Testicular adrenal rests: evidence for luteinizing hormone receptors and for distinct types of testicular nodules differing for their autonomization

Abstract

We report one patient with 21-hydroxylase deficiency and associated bilateral macro-orchidism caused by nodular hyperplasia of testicular adrenal rests (TAR). The boy, referred to us when 10 years old, was born with bilateral cryptorchidism that was treated unsuccessfully with i.m. injections of human chorionic gonadotropin (hCG) and later on with orchidopexy. He was treated with oral dexamethasone (0.625 mg per day) for the following 13 years.After one year, there was a marked reduction in steroid hormone levels (17-hydroxyprogesterone (17-OH P) from 27.2 to 1.2 nmol/l, testosterone from >104 to 4.8 nmol/l, estradiol (E 2 ) from 481 to 33 pmol/l). After the same period of time, both testicular volume and nodularity decreased: from 45 to 18 ml and from numerous to four nodules in the right testis, and from 40 to 13 ml and from numerous to three nodules in the left testis. At the third year, there were transient increases in serum gonadotropins, testicular volume (right testis = 25 ml, left testis = 20 ml) and steroid hormones, including cortisol (serum ACTH and dehydroepiandrosterone sulfate remained suppressed). At the fourth year of follow-up, there were still four nodules in the right testis and three in the left testis. The LH-dependency (which implies possession of LH/hCG receptors) of these nodules was also substantiated by their steroidogenic response to an acute i.m. hCG test. An exogenous ACTH stimulation test increased serum 17-OH P and cortisol. Since these nodules, unlike the majority of those present initially, were not suppressed by the corticosteroid therapy and since they were not detected when the patient returned for control at 23 years of age, they had partial autonomy from ACTH. At 23 years of age, the patient had a single nodule in the right testis (right testis volume = 13 ml, left testis volume = 10 ml), which should have accounted for the consistent difference in size between the two gonads. Serum LH was about 7 mU/l and FSH about 23 mU/l. The responsiveness of plasma steroid hormones to hCG had changed quantitatively and qualitatively. Secretion of cortisol was absent, secretion of 17-OH P and testosterone was reduced, and secretion of E 2 was much increased. The ACTH stimulation test showed that serum cortisol did not respond, while the other steroids responded in the order of 17-OH P > E 2 > testosterone.We conclude that there were three different groups of TAR when the patient was already 10 years old: (i) ACTH-sensitive (the majority), (ii) partially ACTH-insensitive but LH/hCG-sensitive (three nodules in the left testis and three in the right testis), (iii) almost entirely ACTH-insensitive and partially hCG-insensitive (a single nodule in the right testis). Probably, the never suppressed gonadotropin levels (presumably due to the bilateral testicular damage subsequent to the cryptorchid state) and the hCG therapy were major etiological factors for the appearance of the second and third population of TAR.

Prevalence of testicular adrenal rest tumours in male children with congenital adrenal hyperplasia due to 21-hydroxylase deficiency

“…It can be suggested that hormones whose levels are increased in puberty, such as LH, are additional stimulators of tumour growth. The presence of LH receptors in testicular tumour tissue supports this hypothesis (24).…”

The prevalence of testicular adrenal rest tumors and associated factors in postpubertal patients with congenital adrenal hyperplasia caused by 21-hydroxylase deficiency

“…In multiple regression analysis, the maximal cross-sectional area of a TART was transformed to the logaels, the adrenal tissue remnants become hyperplastic and eventually develop tumors. Thus, TARTs are also found in other diseases with high ACTH levels, such as Nelson's syndrome and Cushing's disease [11], and the size of a TART is reduced by adequate suppression of ACTH secretion by treatment [12]. TARTs do not occur in patients with nonclassic or late-onset CAH, because ACTH level is not elevated enough [3].…”

“…First, we excluded prepubertal patients in our study. ACTH, angiotensin II (AII), and luteinizing hormone (LH) are known as trophic factors of TARTs, and LH receptors may exist in testicular adrenal rest tissue [3,11]. Therefore, increased LH levels might promote the growth of a TART during puberty [11,17].…”

“…ACTH, angiotensin II (AII), and luteinizing hormone (LH) are known as trophic factors of TARTs, and LH receptors may exist in testicular adrenal rest tissue [3,11]. Therefore, increased LH levels might promote the growth of a TART during puberty [11,17]. In a study of 2-18-yearold patients, [17] TARTs were found in eight patients, six of whom were older than 10 years.…”

Tumores testiculares bilaterais por hiperplasia congênita de restos adrenais

“…Como receptores LH são encontrados em HRA, isso poderia explicar o aumento da prevalência de HRA na puberdade e em pacientes pós-púberes com HAC, mesmo quando há bom controle hormonal (8). Assim, é possível que os tumores testiculares encontrados em pacientes portadores de HAC sejam resultantes da hiperplasia desse tecido adrenocortical ectópico na gônada estimulada pelos níveis elevados de ACTH e, provavelmente, também pelo LH e AII (3,8,10).…”