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Estrogens are initially metabolized by a P450 hydroxylase to less biologically
active catechol-estrogens and further degraded by catecholamine-O-methyltransferase
(COMT) to inactive products. COMT transfers a methyl group from S-adenosylmethionine
to the catechol-estrogen. Within the structure of COMT (OMIM 116790,
chromosome 22q11) is a functional polymorphism that results in the substitution
of methionine for valine in codon 158 (val158met). The COMT product
containing val158 is 3 to 4 fold more biologically active than is that with
met158.
Hypothesizing that the COMT val158met polymorphism effect on estrogen catabolism
might be reflected in the biologic activity of endogenous estrogen, the investigators
examined the relationship between linear growth, bone mineralization, and sexual
development in prepubertal and early pubertal, 10-12 year old girls and the
high (H) and low (L) polymorphic variants of COMT (COMTHH and COMTLL, n=43
and n=85, respectively). Although total serum estradiol concentrations were
similar in COMTHH and COMTLL girls, levels of free estradiol as well as IGF-I
were higher in COMTLL subjects. The authors reported that at the time of study
COMTLL subjects were 5.4 cm taller than were COMTHH girls, had greater lean
body mass, and appeared to progress further into puberty at a more rapid rate
than did COMTHH girls. Total bone mineral content (BMC) by DEXA was 12.7%
greater in COMTLL than in COMTHH girls due primarily to increased bone size;
thus, volumetric bone mineral density was similar among groups. Cortical BMC
and cortical cross-sectional area by peripheral quantitative computerized tomography
(pQCT) were highest in COMTLL subjects due primarily to increased periosteal
circumference. There was no relationship between COMT variant and trabecular
volume or mineralization. Serum free estradiol values were related to these
varied aspects of growth and mineral metabolism and thus indirectly to the
COMT polymorphic variants. The authors concluded that the val158met COMT polymorphism
exerted significant effects on growth, pubertal development, and bone mineralization
in pre- and early adolescent girls, primarily by increasing serum concentrations
of free estradiol by altering the rate of catabolism of endogenous estrogens.
Eriksson A-L, Suuriniemi M, Mahonen A, Cheng S, Ohlsson C. The COMT val158met polymorphism is associated with early pubertal development, height and cortical bone mass in girls. Pediatric Res. 2005; 58:71-77.
Editor’s Comment: COMT may now be added to the growing
list of recognized genes that influence the rates of growth and sexual development
and bone mineralization; this report emphasized the extensive genetic variability
in these processes. Although COMT LL girls were 5 cm taller than COMT HH subjects
at 10-12 years of age, the effect of the COMT val158 met polymorphism on adult
height is likely to be less impressive as the COMT LL subjects will probably
complete their pubertal development and achieve their adult height at an earlier
age than the COMT HH children. It would be of interest to learn the bone ages
of the study subjects and later their ages of menarche and their adult heights.
Similar studies relating COMT genotype and growth, pubertal maturation, and
bone mineralization would also be of interest.
Allen W. Root, MD
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Current GGH - Vol. 24 No. 1
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