Headless sperm is a specific type of structural defect. Previous research highlighted that patients with high proportion of headless sperm may face infertility and that their semen parameters are usually relatively lower 13, 15, 16. In addition, the incidence and proportion of headless sperm in the infertile population were higher than those in the fertile population. For fertile men, the headless sperm proportion is typically below 13% 12. Our data shows that semen parameters are negatively correlated with the proportion of headless sperm in the semen. There was no noticeable deterioration in semen parameters when the proportion of headless sperm in the semen was under 10%, and the semen parameters declined significantly when the proportion of headless sperm in semen was more than 20%. Therefore, we suggest that a proportion of headless sperm >10% may be accompanied by a decline in semen parameters and should be considered in clinical diagnosis.
A large amount of literature has confirmed that headless sperm can be caused by mutations in SUN5, PMFBP1, TSGA10, or BRDT 9, 14, 17–21. Male exposure to khat or methyl chloride and ligation of the vas deferens can also lead to the production of headless sperm 22–24. Investigations in male mice have found that loss-of-function mutations in genes involved in the production of headless sperm, such as Spata6, Hook1, Prss21, Oaz3, and Odf1, can cause fertility reduction or infertility25–28. Interestingly, no mutations of these genes have been identified in humans, which might be explained by either genetic heterogeneity underlying this syndrome or differences in the functions of these genes or in the molecular pathogenesis between mice and humans. Research on the causes of headless sperm has focused on patients with a high proportion of headless sperm in the semen. However, it is very important to also study the causes of lower proportions of headless sperm, which may explain some cases of idiopathic male infertility.
Alterations in any of the above factors could lead to abnormalities in HCTA structure, in turn causing the detachment of the sperm tail from the sperm head during spermatid elongation. Because the sperm neck is unstable, sperm heads are usually phagocytosed by Sertoli cells 4, 8, 14, 18, 29, 30 or present a higher risk of sperm fracture when subjected to mechanical stress (mix, centrifugation or micromanipulation) 26, 31. Sperm concentration as evaluated according to the WHO manual (fifth edition) standards considers only whole sperm (i.e., sperm with both a head and a tail), while free tails and heads are not counted 32. This may explain why a higher proportion of headless sperm could be associated with a lower sperm concentration.
Sperm mitochondria play a major role in sperm motility, as they are the powerhouse of the sperm 33, 34. The sperm tail is an important structure for sperm motility, and human sperm swim forward by moving their tail symmetrically from side to side 35. Under transmission electron microscopy, the intact sperm of patients whose semen also contains headless sperm often have abnormal structures, such as disassembled mitochondria and sperm tail malformations15, 36–38. These morphological abnormalities may be responsible for the decrease in sperm motility. In addition, our data also show that the motility parameters (VCL, ALH, VAP, BCF) of intact sperm are lower in semen samples containing headless sperm, confirming that among intact sperm, not only the percentage of progressive motility but also the movement type is altered. These motility parameters were reported to predict the success of IUI and IVF in couples receiving infertility treatment39–42. The results indicate that even with the same semen concentration, semen motility and normal semen morphology, males with headless sperm in semen samples may demonstrate lower fertility.
Our data show that semen samples containing headless sperm present other defects in sperm morphology and a higher incidence of abnormally small acrosomes. Previous studies also reported acrosome abnormalities in the intact sperm of semen samples containing headless sperm 7, 31, 43. The acrosome is formed by the trans-Golgi, and it is the unique structure of mature sperm and plays an important role in the binding of sperm and zona pellucida during fertilization 44. In 1984, Bacetti et al. reported that headless sperm can occur due to overproduction of vesicles by the Golgi complex in the region between the centrioles and nucleus 45. In a patient with headless sperm, the expression of Golgi-related genes (GOPC and VPS54) was changed; GOPC and VPS54 are important constituent proteins in the Golgi apparatus in tissue culture cells, and loss of GOPC and VPS54 affected sperm acrosome formation 19, 46–49. Our data further confirm that headless sperm and small acrosomes may be a possible result of the same pathologic morphogenic mechanism. Sperm acrosomes play an important role in sperm binding to the zona pellucida during fertilization, and abnormal acrosomes may be a reason for male infertility or fertility reduction in semen containing headless sperm.