Epirubicin and paclitaxel with G-CSF support in first line metastatic breast cancer: a randomized phase II study of dose-dense and dose-escalated chemotherapy.

An increased dose-intensity can be achieved by either higher dose of chemotherapy per cycle (dose-escalation) or by shortening the interval between cycles (dose-dense). This multicenter randomized phase II study assessed the efficacy and safety of two different approaches: epirubicin 110 mg/m(2) combined with paclitaxel 200 mg/m(2) every 21 days and epirubicin 75 mg/m(2) combined with paclitaxel 175 mg/m(2) every 10 days, both supported with G-CSF. Patients with advanced breast cancer and without prior palliative chemotherapy were scheduled for 6 cycles. Evaluable for response were 101 patients and for toxicity 106 patients. Grade ≥ 3 toxicities occurred in 39% of patients in the dose-escalated arm and in 29% of the dose-dense arm, mainly febrile neutropenia, thrombocytopenia, neurotoxicity and (asymptomatic) cardiotoxicity. The median delivered cumulative doses for epirubicin/paclitaxel were 656/1194 and 448/1045 mg/m(2), treatment durations were 126 and 61 days, and delivered dose intensities were 36/67 and 51/120 mg/m(2)/week for the dose-escalated and dose-dense arm, respectively. Response rates were 75 and 70%, the progression-free survival 6 and 7 months, respectively. Dose-dense chemotherapy with a lower cumulative dose, a halved treatment time, but a higher dose-intensity may be as effective and safe as dose-escalated chemotherapy. The value of dose-densification over standard scheduled chemotherapy regimes yet needs to be determined.

Unique efficiency of methionine metabolism in premenopausal women may protect against vascular disease in the reproductive years.

Premenopausal women develop occlusive artery disease less frequently than postmenopausal women. In coronary heart disease, higher blood levels of homocysteine-cysteine mixed disulphide have been reported. Therefore, in healthy subjects, we studied the role of menopausal status in the transsulphuration of methionine in 10 premenopausal and 10 postmenopausal women. To exclude the role of aging, we compared these results with those in 10 younger and 10 older men of comparable age groups. An oral methionine load (0.1 g/kg of body weight) was administered after overnight fasting. Before and during 8 h, thereafter, serum levels of methionine, homocystine, and homocysteine-cysteine mixed disulphide were measured. In the fasting state, serum methionine levels were similar in the premenopausal women and both groups of men. Postmenopausal women had significantly lower fasting levels. Peak levels and clearances of methionine after loading did not differ between the groups. In the fasting state, homocystine was never detectable; yet, after methionine loading, slight homocystinemia was present in 12 out of 20 men, and was more pronounced in all postmenopausal women. However, homocystinemia did not occur in any of the premenopausal women after loading. Fasting serum homocysteine-cysteine mixed disulphide levels did not differ between both groups of men and postmenopausal women. In premenopausal women, both fasting and postloading disulphide levels were significantly lower than in any other group. We conclude that premenopausal women have a unique efficiency of methionine handling, and thereby are preserved against the accumulation of homocysteine after methionine loading. We speculate that this phenomenon might account for the lower incidence of vascular disease in women in the reproductive life cycle.

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.

Seasonal variation in serum T3 and T4 levels in man.

In a group of 13 healthy male adults in the Netherlands, a seasonal variation in circulating serum thyroxine (T4) and triiodothyronine (T3) levels was found, inversely correlating with the seasonally altering environmental temperature. Lowest serum T4 and T3 levels were found in the summer.

Dichotomy between serum free triiodothyronine and free thyroxine concentrations in familial thyroxine-binding globulin deficiency.

The mean serum total T4 (3.2 +/- 1.0 micrograms/100 ml) and T3 levels (83 +/- 29 ng/100 ml) in eight euthyroid patients with T4-binding globulin (TBG) deficiency from two families were significantly lower than those in either the unaffected relatives (P less than 0.05) or the control subjects (P less than 0.01). The lowest T4 and T3 values were found in the four hemizygotes (2.4 +/- 0.2 micrograms/100 ml and 69 +/- 25 ng/100 ml, respectively). In contrast to the absolute T4 and T3 levels, the mean percentages of free T4 and free T3 in the affected members were about twice as high as those in either the unaffected relatives or the controls. Despite an elevated percentage of free T4 in each of the TBG-deficient members, the mean absolute free T4 (FT4) level (0.89 +/- 0.20 ng/100 ml) was significantly lower than those in both control groups [1.31 +/- 0.2 ng/100 ml (P less than 0.02) and 1.24 +/- 0.30 ng/100 ml (P less than 0.01), respectively]. Serum FT4 levels were subnormal in three of four hemizygotes. In contrast to FT4, the mean FT3 level in the affected members (0.33 +/- 0.04 ng/100 ml) was significantly higher than that in either the nondeficient relatives (0.25 +/- 0.02 ng/100 ml; P less than 0.02) or the control subjects (0.26 +/- 0.04 ng/100 ml; P less than 0.02), whereas the ratio of FT3 to FT4 was about twice as high. The data suggest that in TBG deficiency, euthyroidism in maintained by a subtle equilibrium between low FT4 and high FT3 levels.

Patient's age is a simple predictive factor for the development of Nelson's syndrome after total adrenalectomy for Cushing's disease.

Reportedly between 8-38% of patients who receive bilateral adrenalectomy for treatment of Cushing's disease will develop Nelson's syndrome. We investigated which factors may predict the development of the syndrome. Eight of 48 patients, bilaterally adrenalectomized for pituitary-dependent Cushing's syndrome 1-30 yr previously, developed Nelson's syndrome 1.5-13 yr (6.6 +/- 4.3 yr) after adrenalectomy. The mean age at adrenalectomy in the group of patients who developed Nelson's syndrome was significantly lower than that in the group without the syndrome (mean +/- SD, 26.0 +/- 6.0 and 35.6 +/- 11.7 yr, respectively; P < 0.02). In the patients adrenalectomized before the age of 35 yr, 8 of 27 (30%) developed Nelson's syndrome, whereas in the patients older than 35 yr, no one did (P < 0.02). No statistically significant differences between the two groups were found in sex ratio, duration of disease before adrenalectomy, or duration of follow-up thereafter. There were no statistically significant differences between the two groups in mean plasma cortisol and ACTH levels before adrenalectomy, cortisol suppressibility after the administration of 8 and 16 mg dexamethasone, or cortisol responses to CRH, TRH, and LH-releasing hormone before adrenalectomy. We conclude that age at the time of adrenalectomy is an important predictive factor for the development of Nelson's syndrome.

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.

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.

Sex difference in human growth hormone (GH) response to intravenous human pancreatic GH-releasing hormone administration in young adults.

Intravenous administration of a 100-micrograms dose of human pancreatic GH-releasing hormone (human pancreatic GHRH1-44, indicated by GHRH) disclosed a sex difference in GH responsiveness. The maximum GH increments [41 +/- 11 (SEM) vs. 15 +/- 4 ng/ml, P* less than 0.05] and the areas under the curves (419 +/- 105 vs. 148 +/- 53 area U, P* less than 0.05) were significantly higher in 12 men than in 10 women. No significant correlation was found in either group between the basal plasma estradiol or testosterone levels and the maximum or integrated GH response to GHRH. Serum PRL levels significantly increased in both groups within 5 min after GHRH injection (men, P less than 0.001 vs. t = 0; women, P less than 0.05 vs. t = 0). The areas under the curves of the PRL responses (355 +/- 184 vs. 189 +/- 73 area U) and the maximum PRL increments (58 +/- 18 vs. 36 +/- 6 mU/l, P* greater than 0.10) were similar. In conclusion, a sex difference in GH responsiveness to GHRH was found between young adult men and women. Recent in vivo and in vitro data reveal a similar sex difference in rodents and an enhancing effect of androgens, but not estrogens, on the GH response to GHRH. These findings support the theory that in humans testosterone also plays a key role in the genesis of this sex difference.

Aromatase inhibition by delta 1-testolactone does not relieve the gonadotropin-induced late steroidogenic block in normal men.

Aromatase inhibition by delta 1-testolactone [(17 oxa-D-homo 1,4 androstanediene-3,17 dione) 500 mg twice daily for 10 days] in nine normal men lowered circulating estradiol (E2) levels by about 25%, enhanced the secretion of FSH, 17-hydroxyprogesterone (17-OHP), and to a lesser degree testosterone (T), but did not affect serum LH levels. Despite E2 lowering there was greater accumulation of 17-OHP than of T after 7 days of treatment, suggesting 17,20-lyase inhibition. Unexpectedly, administration of delta 1-testolactone almost halved the T response to hCG (Pregnyl, 1500 IU), but did not affect the 17-OHP response. Thus, E2 lowering by testolactone aggravated the hCG-induced 17,20-lyase block present before testolactone administration. Although the present data might suggest that estrogens do not play a role in the genesis of the hCG-induced late steroidogenic block, the results suggest that testolactone per se, in addition to its reported antiestrogenic action, inhibits 17,20 lyase.

Predictive factors for initial cure and relapse rate after pituitary surgery for Cushing's disease.

Twenty-seven patients with Cushing's disease underwent transsphenoidal pituitary surgery. After the operation 16 patients were cured, and 11 remained hypercortisolemic. In the cured patients a significantly lower incidence of paradoxical responsiveness to TRH or to LRH was found preoperatively (1 of 16) than in the failures (6 of 11; P less than 0.02, by Fisher's chi 2 test). Furthermore, responsiveness of cortisol to CRH administration was significantly lower in the failures [maximum, 0.30 +/- 0.10 mumol/L (10.8 +/- 3.6 micrograms/dL) vs. 0.50 +/- 0.07 mumol/L (18.1 +/- 2.5 micrograms/dL) in the cured patients; P less than 0.05]. There were no differences in basal plasma cortisol levels, ACTH levels, or suppressibility by dexamethasone between the 2 groups. In the 16 patients who were cured initially, 4 patients relapsed after a mean period of 4 yr. These 4 patients had significantly higher basal cortisol levels postoperatively than those who remained in remission [0.14 +/- 0.03 mumol/L (5.1 +/- 0.8 micrograms/dL) vs. 0.04 +/- 0.01 mumol/L (1.4 +/- 0.3 micrograms/dL); P less than 0.01]. Cortisol responses to CRH after the operation positively correlated with the basal cortisol levels at that time (P less than 0.05, by Spearman's rank correlation test; r = 0.64), thus, the relapsing patients had higher cortisol responses to CRH than patients who stayed in remission [maximum response, 0.31 +/- 0.07 (11.2 +/- 2.5 micrograms/dL) vs. 0.12 +/- 0.03 mumol/L (4.3 +/- 1.1 microgram/dL), respectively; P less than 0.05]. We conclude that 1) patients responding paradoxically to TRH and/or LRH have a lower chance of being cured after pituitary surgery; and 2) patients with higher cortisol levels (greater than 0.10 mumol/L; 3.6 micrograms/dL) after being cured initially have a higher chance of recurrence of their disease.

Gender difference in insulin-like growth factor I response to growth hormone (GH) treatment in GH-deficient adults: role of sex hormone replacement.

GH production in healthy women is about thrice that in men. Yet insulin-like growth factor I (IGF-I) levels are similar, suggesting a lower responsivity to GH in women. In untreated GH-deficient adults, basal IGF-I levels are reportedly lower in females than in males, and the therapeutic recombinant human GH (rhGH) dose required to achieve optimal IGF-I levels is higher in the former, suggesting a pivotal role of estrogens on rhGH requirement in GH-deficient patients. We, therefore, analyzed our 2-yr data on the effect of rhGH on serum IGF-I in 77 GH-deficient patients (33 men, mean +/- SD age, 37.2 +/- 13.8 yr; 44 women, mean +/- SD age, 36.9 +/- 11.9 yr) with due attention to gender differences and to the effects of sex hormone replacement. Of the 44 women, 33 had estrogen substitution. Of the 33 men, 23 were on androgen replacement. Patients (11 premenopausal women and 10 men) not on hormonal replacement were eugonadal. Basal IGF-I levels in untreated GH-deficient women were significantly lower than in men (8.8 +/- 0.7 nmol/L vs. 12.2 +/- 0.9 nmol/L; P < 0.01), despite similar basal GH levels. The daily rhGH dose per kg body weight required to normalize IGF-I in women was higher than in men, the difference being statistically significant at all time points (P < 0.05-0.01). The IGF-I increase (delta) per IU GH/day x kg over the 24-month period was about twice higher in men than in women. Also calculated on a weight basis, rhGH responsivity (rhGH responsivity = (deltaIGF1(nmol/L)/dose (IU/day/kg)) was higher in men than in women at all time intervals (P < 0.05-0.01). Estrogen replacement in women significantly increased rhGH requirement. The rhGH dose per kg body weight required in estrogen-substituted women was significantly higher than in nonestrogen-substituted women (P < 0.01 at t = 18 and 24 months, respectively). In women on estrogen substitution, rhGH responsivity plateaued from 6 months on, whereas in eugonadal women without estrogen substitution the responsivity for rhGH increased over time. In men, the reverse was true; rhGH responsivity increased over time in men on androgen substitution, but plateaued in men without androgen substitution. The mechanisms underlying this gender difference are not known. Differential influences of estrogens and androgens on the expression of the GH receptor gene and IGF-I messenger RNA may be operative. The present study confirms short-term data published in the literature on a sex difference in rhGH dose requirement in GH-deficient patients. It furthers extends the data by demonstrating that this sex difference in GH responsivity persists and changes during the 24 months of the study. Moreover, it shows that estrogen replacement blunts the IGF-I response to rhGH in women, whereas in men with androgen substitution the responsivity increases over time, thus bearing a risk of undertreatment in women and overtreatment in men.

Paradoxical responsiveness of growth hormone to corticotropin-releasing factor in acromegaly.

Corticotropin-releasing factor elicited an increase in serum GH in two of six patients with acromegaly. Both patients also responded paradoxically to LHRH administration and one of them also to TRH, further illustrating the dedifferentiation of the receptors of the somatotrophs in acromegaly.

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.

Macronodular adrenocortical hyperplasia in long-standing Cushing's disease.

Clinical and biochemical findings in 13 patients (11 women and 2 men) with macronodular adrenocortical hyperplasia (MNH; nodule size, greater than 0.5 to 5.3 cm) were compared with those of 18 patients (15 women and 3 men) with Cushing's disease and diffuse (n = 9) or micronodular (n = 9) hyperplasia (DH). All were bilaterally adrenalectomized for their hypercorticism. The clinical picture was almost identical in both groups, except for greater frequency of hypertension (13 of 13 vs. 10 of 18; P less than 0.05), alopecia (4 of 11 vs. 0 of 15; P less than 0.05), and scintigraphic lateralization (6 of 7 vs. 1 of 7; P less than 0.05) in the MNH group than in the DH group. The sella turcica was enlarged in 30% of the patients in both groups. Patients with MNH were significantly older than DH patients [43.5 +/- 7.8 (mean +/- SD) vs. 31.7 +/- 10.1 yr; P less than 0.005] and had a 3-fold longer duration of disease (7.8 +/- 4.6 vs. 2.0 +/- 1.1 yr; P less than 0.001) than those with DH. The mean plasma ACTH and cortisol levels and urinary 17-hydroxycorticosteroid excretion were elevated in both MNH and DH patients and responded similarly to specific (corticotropin-releasing hormone and metyrapone) and nonspecific (TRH and LHRH) stimuli. However, dexamethasone suppressibility and the stimulatory effect of ACTH on adrenocortical function were less in the MNH than in the DH group or its subgroups, suggesting a greater degree of adrenal autonomy in the former. Adrenal weight in MNH (15.8 +/- 12.1 g each) was almost twice as high as in DH (8.2 +/- 2.0 g) patients and positively correlated with the duration of the disease. The data suggest that MNH may be a result of long-standing Cushing's disease with varying degrees of pituitary dependence and adrenocortical autonomy, which may lead to confusing biochemical and radiological findings. Bilateral adrenalectomy, rather than hypophysectomy, is the treatment of choice in MNH.

Short term growth in boys with delayed puberty after diagnostic human chorionic gonadotropin administration.

Using a sensitive measuring device, 3-day hCG administration (Pregnyl; 1500 IU daily) was shown to temporarily increase ulnar growth velocity from prepubertal (0.40 +/- 0.35 mm/3 weeks to pubertal values (1.1 +/- 0.64 mm/3 weeks) in 10 boys with delayed puberty. This growth-promoting effect of diagnostic hCG administration, which was demonstrable for 3--9 weeks, was associated with an overt rise in plasma testosterone from 129 +/- 126 to 818 +/- 419 ng/100 ml and an approximate doubling of the serum alkaline phosphatase activities from 193 +/- 46 to 376 +/- 115 U/liter, suggesting an initiated growth spurt.

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.

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.