Deep inside the testes of many boys and young men living with congenital adrenal hyperplasia, a quiet biological drama unfolds. Clusters of cells that should have become adrenal tissue instead linger within the gonads, where they were deposited during embryonic development. Under the relentless pressure of a hormonal signal the body cannot switch off, these stray cells multiply into what doctors call testicular adrenal rest tumours, or TARTs. A new minireview published in Frontiers in Adolescent Medicine by researchers at the University of Padova pulls together what is known about these benign but consequential growths, arguing that adolescence is the decisive window in which they emerge, progress and may yet be stopped.
Congenital adrenal hyperplasia is a group of inherited disorders of steroid production, caused in more than 90 to 95 percent of cases by a deficiency of the enzyme 21-hydroxylase. The enzyme deficit reduces cortisol output and, in the most severe forms, aldosterone as well. Because cortisol normally exerts negative feedback on the pituitary gland, its loss unleashes chronically elevated adrenocorticotropic hormone, or ACTH, which drives the adrenal cortex to overproduce steroid precursors such as 17-hydroxyprogesterone and a surge of adrenal androgens. The clinical spectrum ranges from classic salt-wasting disease through simple virilizing forms to nonclassic variants, depending on how much residual enzyme activity a patient retains.
TARTs themselves are not cancerous, and they usually do not require surgical removal. Their danger lies in geography rather than malignancy. These lesions characteristically take root near the mediastinum testis, the central hub of the testicle through which the seminiferous tubules drain. As the tumours enlarge, they compress and obstruct those tubules, choking off sperm outflow and eventually causing obstructive azoospermia. Long-standing obstruction can progress to hypospermatogenesis, peritubular fibrosis and tubular hyalinization, culminating in the complete loss of germ cells and Sertoli cells. Steroids produced by the tumour cells themselves may also poison neighbouring Leydig cells and germ cells through a paracrine effect, adding a chemical insult to the mechanical one.
The embryological explanation for why adrenal tissue appears in the testes at all is a story of developmental proximity. During foetal life, the adrenal glands and the gonads arise side by side, and adrenocortical precursor cells can migrate into the rete testis, where they persist as ectopic adrenal-like remnants. Once there, they remain responsive to the same signals that drive the adrenal cortex, carrying receptors for both ACTH and angiotensin II. Chronic ACTH stimulation, beginning in utero and continuing throughout life, is considered the single most important driver of their proliferation. Yet the picture is not so simple: TARTs sometimes appear in patients whose hormonal control appears adequate, while remaining absent in others with persistently poor control, suggesting that ACTH excess alone cannot explain every case.
How common are these tumours? The reported prevalence spans an astonishing range, from zero to 94 percent, depending on the age of the cohort, disease severity, hormonal control and, crucially, the screening method used. In a cross-sectional study of 51 Croatian males with CAH, TARTs were detected in 12.5 percent of children younger than 12 years, 29.4 percent of adolescents aged 12 to 17, and 44.4 percent of adults. Other investigators found prevalence of 11 percent in children aged 5 to 12 and 21 percent in those older than 12. The trend is unmistakable: prevalence climbs steeply through puberty, making adolescence the period of greatest risk and greatest opportunity for intervention.
Several converging factors make puberty a uniquely vulnerable window. Rising luteinizing hormone may directly stimulate the adrenal rest cells, which express LH receptors, potentially explaining tumour expansion even in patients with relatively good biochemical control. Puberty also brings increased adrenal androgen production, accelerated growth and changes in glucocorticoid pharmacokinetics that complicate dosing. Meanwhile, treatment adherence frequently declines as teenagers assert independence, producing stretches of inadequate ACTH suppression. A diagnostic delay of more than one year after birth has been associated with increased TART risk after adjustment for disease phenotype, implicating prolonged early ACTH exposure and lending weight to neonatal screening programmes. Disease severity matters too: TARTs occur predominantly in classic salt-wasting CAH, are less frequent in simple virilizing forms and are rarely reported in nonclassic disease, consistent with the greater cumulative ACTH burden carried by severe CYP21A2 genotypes.
Detecting these lesions early is both a technical and a clinical challenge. Most TARTs are clinically silent and impalpable until they exceed two centimetres in diameter, by which point significant damage may already have occurred. Scrotal ultrasound is the preferred modality, capable of identifying lesions as small as a few millimetres; the tumours typically appear as hypoechoic masses near the mediastinum testis, often with hypervascularity on colour Doppler. Magnetic resonance imaging offers complementary information, generally showing hypointensity on T1 and iso- or hyperintensity on T2 sequences. The main differential diagnosis is Leydig cell tumour, which shares a steroidogenic origin and overlapping morphology, but bilateral lesions near the mediastinum in a CAH patient strongly favour TART, whereas Leydig cell tumours are more often unilateral and carry malignant potential. Expert opinion suggests yearly ultrasound screening until puberty in asymptomatic males, with more frequent surveillance once lesions are detected.
The stakes of this surveillance are captured in the review’s discussion of fertility. Gonadal dysfunction is one of the most relevant long-term complications of CAH and a major cause of male infertility, and signs of it may already appear during puberty. Biochemical monitoring is nuanced: LH and FSH can be misleading because adrenal androgens, partly aromatized to estrogens, may suppress gonadotropins, and testosterone may appear normal despite impaired gonadal function. Inhibin B serves as a more useful marker of Sertoli cell activity, informative even in prepubertal boys, while semen analysis becomes possible after puberty. The androstenedione-to-testosterone ratio offers another clue, with values below 0.5 typical of eugonadal men and values above 2 suggesting inadequate disease control with substantial adrenal contribution to circulating testosterone. The authors emphasize that counselling about infertility risk should begin early, both to inform patients and to improve adherence, and that referral for semen analysis and cryopreservation should be considered when appropriate.
Treatment currently centres on optimizing or intensifying glucocorticoid therapy to suppress ACTH, and tumour shrinkage after such suppression has been described. But the response is variable, and higher glucocorticoid doses carry their own risks, including weight gain, hypertension and impaired final height. During puberty, increased glucocorticoid clearance may require dose adjustments, though treatment should always aim for the lowest effective dose. An emerging concept reframes the problem: cumulative disease burden, rather than any single hormonal measurement, may be what matters most. Long-standing ACTH exposure during childhood may initiate irreversible proliferative and fibrotic changes within adrenal rest tissue, which helps explain why advanced lesions often show only partial regression even after therapy is optimized. A single clinic visit with normal biochemistry therefore cannot rule out TART development.
Into this landscape arrive the new therapies. Modified-release hydrocortisone, designed to mimic the physiological circadian rhythm of cortisol, has demonstrated improved control of adrenal steroid excess in clinical trials, and one male patient with a history of TARTs experienced improved sperm count during the phase 3 trial. More targeted still are the corticotropin-releasing factor type 1 receptor antagonists. Tildacerfont produced significant reductions in ACTH, 17-hydroxyprogesterone and androstenedione in phase 2 studies, and in a small subset of male participants assessed for TARTs as an exploratory outcome, one patient showed an approximately 23 percent reduction in tumour volume after six weeks alongside an 87 percent drop in ACTH, while another showed disappearance of previously detected lesions on ultrasound. Crinecerfont, a second-generation CRF1 antagonist, has since demonstrated efficacy in phase 3 trials in adults and children, though those trials did not include TART-related endpoints. Further ACTH-targeted agents, including the oral melanocortin type 2 receptor antagonist atumelnant and the anti-ACTH monoclonal antibody Lu AG13909, are in ongoing trials. The Padova authors caution that direct evidence that any of these therapies improve TART-specific outcomes remains scarce and largely speculative, but the early signals suggest that pharmacological ACTH suppression may at last offer a way to intervene before puberty’s window closes and testicular damage becomes permanent.
Subject of Research: Testicular adrenal rest tumours in adolescent males with congenital adrenal hyperplasia
Article Title: Testicular adrenal rests tumours in congenital adrenal hyperplasia: unraveling prevalence, risk factors and new therapeutic horizons in adolescents
Article References: Tizianel, I., Bovo, G., Mazzeo, P., Ceccato, F., & Barbot, M. (2026). Testicular adrenal rests tumours in congenital adrenal hyperplasia: unraveling prevalence, risk factors and new therapeutic horizons in adolescents. Frontiers in Adolescent Medicine, 4, Article 1919128. https://doi.org/10.3389/fradm.2026.1919128
Image Credits: AI Generated
DOI: 10.3389/fradm.2026.1919128
Keywords: congenital adrenal hyperplasia, testicular adrenal rest tumours, ACTH, puberty, infertility, 21-hydroxylase deficiency, testicular ultrasound, glucocorticoids, tildacerfont, crinecerfont, adolescent endocrinology, fertility preservation
News Source: Ophelia Keating. (October 16, 2026). The Silent Testicular Tumors Threatening Fertility in Boys With Congenital Adrenal Hyperplasia. Scienmag.
