Pain Medications and Male Reproduction

  • Erma Z. Drobnis
  • Ajay K. Nangia
Chapter
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 1034)

Abstract

The increasing use of opioid medications has become a crisis in developed countries. The profound negative effects of opioids on male reproduction are well known, but this topic is absent from the current conversations about these medications. In the fertility clinic, a significant proportion of our patients are using opioids for pain management, and the options for these men are unclear. Opioids exert their negative effects by a variety of mechanisms. At high doses, testosterone levels fall significantly and hypogonadism is seen. In part, this results from increased prolactin and inhibition of gonadotropin production/secretion by the pituitary. However, negative effects on the testis are seen even in the absence of decreased androgen levels. As we review in this chapter, Leydig and germ cells produce endogenous opioids, and receptors for these substances are present throughout the testis. For example, endogenous opioids produced by Leydig and germ cells provide paracrine inhibition at Sertoli cell receptors, decreasing the production of androgen binding protein, which is required for intra-testis transport of androgens. Morphine also increases the expression of aromatase in the brain and testis and acts directly on the testis and germ cells to decrease testicular function. Exogenous opioids in men reduce semen quality, including increased DNA fragmentation. All opioids have these effects, but less damage is caused by lower doses, shorter-acting opioids, and by some drugs with mixed receptor activity, such as tramadol and tapentadol. The non-steroid anti-inflammatory drugs (NSAIDS) have much less effect on the male reproductive system, although there is a paucity of human studies. Paracetamol has been shown to cause sperm abnormalities, including DNA fragmentation, and to increase time to pregnancy and may prove to be of greater concern. In rodents, paracetamol has negative impacts on seminiferous tubule histology and fertility. Robust, well-designed studies in humans are needed.

References

  1. Abbatiello ER, Kaminsky M, Weisbroth S. The effect of prostaglandins and prostaglandin inhibitors on spermatogenesis. Int J Fertil. 1975;20:177–82. PMID: 4399.PubMedGoogle Scholar
  2. Abs R, Verhelst J, Maeyaert J, Van Buyten JP, Opsomer F, Adriaensen H, Verlooy J, Van Havenbergh T, Smet M, Van Acker K. Endocrine consequences of long-term intrathecal administration of opioids. J Clin Endocrinol Metab. 2000;85:2215–22. PMID: 10852454.PubMedCrossRefGoogle Scholar
  3. Adams ML, Sewing B, Forman JB, Meyer ER, Cicero TJ. Opioid-induced suppression of rat testicular function. J Pharmacol Exp Ther. 1993;266:323–8. PMID: 8392556.PubMedGoogle Scholar
  4. Agirregoitia E, Valdivia A, Carracedo A, Casis L, Gil J, Subiran N, Ochoa C, Irazusta J. Expression and localization of delta-, kappa-, and mu-opioid receptors in human spermatozoa and implications for sperm motility. J Clin Endocrinol Metab. 2006;91:4969–75.  https://doi.org/10.1210/jc.2006-0599. PMID: 16984994.PubMedCrossRefGoogle Scholar
  5. Ahmed MA, Kurkar A. Effects of opioid (tramadol) treatment on testicular functions in adult male rats: the role of nitric oxide and oxidative stress. Clin Exp Pharmacol Physiol. 2014;41:317–23.  https://doi.org/10.1111/1440-1681.12213. PMID: 24472030.PubMedCrossRefGoogle Scholar
  6. Albert O, Desdoits-Lethimonier C, Lesné L, Legrand A, Guillé F, Bensalah K, Dejucq-Rainsford N, Jégou B. Paracetamol, aspirin and indomethacin display endocrine disrupting properties in the adult human testis in vitro. Hum Reprod. 2013;28:1890–8.  https://doi.org/10.1093/humrep/det112. PMID: 23670170.PubMedCrossRefGoogle Scholar
  7. Aloisi AM, Aurilio C, Bachiocco V, Biasi G, Fiorenzani P, Pace MC, Paci V, Pari G, Passavanti G, Ravaioli L, Sindaco G, Vellucci R, Ceccarelli I. Endocrine consequences of opioid therapy. Psychoneuroendocrinology. 2009;34(Suppl 1):S162–8.  https://doi.org/10.1016/j.psyneuen.2009.05.013. PMID: 19540049.PubMedCrossRefGoogle Scholar
  8. Aloisi AM, Ceccarelli I, Fiorenzani P, Maddalena M, Rossi A, Tomei V, Sorda G, Danielli B, Rovini M, Cappelli A, Anzini M, Giordano A. Aromatase and 5-alpha reductase gene expression: modulation by pain and morphine treatment in male rats. Mol Pain. 2010;6:69.  https://doi.org/10.1186/1744-8069-6-69. PMID: 20977699.PubMedPubMedCentralCrossRefGoogle Scholar
  9. Aloisi AM, Ceccarelli I, Carlucci M, Suman A, Sindaco G, Mameli S, Paci V, Ravaioli L, Passavanti G, Bachiocco V, Pari G. Hormone replacement therapy in morphine-induced hypogonadic male chronic pain patients. Reprod Biol Endocrinol. 2011;9:26.  https://doi.org/10.1186/1477-7827-9-26. PMID: 19540049.PubMedPubMedCentralCrossRefGoogle Scholar
  10. Altintas R, Polat A, Parlakpinar H, Vardi N, Beytur A, Oguz F, Sagir M, Yildiz A, Duran ZR. The effect of melatonin on acetylsalicylic acid-induced kidney and testis damage. Hum Exp Toxicol. 2014;33:383–95.  https://doi.org/10.1177/0960327113506240. PMID: 24107454.PubMedCrossRefGoogle Scholar
  11. Aono T, Kurachi K, Mizutani S, Hamanaka Y, Uozumi T, Nakasima A, Koshiyama K, Matsumoto K. Influence of major surgical stress on plasma levels of testosterone, luteinizing hormone and follicle-stimulating hormone in male patients. J Clin Endocrinol Metab. 1972;35:535–42.  https://doi.org/10.1210/jcem-35-4-535. PMID: 5052974.PubMedCrossRefGoogle Scholar
  12. Asok Kumar R, Chinoy NJ. Effects of acetylsalicylic acid on reproductive organs of adolescent male rats. Endocrinol Exp. 1988;22:187–95. PMID: 3265382.PubMedGoogle Scholar
  13. Azizi F, Vagenakis AG, Longcope C, Ingbar SH, Braverman LE. Decreased serum testosterone concentration in male heroin and methadone addicts. Steroids. 1973;22:467–72. PMID: 4747447.PubMedCrossRefGoogle Scholar
  14. Badr FM, Rabouh SA. Effects of morphine sulphate on the germ cells of male mice. Teratog Carcinog Mutagen. 1983;3:19–26. PMID: 6132454.PubMedCrossRefGoogle Scholar
  15. Badr FM, Rabouh SA, Badr RS. On the mutagenicity of methadone hydrochloride. Induced dominant lethal mutation and spermatocyte chromosomal aberrations in treated males. Mutat Res. 1979;68:235–49. PMID: 514304.PubMedCrossRefGoogle Scholar
  16. Balaji T, Ramanathan M, Menon VP. Localization of cyclooxygenase-2 in mice vas deferens and its effects on fertility upon suppression using nimesulide: a preferential cyclooxygenase-2 inhibitor. Toxicology. 2007a;234:135–44.  https://doi.org/10.1016/j.tox.2007.02.011. PMID: 17382448.PubMedCrossRefGoogle Scholar
  17. Balaji T, Ramanathan M, Padmanabhan Menon V. Localization of cyclooxygenase-2 in mice testis and assessment of its possible role through suppressing its expression using nimesulide: a preferential cyclooxygenase-2 inhibitor. Prostaglandins Leukot Essent Fatty Acids. 2007b;76:341–8.  https://doi.org/10.1016/j.plefa.2007.04.006. PMID: 17624748.PubMedCrossRefGoogle Scholar
  18. Balaji T, Aruna S, Ramanathan M, Srinivasan M, Menon VP. Suppression of constitutively expressed cyclooxygenase-2 in the epididymis of mice by nimesulide decreases sperm motility. J Basic Clin Physiol Pharmacol. 2009;20:357–76. PMID: 20214021.PubMedCrossRefGoogle Scholar
  19. O’Rourke TK Jr, Wosnitzer MS. Opioid-induced androgen deficiency (OPIAD): diagnosis, management, and literature review. Curr Urol Rep. 2016;17:76.  https://doi.org/10.1007/s11934-016-0634-y. PMID: 27586511.PubMedCrossRefGoogle Scholar
  20. Paice JA, Penn RD, Ryan WG. Altered sexual function and decreased testosterone in patients receiving intraspinal opioids. J Pain Symptom Manage. 1994;9:126–31. PMID: 7517429.PubMedCrossRefGoogle Scholar
  21. Pan JT, Teo KL. Fentanyl stimulates prolactin release through mu-opiate receptors, but not the serotonergic system. Endocrinology. 1989;125:1863–9. PMID: 2551630.PubMedCrossRefGoogle Scholar
  22. Patil SR, Sonar A, Londonkar R, Patil SR, Patil SB. Efficacy of exogenous gonadotropins on the maintenance of spermatogenesis in pethidine treated albino rats. Indian J Physiol Pharmacol. 1998;42:509–14. PMID: 10874352.PubMedGoogle Scholar
  23. Barreca T, Magnani G, Sannia A, Rolandi E. Changes in nalorphine-induced hyperprolactinaemia after bromocriptine or sulpiride administration. Eur J Clin Pharmacol. 1982;22(4):375–6. PMID: 7106173.PubMedCrossRefGoogle Scholar
  24. Pende A, Musso NR, Montaldi ML, Pastorino G, Arzese M, Devilla L. Evaluation of the effects induced by four opiate drugs, with different affinities to opioid receptor subtypes, on anterior pituitary LH, TSH, PRL and GH secretion and on cortisol secretion in normal men. Biomed Pharmacother. 1986;40:178–82. PMID: 3024754.PubMedGoogle Scholar
  25. Pimpinelli F, Parenti M, Guzzi F, Piva F, Hokfelt T, Maggi R. Presence of delta opioid receptors on a subset of hypothalamic gonadotropin releasing hormone (GnRH) neurons. Brain Res. 2006;1070:15–23. PMID: 16405927.PubMedCrossRefGoogle Scholar
  26. Placke ME, Wyand DS, Cohen SD. Extrahepatic lesions induced by acetaminophen in the mouse. Toxicol Pathol. 1987;15:381–7.  https://doi.org/10.1177/019262338701500401. PMID: 3432938.PubMedCrossRefGoogle Scholar
  27. Ragni G, De Lauretis L, Gambaro V, Di Pietro R, Bestetti O, Recalcati F, Papetti C. Semen evaluation in heroin and methadone addicts. Acta Eur Fertil. 1985;16:245–9. PMID: 4072581.PubMedGoogle Scholar
  28. Ragni G, De Lauretis L, Bestetti O, Sghedoni D, Gambaro V. Gonadal function in male heroin and methadone addicts. Int J Androl. 1988;11:93–100. PMID: 3372047.PubMedCrossRefGoogle Scholar
  29. Rajagopal A, Vassilopoulou-Sellin R, Palmer JL, Kaur G, Bruera E. Symptomatic hypogonadism in male survivors of cancer with chronic exposure to opioids. Cancer. 2004;100:851–858. PMID: 14770444.  https://doi.org/10.1002/cncr.20028.PubMedCrossRefGoogle Scholar
  30. Rasheed A, Tareen IA. Effects of heroin on thyroid function, cortisol and testosterone level in addicts. Pol J Pharmacol. 1995;47:441–4. PMID: 8868137.PubMedGoogle Scholar
  31. Ratnasooriya WD, Jayakody JR. Long-term administration of large doses of paracetamol impairs the reproductive competence of male rats. Asian J Andro. 2000;2:247–55. PMID: 11202412.Google Scholar
  32. Rhodin A, Stridsberg M, Gordh T. Opioid endocrinopathy: a clinical problem in patients with chronic pain and long-term oral opioid treatment. Clin J Pain. 2010;26:374–80.  https://doi.org/10.1097/AJP.0b013e3181d1059d.PubMedCrossRefGoogle Scholar
  33. Basaria S, Jasuja R, Huang G, Wharton W, Pan H, Pencina K, Li Z, Travison TG, Bhawan J, Gonthier R, Labrie F, Dury AY, Serra C, Papazian A, O’Leary M, Amr S, Storer TW, Stern E, Bhasin S. Characteristics of men who report persistent sexual symptoms after finasteride use for hair loss. J Clin Endocrinol Metab. 2015;101:4669–80.  https://doi.org/10.1210/jc.2016-2726. PMID: 27662439.CrossRefGoogle Scholar
  34. Roberts LJ, Finch PM, Pullan PT, Bhagat CI, Price LM. Sex hormone suppression by intrathecal opioids: a prospective study. Clin J Pain. 2002;18:144–8. PMID: 12048415.PubMedCrossRefGoogle Scholar
  35. Rolandi E, Magnani G, Sannia A, Barreca T. Hormonal changes induced by a partial opiate antagonist, nalorphine. Evaluation of PRL, GH, TSH, LH, FSH and cortisol secretion. Eur J Clin Pharmacol. 1981;21(1):23–5. PMID: 6800826.PubMedCrossRefGoogle Scholar
  36. Rolandi E, Marabini A, Franceschini R, Messina V, Bongera P, Barreca T. Changes in pituitary secretion induced by an agonist-antagonist opioid drug, buprenorphine. Acta Endocrinol (Copenh). 1983;104:257–60. PMID: 6415992.Google Scholar
  37. Rubinstein AL, Carpenter DM, Minkoff JR. Hypogonadism in men with chronic pain linked to the use of long-acting rather than short-acting opioids. Clin J Pain. 2013;29:840–5.  https://doi.org/10.1097/AJP.0b013e31827c7b5d.PubMedCrossRefGoogle Scholar
  38. Saarialho-Kere U, Mattila MJ, Paloheimo M, Seppälä T. Psychomotor, respiratory and neuroendocrinological effects of buprenorphine and amitriptyline in healthy volunteers. Eur J Clin Pharmacol. 1987;33:139–46. PMID: 3691607.PubMedCrossRefGoogle Scholar
  39. Saeed SA, Anwar N, Khan KM, Sarfraz N. Effect of chronic treatment with a cyclooxygenase inhibitor on reproductive parameters in male rat. J Ayub Med Coll Abbottabad. 2009;21:66–71. PMID: 20929017.PubMedGoogle Scholar
  40. Saksena SK, Lau IF, Bartke A, Chang MC. Effect of indomethacin on blood plasma levels of LH and testosterone in male rats. J Reprod Fertil. 1975;42:311–7. PMID: 1117445.PubMedCrossRefGoogle Scholar
  41. Bawor M, Dennis BB, Samaan MC, Plater C, Worster A, Varenbut M, Daiter J, Marsh DC, Desai D, Steiner M, Anglin R, Coote M, Pare G, Thabane L, Samaan Z. Methadone induces testosterone suppression in patients with opioid addiction. Sci Rep. 2014;4:6189.  https://doi.org/10.1038/srep06189. PMID: 25155550.PubMedPubMedCentralCrossRefGoogle Scholar
  42. Bawor M, Bami H, Dennis BB, Plater C, Worster A, Varenbut M, Daiter J, Marsh DC, Steiner M, Anglin R, Coote M, Pare G, Thabane L, Samaan Z. Testosterone suppression in opioid users: a systematic review and meta-analysis. Drug Alcohol Depend. 2015;149:1–9.  https://doi.org/10.1016/j.drugalcdep.2015.01.038. PMID: 25702934.PubMedCrossRefGoogle Scholar
  43. Schneider J. Hypogonadism in men treated with chronic opioids. Arch Phys Med Rehabil. 2008;89:1414.  https://doi.org/10.1016/j.apmr.2008.05.001.PubMedCrossRefGoogle Scholar
  44. Scott JE, Persaud TV. A quantitative study of the effects of acetylsalicylic acid on spermatogenesis and organs of the rat. Int J Fertil. 1978;23:282–7. PMID: 33922.PubMedGoogle Scholar
  45. Shin D, Palermo GD, Goldstein M, Rosenwaks Z, Schlegel PN. Indications for corticosteroids prior to epididymal sperm retrieval. Int J Fertil Womens Med. 1988;43:165–70. PMID: 9692540.Google Scholar
  46. Shuey DL, Stump DG, Carliss RD, Gerson RJ. Effects of the opioid analgesic oxymorphone hydrochloride on reproductive function in male and female rats. Birth Defects Res B Dev Reprod Toxicol. 2008;83:12–8. PMID: 18088051.PubMedCrossRefGoogle Scholar
  47. Smarr MM, Grantz KL, Sundaram R, Maisog JM, Honda M, Kannan K, Buck Louis GM. Urinary paracetamol and time-to-pregnancy. Hum Reprod. 2016;31:2119–2127. PMID: 27412248.  https://doi.org/10.1093/humrep/dew172.PubMedPubMedCentralCrossRefGoogle Scholar
  48. Smith HS, Elliott JA. Opioid-induced androgen deficiency (OPIAD). Pain Physician. 2012;15(Suppl 3):ES145–56. PMID: 22786453.PubMedGoogle Scholar
  49. Stutz G, Martini AC, Ruiz RD, Fiol De Cuneo M, Munoz L, Lacuara JL. Functional activity of mouse sperm was not affected by low doses of aspirin-like drugs. Arch Androl. 2000;44:117–28. PMID: 10746868.PubMedCrossRefGoogle Scholar
  50. Subirán N, Casis L, Irazusta J. Regulation of male fertility by the opioid system. Mol Med. 2011;17:846–53.  https://doi.org/10.2119/molmed.2010.00268.PubMedPubMedCentralCrossRefGoogle Scholar
  51. Takzare N, Samizadeh E, Shoar S, Majidi Zolbin M, Naderan M, Lashkari A, Bakhtiarian A. Impacts of morphine addiction on spermatogenesis in rats. Int J Reprod Biomed (Yazd). 2016;14:303–8. PMID: 27326414.Google Scholar
  52. Tenhola H, Sinclair D, Alho H, Lahti T. Effect of opioid antagonists on sex hormone secretion. J Endocrinol Invest. 2012;35:227–30.  https://doi.org/10.3275/8181. PMID: 22183092.PubMedGoogle Scholar
  53. Toppozada M, Gerges F, Khalil H, Marzouk S, Kholeif A. Effect of prostaglandin E2 or prostaglandin synthesis inhibitors on human gonadotrophins and prolactin. Eicosanoids. 1992;5:23–7. PMID: 1419076.PubMedGoogle Scholar
  54. United States Food and Drug Administration. FDA drug safety communication: FDA warns about several safety issues with opioid pain medicines; requires label changes. 2016. http://www.fda.gov/Drugs/DrugSafety/ucm489676.htm. Accessed 28 June 2016.
  55. Uzun B, Atli O, Perk BO, Burukoglu D, Ilgin S. Evaluation of the reproductive toxicity of naproxen sodium and meloxicam in male rats. Hum Exp Toxicol. 2015;34:415–29.  https://doi.org/10.1177/0960327114542886. PMID: 25034942.PubMedCrossRefGoogle Scholar
  56. Bhasin S, Cunningham GR, Hayes FJ, Matsumoto AM, Snyder PJ, Swerdloff RS, Montori VM. Testosterone therapy in adult men with androgen deficiency syndromes: an endocrine society clinical practice guideline. J Clin Endocrinol Metab. 2006;91:1995–2010.  https://doi.org/10.1210/jc.2005-2847. PMID: 16720669.PubMedCrossRefGoogle Scholar
  57. Vescovi PP, Pezzarossa A, Ceresini G, Rastelli G, Valenti G, Gerra G. Effects of dopamine receptor stimulation on opiate-induced modifications of pituitary-gonadal function. Horm Res. 1985;21:155–9. PMID: 3997064.PubMedCrossRefGoogle Scholar
  58. Vuong C, Van Uum SH, O’Dell LE, Lutfy K, Friedman TC. The effects of opioids and opioid analogs on animal and human endocrine systems. Endocr Rev. 2010;31:98–132.  https://doi.org/10.1210/er.2009-0009. PMID: 19903933.PubMedCrossRefGoogle Scholar
  59. Wang C, Chan V, Yeung RT. The effect of heroin addiction on pituitary-testicular function. Clin Endocrinol (Oxf). 1978;9:455–61.  https://doi.org/10.1111/j.1365-2265.1978.tb03585.x. PMID: 569031.CrossRefGoogle Scholar
  60. Wehrenberg WB, McNicol D, Wardlaw SL, Frantz AG, Ferin M. Dopaminergic and serotonergic involvement in opiate-induced prolactin release in monkeys. Endocrinology. 1981;109:544–547. PMID: 7250056.  https://doi.org/10.1210/endo-109-2-544.PubMedCrossRefGoogle Scholar
  61. Wei N, Hood JC. Naproxen and ejaculatory dysfunction. Ann Intern Med. 1980;93:933. PMID: 7447198.PubMedCrossRefGoogle Scholar
  62. Wiger R, Hongslo JK, Evenson DP, De Angelis P, Schwarze PE, Holme JA. Effects of acetaminophen and hydroxyurea on spermatogenesis and sperm chromatin structure in laboratory mice. Reprod Toxicol. 1995;9:21–33. PMID: 8520128.PubMedCrossRefGoogle Scholar
  63. Winnall WR, Ali U, O’Bryan MK, Hirst JJ, Whiley PA, Muir JA, Hedger MP. Constitutive expression of prostaglandin-endoperoxide synthase 2 by somatic and spermatogenic cells is responsible for prostaglandin E2 production in the adult rat testis. Biol Reprod. 2007;76:759–68.  https://doi.org/10.1095/biolreprod.106.053124. PMID: 17251525.PubMedCrossRefGoogle Scholar
  64. Biswas NM, Sanyal S, Patra PB. Antispermatogenic effect of aspirin and its prevention by prostaglandin E2. Andrologia. 1978;10:137–41. PMID: 646143.PubMedCrossRefGoogle Scholar
  65. Wong D, Gray DP, Simmonds M, Rashiq S, Sobolev I, Morrish DW. Opioid analgesics suppress male gonadal function but opioid use in males and females does not correlate with symptoms of sexual dysfunction. Pain Res Manag. 2011;16:311–6. PMID: 22059201.PubMedPubMedCentralCrossRefGoogle Scholar
  66. Yano CL, Dolder H. Rat testicular structure and ultrastructure after paracetamol treatment. Contraception. 2002;66:463–7. PMID: 12499042.PubMedCrossRefGoogle Scholar
  67. Blick G, Khera M, Bhattacharya RK, Nguyen D, Kushner H, Miner MM. Testosterone replacement therapy outcomes among opioid users: the Testim Registry in the United States (TRiUS). Pain Med. 2012;13:688–98.  https://doi.org/10.1111/j.1526-4637.2012.01368.x. PMID: 22536837.PubMedCrossRefGoogle Scholar
  68. Zhou Y, Boudreau DM, Freedman AN. Trends in the use of aspirin and nonsteroidal anti-inflammatory drugs in the general U.S. population. Pharmacoepidemiol Drug Saf. 2014;23:43–50.  https://doi.org/10.1002/pds.3463. PMID:23723142.PubMedCrossRefGoogle Scholar
  69. Zis AP, Haskett RF, Albala AA, Carroll BJ. Morphine inhibits cortisol and stimulates prolactin secretion in man. Psychoneuroendocrinology. 1984;9:423–7. PMID: 6514937.PubMedCrossRefGoogle Scholar
  70. Bliesener N, Albrecht S, Schwager A, Weckbecker K, Lichtermann D, Klingmüller D. Plasma testosterone and sexual function in men receiving buprenorphine maintenance for opioid dependence. J Clin Endocrinol Metab. 2005;90:203–6. PMID: 15483091.PubMedCrossRefGoogle Scholar
  71. Bolelli G, Lafisca S, Flamigni C, Lodi S, Franceschetti F, Filicori M, Mosca R. Heroin addiction: relationship between the plasma levels of testosterone, dihydrotestosterone, androstenedione, LH, FSH, and the plasma concentration of heroin. Toxicology. 1979;15:19–29. PMID: 120622.PubMedCrossRefGoogle Scholar
  72. Brune K, Renner B, Tiegs G. Acetaminophen/paracetamol: a history of errors, failures and false decisions. Eur J Pain. 2015;19:953–65.  https://doi.org/10.1002/ejp.621. PMID: 25429980.PubMedCrossRefGoogle Scholar
  73. Ceccarelli I, De Padova AM, Fiorenzani P, Massafra C, Aloisi AM. Single opioid administration modifies gonadal steroids in both the CNS and plasma of male rats. Neuroscience. 2006;140:929–37.  https://doi.org/10.1016/j.neuroscience.2006.02.044. PMID: 16580783.PubMedCrossRefGoogle Scholar
  74. Cenedella RJ. Prostaglandins and male reproductive physiology. Adv Sex Horm Res. 1975;1:325–58. PMID: 1225030.PubMedGoogle Scholar
  75. Choi JC, Chung MI, Lee YD. Modulation of pain sensation by stress-related testosterone and cortisol. Anaesthesia. 2012;67:1146–51.  https://doi.org/10.1111/j.1365-2044.2012.07267.x. PMID: 22804789.PubMedCrossRefGoogle Scholar
  76. Chorbov VM, Todorov AA, Lynskey MT, Cicero TJ. Elevated levels of DNA methylation at the OPRM1 promoter in blood and sperm from male opioid addicts. J Opioid Manag. 2011;7:258–64. PMID: 21957825.PubMedPubMedCentralCrossRefGoogle Scholar
  77. Cicero TJ, Meyer ER, Bell RD, Wiest WG. Effects of morphine on the secondary sex organs and plasma testosterone levels of rats. Res Commun Chem Pathol Pharmacol. 1974;7:17–24. PMID: 4811448.PubMedGoogle Scholar
  78. Cicero TJ, Bell RD, Wiest WG, Allison JH, Polakoski K, Robins E. Function of the male sex organs in heroin and methadone users. N Engl J Med. 1975a;292:882–7. PMID: 1117911.PubMedCrossRefGoogle Scholar
  79. Cicero TJ, Meyer ER, Wiest WG, Olney JW, Bell RD. Effects of chronic morphine administration on the reproductive system of the male rat. J Pharmacol Exp Ther. 1975b;192:542–8. PMID: 1168254.PubMedGoogle Scholar
  80. Cicero TJ, Nock B, O’Connor L, Adams M, Meyer ER. Adverse effects of paternal opiate exposure on offspring development and sensitivity to morphine-induced analgesia. J Pharmacol Exp Ther. 1995;273:386–92. PMID: 7714793.PubMedGoogle Scholar
  81. Cicero TJ, Davis LA, LaRegina MC, Meyer ER, Schlegel MS. Chronic opiate exposure in the male rat adversely affects fertility. Pharmacol Biochem Behav. 2002;72:157–63. PMID: 11900783.PubMedCrossRefGoogle Scholar
  82. Colameco S, Coren JS. Opioid-induced endocrinopathy. J Am Osteopath Assoc. 2009;109:20–5. PMID: 19193821.PubMedGoogle Scholar
  83. Conte D, Nordio M, Fillo S, De Giorgio G, Isidori A, Romanelli F. Aspirin inhibition of naloxone-induced luteinizing hormone secretion in man. J Clin Endocrinol Metab. 1996;81(5):1772. PMID: 8626832.PubMedGoogle Scholar
  84. Conte D, Romanelli F, Fillo S, Guidetti L, Isidori A, Franceschi F, Latini M, di Luigi L. Aspirin inhibits androgen response to chorionic gonadotropin in humans. Am J Physiol. 1999;277(6 Pt 1):E1032–7. PMID: 10600792.PubMedGoogle Scholar
  85. Daniell HW. Hypogonadism in men consuming sustained-action oral opioids. J Pain. 2002;3:377–84.  https://doi.org/10.1054/jpai.2002.126790. PMID: 14622741.PubMedCrossRefGoogle Scholar
  86. Daniell HW. DHEAS deficiency during consumption of sustained-action prescribed opioids: evidence for opioid-induced inhibition of adrenal androgen production. J Pain. 2006;7:901–7.  https://doi.org/10.1016/j.jpain.2006.04.011. PMID: 17157776.PubMedCrossRefGoogle Scholar
  87. Delitala G, Grossman A, Besser M. Differential effects of opiate peptides and alkaloids on anterior pituitary hormone secretion. Neuroendocrinology. 1983a;37:275–9. PMID: 6633817.PubMedCrossRefGoogle Scholar
  88. Delitala G, Giusti M, Mazzocchi G, Granziera L, Tarditi W, Giordano G. Participation of endogenous opiates in regulation of the hypothalamic-pituitary-testicular axis in normal men. J Clin Endocrinol Metab. 1983b;57:1277–81.  https://doi.org/10.1210/jcem-57-6-1277. PMID: 6415088.PubMedCrossRefGoogle Scholar
  89. Devilla L, Pende A, Morgano A, Giusti M, Musso NR, Lotti G. Morphine-induced TSH release in normal and hypothyroid subjects. Neuroendocrinology. 1985;40:303–8. PMID: 3921862.PubMedCrossRefGoogle Scholar
  90. Didolkar AK, Patel PB, Roychowdhury D. Effect of aspirin on spermatogenesis in mature and immature rats. Int J Androl. 1980;3:585–93. PMID: 7440017.PubMedCrossRefGoogle Scholar
  91. Duka T, Hoehe M, Doenicke A, Stephan U, Matussek N. Influence of the histaminergic system on opiate-induced neurosecretion and behaviour. Psychoneuroendocrinology. 1987;12:271–80. PMID: 3659227.PubMedCrossRefGoogle Scholar
  92. Eichenbaum G, Göhler K, Etropolski M, Steigerwald I, Pergolizzi J, Kim M, Vorsanger G. Does tapentadol affect sex hormone concentrations differently from morphine and oxycodone? An initial assessment and possible implications for opioid-induced androgen deficiency. J Opioid Manag. 2015;11:211–27.  https://doi.org/10.5055/jom.2015.0270. PMID: 25985806.PubMedCrossRefGoogle Scholar
  93. Ekaluo U, Ikpeme E, Udokpoh A. Sperm head abnormality and mutagenic effects of aspirin, paracetamol and caffeine containing analgesics in rats. The Internet. J Toxicol. 2008;7:6. https://print.ispub.com/api/0/ispub-article/10849.Google Scholar
  94. Elliott JA, Horton E, Fibuch EE. The endocrine effects of long-term oral opioid therapy: a case report and review of the literature. J Opioid Manag. 2011;7:145–54. PMID: 21561038.PubMedGoogle Scholar
  95. Eriksson PS, Rönnbäck L, Hansson E. Do persistent morphine effects involve interactions with the genome? Drug Alcohol Depend. 1989;24:39–43. PMID: 2758973.PubMedCrossRefGoogle Scholar
  96. Erkan LG, Altinbas B, Guvenc G, Alcay S, Toker MB, Ustuner B, Udum Kucuksen D, Yalcin M. Brain thromboxane A2 via arachidonic acid cascade induces the hypothalamic-pituitary-gonadal axis activation in rats. Auton Neurosci. 2015;189:50–5.  https://doi.org/10.1016/j.autneu.2015.02.005.PMID: 25784152.PubMedCrossRefGoogle Scholar
  97. Estomba H, Muñoa-Hoyos I, Giano M, Urizar-Arenaza I, Casis L, Irazusta J, Subirán N. Expression and localization of opioid receptors in male germ cells and the implication for mouse spermatogenesis. PLoS One. 2016;11(3):e0152162.  https://doi.org/10.1371/journal.pone.0152162.PubMedPubMedCentralCrossRefGoogle Scholar
  98. Finch PM, Roberts LJ, Price L, Hadlow NC, Pullan PT. Hypogonadism in patients treated with intrathecal morphine. Clin J Pain. 2000;16:251–4. PMID: 11014399.PubMedCrossRefGoogle Scholar
  99. Finch PM, Price LM, Pullan PT, Drummond PD. Effects of testosterone treatment on bone mineral density in hypogonadal men receiving intrathecal opioids. Pain Pract. 2015;15:308–13.  https://doi.org/10.1111/papr.12190. PMID: 24690205.PubMedCrossRefGoogle Scholar
  100. Fraser LA, Morrison D, Morley-Forster P, Paul TL, Tokmakejian S, Larry Nicholson R, Bureau Y, Friedman TC, Van Uum SH. Oral opioids for chronic non-cancer pain: higher prevalence of hypogonadism in men than in women. Exp Clin Endocrinol Diabetes. 2009;117:38–43.  https://doi.org/10.1055/s-2008-1076715. PMID: 18523930.PubMedCrossRefGoogle Scholar
  101. Gudin JA, Laitman A, Nalamachu S. Opioid related endocrinopathy. Pain Med. 2015;16(Suppl 1):S9–15.  https://doi.org/10.1111/pme.12926. PMID: 26461076.PubMedCrossRefGoogle Scholar
  102. Hallesy DW, Shott LD, Hill R. Comparative toxicology of naproxen. Scand J Rheumatol Suppl. 1973;2:20–8. PMID: 4204256.PubMedCrossRefGoogle Scholar
  103. Hallinan R, Byrne A, Agho K, McMahon CG, Tynan P, Attia J. Hypogonadism in men receiving methadone and buprenorphine maintenance treatment. Int J Androl. 2009;32:131–9.  https://doi.org/10.1111/j.1365-2605.2007.00824.x. 17971165.PubMedCrossRefGoogle Scholar
  104. Hargreaves WA, Tyler J, Weinberg JA, Sorensen JL, Benowitz N. (--)-alpha-Acetylmethadol effects on alcohol and diazepam use, sexual function and cardiac function. Drug Alcohol Depend. 1983;12:323–32. PMID: 6671416.PubMedCrossRefGoogle Scholar
  105. Hoehe M, Duka T, Doenicke A. Human studies on the mu opiate receptor agonist fentanyl: neuroendocrine and behavioral responses. Psychoneuroendocrinology. 1988;13:397–408. PMID: 2849775.PubMedCrossRefGoogle Scholar
  106. Huang G, Travison T, Maggio M, Edwards RR, Basaria S. Effects of testosterone replacement on metabolic and inflammatory markers in men with opioid-induced androgen deficiency. Clin Endocrinol (Oxf). 2016;85:232–8.  https://doi.org/10.1111/cen.13049. PMID: 26928845.CrossRefGoogle Scholar
  107. Ito H, Kawamura K, Kataumi Z, Sumiya H, Takahara M, Aikawa H, Shimazaki J. Indomethacin suppresses prolactin release in men. Hinyokika Kiyo. 1984;30:17–20. PMID: 6428199.PubMedGoogle Scholar
  108. James RW, Heywood R, Crook D. Effects of morphine sulphate on pituitary-testicular morphology of rats. Toxicol Lett. 1980;7:61–70. PMID: 7292515.PubMedCrossRefGoogle Scholar
  109. Katz N, Mazer NA. The impact of opioids on the endocrine system. Clin J Pain. 2009;25:170–5.  https://doi.org/10.1097/AJP.0b013e3181850df6. PMID: 19333165.PubMedCrossRefGoogle Scholar
  110. Kim CH, Garcia R, Stover J, Ritchie K, Whealton T, Ata MA. Androgen deficiency in long-term intrathecal opioid administration. Pain Physician. 2014a;17:E543–8. PMID: 25054405.PubMedGoogle Scholar
  111. Knuth UA, Kühne J, Crosby J, Bals-Pratsch M, Kelly RW, Nieschlag E. Indomethacin and oxaprozin lower seminal prostaglandin levels but do not influence sperm motion characteristics and serum hormones of young healthy men in a placebo-controlled double-blind trial. J Androl. 1989;10:108–19. PMID: 2497096.PubMedCrossRefGoogle Scholar
  112. Lafisca S, Bolelli G, Franceschetti F, Danieli A, Tagliaro F, Marigo M, Flamigni C. Free and bound testosterone in male heroin addicts. Arch Toxicol Suppl. 1985;8:394–7. PMID: 3938270.PubMedCrossRefGoogle Scholar
  113. Langenbach R, Loftin CD, Lee C, Tiano H. Cyclooxygenase-deficient mice. A summary of their characteristics and susceptibilities to inflammation and carcinogenesis. Ann N Y Acad Sci. 1999;889:52–61.  https://doi.org/10.1111/j.1749-6632.1999.tb08723.x. PMID: 10668482.PubMedCrossRefGoogle Scholar
  114. Löscher W, Blazaki D. Effect of non-steroidal anti-inflammatory drugs on fertility of male rats. J Reprod Fertil. 1986;76:65–73. PMID: 3456056.PubMedCrossRefGoogle Scholar
  115. Lundh D, Hedelin H, Jonsson K, Gifford M, Larsson D. Assessing chronic pelvic pain syndrome patients: blood plasma factors and cortisol saliva. Scand J Urol. 2013;47:521–8.  https://doi.org/10.3109/21681805.2013.769460. PMID: 23394140.PubMedCrossRefGoogle Scholar
  116. Malik SA, Khan C, Jabbar A, Iqbal A. Heroin addiction and sex hormones in males. J Pak Med Assoc. 1992;42:210–2. PMID: 1433805.PubMedGoogle Scholar
  117. Marley PB, Smith CC. Proceedings: the source and a possible function in fertility of seminal prostaglandin-like material, in the mouse. Br J Pharmacol. 1974;52:114P. PMID: 4451775.PubMedPubMedCentralGoogle Scholar
  118. Martini AC, Vincenti LM, Santillán ME, Stutz G, Kaplan R, Ruiz RD, de Cuneo MF. Chronic administration of nonsteroidal-antiinflammatory drugs (NSAIDS): effects upon mouse reproductive functions. Rev Fac Cien Med Univ Nac Cordoba. 2008;65:47–59. PMID: 20803938.PubMedGoogle Scholar
  119. Matsumoto K, Takeyasu K, Mizutani S, Hamanaka Y, Uozumi T. Plasma testosterone levels following surgical stress in male patients. Acta Endocrinol. 1970;65:11–7.  https://doi.org/10.1530/acta.0.0650011. PMID: 5468965.PubMedGoogle Scholar
  120. Mendelson JH, Mello NK. Plasma testosterone levels during chronic heroin use and protracted abstinence: study of Hong Kong addicts. NIDA Res Monogr. 1978;19:142–8. PMID: 106283.Google Scholar
  121. Mendelson JH, Meyer RE, Ellingboe J, Mirin SM, McDougle M. Effects of heroin and methadone on plasma cortisol and testosterone. J Pharmacol Exp Ther. 1975;195:296–302. PMID: 1185598.PubMedGoogle Scholar
  122. Mendelson JH, Mello NK, Teoh SK, Lloyd-Jones JG, Clifford JM. Naloxone suppresses buprenorphine stimulation of plasma prolactin. J Clin Psychopharmacol. 1989;9:105–9. PMID: 2723127.PubMedCrossRefGoogle Scholar
  123. Moshtaghi-Kashanian GR, Esmaeeli F, Dabiri S. Enhanced prolactin levels in opium smokers. Addict Biol. 2005;10:345–9.  https://doi.org/10.1080/13556210500351263. PMID: 16318956.PubMedCrossRefGoogle Scholar
  124. Munjack DJ, Kanno PH. Retarded ejaculation: a review. Arch Sex Behav. 1979;8:139–50. PMID: 112949.PubMedCrossRefGoogle Scholar
  125. Niederberger C. Re: Regulation of male fertility by the opioid system. J Urol. 2012;187:238–9.  https://doi.org/10.1016/j.juro.2011.08.036. PMID: 22153458.PubMedCrossRefGoogle Scholar

Copyright information

© Springer International Publishing AG 2017

Authors and Affiliations

  • Erma Z. Drobnis
    • 1
  • Ajay K. Nangia
    • 2
  1. 1.Obstetrics, Gynecology and Women’s HealthUniversity of Missouri School of MedicineColumbiaUSA
  2. 2.Department of UrologyUniversity of Kansas Medical CenterKansas CityUSA

Personalised recommendations