Testicular adrenal rest tumors - Epidemiology, diagnosis and treatment.

INTRODUCTION: Testicular adrenal rest tumors (TART) are common in males suffering from congenital adrenal hyperplasia (CAH). Correct and timely diagnosis is important for differential diagnosis with malignant testis tumors, related infertility and as TART may worsen in time, especially in the absence of adequate and continuous hormonal control. The rarity of the disease, predominance of small cohorts and case reports and research heterogeneity (concerning type of CAH, patients' age and specific focus of the paper) complicate the understanding of this condition. OBJECTIVES: To review epidemiological and clinical aspects of TART, including treatment and prognosis. METHODS: Non-systematic review of CAH-related TART research. RESULTS: TART's prevalence grows progressively over time, predominating after puberty, affecting a mean of 20-40 % of CAH males. There is no proof of more frequent proportional affection of specific CAH phenotypes or types of enzyme deficiency, but cases of TART among non-classic CAH patients have been rarely reported. Chronic undertreated are more frequently affected and present larger tumors. Systematic ultrasound screening of CAH males is the state-of-the art for diagnosis, but TART are still often diagnosed in CAH adults seeking infertility treatment. TART are usually asymptomatic and present normal testicular volume. Biopsies are not recommended, except when the differential diagnosis between TART and testicular tumors cannot be guaranteed. Abnormal semen analysis is common. Leydig cell tumors are the main differential diagnosis, due to histological similarities to TART. Misdiagnosis may lead to unnecessary orchiectomies. Preservation of gonadal functions is inversely proportional to the total tumor volume. Tumors tend to regress under adequate adrenal suppression with steroids. Surgery in not indicated to treat TART. DISCUSSION: The reported prevalence of TART depends on age, usage of systematic follow-up ultrasound, and adequate CAH control. Timely detection of the disease is important to avoid irreversible gonadal dysfunction (not clinically apparent, due to high serum levels of androgen) and infertility. The relationship between TART and specific CAH phenotypes/genotypes has not been proved, and some cases do not present abnormal serum ACTH levels. Knowledge about TART should be disseminated among non-experts, to avoid unnecessary orchiectomies and false diagnosis of malignant testis tumors. Infertility is frequent, but has not been not satisfactorily addressed by physicians, even among experts. Sperm cryopreservation should be early offered to CAH adult males, but there are offer problems related to high cost.

Hormonal control during infancy and testicular adrenal rest tumor development in males with congenital adrenal hyperplasia: a retrospective multicenter cohort study.

IMPORTANCE: Testicular adrenal rest tumors (TARTs), 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 exposure during early life may promote TART development. OBJECTIVE: This study aimed to examine the association between commencing adequate glucocorticoid treatment early after birth and TART development. DESIGN AND PARTICIPANTS: 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; interquartile range: 10-17) with 21-hydroxylase deficiency (n = 181) or 11-hydroxylase deficiency (n = 7). All patients underwent at least 1 testicular ultrasound. RESULTS: TART was detected in 72 (38%) of the patients. Prevalence varied between centers. When adjusted for CAH phenotype, a delayed CAH diagnosis of >1 year, compared with 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 4 years of life, but increased height standard deviation scores at the end of the 4-year study period were associated with a 27% higher risk of TART diagnosis. CONCLUSIONS AND RELEVANCE: A delayed CAH diagnosis of >1 year vs CAH diagnosis within 1 month after birth was associated with a higher risk of TART development, which may be attributed to poor disease control in early life.

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.

Objective: 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. Design and methods: 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). Results: 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. Conclusion: 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.

Patient and Parent Perspectives on Testicular Adrenal Rest Tumors in Congenital Adrenal Hyperplasia.

BACKGROUND: Testicular adrenal rest tumors (TARTs) increase the risk of infertility in males with classic congenital adrenal hyperplasia (CAH). There is no consensus regarding at what age screening testicular ultrasounds should begin and how often they should be repeated. Furthermore, it is unknown whether patients and parents are aware of the significance of TARTs. OBJECTIVE: The objective of the study was to investigate awareness, concern, and screening rates for TARTs in males with classic CAH. METHODS: Males with CAH and parents completed an online questionnaire from 2019 to 2020. Responses to questions about TARTs were analyzed. Fisher's exact test was used to determine statistical significance. RESULTS: Of 123 responders, 14 were males with CAH (range 16-54 years) and 109 were parents of males with CAH (son's age range infancy to 37 years). Of all responders, 74% were concerned about the possibility of TARTs, 48% had discussions about TARTs with their endocrinologist, and 42% were aware of possible infertility in males with CAH. There was no difference between responses provided by affected males and parents for these topics (p ≥ 0.08). Among male responders with CAH, 93% had at least one testicular ultrasound, and 77% had undergone more than one. Among parent responders, 30% of their sons had at least one testicular ultrasound, and 61% had more than one. The frequency, total number, and age when the first testicular ultrasound was obtained were inconsistent in both groups. Fifty percent of male responders with CAH and 11% of sons were referred to a urologist for evaluation. CONCLUSIONS: Although most responders were concerned about TARTs, less than half recalled discussing this issue with their endocrinologist, and less than half were aware of the possibility of infertility. Although TARTs are most often treated medically, several responders were referred to a urologist. Standardized patient education and consensus guidelines are needed for the surveillance and management of TARTs in males with classic CAH.

Ovarian and paraovarian adrenal rest tumors are not uncommon in gonadectomy materials of historical congenital adrenal hyperplasia cases in childhood.

Objective: The aim of this study was to assess the prevalence of ovarian and paraovarian adrenal rest tumors (ARTs) in gonadectomy materials of a subgroup of congenital adrenal hyperplasia (CAH) patients. Methods: A total of 20 historical cases with clinical/molecular diagnosis of classical CAH were included in the study. All patients had 46,XX karyotype and underwent gonadectomy because of being raised as male. Results: Median age at diagnosis of CAH was 5.7 years and was markedly delayed. All patients revealed severe virilization. Bone age was significantly advanced, and bone age/chronological age ratio was increased with a median ratio of 1.8. Median age at the time of gonadectomy was 9.2 years. Ovarian and paraovarian ARTs were detected during the pathological evaluation of gonadectomy materials in four patients (20%) (two with simple virilizing 21-hydroxylase and two with 11-beta-hydroxylase deficiency) with previously normal pelvic imaging. In three cases with ARTs, paraovarian area was composed of medium-sized polygonal cells, with round or oval monomorphic nuclei and abundant granular eosinophilic cytoplasm which is characteristic of adrenocortical tissue. The fourth case had bilateral ovarian 'steroid cell tumors, not otherwise specified', and the tumor was accepted as benign. Except for the ARTs, heterotopic prostate and bilateral paratubal epididymis tissue were detected in a patient. Conclusions: Ovarian and paraovarian ARTs might be more common than previously described, especially among patients with excessive and prolonged adrenocorticotropic hormone exposure. These tumors could be detected histopathologically even if not detected by classical imaging methods.

Screening for testicular adrenal rest tumors among children with congenital adrenal hyperplasia at King Fahad Medical City, Saudi Arabia.

OBJECTIVES: To assess the incidence of testicular adrenal rest tumors (TARTs) among male children with congenital adrenal hyperplasia (CAH) in tertiary care centers. METHODS: All male children aged 1-14 years diagnosed with CAH due to 21-hydroxylase deficiency (21 HOD), 11ß-hydroxylase deficiency, and 3ß-hydroxysteroid dehydrogenase deficiency, confirmed by biochemical and/or genetic testing, underwent scrotal ultrasound examination to identify TARTs. After receiving the diagnosed patients' data, patients' electronic medical records were accessed to collect demographic data and scrotal ultrasound results, along with growth parameters and specific biochemical test results within 2 months of the ultrasound. RESULTS: TARTs were observed in 5 (10.9%) of 46 male children with CAH. Four patients with positive findings had 21 HOD classical CAH with salt loss and one had 21 HOD simple virilizing classical CAH. All patients had poor compliance and stage 2 bilateral TARTs. Three TART-positive patients (60.0%) had high ACTH levels, 5 patients (100%) had elevated 17-OHP levels, and 5 patients (100%) had advanced bone age. The youngest patient with positive findings was 4 years old. CONCLUSIONS: The prevalence of TARTs increases with age and can be present in young males with classical CAH with 21 HOD. It is associated with elevated 17-hydroxyprogesterone (17-OHP) and advanced bone age SDS. TARTs are less likely to be associated with nonclassical CAH with 21 HOD or other less common CAHs due to 11ß-hydroxylase deficiencies and 3ß-hydroxysteroid dehydrogenase deficiencies in children. Our study recommends early and routine screening of TARTs in children with CAH.

Case Report:clinical experience of bilateral giant pediatric Testicular adrenal rest tumors with 3 Beta-Hydroxysteroid Dehydrogenase-2 family history.

BACKGROUND: We reported a patient with Testicular adrenal rest tumors(TARTs) caused by congenital adrenal hyperplasia(CAH). TARTs occur frequently in CAH population with 21-hydroxylase deficiency(21-OHD). There are few reports of TARTs with 3ß-hydroxysteroid dehydrogenase deficiency-2 (3ß-2HSD).Furthermore,gaint TARTs are rarely mentioned in reported cases involving affected siblings. CASE PRESENTATION: A 14-year-old male patient was admitted by congenital adrenal hyperplasia with progressively increasing bilateral testicular masses.The Patient and his elder brother had been performed mutational and chromosome analysis and biopsy. Hormonal and anthropometric measurements were performed during endocrine treatments. We successfully performed surgery and excised two 83mm×46mm×44mm and 74mm×49mm×31mm tumors. Our pathology and immunochemistry tests have proven TARTs in patient. At first, both siblings received regular doses of hydrocortisone and fludrocortisones and tumor size regressed. During the one-year irregular intake due to Covid-19 pandemic, endocrine treatment became insensitive and tumor size slowly increased. The gene analysis reported two novel mutations C.776 C>T and C.674 T>A. The C.776 C>T is from father and has been reported. The C.674 T>A inherited from mother and cannot found in gene library and may related to TARTs. CONCLUSIONS: This case illustrates inadequate hormone therapy could cause tumor enlargement. It is essential to seek for ultrasound examination once suspected scrotal mass occurred.It is necessary to adjust endocrine medicine or adopt surgery in refractory gaint TARTs. And presence of tunica vaginalis cavity may indicate the severity of TARTs in surgery.

Testicular adrenal rest tumors in children with congenital adrenal hyperplasia.

OBJECTIVES: To identify testicular adrenal rest tumors (TARTs) prevalence among children with congenital adrenal hyperplasia (CAH) and to assess hormonal control role as a contributing factor for TART development. Testicular adrenal rest tumors are benign tumors complicating CAH. It affects adult males with CAH commonly, with a reported prevalence of 40% on average, and up to 94%. There is insufficient data regarding their prevalence in children aged above 4 years and adolescents. METHODS: This descriptive study included 21 children and adolescents with CAH (17 salt wasting type, 4 non salt wasting type) aged 4-20 years who were screened for TARTs by routine testicular ultrasonography from October 2012 to December 2020 at King Abdulaziz University Hospital, Jeddah, Kingdom of Saudi Arabia. Serum adrenocorticotropic hormone, 17-hydroxy progesterone, testosterone, dehydroepiandrosterone, and luteinizing hormone levels were measured. RESULTS: Testicular adrenal rest tumors were detected in 6 (28%) patients (median age: 12.5 years). The youngest affected child was 8 years old. All patients with TARTs were asymptomatic with impalpable testicular masses at the time of detection. Bilateral involvement was observed in 5 patients, while one patient had unilateral involvement. All patients with TARTs had poor hormonal control, and 4 patients had advanced bone age. CONCLUSION: Testicular adrenal rest tumors development has been shown to correlate with poor hormonal control. Annual screening of young children with CAH for TART development is crucial, even for asymptomatic or with impalpable testicular masses.

Semen quality and testicular adrenal rest tumour development in 46,XY congenital adrenal hyperplasia: the importance of optimal hormonal replacement.

OBJECTIVE: To study the impact of the quality of therapeutic control on fertility and on the prevalence of testicular adrenal rest tumours (TART) in young males with congenital adrenal hyperplasia (CAH). DESIGN: Combined cross-sectional and retrospective clinical study. METHODS: Twenty-nine patients and age-matched controls underwent clinical investigation, including semen analysis, testicular and adrenal ultrasound imaging, and serum and hair steroid analysis. The quality of therapeutic control was categorized as 'poor', 'moderate' or 'medium'. Evaluation of current control was based on concentrations of 17-hydroxy-progesterone and androstenedione in serum and 3 cm hair; previous control was categorized based on serum 17-hydroxy-progesterone concentrations during childhood and puberty, anthropometric and puberty data, bone age data and adrenal sizes. RESULTS: Semen quality was similar in males with CAH and controls (P = 0.066), however patients with 'poor' past control and large TART, or with 'poor' current CAH control had low sperm counts. Follicle-stimulating hormone was decreased, if current CAH control was 'poor' (1.8 ± 0.9 U/L; 'good': 3.9 ± 2.2 U/L); P = 0.015); luteinizing hormone was decreased if it was 'poor' (1.8 ± 0.9 U/L; P = 0.041) or 'moderate' (1.9 ± 0.6 U/L; 'good': 3.0 ± 1.3 U/L; P = 0.025). None of the males with 'good' past CAH control, 50% of those with 'moderate' past control and 80% with 'poor past control had bilateral TART. The prevalence of TART in males with severe (class null or A) CYP21A2 mutations was 53% and 25% and 0% in those with milder class B and C mutations, respectively. CONCLUSIONS: TART development is favoured by inadequate long-term hormonal control in CAH. Reduced semen quality may be associated with large TART. Gonadotropin suppression by adrenal androgen excess during the latest spermatogenic cycle may contribute to impairment of spermatogenesis.

Absence of Testicular Adrenal Rest Tumors in Newborns, Infants, and Toddlers with Classical Congenital Adrenal Hyperplasia.

INTRODUCTION: Testicular adrenal rest tumors (TART) are a known consequence for males with classical congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency. TART are associated with potential infertility in adults. However, little is known about TART in very young males with CAH. OBJECTIVE: We assessed the presence of TART in newborn, infant, and toddler males with classical CAH via scrotal ultrasound. METHODS: Males with CAH had scrotal ultrasounds during the first 4 years of life, evaluating testes for morphology, blood flow, and presence of TART. Newborn screen 17-hydroxyprogesterone (17-OHP) and serum 17-OHP at the time of ultrasound were recorded. Bone ages were considered very advanced if ≥2 SD above chronological age. RESULTS: Thirty-one ultrasounds in 16 males were performed. An initial ultrasound was obtained in four newborns at diagnosis (6.8 ± 2.1 days), six infants (2.2 ± 0.9 months), and six toddlers (2.4 ± 0.9 years). Eleven males had at least one repeat ultrasound. A large proportion (11/16) were in poor hormonal control with an elevated 17-OHP (325 ± 298 nmol/L). One infant was in very poor hormonal control (17-OHP 447 nmol/L) at initial ultrasound, and two toddlers had advanced bone ages (+3.2 and +4.5 SD) representing exposure to postnatal androgens. However, no TART were detected in any subjects. CONCLUSIONS: TART were not found by scrotal ultrasound in males up to 4 years of age with classical CAH despite settings with expected high ACTH drive. Further research into the occurrence of TART in CAH may elucidate factors that contribute to the detection and individual predisposition to TART.

Testicular Adrenal Rest Tumors: Current Insights on Prevalence, Characteristics, Origin, and Treatment.

This review provides the reader with current insights on testicular adrenal rest tumors (TARTs), a complication in male patients with congenital adrenal hyperplasia (CAH). In recent studies, an overall TART prevalence of 40% (range, 14% to 89%) in classic patients with CAH is found. Reported differences are mainly caused by the method of detection and the selected patient population. Biochemically, histologically, and molecularly, TARTs exhibit particular adrenal characteristics and were therefore thought to originate from aberrant adrenal cells. More recently, TARTs have been found to also exhibit testicular characteristics. This has led to the hypothesis of pluripotent cells as the origin of TARTs. High concentrations of ACTH could cause hyperplasia of these pluripotent cells, as TARTs appear to be associated with poor hormonal control with concomitant elevated ACTH. Unfortunately, as yet there are no methods to prevent the development of TARTs, nor are there guidelines to treat patients with TARTs. Intensified glucocorticoid treatment could improve fertility status in some cases, although studies report contradicting results. TARTs can also lead to irreversible testicular damage, and therefore semen cryopreservation could be offered to patients with TARTs. Further research should focus on the etiology and pharmacological treatment to prevent TART development or to treat TARTs and improve the fertility status of patients with TARTs.

Prevalence of Testicular Adrenal Rest Tumor and Factors Associated with Its Development in Congenital Adrenal Hyperplasia.

BACKGROUND: Testicular adrenal rest tumors (TART) can cause infertility in congenital adrenal hyperplasia (CAH) males. AIMS: To determine TART prevalence in patients with CAH due to 21-hydroxylase deficiency (21-OHD) and evaluate possible factors associated with its development. METHODS: This is a descriptive and analytical cross-sectional study evaluating males with the classical form of 21-OHD through testicular ultrasonography and serum inhibin B dosages. Data on prescribed glucocorticoid dose and serum levels of 17- hydroxyprogesterone (17-OHP), androstenedione (Andro), ACTH, renin, and LH were obtained from medical records. RESULTS: Thirty-eight males were evaluated. The mean age on ultrasonography was 15.2 ± 6.7 (3-27) years. Nine patients (23.7%) had TART, 4 of them were prepubertal and the youngest was 5 years old. No association was found between TART and 21-OHD phenotype, glucocorticoid dose, or 17-OHP, ACTH, LH, renin, and inhibin B levels measured in the 6 preceding years. However, 50% of the patients who presented increased Andro 2 years prior to the evaluation had TART (p = 0.018, OR = 8.00 [95% CI: 1.42-44.92]), whereas in the normal Andro group only 16.7% had tumors. CONCLUSION: This study showed that TART can occur in prepubertal patients and that disease control could be a factor associated with its development. Therefore, we suggest investigating TART development early in childhood, mainly in poorly controlled 21-OHD patients.

Testicular adrenal rest tumor screening and fertility counseling among males with congenital adrenal hyperplasia.

BACKGROUND: Reduced fertility is a common potential problem among males with congenital adrenal hyperplasia (CAH), with nearly half experiencing impaired sperm production. The major cause of oligo/azoospermia in CAH is testicular adrenal rest tumors (TARTs). Studies indicate that ultrasound screening for TARTs should begin during childhood, yet it remains unclear whether boys with CAH are routinely screened for TARTs and/or counseled about infertility risk and potential interventions such as fertility testing and/or preservation. OBJECTIVE: The purpose of this study was to examine TART screening and fertility counseling practices among boys with CAH. STUDY DESIGN: An IRB-approved retrospective chart review was conducted of all males with ICD-9/10 codes for CAH (2007-2016) at a large pediatric academic center to examine: age and indication for diagnosis; age at first and last documented pediatric endocrinology and urology visit; history of ultrasound examinations; and documentation of fertility counseling. RESULTS: Forty-six patients were included, of whom 38 had 21-hydroxylase deficiency. Median age at diagnosis was 2 weeks (range 7 days-10 years). Median age at the most recent pediatric endocrinology clinic visit was 14 years (range 2-42 years). Twenty-nine patients were >11 years old (63% of the sample) at the time of the study and 14 of these were >18 years old (30% of the sample). Seven patients (15%) had a screening ultrasound at some point in their care, of whom three had TARTs. Fertility was mentioned in the records of six subjects (13% of the sample). Six of the subjects (13%) had any mention of fertility in their records. None of the patients had biochemical testing or semen analysis to assess gonadal function, and none were offered fertility preservation. Only one patient was seen by a pediatric urologist. DISCUSSION: Despite the limitations of a single-center retrospective design, our findings highlight that TART screening and fertility counseling remain underutilized in boys with CAH. There is a need for increased awareness and development of practice guidelines within pediatric urology and endocrinology to address this common and understudied problem. CONCLUSION: In addition to a screening ultrasound in puberty and consideration of semen analysis after puberty, these boys may benefit from seeing a pediatric urologist independently or in an interdisciplinary program. Boys with CAH and their families should be educated about infertility risk and potential interventions, with the goal of improving reproductive outcomes in this population.

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.

Testicular Adrenal Rest Tumors in Boys and Young Adults with Congenital Adrenal Hyperplasia.

PURPOSE: Testicular adrenal rest tumors are a well-known complication in males who have congenital adrenal hyperplasia with potential infertility in adulthood. We assessed the prevalence of testicular adrenal rest tumors in infants to young men presenting to a congenital adrenal hyperplasia Comprehensive Care Center. MATERIALS AND METHODS: A total of 35 males with congenital adrenal hyperplasia due to 21-hydroxylase deficiency underwent scrotal ultrasonography, including 7 younger than 5 years, 9 who were 5 to 12 years old and 19 who were older than 12 years. Three and 35 patients had classic and nonclassic congenital adrenal hyperplasia, respectively. Bone age x-ray or advanced bone age x-ray history, glucocorticoid dose, fludrocortisone dose, and serum 17-hydroxyprogesterone, testosterone and androstenedione levels within 3 months of ultrasound were also recorded. RESULTS: Testicular adrenal rest tumors were detected in 5 of 35 patients (14%), including 1 of 9 (11%) who were 5 to 12 years old and 4 of 19 (21%) who were older than 12 years. The tumors were not detected in any patients younger than 5 years, including 1 infant with poor hormonal control. The youngest patient with positive findings was 6.6 years old. All patients with positive findings had bilateral disease and only 1 had suspicious physical findings. The glucocorticoid dose and 17-hydroxyprogesterone did not differ between patients with vs without a testicular adrenal rest tumor. Those with a tumor were more likely to have advanced bone age x-ray results (100% vs 42%, p = 0.04) and higher fludrocortisone dose (p <0.01). All males with nonclassic congenital adrenal hyperplasia had negative tumor findings. CONCLUSIONS: Testicular adrenal rest tumors were present in young males with classic congenital adrenal hyperplasia but not in infants or toddlers. These tumors were associated with higher fludrocortisone requirements and a history of advanced bone age x-ray results. However, the tumors did not develop in all poorly controlled males. Longitudinal studies are needed to understand the individual predisposition to testicular adrenal rest tumors and the age at which to begin screening patients with congenital adrenal hyperplasia.

Testicular adrenal rest tumours in young adult males with congenital adrenal hyperplasia: prevalence and impact on testicular function.

Testicular adrenal rest tumours (TARTs) have been described in patients with congenital adrenal hyperplasia (CAH). The aim of the study was to determine the prevalence of TARTs in patients with CAH, the associated factors and their impact on gonadal function. It is a prospective study concerning six young adult men with CAH, four cases with 21-hydroxylase deficiency and two cases with 11-hydroxylase deficiency. All patients were under glucocorticoid therapy. The mean age was 25 years (range: 20-31). All patients underwent a physical examination with testicular palpation, scrotal ultrasonography, a blood sample for serum testosterone, FSH, LH, inhibin B, ∆4-androstenedione and 17-OH-progesterone measurements and a semen analysis. Ultrasound revealed TARTs in four patients; three were bilateral. The mean tumour size was 6.3 ml (range: 0.02-14.1). The tumours were palpable in two cases. 17-OH-progesterone was <10 ng/ml in all cases. Decreased testosterone level was found in one case. The semen analysis revealed azoospermia in one case and poor semen quality in four patients. TARTs were common and associated with impaired spermatogenesis.

Clinical Outcome, Hormonal Status, Gonadotrope Axis, and Testicular Function in 219 Adult Men Born With Classic 21-Hydroxylase Deficiency. A French National Survey.

CONTEXT: Outcomes of congenital adrenal hyperplasia due to classic 21-hydroxylase deficiency (21OHD) have been widely studied in children and women, but less so in men. OBJECTIVE: The objective was to analyze data from a network of metropolitan French teaching hospitals on the clinical outcome of classic 21OHD in a large sample of congenital adrenal hyperplasia/21OHD-genotyped adult men, and particularly the impact of 21OHD on the gonadotrope axis, testicular function, and fertility. METHODS: From April 2011 to June 2014, tertiary endocrinology departments provided data for 219 men with 21OHD (ages, 18-70 y; 73.6% salt wasters, 26.4% simple virilizers). Testicular sonography was performed in 164 men, and sperm analysis was performed in 71 men. RESULTS: Mean final height was 7.8 cm lower than in a reference population. Obesity was more common, and mean blood pressure was lower than in the reference population. None of the patients were diabetic, and lipid status was generally normal. Blood electrolyte status was normal in the vast majority of men, despite markedly elevated ACTH and renin levels. Serum progesterone, 17-hydroxyprogesterone, and androstenedione levels were above normal in the vast majority of cases. Hormonal profiling variously showed a normal gonadotrope-testicular axis, gonadotropin deficiency, or primary testicular insufficiency. Testicular sonography revealed testicular adrenal rest tumors (TARTs) in 34% of 164 men. Serum inhibin B and FSH levels were significantly lower and higher, respectively, in patients with TARTs. Severe oligospermia or azoospermia was found in 42% of patients and was significantly more prevalent in men with TARTs (70%) than in men with normal testes (3.6%; P < .0001). Among men living with female partners, TARTs were significantly more prevalent in those who had not fathered children. CONCLUSION: We report the spectrum of testicular/gonadotrope axis impairment in the largest cohort of 21OHD men studied to date. Our results suggest that French men with 21OHD managed in specialized centers frequently have impaired exocrine testicular function but that its reproductive implications are often overlooked.

Increased prevalence of testicular adrenal rest tumours during adolescence in congenital adrenal hyperplasia.

UNLABELLED: Testicular adrenal rest tumours (TART) are one of the most important causes of infertility in adult male patients with congenital adrenal hyperplasia (CAH). These benign tumours are already detected in children, but screening of TART is not routinely performed. OBJECTIVE: To define retrospectively the prevalence of TART in 41 paediatric male CAH patients aged 0-19 years regularly followed by high-frequency (Fcentral 12-MHz) ultrasound techniques. RESULTS: Above the age of 10 years, there was a clear increase in the prevalence of TART: 10-12 years, 28% (2 of 7 patients), 13-14 years, 50% (4/8), and 15-16 years, 75% (3/4). Above the age of 16 years, TART were detected in 100% of the patients (7/7). The tumours were not detectable by palpation. CONCLUSION: TART is already present in childhood with an increasing prevalence after onset of puberty. We recommend regular ultrasound from the onset of puberty in all boys with classic CAH.

Prevalence and long-term follow-up outcomes of testicular adrenal rest tumours in children and adolescent males with congenital adrenal hyperplasia.

OBJECTIVE: There are a few studies regarding the prevalence of testicular adrenal rest tumours (TARTs) in boys and adolescent males with congenital adrenal hyperplasia (CAH), and there is little information regarding the treatment outcomes in patients with TARTs. The aim of this study was to determine the long-term treatment outcomes in boys and adolescent males with CAH. PATIENTS AND METHODS: Sixty boys and adolescent males with CAH, who were between 2 and 18 years of age, were included in the study. Fifty-five patients had 21-hydroxylase deficiency (21-OHD), and five patients had 11-ß hydroxylase deficiency (11ß-OHD). All patients were screened for TARTs by scrotal ultrasonography (US) performed by an experienced radiologist. RESULTS: TART prevalence was 18·3% in 2-18 years' of age; eight patients had 21-OHD, and three had 11ß-OHD. The youngest patient with TART was 4 years old, whereas eight patients with RTs were at puberty. Only two patients had tight metabolic control: eight patients had stage 2, one had stage 4, and two had stage five rest tumours. In four patients with stage 2 TARTs, tumours disappeared after high-dose steroid treatment and did not recur. Shrinkage of tumour was observed in two patients. Testis-sparing surgery was performed in one patient with stage five tumour. Gonadal functions were normal in patients with partially regressed tumours. Two patients became fathers of healthy male off-springs. CONCLUSIONS: Detection and treatment for TARTs in children with CAH at younger ages, earlier stages, may prevent infertility in adulthood. Therefore, we recommend that scrotal US screening should be performed in every 1-2 years starting from early childhood.