Venous thromboembolism in Cushing syndrome: results from an EuRRECa and Endo-ERN survey.

Background: Patients with Cushing syndrome (CS) are at increased risk of venous thromboembolism (VTE). Objective: The aim was to evaluate the current management of new cases of CS with a focus on VTE and thromboprophylaxis. Design and methods: A survey was conducted within those that report in the electronic reporting tool (e-REC) of the European Registries for Rare Endocrine Conditions (EuRRECa) and the involved main thematic groups (MTG's) of the European Reference Networks for Rare Endocrine Disorders (Endo-ERN) on new patients with CS from January 2021 to July 2022. Results: Of 222 patients (mean age 44 years, 165 females), 141 patients had Cushing disease (64%), 69 adrenal CS (31%), and 12 patients with ectopic CS (5.4%). The mean follow-up period post-CS diagnosis was 15 months (range 3-30). Cortisol-lowering medications were initiated in 38% of patients. One hundred fifty-four patients (69%) received thromboprophylaxis (including patients on chronic anticoagulant treatment), of which low-molecular-weight heparins were used in 96% of cases. VTE was reported in six patients (2.7%), of which one was fatal: two long before CS diagnosis, two between diagnosis and surgery, and two postoperatively. Three patients were using thromboprophylaxis at time of the VTE diagnosis. The incidence rate of VTE in patients after Cushing syndrome diagnosis in our study cohort was 14.6 (95% CI 5.5; 38.6) per 1000 person-years. Conclusion: Thirty percent of patients with CS did not receive preoperative thromboprophylaxis during their active disease stage, and half of the VTE cases even occurred during this stage despite thromboprophylaxis. Prospective trials to establish the optimal thromboprophylaxis strategy in CS patients are highly needed. Significance statement: The incidence rate of venous thromboembolism in our study cohort was 14.6 (95% CI 5.5; 38.6) per 1000 person-years. Notably, this survey showed that there is great heterogeneity regarding time of initiation and duration of thromboprophylaxis in expert centers throughout Europe.

Congenital adrenal hyperplasia in patients with adrenal tumors: a population-based case-control study.

PURPOSE: Congenital adrenal hyperplasia (CAH) has been associated with adrenal tumors (ATs) but the relationship is still unclear. The aim was to investigate if CAH was more common in patients with adrenal tumors and their characteristics. METHODS: Using national registers all patients with an AT diagnosis (cases) and selected matched controls without AT diagnosis were included from 1st January 2005 to 31st December 2019. The patients with a CAH diagnosis were scrutinized in detail. RESULTS: ATs were diagnosed in 26,573 individuals and in none of 144,124 controls. In 20 patients with ATs and 1 control, a CAH diagnosis was present. The odds for having CAH in patients with ATs was 109 (95% CI 15-809; P < 0.0001). Among cases, 5 had a CAH diagnosis before the discovery of ATs and 15 afterwards. Half were females and two had been screened for CAH neonatally. The mean age when the ATs was discovered was 55.6 years. Adrenalectomy was performed in seven patients. Five patients had unilateral adrenalectomy before the CAH diagnosis and did not have any glucocorticoid protection. After the CAH diagnosis, 15 were initiated on glucocorticoids and 6 on mineralocorticoids. The majority diagnosed with CAH before index date had classic CAH. In individual diagnosed after index date, only three had classic CAH. The rest had nonclassical CAH. During the follow-up time of 9 years, six deceased, two of them in an adrenal crisis. CONCLUSIONS: The prevalence of CAH was greater in patients with ATs than in patients without. In all patients with ATs, CAH should be considered.

Gonadal function in adult male patients with congenital adrenal hyperplasia.

CONTEXT: Current knowledge on gonadal function in congenital adrenal hyperplasia (CAH) is mostly limited to single-center/country studies enrolling small patient numbers. Overall data indicate that gonadal function can be compromised in men with CAH. OBJECTIVE: To determine gonadal function in men with CAH within the European 'dsd-LIFE' cohort. DESIGN: Cross-sectional clinical outcome study, including retrospective data from medical records. METHODS: Fourteen academic hospitals included 121 men with CAH aged 16-68 years. Main outcome measures were serum hormone concentrations, semen parameters and imaging data of the testes. RESULTS: At the time of assessment, 14/69 patients had a serum testosterone concentration below the reference range; 7 of those were hypogonadotropic, 6 normogonadotropic and 1 hypergonadotropic. In contrast, among the patients with normal serum testosterone (55/69), 4 were hypogonadotropic, 44 normogonadotropic and 7 hypergonadotropic. The association of decreased testosterone with reduced gonadotropin concentrations (odds ratio (OR) = 12.8 (2.9-57.3)) was weaker than the association between serum androstenedione/testosterone ratio ≥1 and reduced gonadotropin concentrations (OR = 39.3 (2.1-732.4)). Evaluation of sperm quality revealed decreased sperm concentrations (15/39), motility (13/37) and abnormal morphology (4/28). Testicular adrenal rest tumor (TART)s were present in 39/80 patients, with a higher prevalence in patients with the most severe genotype (14/18) and in patients with increased current 17-hydroxyprogesterone 20/35) or androstenedione (12/18) serum concentrations. Forty-three children were fathered by 26/113 patients. CONCLUSIONS: Men with CAH have a high risk of developing hypothalamic-pituitary-gonadal disturbances and spermatogenic abnormalities. Regular assessment of endocrine gonadal function and imaging for TART development are recommended, in addition to measures for fertility protection.

Suboptimal psychosocial outcomes in patients with congenital adrenal hyperplasia: epidemiological studies in a nonbiased national cohort in Sweden.

CONTEXT: Congenital adrenal hyperplasia (CAH), CYP21A2 deficiency, results in cortisol and aldosterone deficiency and increased production of androgens, with a good genotype phenotype correlation. OBJECTIVE: The objective of the investigation was to study psychosocial outcomes in relation to clinical severity, CYP21A2 genotype, in men and women. DESIGN: This was an epidemiological study with a matched case control design. SETTING: The setting of the study was all known CAH patients in Sweden. PARTICIPANTS: Five hundred eighty-eight patients, more than 80% with known severity of CAH, and 100 controls per patient matched for sex, year, and place of birth participated in the study. MAIN OUTCOME AND MEASURES: Proxies for quality of life were selected: level of education, employment, income, sick leave, disability pension, marriage, and children. RESULTS: Women with salt-wasting (SW) CAH had completed primary education less often [odds ratio (OR) 0.3], not explained by neonatal salt crisis or hypoglycemia because the men did not differ from controls. Men and women in the less severe I172N genotype group were more likely to have an academic education (OR 1.8). SW women were more likely to have an income in the top 20th percentile (OR 2.0). Both men and women had more disability pension (OR 1.5) and sick leave (OR 1.7). The men more often had long-lasting employment (OR 3.1). Men were more often (OR 1.6) and women were less often married (OR 0.7). Patients had children less often (OR 0.3). CONCLUSIONS: This study shows important outcome differences regarding education; employment; marriage and fertility, depending on sex; and severity of CAH. The mechanisms behind this and the increased risk for sick leave or disability pension in both men and women should be identified to improve medical and psychological care.

Temporary elevated insulin-like growth factor I during lactation.

The measuring of hormones during lactation can result in interpretation difficulties. A 30-year-old woman presented with suspected jaw overgrowth and increased insulin-like growth factor I (IGF-I) (52 nmol/L; reference range 10-40 nmol/L). No other signs of acromegaly were found. She was breastfeeding eight times per day, and when she decreased her breastfeeding to three times per day, IGF-I decreased (41 nmol/L). After the cessation of lactation, IGF-I was normalised (22 nmol/L). No confounding factors which could affect the IGF-I levels, such as nutritional or metabolic factors, were found. Her menstrual cycle was regular all the time. Magnetic resonance imaging of the pituitary gland showed a probably unrelated microadenoma. All other pituitary hormones were normal, indicating that the microadenoma was non-functional. In conclusion, this unique case suggests an association between the frequency of lactation and IGF-I levels, and demonstrates the difficulties encountered when measuring hormones during breastfeeding.

Fertility and pregnancy outcome in women with congenital adrenal hyperplasia due to 21-hydroxylase deficiency.

BACKGROUND: Low pregnancy rate has been reported in women with congenital adrenal hyperplasia (CAH) and little information on pregnancy and children is known. METHODS: In a Swedish study, 62 adult women with CAH, aged 18-63 years, and 62 age-matched controls were followed-up. Medical records, including those concerning pregnancies and deliveries, were examined and the 21-hydroxylase genotype of patients was noted. All women answered a questionnaire concerning sexual and reproductive health including health of the children. RESULTS: Pregnancy and delivery rates were significantly lower in women with CAH (P < 0.001, P < 0.0056, respectively), and the severity of the 21-hydroxylase-mutation correlated with the reduced number of children born. More women with salt-wasting CAH were single and had not attempted pregnancy. Pregnancies were normal except for a significantly increased incidence of gestational diabetes in CAH patients (P < 0.0024). The children had normal birthweight and no malformations were observed. A later follow-up of the children showed a normal intellectual and social development. The sex ratio of the offspring differed significantly, with 25% boys in the CAH group compared with 56% among controls (P < 0.016). CAH women had more gynaecological morbidity during menopause. CONCLUSIONS: Pregnancy and delivery rates are reduced in women with CAH mainly due to psychosocial reasons. The outcome of children did not differ from controls. The unexpected sex ratio in children born to mothers with CAH warrants further research.

A 31-year-old woman with infertility and polycystic ovaries diagnosed with non-classic congenital adrenal hyperplasia due to a novel CYP21 mutation.

A 31-yr-old woman presenting with a history of hirsutism, amenorrhea, and infertility was previously assumed to have polycystic ovary syndrome. A new gynecological-endocrine evaluation demonstrated elevated testosterone/SHBG ratio, serum 17-hydroxyprogesterone (17-OHP), and urinary pregnantriol. She was diagnosed with non-classic congenital adrenal hyperplasia. In spite of treatment with dexamethasone and fludrocortisone in doses that suppressed adrenal androgens and 17-OHP into normal range or below, she did not ovulate. Clomiphene citrate and then FSH/hCG treatment in several cycles gave no consistent ovulation. Progesterone levels remained elevated throughout the cycles indicating a possible contribution from the adrenals. Oral glucose tolerance was normal, but the homeostasis model assessment index indicated insulin resistance. With metformin 1500 mg daily the index decreased remarkably from 2.77 to 0.96 with a few ovulations but no pregnancy occurred. Three cycles of IVF treatment thereafter were unsuccessful. Three months after the last in vitro fertilization (IVF) cycle, still on dexamethasone, fludrocortisone, and metformin, her menstruations became regular and she thereafter became pregnant. During pregnancy metformin was discontinued and dexamethasone replaced with prednisolone. Mild gestational diabetes developed and insulin was given. A healthy boy was born at term by elective Cesarean section. A CYP21- gene analysis had not indicated any of the known mutations but after gene sequencing a novel mutation was found, namely R233G. This case confirms the necessity of adding an analysis of 17-OHP when evaluating women with hirsutism and menstrual disturbances and if an elevated value is found, the advantage of performing a mutation analysis to facilitate counseling and decisions on treatment.

Genetic influences of the intercellular adhesion molecule 1 (ICAM-1) gene polymorphisms in development of Type 1 diabetes and diabetic nephropathy.

AIM: The intercellular adhesion molecule-1 (ICAM-1) gene is located on chromosome 19p13, which is linked to Type 1 diabetes (T1D). ICAM-1 expression is related to development of T1D and diabetic nephropathy. The present study aims to evaluate the genetic influence of ICAM-1 gene polymorphisms on the development of T1D and diabetic nephropathy. METHODS: Five valid single nucleotide polymorphisms (SNPs) were genotyped in 432 T1D patients (196 patients had diabetic nephropathy) and 187 non-diabetic control subjects by using dynamic allele-specific hybridization (DASH) and pyrosequencing. RESULTS: SNPs rs281432(C/G) and rs5498 E469K(A/G) had high heterozygous indexes. They were significantly associated with T1D [P = 0.026, OR = 1.644 (95% CI 1.138-2.376) and P < 0.001, OR = 2.456 (1.588-3.8)]. Frequencies of the C allele in SNP rs281432(C/G) and the A allele in SNP rs5498 E469K(A/G) increased stepwise from non-diabetic control subjects to T1D patients without diabetic nephropathy and T1D patients with diabetic nephropathy. Further analysis for these two SNPs indicated that T1D patients had increased frequency of the common haplotype C-A, in comparison with non-diabetic control subjects (38.1 vs. 32.1%, P = 0.035). CONCLUSION: The present study provided evidence that SNPs rs281432(C/G) and rs5498 E469K(A/G) in the ICAM-1 gene confer susceptibility to the development of T1D and might also be associated with diabetic nephropathy in Swedish Caucasians.

An 88-year-old woman diagnosed with adrenal tumor and congenital adrenal hyperplasia: connection or coincidence?

An 88-yr-old woman presented with a 3x4x5 cm adrenal incidentaloma. Apart from partial cortisol deficiency there were no clinical or laboratory signs of abnormal hormone production. Because of suspicion of carcinoma, a urinary steroid profile was carried out which indicated 21-hydroxylase deficiency with elevated pregnantriol. Biopsy of the tumor showed benign adenoma tissue. The genetic analysis showed two mutations in the CYP21-gene, V281L and 1172N consistent with mild non-classic congenital adrenal hyperplasia (CAH). The patient showed a general improvement with a low prednisolone dose. Previous reports have shown increased prevalence of CAH in patients with adrenal tumors although, to our knowledge, no one has reported the combination in a patient as old as in ours. Thus, clinical signs and symptoms of CAH should be looked for in patients with adrenal incidentalomas, even in the very old ones, and if suspicion further diagnostic work-up should be carried out to provide adequate treatment and follow-up.