NR0B1致病变异可导致儿童早期先天性肾上腺发育不全或原发性肾上腺功能不全,通常与低促性腺激素性腺功能减退有关。NR0B1是肾上腺皮质器官发生和维持正常精子发生所必需的。在人类中,在携带NR0B1致病变异体的患者中恢复生育能力是一项挑战.
这项研究的目的是调查临床,荷尔蒙,组织学,精子学,和NR0B1致病变异患者队列的分子遗传学特征,监测生育力保存。
我们纳入了5名患者,包括四名青少年,具有NR0B1致病性或可能的致病性变体。他们都患有原发性肾上腺功能不全,正在接受糖皮质激素和盐皮质激素的替代疗法。患者接受重组卵泡刺激素和重组人绒毛膜促性腺激素诱导精子发生。四名青少年在13岁至15岁和6个月之间开始联合促性腺激素治疗,唯一的成年人在31岁和2个月之间开始。在开始促性腺激素治疗之前进行物理和激素评估。促性腺激素治疗12个月后,重复体检和荷尔蒙评估,和精液分析。如果在3个月间隔的至少2个精液中没有观察到精子细胞,睾丸活检用于睾丸精子提取。
双侧睾丸体积从8毫升增加(四分位数间距,6-9)至促性腺激素治疗后的12ml(10-16)。抑制素B水平相对稳定:促性腺激素治疗前110ng/L(46-139),促性腺激素治疗结束时91ng/L(20-120)。在促性腺激素治疗期间,在所有病例的所有精液分析中均观察到无精子症。三名患者同意进行睾丸活检;没有任何成熟的精子细胞可以被取回。
我们表征了一组NR0B1致病性或可能致病性变异的患者通过重组促性腺激素治疗保留生育力,开始于青春期或成年期。即使在促性腺激素治疗后,精液样本或睾丸活检中也无法检索到精子细胞,表明促性腺激素治疗,即使从青春期开始,对恢复生育能力无效。
NR0B1 pathogenic variants can cause congenital adrenal hypoplasia or primary adrenal insufficiency in early childhood usually associated with hypogonadotropic hypogonadism. NR0B1 is necessary for organogenesis of the adrenal cortex and to maintain normal spermatogenesis. In humans, restoration of fertility in patients carrying NR0B1 pathogenic variants is challenging.
The aim of the study was to investigate the clinical, hormonal, histological, spermiological, and molecular genetic characteristics of a cohort of patients with NR0B1 pathogenic variants, monitored for fertility preservation.
We included five patients, including four teenagers, with NR0B1 pathogenic or likely pathogenic variants. They all had primary adrenal insufficiency and were receiving replacement therapy with glucocorticoids and mineralocorticoids. Patients received recombinant follicle-stimulating hormone and recombinant human chorionic gonadotropin in order to induce spermatogenesis. Combined gonadotropin treatment was initiated between 13 years and 15 years and 6 months for the four teenagers and at 31 years and 2 months for the only adult. Physical and hormonal assessments were performed just before starting gonadotropin treatment. After 12 months of gonadotropin treatment, physical examination and hormonal assessments were repeated, and semen analyses were performed. If no sperm cells were observed in at least 2 semen collections at 3-month interval, testicular biopsy for testicular sperm extraction was proposed.
Bilateral testicular volume increased from 8 ml (interquartile range, 6-9) to 12 ml (10-16) after gonadotropin treatment. Inhibin B levels were relatively stable: 110 ng/L (46-139) before and 91 ng/L (20-120) at the end of gonadotropin treatment. Azoospermia was observed in all semen analyses for all cases during gonadotropin treatment. Three patients agreed to testicular biopsy; no mature sperm cells could be retrieved in any.
We characterized a cohort of patients with NR0B1 pathogenic or likely pathogenic variants for fertility preservation by recombinant gonadotropin treatment, which began either at puberty or in adulthood. No sperm cells could be retrieved in semen samples or testicular biopsy even after gonadotropin treatment, indicating that gonadotropin treatment, even when started at puberty, is ineffective for restoring fertility.