Effect of estrogen replacement therapy on bone maturation and hormonal parameters after 24 months in a male with congenital aromatase deficiency

Little is known about the aromatase deficiency and the impact of estrogens for bone formation and hormonal parameters in males. In 2002, we described a novel mutation of the CYP19 gene in a 27-year-old homozygous male of consanguinous parents. To substitute for the deficiency, transdermal estrogen (TE) replacement was initiated (0–3 months 100µg/week; 3–12 months 50µg/week; 12–24 months 75µg/week). Estradiol levels increased from <10 at baseline to 23, 42, 26 and 25 pg/ml (normal range 10–50) after 6, 12, 18 and 24 months and were inversely related to LH and FSH levels. Testosterone levels changed from 31.2 nmol/l at baseline to 2.0, 22.0, 9.7 and 7.1 nmol/l (9.5–30) after 6, 12, 18 and 24 months and were closely related to basal and stimulated LH and FSH levels with 100µg GnRH. Bone maturation progressed and metacarpal and phalangeal epiphysis closed after 24 months. Spongiosa-hydroxyapatite of the radius, assessed by quantitative computed tomography, changed from 52 to 83, 51 and 69mg/cm³ (120–160) and bone mineral density of the lumbar spine, assessed by dual energy X-ray-absorptiometry, increased from 0.971 (T-Score -2.24) to 1.043 (-1.64), 1.065 (-1.46) and 1.128 (-0.93)g/cm2 (>1.150) after 6, 12 and 24 months of TE. Osteocalcin as a bone formation parameter increased from 13 to 52, 51 and 35mg/l (normal range 24–70) and aminoterminal collagen typ I telopeptide as a bone resorption parameter first increased from 62.9 to 92.4 after 6 months and then decreased to 58.4 to 38.4 nmol/mmol creatinine (5–54) after 12 and 24 months. Lipoprotein (a) increased from 19.9mg/dl at baseline to 60.0 and 62.0mg/dl after 6 and 12 months and then decreased to 35.4 and 24.1mg/dl after 18 and 24 months, whereas total cholesterol, HDL, LDL and triglycerides did not change.

This study confirms the role of estrogens in achieving and maintaining bone mineral content in human male. Furthermore, estradiol has dual sites of negative feedback, acting at the hypothalamus to decrease GnRH pulse frequency and at the pituitary to decrease responsiveness to GnRH.