Estrogen Excess Associated with Novel Gain-of-Function Mutations Affecting the Aromatase Gene

Shozu, Makio; Sebastian, Siby; Takayama, Kazuto; Hsu, Wei-Tong; Schultz, Roger A.; Neely, Kirk; Bryant, Michael; Bulun, Serdar E.

doi:10.1056/nejmoa021559

Cited by 158Male Breast Health StudiesEstrogen and related hormone effectsSexual Differentiation and Disorders

Estrogen Excess Associated with Novel Gain-of-Function Mutations Affecting the Aromatase Gene

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Shozu, Makio, Sebastian, Siby, Takayama, Kazuto, Hsu, Wei-Tong, Schultz, Roger A., Neely, Kirk, Bryant, Michael, Bulun, Serdar E.·2003·New England Journal of Medicine

DOI 10.1056/nejmoa021559

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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.

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All adult aromatase-deficient men have unfused epiphyses leading to linear growth into adulthood and above-average body length.
“All adult aromatase-deficient men demonstrated a remarkably low bone mass and unfused epiphyses leading to linear growth into adulthood and above-average body length.”
From Aromatase inhibitors in men: effects and therapeutic options (2011) · cites this paper as [21]
Once treated with estradiol, epiphyses closed in most aromatase-deficient men.
“Once treated with estradiol, epiphyses closed, BMD increased and disturbances in the lipid profile improved in most of these patients.”
From Aromatase inhibitors in men: effects and therapeutic options (2011) · cites this paper as [21]
All adult aromatase-deficient men demonstrated a remarkably low bone mass.
“All adult aromatase-deficient men demonstrated a remarkably low bone mass and unfused epiphyses leading to linear growth into adulthood and above-average body length.”
From Aromatase inhibitors in men: effects and therapeutic options (2011) · cites this paper as [21]
Once treated with estradiol, BMD increased in most aromatase-deficient men.
“Once treated with estradiol, epiphyses closed, BMD increased and disturbances in the lipid profile improved in most of these patients.”
From Aromatase inhibitors in men: effects and therapeutic options (2011) · cites this paper as [21]
Once treated with estradiol, disturbances in the lipid profile improved in most aromatase-deficient men.
“Once treated with estradiol, epiphyses closed, BMD increased and disturbances in the lipid profile improved in most of these patients.”
From Aromatase inhibitors in men: effects and therapeutic options (2011) · cites this paper as [21]

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Authors: Shozu, M., Sebastian, S., Takayama, K., Hsu, W.-T., Schultz, R. A., Neely, K., Bryant, M., & Bulun, S. E.
Affiliations: Kanazawa University (JP)
University of Illinois Chicago (US)
Tohoku University (JP)
Rush University Medical Center (US)
The University of Texas Southwestern Medical Center (US)
Stanford University (US)
Children's Hospital Los Angeles (US)
ORCID: Shozu, Makio
Bulun, Serdar E.
Venue: New England Journal of Medicine
Publisher: Massachusetts Medical Society
Published: 2003-05-08
Volume: 348
Issue: 19
Pages: 1855-1865
ISSN: 0028-4793 (ISSN-L)
1533-4406
DOI: 10.1056/nejmoa021559
OpenAlex: W2090793581
Cited by: 158
References: 33
Citations by year: 2026: 6 · 2025: 2 · 2024: 3 · 2023: 5 · 2022: 1 · 2021: 3 · 2020: 5 · 2019: 9 · 2018: 4 · 2017: 5 · 2016: 6 · 2015: 4 · 2014: 11 · 2013: 9 · 2012: 4
FWCI: 9.16
Type: journal article
Language: en
Open access: bronze
doi.org
Locations: New England Journal of Medicine (publishedVersion)
PubMed (publishedVersion)
Funders: National Cancer Institute (CA-67167)
Eunice Kennedy Shriver National Institute of Child Health and Human Development (HD-38691)
Topics: Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Male Breast Health Studies
Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Estrogen and related hormone effects
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Sexual Differentiation and Disorders
Keywords: aromatase, gynecomastia, estrogen excess, hypogonadotropic hypogonadism, 5' untranslated region, cryptic promoter, aromatase inhibitors
MeSH terms: Anastrozole, Adipose Tissue, Adolescent, Adult, Androstenedione, Aromatase, Base Sequence, Child, Chromosome Mapping, Chromosomes, Human, Pair 15, Dexamethasone, Enzyme Inhibitors, Estradiol, Estrone, Fibroblasts, Glucocorticoids, Gynecomastia, Humans, Male, Molecular Sequence Data, Mutation, Nitriles, Promoter Regions, Genetic, RNA, Messenger, Transcription, Genetic, Triazoles, Aromatase Inhibitors

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Estrogen Excess Associated with Novel Gain-of-Function Mutations Affecting the Aromatase Gene

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