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J Weeke

Publications and source records attributed to J Weeke.

At least 19 recordsLinked to original sources

Long-term efficacy and tolerability of octreotide treatment in acromegaly.

Twenty-five acromegalic patients were studied during 6 years of treatment with octreotide, with a particular focus on the following parameters: (1) Administration schedule: in 10 patients, continuous subcutaneous (SC) octreotide infusion was compared with injections of octreotide at three dose levels (100, 250, and 1,500 micrograms/24 h) and was found to induce a greater and less-fluctuating 24-hour growth hormone (GH) suppression. (2) Carbohydrate tolerance: average 24-hour blood glucose levels were unaffected by octreotide, regardless of administration schedule. Oral carbohydrate tolerance and intravenous (IV) glucose tolerance were unaffected by continuous octreotide infusion. However, octreotide injection given shortly before the tests reduced carbohydrate tolerance. (3) Thyroid function: octreotide and somatostatin acutely reduce the response of thyroid-stimulating hormone (TSH) to thyrotropin-releasing hormone (TRH). After a few days of treatment, it was demonstrated that octreotide slightly inhibits iodothyronine deiodination and induces a transient reduction in serum triiodothyronine (T3), rapidly compensated for by a persistent slight elevation of serum TSH. (4) Fat absorption was estimated as 24-hour fecal fat content and found to be in the same high-normal range before and after octreotide treatment. Vitamin K and D absorption were unaffected by octreotide. The incidence of gallstone formation was not greater than in the general Danish population, possibly due to the schedule used for octreotide injections. (5) Foot volume was regularly estimated and found to decrease with time, on average by 12% during the first 18 months.(ABSTRACT TRUNCATED AT 250 WORDS)

Acromegaly

Preliminary results with Sandostatin nasal powder in acromegalic patients.

This report details the first half of a double-blind, crossover sequence (Latin square) study of local and hormonal effects of nasally insufflated Sandostatin compared with those of subcutaneously injected Sandostatin. Nine of the planned 16 patients have been studied. They received a single application of 0.5, 1.0, and 2.0 mg Sandostatin as nasal powder and 0.1 mg by subcutaneous (SC) injection. The results indicate that absorption from the nasal epithelium occurs after approximately 10 minutes and comprises approximately 20% of the dose administered. This indicates that peak serum Sandostatin values occur very rapidly, ie, 10 minutes after application. After approximately 2 hours, the serum disappearance rates are similar to those obtained after SC injection. The suppressive effect on serum growth hormone (GH) levels is equal with the two forms of application and suggests that future clinical treatment with an intranasal application of 0.5 mg thrice daily is feasible. No side effects were noted apart from an immediate swelling of nasal mucosa, which receded gradually over the following 2 hours. This was either unnoticed or considered insignificant by the patients and will probably be deemed harmless by the rhinologist in eventual long-term clinical trials.

Absorption

Effects of growth hormone administration on fuel oxidation and thyroid function in normal man.

In a randomized, double-blind, placebo-controlled, cross-over study, we examined the effects of 14 days of growth hormone (GH) administration (12 IU/d subcutaneously) on energy expenditure (EE), respiratory exchange ratio (RER), and thyroid function in 14 normal adults of normal weight (eight men and six women). EE (kcal/24 h) was significantly elevated after GH administration (2,073 +/- 392, [GH], 1,900 +/- 310, [placebo], P = .01). RER was significantly lowered during GH administration (0.73 +/- 0.04 v 0.78 +/- 0.06, P = .02), reflecting increased oxidation of lipids. Total triiodothyronine (TT3) (nmol/L) and free T3 (FT3) (pmol/L) increased significantly during GH (TT3: 1.73 +/- 0.06 [GH], 1.48 +/- 0.08 [placebo], P = .01; FT3: 6.19 +/- 0.56 [GH], 5.49 +/- 0.56 [placebo], P = .01). Concomitantly, an insignificant decrease in reverse T3 (rT3) (nmol/L) was observed (0.07 +/- 0.01 [GH], 0.15 +/- 0.01 [placebo], P = .08). GH caused a highly significant increase in T3/thyroxine (T4) (x 100) ratio (1.84 +/- 0.12 [GH], 1.37 +/- 0.06 [placebo]). Serum thyrotropin (TSH) was not significantly changed by GH. No changes in total thyroxine (TT4) (nmol/L) (98 +/- 6 [GH], 111 +/- 8 [placebo], P = .40) and free thyroxine (FT4) (pmol/L) (17.4 +/- 1.3 [GH], 18.6 +/- 1.1 [placebo], P = .37) after 14 days of GH administration were observed. In conclusion, 2 weeks of GH administration increases EE and lipidoxidation. This finding may partly be mediated by an increase in peripheral T4 to T3 conversion.

Adult

SMS 201-995 and thyroid function in acromegaly: acute, intermediate and long-term effects.

The acute (TRH-stimulation test), intermediate (0-6 days administration), and long-term (0-30 months administration) effects of SMS 201-995 (octreotide) treatment on thyroid function were studied. Subcutaneous injection of 100 micrograms SMS 201-995 one hour before 200 micrograms TRH intravenously reduced serum TSH response area by more than 50% in 8 healthy volunteers. After 3 days of continuous subcutaneous infusion (CSI) of SMS 201-995 in 9 acromegalic patients (100 micrograms/24 h) a slight but significant decrease in serum total triiodothyronine (TT3) and a concomitant increase in serum TSH were demonstrated, indicating an initial inhibitory effect on peripheral deiodination of thyroxine. After a further 3 days treatment serum T3 and TSH had returned to prevalues. Six of the nine acromegalics were treated with SMS 201-995 (100-1500 micrograms/24 h) and admitted for diurnal hormone profiles on 13 occasions over 30 months. Apart from a barely significant increase in serum TSH, no changes in thyroid function were noted. The study was especially designed to detect minute changes over time in thyroid hormones. The only long-term effect of SMS 201-995 was the barely significant clinically irrelevant increase in serum TSH, possibly caused by a slight inhibition of peripheral deiodination of thyroxine.

Acromegaly

Thyroid function during growth hormone therapy.

Administration of growth hormone (GH) in GH-deficient patients has been reported to cause a variety of perturbations in thyroid function. Reports range from decreased sensitivity of thyrotropin (TSH) to thyrotropin-releasing hormone (TRH) stimulation and induction of hypothyroidism to increased energy expenditure and enhanced peripheral thyroxine (T4) to triiodothyronine (T3) conversion. Some of the diversities may relate to the fact that earlier studies were uncontrolled case reports, which furthermore employed pituitary GH preparations, which may have been contaminated with TSH. A confounding variable in terms of incipient TSH insufficiency in some patients may also have been present. Data from a placebo-controlled crossover study of 4-months GH therapy in GH-deficient adults, some of whom were on ongoing T4 substitution, revealed that the most prominent effect on thyroid function was increased peripheral T4 to T3 conversion without significantly affecting TSH levels or secretion from the thyroid gland. It was furthermore observed that T3 levels during placebo were significantly decreased compared to an untreated healthy control group. Comparable findings have been made in a controlled study of 6-months GH therapy in adult-onset GH-deficient patients. More recent data suggest that these effects prevail after long-term (16 months) therapy. Similar findings have also been reported in healthy subjects receiving pharmacological GH doses. It is likely that this effect is not caused by GH per se inasmuch as reduced T4 to T3 conversion is a common observation in catabolic states with concomitant GH hypersecretion. It remains to be shown whether insulin-like growth factor I (IGF-I) stimulates peripheral deiodination.

Adult

Basal- and insulin-stimulated substrate metabolism in patients with active acromegaly before and after adenomectomy.

Active acromegaly is characterized by inappropriate tissue growth, increased mortality, and perturbations of intermediary metabolism. It is, in general, not well described to which extent these disturbances are normalized after treatment of the disease. To further assess basal and insulin stimulated fuel metabolism in acromegaly six patients with monotropic GH excess were each studied approximately 1 month prior to and 2 months after successful selective pituitary adenomectomy and compared to a control population of seven subjects. The studies consisted of a 3-h basal postabsorptive period and a 2-h hyperinsulinaemic (0.4 mU/kg/min) euglycemic clamp and the methods employed included isotopical measurement of glucose turnover, indirect calorimetry, and the forearm technique. When compared to the control subjects the patients with acromegaly were preoperatively and in the basal state characterized by: 1) increased circulating concentrations of GH, insulin, and C-peptide (P less than 0.05); 2) increased plasma glucose (5.9 +/- 0.2 vs. 5.2 +/- 0.2 mmol/L), blood lactate (710 +/- 90 vs. 580 +/- 70 mumol/L), glucose turnover (2.34 +/- 0.12 vs. 1.93 +/- 0.12 mg/kg/min), and plasma lipid intermediates and a decreased forearm glucose uptake (0.06 +/- 0.02 vs. 0.19 +/- 0.04 mmol/L) (P less than 0.05); and 3) a 20% increase in energy expenditure, a 50% elevation of lipid oxidation rates, and a 130% elevation of nonoxidative glucose turnover (P less than 0.05). During the clamp the patients with active acromegaly were substantially resistant to the actions of insulin on both glucose and lipid metabolism. Following pituitary surgery all of these metabolic abnormalities were abolished. We conclude that active acromegaly is characterized by profound disturbances of not only glucose but also lipid metabolism, which in theory may precipitate the increased mortality in this disease. By showing that these abnormalities and the concomitant overall insulin resistance can be completely reversed our results may also have important implications for other insulin-resistant states and for the potential therapeutic use of GH.

Acromegaly

A randomized comparison of intranasal and injectable octreotide administration in patients with acromegaly.

Fifteen acromegalic patients received four single doses of octreotide in random order (500 micrograms, 1000 micrograms, and 2000 micrograms applied intranasally and 100 micrograms given sc). Serum octreotide and GH data were subjected to pharmacokinetic analyses, and local nasal effects were evaluated by acoustic rhinometry. Average areas (+/- SEM) under the serum octreotide curves were: 2000 micrograms: 4597 +/- 536; 1000 micrograms: 1923 +/- 439; 500 micrograms: 957 +/- 168; and 100 micrograms sc: 896 +/- 81 micrograms.L-1.min (n = 13). The calculated relative availability was 27% +/- 0.03; 22% +/- 0.05; 22% +/- 0.03, respectively, for the three nasal doses. The rate of absorption after intranasally administered octreotide was greater than after sc application: t1/2 ka: 7.1 +/- 1.6; 7.9 +/- 1.6; 11.3 +/- 1.9, respectively, vs. 24.1 +/- 2.5 min, whereas the rates of disappearance were similar. GH suppression started immediately after application and reached minimum levels 1-2 h later. The average intervals during which serum GH was below 50% of preadministration values were: 2000 micrograms: 544 +/- 47; 1000 micrograms: 423 +/- 56; 500 micrograms: 289 +/- 52 vs. 351 +/- 34 min after sc injection of 100 micrograms. With 2000 micrograms intranasally all but one of the 15 patients attained constant suppression of serum GH below 5 micrograms/L for 273 to 680 min. Pharmacokinetic analysis demonstrated that 100 micrograms sc and 1000 micrograms intranasally induced the same GH suppressive effect and that 2000 micrograms intranasally approximately doubled the duration of action. Acoustic rhinometry was performed after nasal application of the largest dose of 2000 micrograms and after carrier (n = 9). A highly significant tumescence of the nasal mucosa was maximal after 10 min and gradually receded over the next 2 h. However, this was felt by the patients to be acceptable. The effect was caused by octreotide per se and was probably due to vasodilation.

Acromegaly

Changes in plasma free thyroid hormones during cardiopulmonary bypass do not indicate triiodothyronine substitution.

Concentrations of free and bound thyroid hormone in plasma during cardiopulmonary bypass were determined in 10 patients. Ages ranged from 50 to 76 years (median 61 years). Apart from thyroxine and triiodothyronine, a number of other variables that might contribute to an altered thyroid state or binding of thyroxine and triiodothyronine to plasma proteins were measured (thyroid stimulating hormone, reverse triiodothyronine, albumin, nonesterified fatty acids, and cortisol). At the end of the observation, total triiodothyronine and total thyroxine concentrations were 86% and 70% (mean) of initial levels, respectively, and reverse triiodothyronine and albumin concentrations were both 74%. On the contrary, free triiodothyronine and free thyroxine levels rose to a maximum of 137% and 203% (mean), but normalized after heparin neutralization (86% and 102%). Thyroid-stimulating hormone concentration declined insignificantly during cardiopulmonary bypass, reaching a minimum at the time when body temperature was maximally depressed (74%), and then it normalized (101%). Plasma cortisol level did not rise above normal limits despite the major stress stimulus. In conclusion, total triiodothyronine and total T4 concentration in plasma of patients undergoing cardiac operations is lowered, while the exchangeable pool concentrations (plasma free triiodothyronine and free thyroxine) are elevated during bypass but return to control levels at the end of the operation. If serum changes truly reflect intracellular events, it does not seem likely that the myocardial cell is depleted of thyroid hormones after cardiopulmonary bypass, as recently claimed by others. This finding does not, however, exclude the possibility that a pharmacologic dose of triiodothyronine may be convenient for improvement of cardiac performance.

Cardiopulmonary Bypass

Reduction in sella turcica volume. An effect of long-term treatment with the somatostatin analogue, SMS 201-995, in acromegalic patients.

Ten patients with acromegaly were treated with the long-acting somatostatin analogue, Sandostatin (SMS 201-995, octreotide) for more than one year. Computerized tomography was performed before and on 4 different occasions during the treatment. Sella turcica volumes were calculated in nine patients and showed a gradual decrease in all, averaging 32% +/- 14.6%, P less than 0.001 at the end of the study, which is probably indicative of a simultaneous reduction in adenoma size.

Acromegaly

Effects of antibodies against octreotide in two patients with acromegaly.

Two patients developed specific IgG antibodies against octreotide after 2-3 years' treatment for acromegaly with this long acting somatostatin analogue. The presence of these antibodies reduced the plasma disappearance rate of total extractable octreotide by 60 and 80% respectively. When compared to that of non-immune acromegalic patients, the plasma half-life of octreotide in these two patients was 300 and 450 vs 110 min in those with no detectable octreotide antibodies. The sole observed consequence of the immunization was a marked prolongation of the interval of maximum GH inhibition from a mean of 5 to 8 and 10 h in the two patients described after octreotide injection.

Acromegaly

The influence of growth hormone and thyroxine on iodothyronine deiodinase activity in the liver, kidney and brown adipose tissue in hypophysectomized rats.

The effects of GH and T4 substitution on peripheral iodothyronine deiodinase activity in the liver, kidney and brown adipose tissue of hypophysectomized rats were investigated. Animals were treated with GH (140 micrograms hGH/day), T4 (3 micrograms/day), GH plus T4 (same doses), or saline. Rats were killed 0, 4, 7 or 11 days after treatment was started. Non-hypophysectomized, age-matched rats were killed after 0 and 11 days and served as controls. GH plus T4 restored body weight gain to normal, whereas GH alone and T4 alone did not. Tissue deiodinase activity and T3 concentrations were severely depressed in the hypophysectomized rats compared with non-hypophysectomized controls (to less than 10%). GH substitution in hypophysectomized rats led to a slight but significant elevation in tissue iodothyronine deiodinase activity in the liver and kidney, without concomitant increases in T3. Deiodinase activity in brown adipose tissue did not differ from that in saline-treated controls. T4 administration normalized deiodinase activity and tissue T3 content in all the evaluated tissues. GH plus T4 resulted in a lesser increase in deiodinase activity than T4 alone in the liver and kidney (p less than 0.01 at day 11), whereas no significant difference was observed in brown adipose tissue. In conclusion, GH stimulates iodothyronine deiodinase activity of the liver and kidney in hypophysectomized rats. Moreover, when GH is administered together with T4, the T4-stimulated enzyme activity in the liver and kidney is downregulated, suggesting that GH attenuates (or modulates) the T4 effect on this specific enzyme activity.

Adipose Tissue, Brown

The role of thyroid tests in handling of patients in general practice. A phenomenologic study.

During a period of 2 months thyroid function tests, performed on out-patients referred to the laboratory from general practitioners, were studied. The relative informative value of the tests was estimated in relation to the reasons given for requesting the tests. In 86% of the samples from patients with no history of earlier thyroid disease the conventional thyroid tests were found within the reference intervals. 3% showed a definite abnormal pattern of values. In 11% the results were in some way abnormal. In the group of patients with earlier history of thyroid disease 50% of the tests were abnormal. The relative merits of adding a sensitive TSH assay test were analyzed, and it was estimated whether using the sensitive TSH as a first-line discrimination test would add or subtract information compared to the conventional thyroid function tests. It was concluded that in the situation where the general practitioner wants laboratory information of thyroid parameters on patients in order to make decisions on the further handling of the patient, the sensitive TSH test is of limited value as a first-line discrimination test and should be supplemented by other tests.

Adolescent

The cardiovascular effects of octreotide treatment in acromegaly: an echocardiographic study.

Nine acromegalic patients were treated by the somatostatin analogue SMS 201-995 octreotide (Sandostatin (octreotide), Sandoz, Basle, Switzerland] 250 micrograms/day in 4 divided s.c. injections (50 + 50 + 50 + 100 micrograms) for 1 month, 250 micrograms/24 has continuous s.c. infusions for another month and thereafter 200 micrograms three times daily as s.c. injections. Echocardiography was performed before the treatment, following 1 month of octreotide s.c. infusion/injection and after 6 and 12 months of octreotide treatment. No differences in serum growth hormone, heart rate, blood pressure, cardiac contractility or left ventricular wall mass or wall thickness were found between the infusion and the injection periods. As compared to the pretreatment levels serum growth hormone decreased by 62 and 66% respectively following 6 and 12 months octreotide treatment. The heart rate per minute (+/- SD) decreased from the pretreatment level of 75 +/- 12 to 63 +/- 13 (P less than 0.007) at month 12. The systolic and the diastolic blood pressure decreased from the pretreatment level of 121 +/- 8 and 79 +/- 5 mmHg respectively to 108 +/- 7 (P less than 0.0007) and 71 +/- 7 mmHg (P less than 0.0001) respectively at month 12.(ABSTRACT TRUNCATED AT 250 WORDS)

Acromegaly

Effects of growth hormone therapy on thyroid function of growth hormone-deficient adults with and without concomitant thyroxine-substituted central hypothyroidism.

Administration of human GH to GH-deficient patients has yielded conflicting results concerning its impact on thyroid function, ranging from increased resting metabolic rate to induction of hypothyroidism. However, most studies have been casuistic or uncontrolled and have used pituitary-derived GH of varying purity, often contaminated with TSH. Therefore, we conducted a double blind, placebo-controlled cross-over study of the effect of 4 months of biosynthetic human GH therapy (Norditropin; 2 IU/m2.day) on thyroid function in GH-deficient adults (8 females and 14 males; mean +/- SE age, 23.8 +/- 1.2 yr). One group (I) was euthyroid without T4 substitution (n = 13), whereas the other (group II) received T4 (n = 9). Serum T4 (nanomoles per L) decreased in both groups after GH treatment [group I, 100 +/- 8 (mean +/- SE) vs. 89 +/- 8 (P less than 0.01); group II, 145 +/- 18 vs. 115 +/- 10 (P less than 0.05)]. Conversely, GH treatment caused an increase in serum T3 (nanomoles per L) in both groups [group I, 1.9 +/- 0.1 vs. 2.0 +/- 0.1 (P less than 0.1); group II, 1.7 +/- 0.1 vs. 1.9 +/- 0.1 (P less than 0.05)]. Similar changes were seen in serum free T4 and T3. The serum T3 level during the placebo period of group I was significantly lower than that in an age-matched reference group (P less than 0.02). Serum rT3 (nanomoles per L) was low in group I and decreased significantly, as in group II, after GH treatment [group I, 0.26 +/- 0.02 (placebo) vs. 0.20 +/- 0.02 (GH; P less than 0.01); group II, 0.38 +/- 0.05 (placebo) vs. 0.29 +/- 0.02 (GH; P less than 0.01)]. Serum TSH decreased in both groups during GH therapy, though not significantly. Serum thyroglobulin was unaltered and did not differ from that in the reference group. In conclusion, our data are consistent with a GH-induced enhancement of peripheral deiodination of T4 to T3. GH thus seems to play an important role, either directly or indirectly, in the regulation of peripheral T4 metabolism.

Adult

Continuous subcutaneous pump infusion of somatostatin analogue SMS 201-995 versus subcutaneous injection schedule in acromegalic patients.

Diurnal serum GH patterns were determined in 10 acromegalic patients before treatment, after 3 d continuous s.c. pump infusion and then after 3 d with three equal daily s.c. injections in both instances totalling 100 micrograms/24 h. Subcutaneous injections (33 micrograms) induced impressive suppression of serum GH lasting 3-6 h in eight patients followed by escape to pretreatment values before the next injection. In contrast, continuous infusion resulted in greater and more stable 24 h suppression to the levels reached at the nadir between injections. Suppression of mean 24 h serum GH below 5 ng/ml was achieved by pump treatment in four patients, while two patients had mean values between 5 ng/ml and 10 ng/ml. In four patients occasional or all levels were above 10 ng/ml (24 h average 12.4-102 ng/ml) implying either that adequate suppression by the SMS 201-995, was impossible during the 3 d pump infusion period, or that the dose administered was inadequate. Carbohydrate tolerance was unaffected in either regimen, indicating that reduction in insulin antagonistic hormones balanced inhibition of insulin release. Interestingly, and in contrast to somatostatin, SMS 201-995 did not inhibit TSH release. No untoward effects were observed at the moderate dosage and blood clinical chemistry was unchanged. Fairly constant diurnal serum SMS 201-995 values were obtained during pump infusion, while levels undulated inversely with serum GH during injection treatment. Average diurnal serum somatostatin-C immunoreactivity (all patients) decreased from 496 +/- 129 (mean +/- SD) to 385 +/- 100 ng/ml (P less than 0.003) during pump treatment and did not decrease further during the following 3 d injection treatment (363 +/- 76 ng/ml). The normal adult mean is 179 +/- 40 ng/ml. Computer tomographic (CT) scans of the sellar region were performed in all patients before and after the experimental week. Two patients had extracellular tumours whose size decreased from 8.2 to 4.1 cm3 and from 12.6 to 10.5 cm3. The results demonstrate that superior and stable suppression of GH secretion is obtained during continuous s.c. pump infusion of SMS 201-995.

Acromegaly

Plasma growth hormone in acromegalic patients. Demonstration of highly reproducible diurnal profiles in individual patients.

The effects of the selective alpha 2-adrenoreceptor antagonist idazoxan on diurnal variations in plasma growth hormone levels were studied in acromegalic patients. Seven patients entered the study; six patients had been unsuccessfully treated with either pituitary adenotomy, bromocriptine or other drug therapy or a combination of the two procedures. Plasma growth hormone levels were measured at hourly intervals over a period of 24 h under control conditions and following 4 days treatment with either placebo or idazoxan (20 mg po, three times a day); the comparison of idazoxan with placebo was a double blind cross-over study. Except in one patient, the diurnal growth hormone plasma profiles were virtually superimposable under control conditions and following either placebo or idazoxan; each patient had a characteristic profile. Four patients had impressive nocturnal elevations ranging from about 40 to 200 per cent above average daytime levels. Only one had definite paradoxical early postprandial peaks. These observations are contrary to accepted views on growth hormone levels in acromegalic patients. The majority of our patients thus had profiles reminiscent of the normal diurnal plasma growth hormone pattern albeit at a higher level indicating some preserved central drive. The rather high prevalence in the present study of patients having relapses after adenomectomy may indicate that a selection had been made of cases with hypothalamic aetiology. Administration of the selective alpha 2-adrenoreceptor antagonist idazoxan did not modify plasma growth hormone profiles in these patients.

Acromegaly

Evaluation of pituitary-adrenal function after pituitary surgery.

A short overnight metyrapone test and a 30-min ACTH test were performed in ten patients after pituitary surgery. At the initial testing 2 weeks after surgery the 30-min ACTH test was abnormal in two patients while normal increases in s-cortisol were observed in eight patients. These eight patients also had normal responses to ACTH when re-tested after 6-19 months. The short metyrapone test was a much more sensitive indicator of functional disturbances in pituitary/adrenal function. Two weeks after surgery the test was abnormal in seven of the patients. After 6-19 months some normalization of the short metyrapone test had occurred, probably due to disappearance of postoperative oedema and haematoma. However, the test was still abnormal in three patients having normal responses during the 30-min ACTH test. It is suggested that both tests are performed in such patients to specify a high risk group, i.e. both tests abnormal, and a low risk group with a normal 30-min ACTH test but subnormal responses during the short metyrapone test. This would be of help in the decision on cortisol supplementation and offer a high degree of safety for the patients.

17-alpha-Hydroxyprogesterone