Basic & Clinical Pharmacology & Toxicology, 2016, 118, 9–13
Doi: 10.1111/bcpt.12446
MiniReview
Histamine-2 Receptor Antagonists and Semen Quality Saleem A. Banihani Department of Medical Laboratory Sciences, Jordan University of Science and Technology, Irbid, Jordan (Received 16 March 2015; Accepted 6 July 2015) Abstract: Histamine-2 receptor antagonists are a class of drugs used to treat the acid-related gastrointestinal diseases such as ulcer and gastro-oesophageal reflux disease. Although such drugs, especially ranitidine and famotidine, are still widely used, their effects on semen quality, and hence on male infertility, is still unclear. This MiniReview systematically addresses and summarizes the effect of histamine-2 receptor antagonists (cimetidine, ranitidine, nizatidine and famotidine) on semen quality, particularly, on sperm function. Cimetidine appears to have adverse effects on semen quality. While the effects of ranitidine and nizatidine on semen quality are still controversial, famotidine does not appear to change semen quality. Therefore, additional studies will be required to clarify whether histamine-2 receptor-independent effects of these drugs play a role in semen quality as well as further clinical studies including direct comparison of the histamine-2 receptor antagonists.
The histamine-2 (H2) receptors are widely expressed and can be found in gastric mucosal cells, heart, central nervous system, immune cells, smooth muscles of the airway, vasculature and uterus [1]. They are positively coupled to adenylate cyclase via Gs alpha subunit [2,3]. The activation of histamine-2 receptors by histamine alters the activity of Gs and therefore enhances the intracellular cyclic AMP (cAMP) production [3]. cAMP activates protein kinase A, which phosphorylates the cytoskeletal proteins, leading to the transport of the H+/K+ ATPase (proton pump) from the cytoplasm to the plasma membrane of parietal cells [3,4]. H2 receptor activation stimulates hydrochloric acid secretion from the acidsecreting parietal cells of the gastric mucosa, leads to smooth muscle relaxation in the vasculature and airways, increases cardiac rate and contractility, and mediates some of the immunomodulatory effects of histamine [1]. Histamine-2 receptor antagonists (H2RAs), also called H2blockers (e.g. cimetidine, ranitidine, nizatidine and famotidine), are the medications used to reduce the amount of hydrochloric acid produced by the stomach [5–7]. Mechanistically, these drugs are competitive antagonists of histamine-2 receptors [6,7]. In view of that, H2RAs are used to treat the acid-related gastrointestinal diseases such as gastrooesophageal reflux disease [8,9], dyspepsia [10–12], Zollinger–Ellison syndrome [13,14] and ulcer [15–17]. Various studies have shown that proton pump inhibitors (e.g. omeprazole, lansoprazole, esomeprazole), another class of acid reducers with long-lasting reduction of gastric acid Author for correspondence: Saleem A. Banihani, Clinical bio-analytical chemistry and Molecular Medicine, Department of Medical Laboratory Sciences, Jordan University of Science and Technology, P.O. Box 3030, Irbid 22110, Jordan (fax +962-2-7201087, e-mail sabani [email protected]).
production [18,19], are more effective than H2RAs in treating acid-related gastrointestinal diseases such as gastrooesophageal reflux disease [20–23], ulcer [21,24], dyspepsia [25] and Zollinger–Ellison syndrome [26]; however, H2RAs are still widely used in the treatment of acid-related gastrointestinal diseases. One reason for this is that proton pump inhibitors therapy is more expensive and less cost-effective, at least in certain cases of acid-related gastrointestinal diseases, compared with H2RAs [10,27]. In addition, various studies are still appreciating the efficacy of H2RAs in treating acidrelated gastrointestinal diseases same as proton pump inhibitors [28–30]. Moreover, studies have presented a synergistic effect between proton pump inhibitors and H2RAs in treating acid-related gastrointestinal diseases such as gastrooesophageal reflux disease [28,31]. Although H2RAs therapy is still extensively used to treat acid-related gastrointestinal diseases since beginning of the 1970s, its effect on semen quality, and thus on male infertility, at least in all of its forms, is still unclear. Such effect of the H2RAs should be clearly determined, especially for men with poor semen quality (i.e. oligospermia, asthenospermia) to avoid side effects that may worsen their fertilizing ability. In addition, this effect should be underlined in certain cases that may negatively affect sperm parameters such as testicular cancers, chemotherapy treatments and surgical infertility interventions. In this MiniReview, we address and summarize previous studies linking H2RAs with semen quality. We searched the MEDLINE electronic database for English-language articles using the key words ‘H2 receptor antagonist’, ‘semen’ and ‘sperm’. The reference lists of the relevant articles were scanned for additional studies. Given that semen quality is a measure of the ability of semen to achieve fertilization [32], and that sperm is the
© 2015 Nordic Association for the Publication of BCPT (former Nordic Pharmacological Society)
MiniReview
SALEEM A. BANIHANI
10
study on albino rats carried out by Sinha et al. [43] also showed a decrease in sperm count in addition to a decrease in sperm motility and morphology when using cimetidine at 20 mg/mL for 15 days. Whether such effect of cimetidine on sperm parameters is reversible requires further investigation. Actually, the results by Nayeri and Kazerouni [44] showed that male rats treated with cimetidine at 100 mg/kg for 5 weeks had lower weights of seminal vesicles compared with the untreated group, and this change was found to be reversible one week after the termination of treatment. One explanation for the adverse effects of cimetidine on sperm parameters is that cimetidine increases the level of intrasperm Ca2+, which also found to reduce sperm viability [45]. Moreover, cimetidine decreased the diameter of seminiferous tubules of mice testis and the germinal epithelial cell heights when administered at 10–100 mg/day for 15 days [46]. Similar results were observed in male albino Wistar rats which received intraperitoneal injections of cimetidine at 50 mg/kg for 52 days [47]. A later in vivo system study conducted by Sasso-Cerri and Miraglia [48] found that cimetidine may lead to detachment and apoptosis of Sertoli cells and thus affect negatively sperm quality. In 2009, Sasso-Cerri confirmed these findings and showed that cimetidine at the same concentration enhances oestrogen receptor beta, a nuclear receptor activated by the sex hormone oestrogen, immunoexpression and apoptosis in germ cells of adult male rats [49].
central part in this context, then semen quality is discussed here through the main sperm function parameters such as quantity (i.e. count) and quality (i.e. motility, morphology, and viability or vitality). Effect of H2RAs on Sperm Parameters Various studies (clinical, in vitro and in vivo) have presented the effect of H2RAs on sperm function. To date, the clinical studies that have explored the effect of orally administered H2-blockers (cimetidine, ranitidine and nizatidine) on sperm parameters (count, motility and morphology) are summarized in table 1. The effect of orally administered H2RAs on pituitary– gonadal hormones (LH, FSH and testosterone) and prolactin in men are summarized in table 2. Effect of cimetidine. In human beings, cimetidine was found to decrease the number of ejaculated sperm, especially when used at high concentrations (≥1000 mg/day) [33–39], but it showed mild effects on sperm motility and morphology [37,38,40,41]. This unfavourable effect of cimetidine on sperm count has been approved recently in an in vivo system study carried out by Aprioku et al. [42]. In this study, the effect of cimetidine on sperm count was found to be dose dependent [42]. A previous
Table 1. Effect of orally administered H2RAs (cimetidine, ranitidine and nizatidine) on human sperm parameters (count, motility and morphology) in men. Effect on sperm parameters H2RA Cimetidine
Ranitidine
Nizatidine
Dose (mg/day) 1200 1000 400 400 300 150 ~150–300 150
Treatment duration
Count
Motility
Morphology
/+ /+
/+
/+ /+
/+ /+
/+ /+ /+
9 weeks 3 months 18–36 months 6 weeks 3 months 9 months >12 month 6 weeks
References [33–36] [37,38] [40] [39] [52] [52] [53] [39]
H2RA, histamine-2 receptor antagonist. () decrease; (/+) no effect.
Table 2. Effect of orally administered H2RAs on pituitary–gonadal hormones and prolactin in men. Pituitary–gonadal hormones and prolactin H2RA Cimetidine
Ranitidine Nizatidine Famotidine
Dose (mg/day)
LH
1200 1000 400 400 300 150 150 40
/+ /+ /+ /+ /+ /+ /+
FSH + /+
Testosterone
Prolactin
+
/+ /+
/+ /+
/+
/+
H2RA, histamine-2 receptor antagonist; LH, Luteinizing hormone; FSH, follicle stimulating hormone. () decrease; (+) increase; (/+) no effect.
© 2015 Nordic Association for the Publication of BCPT (former Nordic Pharmacological Society)
/+ /+ /+ /+ /+
References [33–36] [37,38] [40] [39] [52] [53] [39] [62]
MiniReview
H2RAS AND SEMEN
Further, a number of studies reported that consuming approximately 1200 mg/day cimetidine may reduce luteinizing hormone (LH) and testosterone levels [33–36], which negatively affects sperm parameters, particularly sperm count (table 2) [50]. Given that cimetidine exerts an anti-androgenic effect and that histamine has a steroidogenic activity, the reduction in sperm population may be due to a decrease in the number of epididymal mast cells and thereby histamine content after cimetidine treatment [43,51]. Also, cimetidine was found to reduce the synthesis of sperm adhesion molecule-1 (SPAM-1), a protein present in the principal cells of the epididymal epithelium and plays an important role in sperm maturation, and decrease the availability of b-defensins, an antimicrobial peptide, which ultimately affects the number of sperm produced [43]. Effect of ranitidine. The effect of ranitidine on human sperm function is still controversial. An earlier clinical study carried out by Wang et al. [52] concluded that ranitidine (300 mg/day) does not affect sperm count, motility and morphology. The same authors supported their conclusion by showing an insignificant effect of ranitidine administration on pituitary–gonadal hormones (LH, FSH and testosterone) and prolactin [52]. In contrast, a recent case–control study (2014) showed that ranitidine reduces all of these sperm parameters [53]. Therefore, the robust clinical studies that underline the effect of ranitidine on sperm parameters and thus on sperm function are highly desired. The same controversial effect of ranitidine on sperm function is also found in the in vivo system studies. Oral adminstration of ranitidine at 8 or 16 mg/kg/day for 2 weeks did not change sperm parameters (motility, count, vitality and morphology) of Wister rats, although increasing the dose of ranitidine to 30 or 60 mg/kg/day found to decrease these parameters [42]. The reduced sperm motility and vitality when applying higher concentrations of ranitidine may be due to the increased levels of intrinsic ionized calcium of sperm [45]. In another in vivo system study on male mice, the histological parameters (shape of seminiferous tubules of testis, shape of germ cells and sperm morphology) remained normal after treatment with ranitidine at 10–70 mg/kg/day for 15 days [46].
11
stomach acidity [55,56]. However, its effect on human semen quality and sperm function is still undetermined. To date, to the best of our knowledge, almost all research studies that have directly linked famotidine with sperm function are nonclinical. Although some researches have shown that famotidine affects negatively the quality of sperm (e.g. viability) in vitro in a time- and dose-dependent manner [45], others have suggested beneficial effects of famotidine on sperm function because of its antioxidant activity [57,58]. The adverse effects of famotidine on sperm viability may be due to the increased Ca2+ influx into sperm [45,59]. Actually, the elevation of intrasperm Ca2+ by H2RAs (e.g. cimetidine, ranitidine and famotidine) may be attributed to their ability to inhibit Na+/K+ pump on sperm membrane, which possibly leads to the increase of Na+ in sperm cytosol [45,60]. Such build-up prevents the further influx of Na+ via Na+/Ca2+ exchanger, which in turn stops the efflux Ca2+ [45]. Conversely, Mahdavi and Mozdarani (2011) suggested that famotidine could reduce the cytotoxic effect of radiation in mouse spermatogenesis [61], which may improve the quality of ejaculated sperm. A previous study by Savarino et al. [62] supports this suggestion by showing that administration of famotidine at 40 mg/day for 4 weeks did not affect the gonadal function in men (i.e. normal LH, FSH and testosterone).
Conclusions and Future Perspectives
Effect of nizatidine. In 1987, Van et al. [39] showed that administration of nizatidine at 150 mg/day decreases the number of ejaculated sperm, but it did not show any change in serum levels of prolactin and LH hormones. In fact, few reports have discussed the effect of nizatidine on sperm function; this could be because nizatidine is a less effective and thus less commonly used drug, compared with the other H2RAs (e.g. famotidine, ranitidine) [54,55].
In summary, cimetidine appears to have adverse effects on semen quality, especially when used at high concentrations in men (i.e. ≥100 mg/day), and affects almost all sperm parameters (count, motility, vitality and morphology). This effect was found to be dose dependent and may be due to a reduction in some hypothalamic–pituitary–testicular axis hormones such as LH and testosterone, abnormal changes in the seminiferous tubules and germinal cells of the testis, and increased intrasperm Ca2+. Until now, the effect of ranitidine on semen quality is still controversial to the favour of using lower doses in human beings (≤150 mg/day). Further studies, particularly clinical, are required to approve the effect of ranitidine on semen quality. As nizatidine is not effective in reducing stomach acidity and therefore is not a commonly used drug, further studies on nizatidine to explain its effects on semen quality appear not to be a priority in this research basis. Regardless of its effectiveness as an acid reducer over all other H2RAs, famotidine is an encouraging drug when considering its effects on semen quality. To date, it is the only H2RA that has been found to be beneficial to sperm physiology; however, non-clinical experiments presented adverse effects for its use on some sperm parameters. Further studies, mainly clinical, will be of great value to confirm the effects (positive or negative) of famotidine on semen quality.
Effect of famotidine. At the present time, among all H2RAs, famotidine is preferred and commonly used because of its effectiveness in reducing
Acknowledgement This study was supported by research deanship at Jordan University of Science and Technology Grant no. 20150176.
© 2015 Nordic Association for the Publication of BCPT (former Nordic Pharmacological Society)
SALEEM A. BANIHANI
12 Disclosure Statement The authors declare no conflict of interest. References
1 Mahdy AM, Webster NR. Histamine and antihistamines. Anaesth Intensive Care Med 2014;15:250–5. 2 Fukushima Y, Ohmachi Y, Asano T, Nawano M, Funaki M, Anai M et al. Localization of the histamine H(2) receptor, a target for antiulcer drugs, in gastric parietal cells. Digestion 1999;60:522–7. 3 Hill SJ, Ganellin CR, Timmerman H, Schwartz JC, Shankley NP, Young JM et al. International Union of Pharmacology. XIII. Classification of histamine receptors. Pharmacol Rev 1997;49:253–78. 4 Shin JM, Munson K, Vagin O, Sachs G. The gastric HK-ATPase: structure, function, and inhibition. Pflugers Arch 2009;457:609–22. 5 Soll AH. Effects of the H2-antagonists on histamine action and interaction with gastrin in isolated parietal cells. Gastroenterology 1978;74:355. 6 Shamburek RD, Schubert ML. Control of gastric acid secretion. Histamine H2-receptor antagonists and H+K(+)-ATPase inhibitors. Gastroenterol Clin North Am 1992;21:527–50. 7 Cross SA. Localization of histamine and histamine H2-receptor antagonists in the gastric mucosa. Histochem J 1977;9:619–44. 8 Vela MF. Medical treatments of GERD: the old and new. Gastroenterol Clin North Am 2014;43:121–33. 9 Shawyer AC, Pemberton J, Flageole H. Post-operative management of esophageal atresia-tracheoesophageal fistula and gastroesophageal reflux: a Canadian Association of Pediatric Surgeons annual meeting survey. J Pediatr Surg 2014;49:716–9. 10 Moayyedi P, Soo S, Deeks J, Forman D, Harris A, Innes M et al. Systematic review: antacids, H2-receptor antagonists, prokinetics, bismuth and sucralfate therapy for non-ulcer dyspepsia. Aliment Pharmacol Ther 2003;17:1215–27. 11 Simadibrata M. Dyspepsia and gastroesophageal reflux disease (GERD): is there any correlation? Acta Med Indones 2009;41:222–7. 12 Bello A, Kent J, Grahn A, Ball J, Holt R. One-year open-label safety evaluation of the fixed combination of ibuprofen and famotidine with a prospective analysis of dyspepsia. Curr Med Res Opin 2014;31:1–34. 13 Howard JM, Vinayek R, Maton PN, Wank SA, Gardner JD, Jensen RT. Famotidine: effective treatment of Zollinger-Ellison syndrome. J Clin Gastroenterol 1987;9(Suppl 2):23–5. 14 Howard JM, Chremos AN, Collen MJ, McArthur KE, Cherner JA, Maton PN et al. Famotidine, a new, potent, long-acting histamine H2-receptor antagonist: comparison with cimetidine and ranitidine in the treatment of Zollinger-Ellison syndrome. Gastroenterology 1985;88:1026–33. 15 Takeuchi T, Ota K, Harada S, Kojima Y, Inoue T, Iwakiri R et al. Comparison of teprenone and famotidine against gastroduodenal mucosal damage in patients taking low-dose aspirin. J Gastroenterol Hepatol 2014;29(Suppl 4):11–5. 16 Shikama N, Ichikawa T, Iwai T, Yamamoto H, Kida M, Koizumi W et al. Different effects of two types of H2-receptor antagonists, famotidine and roxatidine, on the mucus barrier of rat gastric mucosa. Biomed Res 2012;33:45–51. 17 Barletta JF. Histamine-2-receptor antagonist administration and gastrointestinal bleeding when used for stress ulcer prophylaxis in patients with severe sepsis or septic shock. Ann Pharmacother 2014;48:1276–81. 18 Kim T, Han N, Sohn M, Oh JM, Lee EK, Ji E et al. Pharmacogenomic Biomarker Information in FDA-approved Paediatric Drug Labels. Basic Clin Pharmacol Toxicol 2014;116:438–44. 19 Rezin GT, Petronilho FC, Araujo JH, Goncalves CL, Daufenbach JF, Cardoso MR et al. Gastrin-releasing peptide receptor antagonist or N-acetylcysteine combined with omeprazol protect against mitochondrial complex II inhibition in a rat model of gastritis. Basic Clin Pharmacol Toxicol 2011;108:214–9.
MiniReview
20 Sigterman KE, van Pinxteren B, Bonis PA, Lau J, Numans ME. Short-term treatment with proton pump inhibitors, H2-receptor antagonists and prokinetics for gastro-oesophageal reflux diseaselike symptoms and endoscopy negative reflux disease. Cochrane Database Syst Rev 2013;(5):CD002095. 21 Hrelja N, Zerem E. Proton pump inhibitors in the management of gastroesophageal reflux disease. Med Arh 2011;65:52–5. 22 van Pinxteren B, Sigterman KE, Bonis P, Lau J, Numans ME. Short-term treatment with proton pump inhibitors, H2-receptor antagonists and prokinetics for gastro-oesophageal reflux diseaselike symptoms and endoscopy negative reflux disease. Cochrane Database Syst Rev 2010;(11):CD002095. 23 Kushner PR. Role of the primary care provider in the diagnosis and management of heartburn. Curr Med Res Opin 2010;26:759–65. 24 Yang Z, Wu Q, Liu Z, Wu K, Fan D. Proton pump inhibitors versus histamine-2-receptor antagonists for the management of iatrogenic gastric ulcer after endoscopic mucosal resection or endoscopic submucosal dissection: a meta-analysis of randomized trials. Digestion 2011;84:315–20. 25 Nagahara A, Asaoka D, Hojo M, Oguro M, Shimada Y, Ishikawa D et al. Observational comparative trial of the efficacy of proton pump inhibitors versus histamine-2 receptor antagonists for uninvestigated dyspepsia. J Gastroenterol Hepatol 2010;25(Suppl 1):S122–8. 26 Wilcox CM, Hirschowitz BI. Treatment strategies for Zollinger-Ellison syndrome. Expert Opin Pharmacother 2009;10:1145–57. 27 MacLaren R, Campbell J. Cost-effectiveness of histamine receptor2 antagonist versus proton pump inhibitor for stress ulcer prophylaxis in critically ill patients*. Crit Care Med 2014;42:809–15. 28 Xue S, Katz PO, Banerjee P, Tutuian R, Castell DO. Bedtime H2 blockers improve nocturnal gastric acid control in GERD patients on proton pump inhibitors. Aliment Pharmacol Ther 2001;15:1351–6. 29 Tighe M, Afzal NA, Bevan A, Hayen A, Munro A, Beattie RM. Pharmacological treatment of children with gastro-oesophageal reflux. Cochrane Database Syst Rev 2014;(11):CD008550. 30 Bello AE, Kent JD, Grahn AY, Rice P, Holt RJ. Risk of upper gastrointestinal ulcers in patients with osteoarthritis receiving single-tablet ibuprofen/famotidine versus ibuprofen alone: pooled efficacy and safety analyses of two randomized, double-blind, comparison trials. Postgrad Med 2014;126:82–91. 31 Adachi K, Komazawa Y, Mihara T, Fujishiro H, Ishihara S, Amano Y et al. Administration of H2 receptor antagonist with proton pump inhibitor is effective for long-term control of refractory reflux esophagitis. J Clin Gastroenterol 2004;38:297–8. 32 Banihani S. Semen Quality and Chemical Oxidative Stress; Quantification and Remediation. Cleveland State University and OhioLINK, Columbus, 2011. 33 Van Thiel DH, Gavaler JS, Smith WI Jr, Paul G. Hypothalamic-pituitary-gonadal dysfunction in men using cimetidine. N Engl J Med 1979;300:1012–5. 34 Elliott J. Side effects of cimetidine use coming under scrutiny. JAMA 1979;242:13. 35 Fuentes RJ Jr, Dolinsky D. Endocrine function after cimetidine. N Engl J Med 1979;301:501–2. 36 Babb RR. Cimetidine: clinical uses and possible side effects. Postgrad Med 1980;68:87–93. 37 Wang C, Lai CL, Lam KC, Yeung KK. Effect of cimetidine on gonadal function in man. Br J Clin Pharmacol 1982;13:791–4. 38 Buchanan JF, Davis LJ. Drug-induced infertility. Drug Intell Clin Pharm 1984;18:122–32. 39 Van Thiel DH, Gavaler JS, Heyl A, Susen B. An evaluation of the anti-androgen effects associated with H2 antagonist therapy. Scand J Gastroenterol Suppl 1987;136:24–8. 40 Bianchi Porro G, Ragni G, Ruspa M, Petrillo M, Barattini G. Longterm treatment with cimetidine does not essentially affect the hypothalamic-pituitary-gonadal axis in man. Hepatogastroenterology 1985;32:77–80.
© 2015 Nordic Association for the Publication of BCPT (former Nordic Pharmacological Society)
MiniReview
H2RAS AND SEMEN
41 Thomas M, Turner P. Effect of chlorpheniramine, promethazine and cimetidine on human sperm motility in-vitro. J Pharm Pharmacol 1983;35:761–2. 42 Aprioku JS, Ibeachu C, FS A-T. Differential effects of H2 receptor antagonists on male reproductive function and hepatic enzymes in wistar rats. Asian J Biomed Pharm Sci 2014;4:1–6. 43 Sinha RB, Banerjee P, Ganguly AK. Serum concentration of testosterone, epididymal mast cell population and histamine content in relation to sperm count and their motility in albino rats following H2 receptor blocker treatment. Nepal Med Coll J 2006;8:36–9. 44 Nayeri KGD, Kazerouni M. The effect of cimetidine on serum testosterone, testes, prostate and seminal vesicle and its reversibility in rats. J Med Res 2002;1:1–9. 45 Gupta A, Gupta S, Tiwary AK. Spermicidal efficacy of H2-receptor antagonists and potentiation with 20 ,40 -dichlorobenzamil hydrochloride: role of intrasperm Ca2+. Contraception 2003;68:61–4. 46 Gill M, Sareen ML, Sanyal SN. Effect of H2-receptor antagonists, cimetidine and ranitidine on reproductive functions in male mice. Indian J Exp Biol 1991;29:900–6. 47 Sasso-Cerri E, Miraglia SM. In situ demonstration of both TUNEL-labeled germ cell and Sertoli cell in the cimetidine-treated rats. Histol Histopathol 2002;17:411–7. 48 Sasso-Cerri E, Cerri PS. Morphological evidences indicate that the interference of cimetidine on the peritubular components is responsible for detachment and apoptosis of Sertoli cells. Reprod Biol Endocrinol 2008;6:18. 49 Sasso-Cerri E. Enhanced ERbeta immunoexpression and apoptosis in the germ cells of cimetidine-treated rats. Reprod Biol Endocrinol 2009;7:127. 50 McLachlan RI, Matsumoto AM, Burger HG, de Kretser DM, Bremner WJ. Relative roles of follicle-stimulating hormone and luteinizing hormone in the control of inhibin secretion in normal men. J Clin Invest 1988;82:880–4. 51 Albrecht M, Frungieri MB, Gonzalez-Calvar S, Meineke V, Kohn FM, Mayerhofer A. Evidence for a histaminergic system in the human testis. Fertil Steril 2005;83:1060–3.
13
52 Wang C, Wong KL, Lam KC, Lai CL. Ranitidine does not affect gonadal function in man. Br J Clin Pharmacol 1983;16:430–2. 53 Mahboubi M, Foroughi F, Ghahramani F, Shahandeh H, Moradi S, Shirzadian T. A case–control study of the factors affecting male infertility. Turk J Med Sci 2014;44:862–5. 54 Savarino V, Mela GS, Zentilin P, Scalabrini P, Bonifacino G, Gambaro P et al. Comparison of the effects of placebo, ranitidine, famotidine and nizatidine on intragastric acidity by means of continuous pH recording. Digestion 1989;42:1–6. 55 Savarino V. Continuous intragastric pH monitoring: a real progress in the assessment of antisecretory drugs. Ital J Gastroenterol 1990;22(Suppl 2):20–3. 56 Madani S, Kauffman R, Simpson P, Lehr VT, Lai ML, Sarniak A et al. Pharmacokinetics and pharmacodynamics of famotidine and ranitidine in critically ill children. J Clin Pharmacol 2014;54:201– 5. 57 Kesiova M, Alexandrova A, Yordanova N, Kirkova M, Todorov S. Effects of diphenhydramine and famotidine on lipid peroxidation and activities of antioxidant enzymes in different rat tissues. Pharmacol Rep 2006;58:221–8. 58 Sener-Muratoglu G, Paskaloglu K, Arbak S, Hurdag C, AyanogluDulger G. Protective effect of famotidine, omeprazole, and melatonin against acetylsalicylic acid-induced gastric damage in rats. Dig Dis Sci 2001;46:318–30. 59 Gupta A, Khosla R, Gupta S, Tiwary AK. Influence of histamine and H1-receptor antagonists on ejaculated human spermatozoa: role of intrasperm Ca2+. Indian J Exp Biol 2004;42:481–5. 60 Breitbart H, Rubinstein S, Nass-Arden L. The role of calcium and Ca2+-ATPase in maintaining motility in ram spermatozoa. J Biol Chem 1985;260:11548–53. 61 Mahdavi M, Mozdarani H. Protective effects of famotidine and vitamin C against radiation induced cellular damage in mouse spermatogenesis process. Iran J Radiat Res 2011;8:223–30. 62 Savarino V, Giusti M, Scalabrini P, Bessarione D, Magnolia MR, Percario G et al. Famotidine has no significant effect on gonadal function in man. Gastroenterol Clin Biol 1988;12:19–22.
© 2015 Nordic Association for the Publication of BCPT (former Nordic Pharmacological Society)
Doi: 10.1111/bcpt.12446
MiniReview
Histamine-2 Receptor Antagonists and Semen Quality Saleem A. Banihani Department of Medical Laboratory Sciences, Jordan University of Science and Technology, Irbid, Jordan (Received 16 March 2015; Accepted 6 July 2015) Abstract: Histamine-2 receptor antagonists are a class of drugs used to treat the acid-related gastrointestinal diseases such as ulcer and gastro-oesophageal reflux disease. Although such drugs, especially ranitidine and famotidine, are still widely used, their effects on semen quality, and hence on male infertility, is still unclear. This MiniReview systematically addresses and summarizes the effect of histamine-2 receptor antagonists (cimetidine, ranitidine, nizatidine and famotidine) on semen quality, particularly, on sperm function. Cimetidine appears to have adverse effects on semen quality. While the effects of ranitidine and nizatidine on semen quality are still controversial, famotidine does not appear to change semen quality. Therefore, additional studies will be required to clarify whether histamine-2 receptor-independent effects of these drugs play a role in semen quality as well as further clinical studies including direct comparison of the histamine-2 receptor antagonists.
The histamine-2 (H2) receptors are widely expressed and can be found in gastric mucosal cells, heart, central nervous system, immune cells, smooth muscles of the airway, vasculature and uterus [1]. They are positively coupled to adenylate cyclase via Gs alpha subunit [2,3]. The activation of histamine-2 receptors by histamine alters the activity of Gs and therefore enhances the intracellular cyclic AMP (cAMP) production [3]. cAMP activates protein kinase A, which phosphorylates the cytoskeletal proteins, leading to the transport of the H+/K+ ATPase (proton pump) from the cytoplasm to the plasma membrane of parietal cells [3,4]. H2 receptor activation stimulates hydrochloric acid secretion from the acidsecreting parietal cells of the gastric mucosa, leads to smooth muscle relaxation in the vasculature and airways, increases cardiac rate and contractility, and mediates some of the immunomodulatory effects of histamine [1]. Histamine-2 receptor antagonists (H2RAs), also called H2blockers (e.g. cimetidine, ranitidine, nizatidine and famotidine), are the medications used to reduce the amount of hydrochloric acid produced by the stomach [5–7]. Mechanistically, these drugs are competitive antagonists of histamine-2 receptors [6,7]. In view of that, H2RAs are used to treat the acid-related gastrointestinal diseases such as gastrooesophageal reflux disease [8,9], dyspepsia [10–12], Zollinger–Ellison syndrome [13,14] and ulcer [15–17]. Various studies have shown that proton pump inhibitors (e.g. omeprazole, lansoprazole, esomeprazole), another class of acid reducers with long-lasting reduction of gastric acid Author for correspondence: Saleem A. Banihani, Clinical bio-analytical chemistry and Molecular Medicine, Department of Medical Laboratory Sciences, Jordan University of Science and Technology, P.O. Box 3030, Irbid 22110, Jordan (fax +962-2-7201087, e-mail sabani [email protected]).
production [18,19], are more effective than H2RAs in treating acid-related gastrointestinal diseases such as gastrooesophageal reflux disease [20–23], ulcer [21,24], dyspepsia [25] and Zollinger–Ellison syndrome [26]; however, H2RAs are still widely used in the treatment of acid-related gastrointestinal diseases. One reason for this is that proton pump inhibitors therapy is more expensive and less cost-effective, at least in certain cases of acid-related gastrointestinal diseases, compared with H2RAs [10,27]. In addition, various studies are still appreciating the efficacy of H2RAs in treating acidrelated gastrointestinal diseases same as proton pump inhibitors [28–30]. Moreover, studies have presented a synergistic effect between proton pump inhibitors and H2RAs in treating acid-related gastrointestinal diseases such as gastrooesophageal reflux disease [28,31]. Although H2RAs therapy is still extensively used to treat acid-related gastrointestinal diseases since beginning of the 1970s, its effect on semen quality, and thus on male infertility, at least in all of its forms, is still unclear. Such effect of the H2RAs should be clearly determined, especially for men with poor semen quality (i.e. oligospermia, asthenospermia) to avoid side effects that may worsen their fertilizing ability. In addition, this effect should be underlined in certain cases that may negatively affect sperm parameters such as testicular cancers, chemotherapy treatments and surgical infertility interventions. In this MiniReview, we address and summarize previous studies linking H2RAs with semen quality. We searched the MEDLINE electronic database for English-language articles using the key words ‘H2 receptor antagonist’, ‘semen’ and ‘sperm’. The reference lists of the relevant articles were scanned for additional studies. Given that semen quality is a measure of the ability of semen to achieve fertilization [32], and that sperm is the
© 2015 Nordic Association for the Publication of BCPT (former Nordic Pharmacological Society)
MiniReview
SALEEM A. BANIHANI
10
study on albino rats carried out by Sinha et al. [43] also showed a decrease in sperm count in addition to a decrease in sperm motility and morphology when using cimetidine at 20 mg/mL for 15 days. Whether such effect of cimetidine on sperm parameters is reversible requires further investigation. Actually, the results by Nayeri and Kazerouni [44] showed that male rats treated with cimetidine at 100 mg/kg for 5 weeks had lower weights of seminal vesicles compared with the untreated group, and this change was found to be reversible one week after the termination of treatment. One explanation for the adverse effects of cimetidine on sperm parameters is that cimetidine increases the level of intrasperm Ca2+, which also found to reduce sperm viability [45]. Moreover, cimetidine decreased the diameter of seminiferous tubules of mice testis and the germinal epithelial cell heights when administered at 10–100 mg/day for 15 days [46]. Similar results were observed in male albino Wistar rats which received intraperitoneal injections of cimetidine at 50 mg/kg for 52 days [47]. A later in vivo system study conducted by Sasso-Cerri and Miraglia [48] found that cimetidine may lead to detachment and apoptosis of Sertoli cells and thus affect negatively sperm quality. In 2009, Sasso-Cerri confirmed these findings and showed that cimetidine at the same concentration enhances oestrogen receptor beta, a nuclear receptor activated by the sex hormone oestrogen, immunoexpression and apoptosis in germ cells of adult male rats [49].
central part in this context, then semen quality is discussed here through the main sperm function parameters such as quantity (i.e. count) and quality (i.e. motility, morphology, and viability or vitality). Effect of H2RAs on Sperm Parameters Various studies (clinical, in vitro and in vivo) have presented the effect of H2RAs on sperm function. To date, the clinical studies that have explored the effect of orally administered H2-blockers (cimetidine, ranitidine and nizatidine) on sperm parameters (count, motility and morphology) are summarized in table 1. The effect of orally administered H2RAs on pituitary– gonadal hormones (LH, FSH and testosterone) and prolactin in men are summarized in table 2. Effect of cimetidine. In human beings, cimetidine was found to decrease the number of ejaculated sperm, especially when used at high concentrations (≥1000 mg/day) [33–39], but it showed mild effects on sperm motility and morphology [37,38,40,41]. This unfavourable effect of cimetidine on sperm count has been approved recently in an in vivo system study carried out by Aprioku et al. [42]. In this study, the effect of cimetidine on sperm count was found to be dose dependent [42]. A previous
Table 1. Effect of orally administered H2RAs (cimetidine, ranitidine and nizatidine) on human sperm parameters (count, motility and morphology) in men. Effect on sperm parameters H2RA Cimetidine
Ranitidine
Nizatidine
Dose (mg/day) 1200 1000 400 400 300 150 ~150–300 150
Treatment duration
Count
Motility
Morphology
/+ /+
/+
/+ /+
/+ /+
/+ /+ /+
9 weeks 3 months 18–36 months 6 weeks 3 months 9 months >12 month 6 weeks
References [33–36] [37,38] [40] [39] [52] [52] [53] [39]
H2RA, histamine-2 receptor antagonist. () decrease; (/+) no effect.
Table 2. Effect of orally administered H2RAs on pituitary–gonadal hormones and prolactin in men. Pituitary–gonadal hormones and prolactin H2RA Cimetidine
Ranitidine Nizatidine Famotidine
Dose (mg/day)
LH
1200 1000 400 400 300 150 150 40
/+ /+ /+ /+ /+ /+ /+
FSH + /+
Testosterone
Prolactin
+
/+ /+
/+ /+
/+
/+
H2RA, histamine-2 receptor antagonist; LH, Luteinizing hormone; FSH, follicle stimulating hormone. () decrease; (+) increase; (/+) no effect.
© 2015 Nordic Association for the Publication of BCPT (former Nordic Pharmacological Society)
/+ /+ /+ /+ /+
References [33–36] [37,38] [40] [39] [52] [53] [39] [62]
MiniReview
H2RAS AND SEMEN
Further, a number of studies reported that consuming approximately 1200 mg/day cimetidine may reduce luteinizing hormone (LH) and testosterone levels [33–36], which negatively affects sperm parameters, particularly sperm count (table 2) [50]. Given that cimetidine exerts an anti-androgenic effect and that histamine has a steroidogenic activity, the reduction in sperm population may be due to a decrease in the number of epididymal mast cells and thereby histamine content after cimetidine treatment [43,51]. Also, cimetidine was found to reduce the synthesis of sperm adhesion molecule-1 (SPAM-1), a protein present in the principal cells of the epididymal epithelium and plays an important role in sperm maturation, and decrease the availability of b-defensins, an antimicrobial peptide, which ultimately affects the number of sperm produced [43]. Effect of ranitidine. The effect of ranitidine on human sperm function is still controversial. An earlier clinical study carried out by Wang et al. [52] concluded that ranitidine (300 mg/day) does not affect sperm count, motility and morphology. The same authors supported their conclusion by showing an insignificant effect of ranitidine administration on pituitary–gonadal hormones (LH, FSH and testosterone) and prolactin [52]. In contrast, a recent case–control study (2014) showed that ranitidine reduces all of these sperm parameters [53]. Therefore, the robust clinical studies that underline the effect of ranitidine on sperm parameters and thus on sperm function are highly desired. The same controversial effect of ranitidine on sperm function is also found in the in vivo system studies. Oral adminstration of ranitidine at 8 or 16 mg/kg/day for 2 weeks did not change sperm parameters (motility, count, vitality and morphology) of Wister rats, although increasing the dose of ranitidine to 30 or 60 mg/kg/day found to decrease these parameters [42]. The reduced sperm motility and vitality when applying higher concentrations of ranitidine may be due to the increased levels of intrinsic ionized calcium of sperm [45]. In another in vivo system study on male mice, the histological parameters (shape of seminiferous tubules of testis, shape of germ cells and sperm morphology) remained normal after treatment with ranitidine at 10–70 mg/kg/day for 15 days [46].
11
stomach acidity [55,56]. However, its effect on human semen quality and sperm function is still undetermined. To date, to the best of our knowledge, almost all research studies that have directly linked famotidine with sperm function are nonclinical. Although some researches have shown that famotidine affects negatively the quality of sperm (e.g. viability) in vitro in a time- and dose-dependent manner [45], others have suggested beneficial effects of famotidine on sperm function because of its antioxidant activity [57,58]. The adverse effects of famotidine on sperm viability may be due to the increased Ca2+ influx into sperm [45,59]. Actually, the elevation of intrasperm Ca2+ by H2RAs (e.g. cimetidine, ranitidine and famotidine) may be attributed to their ability to inhibit Na+/K+ pump on sperm membrane, which possibly leads to the increase of Na+ in sperm cytosol [45,60]. Such build-up prevents the further influx of Na+ via Na+/Ca2+ exchanger, which in turn stops the efflux Ca2+ [45]. Conversely, Mahdavi and Mozdarani (2011) suggested that famotidine could reduce the cytotoxic effect of radiation in mouse spermatogenesis [61], which may improve the quality of ejaculated sperm. A previous study by Savarino et al. [62] supports this suggestion by showing that administration of famotidine at 40 mg/day for 4 weeks did not affect the gonadal function in men (i.e. normal LH, FSH and testosterone).
Conclusions and Future Perspectives
Effect of nizatidine. In 1987, Van et al. [39] showed that administration of nizatidine at 150 mg/day decreases the number of ejaculated sperm, but it did not show any change in serum levels of prolactin and LH hormones. In fact, few reports have discussed the effect of nizatidine on sperm function; this could be because nizatidine is a less effective and thus less commonly used drug, compared with the other H2RAs (e.g. famotidine, ranitidine) [54,55].
In summary, cimetidine appears to have adverse effects on semen quality, especially when used at high concentrations in men (i.e. ≥100 mg/day), and affects almost all sperm parameters (count, motility, vitality and morphology). This effect was found to be dose dependent and may be due to a reduction in some hypothalamic–pituitary–testicular axis hormones such as LH and testosterone, abnormal changes in the seminiferous tubules and germinal cells of the testis, and increased intrasperm Ca2+. Until now, the effect of ranitidine on semen quality is still controversial to the favour of using lower doses in human beings (≤150 mg/day). Further studies, particularly clinical, are required to approve the effect of ranitidine on semen quality. As nizatidine is not effective in reducing stomach acidity and therefore is not a commonly used drug, further studies on nizatidine to explain its effects on semen quality appear not to be a priority in this research basis. Regardless of its effectiveness as an acid reducer over all other H2RAs, famotidine is an encouraging drug when considering its effects on semen quality. To date, it is the only H2RA that has been found to be beneficial to sperm physiology; however, non-clinical experiments presented adverse effects for its use on some sperm parameters. Further studies, mainly clinical, will be of great value to confirm the effects (positive or negative) of famotidine on semen quality.
Effect of famotidine. At the present time, among all H2RAs, famotidine is preferred and commonly used because of its effectiveness in reducing
Acknowledgement This study was supported by research deanship at Jordan University of Science and Technology Grant no. 20150176.
© 2015 Nordic Association for the Publication of BCPT (former Nordic Pharmacological Society)
SALEEM A. BANIHANI
12 Disclosure Statement The authors declare no conflict of interest. References
1 Mahdy AM, Webster NR. Histamine and antihistamines. Anaesth Intensive Care Med 2014;15:250–5. 2 Fukushima Y, Ohmachi Y, Asano T, Nawano M, Funaki M, Anai M et al. Localization of the histamine H(2) receptor, a target for antiulcer drugs, in gastric parietal cells. Digestion 1999;60:522–7. 3 Hill SJ, Ganellin CR, Timmerman H, Schwartz JC, Shankley NP, Young JM et al. International Union of Pharmacology. XIII. Classification of histamine receptors. Pharmacol Rev 1997;49:253–78. 4 Shin JM, Munson K, Vagin O, Sachs G. The gastric HK-ATPase: structure, function, and inhibition. Pflugers Arch 2009;457:609–22. 5 Soll AH. Effects of the H2-antagonists on histamine action and interaction with gastrin in isolated parietal cells. Gastroenterology 1978;74:355. 6 Shamburek RD, Schubert ML. Control of gastric acid secretion. Histamine H2-receptor antagonists and H+K(+)-ATPase inhibitors. Gastroenterol Clin North Am 1992;21:527–50. 7 Cross SA. Localization of histamine and histamine H2-receptor antagonists in the gastric mucosa. Histochem J 1977;9:619–44. 8 Vela MF. Medical treatments of GERD: the old and new. Gastroenterol Clin North Am 2014;43:121–33. 9 Shawyer AC, Pemberton J, Flageole H. Post-operative management of esophageal atresia-tracheoesophageal fistula and gastroesophageal reflux: a Canadian Association of Pediatric Surgeons annual meeting survey. J Pediatr Surg 2014;49:716–9. 10 Moayyedi P, Soo S, Deeks J, Forman D, Harris A, Innes M et al. Systematic review: antacids, H2-receptor antagonists, prokinetics, bismuth and sucralfate therapy for non-ulcer dyspepsia. Aliment Pharmacol Ther 2003;17:1215–27. 11 Simadibrata M. Dyspepsia and gastroesophageal reflux disease (GERD): is there any correlation? Acta Med Indones 2009;41:222–7. 12 Bello A, Kent J, Grahn A, Ball J, Holt R. One-year open-label safety evaluation of the fixed combination of ibuprofen and famotidine with a prospective analysis of dyspepsia. Curr Med Res Opin 2014;31:1–34. 13 Howard JM, Vinayek R, Maton PN, Wank SA, Gardner JD, Jensen RT. Famotidine: effective treatment of Zollinger-Ellison syndrome. J Clin Gastroenterol 1987;9(Suppl 2):23–5. 14 Howard JM, Chremos AN, Collen MJ, McArthur KE, Cherner JA, Maton PN et al. Famotidine, a new, potent, long-acting histamine H2-receptor antagonist: comparison with cimetidine and ranitidine in the treatment of Zollinger-Ellison syndrome. Gastroenterology 1985;88:1026–33. 15 Takeuchi T, Ota K, Harada S, Kojima Y, Inoue T, Iwakiri R et al. Comparison of teprenone and famotidine against gastroduodenal mucosal damage in patients taking low-dose aspirin. J Gastroenterol Hepatol 2014;29(Suppl 4):11–5. 16 Shikama N, Ichikawa T, Iwai T, Yamamoto H, Kida M, Koizumi W et al. Different effects of two types of H2-receptor antagonists, famotidine and roxatidine, on the mucus barrier of rat gastric mucosa. Biomed Res 2012;33:45–51. 17 Barletta JF. Histamine-2-receptor antagonist administration and gastrointestinal bleeding when used for stress ulcer prophylaxis in patients with severe sepsis or septic shock. Ann Pharmacother 2014;48:1276–81. 18 Kim T, Han N, Sohn M, Oh JM, Lee EK, Ji E et al. Pharmacogenomic Biomarker Information in FDA-approved Paediatric Drug Labels. Basic Clin Pharmacol Toxicol 2014;116:438–44. 19 Rezin GT, Petronilho FC, Araujo JH, Goncalves CL, Daufenbach JF, Cardoso MR et al. Gastrin-releasing peptide receptor antagonist or N-acetylcysteine combined with omeprazol protect against mitochondrial complex II inhibition in a rat model of gastritis. Basic Clin Pharmacol Toxicol 2011;108:214–9.
MiniReview
20 Sigterman KE, van Pinxteren B, Bonis PA, Lau J, Numans ME. Short-term treatment with proton pump inhibitors, H2-receptor antagonists and prokinetics for gastro-oesophageal reflux diseaselike symptoms and endoscopy negative reflux disease. Cochrane Database Syst Rev 2013;(5):CD002095. 21 Hrelja N, Zerem E. Proton pump inhibitors in the management of gastroesophageal reflux disease. Med Arh 2011;65:52–5. 22 van Pinxteren B, Sigterman KE, Bonis P, Lau J, Numans ME. Short-term treatment with proton pump inhibitors, H2-receptor antagonists and prokinetics for gastro-oesophageal reflux diseaselike symptoms and endoscopy negative reflux disease. Cochrane Database Syst Rev 2010;(11):CD002095. 23 Kushner PR. Role of the primary care provider in the diagnosis and management of heartburn. Curr Med Res Opin 2010;26:759–65. 24 Yang Z, Wu Q, Liu Z, Wu K, Fan D. Proton pump inhibitors versus histamine-2-receptor antagonists for the management of iatrogenic gastric ulcer after endoscopic mucosal resection or endoscopic submucosal dissection: a meta-analysis of randomized trials. Digestion 2011;84:315–20. 25 Nagahara A, Asaoka D, Hojo M, Oguro M, Shimada Y, Ishikawa D et al. Observational comparative trial of the efficacy of proton pump inhibitors versus histamine-2 receptor antagonists for uninvestigated dyspepsia. J Gastroenterol Hepatol 2010;25(Suppl 1):S122–8. 26 Wilcox CM, Hirschowitz BI. Treatment strategies for Zollinger-Ellison syndrome. Expert Opin Pharmacother 2009;10:1145–57. 27 MacLaren R, Campbell J. Cost-effectiveness of histamine receptor2 antagonist versus proton pump inhibitor for stress ulcer prophylaxis in critically ill patients*. Crit Care Med 2014;42:809–15. 28 Xue S, Katz PO, Banerjee P, Tutuian R, Castell DO. Bedtime H2 blockers improve nocturnal gastric acid control in GERD patients on proton pump inhibitors. Aliment Pharmacol Ther 2001;15:1351–6. 29 Tighe M, Afzal NA, Bevan A, Hayen A, Munro A, Beattie RM. Pharmacological treatment of children with gastro-oesophageal reflux. Cochrane Database Syst Rev 2014;(11):CD008550. 30 Bello AE, Kent JD, Grahn AY, Rice P, Holt RJ. Risk of upper gastrointestinal ulcers in patients with osteoarthritis receiving single-tablet ibuprofen/famotidine versus ibuprofen alone: pooled efficacy and safety analyses of two randomized, double-blind, comparison trials. Postgrad Med 2014;126:82–91. 31 Adachi K, Komazawa Y, Mihara T, Fujishiro H, Ishihara S, Amano Y et al. Administration of H2 receptor antagonist with proton pump inhibitor is effective for long-term control of refractory reflux esophagitis. J Clin Gastroenterol 2004;38:297–8. 32 Banihani S. Semen Quality and Chemical Oxidative Stress; Quantification and Remediation. Cleveland State University and OhioLINK, Columbus, 2011. 33 Van Thiel DH, Gavaler JS, Smith WI Jr, Paul G. Hypothalamic-pituitary-gonadal dysfunction in men using cimetidine. N Engl J Med 1979;300:1012–5. 34 Elliott J. Side effects of cimetidine use coming under scrutiny. JAMA 1979;242:13. 35 Fuentes RJ Jr, Dolinsky D. Endocrine function after cimetidine. N Engl J Med 1979;301:501–2. 36 Babb RR. Cimetidine: clinical uses and possible side effects. Postgrad Med 1980;68:87–93. 37 Wang C, Lai CL, Lam KC, Yeung KK. Effect of cimetidine on gonadal function in man. Br J Clin Pharmacol 1982;13:791–4. 38 Buchanan JF, Davis LJ. Drug-induced infertility. Drug Intell Clin Pharm 1984;18:122–32. 39 Van Thiel DH, Gavaler JS, Heyl A, Susen B. An evaluation of the anti-androgen effects associated with H2 antagonist therapy. Scand J Gastroenterol Suppl 1987;136:24–8. 40 Bianchi Porro G, Ragni G, Ruspa M, Petrillo M, Barattini G. Longterm treatment with cimetidine does not essentially affect the hypothalamic-pituitary-gonadal axis in man. Hepatogastroenterology 1985;32:77–80.
© 2015 Nordic Association for the Publication of BCPT (former Nordic Pharmacological Society)
MiniReview
H2RAS AND SEMEN
41 Thomas M, Turner P. Effect of chlorpheniramine, promethazine and cimetidine on human sperm motility in-vitro. J Pharm Pharmacol 1983;35:761–2. 42 Aprioku JS, Ibeachu C, FS A-T. Differential effects of H2 receptor antagonists on male reproductive function and hepatic enzymes in wistar rats. Asian J Biomed Pharm Sci 2014;4:1–6. 43 Sinha RB, Banerjee P, Ganguly AK. Serum concentration of testosterone, epididymal mast cell population and histamine content in relation to sperm count and their motility in albino rats following H2 receptor blocker treatment. Nepal Med Coll J 2006;8:36–9. 44 Nayeri KGD, Kazerouni M. The effect of cimetidine on serum testosterone, testes, prostate and seminal vesicle and its reversibility in rats. J Med Res 2002;1:1–9. 45 Gupta A, Gupta S, Tiwary AK. Spermicidal efficacy of H2-receptor antagonists and potentiation with 20 ,40 -dichlorobenzamil hydrochloride: role of intrasperm Ca2+. Contraception 2003;68:61–4. 46 Gill M, Sareen ML, Sanyal SN. Effect of H2-receptor antagonists, cimetidine and ranitidine on reproductive functions in male mice. Indian J Exp Biol 1991;29:900–6. 47 Sasso-Cerri E, Miraglia SM. In situ demonstration of both TUNEL-labeled germ cell and Sertoli cell in the cimetidine-treated rats. Histol Histopathol 2002;17:411–7. 48 Sasso-Cerri E, Cerri PS. Morphological evidences indicate that the interference of cimetidine on the peritubular components is responsible for detachment and apoptosis of Sertoli cells. Reprod Biol Endocrinol 2008;6:18. 49 Sasso-Cerri E. Enhanced ERbeta immunoexpression and apoptosis in the germ cells of cimetidine-treated rats. Reprod Biol Endocrinol 2009;7:127. 50 McLachlan RI, Matsumoto AM, Burger HG, de Kretser DM, Bremner WJ. Relative roles of follicle-stimulating hormone and luteinizing hormone in the control of inhibin secretion in normal men. J Clin Invest 1988;82:880–4. 51 Albrecht M, Frungieri MB, Gonzalez-Calvar S, Meineke V, Kohn FM, Mayerhofer A. Evidence for a histaminergic system in the human testis. Fertil Steril 2005;83:1060–3.
13
52 Wang C, Wong KL, Lam KC, Lai CL. Ranitidine does not affect gonadal function in man. Br J Clin Pharmacol 1983;16:430–2. 53 Mahboubi M, Foroughi F, Ghahramani F, Shahandeh H, Moradi S, Shirzadian T. A case–control study of the factors affecting male infertility. Turk J Med Sci 2014;44:862–5. 54 Savarino V, Mela GS, Zentilin P, Scalabrini P, Bonifacino G, Gambaro P et al. Comparison of the effects of placebo, ranitidine, famotidine and nizatidine on intragastric acidity by means of continuous pH recording. Digestion 1989;42:1–6. 55 Savarino V. Continuous intragastric pH monitoring: a real progress in the assessment of antisecretory drugs. Ital J Gastroenterol 1990;22(Suppl 2):20–3. 56 Madani S, Kauffman R, Simpson P, Lehr VT, Lai ML, Sarniak A et al. Pharmacokinetics and pharmacodynamics of famotidine and ranitidine in critically ill children. J Clin Pharmacol 2014;54:201– 5. 57 Kesiova M, Alexandrova A, Yordanova N, Kirkova M, Todorov S. Effects of diphenhydramine and famotidine on lipid peroxidation and activities of antioxidant enzymes in different rat tissues. Pharmacol Rep 2006;58:221–8. 58 Sener-Muratoglu G, Paskaloglu K, Arbak S, Hurdag C, AyanogluDulger G. Protective effect of famotidine, omeprazole, and melatonin against acetylsalicylic acid-induced gastric damage in rats. Dig Dis Sci 2001;46:318–30. 59 Gupta A, Khosla R, Gupta S, Tiwary AK. Influence of histamine and H1-receptor antagonists on ejaculated human spermatozoa: role of intrasperm Ca2+. Indian J Exp Biol 2004;42:481–5. 60 Breitbart H, Rubinstein S, Nass-Arden L. The role of calcium and Ca2+-ATPase in maintaining motility in ram spermatozoa. J Biol Chem 1985;260:11548–53. 61 Mahdavi M, Mozdarani H. Protective effects of famotidine and vitamin C against radiation induced cellular damage in mouse spermatogenesis process. Iran J Radiat Res 2011;8:223–30. 62 Savarino V, Giusti M, Scalabrini P, Bessarione D, Magnolia MR, Percario G et al. Famotidine has no significant effect on gonadal function in man. Gastroenterol Clin Biol 1988;12:19–22.
© 2015 Nordic Association for the Publication of BCPT (former Nordic Pharmacological Society)
