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Frontiers in Endocrinology 2024Prenatal-onset androgen excess leads to abnormal sexual development in 46,XX individuals. This androgen excess can be caused endogenously by the adrenals or gonads or by... (Review)
Review
Prenatal-onset androgen excess leads to abnormal sexual development in 46,XX individuals. This androgen excess can be caused endogenously by the adrenals or gonads or by exposure to exogenous androgens. The most common cause of 46,XX disorders/differences in sex development (DSD) is congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency, comprising >90% of 46,XX DSD cases. Deficiencies of 11β-hydroxylase, 3β-hydroxysteroid dehydrogenase, and P450-oxidoreductase (POR) are rare types of CAH, resulting in 46,XX DSD. In all CAH forms, patients have normal ovarian development. The molecular genetic causes of 46,XX DSD, besides CAH, are uncommon. These etiologies include primary glucocorticoid resistance (PGCR) and aromatase deficiency with normal ovarian development. Additionally, 46,XX gonads can differentiate into testes, causing 46,XX testicular (T) DSD or a coexistence of ovarian and testicular tissue, defined as 46,XX ovotesticular (OT)-DSD. PGCR is caused by inactivating variants in , resulting in glucocorticoid insensitivity and the signs of mineralocorticoid and androgen excess. Pathogenic variants in the gene lead to aromatase deficiency, causing androgen excess. Many genes are involved in the mechanisms of gonadal development, and genes associated with 46,XX T/OT-DSD include translocations of the ; copy number variants in , , , , , and , and sequence variants in , , , , , , and . Progress in cytogenetic and molecular genetic techniques has significantly improved our understanding of the etiology of non-CAH 46,XX DSD. Nonetheless, uncertainties about gonadal function and gender outcomes may make the management of these conditions challenging. This review explores the intricate landscape of diagnosing and managing these conditions, shedding light on the unique aspects that distinguish them from other types of DSD.
Topics: Humans; Adrenal Hyperplasia, Congenital; 46, XX Disorders of Sex Development; Female; Male; Disorders of Sex Development
PubMed: 38812815
DOI: 10.3389/fendo.2024.1354759 -
Archives of Medical Research Jun 2024Few data are available on adrenal morphology in patients with acute diseases, although it is known that endogenous glucocorticoids are essential for survival under...
BACKGROUND
Few data are available on adrenal morphology in patients with acute diseases, although it is known that endogenous glucocorticoids are essential for survival under stress conditions and that an adequate response is driven by activation of the hypothalamic-pituitary-adrenal (HPA) axis.
AIMS
The aim of this study was to assess adrenal morphology in patients with acute disease compared with patients with non-acute disease.
METHODS
This cross-sectional study included: 402 patients admitted to the emergency department (ED) for suspected SARS-CoV-2 infection (March-May, 2020) [main cohort]; 200 patients admitted to the ED for acute conditions (December 2018-February 2019) [control group A]; 200 outpatients who underwent radiological evaluation of non-acute conditions (January-February 2019) [control group B]. Chest and/or abdominal CT scans were reviewed to identify adrenal nodules or hyperplasia.
RESULTS
In the main cohort, altered adrenal morphology was found in 24.9% of the patients (15.4% adrenal hyperplasia; 9.5% adrenal nodules). The frequency of adrenal hyperplasia was higher both in the main cohort (15.4%) and control group A (15.5%) compared to control group B (8.5%; p = 0.02 and p = 0.03, respectively). In the main cohort, 14.9% patients died within 30 d. According to a multivariate analysis, adrenal hyperplasia was an independent risk factor for mortality (p = 0.04), as were older age (p <0.001) and active cancer (p = 0.01).
CONCLUSIONS
The notable frequency of adrenal hyperplasia in patients with acute diseases suggests an exaggerated activation of the HPA axis due to stressful conditions. The increased risk of short-term mortality found in patients with adrenal hyperplasia suggests that it may be a possible hallmark of worse prognosis.
Topics: Humans; COVID-19; Male; Female; Middle Aged; Emergency Service, Hospital; Aged; Cross-Sectional Studies; Hyperplasia; Adrenal Glands; Adult; SARS-CoV-2; Aged, 80 and over; Tomography, X-Ray Computed
PubMed: 38805767
DOI: 10.1016/j.arcmed.2024.103010 -
JCEM Case Reports Jun 2024A mutation in the steroidogenic acute regulatory protein () gene, which encodes a protein that plays a crucial role in steroid hormone synthesis, causes a severe form of...
A mutation in the steroidogenic acute regulatory protein () gene, which encodes a protein that plays a crucial role in steroid hormone synthesis, causes a severe form of congenital adrenal hyperplasia (CAH) known as lipoid CAH (LCAH). LCAH presents with primary adrenal insufficiency (PAI) as well as atypical genitalia. Individuals with LCAH require adrenal steroid hormone supplements for survival. Masculinization in males with deficiency varies from incomplete to normal virilization. Radiological examinations reveal enlarged and lipid-laden adrenals. A 10-year-old boy born of second-degree consanguinity presented with weight gain and hyperpigmentation for 1 year. He was diagnosed with PAI at age 7 months and treated with hydrocortisone and fludrocortisone. Dynamic adrenal gland testing revealed undetectable hormone reserves. Imaging detected hypoplastic adrenals and a small testis with testicular adrenal rests (TART). Genetic analysis indicated a novel homozygous pathogenic variant of in exon 7, c.814C > G(pArg272Gly) associated with LCAH (OMIM No. 201710). Testing revealed that asymptomatic family members and relatives were heterozygotes for the variant. The patient was diagnosed with nonclassic LCAH with hypoplastic adrenals and TART. Adequate hormone supplementation resulted in TART regression. This genetic variation is reported for the first time.
PubMed: 38803511
DOI: 10.1210/jcemcr/luae089 -
Scientific Reports May 2024Testicular adrenal rest tumor (TART) is a prevalent complication associated with congenital adrenal hyperplasia (CAH), culminating in gonadal dysfunction and...
Testicular adrenal rest tumor (TART) is a prevalent complication associated with congenital adrenal hyperplasia (CAH), culminating in gonadal dysfunction and infertility. Early hormonal intervention is preventive, but excessive glucocorticoid poses risks. Developing reliable methods for early TART diagnosis and monitoring is crucial. The present study aims to formulate a scoring system to identify high-risk infertility through analysis of TART ultrasound features. Grayscale and power Doppler ultrasound were employed in this retrospective study to evaluate testicular lesions in male CAH patients. Lesion assessment encompassed parameters such as range, echogenicity, and blood flow, and these were subsequently correlated with semen parameters. Results of 49 semen analyzes from 35 patients demonstrated a notable inverse correlation between lesion scores and both sperm concentration (r = - 0.83, P < 0.001) and progressive motility (r = - 0.56, P < 0.001). The ROC curve areas for evaluating oligospermia and asthenozoospermia were calculated as 0.94 and 0.72, respectively. Establishing a lesion score threshold of 6 revealed a sensitivity of 75.00% and specificity of 93.94% for oligospermia and a sensitivity of 53.85% and specificity of 100.00% for asthenozoospermia. These findings underscore the potential utility of incorporating ultrasound into routine CAH patient management, facilitating timely interventions to preserve male fertility.
Topics: Humans; Male; Adrenal Hyperplasia, Congenital; Adult; Retrospective Studies; Infertility, Male; Ultrasonography; Risk Assessment; Semen Analysis; Testis; Young Adult; Adrenal Rest Tumor
PubMed: 38802468
DOI: 10.1038/s41598-024-62954-8 -
JCEM Case Reports Jun 2024We present the case of a 20-year-old woman with classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency, with uncontrolled hyperandrogenemia despite...
We present the case of a 20-year-old woman with classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency, with uncontrolled hyperandrogenemia despite supraphysiological glucocorticoid therapy. We used abiraterone acetate, an inhibitor of the 17-hydroxylase/17,20-lyase enzyme, to suppress adrenal androgen synthesis and allow physiological glucocorticoid and mineralocorticoid therapy, as a proof-of-concept, before proceeding to bilateral adrenalectomy. We report the patient's clinical course, the changes in adrenal steroids, and the immunohistochemistry of the adrenals.
PubMed: 38798742
DOI: 10.1210/jcemcr/luae077 -
F&S Science May 2024To investigate potential differences in pregnancy, delivery, and neonatal outcomes between 2 hyperandrogenic conditions in reproductive-aged women: polycystic ovary...
OBJECTIVE
To investigate potential differences in pregnancy, delivery, and neonatal outcomes between 2 hyperandrogenic conditions in reproductive-aged women: polycystic ovary syndrome (PCOS) and congenital adrenal hyperplasia (CAH).
DESIGN
Retrospective population-based study with data from the Health Care Cost and Utilization Project-Nationwide Inpatient Sample Database from 2004-2014.
SETTING
Not applicable.
PATIENT(S)
A total of 14,881 women with PCOS and 298 women with CAH.
INTERVENTION(S)
Not applicable.
MAIN OUTCOME MEASURE(S)
Gestational diabetes mellitus, placenta previa, pregnancy-induced hypertension (HTN), gestational HTN, preeclampsia, eclampsia, preeclampsia and eclampsia superimposed on HTN, preterm birth, preterm premature rupture of membrane, abruptio placenta, chorioamnionitis, mode of delivery, maternal infection, hysterectomy, blood transfusion, venous thromboembolism (deep vein thrombosis and pulmonary embolism during pregnancy, intrapartum, or postpartum), maternal death, chorioamnionitis, septicemia during labor, postpartum endometritis, septic pelvic, peritonitis, small for gestational age, congenital anomalies, and intrauterine fetal demise.
RESULT(S)
After adjusting for potential confounders, we found that women with PCOS were at increased risk of developing pregnancy-induced HTN (adjusted odds ratio [OR] = 1.76; 95% confidence interval [CI]: 1.12-2.77) and gestational diabetes (adjusted OR = 1.68; 95% CI: 1.12-2.52) when compared with women with CAH. Contrary women with CAH were at increased risk for delivery via cesarean section (adjusted OR = 0.59; 95% CI: 0.44-0.80) and small for gestational age neonates (adjusted OR = 0.32; 95% CI: 0.20-0.52).
CONCLUSION(S)
To our knowledge, this study is the first to directly compare obstetric and neonatal outcomes between patients with PCOS and CAH. Despite the similar phenotypes and some common hormonal and biochemical profiles, such as insulin resistance, hyperinsulinemia, and hyperandrogenism, our results suggest the existence of additional metabolic pathways implicated in the pathogenesis of pregnancy complications.
PubMed: 38795844
DOI: 10.1016/j.xfss.2024.05.001 -
International Journal of Molecular... May 2024Congenital Adrenal Hyperplasia (CAH) is an autosomal recessive disorder impairing cortisol synthesis due to reduced enzymatic activity. This leads to persistent...
Congenital Adrenal Hyperplasia (CAH) is an autosomal recessive disorder impairing cortisol synthesis due to reduced enzymatic activity. This leads to persistent adrenocortical overstimulation and the accumulation of precursors before the blocked enzymatic step. The predominant form of CAH arises from mutations in , causing 21-hydroxylase deficiency (21-OHD). Despite emerging treatment options for CAH, it is not always possible to physiologically replace cortisol levels and counteract hyperandrogenism. Moreover, there is a notable absence of an effective in vivo model for pre-clinical testing. In this work, we developed an animal model for CAH with the clinically relevant point mutation p.R484Q in the previously humanized mouse strain. Mutant mice showed hyperplastic adrenals and exhibited reduced levels of corticosterone and 11-deoxycorticosterone and an increase in progesterone. Female mutants presented with higher aldosterone concentrations, but blood pressure remained similar between wildtype and mutant mice in both sexes. Male mutant mice have normal fertility with a typical testicular appearance, whereas female mutants are infertile, exhibit an abnormal ovarian structure, and remain in a consistent diestrus phase. Conclusively, we show that the animal model has the potential to contribute to testing new treatment options and to prevent comorbidities that result from hormone-related derangements and treatment-related side effects in CAH patients.
Topics: Animals; Adrenal Hyperplasia, Congenital; Disease Models, Animal; Steroid 21-Hydroxylase; Mice; Female; Male; Humans; Corticosterone; Aldosterone; Adrenal Glands; Mutation; Progesterone
PubMed: 38791102
DOI: 10.3390/ijms25105062 -
Current Issues in Molecular Biology May 2024Congenital adrenal hyperplasia (CAH) is a group of autosomal recessive genetic defects in cortisol synthesis and shows elevated ACTH concentrations, which in turn has...
Congenital adrenal hyperplasia (CAH) is a group of autosomal recessive genetic defects in cortisol synthesis and shows elevated ACTH concentrations, which in turn has downstream effects. The most common variant of CAH, 21-hydroxylase deficiency (21OHD), is the result of pathogenic variants in the gene and is one of the most common monogenic disorders. However, the genetics of 21OHD is complex and challenging. The gene is located in the RCCX copy number variation (CNV), a complex, multiallelic, and tandem CNV in the major histocompatibility complex (MHC) class III region on chromosome 6 (band 6p21.3). Here, and its pseudogene are located 30 kb apart and share a high nucleotide homology of approximately 98% and 96% in exons and introns, respectively. This high-sequence homology facilitates large structural rearrangements, copy number changes, and gene conversion through intergenic recombination. There is a good genotype-phenotype correlation in 21OHD, and genotyping can be performed to confirm the clinical diagnosis, predict long-term outcomes, and determine genetic counseling. Thus, genotyping in CAH is clinically relevant but the interpretations can be challenging for non-initiated clinicians. Here, there are some concrete examples of how molecular diagnosis can sometimes require the use of multiple molecular strategies.
PubMed: 38785559
DOI: 10.3390/cimb46050291 -
Oxford Medical Case Reports May 2024We report the case of a 5-year-old boy diagnosed with congenital adrenal hyperplasia due to 11-hydroxylase deficiency, revealed by disorders of sex development (DSD) and...
We report the case of a 5-year-old boy diagnosed with congenital adrenal hyperplasia due to 11-hydroxylase deficiency, revealed by disorders of sex development (DSD) and acute pulmonary edema due to severe hypertension. We considered the diagnosis based on biological and radiological examinations. The sociocultural background and the delayed diagnosis had a significant impact on the therapeutic decisions. All babies should be screened for 11 beta-hydroxylase deficiency, there should be specialized and interdisciplinary medical centers, and early detection is essential to avoiding serious complications of this disease.
PubMed: 38784773
DOI: 10.1093/omcr/omae042 -
Frontiers in Endocrinology 2024Differences/disorders of sex development (DSD) comprise a large group of rare congenital conditions. 46,XX DSD, excluding congenital adrenal hyperplasia (CAH), represent... (Review)
Review
Differences/disorders of sex development (DSD) comprise a large group of rare congenital conditions. 46,XX DSD, excluding congenital adrenal hyperplasia (CAH), represent only a small number of these diseases. Due to the rarity of non-CAH 46,XX DSD, data on this sex chromosomal aberration were confined to case reports or case series with small numbers of patients. As the literature is still relatively sparse, medical data on the long-term effects of these pathologies remain scarce. In this review, we aim to provide an overview of current data on the long-term follow-up of patients with non-CAH 46,XX DSD, by covering the following topics: quality of life, gender identity, fertility and sexuality, global health, bone and cardiometabolic effects, cancer risk, and mortality. As non-CAH 46,XX DSD is a very rare condition, we have no accurate data on adult QoL assessment for these patients. Various factors may contribute to a legitimate questioning about their gender identity, which may differ from their sex assigned at birth. A significant proportion of gender dysphoria has been reported in various series of 46,XX DSD patients. However, it is difficult to give an accurate prevalence of gender dysphoria and gender reassignment in non-CAH 46,XX DSD because of the rarity of the data. Whatever the aetiology of non-CAH 46,XX DSD, fertility seems to be impaired. On the other hand, sexuality appears preserved in 46,XX men, whereas it is impaired in women with MRKH syndrome before treatment. Although there is still a paucity of data on general health, bone and cardiometabolic effects, and mortality, it would appear that the 46,XX DSD condition is less severely affected than other DSD conditions. Further structured and continued multi-center follow-up is needed to provide more information on the long-term outcome of this very rare non-CAH 46,XX DSD condition.
Topics: Female; Humans; Male; 46, XX Disorders of Sex Development; Adrenal Hyperplasia, Congenital; Disorders of Sex Development; Fertility; Gender Identity; Quality of Life
PubMed: 38752171
DOI: 10.3389/fendo.2024.1372887