Effects of estrogen replacement therapy on bone and glucose metabolism in a male with congenital aromatase deficiency

Little is known about the impact of estrogen replacement therapy for bone formation, glucose metabolism and hormonal parameters on males with aromatase deficiency. Transdermal estrogen (TE) replacement was initiated at 100 mu g/week in months 0 - 3, 50 mu g/week in months 3 - 6, 25 mu g/week in months 6-12, 75 mu g/week in months 12-24, and 25 mu g/week in months 24-36 to substitute for the deficiency in a 27-year-old homozygous male with a mutation on the CYP19 gene. Estradiol levels increased from < 10 at baseline to 45,12, 27 and 17 pg/ml (normal range 10-50) after 6,12, 24 and 36 months, and inversely correlated to LH and FSH levels. Testosterone levels changed from 31.2 nmol/l at baseline to 3.8, 22.1, 7.1 and 22.0 nmol/l (9.5 - 30) after 6, 12, 24 and 36 months, respectively, and correlated closely to basal and stimulated LH and FSH levels at 100 mu g GnRH. Bone maturation progressed, and metacarpal and phalangeal epiphysis closed after 12 months. Spongiosa-hydroxyapatite of the radius assessed by quantitative computed tomography changed from 52 to 83, 51, 69 and 71 Mg/cm(3) (120 - 160); bone mineral density of the lumbar spine assessed by dual energy X-ray-absorptiometry (normal value > 1.150) increased from 0.971 (T-Score -2.24) to 1.043 (-1.64), 1.065 (1.46), 1.128 (-0.93) g/cm(2) and 1.021 (-1.82) after 6, 12, 24 and 36 months of TE, respectively. Osteocalcin as a bone formation parameter and aminoterminal collagen type I telopeptide as a bone resorption parameter increased during high-dose estrogen supplementation, and then decreased during the lower doses. Lipoprotein (a) increased from 20mg/dl at baseline to 60 and 62 mg/dl after 6 and 12 months, and then decreased to 24 and 25 mg/dl after 24 and 36 months, respectively, while total cholesterol, HDL, LDL and triglycerides did not change. AUC glucose decreased continuously after oral glucose load, and HOMA IR reached its lowest value the 75 mu g weekly estradiol dose. This study confirms the role of estrogens in achieving bone mineralization and maturation in human males. Additionally, estradiol has dual negative feedback sites that on the hypothalamus to decrease GnRH pulse frequency, and on the pituitary to decrease responsiveness to GnRH. The improvement in glucose metabolism after estrogen replacement therapy suggests a probable role of sex steroids in insulin sensitivity. The optimal weekly dose of transdermal estrogen replacement for normalizing estrogen levels and maintain bone mass in adult males with aromatase deficiency may be 50 - 75 mu g spread over two doses.