Impact of estrogen replacement therapy in a male with congenital aromatase deficiency caused by a novel mutation in the CYP19 gene
Impact of estrogen replacement therapy in a male with congenital aromatase deficiency caused by a novel mutation in the CYP19 gene
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DOI：
10.1210/jc.2002-020498
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发表时间：
2002-12-01
影响因子：
5.8
通讯作者：
Broecker, M
中科院分区：
文献类型：
--
作者：
Herrmann, BL;Saller, B;Broecker, M
最近关于雌激素受体a和芳香化酶缺乏影响的报道，揭示了雌激素对人类骨形成的重要性。我们描述了一个新的突变CYP19基因在一个27岁的纯合子男性的近亲父母。CYP19基因外显子VI前剪接受体位点-3位置的内含子V中的C到A的替换可能是芳香酶活性丧失的原因。患者的mRNA导致外显子v末端下游的一个移码和一个过早停止密码子8核苷酸，双亲对同一突变显示为杂合的。除膝外翻、脊柱后凸和肉胸外，体格检查正常，包括次要男性特征，睾丸大小正常。为了弥补这一缺陷，患者接受50毫克雌二醇透皮治疗，每周2次，连续3个月，然后每周2次，每次25马克。6个月后雌激素水平（1.150）。骨形成参数骨钙素从13微克/升增加到52微克/升（正常范围，24-70微克），骨吸收参数氨基末端胶原型端肽从62.9微克/升增加到92.4微克/升（正常范围，5-54微克）。精液分析显示少精症（1740万/ml，正常bbb20）。治疗3个月后，精子数量上升（2310万/ml），随后3个月迅速下降（110万/ml）。精子活力在基线时降低，在治疗期间进一步降低。6个月后口服糖耐量试验中胰岛素、c肽和血糖水平曲线下面积下降（胰岛素：277 vs 139 muU/ml.h； c肽：52 vs 15 ng/m.h；葡萄糖曲线下面积：17316 vs 12780 mg/d-min）。甘油三酯（268 vs 261 mmol/l）和总胆固醇水平（176 vs 198 mmol/l）没有显著变化，但低密度脂蛋白/高密度脂蛋白比值从5.37下降到3.56，脂蛋白(a)从19.9增加到60.0 mg/dl（正常范围）。
Recent reports of the impact of estrogen receptor a and aromatase deficiency have shed new light on the importance of estrogen for bone formation in man. We describe a novel mutation of the CYP19 gene in a 27-yr-old homozygous male of consanguinous parents. A C to A substitution in intron V, at position -3 of the splicing acceptor site before exon VI of the CYP19 gene, is the likely cause of loss of aromatase activity. The mRNA of the patient leads to a frameshift and a premature stop codon 8 nucleotides downstream the end of exon V. Both parents were shown to be heterozygous for the same mutation. Apart from genua valga, kyphoscoliosis, and pectus carniatus, the physical examination was normal including secondary male characteristics with normal testicular size. To substitute for the deficiency, the patient was treated with 50 jig transdermal estradiol twice weekly for 3 months, followed by 25 mug twice weekly. After 6 months estrogen levels ( 1.150). Osteocalcin as a bone formation parameter increased from 13 to 52 mug/l (normal range, 24-70) and aminoterminal collagen type I telopeptide as a bone resorption parameter increased from 62.9 to 92.4 nmol/ mmol creatinine (normal range, 5-54). Semen analysis revealed oligoazoospermia (17.4 million/ml; normal >20) at baseline. After 3 months of treatment, the sperm count increased (23.1 million/ml) and decreased rapidly (1.1 million/ml) during the following 3 months. The sperm motility was reduced at baseline and decreased further during treatment. Area under the curve of insulin, C-peptide, and blood glucose levels during oral glucose tolerance test decreased after 6 months (insulin: 277 vs. 139 muU/ml.h; C-peptide 52 vs. 15 ng/m.h; area under the curve glucose: 17316 vs. 12780 mg/d-min). Triglycerides (268 vs. 261 mmol/liter) and total cholesterol levels (176 vs. 198 mmol/liter) did not change significantly, but the low-density lipoprotein/high-density lipoprotein ratio decreased from 5.37 to 3.56 and lipoprotein (a) increased from 19.9 to 60.0 mg/dl (normal range,