库欣综合征（CS）是否根据高皮质酮症的强度和潜在病因对促性腺激素轴和睾丸功能（GA/TF）产生不同的影响？CS引起的内源性皮质醇过量导致不同程度的性腺激素分泌减少（HH），与异位分泌腺环化皮质激素（ACTH）相关的强烈高皮质酮症（EAS）患者表现出更严重的GA/TF损害和改变，影响精子生成。由于男性Cushing病（CD）的患病率较女性低，因此CS在男性中研究得很少。在少数关注CD的男性的早期报告中，曾报道了性腺功能减退。然而，迄今为止，尚未开展有关CS对重要患者群体的GA/TF影响的详细评估，而性腺功能减退可能会加重CS相关的骨质疏松和肌无力等合并症。目前，对不同病因和强度CS患者的GA/TF损害的完整范围尚不清楚。 在这项单中心研究中，评估了1990年1月至2021年7月期间巴黎萨克雷大学心内分泌医学中心（Bicêtre）诊断的89名CS男性患者，并与40名相同年龄的正常男性进行比较。CS患者群包括51例CD、29例EAS和9例肾上腺CS（ACTH非依赖性CS（AI-CS））。他们所有人都有明显的高皮质酮症，两个独立样本中尿24小时游离皮质醇（24小时- UFC）增加。进行了一个以垂体性促性腺激素功能和睾丸性激素和多肽为重点的病例对照研究。另外，六位CS男性进行了包括精液分析在内的评估。在20位有可用数据的CS男性亚组中，进行了纵向分析，评估了GA/TF缺陷的可逆性。 与对照组相比，CS男性的总睾酮（TT）、生物活性TT和游离TT明显降低（P<0.0001）。在EAS男性中，83%的人存在低于3.0ng/ml的血清TT水平，CD男性中为61%，AI-CS男性中为33%。高皮质酮症患者中的低正常LH浓度表明HH。在CD男性中，血清性激素结合球蛋白水平适度降低（P=0.01，与对照组相比）。在CS男性中，EAS组的TT、LH和FSH水平明显低于CD组和AI-CS组。与对照组相比，EAS患者是仅有的一个显示血清FSH（P=0.002）以及睾丸多肽抑制素B（P<0.0001）和抗Müllerian激素（P=0.003）明显降低的组。CD男性的血清INSL3水平显著低于对照组（P=0.03）。值得注意的是，24小时- UFC和ACTH与大多数生殖激素包括LH、FSH、TT和抑制素B呈显著的逆相关。成功治疗后，对受影响男性进行的生殖评估，平均6.0 ± 4.3年显示血清TT（P<0.0001）和血浆LH（P=0.02）水平显著增加，表明HH逆转了75%的受影响男性。在六例有可用精液分析数据的患者中，两例EAS病例表现出Sertoli细胞多肽降低，伴有严重的少精子症，而一旦摘除高皮质酮源，这些患者的情况完全恢复正常。 由于回顾性设计的潜在偏倚，通过对迄今最大的男性CS群体进行分析以及采用严格的纳入和排除标准，可消除偏倚。由于本研究中精液分析患者数量较少，仍需要进一步研究以揭示男性CS患者精子生成缺陷的全面范围。 这项研究揭示了CS男性生殖影响的可变谱。我们证明了GA/TF损害取决于高皮质酮症的强度，而高皮质酮症又与潜在病因相关。多数患者在CS缓解后GA/TF缺陷逆转，从而证明了高皮质酮症与GA/TF损害之间的因果关系。我们的发现的更广泛的意义在于可能普遍应用于一种更常见的病因，即由于慢性外源性糖皮质激素暴露引起的医源性CS。 J.Y.获得了多项研究经费支持：（i）法国临床研究医院计划（PHRC＃P081212 HYPOPROTEO）的经费；（ii）法国肾上腺疾病患者协会（'Association surrénales'）的经费；（iii）独立的研究员研究经费，来自HRA Pharma、诺华和Recordati Pharma。SICPA基金会授予了G.E.P保护性研究时间的经费。上述赞助商未参与研究的任何部分。作者声明无竞争或其他利益冲突。 N/A. © 作者 2023。由牛津大学出版社代表欧洲人类生殖和胚胎学学会发表。版权所有，保留所有权利。如需权限，请发送电子邮件至：journals.permissions@oup.com。

Does Cushing's syndrome (CS) differently affect the gonadotrope axis and testicular functions (GA/TF) according to the hypercortisolism intensity and underlying etiology?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).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.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.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.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.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.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.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.N/A.© The Author(s) 2023. Published by Oxford University Press on behalf of European Society of Human Reproduction and Embryology. All rights reserved. For permissions, please email: journals.permissions@oup.com.