The Intimate Interplay Between Keratoconus, Sex Hormones, and the Anterior Pituitary

PROJECT SUMMARY/ABSTRACT Keratoconus (KC) is a progressive, non-inflammatory ectatic corneal disorder that is characterized by steepening and thinning of the cornea, irregular astigmatism, myopia, and scarring. Despite the introduction of corneal crosslinking to stop progression and improvements in scleral contact lens designs, corneal transplants remain the holy grail of treating KC. KC is currently one of the most common indications leading to corneal transplants. Furthermore, there is now increasing evidence that KC recurs even following corneal transplantation. To-date, the KC etiology and pathogenesis remains unclear, including the reasons for recurrence. As such, there is an urgent need to understand and define the onset/progression of KC. Our group is spearheading KC research on sex hormones and gonadotropins, which will provide valuable contributions to a topic that is largely ignored despite clinical observations and findings. Our group reported a novel sex hormone-regulated KC biomarker, prolactin-induced protein (PIP), and discovered the existence of gonadotropins and their receptors in KC. It is therefore fair to ask, “what is the role of gonadotropins in the human cornea and KC?” and “Is there a functional role of these gonadotropins and their receptors that can explain KC pathobiology?”. Our preliminary data shows dysregulation of what many consider the “king of all hormones”, Gonadotropin-releasing hormone (GnRH), in KCs when compared to healthy controls. GnRH receptor (GnRH-R) is found in KC stromal cells and is modulated by luteinizing hormone (LH) gonadotropin. LH and follicle-stimulating hormone (FSH), in turn, are modulated by gonadal and adrenal sex hormones (Dehydroepiandrosterone-DHEA, Estrone, and Estriol) previously shown by us to be imbalanced in KCs. These same sex hormones are modulated, systemically, following corneal crosslinking. Together, our data suggests that KC is highly dependent on the balance and interactions of gonadotrophins and sex hormones. Specifically, we hypothesize that hormonal secretion abnormalities are associated with FSH and LH, followed by sex hormone dysregulation that ultimately affects the corneal microenvironment mediating KC onset and progression. The current proposal is designed so that findings are validated both in vitro, ex vivo and in vivo, in order to maximize translatability. To ensure that we achieve our goals, we have assembled a large cohort of experts in the field from multiple centers. Successful completion of the studies proposed will be a breakthrough, altering the current standards of care for patients with KC. Relevance to Public Health – KC is a major clinical problem resulting in visual impairment worldwide. There is an urgent need to delineate the KC pathobiology and develop novel tools for its detection and treatment. Ultimately, the goal is to enable people with KC to live a normal life with little or no visual disability. The proposed work is translational, clinically relevant, and in line with NEI’s program goals: “Apply the knowledge acquired from discoveries in the basic science of the cornea and other tissues of the ocular surface to the diagnosis, prevention, and treatment of ocular injury and disease”.