We measured bone mineral density (BMD) using dual-energy x-ray absorptiometry in 20 patients with Cushing's syndrome (CS) (14 preand 2 postmenopausal women, 4 men) before and in 18 of them also at regular intervals after surgical cure (median duration of follow-up, 36 months). In addition, in the premenopausal women with CS, fast ing blood samples and 2-h fasting urine samples for measurement of biochemical parameters of bone and collagen metabolism were col lected before and in 9 of them also at regular intervals during the first 2 yr after surgery. Marked osteopenia was present in'most patients with active CS (Z-scores: lumbar spine -1.45 ± 1,44 and femoral neck ~ 1.50 ± 1 .02; mean ± sd). No consistent change in BMD was observed at 3 and 6 months after surgery. Thereafter BMD increased consid erably in almost all patients. For the 15 patients with a follow-up of at least 1 yr, Z-scores at the last evaluation were -0.65 ± 1.27 for the lumbar spine and -0.98 ± 1.02 for the femoral neck (both/5 < 0.002 compared with pretreatment values). In the premenopausal patients, the increase in BMD both in the lumbar spine and in the femoral neck at 24 months was inversely correlated with age (r = -0.733, P < 0.03, and r ~ -0.667, P < 0.05, respectively). Serum levels of osteocalcin, bone alkaline phosphatase, carboxyterminal propeptide of type I pro

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.

Objective and design: The endoscopic technique has been recently introduced in the field of transsphenoidal pituitary surgery. This technique allows inspection of sellar, supra-and parasellar structures and removal of the tumor under direct visualization, is minimally traumatic and permits easier reoperations. This is the first report on the results of endoscopic surgery for patients with Cushing's disease. Our aim was to retrospectively analyze the results of pituitary surgery in 35 consecutive patients with Cushing's disease operated in our hospital after the introduction of the endoscopic technique (1998 -2004). Methods: Remission was defined as suppression of plasma cortisol (# 50 nmol/L) after 1 mg dexamethasone overnight determined in the first 3 months after surgery and disappearance of clinical signs and symptoms of hypercortisolism. The patients were followed for an average of 27 months (range 4 to 81 months, median 20 months). Results: Pituitary MRI showed a macroadenoma in 6 patients, a microadenoma in 17 patients and no adenoma in 12 patients. After the initial surgery 27 patients (77%) were in remission. None of the patients had a relapse during follow-up. In the remaining 8 patients hypercortisolemia persisted after surgery. Three of them had a second endoscopic pituitary surgery resulting in remission in two patients. In one patient a second endoscopic pituitary surgery will soon follow. The remaining four patients were treated with radiotherapy postoperatively. Two of them were at the time of data collection in remission. One patient from the remission group had a serious epistaxis and three patients had cerebrospinal fluid leakage, one requiring an external lumbar drain, shortly after surgery. No complications were recorded in the failure group. Postoperatively 34% of all patients required substitution with levothyroxine, 40% required substitution with glucocorticoids, 17% received estrogens or testosterone and 6% still required desmopressin. Conclusions: Endoscopic transsphenoidal pituitary surgery resulted in our series of patients with Cushings disease in an excellent postoperative remission rate. A randomized clinical trial, comparing endoscopic and conventional pituitary surgery in patients with Cushings disease, is needed to determine the pros and cons of both techniques.European Journal of Endocrinology 154 675-684

Our results demonstrate that pituitary surgery of Nelson's macroadenomas is more successful when Nelson's adenomas are relatively small. Pituitary surgery should be performed before extrasellar expansion of the tumour occurs in order to attain long lasting remissions. Pituitary irradiation should be performed postoperatively in all patients with residual tumour. Our data also illustrate that in patients with Nelson's syndrome, plasma ACTH levels can reliably be used as an indirect approximation for tumour volume.

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.

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.

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.

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