The High Prevalence of Testicular Adrenal Rest Tumors in Adult Men With Congenital Adrenal Hyperplasia Is Correlated With ACTH Levels

Abstract

Introduction: The aims of this study were to determine the prevalence of testicular-adrenal rest tumors (T-ARTs) in patients with congenital adrenal hyperplasia (CAH) and to evaluate the related ultrasound (US) features, hormonal profiles, and semen parameters. Therefore, we attempted to understand the potential impact of adrenocorticotropic hormone (ACTH) on the persistence or disappearance of T-ART. Methods: We conducted a longitudinal cohort study including patients with CAH who were undergoing treatment with cortisone and, when indicated, fludrocortisone replacement therapy. We performed andrological examinations, US of the testis, hormone profiling, and semen analysis. Results: Of the 25 patients (mean ± SD age, 32.2 ± 7.5 years), T-ARTs were detected by US in 14 (56.0%) patients. The mean ± SD diameter of the lesions was 13.2 ± 6.8 mm. Among 3 (21.4%) patients, the lesions were observed in one testis, whereas both testes were affected in the remaining 11 (78.6%) patients. The lesions were hypoechoic in 12 (85.7%) patients and hyperechoic in 2 (14.3%). Plasma ACTH and 17-hydroxyprogesterone (17-OHP) levels were significantly higher in patients with T-ART than in patients without lesions (319.4 ± 307.0 pg/ml and 12.4 ± 2.7 ng/ml vs. 33.5 ± 10.7 pg/ml and 8.2 ± 1.8 ng/ml, respectively; p < 0.01). The mean values of sperm concentration and motility were significantly lower in patients with T-ART than in patients without lesions (12.1 ± 12.4 × 10 6 cells/ml and 18.4 ± 11.1% vs. 41.5 ± 23.2 × 10 6 cells/ml and 30.8 ± 15.4%, respectively; p < 0.05). Logistic regression analysis showed ACTH level as a significant predictor of T-ART ( p < 0.05). In patients with T-ART, the dose of hydrocortisone was increased by ~25–30%, while the fludrocortisone treatment remained unchanged. After 6 months of steroid treatment, patients underwent US and hormonal evaluation. Disappearance and a reduction in T-ART were observed in 6 (42.9%) and 5 (35.7%) patients, respectively; a reduction in ACTH levels (from 319.4 ± 307.0 to 48.1 ± 5.1 pg/ml; p < 0.01) was reported. A significant correlation between ACTH level reduction and T-ART diameter reduction was observed ( p < 0.5; r = 0.55). Conclusions: T-ARTs were detected in 56% of patients with CAH and were associated with impaired semen parameters. However, these lesions are potentially reversible, as demonstrated by the disappearance/reduction after adjustment of cortisone therapy and by the reduction in plasma ACTH level. Our study supports the importance of periodic US evaluation and maintenance of plasma ACTH levels within the normal range in men with CAH.

Transcriptional comparison of Testicular Adrenal Rest Tumors with fetal and adult tissues

“…ACTH is considered to be a growth promoting factor of TART, as the growth of TART is associated with poor hormonal control (11) and correlates with increased ACTH levels (12,13). Besides, intensifying glucocorticoid treatment is sometimes effective in reducing tumor size, most likely due to the suppressing effects on ACTH levels (12,(14)(15)(16). However, an association between (long-term) hormonal control and the development or size of TART is not observed in all association studies (17,18) and intensified glucocorticoid treatment does not result in tumor shrinkage in all cases (4).…”

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

“…Futhermore, newborns with CAH have significantly lower cortisol concentrations with compensatory elevation of plasma ACTH levels, which should theoretically promote growth of adrenal rest tissue and lead to development of TART [3, 15]. ACTH levels have been previously correlated to the prevalence of TART in adult males [16]. One possible explanation for the decreased prevalence of TART in pediatric patients, however, is that a prolonged postnatal duration of exposure to elevated ACTH levels is important in stimulating the growth of TART [17].…”

Testicular Adrenal Rest Tumours: fisiopatologia, diagnosi e trattamento

“…Infine, la presenza dei TARTs si associa a un peggior controllo ormonale nei pazienti con CAH, con livelli di ACTH [18], 17-OH-progesterone e androstenedione significativamente più elevati rispetto ai pazienti privi di queste [13,19] manifestazioni. Un inadeguato compenso ormonale, specialmente se protratto nel tempo, può avere notevoli implicazioni cliniche, come età ossea avanzata e bassa statura in pazienti pediatrici [20].…”

“…A differenza dei tumori a cellule di Leydig, i TARTs sono tipicamente bilaterali e hanno origine a livello del mediastino testicolare Inoltre, non è chiaro se il contributo della terapia corticosteroidea alla riduzione dei TARTs sia dovuto all'incremento della dose totale di glucocorticoidi, alla somministrazione anti-circadiana degli stessi o all'utilizzo di formulazioni a base di steroidi a più lunga emivita (desametasone piuttosto che prednisone). Ad ogni modo, l'adozione di un dosaggio modificato di glucocorticoidi non sembra determinare un significativo miglioramento dei parametri seminologici [18] e, allo stesso tempo, aumenta il rischio di sviluppo di effetti collaterali legati all'eccesso di glucocorticoidi, come ipertensione arteriosa, striae rubrae, incremento ponderale, riduzione dell'altezza target negli adolescenti.…”