Table 1: Summary of clinical studies in male patients with aromatase excess syndrome (modified from [4]).
(a)

FamilyFamily AFamily BFamily CFamily DFamily E
Mutation typesDuplicationDuplicationDeletionDeletionDeletion
The promoter involved in CYP19A1 overexpressionCYP19A1CYP19A1CYP19A1DMXL2DMXL2
1 2 3 4 5 6 7 8 9 10
Age at examination (year)6615201515134291213

<Phenotypic findings>
Gynecomastia (tanner breast stage)2223444344
Onset of gynecomastia (year)131310111211117910
Mastectomy (year)NoYes (15)NoYes (15)Yes (15)Yes (13)NoNoYes (12)Yes (13)
Testis (ml)N.E.1212121212N.E.31220
Pubic hair (tanner stage)N.E.2-34543N.E.134
Facial hairNormalScarceScarceNormalAbsentAbsentN.E.AbsentAbsentAbsent
Height (SDS)a−1.2−0.3+0.4+0.8−2.0−1.0−1.6+2.7±0+1.8
Bone age (year)bN.E.N.E.N.E.16.016.013.5N.E.13.015.017.0
Fertility (spermatogenesis)Yes?(Yes)h???Yes???

<Endocrine findings>cBBSBSBSBSBSBBSBSBS
<At Dx>Stimulus
LH (mIU/mL)GnRHe3.82.314.32.117.02.429.41.940.61.869.21.111.50.639.56.714.8
LH (mIU/mL)GnRH (after priming)f1.89.51.310.7
FSH (mIU/mL)GnRHe1.73.15.3<0.51.20.92.41.44.22.07.83.26.60.62.90.71.0
FSH (mIU/mL)GnRH (after priming)f2.63.2<0.50.9
Prolactin (ng/ml)4.35.38.29.111.318.8
Δ4A (ng/mL)0.51.11.20.60.72.42.9
T (ng/mL)hCGg2.91.62.24.02.67.21.47.90.63.62.43.29.7
DHT (ng/mL)0.40.20.41.2
Inhibin B (pg/mL)61.674.683.575.2
E1 (pg/mL)157120124576353
E2 (pg/mL)29152259563824192558
E2/T ratio (×103)10.09.410.014.821.527.131.710.418.1

(b)

FamilyFamily FFamily GFamily HSporadic
Mutation typesDeletionInversionInversionInversion
The promoter involved in CYP19A1 overexpressionDMXL2CGNL1MAPK6TMOD3TLN2
11 12 13 14 15 16 17 18 19 20 21j 22 23
Age at examination (year)69354445981310357131736

<Phenotypic findings>
Gynecomastia (tanner breast stage)Yes iYes iYes iYes i2333Yes35N.E.Yes
Onset of gynecomastia (year)????8811105587?
Mastectomy (year)Yes iYes iYes iYes iNoNoYes (?)Yes (?)Yes (16)NoYes (?)Yes (?)Yes (19)
Testis (ml)N.E.N.E.N.E.N.E.21.522N.E.N.E.N.E.NormalN.E.
Pubic hair (tanner stage)N.E.N.E.N.E.N.E.1121Normal12-3 (at 21.0)N.E.N.E.
Facial hairN.E.N.E.N.E.N.E.AbsentAbsentAbsentAbsentAbsentAbsentN.E.ScarceN.E.
Height (SDS)aN.E.~−1.5~−1.5~−1.5+1.4N.E.+2.0+2.4Short>+2.5−1.6 (at 21.0)ShortN.E.
Bone age (year)bN.E.N.E.N.E.N.E.12.513.015.014.5
(at 12.5)
N.E.13.0
(at 5.5)
17.0N.E.N.E.
Fertility (spermatogenesis)YesYesYesYes????Yes????

<Endocrine findings>cBBBBBBBSBBBBSB
<At Dx>Stimulus
LH (mIU/mL)GnRHe0.23.51.73.00.2<0.12.66.31.51.70.12.610.04.3
LH (mIU/mL)GnRH (after priming)f
FSH (mIU/mL)GnRHe1.42.30.80.81.40.50.81.21.21.50.3<0.1<0.12.7
FSH (mIU/mL)GnRH (after priming)f
Prolactin (ng/ml)
Δ4A (ng/mL)1.40.41.70.50.3<0.30.91.51.30.80.32.40.9
T (ng/mL)hCGg2.62.52.12.5<0.1<0.12.79.22.73.2<0.11.23.82.3
DHT (ng/mL)0.20.5
Inhibin B (pg/mL)
E1 (pg/mL)3234593426417786903119544556
E2 (pg/mL)10192431117254022315178392
E2/T ratio (×103)3.87.611.412.49.314.869.6148.3170.4

SDS: standard deviation score; Dx: diagnosis; Tx: therapy; LH: luteinizing hormone; FSH: follicle stimulating hormone; Δ4A: androstenedione; T: testosterone; DHT: dihydrotestosterone;
E1: estrone; E2: estradiol; GnRH: gonadotropin-releasing hormone; hCG: human chorionic gonadotropin; N.E.: not examined; B: basal; and S: stimulated.
Abnormal clinical findings are boldfaced.
Abnormally low hormone values are boldfaced, and abnormally high hormone values are underlined.
aEvaluated by age- and ethnicity-matched growth references; heights ≥+2.0 SD or below ≤−2.0 SD were regarded as abnormal.
bAssessed by the Tanner-Whitehouse 2 method standardized for Japanese or by the Greulich-Pyle method for Caucasians; bone age was assessed as advanced when it was accelerated a year or more.
cEvaluated by age-matched male reference data, except for inhibin B and E1 that have been compared with data from 19 adult males.
dTreated with aromatase inhibitors (anastrozole).
eGnRH 100 μg/m2 (max. 100 μg) bolus i.v.; blood sampling at 0, 30, 60, 90, and 120 minutes.
fGnRH test after priming with GnRH 100 μg i.m. for 5 consecutive days.
ghCG 3000 IU/m2 (max 5000 IU) i.m. for 3 consecutive days; blood sampling on days 1 and 4.
hAlthough 3 has not yet fathered a child, he has normal spermatogenesis with semen volume of 2.5 ml (reference value: >2 ml), sperm count of 105 × 106/ml (>20 × 106/ml), total sperm count of 262.5 × 106 (>40 × 106), motile cells of 70% (>50%), and normal morphological sperms 77% (>30%).
iThese four patients allegedly had gynecomastia that required mastectomy (age unknown).
jThe sister has macromastia, large uterus, and irregular menses; the parental phenotype has not been described.
The conversion factor to the SI unit: LH 1.0 (IU/L), FSH 1.0 (IU/L), E1 3.699 (pmol/L), E2 3.671 (pmol/L), Δ4A 3.492 (nmol/L), and T 3.467 (nmol/L).