Management of Nelson's syndrome: observations in fifteen patients.

OBJECTIVE: To analyse the results of different treatment modalities for Nelson's syndrome, which was defined as radiological evidence of a pituitary macroadenoma, fasting plasma ACTH levels of more than 200 pmol/l after stopping glucocorticoid substitution for at least 24 h in a patient who had undergone bilateral adrenalectomy for Cushing's disease. DESIGN: The medical reports of all Nelson's patients known in our hospital were studied with regard to treatment modalities and result of treatment. Clinical remission of Nelson's syndrome was defined as a reduction of tumour size to a diameter of 10 mm or less and fasting plasma ACTH levels less than 200 pmol/l after stopping glucocorticoid substitution for at least 24 h. PATIENTS: Fifteen women with Nelson's syndrome were studied. Bilateral adrenalectomy had been performed 1-29 years before Nelson's syndrome was diagnosed. Before adrenalectomy eight patients had undergone unsuccessful transsphenoidal pituitary surgery. RESULTS: Eight patients were initially followed without surgical or radiotherapeutical intervention during 1-7 years. In seven of them, plasma ACTH levels and tumour volumes increased progressively during this rather short observation period, with development of extrasellar extension in four patients. In one of these patients, who was planned for elective pituitary surgery, massive pituitary haemorrhage occurred which was fatal despite emergency pituitary surgery. Elective pituitary surgery was performed in 11 patients, of whom three were operated twice. Clinical remission was documented in five patients in the first year after operation. In one patient postoperative MR-imaging revealed no residual tumour mass but the postoperative plasma ACTH level was still elevated. In another patient a residual intrasellar macroadenoma and an increased plasma ACTH level remained stable for 22 years. The remaining four patients received postoperative radiotherapy because of residual tumour masses. Of these patients, one had a clinical remission. In two others relatively small residual intrasellar tumour masses remain, with a fasting plasma ACTH level of more than 200 pmol/l in one of them. The fourth patient died of the consequences of progressive tumour growth. Radiotherapy was the only treatment in two patients and did not result in clinical remission. Tumour volumes and plasma ACTH levels at the time of diagnosis of Nelson's syndrome were positively correlated (r = + 0.61, P < 0.05). This correlation was stronger at the moment of decision of either pituitary surgery or radiotherapy (r = + 0.85, P < 0.001). At the end of the follow-up period the correlation between tumour volumes and plasma ACTH levels in the combined pituitary surgery and/or irradiation only group was + 0.77 (P < 0.001). In the pituitary surgery group tumour volumes before and after surgery were directly correlated (r = + 0.70, P < 0.05). CONCLUSIONS: 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.

Measuring skeletal changes with calcaneal ultrasound imaging in healthy children and adults: the influence of size and location of the region of interest.

We measured the quantitative ultrasound (QUS) parameters broadband ultrasound attenuation (BUA) and speed of sound (SOS) at the calcaneus using an ultrasound imaging device (UBIS 3000) in 698 healthy Caucasian male and female subjects (110 prepubertal, 356 pubertal/adolescent and 210 adult) between 6 and 77 years of age. The influence of different region of interest (ROI) diameters (6-20 mm) and software techniques (automatic (ROIaut), copied (ROIcop) and fixed coordinate (ROIfix) measurements) on annual rate of change, trend assessment interval (TAI; an estimate of the follow-up time required for measuring a true change), percentage of positioning errors (positioning of the ROI partly at the cortical edge or even partly beyond the calcaneus) and short-term precision error was studied. When using ROI diameters increasing from 8 to 20 mm, the annual rate of change of BUA and SOS did not change in adults, but was higher in prepubertal subjects (when subjects with positioning errors were excluded) as well as in pubertal/adolescent subjects. TAIs for BUA were shortest when using ROIaut with ROI diameters between 8 and 14 mm (TAI between 1.2 and 1.5 years for prepubertal boys and pubertal/adolescent subjects, 2.4 years for prepubertal girls, 2.7 years for postmenopausal women, and 9 years in men and premenopausal women). TAIs for SOS were 4 years or more, except for postmenopausal women (2.1 years) and prepubertal boys (3.2 years). Measurements with large ROI diameters, especially with fixed region coordinates, resulted in a high percentage of positioning errors and mostly in longer TAIs. Analysis of the short-term precision errors did not reveal these important differences between the various ROI diameters. Our results indicate that calcaneal ultrasound imaging may be useful for measuring skeletal changes in healthy children, especially with BUA, and in postmenopausal women with BUA and SOS using an automatic measurement in the region of lowest attenuation. ROI diameters of 12 mm should be used in prepubertal subjects and of 14 mm in pubertal/adolescent and adult subjects.

Osteopenia in insulin-dependent diabetes mellitus; prevalence and aspects of pathophysiology.

The objective was to evaluate the prevalence and severity of osteopenia in patients with uncomplicated insulin-dependent diabetes mellitus (IDDM) and to obtain more information on the pathophysiology of diabetic osteopenia. In 35 patients with uncomplicated IDDM (21 men and 14 women; age 37.6+/-9.9 yr; duration of disease 8.5+/-3.5 years) bone mineral density was measured by dual energy X-ray absorptiometry (DEXA). In addition, markers of bone formation [plasma insulin-like growth factor I (IGF-I), serum alkaline phosphatase (ALP), serum bone alkaline phosphatase (BAP) and serum osteocalcin] and bone resorption [urinary excretion of calcium and of the cross-linked N-telopeptide of type 1 collagen, both corrected for the excretion of creatinine] were measured in the diabetic patients and in 33 healthy controls, matched for sex, age, height, weight and body mass index (BMI). In 67% of the diabetic men and 57% of the diabetic women osteopenia of the femoral neck and/or the lumbar spine (T-value < or = -1 SD) was present. Fourteen percent of the male patients, but none of the female patients, met the criteria for osteoporosis (T-value < or = -2.5 SD). In the whole group of diabetic patients the mean plasma IGF-I level tended to be lower (p<0.10) as compared to that in the controls. In the diabetic patients with femoral neck osteopenia, the mean plasma IGF-I level was significantly lower (p<0.05) than in those without osteopenia at this site. There were no differences in the mean serum ALP, BAP and osteocalcin levels between the diabetic patients and the controls, nor between the diabetic patients with and without femoral neck osteopenia. Considering only the male diabetic patients, significantly lower mean plasma IGF-I (-26%), serum ALP (-24%) and serum osteocalcin (-38%) levels were present in the patients with femoral neck osteopenia than in those without osteopenia at this site, suggesting lowered bone formation. The bone resorption markers were similar in all (sub)groups of diabetic patients and not different between diabetic patients and controls. Bone mineral density (BMD) did not correlate with plasma levels of glycosylated hemoglobin (HbA1c). BMD values were not related to any of the bone resorption or formation markers, except for plasma IGF-I both in the femoral neck (r=+0.38, p=0.026) and the lumbar spine (r=+0.34, p=0.043). Our data demonstrate that at least in male patients with IDDM, osteopenia is the consequence of a lowered bone formation with a predominance of bone resorption over formation.

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.

Body composition determined by six different methods in women bilaterally adrenalectomized for treatment of Cushing's disease.

In 14 women, aged 47.2 +/- 10.5 yr, bilaterally adrenalectomized for Cushing's disease 13.6 +/- 7.7 yr before, all receiving conventional doses of glucocorticoid and mineralocorticoid substitution, body composition was studied with regard to body fat, body fat distribution, fat-free mass, and bone mineral density. The data were compared with those of 14 healthy women of similar age, body mass index, and menopausal state. Five different body composition measurement methods were compared, i.e. body densitometry by underwater weighing (UWW), total body water measurement by deuterium dilution (D2O dilution), dual energy x-ray absorptiometry (DXA), bioelectrical impedance spectrometry (BIS), and skinfold measurements, using a four-component model (4C-model) as the reference method. In the patients the percent body fat was significantly higher than that in the controls as determined by all methods, whereas fat-free mass was significantly lower when measured with the 4C-model, UWW, D2O dilution, DXA, or BIS. Measured by DXA, the percent trunk fat, estimated as [fat mass of the trunk (g)/total fat mass (g)] x 100%, was significantly higher in the patients than in the controls (39.3 +/- 6.4% and 29.9 +/- 7.8%, respectively; P < 0.001). Measured by DXA, there was no difference in total bone mineral density between the groups. Differences between the 4C-model, UWW, D2O dilution, and DXA for determination of percent body fat were rather small. Skinfold measurements and BIS results, however, deviated substantially from those obtained using the 4C-model. The study indicates that adrenalectomized patients receiving conventional glucocorticoid substitution have increased body fat percentages with a centripetal fat distribution and lowered fat-free mass, but normal bone mineral density. Furthermore, the study indicates that for clinical practice, DXA, D2O dilution, UWW, and the 4C-model can be used for determination of body composition in this patient group, whereas the more convenient bedside methods, BIS and skinfold measurements, did not give reliable results. We suppose that glucocorticoid overreplacement in adrenalectomized patients might be the cause of their abnormal body composition, although GH deficiency after pituitary surgery could have played a contributory role in some of the patients.

Progression of a Nelson's adenoma to pituitary carcinoma; a case report and review of the literature.

A 25-year-old woman developed Nelson's syndrome, 3 years after successful bilateral adrenalectomy for Cushing's disease. Despite pituitary surgery and radiotherapy the tumour showed invasive growth, leading to visual disturbance, paresis of the oculomotor nerve and, 34 years after adrenalectomy, to death by widespread purulent leptomeningitis. Autopsy revealed a large adenohypophyseal carcinoma with a metastasis attached to the dura, both tumours showing immunocytochemical staining for ACTH and TSH. We review the literature on metastatic adenohypophyseal carcinoma in Cushing's disease and Nelson's syndrome and discuss the role of proliferation markers as indicators of malignant progression.

Selectivity of finasteride as an in vivo inhibitor of 5alpha-reductase isozyme enzymatic activity in the human prostate.

The type II 5alpha-reductase inhibitor finasteride is used in the treatment of benign prostatic hyperplasia (BPH), reducing local production of the growth promoting androgen dihydrotestosterone (DHT). The effect of prolonged treatment with this time-dependent irreversible inhibitor on the recently described prostatic type I 5alpha-reductase, however, is not clear. Therefore, we assessed the effects of 5 mg. finasteride per day for 6 months on prostatic 5alpha-reductase isozymes, and prostatic tissue composition and androgen content of patients suffering from BPH. In prostatic tissue from these patients, the type II enzymatic activity is inhibited 100-fold compared with tissues obtained from placebo treated patients. The type II immunoreactivity is up regulated 2-fold. The type I isozyme is inhibited 3-fold and potentially still contributes to DHT production. In conclusion, finasteride is a selective type II inhibitor in vivo. Further research is warranted to assess the possibly distinct roles of the 5alpha-reductase isozymes in the normal prostate, in BPH, and during finasteride treatment.

Preclinical Cushing's syndrome in patients with an adrenal incidentaloma.

BACKGROUND: Autonomous (hyper-)secretion of cortisol without classical stigmata of Cushing's syndrome occurs in 10-15% of patients with incidentally detected adrenal tumors (incidentalomas). METHODS: We present the clinical and biochemical data of four such patients. Two patients had hypertension and one both hypertension and non-insulin-dependent diabetes mellitus, but none showed classical stigmata of Cushing's syndrome. RESULTS: All patients showed insufficient suppression of plasma cortisol during a 1 mg dexamethasone screening test. Plasma ACTH levels were suppressed in all patients. However, in three out of four patients the diurnal rhythm of plasma cortisol was intact and these three patients also showed a response of plasma cortisol after administration of corticotropin-releasing hormone. All patients underwent unilateral adrenalectomy. A carcinoma was found in one patient and an adenoma in the remaining three. Postoperatively, blood pressure had normalized in 2 out of 3 hypertensive patients, whereas non-insulin-dependent diabetes mellitus had disappeared in 1 patient. Postoperative endocrine evaluation showed no abnormalities anymore. CONCLUSIONS: We conclude that dexamethasone testing may reveal autonomous (hyper-)secretion of cortisol in adrenal incidentalomas. Adrenalectomy should be considered, especially when hypertension and/or non-insulin-dependent diabetes mellitus are present. One should be alert to the development of adrenal insufficiency after unilateral adrenalectomy.

[Systemic mastocytosis as a cause of osteoporosis]. / Systemische mastocytose als oorzaak van osteoporose.

Out of 21 male patients with osteoporosis who visited an outpatient clinic for endocrine diseases in two years (1994-1995), three had systemic mastocytosis as diagnosed histopathologically. Two of these had characteristic features of urticaria pigmentosa, consisting of multiple brown nodules on the skin of trunk and extremities, and a positive Darier sign. In all of them the excretion of the histamine metabolites methylhistamine and methylimidazoleacetic acid in a 24-hour urine specimen was increased. When osteoporosis is diagnosed in men or premenopausal women, underlying pathology could be considered. Cautious investigation of signs and symptoms of systemic mastocytosis in such patients might prove this disease be less rare than is often assumed.

Kinetic analysis of steroid 5alpha-reductase activity at neutral pH in benign prostatic hyperplastic tissue: evidence for type I isozyme activity in the human prostate.

In human benign prostatic hyperplastic (BPH) tissue homogenates 5alpha-reduction of testosterone was examined at neutral pH. As Lineweaver-Burk and Eadie-Scatchard plots of estimated initial velocities against a wide range of substrate concentrations of 2 nM to 3.2 microM were non-linear, the existence of two 5alpha-reductase isozymes in this tissue was surmised. Indeed, enzyme parameters at pH 7.0 suggested the presence of two isozymes with affinity constants of 1995 and 11.8 nM, characteristic of the well established human steroid 5alpha-reductase isozymes type I and II, respectively. The physiological roles of these isozyme activities remain puzzling. The specific activities, Vmax, of these subtypes indicated an approx. 6-fold higher maximum velocity of type I than of type II 5alpha-reductase in the human hyperplastic prostate at this pH. In contrast, the efficiency ratios, Vmax/Km, demonstrated that the type II isozyme had a nearly 27 times higher potential in vivo activity than the type I isozyme, and is therefore most probably quantitatively responsible for dihydrotestosterone formation at physiological testosterone levels in this tissue at neutral pH. This is the first full paper on type I 5alpha-reductase activity in human BPH tissue.

Bone mineral density and bone turnover before and after surgical cure of Cushing's syndrome.

We measured bone mineral density (BMD) using dual-energy x-ray absorptiometry in 20 patients with Cushing's syndrome (CS) (14 pre- and 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, fasting blood samples and 2-h fasting urine samples for measurement of biochemical parameters of bone and collagen metabolism were collected 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 considerably 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 P < 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 procollagen, aminoterminal propeptide of type III procollagen, and the cross-linked telopeptide of type I collagen were not significantly different between the group of 14 premenopausal patients with active CS and a control group of 18 age-matched healthy premenopausal women. However, the urinary hydroxyproline/creatinine ratio was significantly higher in patients with CS (24.6 +/- 9.6 vs. 16.2 +/- 3.5 mumol/mmol, P < 0.01). In all 9 premenopausal patients, serum levels of osteocalcin increased considerably between 0 and 3 months (from 1.04 +/- 0.20 to 3.82 +/- 0.30 nmol/L) (mean +/- SEM, P < 0.0001), indicating a prompt increase of osteoblast activity. Also serum levels of carboxyterminal propeptide of type I procollagen, aminoterminal propeptide of type III procollagen, and cross-linked telopeptide of type I collagen, and the urinary hydroxyproline/creatinine ratio increased significantly between 0 and 3 months. Thereafter these levels decreased gradually. We conclude that marked osteopenia in the lumbar spine and femoral neck is present in most patients with active Cushing's syndrome.(ABSTRACT TRUNCATED AT 400 WORDS)

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)

Multiple forms of bioactive and immunoreactive adrenocorticotropin in human pituitary and blood of patients with Nelson's syndrome.

A pool of human pituitaries obtained from allegedly healthy subjects (traffic victims) and plasma samples from patients with Nelson's syndrome were analyzed by high performance liquid chromatography, and the corticosteroidogenic bioactivity and ACTH immunoreactivity were measured. Three bioactive forms of ACTH were detected in plasma samples and pituitary extract. The major form (peak III) coeluted with human ACTH-(1-39), showed a bioactive to immunoreactive ratio (B/I ratio) of about 1, and represented about 80% of the total bioactivity in both the plasma samples and the pituitary extract. Peak I, with a B/I ratio greater than 1, represented about 5%, and peak II, with a highly variable B/I ratio, represented about 7% of the bioactivity in both the plasma and pituitary extracts. A fraction with a very low B/I ratio was found to coelute with corticotropin-like intermediate lobe peptide. These data suggest that in Nelson's syndrome, ACTH secretion by the pituitary gland does not differ from that in normal subjects, at least qualitatively.

[Compared to whole body scanning thyroglobulin assay is reliable in the follow-up of thyroidectomized patients with thyroid carcinoma]. / Thyreoglobulinebepaling goed bruikbaar in de follow-up van schildkliercarcinoompatiënten na thyreoïdectomie, in vergelijking met lichaamsscintigrafie.

OBJECTIVE: To determine whether it is reliable to do thyroglobulin measurements during thyroid hormone substitution (Tg ON) alone or whether it is also necessary to do 131I total body scanning (TBS) and Tg measurements after withdrawal of thyroid hormone substitution (Tg OFF) in the follow-up of patients with differentiated thyroid carcinoma. DESIGN: Retrospective. SETTING: University Hospital Nijmegen. METHODS: 202 Patients (151 females and 51 males, mean age 50.6 years) with differentiated thyroid carcinoma were examined in the period 1970-90. All patients had undergone total thyroidectomy and if necessary 131I ablation. 27 Patients with Tg antibodies were excluded (13.4%). In 175 patients Tg OFF levels were compared with TBS and clinical and radiological data. In 81 of them Tg ON levels were also compared. RESULTS: Specificity of Tg OFF and Tg ON measurement was 83 and 88%. Sensitivity of Tg OFF and Tg ON measurement was 100 and 92%. In detecting local residual thyroid tissue Tg OFF was superior to Tg ON. In detecting metastases Tg OFF and Tg ON were both superior to TBS. CONCLUSION: In the follow-up of patients with differentiated thyroid carcinoma it is reliable to do Tg measurements during thyroid hormone suppression. When Tg ON is detectable (> 3 pmol/l) TBS and Tg OFF measurement and if necessary further investigations have to be performed.

Unpredictable hypersecretion of cortisol in Cushing's disease: detection by daily salivary cortisol measurements.

A 70-year-old man with mild signs and symptoms of Cushing's syndrome due to an ACTH-secreting pituitary adenoma is described. He had a completely unpredictable pattern of urinary excretion of cortisol; 24 h urine for determination of cortisol excretion was collected daily at home on 725 consecutive days. During this period there were eight episodes in which urinary cortisol excretion exceeded the upper limit of normal. Within these episodes the pattern of cortisol secretion was extremely unpredictable, with cortisol excretion ranging from normal to highly elevated. Using a Cluster Analysis Program 61 pulses of cortisol excretion were detected within the eight periods of cortisol hypersecretion. The interval between two pulses varied from 2 to 12 days. Between the periods of cortisol hypersecretion, urinary cortisol excretion was completely normal, lasting from 4 to 102 days. There was no difference in the clinical expression of Cushing's syndrome between the periods of elevated and normal urinary cortisol excretion. During the last 439 days of the observation, cortisol was also measured in saliva collected at home at 09.00 after an overnight fast. The salivary cortisol pattern closely resembled that of urinary cortisol excretion and there was a significant correlation between salivary cortisol levels and 24 h urinary cortisol excretion in the 24 h after (r = 0.42, p < 0.0001, Spearman) and before saliva collection (r = 0.44, p < 0.0001). On 71% of occasions cortisol peaks in saliva, as detected by the Cluster Analysis Program, coincided with urinary cortisol peaks. We conclude that daily measurement of cortisol in saliva, collected at home, is a convenient and reliable method for detecting intermittent hypercortisolism in patients with Cushing's syndrome.

Postprandial gallbladder motility and plasma cholecystokinin at regular time intervals after injection of octreotide in acromegalics on long-term treatment.

The increased risk of gallstone formation in acromegalics treated with the somatostatin analog octreotide has been related to an impaired gallbladder emptying. To determine the duration of these inhibitory effects, meal-stimulated gallbladder motility, plasma cholecystokinin (CCK), and pancreatic polypeptide (PP) were measured in five acromegalics treated for 6-32 months with 200-300 micrograms octreotide daily. Meal tests were performed 45 min, 8 hr and two weeks after the last 100-micrograms subcutaneous dose. Results were compared with those in normal subjects. Integrated postprandial gallbladder contraction (-125 +/- 194 cm3/120 min) and integrated PP secretion (-0.1 +/- 0.2 nmol/liter/120 min) were completely suppressed in the 45-min study, but significantly improved (P < 0.05) when measured 8 hr (1376 +/- 322 cm3/120 min and 3.0 +/- 1.0 nmol/liter/120 min) and two weeks (1437 +/- 263 cm3/120 min and 10.6 +/- 1.6 nmol/liter/120 min) after the last dose of octreotide. The integrated gallbladder contraction in acromegalics at 8 hr was comparable to that at two weeks and to that in normal subjects, but the integrated PP response at 8 hr was significantly smaller (P < 0.05 vs two weeks and vs normals). Integrated plasma CCK secretion at 45 min (0.13 +/- 0.06 nmol/liter/120 min) was not statistically significantly different from the response at 8 hr (0.15 +/- 0.02 nmol/liter/120 min) and from that in normal subjects, but it was significantly increased at two weeks after cessation of octreotide (P < 0.05 vs 45 min and 8 hr).(ABSTRACT TRUNCATED AT 250 WORDS)

TSH-dependent production of T4 and T3 by metastases of a thyroid carcinoma.

A patient with T4 and T3 production by metastases of a follicular thyroid carcinoma leading to TSH suppression is described. During a period of three years, plasma T4, T3 and TSH levels were measured in the substitution-free periods before the successive iodine-131 retention measurements and iodine-131 therapies, when the patient was at least two weeks without thyroid hormones. From the presented data it can be derived that the production of thyroid hormones by metastases was enhanced by endogenous TSH.

Body weight and/or endogenous estradiol as determinants of cortical bone mass and bone loss in healthy early postmenopausal women.

The objective was to study the independent relationships of body mass index and endogenous estradiol to cortical bone mineral density and the rate of cortical bone loss at the radius in healthy early postmenopausal women. Fifty-one healthy early postmenopausal women (aged 58-66 years) participated. The women were a subset of a population participating in a 10-year longitudinal study to elucidate the influence of dietary calcium on the rate of cortical bone loss. Cortical bone mineral density at the radius, body weight and body height were measured annually (1979-89). Concentrations of sex steroids were measured in serum samples collected during the last year of follow-up (1989). Endogenous estradiol levels, although significantly positively correlated with body mass index, were not independently related to bone mass indices of the radius. Body mass index, on the other hand, was found to be positively related to cortical bone mineral density and negatively to the rate of bone loss, even after adjustments had been made for confounding factors. Our results suggest that the level of total estradiol is not an important determinant of cortical bone mass indices in healthy early postmenopausal women. Other factors of overweight such as mechanical loading may be important.