Histamine‐2 Receptor Antagonists and Semen Quality

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 H 2 -blockers (e.g. cimetidine, ranitidine, nizatidine and famotidine), are the medications used to reduce the amount of hydrochloric acid produced by the stomach [5][6][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][16][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 production [18,19], are more effective than H2RAs in treating acid-related gastrointestinal diseases such as gastrooesophageal reflux disease [20][21][22][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, ...

Vitamin B12 and Semen Quality

“…Cimetidine, a member of the histamine-2 receptor (also called beta-blockers) antagonists family, was found to induce abnormal changes in the seminiferous tubules in the testis, which consequently negatively affects spermatogenesis, and hence semen quality [43]. B 12 supplement was found to soften the detrimental effect of cimetidine on spermatogenesis and restore the number of Sertoli cells in adult male rates [44].…”

Omeprazole does not alter human sperm motility, viability or DNA integrity in vitro

“…Omeprazole (6‐methoxy‐2‐[(4‐methoxy‐3, 5‐dimethylpyridin‐2‐yl) methyl‐sulfinyl]‐1H benzimidazole) is a drug commonly used to treat acid‐related gastrointestinal diseases such as gastroesophageal reflux disease, dyspepsia, Zollinger–Ellison disease and peptic ulcer (Banihani, ; Gesheff et al, ; Witteman et al, ). Mechanistically, omeprazole is a proton pump inhibitor acts by inhibiting H+/K(+)‐ATPase activity in the parietal cells in the stomach, leading to a reduction in hydrochloric acid (gastric acid) secretion (Horn, ).…”

Famotidine does not affect human sperm fertility characteristics (motility, viability and DNA integrity) in vitro

“…Famotidine (3‐[({2‐[(diaminomethylidene)amino]‐1, 3‐thiazol‐4‐yl} methyl) sulfanyl]‐N‐sulfamoylpropanimidamide) is an acid inhibitor belonging to the histamine‐2 receptor antagonists' (also called H 2 blockers) class of drugs (Banihani, ). It reduces the production of hydrochloric acid (gastric acid) in the stomach; therefore, it is used to relieve acid‐related gastrointestinal diseases/disorders such as acid indigestion (Kinoshita & Chiba, ), heartburn (Mann, Cottrell, Murakami, Stauffer, & Rao, ), gastroesophageal reflux disease (Wesdorp, ), Zollinger–Ellison syndrome (Howard et al, ), ulcers (e.g., gastric, duodenal and drug induced; Laine et al, ), and multiple endocrine adenomas (Jensen, Maton, & Gardner, ).…”

“…Mechanistically, in general, histamine‐2 receptor antagonists (e.g., ranitidine, famotidine, cimetidine and nizatidine) are considered as competitive antagonists of histamine‐2 receptors on the stomach parietal cells (Osawa et al, ). At present, among all the histamine‐2 receptor antagonists, famotidine is favoured and commonly used in patients with acid‐related gastrointestinal diseases because of its effectiveness in relieving pain and reducing the acidity of the stomach (Banihani, ).…”

“…It has been concluded that even though famotidine is extensively used to treat acid‐related gastrointestinal disorders, its influence on human semen quality and sperm parameters is still undetermined (Banihani, ). In fact, to date, almost all research studies that have linked sperm function with famotidine are nonhuman studies (Agrawal & Alvin Jose, ; Banihani, ).…”