Overexpression of aromatase associated with loss of heterozygosity of the STK11 gene accounts for prepubertal gynecomastia in boys with Peutz-Jeghers syndrome.

Context: Peutz-Jeghers syndrome (PJS) is an autosomal-dominant disorder that arises as a consequence of mutations in the STK11 gene that encodes LKB1. PJS males often have estrogen excess manifesting as gynecomastia and advanced bone age. We and others have previously described an increase in testicular aromatase expression in PJS patients. However, the underlying mechanism has not yet been explored.

Objective: The aim of this study was to characterize the role of LKB1 in regulating the expression of aromatase in boys with PJS via signaling pathways involving AMP-activated protein kinase (AMPK) and cyclic AMP-responsive element binding protein-regulated transcription coactivators (CRTCs).

Patients: We studied testicular biopsies from two boys with STK11 mutations: a 13-year-old boy and an unrelated 4-year-old boy with prepubertal gynecomastia and advanced bone age, as well as breast tissue from the 13-year-old boy.

Results: Loss of heterozygosity of STK11, measured by the absence of LKB1 immunofluorescence, was observed in Sertoli cells of abnormal cords of testis samples from affected individuals. This was associated with loss of p21 expression and decreased phosphorylation of AMPK, known downstream targets of LKB1, as well as the increased expression of aromatase. Similar results of low LKB1 expression in cells expressing aromatase were observed in the mammary epithelium from one of these individuals. Nuclear expression of the CRTC proteins, potent stimulators of aromatase and known to be inhibited by AMPK, was significantly correlated with aromatase.

Conclusions: Loss of heterozygosity of the STK11 gene leads to an increase in aromatase expression associated with an increase in CRTC nuclear localization, thereby providing a mechanism whereby PJS results in increased endogenous estrogens in affected males.