Testicular Adrenal Rest Tumors Research Articles

Service evaluation suggests variation in clinical care provision in adults with congenital adrenal hyperplasia in the UK and Ireland.

Congenital adrenal hyperplasia (CAH) encompasses a rare group of autosomal recessive disorders, characterised by enzymatic defects in steroidogenesis. Heterogeneity in management practices has been observed internationally. The International Congenital Adrenal Hyperplasia registry (I-CAH, https://sdmregistries.org/) was established to enable insights into CAH management and outcomes, yet its global adoption by endocrine centres remains unclear. We sought (1) to assess current practices amongst clinicians managing patients with CAH in the United Kingdom and Ireland, with a focus on choice of glucocorticoid, monitoring practices and screening for associated co-morbidities, and (2) to assess use of the I-CAH registry. We designed and distributed an anonymised online survey disseminated to members of the Society for Endocrinology and Irish Endocrine Society to capture management practices in the care of patients with CAH. Marked variability was found in CAH management, with differences between general endocrinology and subspecialist settings, particularly in glucocorticoid use, biochemical monitoring and comorbidity screening, with significant disparities in reproductive health monitoring, notably in testicular adrenal rest tumours (TARTs) screening (p = .002), sperm banking (p = .0004) and partner testing for CAH (p < .0001). Adoption of the I-CAH registry was universally low. Differences in current management of CAH continue to exist. It appears crucial to objectify if different approaches result in different long-term outcomes. New studies such as CaHASE2, incorporating standardised minimum datasets including replacement therapies and monitoring strategies as well as longitudinal data collection, are now needed to define best-practice and standardise care.

[Testicular adrenal rest tumors (TARTs) and adrenogenital syndrome (AGS) - Do not mix up with malignant testicular tumors!]

Testicular adrenal rest tumors and adrenogenital syndrome (AGS) - Do not mix up with malignant testicular tumors! Testicular adrenal residual tumors (TARTs) frequently occur in men with adrenogenital syndrome. Without knowledge of AGS, diagnosis is problematic due to difficult differentiation from other testicular tumors. However, early treatment is crucial for maintaining or regaining fertility, among other aspects. This article provides background knowledge for general practitioners.

Quantitative Characterization of Ectopic Adrenal Gene Expression in Fetal Testes in 21-Hydroxylase Deficient Mice.

Testicular adrenal rest tumors (TART) are a frequent and fertility impairing long-term complication in males with classic congenital adrenal hyperplasia. Due to lack of clear experimental data on their origin, they are hypothesized to be derived from ectopic adrenocortical cells within testicular tissue mainly growing upon stimulation by chronically elevated levels of adrenocorticotropin (ACTH). Alternatively, a more totipotent embryological origin has been discussed as the potential source of these tumors. The aim of this study was to quantify alterations of ectopic expression of adrenocortical genes (CYP11B1, CYP11B2, CYP21, MC2R) and the Leydig cell specific marker (INSL3) in testicular tissue of fetal 21-hydroxylase deficient (21OHD) mice. Timed-pregnancy studies were performed using H-2aw18 (aw18)-mice. Testes and adrenals of E15.5 and E18.5 mouse fetuses were used for real-time PCR and immunohistochemistry. Gene expression levels were analyzed for genotype-dependent alterations and compared with immunohistochemistry. While enzymes of steroidogenesis showed a significant increased expression in adrenals of 21OHD mice at both E15.5 and E18.5 compared to wild-type (WT) mice, expression levels were unaltered in testes of 21OHD mice. When compared to WT adrenals a significant increase of INSL3 expression in adrenals of 21OHD mice at E15.5 and E18.5 was detected. Cells with adrenocortical properties in mice fetal testis differ from in situ adrenocortical cells in gene expression and growth at E15.5 and E18.5. These findings suggest that the different local regulation and different local niche in adrenals and testes influence growth of aberrant adrenal cells.

Bilateral giant adrenal myelolipoma associated with congenital adrenal hyperplasia

Adrenal myelolipomas are rare benign tumors, often non-functioning, located in the adrenal cortex, consisting mainly of mature adipose tissue and hematopoietic tissue. Although uncommon, the number of reported cases has increased due to the greater use of diagnostic imaging techniques. This tumor is usually unilateral and found as an adrenal incidentaloma, although there is a predominance of bilaterality in patients with congenital adrenal hyperplasia (CAH). In this study, we report the case of a 33-year-old male patient with CAH due to 21-hydroxylase deficiency, in non-regular use of the control medication, with bilateral giant adrenal myelolipoma and subsequent evolution of bilateral testicular adrenal rest tumors. He underwent bilateral adrenalectomy by video laparoscopy. The anatomopathological analysis, which confirmed myelolipomas’ diagnosis, revealed the right adrenal with 430 g and 12.5 x 9.3 cm and the left with 257 g and 11.5 x 10.4 cm. This tumor may be accompanied by adrenocortical adenoma and carcinoma, ganglioneuroma, pheochromocytoma, Addison’s disease, Cushing’s syndrome, or CAH.Among the hypotheses of its pathogenesis, we highlight an association between the development of adrenal myelolipoma and chronic hormonal stimulation by the adrenocorticotrophic hormone (ACTH), especially in CAH. The non-regular treatment of CAH with glucocorticoids may have contributed to the chronic and elevated secretion of ACTH and, consequently, to the development of bilateral giant adrenal myelolipoma.

Первичная надпочечниковая недостаточность с Х-сцепленным наследованием у детей

Primary adrenal insufficiency (PAI) is a rare pathology with a prevalence of 100 to 140 cases per one million. X-linked adrenoleukodystrophy (X-ALD) and X-linked congenital adrenal hypoplasia (X-CAH) are the leading pathologies among boys (after congenital cortical dysfunction adrenal glands) and account for 3.1% and 2.0% of all PAI, respectively. Establishing the PAI etiology is necessary to predict the course of the disease and adhere to special protocols for examining patients. The purpose of this research was to compare the PAI course in diseases with an X-linked type of inheritance. Materials and methods used: a single-center, one-stage observational comparative retrospective study was conducted in 25 male patients with genetically confirmed diagnoses of X-ALD, X-CAH and who had PAI as a component of the disease. The study was conducted at the Pediatric Endocrinology Institute with the Endocrinology Research Centre of the Ministry of Healthcare of Russia (Moscow, Russia) in 2019-2022 as well as based on the patients’ medical records that have been forwarded for a genetic search for the causes of adrenal insufficiency under the “Alfa-Endo” Charity Program for children with endocrine diseases in the same period of time. Results: X-ALD was detected in 11/25 (44%) patients, median age of manifestation was 6.2 [4.5; 7.2] y/o and 2 y/o was the earliest. A single patient with X-ALD was found to have TARTs (testicular adrenal rest tumors). X-CAH was diagnosed in the remaining 14/25 (56%) patients, median age of manifestation was 1.9 [0.04; 3.9] y/o, p=0.015. The oldest age of manifestation was 14 y/o. A single patient was found to have hypogonadotropic hypogonadism (HH) and another one had bilateral cryptorchidism. There were no statistically significant differences in symptoms, adrenocorticotropic hormone (ACTH), cortisol levels during the manifestation of PAI and doses of replacement therapy (p=0.756 for ACTH, p=0.591 for cortisol, p=0.825 for hydrocortisone and p=0.148 for fludrocortisone). Conclusion: it is necessary to exclude X-ALD and X-CAH when diagnosing PAI in boys regardless of the age of the disease manifestation. It is highly recommended to conduct a genetic study of a panel of genes responsible for the development of PAI in order to establish the PAI etiology, and regardless of the established PAI etiology it is necessary to perform an ultrasonic study of the testicles with the purpose of excluding the space-occupying formations. It is necessary to evaluate ACTH levels in patients with testicular masses for timely diagnosis of PAI and optimal treatment.

Evaluation of Ex Vivo Adrenocorticotropic Hormone Responsiveness of Human Fetal Testis.

Testicular adrenal rest tumors (TARTs), commonly occurring in males with congenital adrenal hyperplasia, may arise from chronic stimulation of adrenocorticotropic hormone (ACTH)-sensitive cells in the testes. It is not yet established whether the human fetal testis (HFT) is responsive to ACTH. To investigate this, we cultured HFT tissue with and without ACTH for up to 5 days, and quantified adrenal steroid hormones and expression of adrenal steroidogenic enzymes. Fetal testis and adrenal tissue produced high levels of testosterone and cortisol, respectively, indicating viability. In contrast to fetal adrenal tissues, the expression of ACTH receptor MC2R was either absent or expressed at extremely low levels in ex vivo HFT tissue and no clear response to ACTH in gene expression or steroid hormone production was observed. Altogether, this study suggests that the HFT is unresponsive to ACTH, which would indicate that a TART does not arise from fetal testicular cells chronically exposed to ACTH in utero.

Hormonal control during infancy and testicular adrenal rest tumor development in CAH males - a retrospective multi-center cohort study.

Testicular adrenal rest tumors (TART), often found in male patients with congenital adrenal hyperplasia (CAH), are benign lesions causing testicular damage and infertility. We hypothesize that chronically elevated adrenocorticotropic hormone (ACTH) exposure during early life may promote TART development. This study aimed to examine the association between commencing adequate glucocorticoid treatment early after birth and TART development. This retrospective multicenter (n = 22) open cohort study collected longitudinal clinical and biochemical data of the first 4 years of life using the I-CAH registry and included 188 male patients (median age 13 years; IQR: 10-17) with 21-hydroxylase deficiency (n = 181) or 11-hydroxylase deficiency (n = 7). All patients underwent at least one testicular ultrasound. TART were detected in 72 (38%) of the patients. Prevalence varied between centers. When adjusted for CAH phenotype, a delayed CAH diagnosis of more than 1 year, compared to a diagnosis within 1 month of life, was associated with a 2.6 times higher risk of TART diagnosis. TART onset was not predicted by biochemical disease control or bone age advancement in the first four years of life, but increased height SDS at the end of the four-year study period was associated with a 27% higher risk of TART diagnosis. A delayed CAH diagnosis of more than 1 year versus CAH diagnosis within one month after birth was associated with a higher risk of TART development, which may be attributed to poor disease control in early life.

SAT282 Hypogonadism In Men With Congenital Adrenal Hyperplasia. A Retrospective Longitudinal Analysis With A Special Focus On Testicular Adrenal Rest Tumors And 11-oxygenated Androgens

Abstract Disclosure: M.K. Auer: None. C. Lottspeich: None. M. Bidlingmaier: None. H.F. Nowotny: None. L. Tschaidse: None. R.J. Auchus: None. N. Reisch: None. Background: Hypogonadism is a common issue in men with congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency (21OHD). While this is mostly resulting from extra-gonadal steroid production, testicular function may also be impaired due to the presence of testicular adrenal rest tumors (TART). In addition to their local compressive effects, it has recently been demonstrated that TART are a source of 11-oxygenated androgens that might impair testicular function. Little is known about the long-term course of testicular function in men with 21OHD in general and the role of potential influential factors such as presence of TART and 11-oxygenated androgen formation in particular. Methods: Retrospective single-center study in 30 men with classic 21OHD (N = 11 with TART, N = 16 without TART, N = 3 unknown TART status). Median age at baseline was 31.0 years (IQR 26-38). Median observation period was 12 years (IQR 8-13). The median number of outpatient visits and blood samplings per patient during this time was 8.5 (IQR 6-10). Testosterone (T), 17-hydroxyprogesterone (17-OHP), androstenedione (A4) and 11-oxygenated androgens were measured simultaneously from stored serum samples by LC-MS/MS. Results: On average, 43.2% (No TART) and 54.6% (TART) of all T measurements in each patient were below the reference range (n.s.). In most patients, gonadotropin levels were normal or suppressed. In univariate as well as multivariate mixed model analysis, including age, BMI, type of glucocorticoid (GC), GC-equivalence dosage and phenotype (salt wasting vs simply virilizing), T levels were comparable between men with and without TART. While T levels remained stable during the observation period in men without TART (Baseline 11.37 ± 1.52 nmol/l, last visit 12.1 ± 2.1 nmol/l) they increased in those with TART (Baseline 9.48 ± 1.68 vs. last visit 14.9 ± 2.3 nmol/l (Time*Group F1,7.247 = 7.558; p = 0.006). At baseline, the A4/T-ratio as a marker of adrenal T production was significantly higher in men with TART (1.39 ± 1.63) than in those without (0.27 ± 1.63), and there was a Time*Group interaction, again indicating a decrease in the A4/T-ratio in men with TART (F1,47.843 = 2.008; p = 0.04). This resulted in only a trend for the A/T-ratio being higher in men with TART (0.5 ± 1.6 vs 0.3 ± 1.5; p = 0.057) across the whole observation period. 11-ketotestosterone levels were higher in men with TART (1.8 ± 0.006 pg/ml) than in men without TART (0.68 ± 0.006 nmol/l) but remained unchanged over time in both groups. Conclusion: A normal serum T does not exclude hypogonadotropic hypogonadism in men with 21OHD, which is a common problem that appears to remain stable in the long run. The presence of TART does not have a negative effect on T-levels. In contrast, the detection of TART should prompt further assessment, including A4, gonadotropins, and 11-ketotestosterone, followed by treatment optimization to improve gonadal T production. Presentation: Saturday, June 17, 2023

THU620 Metastatic Adrenocortical Carcinoma Arising From A Testicular Rest Tumor

Abstract Disclosure: L.E. Chozet: None. J.M. Bruder: None. R. Flores: None. S. Hackman: None. K. highes: None. L. Vasquez: None. G. Le: None. T. cortez: None. M.A. Escobar Vasco: None. Background: Congenital adrenal hyperplasia (CAH) involves a range of autosomal recessive disorders characterized by abnormalities in the adrenal biosynthesis pathway. Testicular adrenal rest tumors (TARTs) are a complication mostly seen in male patients with congenital adrenal hyperplasia which can lead to infertility. These tumors are known to have benign characteristics. We present a unique case of a male patient with CAH diagnosed with metastatic adrenocortical carcinoma arising from a TART. Clinical Case: A 40-year-old man with poorly controlled congenital adrenal hyperplasia from 21-hydroxylase deficiency and bilateral testicular adrenal rest tumors presented with syncope and worsening left testicular pain for 2 months. Scrotal ultrasound showed enlarged bilateral scrotal masses (left bigger than right). Initial evaluation for his syncopal event included CTA chest which showed an incidental finding of innumerable bilateral solid pulmonary nodules. 17-hydroxyprogesterone levels were elevated at 5273 ng/dL (normal less than 138 ng/dL). Additional biochemical workup of the testicular mass was unremarkable. The patient underwent left radical orchiectomy with pathology showing high-grade carcinoma with adrenocortical differentiation. A right upper lobe lung biopsy was done which demonstrated metastatic carcinoma with adrenocortical differentiation, morphologically similar to the testicular tumor. The initial patient presentation of progressively worsening left testicular pain in the setting of testicular adrenal rest tumors (TARTs) led to the diagnosis of adrenal carcinoma. Conclusion: This case presents a unique presentation of adrenal carcinoma in a patient with congenital adrenal hyperplasia arising in the setting of testicular adrenal rest tumors (TARTs). This case demonstrates a unique presentation of adrenal carcinoma, as malignant degeneration has not been described in patients with TARTs. It also highlights the importance of close monitoring even if these tumors are thought to be of benign origin. Presentation: Thursday, June 15, 2023

SAT286 Effect of Tildacerfont On Gonadotropins And Testicular Steroidogenesis In Men With Classic 21-hydroxylase Deficiency

Abstract Disclosure: R. Charlton: Employee; Self; Spruce Biosciences, Inc. A. Khattab: Consulting Fee; Self; Antares Pharma, Inc. R.J. Auchus: Grant Recipient; Self; Spruce Biosciences, Inc. Research Investigator; Self; Spruce Biosciences, Inc. Impaired testicular function is a common comorbidity of classic 21-hydroxylase deficiency (21OHD). Testicular adrenal rest tumors (TART) can disrupt testicular architecture and cause primary hypogonadism. Both supraphysiologic glucocorticoid doses and adrenal-derived androgens and estrogens can suppress gonadotropins and cause secondary hypogonadism. We conducted a post-hoc analysis of gonadal axis function in men with 21OHD participating in SPR001-201 and SPR001-202, two phase 2 studies of tildacerfont, a once-daily oral corticotrophin-releasing factor receptor 1 (CRFR1) antagonist, designed to reduce ACTH and adrenal steroid production, including androstenedione (A4). Study 201 included 3 cohorts: Cohort A, 5 men who received tildacerfont in a 6-week dose escalation - 2 weeks at 200 mg QD, 2 weeks at 600 mg QD, and 2 weeks at 1000 mg QD without washout between doses; Cohort B, 1 man who received tildacerfont for 2 weeks at 200 mg BID; and Cohort C, 4 men who received tildacerfont for 2 weeks at 100 mg BID. Study 202 included 4 men who received tildacerfont 400 mg QD for 12 weeks. Participants continued their previously prescribed glucocorticoid ± mineralocorticoid replacement without dose adjustments. Geometric means were used to describe hormone levels due to the small participant numbers. Mean and median ages were 46/32y in Study 201 and 32/35y in Study 202 (range 18-54 in both studies). All participants reported race as white except one who identified as white and Asian. Four reported ethnicity as Hispanic or Latino. At baseline, testosterone (T) levels were normal except for four 201 participants that had T &amp;lt;300 ng/dL. At baseline, 6/11 (55%) had suppressed LH (including the four with low T), and 11/14 (79%) had A4/T ratios &amp;gt;1, indicating a predominantly adrenal origin of T. In Study 201, mean T levels increased in Study 201 from 375.5 ng/dL to 390.5 ng/dL at week 2 (n=9), 485.4 ng/dL at week 4 (n=4) and 420.7 ng/dL at week 6 (n=4). In Study 202, mean T levels were 448.4 ng/dL at baseline and 412.0 ng/dL at week 12. Mean LH levels increased in Study 201 from 0.68 IU/L to 1.59 IU/L at week 2 (n=10), 1.62 IU/L at week 4 (n=5) and 0.85 IU/L at week 6 (n=4) (normal 1.8-8.6IU/L). In Study 202, mean LH levels increased from 0.44 IU/L at baseline to 0.87 IU/L at week 12. Of the four men who had low T and suppressed LH (hypogonadotropic hypogonadism), LH rose in all 4 and normalized in 3/4 (75%). Mean A4/T ratios decreased across both studies. In Study 201, the mean declined from a baseline of 1.28 to 0.59 at week 2 (n=9), 0.87 at week 4 (n=4), and 1.03 at week 6 (n=4). In Study 202, the A4/T ratio decreased from baseline of 2.44 to 0.68 at week 12. All the hypogonadal men experienced reductions in A4/T ratios, and 3/4 (75%) achieved A4/T &amp;lt;1. This post-hoc analysis highlights that gonadal axis disruption is common in men with 21OHD and suggests that modulation of adrenal androgen production via CRFR1 antagonism may improve testicular function. Presentation: Saturday, June 17, 2023

Testicular Adrenal Rest Tumors in Congenital Adrenal Hyperplasia: Study of a Cohort of Patients from a Single Italian Center.

Testicular adrenal rest tumors (TARTs) are a common complication in male patients with congenital adrenal hyperplasia (CAH). The aim of our cross-sectional cohort study is to estimate the frequency of TARTs with the correlation of genotype and disease control on tumor development. Thirty-five male patients, aged 14-26 years, were included in the study, all followed by the same center of pediatric endocrinology in Bologna. We studied genotypes, hormonal profiles at different time intervals and testicular ultrasound. A logistic regression model with multivariant analysis was developed for the statistical analysis. TARTs were detected in 31.4% of the cases, 90.9% of them had a classic form with salt wasting, while 9.1% had a non-classic form. Additionally, a significant correlation between the incidence of TARTs and severity of genotype was detected. Patients with TARTs had markedly worse metabolic control on average (p = 0.027), reflected by high ACTH, 17OH progesterone, and overall delta4-androstenedione. In conclusion, a screening tool is mandatory, especially (but not exclusively) in patients with the most severe forms of CAH and poor endocrine control of the disease.

Reduced serum concentrations of biomarkers reflecting Leydig and Sertoli cell function in male patients with congenital adrenal hyperplasia.

Congenital adrenal hyperplasia (CAH) is a recessive condition that affects the adrenal glands. Despite life-long replacement therapy with glucocorticoids and mineralocorticoids, adult patients with CAH often experience impaired gonadal function. In pubertal boys and in men with CAH, circulating testosterone is produced by the adrenal glands as well as the testicular, steroidogenic cells. In this European two-center study, we evaluated the function of Leydig and Sertoli cells in 61 boys and men with CAH, primarily due to 21-hydroxylase deficiency. Despite conventional hormone replacement therapy, our results indicated a significant reduction in serum concentrations of both Leydig cell-derived hormones (i.e. insulin-like factor 3 (INSL3) and testosterone) and Sertoli cell-derived hormones (i.e. inhibin B and anti-Müllerian hormone) in adult males with CAH. Serum concentrations of INSL3 were particularly reduced in those with testicular adrenal rest tumors. To our knowledge, this is the first study to evaluate circulating INSL3 as a candidate biomarker to monitor Leydig cell function in patients with CAH.

Congenital Adrenal Hyperplasia and Testicular Adrenal Rest Tumors Causing Infertility and Detected by 18F-FDG PET/CT

Congenital Adrenal Hyperplasia and Testicular Adrenal Rest Tumors Causing Infertility and Detected by 18F-FDG PET/CT

Approach to testicular adrenal rest tumors in children and adolescents with congenital adrenal hyperplasia

Testicular adrenal rest tumor (TART) is a long-standing, significant complication of congenital adrenal hyperplasia (CAH). Although it is the main reason for infertility in adult patients with CAH, little is known about the development mechanism, genotype-phenotype features, and exact treatment options of TART. However, in the literature, there are mainly case reports and only a few studies in the pediatric period on this subject. The critical point is the early detection of tumors to prevent infertility in adulthood. This paper reviews the embryological, clinical, diagnostic, genetic features, and treatment alternative of TART and discusses the early screening options.

Corticotropin releasing factor-1 receptor antagonism associated with favorable outcomes of male reproductive health biochemical parameters.

Disruption in androgen profiles and testicular adrenal rest tumors in males with congenital adrenal hyperplasia (CAH) can negatively affect sexual activity and fertility. Adrenal hyperandrogenism suppresses gonadotropin secretion and testicular adrenal rest tumors (TARTS), despite being noncancerous lesions, cause obstructive azoospermia and impaired testosterone (T) production. Circulating T in men with uncontrolled CAH is often predominantly adrenal in origin, which is reflected in high androstenedione/testosterone ratios (A4/T). Therefore, decreased luteinizing hormone (LH) levels and an increased A4/T are markers of impaired fertility in these individuals. Oral tildacerfont 200 to 1000 mg once daily (QD) (n=10) or 100 to 200 mg twice daily (n=9 and 7) for 2 weeks (Study 201), and 400 mg QD (n=11) for 12 weeks (Study 202). Outcomes measured changes from baseline in A4, T, A4/T, and LH. Mean T levels increased in Study 201 from 375.5 ng/dL to 390.5 ng/dL at week 2 (n=9), 485.4 ng/dL at week 4 (n=4) and 420.7 ng/dL at week 6 (n=4). In Study 202, T levels fluctuated in the normal range from 448.4 ng/dL at baseline to 412.0 ng/dL at week 12. Mean LH levels increased in Study 201 from 0.68 IU/L to 1.59 IU/L at week 2 (n=10), 1.62 IU/L at week 4 (n=5) and 0.85 IU/L at week 6 (n=4). In Study 202, mean LH levels increased from 0.44 IU/L at baseline to 0.87 IU/L at week 12. Mean A4/T decreased across both studies. In Study 201, the mean A4/T changed from a baseline of 1.28 to 0.59 at week 2 (n=9), 0.87 at week 4 (n=4), and 1.03 at week 6 (n=4). In Study 202, the A4/T decreased from baseline of 2.44 to 0.68 at week 12. Four men were hypogonadal at baseline; all experienced improved A4/T and 3/4 (75%) reached levels <1. Tildacerfont treatment demonstrated clinically meaningful reductions in A4 levels, and A4/T with concomitant increased LH levels indicating increased testicular T production. The data suggests improvement in hypothalamic-pituitary-gonadal axis function, but more data is required to confirm favorable male reproductive health outcomes.

Hypogonadism in men with congenital adrenal hyperplasia. A retrospective longitudinal analysis with a special focus on testicular adrenal rest tumors and 11-oxygenated androgens

Searchable abstracts of presentations at key conferences in endocrinology ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

The association between hormonal control during infancy and testicular adrenal rest tumor development in males with congenital adrenal hyperplasia

Searchable abstracts of presentations at key conferences in endocrinology ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

Risk factors for testicular adrenal rest tumors in pediatric patients with congenital adrenal hyperplasia

Testicular adrenal rest tumors (TARTs) predominantly occur in patients with congenital adrenal hyperplasia (CAH) and may interfere with the function of the testicles. This study aimed to identify the factors that contribute to the occurrence of TARTs in patients with CAH and influence their volume. This was a comparative cross-sectional study. Male patients aged 0-16 years with CAH were included. Weight, height, bone age determination, biochemical and androgenic profiles, and testicular ultrasound were performed. Patients were divided into those with and without TARTs and the between-group differences were assessed using the Mann-Whitey U test and Fisher's exact test. A ROC curve was created for serum ACTH levels to identify the cut-off point to diagnose TARTs. Variables that influenced the volume of the TARTs were identified using Spearman's correlation coefficient. TARTs were observed in seven (19.4%) of 36 male children with CAH. Of the patients with TARTs, 85.7% were pubertal. Serum concentrations of adrenocorticotropic hormone (ACTH) levels were significantly higher in patients with TARTs than in those without (309.0pg/mL vs. 45.2pg/mL; p=0.006). ACTH levels >200pg/mL were found to predict the presence of TARTs (sensitivity 85.7%; specificity 86.2%) (Figure). The factors found to correlate with TARTs volume were ACTH levels (coefficient 0.004; p=0.009) and the three-year average of serum testosterone levels (coefficient 9.64; p=0.003).] DISCUSSION: The main limitation of this study was the small sample size. However, an ACTH cut-off point to predict insufficient hormonal treatment and consequently the presence of TART had not been described. High ACTH (>200pg/mL) was found to be predictive insufficient hormonal treatment in patients with CAH. The three-year average of serum testosterone levels and ACTH concentrations were correlated with the volume of TARTs.

Genetic and clinical characteristics including occurrence of testicular adrenal rest tumors in Slovak and Slovenian patients with congenital adrenal hyperplasia due to 21-hydroxylase deficiency.

To analyze the mutational spectrum, clinical characteristics, genotype-phenotype correlations, testicular adrenal rests tumor prevalence, and role of neonatal screening in congenital adrenal hyperplasia (CAH) patients from Slovakia and Slovenia. Data were obtained from 104 patients with CAH registered in Slovak and Slovenian databases. Low-resolution genotyping was performed to detect the most common point mutations. To detect deletions, conversions, point mutations, or other sequence changes in the CYP21A2 gene, high-resolution genotyping was performed. Genotypes were classified according to residual 21-hydroxylase activity (null, A, B, C). 64% of the individuals had the salt-wasting form (SW-CAH), 15% the simple virilizing form (SV-CAH), and 21% the non-classic (NC-CAH). CYP21A2 gene deletion/conversion and c.293-13A/C>G pathogenic variant accounted together for 55.5% of the affected alleles. In SV-CAH p.Ile172Asn was the most common pathogenic variant (28.13%), while in NC-CAH p.Val282Leu (33.33%), CYP21A2 gene deletion/conversion (21.43%), c.293-13A/C>G (14.29%), Pro30Leu (11.90%). The frequency of alleles with multiple pathogenic variants was higher in Slovenian patients (15.83% of all alleles). Severe genotypes (0 and A) correlated well with the expected phenotype (SW in 94.74% and 97.3%), while less severe genotypes (B and C) correlated weaklier (SV in 50% and NC in 70.8%). The median age of SW-CAH patients at the time of diagnosis was 6 days in Slovakia vs. 28.5 days in Slovenia (p=0.01). Most of the Slovak patients in the cohort were detected by NBS. (24 out of 29). TARTs were identified in 7 out of 24 male patients, of whom all (100%) had SW-CAH and all had poor hormonal control. The median age at the diagnosis of TARTs was 13 years. The study confirmed the importance of neonatal screening, especially in the speed of diagnosis of severe forms of CAH. The prediction of the 21-OH deficiency phenotype was reasonably good in the case of severe pathogenic variants, but less reliable in the case of milder pathogenic variants, which is consistent compared to data from other populations. Screening for TARTs should be realized in all male patients with CAH, since there is possible remission when identified early.

Testicular impairment in Primary Adrenal Insufficiency caused by Nicotinamide Nucleotide Transhydrogenase (NNT) deficiency - a case report: implication of oxidative stress and importance of fertility preservation

IntroductionNicotinamide nucleotide transhydrogenase (NNT) gene deficiency has recently been shown to be involved in Primary Adrenal Insufficiency (PAI). NNT encodes an inner mitochondrial membrane protein that produces large amounts of NADPH. NADPH is used in several biosynthesis pathways and the oxidoreduction of free radicals by the glutathione and thioredoxin systems in mitochondria. Patients with PAI due to NNT deficiency may also exhibit extra-adrenal manifestations, usually including gonadal impairment.Case reportWe present the case of a 35-year-old patient referred to our center for primary infertility with non-obstructive azoospermia, in a context of PAI and obesity. PAI genetic exploration carried out at the age of thirty revealed NNT deficiency due to the presence of two deleterious mutations (one on each allele) in the NNT gene. Scrotal ultrasound revealed a right Testicular Adrenal Rest Tumor (TART). Intensification of glucocorticoid therapy over the course of 8 months failed to reduce the TART volume or improve sperm production and endocrine function. No spermatozoa were found after surgical exploration of both testes, and subsequent histopathological analysis revealed bilateral Sertoli cell-only syndrome. A retrospective review of the hypothalamic-pituitary-gonadic axis hormonal assessment over 20 years showed progressive impairment of testicular function, accelerated during adulthood, leading to hypergonadotropic hypogonadism and non-obstructive azoospermia when the patient reached his thirties, while the PAI remained controlled over the same period.ConclusionThis case report provides, for the first time, direct evidence of complete germ line loss in an azoospermic man with NNT deficiency. Additional data further support the hypothesis of a determinant role of oxidative cellular damage due to reactive oxygen species (ROS) imbalance in the severe gonadal impairment observed in this NNT-deficient patient. Early and regular evaluation of gonadal function should be performed in patients with PAI, especially with NNT deficiency, as soon as the patients reach puberty. Fertility preservation options should then be provided in early adulthood for these patients.