Background: Symptoms of hyperandrogenism are common in patients with Cushing’s disease (CD), yet they are not sufficiently explained by androgen concentrations. In this study we analyzed the contribution of 11-oxygenated C19 steroids (11oxC19) to hyperandrogenemia in female patients with CD. Methods: We assessed saliva day profiles in females with CD pre (n = 23) and post (n = 13) successful transsphenoidal surgery, 26 female controls, 5 females with CD treated with metyrapone and 5 treated with osilodrostat for cortisol, cortisone, androstenedione (A4), 11-hydroxyandrostenedione (11OHA4), testosterone (T), 11-ketotestosterone (11KT) as well as metabolites of classic and 11oxygenated androgens in 24-hour urine. In addition, morning baseline levels of gonadotropins and estradiol, sex hormone-binding globulin, cortisol and dehydroepiandrosterone sulfate (DHEAS) in serum and adrenocorticotropic hormone in plasma in patients and controls were investigated. Results: Treatment naïve females with CD showed significantly elevated area under the curve (AUC) of 11OHA4 and 11KT in saliva throughout the day compared to controls (11OHA4 mean rank difference (mrd) 18.13, p = 0.0002; 11KT mrd 17.42; p = 0.0005) whereas A4, T and DHEAS were comparable to controls. Gonadotropin concentrations were normal in all patients with CD. After transphenoidal surgery 11oxC19 and their metabolites dropped significantly in saliva (11OHA4 p < 0.0001; 11KT p = 0.0010) and urine (11-O-An p = 0.0011; 11-OH-AN p < 0.0001), treatment with osilodrostat and metyrapone efficaciously blocked 11oxC19 synthesis. Conclusion Hyperandrogenemia in CD is predominantly caused by excess of 11oxC19 steroids.

Background: Information on clinical outcome of coronavirus disease 19 (COVID-19) infection in patients with adrenal disorders is scarce. Methods: A collaboration between the ESE Rare Disease Committee and ENDO-ERN via the European Registries for Rare Endocrine Conditions (EuRRECa) allowed the collection of data of 64 cases (57 adrenal insufficiency (AI), 7 Cushing’s syndrome) that had been reported by 12 centres in 8 European between January 2020 and December 2021. Results: Of all 64 patients, 23 were males and 41 females (13 of those children) with a median age of 37 and 51 years. In 45/57 (95%) AI cases, COVID-19 infection was confirmed by testing. Primary insufficiency was present in 45/57 patients; 19 were affected by Addison’s disease (AD), 19 by congenital adrenal hyperplasia, 7 by PAI due to other causes. Most relevant comorbidities were hypertension (12%), obesity (n = 14%) and diabetes mellitus (9%). An increase by a median of 2.0 (IQR 1.4) times the daily replacement dose was reported in 42 (74%) patients. Two patients administered i.m. injection of 100 mg hydrocortisone, 11/64 were admitted to hospital. Two patients had to be transferred to the intensive care unit, one with lethal outcome. Four patients reported persistent SARS-CoV-2 infection, all others complete remission. Conclusion: This European multicentric questionnaire is the first to collect data on the outcome of COVID-19 infection in patients with adrenal gland disorders. It suggests good clinical outcome in case of duly dose adjustments and emphasizes the importance of patient education on sick day rules.

First-trimester prenatal treatment with the glucocorticoid (GC) dexamethasone (DEX) in pregnancies at risk for classic congenital adrenal hyperplasia (CAH) is associated with ethical dilemmas. Though effective in reducing virilisation in girls with CAH, it entails exposure to high doses of GC in foetuses that do not benefit from the treatment. The current paper provides an update on the literature on outcomes of prenatal DEX treatment in CAH cases and unaffected subjects. Long-term follow up research is still needed to determine treatment safety. In addition, advances in early prenatal diagnostics for CAH and sex-typing, as well as studies assessing dosing effects of DEX may avoid unnecessary treatment and improve treatment safety.

Background There is overlap between movement disorders and neuroendocrine abnormalities. Objectives and methods To provide a systematic review on the association of thyroid dysfunction and movement disorders. Thyroid physiological function and classical thyroid disorders highlighting typical and atypical manifestations including movement disorders, as well as diagnostic procedures, and treatments are discussed. Results Hypothyroidism may be associated with hypokinetic and hyperkinetic disorders. There is debate whether their concomitance reflects a causal link, is coincidence, or the result of one unmasking the other. Hypothyroidism‐associated parkinsonism may resemble idiopathic Parkinson's disease. Hypothyroidism‐associated hyperkinetic disorders mainly occur in the context of steroid‐responsive encephalopathy with autoimmune thyroiditis, that is, Hashimoto disease, mostly manifesting with tremor, myoclonus, and ataxia present in 28–80%, 42–65% and 33–65% in larger series. Congenital hypothyroidism manifesting with movement disorders, mostly chorea and dystonia, due to Mendelian genetic disease are rare. Hyperthyroidism on the other hand mostly manifests with hyperkinetic movement disorders, typically tremor (present in three quarters of patients). Chorea (present in about 2% of hyperthyroid patients), dystonia, myoclonus, ataxia and paroxysmal movement disorders, as well as parkinsonism have also been reported, with correlation between movement intensity and thyroid hormone levels. On a group level, studies on the role of thyroid dysfunction as a risk factor for the development of PD remain non‐conclusive. Conclusions In view of the treatability of movement disorders associated with thyroid disease, accurate diagnosis is important. The pathophysiology remains poorly understood. More detailed case documentation and systematic studies, along with experimental studies are needed.

Objective Differentiation of an adrenal from an ovarian source of hyperandrogenemia can be challenging. Recent studies have highlighted the importance of 11-oxygenated C19 steroids to the androgen pool in humans. The aim of this study was to determine the origin of 11-oxygented androgens in females and to explore their potential use in the diagnostics of hyperandrogenic disorders. Methods We measured testosterone and its precursors (dehydroepiandrosterone-sulfate and, androstenedione) and 11-oxygenated androgens (11-hydroxyandrostendione (11-OHA4) and, 11-ketotestosterone (KT)) in the periphery, adrenal and ovarian veins in four different cases of hyperandrogenism in females (polycystic ovary syndrome (PCOS), primary bilateral macronodular adrenal hyperplasia (PBMA), Sertoli-Leydig cell tumor, and ovarian steroid cell tumor). Results Two patients demonstrate excessive testosterone (T) secretion in neoplastic ovarian tumors which was not paralleled by a significant secretion of 11-oxygenated androgens as determined by adrenal and ovarian vein sampling. In androgen-secreting bilateral adrenal macronodular hyperplasia, steroid profiles were characterized by elevated 11-KT and 11-OHA4 concentrations in adrenal veins and the periphery. In the patient with PCOS, peripheral 11-KT concentrations were slightly elevated in comparison to the other patients but the 11-KT and 11-OHA4 concentrations were comparable in ovarian veins and in the periphery. Conclusion This study confirms that 11-OHA4 and 11-KT are not synthesized by the ovary. We propose that the T/11-KT ratio as well as 11-OHA4 could help identify predominant adrenal androgen excess and distinguish neoplastic and non-neoplastic ovarian androgen source.