degradation in the uterus during embryo implantation. Prostaglandins Other Lipid Mediat. 2007;83(l–2): 62–74.

    Article  CAS  PubMed  Google Scholar 

  15. Maccarrone M, Defelici M, Klinger F, et al. Mouse blastocysts release a lipid which activates anandamide hydrolase in intact uterus. Mol Hum Reprod. 2004;10(4):215–221.

    Article  CAS  PubMed  Google Scholar 

  16. Wang H, Xie H, Guo Y, et al. Fatty acid amide hydrolase deficiency limits early pregnancy events. J Clin Invest. 2006; 116(8):2122–2131.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Paria B, Song H, Wang X, et al. Dysregulated cannabinoid signaling disrupts uterine receptivity for embryo implantation. J Biol Chem. 2001;276(23):20523–20528.

    Article  CAS  PubMed  Google Scholar 

  18. Maccarrone M, Valensise H, Bari M, Lazzarin N, Romanini C, Finazzi-Agro A. Relation between decreased anandamide hydrolase concentrations in human lymphocytes and miscarriage. Lancet. 2000;355(9212):1326–1329.

    Article  CAS  PubMed  Google Scholar 

  19. Maccarrone M, Valensise H, Bari M, Lazzarin N, Romanini C, Finazzi-Agro A. Progesterone up-regulates anandamide hydrolase in human lymphocytes: Role of cytokines and implications for fertility. J Immunol. 2001;166(12):7183–7189.

    Article  CAS  PubMed  Google Scholar 

  20. Maccarrone M, Bisogno T, Valensise H, et al. Low fatty acid amide hydrolase and high anandamide levels are associated with failure to achieve an ongoing pregnancy after ivf and embryo transfer. Mol Hum Reprod. 2002;8(2):188–195.

    Article  CAS  PubMed  Google Scholar 

  21. Habayeb O, Taylor A, Finney M, Evans M, Konje J. Plasma anandamide concentration and pregnancy outcome in women with threatened miscarriage. JAMA. 2008;299(10):1135–1136.

    Article  CAS  PubMed  Google Scholar 

  22. Taylor A, Abbas M, Habiba M, Konje J. Histomorphometric evaluation of cannabinoid receptor and anandamide modulating enzyme expression in the human endometrium through the menstrual cycle. Histochem Cell Biol. 2010;133(5):557–565.

    Article  CAS  PubMed  Google Scholar 

  23. Andersen C, Jensen J, Orntoft T. Normalization of real-time quantitative reverse transcription-pcr data: A model-based variance estimation approach to identify genes suited for normalization, applied to bladder and colon cancer data sets. Cancer Res. 2004;64(15):5245–5250.

    Article  CAS  PubMed  Google Scholar 

  24. Plante B, Lessey B, Taylor R, et al. G protein-coupled estrogen receptor (gper) expression in normal and abnormal endometrium. Reprod Sci. 2012;19(7):684–693.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Budwit-Novotny DA, Mccarty K, Cox E, et al. Immunohistochem-ical analyses of estrogen receptor in endometrial adenocarcinoma using a monoclonal antibody. Cancer Res. 1986;46(10):5419–5425.

    CAS  PubMed  Google Scholar 

  26. Fuhrich D, Lessey B, Savaris R. Comparison of hscore assessment of endometrial beta3 integrin subunit expression with digital hscore using computerized image analysis (imagej). Anal Quant Cytol Histol. 2013;35(4):210–216.

    Google Scholar 

  27. Blitek A, Waclawik A, Kaczmarek M, Stadejek T, Pejsak Z, Zie-cik A. Expression of cyclooxygenase-1 and -2 in the porcine endometrium during the oestrous cycle and early pregnancy. Reprod Domest Anim. 2006;41(3):251–257.

    Article  CAS  PubMed  Google Scholar 

  28. Gebeh A, Marczylo E, Amoako A, Willets J, Konje J. Variation in stability of endogenous reference genes in fallopian tubes and endometrium from healthy and ectopic pregnant women. Int J Mol Sci. 2012;13(3):2810–2826.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Vogel C, Marcotte E. Insights into the regulation of protein abundance from proteomic and transcriptomic analyses. Nat Rev Genet. 2012;13(4):227–232.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Maia HJ, Haddad C, Pinheiro N, Casoy J. The effect of oral contraceptives on aromatase and cox-2 expression in the endometrium of patients with idiopathic menorrhagia or adenomyosis. Int J Womens Health. 2013;5:293–299.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Smith O, Jabbour H, Critchley H. Cyclooxygenase enzyme expression and e series prostaglandin receptor signalling are enhanced in heavy menstruation. Hum Reprod. 2007;22(5): 1450–1456.

    Article  CAS  PubMed  Google Scholar 

  32. Koike H, Ikenoue T, Mori N. [Studies on prostaglandin production relating to the mechanism of dysmenorrhea in endometriosis]. Nihon Naibunpi Gakkai Zasshi. 1994;70(l):43–56.

    CAS  PubMed  Google Scholar 

  33. Brady P, Stanic A, Styer A. Uterine fibroids and subfertility: an update on the role of myomectomy. Curr Opin Obstet Gynecol. 2013;25(3):255–259.

    Article  PubMed  Google Scholar 

  34. Diagnostic evaluation of the infertile female: a committee opinion. Fertil Steril. 2012;98(2):302–307.

    Google Scholar 

  35. Melford S, Taylor A, Konje J. Of mice and (wo)men: factors influencing successful implantation including endocannabinoids. Hum Reprod Update. 2014;20(3):415–428.

    Article  PubMed  Google Scholar 

  36. Baek J, Darlington C, Smith P, Ashton J. Antibody testing for brain immunohistochemistry: brain immunolabeling for the cannabinoid cb(2) receptor. J Neurosci Methods. 2013;216(2): 87–95.

    Article  CAS  PubMed  Google Scholar 

  37. Marions L, Danielsson K. Expression of cyclo-oxygenase in human endometrium during the implantation period. Mol Hum Reprod. 1999;5(10):961–965.

    Article  CAS  PubMed  Google Scholar 

  38. Tokyol C, Aktepe F, Dilek F, Sahin O, Arioz D. Expression of cyclooxygenase-2 and matrix metalloproteinase-2 in adenomyosis and endometrial polyps and its correlation with angiogenesis. Int J Gynecol Pathol. 2009;28(2): 148–156.

    Article  PubMed  Google Scholar 

  39. Jones R, Kelly R, Critchley H. Chemokine and cyclooxygenase-2 expression in human endometrium coincides with leukocyte accumulation. Hum Reprod. 1997;12(6): 1300–1306.

    Article  CAS  PubMed  Google Scholar 

  40. Stavreus-Evers A, Koraen L, Scott J, Zhang P, Westlund P. Distribution of cyclooxygenase-1, cyclooxygenase-2, and cytosolic phospholipase a2 in the luteal phase human endometrium and ovary. Fertil Steril. 2005;83(1):156–162.

    Article  CAS  PubMed  Google Scholar 

  41. Smith G, Roberts R, Hall C, Nuki G. Reversible ovulatory failure associated with the development of luteinized unruptured follicles in women with inflammatory arthritis taking non-steroidal antiinflammatory drugs. Br J Rheumatol. 1996;35(5):458–462.

    Article  CAS  PubMed  Google Scholar 

  42. Diao H, Zhu H, Ma H, et al. Rat ovulation, implantation and decidualization are severely compromised by cox-2 inhibitors. Front Biosci. 2007;12:3333–3342.

    Article  CAS  PubMed  Google Scholar 

  43. Lim H, Paria B, Das S, et al. Multiple female reproductive failures in cyclooxygenase 2-deficient mice. Cell. 1997;91(2):197–208.

    Article  CAS  PubMed  Google Scholar 

  44. Nakhai-Pour HR, Broy P, Sheehy O, Berard A. Use of nonaspirin nonsteroidal anti-inflammatory drugs during pregnancy and the risk of spontaneous abortion. CMAJ. 2011;183(15): 1713–1720.

    Article  PubMed  PubMed Central  Google Scholar 

  45. Li D, Liu L, Odouli R. Exposure to non-steroidal antiinflammatory drugs during pregnancy and risk of miscarriage: Population based cohort study. BMJ. 2003;327(7411):368.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Nielsen G, Sorensen H, Larsen H, Pedersen L. Risk of adverse birth outcome and miscarriage in pregnant users of non-steroidal antiinflammatory drugs: population based observational study and case-control study. BMJ. 2001;322(7281):266–270.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Keim S, Klebanoff M. Aspirin use and miscarriage risk. Epidemiology. 2006;17(4):435–439.

    Article  PubMed  Google Scholar 

  48. El-Talatini MR, Taylor A, Konje J. The relationship between plasma levels of the endocannabinoid, anandamide, sex steroids, and gonadotrophins during the menstrual cycle. Fertil Steril. 2010;93(6):1989–1996.

    Article  CAS  PubMed  Google Scholar 

  49. Trabucco E, Acone G, Marenna A, et al. Endocannabinoid system in first trimester placenta: low FAAH and high cbl expression characterize spontaneous miscarriage. Placenta. 2009;30(6): 516–522.

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Obstetrics and Gynecology, University of North Carolina at Chapel Hill, Old Clinic Building, Campus Box 7570, 27599-7570, Chapel Hill, NC, USA

    Jessica G. Scotchie MD & Steven L. Young MD, PhD

  2. Departamento de Ginecologia e Obstetrícia, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil

    Ricardo F. Savaris MD, MSc, PhD & Caitlin E. Martin MD

Authors
  1. Jessica G. Scotchie MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Ricardo F. Savaris MD, MSc, PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Caitlin E. Martin MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Steven L. Young MD, PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Steven L. Young MD, PhD.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Scotchie, J.G., Savaris, R.F., Martin, C.E. et al. Endocannabinoid Regulation in Human Endometrium Across the Menstrual Cycle. Reprod. Sci. 22, 113–123 (2015). https://doi.org/10.1177/1933719114533730

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1177/1933719114533730

Keywords

Search

Navigation