21-羟化酶缺陷型先天性肾上腺皮质增生症治疗现状

21-羟化酶缺陷型先天性肾上腺皮质增生症是一类常见的人类常染色体隐性遗传病.患儿可具有失盐、脱水、两性畸形、假性性甲熟及肾上腺危象等临床征象,如何治疗该病一直为学者们所关注.近年来,在产前及出生后药物治疗领域,一些新兴药物及治疗方案在减轻患儿代谢紊乱,改善患儿身高等方面显示出了良好疗效.此外,针对该遗传性疾病的基因治疗...     

Hormonal treatment of congenital adrenal hyperplasia due to 21-hydroxylase deficiency

During childhood, the main aims of the medical treatment of congenital adrenal hyperplasia (CAH) secondary to 21-hydroxylase deficiency, are to prevent salt loss and virilization and to achieve normal stature and normal puberty. As such, there is a narrow therapeutic window through which the intended results can be achieved. In adulthood, the clinical management has received little attention, but recent studies have shown the relevance of long-term follow-up of these patients. Indeed, long-term evaluation of adult CAH patients enables the identification of multiple clinical, hormonal and metabolic abnormalities as bone mineral density alteration, overweight and disturbed reproductive functions. In women with classic CAH, low fertility rate is reported, and is probably the consequence of multiple factors, including neuroendocrine and hormonal factors, feminizing surgery, and psychological factors. Men with CAH may present hypogonadism either through the effect of adrenal rests or from suppression of gonadotropins resulting in infertility. These patients should therefore be carefully followed-up, from childhood through to adulthood, to avoid these complications and to ensure treatment compliance and tight control of the adrenal androgens, by multidisciplinary teams who have knowledge of CAH.     

Prenatal diagnosis and treatment of congenital adrenal hyperplasia due to 21-hydroxylase deficiency

Congenital adrenal hyperplasia (CAH) applies to a group of inherited disorders caused by an enzyme deficiency in steroid biosynthesis. The most common form of CAH is 21-hydroxylase deficiency (21-OHD), which in its severe form can cause genital ambiguity in females. Affected females experience virilization both physically and psychologically. Steroid 21-OHD can be diagnosed in utero through molecular genetic analysis of fetal DNA. Appropriate prenatal treatment by dexamethasone administration to the at-risk pregnant mother is effective in reducing genital virilization in the fetus, thus avoiding unnecessary genitoplasty in affected females. Current data from large human studies show that prenatal diagnosis and treatment are safe in the short term for both the fetus and the mother. Preliminary data from long-term studies support these results.     

Recent advances in diagnosis,treatment, and outcome of congenital adrenal hyperplasia due to 21-hydroxylase deficiency

Congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency (21-OHD) is an autosomal-recessive disease causing cortisol deficiency, aldosterone deficiency and hyperandrogenism. Diagnosis of 21-OHD is confirmed by steroid analysis in newborn screening or later on. Standard medical treatment consists of oral glucocorticoid and mineralocorticoid administration in order to suppress adrenal androgens and to compensate for adrenal steroid deficiencies. However, available treatment is far from ideal, and not much is known about the long-term outcome in CAH as trials in patients in adulthood or old age are rare. Here we briefly describe the pathophysiology, clinical picture, genetics and epidemiology of 21-OHD. This is followed by a comprehensive review of the recent advances in diagnosis, treatment and outcome. Novel insights have been gained in the fields of newborn screening, specific steroid measurement utilizing mass spectrometry, genetics, glucocorticoid stress dosing, additive medical therapy, prenatal treatment, side-effects of medical treatment, adrenomedullary involvement, metabolic morbidity, fertility and gender identity. However, many issues are still unresolved, and novel questions, which will have to be answered in the future, arise with every new finding.     

Ambiguous genitalia and hypertension in a patient with congenital adrenal hyperplasia

Congenital adrenal hyperplasia (CAH) is an uncommon condition. Its clinical presentation with hypertension is rare. Deficiency of the steroid 11‐beta‐hydroxylase accounts for less than 10% of CAH. We report a case of a 19‐year‐old patient who presents with hypertension with ambiguous genitalia secondary to adrenal steroidogenesis dysfunction. We also discuss the defects in adrenal steroidogenesis and clinical phenotypes of CAH.     

先天性肾上腺皮质增生症合并中枢性性早熟的临床分析

目的对先天性肾上腺皮质增生症（CAH）合并中枢性性早熟进行临床分析,提高对CAH合并性早熟的认识。方法回顾分析我院2003年1月至2010年9月住院的所有CAH患者,挑选合并中枢性性早熟的患者,结合文献,对其临床表现、实验室检查和影像学检查等特点加以讨论。结果 50例CAH患者中,4例合并中枢性性早熟,年龄4.1-7.7岁,骨龄9.5-12.0岁,骨龄提前3.9-5.4岁,均为21羟化酶缺乏,女性单纯男性化型。其中,2例为初诊,另2例分别发生在糖皮质激素抑制替代治疗后的9个月和12个月。结论对CAH患儿,尤其是骨龄明显提前者,应注意排查中枢性性早熟;在随后的糖皮质激素抑制替代治疗过程中,有部分患儿会出现性早熟,应定期密切随访。以便早诊、早治,及时调整治疗策略,改善终身高。     

Successful pregnancy and live birth in woman with congenital adrenal hyperplasia: A case report

Rationale:Women with congenital adrenal hyperplasia (CAH) can suffer from impaired fertility rates as a result of increased androgen secretion or impaired sex steroid production. CAH patients have lower pregnancy rate compared to normal women. Only a few cases with successful pregnancy have been reported in the literature. This report described a case of CAH with successful pregnancy and live birth.Patient concerns:A 23-year-old woman visited our endocrinology department for clitoral hypertrophy and primary amenorrhea.Diagnoses:The patient was diagnosed as CAH.Intervention:Prednisone was initially started to improve the patient''s symptoms. Then she underwent clitoral resection and vaginoplasty several months later. She continuously took the prednisolone after the operation and had been undergoing regular checkups.Outcomes:She was pregnant spontaneously without assisted reproductive technology and had a successful live birth. Her baby had shown normal external genitalia with normal karyotype and normal development up to 6 years of age.Lessons:Some mild CAH patients with certain types can achieved successful pregnancy without any assisted reproductive technology after treatment with steroid. The pregnancy rate among CAH women who wish to conceive may be much more optimistic than previous researches.     

Health problems in congenital adrenal hyperplasia due to 21-hydroxylase deficiency

Following the introduction of life-saving glucocorticoid replacement 60 years ago, congenital adrenal hyperplasia (CAH) has evolved from being perceived as a paediatric disorder to being recognized as a lifelong, chronic condition affecting patients of all age groups. Increasing evidence suggests that patients with CAH have an increased risk to develop health problems during adult life, with signs and symptoms of forerunner conditions of adult disease already emerging during the time of paediatric care. Transition of paediatric CAH patients to medical care in the adult setting is an important step to ensure optimal lifelong treatment, aiming to achieve good health and normal life expectancy and quality of life. Thus, primary and secondary prevention of health problems has to become a task of increasing importance for those involved in the care of CAH patients throughout their life.     

Bioavailability of oral hydrocortisone in patients with congenital adrenal hyperplasia due to 21-hydroxylase deficiency

The management of congenital adrenal hyperplasia due to 21-hydroxylase (CYP21) deficiency requires glucocorticoid substitution with oral hydrocortisone given twice or thrice daily. In paediatric practice little is known of the bioavailability of oral hydrocortisone tablets used in these patients. The aim of this study was to assess the bioavailability of oral hydrocortisone and to evaluate current replacement therapy in the light of cortisol pharmacokinetic properties. We determined the bioavailability of hydrocortisone following oral and intravenous administration in sixteen (median age: 10.9 years, range: 6.0-18.4 years) adequately controlled CYP21 deficient patients. Serum total cortisol concentrations were measured at 20-min intervals for 24 h while patients were on oral substitution therapy, and at 10-min intervals for 6 h following an intravenous bolus of hydrocortisone in a dose of 15 mg/m(2) body surface area. The area under the serum total cortisol concentration versus time curve (AUC) following oral and intravenous administration of hydrocortisone was calculated using the trapezoid method. The bioavailability was estimated by dividing the corrected for dose AUC after oral hydrocortisone administration by the corrected for dose AUC after the intravenous hydrocortisone administration and was exemplified as a percentage. After oral administration of hydrocortisone in the morning, median serum total cortisol concentrations reached a peak of 729.5 nmol/l (range: 492-2520 nmol/l) at 1.2 h (range: 0.3-3.3 h) and declined monoexponentially thereafter to reach undetectable concentrations 7 h (range: 5-12 h) after administration. Following administration of the evening hydrocortisone dose, median peak cortisol concentration of 499 nmol/l (range: 333-736 nmol/l) was attained also at 1.2 h (range: 0.3-3.0 h) and subsequently declined gradually, reaching undetectable concentrations at 9 h (5-12 h) after administration of the oral dose. After the intravenous hydrocortisone bolus a median peak serum total cortisol concentration of 1930 nmol/l (range: 1124-2700 nmol/l) was observed at 10 min (range: 10-20 min). Serum cortisol concentrations fell rapidly and reached undetectable levels 6 h after the hydrocortisone bolus. The absolute bioavailability of oral hydrocortisone in the morning was 94.2% (90% confidence interval (CI): 82.8-105.5%) whereas the apparent bioavailability in the evening was estimated to be 128.0% (90% CI: 119.0-138.0%). We conclude that the bioavailability of oral hydrocortisone is high and may result in supraphysiological cortisol concentrations within 1-2 h after administration of high doses. The even higher bioavailability in the evening, estimated using as reference the data derived from the intravenous administration of hydrocortisone bolus in the morning, is likely to reflect a decrease in the hydrocortisone clearance in the evening. Decisions on the schedule and frequency of administration in patients with congenital adrenal hyperplasia should be based on the knowledge of the bioavailability and other pharmacokinetic parameters of the hydrocortisone formulations currently available.     

Effects of 25-hydroxycholesterol and aminoglutethimide in isolated rat adrenal cells. A model for congenital lipoid adrenal hyperplasia?

The production of corticosterone from 25-hydroxycholesterol by isolated rat adrenal cells is inhibited by aminoglutethimide phosphate (AGI); half-maximal inhibition is obtained at ca. 10 muM. AGI also inhibits ACTH-stimulated steroid production from endogeneous substrates; here half-maximal inhibition is obtained with ca. 40 muM AGI. In the presence of ACTH + AGI, 25-hydroxycholesterol causes additive inhibition. This effect of 25-hydroxycholesterol is dose-dependent. ACTH-stimulated steroid production from endogeneous substrates is partially inhibited by 5-cholene-3 beta,24-diol. These results may just reflect substrate competition for the side-chain cleaving system or may be due to some seocndary toxic effect on the cells.