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Previous Volume 348:1855-1865 May 8, 2003 Number 19 Next

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ABSTRACT

Background Gynecomastia of prepubertal onset may result from increased estrogen owing to excessive aromatase activity in extraglandular tissues. A gene in chromosome 15q21.2 encodes aromatase, the key enzyme for estrogen biosynthesis. Several physiologic tissue-specific promoters regulate the expression of aromatase, giving rise to messenger RNA (mRNA) species with an identical coding region but tissue-specific 5'-untranslated regions in placenta, gonads, brain, fat, and skin.

Methods We studied skin, fat, and blood samples from a 36-year-old man, his 7-year-old son, and an unrelated 17-year-old boy with severe gynecomastia of prepubertal onset and hypogonadotropic hypogonadism caused by elevated estrogen levels.

Results Aromatase activity and mRNA levels in fat and skin and whole-body aromatization of androstenedione were severely elevated. Treatment with an aromatase inhibitor decreased serum estrogen levels and normalized gonadotropin and testosterone levels. The 5'-untranslated regions of aromatase mRNA contained the same sequence (FLJ) in the father and son and another sequence (TMOD3) in the unrelated boy; neither sequence was found in control subjects. These 5'-untranslated regions normally make up the first exons of two ubiquitously expressed genes clustered in chromosome 15q21.2–3 in the following order (from telomere to centromere): FLJ, TMOD3, and aromatase. The aromatase gene is normally transcribed in the direction opposite to that of TMOD3 and FLJ. Two distinct heterozygous inversions reversed the direction of the TMOD3 or FLJ promoter in the patients.

Conclusions Heterozygous inversions in chromosome 15q21.2–3, which caused the coding region of the aromatase gene to lie adjacent to constitutively active cryptic promoters that normally transcribe other genes, resulted in severe estrogen excess owing to the overexpression of aromatase in many tissues.

Source Information

From the Departments of Obstetrics and Gynecology and Molecular Genetics, University of Illinois at Chicago, Chicago (M.S., S.S., S.E.B.); the Department of Obstetrics and Gynecology, Kanazawa University, Kanazawa, Japan (M.S.); the Department of Obstetrics and Gynecology, Tohoku University, Sendai, Japan (K.T.); the Department of Pediatrics, Rush Medical School, Chicago (W.-T.H.); the Department of Pathology, University of Texas Southwestern Medical Center at Dallas, Dallas (R.A.S.); the Department of Pediatrics, Stanford University, Palo Alto, Calif. (K.N.); and the Department of Pediatrics, Children's Hospital, Los Angeles (M.B.).

Drs. Shozu and Sebastian contributed equally to the article.

Address reprint requests to Dr. Bulun at the Department of Obstetrics and Gynecology, Northwestern University Medical School, 333 E. Superior, Suite 490, Chicago, IL 60611, or at s-bulun{at}northwestern.edu.

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