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.

Sex difference in the relation between sellar volume and basal and GH-releasing hormone stimulated GH in acromegaly.

Sellar volume and both basal (r = +0.54, P less than 0.02) and GHRH-stimulated (r = +0.41, P less than 0.05) GH levels were directly correlated in a group of 28 patients with acromegaly as were the latter indices (r = +0.82, P less than 0.001). By subdividing the patients according to sex, a close relation between sellar size and both basal (r = +0.77, P less than 0.02) and stimulated GH (r = +0.71, P less than 0.02) was found only in the men, not in the women (r = +0.12 and r = +0.02, respectively, P greater than 0.10). The presence of a tight relation between sellar volume and basal and GHRH stimulated GH levels in male patients with acromegaly and its complete absence in women are equally intriguing and await further elucidation. A modulating role of gonadal steroids in the genesis of this sex differences remain to be assessed.

Reciprocal inhibition of the long-acting luteinizing hormone releasing hormone agonist Buserelin and human chorionic gonadotropin in stimulating Leydig cell steroidogenesis.

The interference between human chorionic gonadotropin (hCG, Pregnyl, Organon 1500 IU i.m.) and the long acting LHRH agonist Buserelin (500 micrograms s.c.) in stimulating Leydig cell steroidogenesis was studied in 6 eugonadal men. Simultaneous administration of a single injection of the agonist (LHRH alpha) and hCG blunted the plasma testosterone response observed 24 h after LHRH alpha alone, enhanced the secretion of oestradiol without affecting 17-hydroxy-progesterone and aggravated the late steroidogenic block at the 17,20-lyase locus. As compared to hCG alone, combined LHRH alpha and hCG administration also decreased the maximum and 48 h testosterone increments and the testosterone production reflected by the area under the curve, enhanced the production of oestradiol and again aggravated the 17,20-lyase lesion. The data show that the long acting agonist LHRH alpha and hCG reciprocally inhibit their stimulatory effect on Leydig cell testosterone secretion probably by a suppressive effect of oestrogens on the conversion of C21- to C19-steroids. The mechanism underlying this reciprocal inhibition remains to be elucidated.

Sex difference in growth hormone response to growth hormone-releasing hormone between pubertal tall girls and boys.

In adult rats and also in young adults, a sex difference in GH responsiveness to GHRH has been reported with the higher responses in males. In young rats, however, the reverse has been found, i.e. a higher GH response in females than in males. This discrepancy promoted us to compare GH responsiveness to GHRH in midpubertal tall girls (N = 10) and boys (N = 8). An iv bolus administration of 100 micrograms of GHRH to these adolescents disclosed a sex difference in GH responsiveness. At all time intervals up to 30 min after the bolus, the GH responses to GHRH in the girls were significantly higher than in the boys (P less than 0.025 - P less than 0.05), whereas the peak GH increments (34 +/- 4 vs 19 +/- 3 micrograms/l; P less than 0.02) were about twice as high in the former as in the latter. The data suggest that like in rats, also in humans, sex-related changes in pituitary GH sensitivity to GHRH may be an important factor in the pubertal growth and development at least in tall girls and boys.

Growth hormone responses to the releasing hormones GHRH and GnRH and the inhibitors somatostatin and bromocriptine in TRH-responsive and non-responsive acromegalics.

In acromegalics, the percent peak GH responses to TRH (pTRH) and bromocriptine (pBr) are inversely related with those to GHRH, favouring the hypothesis that in the adenomas of some patients there is a preponderance of GH-producing cells with lactotrope-like characteristics, whereas in others pure somatotropes predominate. The aim of the present study was to investigate whether patients responsive to TRH with allegedly lactotrope-like tumours differ from those patients not responding to TRH with more somatotrope-like adenomas in their answer to the GH inhibitors Br and SRIH and the releasing hormones GHRH and GnRH. The present study demonstrates that the observed reciprocal relations between the GH responses to GHRH, TRH and Br are only present in acromegalics paradoxically responding to TRH (pGHRH vs pTRH -0.73, pGHRH vs pBr -0.60, pTRH vs pBr +0.54, P less than 0.0002-P less than 0.02, N = 20), not in TRH-non-responders (N = 10). In contrast, in these latter patients, not in the former, close relations were found between the percent peak GH responses to GnRH (pGnRH) and pGHRH (r = +0.81, P less than 0.005) and between pGnRH and the percent maximum GH decrements in response to SRIH (pSRIH) (r = +0.64, P less than 0.05). Expectedly, the GH response to Br in the TRH-responders was significantly higher than in the non-responders (75 +/- 4% vs 54 +/- 3%, P less than 0.02), although it was also substantial in the latter. The GH response to SRIH was remarkedly similar in both groups (64 +/- 5 vs 57 +/- 9%, P greater than 0.10).(ABSTRACT TRUNCATED AT 250 WORDS)

The higher the growth hormone response to growth hormone releasing hormone the lower the response to bromocriptine and thyrotrophin releasing hormone in acromegaly.

In acromegaly a direct relationship has been demonstrated between GH responsiveness to TRH and to the dopaminergic agent bromocriptine (Br). Recent data show an inverse relationship between GH responsiveness to Br and to GH releasing hormone (GHRH), but not between the GH responses to GHRH and TRH. Thirty-one acromegalic patients, 18 women and 13 men (age 46.2 +/- (SD) 13 years) were studied. Four patients had been treated, but all still had active disease. The GH responses to GHRH (hpGHRH1-44, Bachem 100 micrograms i.v. bolus), TRH (Thyroliberin, Hoechst 200 micrograms i.v. bolus) and Br (Parlodel 5 mg orally) were assessed in most of the patients. The GH responses to GHRH showed a wide interindividual variation (delta GH 1-995 ng/ml), which correlated significantly with the basal GH levels (r = +0.85, P less than 0.0001, n = 31). GH increments in response to GHRH were inversely related to the responses to Br, i.e. the lower the GH increase after GHRH the greater the GH decrease after Br (r = -0.49, P less than 0.01, n = 30). This decrease correlated with the basal PRL level (r = +0.45, P less than 0.02, n = 29) and also the GH response to TRH (r = +0.66, P less than 0.0001, n = 30). An inverse correlation was also found between the GH responses to TRH and to GHRH (r = -0.43, P less than 0.02, n = 29). The data are consistent with the existence of GH-secreting adenomas which are more sensitive to GHRH and less to Br and TRH (pure somatotroph adenomas) and of mixed (lactotroph-like adenomas) responsive to TRH and Br but less responsive to GHRH.

The effect of minisomatostatin on anomalous growth hormone responses in acromegaly.

Twelve patients with active acromegaly were treated with the long-acting somatostatin analogue SMS 201-995 at a dose of 50 micrograms sc twice daily in the first 2 weeks of treatment and 100 micrograms twice daily thereafter. Four hours after the first injection of SMS, GH levels became normal in 8 of the 12 patients. The GH response after hpGRF administration was strongly suppressed by SMS. Paradoxical GH responses to TRH disappeared in 6 out of 7 patients during SMS. Paradoxical GH responses to LHR, however, persisted in 4 out of 4 patients. Paradoxical responses of GH after glucose loading disappeared in 2 out of 2 patients. We conclude that SMS normalizes most anomalous growth hormone kinetics in acromegaly. This drug offers a new tool in the treatment of this disease.

Human pancreatic growth hormone releasing hormone fails to stimulate human growth hormone both in Cushing's disease and in Cushing's syndrome due to adrenocortical adenoma.

An absent or severely blunted hGH response to an i.v. bolus injection (100 micrograms) of human pancreatic growth hormone releasing hormone (hpGRF 1-44) was found in seven female patients with Cushing's syndrome (five with pituitary dependent Cushing's disease and two due to an adrenal adenoma) and four men with pituitary dependent Cushing's disease. Three of the female and three of the male patients had an adequate hypoglycaemia after insulin administration. All these patients showed an absent or blunted hGH response after insulin induced hypoglycaemia. The GHRH data in these patients are in agreement with those in older literature on hGH responsiveness to stimuli such as L-dopa, arginine and insulin induced hypoglycaemia. It is concluded that hypercortisolism inhibits hGH release to various stimuli at the pituitary level.

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.

Growth hormone responsiveness to human pancreatic growth hormone releasing factor in acromegaly: modulatory effects of basal hormone levels and of concomitant somatostatin administration.

Human pancreatic growth hormone releasing factor 1-44 (hpGRF), 100 micrograms was administered as an i.v. bolus injection to eleven patients with acromegaly. The mean serum growth hormone (GH) levels rose (P less than 0.001) from 54 +/- 20 ng/ml to 215 +/- 126 ng/ml (+/- SEM) 20 min after the injection. Although the maximum response of GH levels was highly variable it correlated positively with the individual GH levels (P less than 0.01, Rs = +0.80). Thus the higher the GH levels, the greater the responsiveness to hpGRF. Administration of somatostatin (SRIF), 300 micrograms/h, lowered basal GH levels from 76 +/- 38 ng/ml to 13 +/- 5 ng/ml (P less than 0.01) after 1 h. hpGRF administration during concomitant SRIF infusion also led to highly variable growth hormone responses. The maximum GH responses again correlated positively with the GH level before hpGRF after 1 h of SRIF administration (P less than 0.05, Rs = +0.79). GH responses to hpGRF were completely blocked by SRIF in three out of four patients whose GH levels decreased to normal levels during SRIF infusion. Our data illustrate that the pituitary in acromegaly is normally responsive to both SRIF and hpGRF but at a higher setting of basal GH levels.