Harmful Consequences of Proton Pump Inhibitors on Male Fertility: An Evidence from Subchronic Toxicity Study of Esomeprazole and Lansoprazole in Wistar Rats

Abstract

Proton pump inhibitors (PPIs) are frequently prescribed as gastric acid-suppressing agents. Nevertheless, there is limited evidence supporting the risk of detrimental effects of PPIs on male fertility. The purpose of the current study was to evaluate the effect of subchronic use of proton pump inhibitors on male fertility. Seventy adult male Wistar rats were assigned into seven groups. The normal control group orally received solvent only. Groups 2, 3, and 4 were orally given esomeprazole while groups 5, 6, and 7 received lansoprazole at 2.5, 5, and 10 mg/kg/day, respectively. After 45 days of treatment, blood samples, epididymis, and testis were collected. Sperm count, motility, and morphology were determined. The level of hormones such as testosterone, follicle-stimulating hormone (FSH), and luteinizing hormone (LH) and oxidative status of testis tissue, such as superoxide dismutase, catalase, reduced glutathione, malondialdehyde (MDA), and nitric oxide (NO) were estimated. Results demonstrated a significant decline in sperm count, motility, morphology, testosterone, and catalase at 10 mg/kg/day and GSH at 2.5 mg/kg/day. A significant increase in FSH, LH, and MDA at 10 mg/kg/day and NO at 2.5 mg/kg/day was found as compared to the control group. The pathological alterations specifically dilation of Leydig cells, vacuolization, and degeneration of the seminiferous tubules were also evident. It is concluded that PPIs had caused male reproductive toxicity in Wistar rats due to altered levels of hormones such as testosterone, FSH, and LH, elevated levels of NO, and oxidative stress.

Figure 1

Sperm morphology of esomeprazole-treated rats at 2.5, 5, and 10 mg/kg/day (40 x). (a) Normal sperm, (b) bent neck sperm, (c) bent tail sperm, (d) headless tail sperm, (e) banana head sperm, and (f) detached head.

Figure 2

Sperm morphology in lansoprazole treated rats at 2.5, 5, and 10 mg/kg/day (40 x). (a) Normal sperm, (b) banana head sperm, (c) bent tail sperm, (d) amorphous head with a broken tail, (e) detached head, and (f) double head.

Figure 3

Effect of esomeprazole (ES) and lansoprazole (LN) treatment on sex hormones in male rats ^∗∗∗ and ^∗∗∗∗ showed significant results at P < 0.001 and P < 0.0001 contrary to control group. ^# and ^#### showed significant results at P < 0.05 and 0.0001 on contrary to esomeprazole/lansoprazole 2.5 mg/kg/day. ^&, ^&&, and ^&&&& showed significant results at P < 0.05, 0.01, and 0.0001 on contrary to esomeprazole/lansoprazole 5 mg/kg/day.

Figure 4

Effect of esomeprazole (ES) and lansoprazole (LN) treatment on oxidative stress biomarkers in rat testis. ^∗, ^∗∗, ^∗∗∗, and ^∗∗∗∗ showed significant results at P < 0.05, 0.01, 0.001, and 0.0001 on contrary to control group. ^#, ^##, and ^#### showed significant results at P < 0.05, 0.01, and 0.0001 on contrary to esomeprazole/lansoprazole 2.5 mg/kg/day.^&,^&&, and ^&&&& showed significant results at P < 0.05, 0.01, and 0.0001 in contrary to esomeprazole/lansoprazole 5 mg/kg/day.

Figure 5

Photomicrograph of sections of seminiferous tubules and interstitial cells in esomeprazole (ES) and lansoprazole (LN) treated rats under magnification 100 x. (a) Control rats showed normal seminiferous tubules, (b) ES at 2.5 mg/kg/day showed oligospermia, vacuolization, and dilation/swelling of sperm cells, (c) ES at 5 mg/kg/day showed dilation of seminiferous tubules, (d) esomeprazole at 10 mg/kg/day showed swelling of Leydig cells, (e) control rats showed normal seminiferous tubules, (f) LN at 2.5 mg/kg/day showed oligospermia, vacuolization, dilation/swelling of sperm cells, and degenerated seminiferous tubules, (g) LN at 5 mg/kg/day showed dilation of seminiferous tubules, oligospermia dilation/swelling of sperm cells, vacuolization, necrosis, and swelling of Leydig cells, and (h) LN at 10 mg/kg/day showed vacuolization, dilation/swelling of sperm cells, and necrosis.

Figure 6

Histopathological scoring of testes from esomeprazole (ES) and lansoprazole (LN) treated rats. ^∗P < 0.05 and ^∗∗∗∗P < 0.0001 showed a significant difference from the normal control group.