Protective effects of melatonin against physical injuries to testicular tissue: A systematic review and meta-analysis of animal models

Abstract

Background: Modern societies face infertility as a global challenge. There are certain environmental conditions and disorders that damage testicular tissue and may cause male infertility. Melatonin, as a potential antioxidant, may protect testicular tissue. Therefore, we conducted this systematic review and meta-analysis to evaluate the effects of melatonin in animal models against physical, heat, and ischemic damage to the testicular tissue.

Methods: PubMed, Scopus, and Web of Science were systematically searched to identify animal trials evaluating the protective effect of melatonin therapy on rodent testicular tissue when it is exposed to physical, thermal, ischemic, or hypobaric oxygen stress. Random-effect modeling was used to estimate the standardized mean difference and 95% confidence intervals based on the pooled data. Additionally, the Systematic Review Centre for Laboratory Animal Experimentation (SYRCLE) tool was used to assess the risk of bias. The study protocol was prospectively registered in PROSPERO (CRD42022354599).

Results: A total of 41 studies were eligible for review out of 10039 records. Studies employed direct heat, cryptorchidism, varicocele, torsion-detorsion, testicular vascular occlusion, hypobaric hypoxia, ischemia-reperfusion, stress by excessive or restraint activity, spinal cord injury, and trauma to induce stress in the subjects. The histopathological characteristics of testicular tissue were generally improved in rodents by melatonin therapy. Based on the pooled data, sperm count, morphology, forward motility, viability, Johnsen's biopsy score, testicular tissue glutathione peroxidase, and superoxide dismutase levels were higher in the melatonin treatment rodent arms. In contrast, the malondialdehyde level in testicular tissue was lower in the treatment rodent arms. The included studies suffered from a high risk of bias in most of the SYRCLE domains.

Conclusion: This study concludes that melatonin therapy was associated with improved testicular histopathological characteristics, reproductive hormonal panel, and tissue markers of oxidative stress in male rodents with physical, ischemic, and thermal testicular injuries. In this regard, melatonin deserves scientific investigations as a potential protective drug against rodent male infertility.

Systematic review registration: https://www.crd.york.ac.uk/PROSPERO/, identifier CRD42022354599.

Keywords: heat; infertility; ischemia; melatonin; oxidative stress; reperfusion; rodents.

Figure 1

PRISMA flow diagram illustrating the process of selection of the studies.

Figure 2

Analysis of study characteristics. Pie chart of (A) the countries that studies were published from, (B) the subject rodents across the studies, (C) the stress mechanism used in the studies, (D) the side that stresses were induced in the subjects, (E) the route of melatonin administration across the studies, (F) bar chart, illustrating the distribution of the methodological quality scores across the studies, and (G) violin plot demonstrating the distribution of overall cumulative dosages that were administered to the rodents (mg/kg).

Figure 3

Forest plots for the overall pooled effects sizes of sperm parameters. (A) normal morphology (n=6), (B) total motility (n=4), (C) viability (n=6), (D) forward progressive motility (n=4), (E) total count (n=9), (F) Johnsen’s biopsy score (n=11).

Figure 4

Forest plots for the overall pooled effects sizes of serum level of reproductive hormones. (A) Serum Inhibin-B (n=4), (B) testosterone (n=4).

Figure 5

Forest plots for the overall pooled effects sizes of the testicular tissue oxidative stress markers. (A) CAT (n=5), (B) GPx (n=7), (C) SOD (n=9), (D) MDA (n=15). MDA, Malondialdehyde; GPx, Glutathione Peroxidase; CAT, Catalase; SOD, Superoxide Dismutase.

Figure 6

Forest plots for the overall pooled effects sizes of body weight and testicular somatic indices. (A) total testicular weight (n=3), (B) seminiferous tubular diameter (n=4), (C) final body weight (n=3), (D) testis to body relative weight (n=5).

Figure 7

Forest plots for the overall pooled effects sizes of exploratory outcomes, including (A) the percentage of tubules with TUNEL-positive cells (n=3) and (B) the number of TUNEL-positive cells per tubule (n=3). TUNEL, Terminal deoxynucleotidyl transferase dUTP nick end labeling.

Figure 8

Risk of bias graph on judgements about each risk of bias item presented as proportions across all included studies (n=41).