Epidermal growth factor receptor-negative tumors are predominantly confined to the subgroup of estradiol receptor-positive human primary breast cancers.

A total of 725 human primary breast tumor biopsy samples were analyzed for epidermal growth factor receptor (EGFR) content, using a multiple-point EGFR assay standardized in accordance with the recommendations of the European Organization for Research and Treatment of Cancer Receptor Study Group. After the establishment of a lower cell membrane protein threshold of 0.2 mg of membrane protein per ml of assay buffer, the results of 27% (194 samples) of the EGFR determinations were excluded from the study because of insufficient assay membrane protein content. Of the remaining 531 breast tumor biopsy samples, 57% (302 samples) were shown to be EGFR positive by Scatchard analysis, with a median value of 40 fmol/mg of membrane protein. Of the breast tumor biopsy samples, 72% (380 samples) were estrogen receptor (ER) positive, and 65% (344 samples) were progesterone receptor (PgR) positive. EGFR positivity was found in 46% (173 of 380) of ER-positive and in 85% (129 of 151) of ER-negative breast tumor biopsy samples (P less than 0.0001), as well as in 49% (168 of 344) of PgR-positive and in 72% (134 of 186) of PgR-negative breast tumor biopsy samples (P less than 0.0001). Mean EGFR levels in ER-positive breast tumor biopsy samples were lower than they were in ER-negative ones, 40 +/- 31 (SD) against 72 +/- 55 fmol/mg of membrane protein (P less than 0.0001). Similarly, mean EGFR levels in PgR-positive breast tumor biopsy samples were lower than they were in PgR-negative ones, 41 +/- 29 against 70 +/- 56 fmol/mg of membrane protein (P less than 0.0001). Both EGFR positivity and EGFR levels decreased with increasing steroid hormone receptor levels. A multivariate analysis showed only ER to be independently associated with EGFR.

p53 protein accumulation predicts poor response to tamoxifen therapy of patients with recurrent breast cancer.

PURPOSE: Mutations of the p53 gene are frequently observed in primary breast cancer and accumulation of p53 protein has been used as a surrogate marker of p53 inactivation. Previous studies have shown that p53 accumulation is related to poor prognosis in primary breast cancer. We studied whether p53 protein accumulation is a predictive factor for response to tamoxifen treatment in patients with recurrent breast cancer. PATIENTS AND METHODS: Levels of p53, estrogen receptor (ER), progesterone receptor (PgR), and urokinase-type plasminogen activator (uPA) were assayed in cytosolic extracts derived from primary tumors of 401 tamoxifen-naive patients who developed recurrent disease. All patients in the study received tamoxifen therapy upon relapse (median follow-up, 69 months). Association of tested factors with response to tamoxifen treatment was studied by logistic regression analysis, and with survival after the start of treatment by Cox univariate and multivariate regression analysis. RESULTS: p53 levels (median, 0.23 ng/mg protein) were not related to ER or PgR levels, but positively correlated with uPA (P < .0001). In a test for trend, we observed an association of p53 protein levels with response to tamoxifen therapy. When dichotomized (at the median value), 42% in the p53-high versus 56% in the p53-low group showed a response. In multivariate analysis, including patient and tumor characteristics, p53 accumulation retained significance with the rate of response (odds ratio [OR], 0.48; 95% confidence interval [CI], 0.31 to 0.74; P < .001). Also in multivariate analysis, reduced survival after the start of tamoxifen therapy was observed in the p53-high group (relative hazards rate [RHR], 1.56, 95% CI, 1.17 to 2.10; P = .002). A statistically significant association between p53 levels and decreased tamoxifen response was seen only in the subset of patients whose tumors expressed low levels of ER or PgR (<75 fmol/mg protein). CONCLUSION: Measurement of primary tumor p53 levels may be effective in predicting response to tamoxifen therapy in recurrent breast disease. However, more confirming studies on the association between p53 protein accumulation and response to antiestrogen therapy are needed before tumor p53 levels can be used in routine clinical practice.

Early time sequence in pregnenolone metabolism to testosterone in homogenates of human and rat testis.

The time sequence of the metabolism of [4-14C] pregnenolone to testosterone in homogenates of human and rat testis was studied with special emphasis on the chain of events in the early 15 min of incubation. The incubations were performed at 32 C in the presence of NAD and a NADPH-generating system. The various intermediate steroids were separated by means of HPLC using a silica aliphatic diol column. Correction for procedural losses was performed by dual labeling. The present study confirms earlier reported results which showed that in the rat metabolism of pregnenolone to testosterone proceeds via the delta 4 pathway. However, this discloses for the first time that the conversion of pregnenolone proceeds very fast: progesterone, 17 alpha-hydroxyprogesterone, and 17 alpha-hydroxypregnenolone as the only important delta 5 intermediate, peak and decline again to almost undetectable levels within the first 15 min of incubation. Androstenedione and testosterone start to accumulate from 1 min on under the conditions used. In contrast, in the human testis, homogenates metabolism of pregnenolone to testosterone proceeds comparatively slowly and almost exclusively via the delta 5 intermediates dehydroepiandrosterone and androstenediol. Testosterone makes its appearance only after about 8 min of incubation. The data illustrate the importance of short-term incubations in evaluating the metabolism of steroids.

Continuous infusion of interleukin-1 beta induces a nonthyroidal illness syndrome in the rat.

We studied the effects of continuous administration of recombinant human interleukin-1 beta (IL-1) on pituitary-thyroid function. Rats were equipped with minipumps loaded with either IL-1 (delivery rate, 0.5, 2.0, or 4.0 micrograms/day, ip, for 1 week) or saline. Infusion of 2.0 and 4.0 micrograms IL-1/day caused a significant decrease in plasma free T4 levels during the first 2-4 days, whereas plasma total T4 levels and T4 binding were significantly lowered throughout the week of the study. The infusion of 0.5 micrograms IL-1/day did not significantly change plasma TSH or total and free T4 levels. During the infusion of 2.0 micrograms IL-1/day, the decrease in plasma free T4 levels was paralleled by a significant decline in plasma TSH values and an impaired TSH responsiveness to TRH administration on the second day of infusion. IL-1 (2.0 micrograms/day) treatment significantly lowered plasma levels of T4-binding prealbumin, whereas it did not influence the plasma T3/T4 ratio or hepatic 5'-deiodinase activity. Plasma rT3 levels remained undetectable in both control and IL-1-treated rats. Chronic infusion of rats with 4.0 micrograms IL-1/day induced prolonged fever, whereas at the lower doses of IL-1, temperatures were elevated only on the first 2 days. IL-1 at doses of 2.0 and 4.0 micrograms/day induced a transient decrease in food intake and a suppression of body weight gain. Restriction of food consumption to the level observed in the 2.0 micrograms IL-1 experiment caused small decreases in T3, total and free T4, and TSH levels compared to those in ad libitum fed rats, but had no effects on T4 binding. We conclude that 1) continuous infusion of rats with 2.0 and 4.0 micrograms IL-1/day induces changes in thyroid economy commonly seen during infectious diseases and other systemic illnesses in rats [decreased plasma levels of TSH, T3, and (free) T4; diminished T4 binding; and decreased plasma T4-binding prealbumin levels], 2) the decrease in food intake during IL-1 treatment cannot completely explain the observed changes in thyroid hormone and TSH levels; and 3) it is highly unlikely that the decrease in thyroid hormone binding during chronic IL-1 infusion is caused by decreased food intake. Further studies are needed to clarify whether the observed alterations in thyroid economy during IL-1 infusion reflect direct effects of IL-1 per se or indirect effects caused by the mild illness induced by the cytokine.

Chronic stimulation of the pituitary-adrenal axis in rats by interleukin-1 beta infusion: in vivo and in vitro studies.

It has been shown that acute administration of interleukin-1 (IL-1) to rats elicits a transitory increase in plasma ACTH and corticosterone (B) levels. To investigate the effects of chronic administration of IL-1 on plasma ACTH and B levels, in the present study rats were equipped with Alzet osmotic minipumps loaded with either IL-1 (delivery rate 0.5, 2.0, or 4.0 micrograms/24 h, ip, for 1 week) or saline. At the end of the treatment the rats were decapitated, the adrenals were weighed, and the in vitro release of beta-endorphin (beta E) by the anterior pituitary and that of B by the adrenal gland were measured. Continuous administration of 2.0 and 4.0 micrograms IL-1/24 h resulted in a persistent increase in plasma ACTH and B concentrations compared to the levels in saline-infused rats, with peak levels on the first day of administration. In addition, adrenal weights of IL-1 rats were significantly higher than those of saline rats. The 4.0-micrograms IL-1/day in vivo treatment induced an increase in spontaneous in vitro secretion of beta E and B, while the in vitro responses of the pituitary (to CRF) and the adrenal (to ACTH) of animals treated in vivo with IL-1 were significantly diminished. IL-1 at a dose of 0.5 microgram failed to affect plasma ACTH and B values, adrenal weight, and in vitro beta E and B secretion. Chronic infusion of rats with 4.0 micrograms IL-1/day induced prolonged fever, whereas at lower doses of IL-1 (2.0 and 0.5 micrograms), temperatures were elevated only on the first 2 days of infusion. IL-1 at doses of 2.0 and 4.0 micrograms/day induced suppression of body weight gain on the first 2 days of the treatment period compared to saline treatment. Plasma norepinephrine and/or epinephrine concentrations were raised only on day 1 of the 2.0- and 4.0-micrograms IL-1 experiments. Thus, the observed effects of IL-1 on the hypothalamo-pituitary-adrenal axis probably do not result merely from stress induced by the treatment. Taken together, our data show the potential of IL-1 to induce a dose-dependent and long term activation of the pituitary-adrenal axis.

Plasma testosterone profiles in Cushing's syndrome.

Elevated plasma testosterone levels were found in 8 women with Cushing's disease and oligo-or amenorrhea and/or hirsutism. In 4 men with Cushing's syndrome either due to adrenal hyperplasia or adenoma, plasma testosterone levels were lowered. Three of these 4 men complained of impotence or loss of libodo. Evidence for a major adrenal origin of the elevated testosterone values in the women with Cushing's disease was derived from the parallel suppression of cortisol and testosterone during dexamethasone administration, the testosterone responsiveness to ACTH and its dramatic fall after adrenalectomy. In the men with Cushing's syndrome the lowered plasma testosterone values were further suppressed by high doses of dexamethasone irrespective of concomitant cortisol suppression. Adrenalectomy or adenotomy restored the decreased plasma testosterone levels to normal. In women with Cushing's syndrome adrenal hyperandrogenism may account for the sexual and gonadal disturbances, in men glucocorticoid induced suppression of Leydig cell function may be responsible.

Circannual cycle in plasma testosterone levels in man.

In a groups of 15 healthy male subjects a statistically significant circannual cycle in plasma testosterone levels was assessed by sampling blood at 3-monthly intervals. Peak levels were found in summer and early autumn and a nadir in the winter and early spring.

Nocturnal, daytime, and postural changes of plasma aldosterone before and during dexamethasone in adenomatous and idiopathic aldosteronism.

The relative importance of ACTH and the renin angiotensin system for control of aldosterone was studied in eight patients with adenomatous primary (APA) and four with idiopathic aldosteronism (IHA). Plasma aldosterone (PA) and cortisol (PC) were measured in blood collected during the night at 15-min intervals between 0500--0800 h by integrated sampling on day 1 and in casual samples during the daytime while patients were in the upright and in the supine position (days 1 and 2, at 1200, 1600, and 2000 h). PRA was measured in all daytime samples. On days 3, 4, and 5, 2 mg dexamethasone were given, and the same protocol for blood sampling was repeated on days 4 and 5. During the night, mean PA in IHA patients was markedly lower than that in APA patients. PA patients correlated with PC in both groups. Dexamethasone reduced the mean nocturnal PA in both groups to equal proportions. In the daytime, the mean recumbent PA in IHA patients was also significantly lower than that in APA patients but was equal in both groups while subjects were in the upright posture. Daytime PA significantly correlated with PC in APA patients and with PRA in IHA patients. During upright posture, dexamethasone did not reduce daytime PA in either group. In the supine position, dexamethasone reduced daytime PA values in APA but not in IHA patients. Thus, short time fluctuations of PA during the night are equally influenced by ACTH in APA and IHA patients, though at markedly different levels of aldosterone production. During the daytime, the influence of ACTH on PA remains apparent in the group with APA. However, the renin-angiotensin system seems to play a predominant role in the control of PA during the daytime in patients with IHA. During dexamethasone and ACTH suppression, PA in APA patients rises in response to upright posture as it does in IHA patients.

Lack of a biphasic steroid response to single human chorionic gonadotropin administration in patients with isolated gonadotropin deficiency.

Single im administration of 1500 IU hCG evoked a biphasic response of 17-hydroxyprogesterone (17-OHP) and testosterone (T) in six eugonadotropic men, with an early peak after 4 h, a nadir at 5 h, and a second peak 24 and 72 h after hCG loading, respectively. Remarkably, in six patients with isolated gonadotropin deficiency, the early rise of both 17-OHP and T was absent, whereas the late peak was attenuated and somewhat delayed. This lack of an immediate response in these hypogonadotropic patients might be accounted for by the lack of gonadotropin-induced enzyme systems capable of rapid steroid synthesis. In the normal men, the 17-OHP rise was more pronounced than the T increase, and thus, from 4 h on, a gradually rising 17-OHP to T ratio was observed, which reached its maximum 24 h after the hCG injection. In contrast, in the hypogonadotropic patients, the 17-OHP to T ratio did not rise but rather decreased to minimal values 72 h after hCG loading. These data suggest that in normal men, but not in hypogonadotropic patients, hCG may rapidly modify steroidogenesis by temporarily depressing the conversion of 17-OHP to T.

Dissociated responses of plasma testosterone and 17-hydroxyprogesterone to single or repeated human chorionic gonadotropin administration in normal men.

After both single (1500 IU) and daily repeated (1500 IU daily for 3 days) im administration of hCG, peak values of 17-hydroxyprogesterone (17OHP) were achieved 24 h after the single or first injection, whereas plasma testosterone (T) levels reached their maximum 48 h later. After the peak value of 17-OHP at 24 h, both steroids ran dissociated courses with the T levels rising and the 17-OHP levels falling. In both the single and repeated hCG experiments, the initial rise of 17-OHP was more pronounced than that of T, leading to a steep temporary increase of the 17-OHP to T ratio in the first 24 h. Repeated hCG administration for 3 days to the same subjects elicited T responses at 48 and 72 h quantitatively similar to those produced by single hCG loading, although the 17-OHP response appeared slightly higher in the multiple dose experiment. The data indicate that exogenous gonadotropins may influence testicular steroidogenesis not only quantitatively, but also qualitatively, possibly by altering enzyme activities.

Residual adrenocortical function after bilateral adrenalectomy for pituitary-dependent Cushing's syndrome.

The incidence of residual, functioning adrenal tissue in patients treated by total bilateral adrenalectomy for Cushing's disease is not known. Between 1962 and May 1988 50 patients with Cushing's disease were treated by bilateral adrenalectomy. Of these patients, 29 underwent surgery between 1962 and 1980, when bilateral adrenalectomy was the treatment of first choice in our hospital in patients with pituitary-dependent Cushing's syndrome. In 37 patients the presence or absence of cortisol-producing tissue could be evaluated (follow-up period, median and range, 8.3 and 0.1-18.9 yr). Evidence of functioning cortisol-producing tissue (plasma cortisol level > 50 nmol/L after stopping glucocorticoid and mineralocorticoid substitution therapy for 24 h) was found in 9 patients (24%). Plasma cortisol levels in these 9 patients varied between 60 and 330 nmol/L (mean +/- SD, 180 +/- 100 nmol/L). Signs and symptoms of recurrent Cushing's syndrome were present in only 1 patient. There was no difference in plasma ACTH levels and duration of follow-up between the patients with and without evidence of functioning cortisol-producing tissue. In all 9 patients detectable aldosterone levels indicated endogenous mineralocorticoid production, whereas in only 1 patient adrenaline was detectable in the circulation. In 8 of the 9 patients suspected of functioning cortisol-producing tissue we performed a stimulation test with synthetic ACTH (1-24). In 2 patients plasma cortisol levels rose, in 6 they remained virtually unchanged. Although we found clinically relevant signs and symptoms of Cushing's syndrome in only 1 of the 50 patients, the relatively high incidence of residual, functioning adrenal tissue after "total" adrenalectomy for pituitary-dependent Cushing's syndrome necessitates continuous surveillance for recurrent Cushing's syndrome. There is no place for routine administration of full replacement doses of glucocorticoids after total adrenalectomy.

Plasma cortisol response to thyrotropin-releasing hormone and luteinizing hormone-releasing hormone in Cushing's disease.

In 3 of 6 patients with pituitary-dependent Cushing's disease, a paradoxical increase of plasma cortisol was observed both after LRH (delta max, 13.9 +/- 3.7 microgram/100 ml; 113 +/- 52%) and TRH (delta max, 8.0 +/- 2.9 microgram/100 ml; 53 +/- 18%) administration, the maximum values being achieved 30--60 min after the iv bolus injection. In the remaining 3 patients and in 15 control subjects, plasma cortisol levels did not rise in response to either LRH or TRH administration but rather showed a slight to distinct decrease during the study period. The paradoxical cortisol response in half of the patients with Cushing's disease may be the consequence of loss of specificity of the pituitary receptor or alteration in the hypothalamo-pituitary pathways.

Leydig cell responsiveness to single and repeated human chorionic gonadotropin administration.

A single im injection of 1500 IU hCG significantly increased plasma testosterone levels for at least 96--120 h in normal men (n = 7), patients with isolated gonadotropin deficiency (n = 6), and boys with delayed puberty (n = 7); the maximum values [1315 +/- 309, 370 +/- 177, and 963 +/- 249 ng/100 ml (mean +/- SD), respectively] were achieved after 72 h in each group. Repeated daily injections of 1500 IU hCG for 3 days increased plasma testosterone levels in the same subjects at 72 h after the start to levels (1342 +/- 412, 407 +/- 199, and 1052 +/- 449 ng/100 ml, respectively) similar to those found in the single dose experiment. The levels achieved at 24 and 48 h also did not differ significantly in the two experiments. The data indicate the lack of additional leydig cell stimulation by repeated hCG injections given within 48 h after a single dose.

Basal and human chorionic gonadotropin-stimulated 17 alpha-hydroxyprogesterone and testosterone levels in Klinefelter's syndrome.

In nine patients with Klinefelter's syndrome, mean basal plasma levels of testosterone (302 +/- 145 ng/100 ml) and its major precursor, 17 alpha-hydroxyprogesterone (17-OHP; 86 +/- 46 ng/100 ml), were significantly lower (P less than 0.01 to less 0.05) than in eight eugonadal men (605 +/- 180 and 136 +/- 39 ng/100 ml, respectively). The ratio of 17-OHP to testosterone, however, was comparable in both groups (0.29 +/- 0.09 vs. 0.24 +/- 0.08; P less than 0.10). In the Klinefelter patients, basal plasma testosterone and 17-OHP levels were positively correlated (rs = 0.87). Administration of hCG for 3 days raised plasma testosterone and 17-OHP levels in both groups. In the Klinefelter patients, the plasma 17-OHP rise exceeded the testosterone increment, leading to a statistically significant increase (0.48 +/- 0.19) of the 17-OHP to testosterone ratio, whereas this ratio remained virtually unchanged in the control subjects (0.20 +/- 0.06). Together, these findings indicate that in the basal state testicular steroidogenesis is globally attenuated, whereas short term hCG stimulation shows that the later steps in the biosynthesis of testosterone may be rate limiting in Klinefelter's syndrome.

Salivary and plasma androstenedione and 17-hydroxyprogesterone levels in congenital adrenal hyperplasia.

Androstenedione (A-dione) and 17-hydroxyprogesterone (17-OHP) levels were measured in matched samples of saliva and of plasma collected from patients with congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency (eight patients) and 11-hydroxylase deficiency (one patient). Positive correlations were found between salivary and plasma values of either steroid with correlation coefficients of 0.968 for A-dione and 0.935 for 17-OHP. All five inadequately treated patients with 21-hydroxylase deficiency had greatly elevated plasma and salivary 17-OHP concentrations compared to values in age matched controls. In two of three well controlled patients plasma 17-OHP levels were less than 40 nmol/liter and salivary levels were less than 1.5 nmol/liter, the upper limits which have been formulated as a guideline for monitoring control in treated CAH patients. Patients in good control had A-dione levels in plasma (0.6-2.2 nmol/liter) and saliva (0.04-0.15 nmol/liter) which were both within the normal range for prepubertal children (0.14-2.40 nmol/liter and 0.02-0.25 nmol/liter respectively). Patients in poor control had A-dione levels in plasma of 5.2-25.4 nmol and in saliva of 0.50-2.21 nmol/liter. These values exceeded without exception the normal ranges for their respective ages. Salivary A-dione and 17-OHP determinations are a useful adjunct in the diagnosis and the monitoring of CAH patients since they can be obtained easily and nonstressfully.

The sex pheromone precursor androsta-5,16-dien-3 beta-ol is a major early metabolite in in vitro pregnenolone metabolism in human testicular homogenates.

In an earlier report we described the early time sequence of the in vitro metabolism of [4-14C]pregnenolone ([4-14C]P5) to testosterone in homogenates of human and rat testes and demonstrated the appearance of mainly delta 5 (humans)- and delta 4 (rats)-steroids within minutes after starting the incubation. In this study strong evidence is presented for the substantial synthesis from P5 of the sex pheromone precursor androsta-5,16-dien-3 beta-ol (ADL) in human, but not rat, testicular homogenates. The 16-unsaturated C19 steroid ADL appeared after 1 min of incubation, and within 5 min reached values (17-23% of total radioactivity added as [4-14C]P5) comparable to those of the major delta 5-steroids 17 alpha-hydroxypregnenolone and dehydroepiandrosterone. Thus, in humans, as in boars, the sex attractant precursor ADL is a major early testicular metabolite of P5.

The influence of glycyrrhetinic acid on plasma cortisol and cortisone in healthy young volunteers.

Based on studies in laboratory animals and on measurements of the urinary metabolites (allo)tetrahydrocortisol and tetrahydrocortisone in human volunteers it has been claimed that liquorice-induced mineralocorticoid excess is caused by a unique defect in the conversion of cortisol to cortisone. To further evaluate this hypothesis we have investigated the influence of glycyrrhetinic acid (GA), the mineralocorticoid-active constituent of liquorice, on plasma cortisol and cortisone in 10 healthy young normotensive volunteers. Pure GA (500 mg/day), administered orally from days 3-10 of the study, exerted pronounced mineralocorticoid activity. Ingestion of GA resulted in an elevated urinary excretion of free cortisol and virtually unchanged plasma cortisol levels in the presence of markedly decreased levels of both plasma cortisone and urinary free cortisone. These results provide direct clinical support for the hypothesis that GA induces an inhibition of the activity of 11 beta-dehydrogenase, resulting in a blockade in the conversion of cortisol to cortisone.

Plasma adrenocorticotropin, cortisol, and aldosterone responses to corticotropin-releasing factor: modulatory effect of basal cortisol levels.

Two hundred micrograms of corticotropin-releasing factor (CRF) were administered as an iv bolus injection to 10 normal subjects (5 men and 5 women). Mean plasma ACTH levels rose significantly (P less than 0.0005, by Friedman's nonparametric analysis of variance) from a basal value of 27 +/- 5 pg/ml (mean +/- SEM) to a peak value of 63 +/- 8 pg/ml 30 min after CRF administration. This ACTH response was followed by a rise in plasma mean cortisol levels (P less than 0.0005, by Friedman's test) from a baseline value of 12.3 +/- 1.4 micrograms/100 ml to a peak value of 21.0 +/- 0.7 micrograms/100 ml 60 min after CRF and a rise in mean plasma aldosterone levels from a basal value of 13 +/- 2 ng/100 ml to a peak value of 23 +/- 2 ng/100 ml. There was no significant difference between men and women in the responsiveness of ACTH, cortisol, and aldosterone to CRF administration. The individual basal cortisol levels were highly significantly and negatively correlated with the areas under the individual ACTH curves (r = -0.76; P less than 0.005, by Pearson's correlation test) and cortisol curves (r = -0.91; P less than 0.001, by Pearson's test). These data suggest a modulatory effect of physiological cortisol levels on the response of the pituitary-adrenal axis to CRF.

Tamoxifen suppresses gonadotropin-induced 17 alpha-hydroxyprogesterone accumulation in normal men.

Intramuscular administration of 1500 IU hCG daily for 3 days induced a transient accumulation of 17 alpha-hydroxyprogesterone (17 OHP) relative to testosterone (T) in normal men, reaching its maximum 24 h after the first injection (17 OHP to T ratio, 1.7 +/- 0.3 times baseline; P < 0.01). Simultaneous administration of hCG and the estrogen antagonist tamoxifen (20 mg twice daily) almost completely abolished the hCG-induced steroidogenic block localized between 17 OHP and T (17 OHP to T ratio at 24 h, 1.1 +/- 0.1 times baseline; P < 0.01 vs. hCG alone). These data indirectly suggest that, in man, the hCG-induced steroidogenic lesion might be mediated through its estrogen-stimulating effect.

Predictive value of luteinizing hormone releasing hormone (LHRH) bolus testing before and after 36-hour pulsatile LHRH administration in the differential diagnosis of constitutional delay of puberty and male hypogonadotropic hypogonadism.

Intravenous LHRH bolus testing (100 micrograms) after 36 h of pulsatile LHRH administration (5 micrograms/90 min) preliminary has been reported to allow complete differentiation between constitutional delay of puberty (DP) and hypogonadotropic hypogonadism (HH) in a small group of sexually immature patients. So far, these data have never been confirmed. To assess the discriminatory power of the test, 33 patients with a presumptive diagnosis of either DP (n = 17) or HH (n = 16), confirmed by clinical follow-up, were studied accordingly. Both groups of patients had similar mean basal LH and FSH levels (P > 0.10). The mean basal plasma testosterone level was three times higher in DP than in HH (4.2 +/- 1.0 vs. 1.4 +/- 0.2 nmol/L, P* < 0.001), but there was a wide overlap. In response to the first LHRH bolus test, the mean LH increment was significantly lower in HH than in DP patients (P < 0.001), but, in 44% of the patients, the values overlapped. The FSH increments were similar in HH and DP. Pulsatile LHRH administration for 36 h similarly increased LH levels in HH and DP to values (2.7 +/- 0.4 and 3.8 +/- 0.5, respectively) slightly higher than before (P < 0.01), but again, not statistically significantly different from each other. The mean testosterone levels increased 2-fold in both groups and remained significantly higher in DP than in HH (7.6 +/- 2.1 vs. 2.8 +/- 0.5 nmol/L P* < 0.05). The mean FSH levels after priming also rose, however, to levels significantly higher in HH than in DP (5.2 +/- 0.8 vs. 3.5 +/- 0.4, P* < 0.05). In HH the ratio of FSH to LH almost doubled, whereas it virtually remained unchanged in DP. LHRH bolus testing after LHRH priming evoked a significantly lower LH response in both HH and DP than before priming despite only slightly higher baseline LH values. The LH increment in HH was five times lower in HH than in DP. In any of the 16 HH patients, the LH increment was < or = 3 IU/L, whereas in 15 out of 17 DP patients the increase was higher (sensitivity of the test 100%, specificity 88%, and diagnostic efficiency 94% after LHRH priming against 56%, 94%, and 75% respectively, before LHRH priming.(ABSTRACT TRUNCATED AT 400 WORDS)