Impact of Cushing's syndrome on the gonadotrope axis and testicular functions in men.

STUDY QUESTION: Does Cushing's syndrome (CS) differently affect the gonadotrope axis and testicular functions (GA/TF) according to the hypercortisolism intensity and underlying etiology? SUMMARY ANSWER: 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). WHAT IS KNOWN ALREADY: 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. STUDY DESIGN, SIZE, DURATION: 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. PARTICIPANTS/MATERIALS, SETTING, 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. MAIN RESULTS AND THE ROLE OF CHANCE: 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. LIMITATIONS, REASONS FOR CAUTION: 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. WIDER IMPLICATIONS OF THE FINDINGS: 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. STUDY FUNDING/COMPETING INTEREST(S): 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. TRIAL REGISTRATION NUMBER: N/A.

[Prevention and remission of diabetes: is it feasible?]. / Prévention et guérison du diabète: est-ce possible?

Prevention of type 2 diabetes is a major public health objective in view of the increasing prevalence of obesity in the population, the medical community and politicians to develop preventive strategies as well as effective interventions to induce remission of diabetes. Clinical studies indicate that intensive medical treatment through lifestyle adaptations and even more bariatric surgery can prevent or rather delay type 2 diabetes onset and factor remission but with a positive effect which progressively decreases with time. Duration of diabetes and weight loss are major prognostic factors. New strategies are necessary to improve both short- and long-term efficacy of diabetes prevention and remission.

[GLP-1 receptor agonists versus SGLT-2 inhibitors in obese type 2 diabetes patients]. / Analogues du GLP-1 versus inhibiteurs du SGLT-2 pour les diabétiques de type 2 obèses.

Who never had a type 2 obese diabetic patient, treated by several oral antidiabetic drugs and insulin, with consequent weight gain associated with the therapeutic escalation and uncontrolled diabetes? The arrival of GLP-1 agonists and SGLT-2 inhibitors allows to reevaluate the management of these patients, with their favorable effects on glycemic control, weight and the risk of hypoglycemia and their complementary mechanisms to conventional treatments. The vicious cycle of weight gain and increased need of insulin is limited. The choice between these two molecules must be based on several factors (glycemic target, weight, comorbidities, route of administration, side effects, etc.), and the balanced enthusiasm of these new treatments with the insufficient data regarding their long-term safety and their impact on micro- and macrovascular complications.

[Combined treatment of insulin and GLP-1 analogs: what do we expect?]. / Traitement combiné d'insuline et d'analogue du GLP-1: qu'en attendre?

Type 2 diabetes mellitus is a progressive and heterogeneous disease. The decrease in insulin secretion by pancreatic beta cells and the increase of glucagon secretion by pancreatic beta cells, are the two major pathophysiologic characteristics. The majority of type 2 diabetics will therefore require insulin in the evolution of their disease, with weight gain and hypoglycaemia as side effects. GLP-1 analogs are effective therapeutic alternatives due to their actions on glucagon and insulin secretion, on satiety and gastric emptying. For patients inadequately controlled with conventional antidiabetics, GLP-1 analogs, introduced as an alternative or in combination with insulin, can prevent or reduce the side effects associated with insulin. Indeed, the risk of hypoglycaemia is reduced and the vicious circle of weight gain secondary to insulin/need to increase insulin doses is limited.

[Chronic liver diseases and diabetes]. / Maladies hépatiques chroniques et diabète.

The presence of chronic liver diseases may drastically limit the use of anti-diabetic drugs. Chronic liver diseases increase insulin resistance, and in some risk groups promote the development of diabetes. Therefore, antidiabetic treatment should be adapted to the severity of liver disease. However, diabetes, notably when associated with obesity and dyslipidemia, participates in the development of nonalcoholic fatty liver disease and to steato-hepatitis that may progress to cirrhosis and hepatocellular carcinoma. Other relations between diabetes and chronic liver disease will be discussed in this article. Finally, the indications and limits of each anti-diabetic therapy group will be discussed according to the degree of liver damage.

Associations of diabetes mellitus with orthopaedic infections.

BACKGROUND: Clinical experience suggests that a high proportion of orthopaedic infections occur in persons with diabetes. METHODS: We reviewed several databases of adult patients hospitalized for orthopaedic infections at Geneva University Hospitals from 2004 to 2014 and retrieved 2740 episodes of infection. RESULTS: Overall, diabetes was noted in the medical record for 659 (24%) of these cases. The patients with, compared with those without, diabetes had more than five times more foot infections (274/659 [42%] vs 155/2081 [7%]; p < 0.01) and a significantly higher serum C-reactive protein level at admission (median 96 vs 70 mg/L; p < 0.01). Diabetic patients were older (median 67 vs 52 years; p < 0.01), more often male (471 [71%] vs 1398 [67%]; p = 0.04), and had more frequent polymicrobial infections (219 [37%] vs 353 [19%]; p < 0.01), including more gram-negative non-fermenting rods (90 [15%] vs 168 [9%]; p < 0.01). Excluding foot infections from these analyses did not change the statistically significant differences. Diabetes was present in 17% of all infected orthopaedic patients without foot involvement. In Geneva canton, the overall prevalence of diabetes is estimated at 5.1%, while we have found that the prevalence is 13% in our hospitalized adults. CONCLUSIONS: Diabetes is present in 24% of all adult patients hospitalized for surgery for an orthopaedic infection, a prevalence that is several times higher than for the general population and twice as high as that for the population of hospitalized patients. Compared with non-diabetics, patients with diabetes have significantly more infections that are polymicrobial, including gram-negative non-fermenting rods.