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

We report one patient with 21-hydroxylase deficiency and associated bilater al macro-orchidism caused by nodular hyperplasia of testicular adrenal rest s (TAR). The boy, referred to us when 10 years old, was born with bilateral cryptorchidism that was treated unsuccessfully with i.m. injections of hum an chorionic gonadotropin (hCG) and later on with orchidopexy. He was treat ed 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 >1 04 to 4.8 nmol/l, estradiol (E-2) from 481 to 33 pmol/l), After the same pe riod of time, both testicular volume and nodularity decreased: from 45 to 1 8 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 y ear, there were transient increases in serum gonadotropins, testicular volu me (right testis = 25 ml, left testis = 20 ml) and steroid hormones, includ ing cortisol (serum ACTH and dehydroepiandrosterone sulfate remained suppre ssed). At the fourth year of follow-up, there were still four nodules in th e right testis and three in the left testis. The LH-dependency (which impli es possession of LH/hCG receptors) of these nodules was also substantiated by their steroidogenic response to an acute i.m. hCG test, An exogenous ACT H stimulation test increased serum 17-OH P and cortisol. Since these nodule s, unlike the majority of those present initially were not suppressed by th e corticosteroid therapy and since they were not detected when the patient returned for control at 23 years of age, they had partial autonomy from ACT H. 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 hav e accounted for the consistent difference in size between the two gonads. S erum LH was about 7 mU/l and FSH about 23 mU/l. The responsiveness of plasm a steroid hormones to hCG had changed quantitatively and qualitatively. Sec retion of cortisol was absent, secretion of 17-OH P and testosterone was re duced, and secretion of E-2 was much increased. The ACTH stimulation test s howed that serum cortisol did not respond, while the other steroids respond ed 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 an d three in the right testis), (iii) almost entirely ACTH-insensitive and pa rtially hCG-insensitive (a single nodule in the right testis). Probably, th e never suppressed gonadotropin levels (presumably due to the bilateral tes ticular damage subsequent to the cryptorchid state) and the hCG therapy wer e major etiological factors for the appearance of the second and third popu lation of TAR.