DAX-1基因突变所致先天性肾上腺发育不良患者下丘脑-垂体-睾丸轴功能分析

Dysfunction of hypothalamic-pituitary-testicular axis in patients with adrenal hypoplasia congenita due to DAX-1 gene mutation

目的 分析DAX-1基因突变所致X连锁先天性肾上腺发育不良（AHC）患者下丘脑-垂体-睾丸轴（HPTA）功能损伤的部位、程度及生精疗效.方法 回顾性分析北京协和医院2007年11月至2014年12月收治的经基因测序确诊为DAX-1基因突变的24例成年男性患者的临床表现、激素测定和精液分析结果,探讨其HPTA功能损伤的部位及程度.结果 所有患者均有原发性肾上腺皮质功能减退症的表现,21例（87.5％）患者在10岁前发病.患者治疗前睾丸体积2.0（2.0,3.8） ml,3例有隐睾史.经人绒毛膜促性腺激素（HCG）刺激后（16例）,血总睾酮从0.1（0,0.5） nmol/L升高至13.5（7.6,15.4） nmol/L.23例患者确诊为低促性腺激素性性腺功能减退症（HH）;仅1例患者的血促性腺激素[黄体生成素（LH） 5.2 U/L,卵泡刺激素（FSH） 15.7 U/L]和睾酮水平（13.4 nmol/L）均正常,但精液中无精子.7例患者接受HCG联合人绝经期促性腺激素（HMG）治疗,总治疗时间为80人月,治疗期间血总睾酮水平达15.3（8.4,25.3） nmol/L;睾丸体积从（4.0±2.9） ml增加到（4.9±3.3）ml,但差异无统计学意义（P =0.270）,均未见到精子生成.另1例患者接受GnRH脉冲治疗2个月,LH从1.0 U/L增加至9.3 U/L,FSH从3.0 U/L增加至13.5 U/L,总睾酮从0 nmol/L增加至10.0 nmol/L,但治疗前后睾丸体积均为3 ml.结论 DAX-1基因突变所致AHC患者HPTA功能损伤主要表现为HH和原发性生精障碍.患者睾丸间质细胞功能基本正常,但支持细胞和曲细精管功能低下,呈现间质细胞功能和曲细精管功能明显分离.

Objective To evaluate the hypothalamic-pituitary-testicular axis （HPTA） function and spermatogenesis in male patients with X-linked adrenal hypoplasia congenita （AHC） due to DAX-1 gene mutation.Methods Twenty-four adult male patients from Peking Union Medical College Hospital between November 2007 and December 2014 were included.Their DAX-1 gene mutations were confirmed by polymerase chain reaction （PCR） and clinical features,hormone level and semen assay were collected.Results All patients presented with adrenal deficiency symptom.21 patients （87.5％） showed the symptoms before the age of 10 years old.The average testicular volume was 2.0 （2.0,3.8） ml at the baseline in 24 patients.Three patients had cryptorchidism.Serum testosterone level increased from 0.1 （0,0.5） nmol/L to 13.5 （7.6,15.4） nmol/L （n =16） after human chorionic gonadotropin （HCG） stimulation.23 out of 24 patients were diagnosed as hypogonadotropic hypogonadism （HH） and only one patient was diagnosed as azoospermia with normal gonadotropin and testosterone level.Combined gonadotropin therapy was administered in seven patients and their serum testosterone level reached 15.3（8.4,25.3） nmol/L,but no obvious testicular enlargement was observed [（4.0 ± 2.9） vs （4.9 ± 3.3） ml,P =0.270] and seminal analysis revealed persistent azoospermia.Another patient showed response to pulsatile GnRH therapy.Luteinizing hormone （LH） level increased from 1.0 U/L to 9.3 U/L,and follicle stimulating hormone（FSH） level increased from 3.0 U/L to 13.5 U/L.Serum testosterone level increased from 0 nmol/L to 10.0 nmol/L,but testicular volume maintained 3 ml after treatment for two months.Conclusions Male patients with DAX-1 gene mutations presented with primary defect in spermatogenesis and hypogonadotropic hypogonadism.Their Leydig cell function was almost normal,while Sertoli cell and seminiferous tubule function were seriously damaged.