目的:库欣综合征(CS)是否根据皮质醇增多的强度和潜在病因对促性腺激素轴和睾丸功能(GA/TF)有不同的影响?
结论:由CS引起的内源性皮质醇过量导致不同程度的低促性腺激素性性腺功能减退(HH),与更为严重的促皮质醇/TF和促精子生成相关
背景:CS在男性中的研究很少,因为男性的患病率低于女性。在一些旧的报道中,专门针对少数患有库欣病(CD)的男性,报告了性腺机能减退的发生。然而,在大量患者中,尚未对CS对GA/TF的影响进行详细评估.然而,性腺功能减退症可加重CS相关的合并症,如骨质疏松症和肌病。迄今为止,不同病因和强度的CS男性的GA/TF损伤的全谱仍未知.
方法:在这项单中心研究中,在高等内分泌大学中心诊断出89名患有CS的男性(Bictre,ParisSaclay)在1990年1月至2021年7月之间进行了评估,并与40名年龄相仿的正常男性进行了比较。
方法:CS患者队列的89名男性包括51名CD,29具有EAS,9具有肾上腺起源的CS,即(ACTH非依赖性CS(AI-CS))。他们都有坦率的皮质醇增多症,在两个单独的样品中增加了24h无尿皮质醇(24h-UFC)。进行了一项病例对照研究,重点是垂体促性腺激素功能和睾丸性类固醇和肽。另外一组六名CS男子进行了包括精液分析的评估。在一个由20名男性组成的亚组中,有CS缓解后的可用数据,进行了纵向分析以评估GA/TF缺陷的可逆性.
结果:与对照组相比,患有CS的男性总睾酮(TT)显着降低,生物利用度TT,游离TT(P<0.0001)。性腺功能减退,定义为血清TT水平<3.0ng/ml,在83%的EAS男性中,在61%的有CD的男性中,和33%的男性与AI-CS。所包括的皮质醇增多症男性的正常LH浓度低表明为HH。CD患者血清性激素结合球蛋白水平中度降低(与对照组相比,P=0.01)。在CS男性中,EAS患者的TT明显较低,LH,和FSH水平高于CD或AI-CS。与对照组相比,EAS患者是唯一血清FSH(P=0.002),睾丸肽抑制素B(P<0.0001)和抗苗勒管激素(P=0.003)均显着降低的组。CD患者的血清INSL3水平显着低于对照组(P=0.03)。值得注意的是,24h-UFC和ACTH与包括LH在内的大多数生殖激素呈负相关且显着相关。FSH,TT,和抑制素B在成功治愈治疗后,平均6.0±4.3年的生殖评估显示,血清TT(P<0.0001)和血浆LH(P=0.02)水平显着增加,表明75%的受影响男性的HH逆转。在有精液分析的六名患者中,两个EAS病例显示与严重的少精子症相关的支持细胞肽减少,在去除皮质醇增多症后完全正常化。
结论:对迄今为止最大的男性CS队列的分析以及严格的纳入和排除标准的使用抵消了由于回顾性设计导致的潜在偏倚。由于本研究中精液分析的患者数量较少,需要进一步的研究来揭示男性CS患者精子发生缺陷的全谱。
结论:这项工作揭示了CS男性生殖影响的不同范围。我们证明GA/TF损伤取决于皮质醇增多症的强度,而皮质醇增多症又与潜在的病因有关。在CS缓解后,大多数患者的可逆性证明了皮质醇增多症与GA/TF受损之间的因果关系。我们发现的更广泛的含义在于对一个平民实体的潜在概括,由于长期暴露于外源性糖皮质激素引起的医源性CS。
背景:一些研究资助被授予J.Y.:(i)来自诊所诊所医院计划的资助(PHRC#P081212HYPOPROTEO);(ii)来自法国肾上腺疾病患者协会的资助(“协会surrénales”);(iii)来自HRAPharma的独立研究者研究资助,诺华和Recordati制药公司。SICPA基金会赠款(洛桑,瑞士)为G.E.P.提供了受保护的研究时间。上述赞助商未参与研究的任何部分。作者没有竞争或其他利益冲突要声明。
背景:不适用。
OBJECTIVE: Does Cushing\'s syndrome (CS) differently affect the gonadotrope axis and testicular functions (GA/TF) according to the hypercortisolism intensity and underlying etiology?
CONCLUSIONS: Endogenous cortisol excess caused by CS leads to varying degrees of hypogonadotropic hypogonadism (HH) with more severe GA/TF impairment and altered spermatogenesis in men with intense hypercortisolism associated with paraneoplastic/ectopic adrenocorticotrophic hormone (ACTH) secretion (EAS).
BACKGROUND: CS is very rarely studied in men due to its lower prevalence in men than in women. In a few old reports focusing exclusively on a limited number of men with Cushing\'s disease (CD), the occurrence of hypogonadism was reported. However, a detailed assessment of the impact of CS on the GA/TF in a significant series of patients has not been performed. Yet, hypogonadism could worsen CS-associated comorbidities such as osteoporosis and myopathy. To date, the full spectrum of GA/TF impairment in men with CS of different etiologies and intensity remains unknown.
METHODS: In this monocentric study, 89 men with CS diagnosed at a tertiary endocrine university center (Bicêtre, Paris Saclay) between January 1990 and July 2021 were evaluated and compared to 40 normal men of similar age.
METHODS: The CS patient cohort of 89 men included 51 with CD, 29 with EAS and 9 with CS of adrenal origin i.e. (ACTH-independent CS (AI-CS)). They all had frank hypercortisolism, with increased 24 h-urinary-free cortisol (24 h-UFC) in two separate samples. A case-control study was performed focusing on pituitary gonadotrope function and testicular sex steroids and peptides. An additional set of six CS men had an evaluation including semen analysis. In a subgroup of 20 men with available data after CS remission, a longitudinal analysis was conducted to assess the reversibility of GA/TF defects.
RESULTS: Compared to controls, men with CS had significantly lower total testosterone (TT), bioavailable TT, and free TT (P < 0.0001). Hypogonadism, defined as serum TT levels <3.0 ng/ml, was present in 83% of men with EAS, in 61% of men with CD, and in 33% of men with AI-CS. Low-normal LH concentrations in the included men with hypercortisolism indicated HH. Serum sex hormone-binding globulin levels were moderately decreased in men with CD (P = 0.01 vs controls). Among the CS men, those with EAS had significantly lower TT, LH, and FSH levels than those with CD or AI-CS. When compared to controls, patients with EAS were the only group exhibiting a significant decrease in both serum FSH (P = 0.002) and the testicular peptides inhibin B (P < 0.0001) and anti-Müllerian hormone (P = 0.003). Serum
INSL3 levels were significantly lower in men with CD than in the controls (P = 0.03). Of note, 24 h-UFC and ACTH were inversely and significantly associated with the majority of reproductive hormones including LH, FSH, TT, and inhibin B. Following successful curative therapy, reproductive assessment at a mean of 6.0 ± 4.3 years showed a significant increase in serum TT (P < 0.0001) and plasma LH (P = 0.02) levels, indicating a reversal of HH in 75% of the affected males. Among the six patients with available semen analysis, the two EAS cases exhibited a decrease in Sertoli cell peptides associated with a severe oligozoospermia, which completely normalized following removal of the source of hypercortisolism.
CONCLUSIONS: The potential bias due to the retrospective design is counteracted by the analysis of the largest male CS cohort to date as well as the use of stringent inclusion and exclusion criteria. Due to the low number of patients with semen analysis in this study, further research is needed to unravel the full spectrum of spermatogenesis defects in men with CS.
CONCLUSIONS: This work reveals the variable spectrum of reproductive impact in men with CS. We demonstrate that GA/TF impairment depends on the intensity of hypercortisolism which in turn is related to the underlying etiology. The causal link between hypercortisolism and GA/TF impairment was attested by its reversibility in most patients after CS remission. The wider implications of our findings lie in the potential generalization to a much commoner entity, iatrogenic CS due to chronic exposure to exogenous glucocorticoids.
BACKGROUND: Several research grants were attributed to J.Y.: (i) a grant from Programme Hospitalier de Recherche Clinique (PHRC # P081212 HYPOPROTEO); (ii) a grant from the French Association of Patients with Adrenal Diseases (\'Association surrénales\'); and (iii) independent Investigator Research Grants from HRA Pharma, Novartis and Recordati Pharma. A SICPA Foundation grant (Lausanne, Switzerland) allowed protected research time for G.E.P. The above sponsors were not involved in any part of the study. The authors have no competing or other conflicts of interest to declare.
BACKGROUND: N/A.