Iatrogenic Cushing’s syndrome (CS) is a severe adverse effect of systemic glucocorticoid (GC) therapy in children, but is extremely rare in the setting of topical ocular GC therapy. In this article, we report the case of a 9-year-old girl suffering from idiopathic uveitis who developed CS due to topical ocular GC treatment. She was referred to the ophthalmology department with a complaint of painful eyes, at which time she was diagnosed with bilateral iridocyclitis and started on a treatment of betamethasone sodium phosphate eye drops. Six months after the initiation of topical ocular GC treatment, she was referred to our pediatric department with stunted growth, truncal obesity, purple skin striate, buffalo hump, and moon face. Because her serum cortisol and plasma adrenocorticotropic hormone levels were undetectable, she was diagnosed with iatrogenic CS. After the doses of topical ocular GC were reduced, the clinical symptoms of CS were improved. The fact that the amount of topical ocular GC with our patient was apparently less than that of similar previous cases tempted us to perform genetic analysis of her NR3C1 gene. We found that our patient had a single heterozygous nucleotide substitution in the 3′ untranslated region of the NR3C1 gene, which may explain why she developed CS. However, additional investigations are required to determine if our findings can be extrapolated to other patients. In conclusion, clinicians should be aware that even extremely low doses of topical ocular steroid therapy can cause iatrogenic CS.

Spermatid production is a complex regulatory process in which coordination between hormonal control and apoptosis plays a pivotal role in maintaining a balanced number of sperm cells. Apoptosis in spermatogenesis is controlled by pro‐apoptotic and anti‐apoptotic molecules. Hormones involved in the apoptotic process during spermatogenesis include gonadotrophins, sex hormones, and glucocorticoid (GC). GC acts broadly as an apoptosis inducer by binding to its receptor (glucocorticoid receptor: GR) during organ development processes, such as spermatogenesis. However, the downstream pathway induced in GC‐GR signaling and the apoptotic process during spermatogenesis remains poorly understood. We reported previously that GC induces full‐length glucocorticoid‐induced transcript 1 (GLCCI1‐long), which functions as an anti‐apoptotic mediator in thymic T cell development. Here, we demonstrate that mature murine testis expresses a novel isoform of GLCCI1 protein (GLCCI1‐short) in addition to GLCCI1‐long. We demonstrate that GLCCI1‐long is expressed in spermatocytes along with GR. In contrast, GLCCI1‐short is primarily expressed in spermatids where GR is absent; instead, the estrogen receptor is expressed. GLCCI1‐short also binds to LC8, which is a known mediator of the anti‐apoptotic effect of GLCCI1‐long. A luciferase reporter assay revealed that β‐estradiol treatment synergistically increased Glcci1‐short promotor‐driven luciferase activity in Erα‐overexpressing cells. Together with the evidence that the conversion of testosterone to estrogen is preceded by aromatase expression in spermatids, we hypothesize that estrogen induces GLCCI1‐short, which, in turn, may function as a novel anti‐apoptotic mediator in mature murine testis.

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