Prevalent decrease of the EGF content in the periurethral zone of BPH tissue induced by treatment with finasteride or flutamide.

The aim of the present investigation is to verify whether treatment with Finasteride or Flutamide influences the regional distribution of testosterone (T), dihydrotestosterone (DHT), and epidermal growth factor (EGF) in benign prostatic hyperplasia (BPH) tissue. Thirty seven BPH patients were studied: 15 untreated, 9 treated with Flutamide (750 mg/day for 2 months), and 13 treated with Finasteride (5 mg/day for 3 months). Testosterone and DHT were evaluated by radioimmunoassay (RIA) after purification of the extracts on celite columns, and EGF was evaluated by RIA after purification on Sep-pak C18 cartridges in total tissue and in periurethral, subcapsular, and intermediate zone. In the untreated group, T, DHT, and EGF of the periurethral region are higher than those of the subcapsular zone (P < 0.01 for T and P < 0.001 for DHT and EGF). In the Flutamide group, DHT is not modified, T is increased (P = 0.045), and EGF is decreased in total tissue (P < 0.02) and in the periurethral zone (P < 0.01). In the Finasteride group, T is increased (P < 0.001), and DHT and EGF are decreased (P < 0.001), particularly in the periurethral zone. A positive linear correlation between DHT and EGF is observed in the Finasteride and in the untreated groups. In conclusion, in BPH the production of EGF is a DHT-dependent receptor-mediated function. The reduction of this growth factor during both treatments, associated with a fall of DHT in only the Finasteride group, is particularly evident in the periurethral zone. Since Finasteride reduces prostatic volume, mainly of the periurethral zone, we can speculate that DHT is responsible, either directly or indirectly through growth factors such as EGF for the enlargement of this region and thus responsible for urinary obstruction.

Regional distribution of epidermal growth factor, testosterone and dihydrotestosterone in benign prostatic hyperplasia tissue.

In benign prostatic hyperplasia (BPH), basic fibroblast growth factor (bFGF) is found to have a regional distribution, with concentrations in the periurethral zone (where the primitive fibrostromal nodule originates) higher than those of the peripheral subcapsular zone. The aim of the present investigation was to verify whether androgens and epidermal growth factor (EGF) are uniformly distributed from the periurethral to the peripheral zone or whether they show regional differences. Tissue samples, removed by transvesical resection from nine untreated BPH patients, sectioned in periurethral, subcapsular, and intermediate zones, were examined. In the periurethral zone, dihydrotestosterone (DHT), testosterone, and EGF, determined by radioimmunoassay (RIA) techniques after purification on Celite microcolumns and Sep-pak C18 cartridge, showed values significantly higher (mean +/- SD: 1121 +/- 482 pg, 250 +/- 129 pg, and 6.89 +/- 3.28 ng/mg DNA, respectively; P < 0.01) than those of the subcapsular zone (489 +/- 190 pg, 114 +/- 70 pg, and 3.40 +/- 1.90 ng/mg DNA, respectively). A positive linear correlation between EGF, testosterone, and DHT was also observed. The regional distribution of EGF, testosterone, and DHT was similar to that found for bFGF: the highest levels of these factors in the periurethral region allow us to hypothesize on their possible involvement in the rewakening of mesenchymal tissue, leading to the formation of the primitive fibrostromal nodule and then to BPH development.

Effects of dihydrotestosterone treatment on adrenal gland function and morphology in adult female guinea-pigs.

The effect of chronic treatment of female guinea-pigs with dihydrotestosterone (DHT) on growth and function of the adrenal gland and, in particular, on the reticular zone is described. Two groups of 6 young adult, female guinea-pigs were treated with DHT (1 mg/kg dissolved in peanut oil and injected s.c.) for 30 and 60 days. Two other groups of animals, treated only with oil, were used as controls. At the end of treatment, animals were killed and adrenal glands were quickly removed. Plasma levels of pregnenolone, dehydroepiandrosterone (DHA) and its sulfate (DHA-S), 17 alpha-hydroxyprogesterone, androstenedione, testosterone, estradiol, 11-deoxycortisol, androstenedione, DHT and 3 alpha-androstanediol were determined by R.I.A. following celite microcolumn chromatography. Animals treated for 30 days showed only elevated DHT and 3 alpha-androstanediol plasma levels, whereas animals treated for 60 days also showed increased values of pregnenolone (251 +/- 62 vs 193 +/- 51 ng/dl; P less than 0.05), DHA-S (12,046 +/- 4110 vs 2780 +/- 888 ng/dl; P less than 0.001) and slightly increased values of DHA (110 +/- 31 vs 86.5 +/- 55.4). In the 30-day-treated animals no histological changes were observed, but in the 60-day-treated group the total size as well as cell volumes of the zona reticularis were significantly increased. Normal estrous cycles were observed in the 30-day-treated animals whereas the 60-day-treated animals showed a progressive acyclicity during the second month of treatment. These results indicate that in guinea-pigs, prolonged treatment with DHT induces a growth of the zona reticularis of the adrenal gland associated with increased levels of 5-ene steroids, particularly DHA-S. The mechanisms inducing these modifications are probably mediated by a DHT effect at the hypothalamic-pituitary level. A direct effect of DHT on the zona reticularis, however, cannot be excluded.

Testicular responsiveness to a single hCG dose in patients with testicular feminization.

The suggestion that androgens may regulate testosterone (T) production in rat Leydig cells by a receptor-mediated feed-back mechanism, led us to investigate whether in vivo the absence of testicular androgen receptors, as it occurs in testicular feminization (TF), may modify the characteristic testicular response observed in men and prepubertal children after a single dose of hCG. Subjects consist of: 1) six normal men, 2) two adult patients with the complete form of androgen insensitivity syndrome (TF), 3) 12 normal prepubertal boys, 4) one prepubertal boy with the same form of TF. Each subject received i.m. a single dose of hCG 3500 IU/m2 b.s. and blood samples were collected basally and 2, 4, 24, 48, 72 and 96 hours after the hormonal stimulus. Serum levels of T, 17 alpha hydroxyprogesterone (17OHP) and 17 beta estradiol (E2) were measured at each collection time. In normal men a significant increase in T (M +/- SE) was observed at 4 h (758.6 +/- 135 ng/dl, P less than 0.05) and a more significant increase at 48 h (1082 +/- 60.3 ng/dl, P less than 0.001). E2 and 17OHP peaked significantly at 24 h (81.5 +/- 9.6 pg/ml and 460.7 +/- 90.9 ng/dl respectively). This response pattern is characteristic of the testicular desensitization which occurs in normal man after a single hCG dose. The same response pattern has been observed in the two TF adult patients suggesting that human testicular desensitization in vivo does not depend on androgen receptors.(ABSTRACT TRUNCATED AT 250 WORDS)

Changes in steroid pattern following acute and chronic adrenocorticotropin administration in premature adrenarche.

Biochemically adrenarche is characterized by increased production of 5-ene steroids, in particular Dehydroepiandrosterone (DHA) and its sulphate (DHA-S). It is still not clear if ACTH is responsible for this adrenal steroid production. The aim of the present study was to evaluate the effect of acute and chronic ACTH administration, without dexamethasone pretreatment, on hormonal patterns in 20 patients (5 males aged between 6 8/12 and 7 10/12 years and 15 females aged between 5 9/12 and 7 6/12 years) with idiopathic premature adrenarche. Pregnenolone (5P), DHA, DHA-S, 17-hydroxyprogesterone (17-OHP), androstenedione (A), 11-deoxycortisol (S) and cortisol (F) have been determined by Radioimmunoassay. The results of the hormonal evaluation (means +/- standard error) showed high plasma levels of DHA [329.2 +/- 41.7 ng/100 ml (dl)] and DHA-S (169.1 +/- 54 micrograms/dl) and slightly increased levels of 5P (74.4 +/- 7.1 ng/dl), of A (45.4 +/- 4.6 ng/dl) and 17-OHP (69.3 +/- 11.3 ng/dl) in comparison to those of controls, thus indicating a decrease in 3 beta-hydroxysteroid dehydrogenase activity and an increase in 17-20-lyase and 17-hydroxylase activities, characteristic for adrenarche. Acute and chronic ACTH stimulation did not amplify the characteristic basal hormonal pattern, but they induced a shift of adrenal steroid metabolism to 4-ene pathway, suggesting that the basal hormonal pattern in premature adrenarche may be independent or, at least, not exclusively dependent on ACTH control.

Spermatic and peripheral venous plasma concentrations of testosterone, 17-hydroxyprogesterone, androstenedione, dehydroepiandrosterone, delta 5-androstene-3 beta,17 beta-diol, dihydrotestosterone, 5 alpha-androstane-3 alpha,17 beta-diol, 5 alpha-androstane-3 beta,17 beta-diol, and estradiol in boys with idiopathic varicocele in different stages of puberty.

Serum testosterone (T), 17-hydroxyprogesterone (17P), androstenedione (delta 4-dione), dehydroepiandrosterone (DHA), delta 5-androstene-3 beta, 17 beta-diol (delta 5-diol), estradiol (E2), dihydrotestosterone (DHT),5 alpha-androstane-3 alpha,17 beta-diol (3 alpha diol), and 5 alpha-androstane-3 beta,17 beta-diol (3 beta diol) were measured in the peripheral and spermatic venous blood of 21 boys undergoing surgery for idiopathic left varicocele. The boys were divided into 3 groups according to their pubertal development: prepubertal (group 1 or P1; n = 8), pubertal stage 2 (group II or P2; n = 6), and pubertal stages 3-4 (group III or P3-4; n = 7). The testes of the prepubertal boys secreted T, 17P, DHA, delta 5-diol, DHT, and 3 alpha diol, but not delta 4-dione, E2, and 3 beta diol. In pubertal stage P2, the mean spermatic-peripheral secretory gradients of T, 17P, DHA, delta 5-diol, DHT, and 3 alpha diol were significantly higher than those in the prepubertal stage, and there was testicular secretion of delta 4-dione, E2, and 3 beta diol. In pubertal stage P3-4, the mean spermatic-peripheral secretory gradients of most of these steroids, even if increased, were not significantly different from those in stage P2 (with the exception of 17P, delta 5-diol, and DHA). We suggest that after the important modifications of testicular secretion occurring in pubertal stage P2, the testicular secretory pattern of the pubertal testis is similar to the pattern of the adult testis. We suggest also that these results, obtained in boys with idiopathic varicocele, can probably be extended to the secretory activity of the testes of normal pubertal boys.

Response to a single dose of human chorionic gonadotropin in prepubertal boys.

In normal men a single dose of hCG induces an increase in plasma testosterone (T) and 17 alpha-hydroxyprogesterone (17 alpha-OHP) 2-4 h after the injection; after 24-36 h a maximum increase in plasma 17 beta-estradiol (E2) and 17 alpha-OHP occurs followed by a second surge in T after 48-96 h. The present investigation focuses on the effect of a single dose of hCG (3500 IU/m2 body surface) on testicular steroid production in 12 boys aged 13 months to 12 yr. Plasma hCG, 17 alpha-OHP, androstenedione (A), T, dihydrotestosterone, and E2 were measured basally and 2, 4, 24, 48, 72, and 96 h after hCG administration. Plasma hCG was measured using a double antibody RIA technique and steroids by RIA after celite chromatography. The results show that hCG peaked 2 h after administration of the hormone and high levels persisted for up until 72 h. Plasma T and dihydrotestosterone increased after 48 h and remained significantly high for another 48 h; 17 alpha-OHP, A, and E2 did not change. These findings show that hCG stimulation in prepubertal boys induces significant production of T without affecting the precursors or aromatization product, in contrast to observation in the adult man, where 17 alpha-OHP, A, and E2 increase significantly. A response comparable to that observed in children has been recorded in adult males with hypogonadotropic hypogonadism.

Is hirsutism an evolving syndrome?

The possibility that hirsutism is an evolving syndrome rather than a static condition involving only one gland has been considered. To assess this proposal 60 untreated hirsute patients aged 12-32 years were divided into five groups according to the duration of the hirsutism (less than 1, 1-2, 2-3, 3-5 and greater than 5 years). Peripheral plasma concentrations of LH and FSH, androstenedione, dehydroepiandrosterone sulphate, testosterone, 5 alpha-dihydrotestosterone, 5 alpha-androstane-3 alpha, 17 beta-diol, 5 alpha-androstane-3 beta, 17 beta-diol, cortisol, oestradiol-17 beta and oestrone were determined by radioimmunoassay. When the values obtained were compared with those from normal menstruating women, the results showed that in group I there was a significant increase only in the mean plasma 5 alpha-androstane-3 alpha, 17 beta-diol concentration. The mean concentration of this steroid was also raised in all other groups. In groups II and III mean basal levels of plasma dehydroepiandrosterone sulphate were also significantly increased and showed a marked increase after ACTH stimulation (1 mg tetracosactide acetate, i.m.) as did the concentrations of androstenedione and 17 alpha-hydroxyprogesterone. Finally, in groups IV and V, a significant increase in mean plasma concentrations of LH, androstenedione, oestrone and testosterone was found in the basal condition. The clinical picture also became gradually more severe from group I to group V. These data suggest that hirsutism could be an evolving syndrome progressively involving peripheral androgen metabolism, the adrenal gland and finally the ovary possibly through alterations of hypothalamic-pituitary function.

Is 3 alpha-androstanediol a marker of peripheral hirsutism?

The behaviour of 5 alpha-reduced metabolites of testosterone, dihydrotestosterone1, 3 alpha-androstanediol and 3 beta-androstanediol, was studied in 36 hirsute women: Group I: 24 patients with high plasma levels of testosterone, androstenedione and/or dehydroepiandrosterone sulphate and Group II: 12 patients with normal plasma concentrations of these steroids. Testosterone and its 5 alpha-reduced metabolites were determined by radioimmunoassay after chromatographic separation on celite 535 microcolumns. Plasma 3 alpha-androstanediol was found to be elevated both in Group I (26.9 +/- 10.8 SD ng/100 ml) and in Group II patients (23.2 +/- 10.5 SD ng/100 ml). 3 beta-Androstanediol and dihydrotestosterone, on the contrary, were elevated in only a few cases: in 6 cases in Group I and in 2 and in 1 case, respectively, in Group II. The finding of high plasma 3 alpha-androstanediol levels in hirsute women, with normal values of the other androgens, may be an index of hirsutism of peripheral origin, since this steroid is produced almost exclusively in the extraglandular compartment.

The hormone pattern in a case of arrhenoblastoma.

A case of ovarian arrhenoblastoma in a 14-year-old girl is reported. The patient presented with primary amenorrhea, severe diffuse hirsutism, moderate clitorial enlargement and slight decrease in breast size. Hormonal examinations revealed high plasma testosterone and androstenedione levels, normal plasma prolactin, drhydroepiandrosterone-sulphate, 17-alpha-hydroxyprogesterone, urinary 17 beta oestradiol, oestrone, FSH and LH. Androgen concentrations decreased under dexamethasone suppression test. Following tumor ablation menses occurred spontaneously and normal hormone patterns were observed.