The aim of this review was to identify a new potential reason for the development of macular holes in relation to the female sex and to explain the possible underlying pathway. This approach was based on the evaluation of anatomical, physiological, and morphological analyses currently available in the literature. The findings showed that estrogen exerts a protective effect on the neuroretina. However, this protection may be lost by sudden decrease in estrogen levels during menopause. A gen analysis in zebra fish showed that estrogen may influence Müller and cone cells. Both cell types are responsible for the binding of the fovea structure. Cone implicit time in full-field 30-Hz flicker electroretinography is a predictor of visual outcome after surgery for macular hole. In conclusion, the fovea cone, through its sensibility to estrogen and high energy consumption, may be very vulnerable to damage caused by a sudden change in the concentration of estrogen in menopausal females. Such changes may result in cone degeneration and the development of a hole in the fovea, as in the case of macular holes. This review revealed that the cone under the decreasing influence of estrogen may play a key role with regards to the etiology of development of macular hole. This aspect may be of strategic importance in prophylactic therapy for the prevention of the development of macular hole in premenopausal females or after ocular trauma.