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Molecular and Cellular Endocrinology Jul 2024Hyperandrogenic disorders, such as polycystic ovary syndrome, are often associated with metabolic disruptions such as insulin resistance and hyperinsulinemia. Studies in...
Hyperandrogenic disorders, such as polycystic ovary syndrome, are often associated with metabolic disruptions such as insulin resistance and hyperinsulinemia. Studies in sheep, a precocial model of translational relevance, provide evidence that in utero exposure to excess testosterone during days 30-90 of gestation (the sexually dimorphic window where males naturally experience elevated androgens) programs insulin resistance and hyperinsulinemia in female offspring. Extending earlier findings that adverse effects of testosterone excess are evident in fetal day 90 pancreas, the end of testosterone treatment, the present study provides evidence that transcriptomic and phenotypic effects of in utero testosterone excess on female pancreas persist after cessation of treatment, suggesting lasting organizational changes, and induce a male-like phenotype in female pancreas. These findings demonstrate that the female pancreas is susceptible to programmed masculinization during the sexually dimorphic window of fetal development and shed light on underlying connections between hyperandrogenism and metabolic homeostasis.
Topics: Animals; Female; Testosterone; Sheep; Transcriptome; Pregnancy; Pancreas; Male; Prenatal Exposure Delayed Effects; Insulin Resistance; Hyperandrogenism; Fetal Development; Sex Characteristics
PubMed: 38588858
DOI: 10.1016/j.mce.2024.112234 -
Endocrine Apr 2024Congenital adrenal hyperplasia (CAH) is a group of disorders that affect the production of steroids in the adrenal gland and are inherited in an autosomal recessive...
BACKGROUND AND AIMS
Congenital adrenal hyperplasia (CAH) is a group of disorders that affect the production of steroids in the adrenal gland and are inherited in an autosomal recessive pattern. The clinical and biochemical manifestations of the disorder are diverse, ranging from varying degrees of anomalies of the external genitalia to life-threatening adrenal insufficiency. This multicenter study aimed to determine the demographics, biochemical, clinical, and genetic characteristics besides the current status of adult patients with CAH nationwide.
METHODS
The medical records of 223 patients with all forms of CAH were evaluated in the study, which included 19 adult endocrinology clinics. A form inquiring about demographical, etiological, and genetic (where available) data of all forms of CAH patients was filled out and returned by the centers.
RESULTS
Among 223 cases 181 (81.16%) patients had 21-hydroxylase deficiency (21OHD), 27 (12.10%) had 11-beta-hydroxylase deficiency (110HD), 13 (5.82%) had 17-hydroxylase deficiency (17OHD) and 2 (0.89%) had 3-beta-hydroxysteroid-dehydrogenase deficiency. 21OHD was the most prevalent CAH form in our national series. There were 102 (56.4%) classical and 79 (43.6%) non-classical 210HD cases in our cohort. The age of the patients was 24.9 ± 6.1 (minimum-maximum: 17-44) for classical CAH patients and 30.2 ± 11.2 (minimum-maximum: 17-67). More patients in the nonclassical CAH group were married and had children. Reconstructive genital surgery was performed in 54 (78.3%) of classical CAH females and 42 (77.8%) of them had no children. Thirty-two (50.8%) NCAH cases had homogenous and 31 (49.2%) had heterogeneous CYP21A2 gene mutations. V281L pathological variation was the most prevalent mutation, it was detected in 35 (55.6%) of 21OHD NCAH patients.
CONCLUSION
Our findings are compatible with the current literature except for the higher frequency of 110HD and 17OHD, which may be attributed to unidentified genetic causes. A new classification for CAH cases rather than classical and non-classical may be helpful as the disease exhibits a large clinical and biochemical continuum. Affected cases should be informed of the possible complications they may face. The study concludes that a better understanding of the clinical characteristics of patients with CAH can improve the management of the disorder in daily practice.
PubMed: 38587785
DOI: 10.1007/s12020-024-03799-z -
European Journal of Endocrinology Mar 2024Patients with congenital adrenal hyperplasia (CAH) require life-long glucocorticoid replacement, including stress dosing (SD). This study prospectively assessed adrenal... (Observational Study)
Observational Study
OBJECTIVE
Patients with congenital adrenal hyperplasia (CAH) require life-long glucocorticoid replacement, including stress dosing (SD). This study prospectively assessed adrenal crisis (AC) incidence, frequency, and details of SD and disease knowledge in adult and paediatric patients and their parents.
DESIGN
Prospective, observational study.
METHODS
Data on AC and SD were collected via a patient diary. In case of AC, medical records were reviewed and patient interviews conducted. Adherence to sick day rules of the German Society of Endocrinology (DGE) and disease knowledge using the German version of the CAH knowledge assessment questionnaire (CAHKAQ) were assessed.
RESULTS
In 187 adult patients, the AC incidence was 8.4 per 100 patient years (py) and 5.1 in 100 py in 38 children. In adults, 195.4 SD episodes per 100 py were recorded, in children 169.7 per 100 py. In children 72.3% and in adults 34.8%, SD was performed according to the recommendations. Children scored higher on the CAHKAQ than adults (18.0 [1.0] vs 16.0 [4.0]; P = .001). In adults, there was a positive correlation of the frequency of SD and the incidence of AC (r = .235, P = .011) and CAHKAQ score (r = .233, P = .014), and between the incidence of AC and CAHKAQ (r = .193, P = .026).
CONCLUSION
The AC incidence and frequency of SD in children and adults with CAH are high. In contrast to the paediatric cohort, the majority of SD in adults was not in accordance with the DGE recommendations, underlining the need for structured and repeated education of patients with particular focus on transition.
Topics: Adult; Child; Humans; Adrenal Hyperplasia, Congenital; Prospective Studies; Adrenal Insufficiency; Glucocorticoids; Acute Disease
PubMed: 38584334
DOI: 10.1093/ejendo/lvae023 -
Giant Bilateral Adrenal Myelolipomas in a Non-Compliant Patient with Congenital Adrenal Hyperplasia.The American Journal of Case Reports Apr 2024BACKGROUND 21-hydroxylase deficiency, an essential enzyme for glucocorticoid and mineralocorticoid synthesis, is the cause of congenital adrenal hyperplasia (CAH) in...
BACKGROUND 21-hydroxylase deficiency, an essential enzyme for glucocorticoid and mineralocorticoid synthesis, is the cause of congenital adrenal hyperplasia (CAH) in more than 95% of cases. It is an autosomal recessive disorder encoded by the CYP21A2 gene, categorized into classical forms, which encompass the salt-wasting (SW) and simple virilizing (SV) forms, as well as the nonclassical form (NC). The aim of medical treatment is to replace missing glucocorticoids and, if necessary, mineralocorticoids, while also reducing elevated adrenal androgens. CASE REPORT We present the case of a 42-year-old woman with CAH who discontinued therapy during adolescence and was admitted to hospital with fatigue, nausea, and severe abdominal pain. A CT scan showed an extreme enlargement of the adrenal glands. Laboratory tests revealed elevated levels of 17-hydroxyprogesterone and other adrenal androgens, along with normal plasma metanephrine levels. Decreased morning cortisol levels suggested partial adrenal insufficiency requiring glucocorticoid replacement therapy. Due to the development of several serious complications and clinical deterioration, the multidisciplinary team recommended bilateral removal of masses measuring 300×250×200 mm on the right side and 250×200×200 mm on the left side. Histological and immunochemical examination confirmed the presence of giant myelolipomas with adrenal cortex hyperplasia. CONCLUSIONS Adrenal tumors, particularly myelolipomas, have a higher prevalence in patients with CAH. Our case report provides further evidence of the suspected link between non-compliant CAH therapy and the development of myelolipomas, along with promotion of their pronounced growth.
Topics: Adult; Female; Humans; Adrenal Gland Neoplasms; Adrenal Glands; Adrenal Hyperplasia, Congenital; Glucocorticoids; Lipoma; Myelolipoma; Steroid 21-Hydroxylase
PubMed: 38582958
DOI: 10.12659/AJCR.943005 -
Anales de Pediatria May 2024
Topics: Humans; Adrenal Gland Neoplasms; Virilism; Female; Diagnosis, Differential; Adrenal Hyperplasia, Congenital
PubMed: 38580598
DOI: 10.1016/j.anpede.2024.03.019 -
Pediatric Annals Apr 2024Acne is a common skin condition in adolescent patients but much less common in childhood. Pediatric providers should be familiar with the varying presentations in the...
Acne is a common skin condition in adolescent patients but much less common in childhood. Pediatric providers should be familiar with the varying presentations in the pediatric population and recognize when additional physical signs of hyperandrogenism are present. This article details the pathogenesis and presentation of acne in infancy, mid-childhood, and preadolescence. The differential diagnosis is discussed and recommendations for initial workup, referral, and treatment are provided. .
Topics: Adolescent; Child; Humans; Acne Vulgaris; Hyperandrogenism; Diagnosis, Differential; Referral and Consultation
PubMed: 38574069
DOI: 10.3928/19382359-20240205-05 -
Clinical Endocrinology Jun 2024To investigate the metabolic, cardiovascular, and neuropsychological phenotype, quality of life (QoL), and hormonal regulation in individuals with congenital adrenal...
OBJECTIVE
To investigate the metabolic, cardiovascular, and neuropsychological phenotype, quality of life (QoL), and hormonal regulation in individuals with congenital adrenal hyperplasia (CAH), a group of autosomal recessive disorders characterized by impaired synthesis of cortisol in the adrenal cortex and, if untreated compensatory hyperandrogenism. CAH is associated with an increased cardiovascular and metabolic morbidity, possibly due to overtreatment with glucocorticoids, leading to weight gain, insulin resistance, and metabolic syndrome.
DESIGN, PARTICIPANTS, MEASUREMENTS
Thirty-seven individuals with CAH and 33 age- and sex-matched controls were evaluated at a single centre at Aarhus University Hospital with echocardiography, electrocardiogram, 24-h blood pressure, biochemistry, anthropometrics, and autism spectrum, anxiety, depression, personality, cognitive failures, and QoL were assessed using questionnaires.
RESULTS
CAH individuals had lower height than controls (170.5 vs. 182.9 cm in males and 160.2 vs. 170.1 cm in females, p < 0.01). Compared with female controls, females with CAH had higher haemoglobin (8.8 vs. 8.2 mmol/L, p = 0.003) and BMI (29.7 vs. 25.5 kg/m, p = 0.006), reduced insulin sensitivity (HOMA-IR): 2.7 vs. 1.9, p = 0.018), prolonged E-wave deceleration time (193 vs. 174 cm, p = 0.015), and E/é ratios (5.4 vs. 4.5, p = 0.017), and lower self-reported QoL. Males with CAH had more cognitive complaints (p = 0.034) and higher autistic scores (19.9 vs. 14.9; p = 0.068) compared with male controls. More individuals with CAH than controls reported writing problems.
CONCLUSION
A sex-specific comorbidity profile is evident in CAH, with females presenting with decreased metabolic and overall self-reported health, whereas males with CAH presented with increased cognitive complaints and autistic traits.
Topics: Humans; Adrenal Hyperplasia, Congenital; Female; Male; Adult; Quality of Life; Middle Aged; Young Adult; Case-Control Studies
PubMed: 38572909
DOI: 10.1111/cen.15055 -
Current Cardiology Reports Jun 2024Polycystic ovary syndrome (PCOS) is a prevalent endocrine disorder in women of reproductive age. It has been associated with metabolic, reproductive, and psychiatric... (Review)
Review
PURPOSE OF REVIEW
Polycystic ovary syndrome (PCOS) is a prevalent endocrine disorder in women of reproductive age. It has been associated with metabolic, reproductive, and psychiatric disorders. Despite its association with insulin resistance (IR) and cardiovascular disease (CVD) risk factors, the association between PCOS and CVD outcomes has been conflicting. This review reports the updated evidence between PCOS, insulin resistance, and CVD events.
RECENT FINDINGS
IR is highly prevalent occurring in 50 to 95% of general and obese PCOS women. The etiology of PCOS involves IR and hyperandrogenism, which lead to CVD risk factors, subclinical CVD, and CVD outcomes. Multiple studies including meta-analysis confirmed a strong association between PCOS and CVD events including ischemic heart disease, stroke, atrial fibrillation, and diabetes, particularly among premenopausal women, and these associations were mediated by metabolic abnormalities. PCOS is highly familial and has substantial CVD risk and transgenerational effects regardless of obesity. A personalized approach to the CVD risk assessment and management of symptom manifestations should be conducted according to its phenotypes. Lifestyle modifications and reduction in environmental stressors should be encouraged for CVD prevention among PCOS women.
Topics: Humans; Polycystic Ovary Syndrome; Insulin Resistance; Female; Cardiovascular Diseases; Obesity; Risk Factors; Risk Assessment; Heart Disease Risk Factors; Prevalence; Hyperandrogenism
PubMed: 38568339
DOI: 10.1007/s11886-024-02050-5 -
Molecular Therapy. Methods & Clinical... Jun 2024Despite the availability of life-saving corticosteroids for 70 years, treatment for adrenal insufficiency is not able to recapitulate physiological diurnal cortisol...
Despite the availability of life-saving corticosteroids for 70 years, treatment for adrenal insufficiency is not able to recapitulate physiological diurnal cortisol secretion and results in numerous complications. Gene therapy is an attractive possibility for monogenic adrenocortical disorders such as congenital adrenal hyperplasia; however, requires further development of gene transfer/editing technologies and knowledge of the target progenitor cell populations. Vectors based on adeno-associated virus are the leading system for direct gene delivery but have limitations in targeting replicating cell populations such as in the adrenal cortex. One strategy to overcome this technological limitation is to deliver the relevant adrenocortical gene to a currently targetable organ outside of the adrenal cortex. To explore this possibility, we developed a vector encoding human 21-hydroxylase and directed expression to the liver in a mouse model of congenital adrenal hyperplasia. This extra-adrenal expression resulted in reconstitution of the steroidogenic pathway. Aldosterone and renin levels normalized, and corticosterone levels improved sufficiently to reduce adrenal hyperplasia. This strategy could provide an alternative treatment option for monogenic adrenal disorders, particularly for mineralocorticoid defects. These findings also demonstrate, when targeting the adrenal gland, that inadvertent liver transduction should be precluded as it may confound data interpretation.
PubMed: 38558568
DOI: 10.1016/j.omtm.2024.101232 -
Journal of Pediatric Endocrinology &... May 2024The most suitable biochemical markers for therapy adjustment in patients with congenital adrenal hyperplasia are controversial. 11-Oxygenated androgens are a promising...
OBJECTIVES
The most suitable biochemical markers for therapy adjustment in patients with congenital adrenal hyperplasia are controversial. 11-Oxygenated androgens are a promising new approach. The objective of this study was to investigate the diurnal rhythm of 11-ketotestosterone in children and adolescents in saliva and to correlate it with salivary 17-hydroxyprogesterone.
METHODS
Fifty-one samples of steroid day-profiles from 17 patients were additionally analysed for 11-ketotestosterone, retrospectively. All patients were treated in our university outpatient clinic for paediatric endocrinology between 2020 and 2022. Steroid day-profiles of 17 patients could be examined. The cohort showed a balanced sex ratio. The median age was 13 years. The measurements for 17-hydroxyprogesterone were carried out during routine care by immunoassay. The measurements of 11-ketotestosterone were performed from frozen saliva samples using an implemented in-house protocol for liquid chromatography-tandem mass spectrometry (LC-MS/MS). The most important outcome were the absolute values for 11-ketotestosterone, their diurnal rhythmicity and the correlation with 17-hydroxyprogesterone.
RESULTS
Both steroids show a circadian diurnal rhythm. 17-hydroxyprogesterone and 11-ketotestosterone correlate significantly. 11-Ketotestosterone showed a positive correlation with BMI at all times of the day.
CONCLUSIONS
11-Ketotestosterone shows circadian rhythmicity in our cohort and correlates with 17-hydroxyprogesterone. These findings serve as an important basis for prospective research into 11-oxygenated androgens as therapeutic markers in paediatrics. However, 11-ketotestosterone appears to be very dependent on BMI.
Topics: Humans; Adrenal Hyperplasia, Congenital; Female; Saliva; 17-alpha-Hydroxyprogesterone; Male; Adolescent; Circadian Rhythm; Child; Testosterone; Retrospective Studies; Biomarkers; Prognosis; Follow-Up Studies; Child, Preschool; Tandem Mass Spectrometry
PubMed: 38557593
DOI: 10.1515/jpem-2024-0027