Arthropathy in long-term cured acromegaly is characterised by osteophytes without joint space narrowing: a comparison with generalised osteoarthritis.

OBJECTIVE: To compare the distribution of osteophytes and joint space narrowing (JSN) between patients with acromegaly and primary generalised osteoarthritis to gain insight into the pathophysiological process of growth hormone (GH) and insulin-like growth factor type I (IGF-I)-mediated osteoarthritis. METHODS: We utilised radiographs of the knee and hip joints of 84 patients with controlled acromegaly for a mean of 14.0 years with 189 patients with primary generalised osteoarthritis. Hips and knees with with doubtful or definite osteoarthritis (Kellgren-Lawrence score of ≥ 1) were compared in the current study. For a semiquantitative assessment of radiological osteoarthritis (range 0-3) osteophytes and JSN of the medial and lateral tibiofemoral and hip joints were scored according to the Osteoarthritis Research Society International atlas. Logistic regression analysis was performed with adjustment for age, sex, body mass index and intrapatient effect. RESULTS: Knee and hip osteoarthritis in patients with cured acromegaly was characterised by more osteophytosis (OR 4.1-9.9), but less JSN (OR 0.3-0.5) in comparison with patients with primary osteoarthritis. Patients with acromegaly and osteoarthritis had significantly less self-reported functional disability than patients with primary osteoarthritis (p < 0.001). Self reported functional disability was associated with JSN rather than with osteophytosis. CONCLUSION: Arthropathy caused by GH oversecretion results in osteophytosis and to a lesser extent in JSN. This observation suggests that the GH-IGF-I system is mainly involved in bone formation resulting in osteophytosis, but may possibly protect against cartilage loss.

Growth hormone and ghrelin secretion are associated with clinical severity in Huntington's disease.

BACKGROUND AND PURPOSE: Huntington's disease (HD) is a fatal hereditary neurodegenerative disorder caused by an increased CAG repeat size in the huntingtin gene. Apart from neurological impairment, the disease is also accompanied by progressive weight loss, abnormalities in glucose homeostasis and a higher prevalence of diabetes mellitus, which may partly be caused by disturbed growth hormone (GH) and ghrelin secretion. Therefore, we aimed to perform a detailed analysis of GH and ghrelin secretion in HD patients in relation to clinical signs and symptoms. METHODS: In nine early-stage, medication-free HD patients and nine age-, gender- and body mass index-matched controls, we measured serum GH levels every 10 min for 24 h and assessed ghrelin response to food intake. Multi-parameter auto-deconvolution and approximate entropy analysis were applied to quantify basal, pulsatile, and total GH secretion rates as well as the regularity of GH secretion. RESULTS: We found no significant differences in GH and ghrelin secretion characteristics between HD patients and controls (total GH secretion: 137 +/- 36 vs. 181 +/- 43 mU/l/24 h, respectively; P = 0.439). However, in HD patients, both GH secretion and its irregularity as well as the degree of postprandial ghrelin suppression significantly increased with worsening motor and functional impairment (all P < 0.05). Moreover, postprandial ghrelin suppression also increased with decreasing body weight and higher CAG repeat number (both P < 0.05). CONCLUSIONS: These findings suggest changes in the regulation of GH and ghrelin secretion dynamics in early stage HD patients that could become more prominent in the later stages of the disease.

Mortality in patients treated for Cushing's disease is increased, compared with patients treated for nonfunctioning pituitary macroadenoma.

CONTEXT: Increased mortality in patients with pituitary tumors after surgical treatment has been reported. However, it is unknown to what extent excess mortality is caused by pituitary tumors and their treatment in general and to what extent by previous exposure to hormonal overproduction. OBJECTIVE: The aim of the study was to compare mortality between patients treated for Cushing's disease and nonfunctioning pituitary macroadenomas (NFMAs). DESIGN: This was a follow-up study. PATIENTS: We included 248 consecutive patients with pituitary adenomas treated by transsphenoidal surgery in our hospital for NFMAs (n = 174) and ACTH-producing adenomas (n = 74). The mean duration of follow-up after surgery was 10.1 +/- 7.2 yr for the whole cohort. OUTCOME MEASURES: The standardized mortality ratio (SMR) was calculated for the whole cohort and also for the two diseases separately. Cox regression analysis was used to compare mortality in patients with Cushing's disease with NFMA patients. RESULTS: Patients with Cushing's disease (39.1 +/- 16.1 yr) were significantly younger at time of operation than NFMA patients (55.3 +/- 13.4 yr). The SMR for the whole cohort was 1.41 [95% confidence interval (CI), 1.05-1.86]. The SMR in NFMA patients was 1.24 (95% CI, 0.85-1.74) vs. 2.39 (95% CI, 1.22-3.9) in patients with Cushing's disease. In patients with Cushing's disease, compared with NFMAs, the age-adjusted mortality was significantly increased: hazard ratio 2.35 (95% CI, 1.13-4.09, P = 0.008). CONCLUSIONS: Mortality in patients previously treated for Cushing's disease is increased, compared with patients treated for NFMAs. This implies that previous, transient overexposure to cortisol is associated with increased mortality.

Sources and quantity of 3,5,3'-triiodothyronine in several tissues of the rat.

The local conversion of thyroxine (T4), which is an important source of intracellular 3,5,3'-triiodothyronine (T3) in several rat tissues, has been subject of recent investigations. In the present study the regulation of this phenomenon in vivo was investigated in various peripheral tissues of the rat. Intact euthyroid and radiothyroidectomized (Tx) rats received a continuous intravenous infusion of [125I]T4 and [131I]T3 until isotope equilibrium was attained. In addition to the labeled iodothyronines, Tx rats received a continuous intravenous infusion of 0.2 or 1.0 microgram carrier T4/100 g body wt per d, to create hypothyroid or slightly hypothyroid conditions, respectively. After the animals were bled and perfused the contribution of T3 derived from local conversion of T4 to T3 [Lc T3(T4)] to the total T3 in homogenates from several tissues and subcellular fractions from the liver, kidney, and anterior pituitary gland could be calculated. In all experiments T3 in muscle was derived exclusively from the plasma. In the cerebral cortex and cerebellum, however, most of the intracellular T3 was derived from the intracellular conversion of T4 to T3. It is demonstrated that for hypothyroid rats an increased relative contribution of Lc T3(T4) reduced the loss of total T3 in the brain. This phenomenon was also encountered for the anterior pituitary gland, although in this tissue the proportion of the total tissue T3, contributed by locally produced T3 was considerably lower than the values found for the cerebral cortex and cerebellum in all experiments. The present findings, regarding the source and quantity of pituitary nuclear T3 strongly suggest that both plasma T3 and T4 (through its local conversion into T3) play a role in the regulation of thyrotropin secretion. The contribution of Lc T3(T4) to the total pituitary nuclear T3 was of minor importance in euthyroid rats (approximately 20%), compared with that found for both groups in T4-supplemented athyreotic rats (approximately 40%). The total T3 concentration in the liver decreased from euthyroid to hypothyroid rats and was associated with a decrease in the tissue/plasma T3 concentration gradient. A minor proportion of hepatic T3 was contributed by Lc T3(T4), which in fact decreased significantly from the euthyroid to the hypothyroid state. In contrast to other subcellular fractions from the liver, no Lc T3(T4) could be demonstrated in the nuclear fraction. It is suggested that the liver plays an important role with respect to regulation of the circulating T3 concentration. In the kidney, a very small proportion of the total T3 was derived from locally produced T3 in all experiments (4-7%). As found in the liver, all nuclear T3 appeared to be derived from the plasma. In contrast to the liver, subcellular T3 pools in the kidney seemed to be exchangeable.

The natural course of non-functioning pituitary macroadenomas.

OBJECTIVE: The natural history of non-functioning pituitary macroadenomas (NFMA) has not been completely elucidated. Therefore, we evaluated pituitary function, visual fields, and tumor size during long-term follow-up of non-operated patients with NFMA. DESIGN: Follow-up study. PATIENTS: Twenty-eight patients (age 55 +/- 3 years) with NFMA, not operated after initial diagnosis, were included. RESULTS: Initial presentation was pituitary insufficiency in 44%, visual field defects in 14%, apoplexy in 14%, and chronic headache in 7% of the patients. The duration of follow-up was 85 +/- 13 months. Radiological evidence of tumor growth was observed in 14 out of 28 patients (50%) after duration of follow-up of 118 +/- 24 months. Six patients (21%) were operated, because tumor growth was accompanied by visual field defects. Visual impairments improved in all the cases after transsphenoidal surgery. Spontaneous reduction in tumor volume was observed in eight patients (29%). No independent predictors for increase or decrease in tumor volume could be found by regression analysis. CONCLUSION: Observation alone is a safe alternative for transsphenoidal surgery in selected NFMA patients, without the risk of irreversibly compromising visual function.

Quality of life is decreased after treatment for nonfunctioning pituitary macroadenoma.

OBJECTIVE: Although a reduced quality of life (QoL) has been reported after long-term cure of functioning pituitary adenomas, the effect of successful treatment of nonfunctioning pituitary macroadenoma (NFMA) on QoL has not been fully addressed. Therefore, we evaluated a broad spectrum of QoL parameters in patients successfully treated for NFMA in our center. DESIGN: We conducted a case-control study. PATIENTS AND METHODS: We assessed QoL in 99 adult patients (mean age, 61.9 yr; range, 24-86 yr) in remission during long-term follow-up after surgical (n = 99) and additional radiotherapeutic (n = 37) treatment for NFMA by four validated health-related questionnaires (Hospital Anxiety and Depression Scale, Multidimensional Fatigue Index, Nottingham Health Profile, and Short Form-36). Patient outcomes were compared with 125 controls and with age-adjusted reference values derived from the literature. RESULTS: NFMA patients reported significantly impaired QoL in all questionnaires compared with the 125 controls and the age-adjusted reference values. All subscales of fatigue, assessed using the Multidimensional Fatigue Index (general fatigue, physical fatigue, reduction in activity, reduction in motivation, and mental fatigue) were impaired. The scores in the Nottingham Health Profile pointed toward reduced energy and affected emotional reaction. In several subscales of the Short Form-36 (social functioning, role limitations due to physical problems, role limitations due to emotional problems, and general health perception), NFMA patients reported a reduced QoL. CONCLUSION: QoL is considerably reduced in patients after successful treatment of NFMA.

Observation alone after transsphenoidal surgery for nonfunctioning pituitary macroadenoma.

OBJECTIVE: Transsphenoidal surgery is the treatment of choice for nonfunctioning pituitary macroadenomas (NFMA). In this study we evaluated the long-term effects of a treatment strategy in which postoperative radiotherapy was not routinely applied to patients with NFMA. DESIGN: This was a retrospective follow-up study. PATIENTS: We included 109 consecutive patients (age 56 +/- 13 yr) operated for NFMA between 1992 and 2004. RESULTS: Radiological imaging revealed a macroadenoma in all patients, with suprasellar extension in 96% and parasellar/infrasellar extension in 36% of cases. Visual field defects were present in 87% of the patients and improved in 84% of these patients after surgery. Only six patients received postoperative radiotherapy. Ten patients died during the follow-up period. Ninety-seven patients could be assessed for tumor regrowth or tumor recurrence after a mean follow-up period of 6.0 +/- 3.7 yr. In nine patients there was evidence for tumor regrowth, and in one patient tumor recurrence was observed. The mean time to tumor growth/recurrence after initial therapy was 6.9 (range 3-12) yr. Follow-up duration was found to be an independent predictor for tumor regrowth. CONCLUSION: Transsphenoidal surgery without postoperative radiotherapy is an effective and safe treatment strategy for NFMA, without evidence for tumor regrowth in 90% of all patients, at least for the duration of follow-up presented in this study. Additional studies are required to exclude higher regrowth and recurrence rates during prolongation of the duration of follow-up.

Sustained effects of recombinant GH replacement after 7 years of treatment in adults with GH deficiency.

CONTEXT: The goal of GH replacement with recombinant human GH (rhGH) is to ameliorate symptoms, signs, and complications of adult GH deficiency (GHD) in the long term. To determine whether the observed short-term beneficial effects of rhGH treatment are sustained in the long term, we evaluated biochemical and anthropometric parameters after 7 years of rhGH replacement. PATIENTS AND METHODS: After 2, 5, and 7 years of rhGH replacement, 63 adult GHD patients (30 men, 52 adult-onset GHD) were assessed. IGF-I increased during rhGH replacement, and a stable dose of rhGH was reached within 1 year of rhGH substitution. Thereafter, this individualized dose was continued. RESULTS: Plasma levels of total cholesterol and low-density lipoprotein cholesterol decreased even after 5 years of rhGH replacement (11% decrease, P < 0.001; 22% decrease, P < 0.001 respectively). High-density lipoprotein cholesterol levels increased during 7 years of rhGH replacement (1.4 +/- 0.5 mmol/l at baseline vs 1.7 +/- 0.5 mmol/l after 7 years, P < 0.001), whereas triglyceride concentrations remained unchanged. Fasting glucose levels increased during follow-up, mainly during the first 2 years of rhGH replacement (4.4 +/- 0.7 mmol/l to 5.0 +/- 1.0 mmol/l, P < 0.001). Body mass index increased during follow-up, whereas waist circumference and waist-to-hip ratio remained unchanged. Diastolic blood pressure decreased (P = 0.002), but when patients using antihypertensive medication were excluded this decrease did not reach significance (P = 0.064). Systolic blood pressure remained unchanged. CONCLUSION: The beneficial effects of rhGH replacement, described after short-term rhGH replacement, are sustained in the long term up to 7 years.

Quality of life in treated adult craniopharyngioma patients.

OBJECTIVE: Quality of life (QoL) has become increasingly important in the evaluation of treatment of pituitary and hormonal diseases. A reduced QoL has been reported in childhood-onset craniopharyngioma; however, reports of QoL in adult craniopharyngioma patients are scarce. In the present study, we assessed QoL in adult patients successfully treated for craniopharyngioma in our centre. DESIGN: This was a case-control study. METHODS: In this study, we assessed QoL in 29 adult patients in remission during long-term follow-up after treatment for craniopharyngioma. Four validated health-related questionnaires (HADS, MFI-20, NHP and SF-36) were used, covering multiple aspects of physical, psychological and social functioning. Patient outcomes were compared to controls (n = 142) and to age-adjusted reference values derived from literature. RESULTS: General fatigue, physical fatigue, energy, physical condition and physical mobility were significantly impaired, compared with controls. The main independent predictors for decreased QoL were visual field defects (depression, total HADS score, activity, motivation and energy), female gender (depression, motivation and pain), repeat surgery (role limitations due to emotional problems) and radiotherapy (mental fatigue) (the last two predictors to a lesser extent). CONCLUSION: Adult patients treated for craniopharyngioma show persistent impairment in QoL, especially in the physical subscales.

GH deficiency in patients irradiated for acromegaly: significance of GH stimulatory tests in relation to the 24 h GH secretion.

BACKGROUND: Radiotherapy for pituitary adenomas frequently leads to GH deficiency (GHD). The characteristics of GH secretion in GHD induced by postoperative radiotherapy for acromegaly are not known. HYPOTHESIS: In the long term, stimulated and spontaneous GH release is not different between patients with GHD treated by postoperative radiotherapy for acromegaly or for other pituitary adenomas. DESIGN/SUBJECTS: We compared the characteristics of basal and stimulated GH secretion in patients with GHD, who had previously received adjunct radiotherapy after surgery for GH-producing adenomas (n=10) vs for other pituitary adenomas (n=10). All patients had a maximal GH concentration by insulin tolerance test (ITT) of 3 microg/l or less, compatible with severe GHD. Mean time after radiation was 17 and 18.7 years, respectively. Stimulated GH release was also evaluated by infusion of growth hormone-releasing hormone (GHRH), GHRH-arginine and arginine, and spontaneous GH by 10 min blood sampling for 24 h. Pulse analyses were performed by Cluster and approximate entropy. OUTCOMES: There were no differences between both patient groups in stimulated GH concentrations in any test. Spontaneous GH secretion was not different between both patient groups, including basal GH release, pulsatility and regularity. Pulsatile secretion was lost in two acromegalic and three non-acromegalic patients. Insulin-like growth factor-I (IGF-I) was below -2 s.d. score in nine patients in each group. CONCLUSION: Acromegalic patients treated by surgery and postoperative radiotherapy with an impaired response to the ITT do not differ, in the long term, in GH secretory characteristics from patients treated similarly for other pituitary tumors with an impaired response to the ITT. The ITT (or the GHRH-arginine test) is therefore reliable in establishing the diagnosis of GHD in patients treated for acromegaly by surgery and radiotherapy.

Uncontrolled acromegaly is associated with progressive mitral valvular regurgitation.

INTRODUCTION: Recent cross-sectional studies have documented an association between acromegaly and regurgitant valvular heart disease. The aim of this study was to evaluate the change in prevalence of valvular heart disease in relation to the clinical activity, because the natural history of valvular changes in acromegaly is unknown. PATIENTS AND METHODS: Valvular regurgitation was assessed in 37 acromegalic patients (18 patients with active disease, and 19 with controlled disease) by conventional two-dimensional and Doppler echocardiography before and after an interval of 1.9 years (range 1.5-3.0 years). RESULTS: At baseline, valvular regurgitation (mitral and aortic sites combined) was present in 46% of the patients and increased to 67% at follow-up (P=0.008). Mitral regurgitation increased significantly from 32% to 60% (P=0.002), but no change was noted for the aortic valve (27% vs. 31%, NS). In patients with active disease, valvular regurgitation increased significantly from 56% at baseline to 88% at follow-up (P=0.031) due to a significant increase of mitral regurgitation from 39% to 78% at follow-up (P=0.016). In contrast, no increase in valvular regurgitation was found in patients with controlled disease. CONCLUSION: The prevalence of mitral, but not aortic, valvular regurgitation increased in patients with active acromegaly during follow-up. Patients with acromegaly require adequate cardiac evaluation and follow-up to establish the extent and progression of valvular involvement.

Irregular and frequent cortisol secretory episodes with preserved diurnal rhythmicity in primary adrenal Cushing's syndrome.

To evaluate the pathophysiology of altered cortisol secretion in patients with primary adrenal hypercortisolism, cortisol secretion was investigated in 12 patients, seven with a unilateral adenoma and five with ACTH-independent macronodular adrenal hyperplasia compared with age- and gender-matched controls and with patients with pituitary-dependent hypercortisolism. Pulsatile secretion was increased 2-fold (P = 0.04), attributable to increased event frequency (P = 0.002). All patients showed a significant diurnal rhythm with a delay in phase shift of 3 h (P = 0.01). Approximate entropy ratio, a feedback-sensitive measure, was increased compared with controls (P = 0.00003) but similar to that of pituitary-dependent hypercortisolism (P = 0.77), denoting loss of autoregulation. Cortisol burst-mass tended to be smaller in patients with ACTH-independent macronodular adrenal hyperplasia than in unilateral adenoma (P = 0.06). In conclusion, increased cortisol secretion in patients with primary adrenal Cushing's syndrome is caused by amplified pulsatile secretion via event frequency modulation. We speculate that partial preservation of secretory regularity and diurnal rhythmicity point to incomplete autonomy of these tumors.

Quality of life in patients after long-term biochemical cure of Cushing's disease.

To evaluate the long-term impact of cured Cushing's disease on subjective well-being, we assessed quality of life by validated health-related questionnaires in 58 patients cured from Cushing's disease by transsphenoidal surgery (n = 58), some of whom received additional radiotherapy (n = 11) and/or bilateral adrenalectomy (n = 3). The mean duration of remission was 13.4 +/- 6.7 yr (range of 2-25 yr). Patient data were compared with a control group of 98 healthy subjects with the same age and sex distribution and with age-adjusted reference values available from the literature. General perceived well-being, measured by the Nottingham Health Profile and the Short Form, was reduced compared with controls for all subscales (P < 0.001). Patients with Cushing's disease had worse scores on subscales of fatigue Multidimensional Fatigue Index and anxiety and depression (Hospital Anxiety and Depression Scale). Compared with reference values from the literature, quality of life was also reduced in the patients according to all questionnaires and all items, except pain (Short Form), sleep (Nottingham Health Profile), and reduced activity (Multidimensional Fatigue Index). Despite conventional hormone replacement therapy, hypopituitarism was an important independent predictor of reduced quality of life. Patients without hypopituitarism (n = 28) showed reduced scores on physical items but normal scores on mental items compared with controls. In conclusion, despite long-term cure of Cushing's disease, patients experience a considerable decrease in quality of life, with physical and psychosocial impairments, especially in the presence of hypopituitarism.

Persistent diastolic dysfunction despite successful long-term octreotide treatment in acromegaly.

INTRODUCTION: This study was designed to evaluate potential reversibility of left-ventricular (LV) dysfunction in patients with acromegaly following long-term control of disease. It is unknown whether the cardiac changes induced by acromegaly can be reversed completely by long-term strict control of growth hormone excess by octreotide. PATIENTS AND METHODS: We compared LV systolic and diastolic function in inactive patients with acromegaly (n = 22), who were divided into patients with long-term control by octreotide (n = 14) and patients with long-term cure by surgery/radiotherapy (n = 8). We also assessed these parameters in patients with active acromegaly (n = 17). RESULTS: In patients with active acromegaly, systolic function at rest was decreased by 18% (P < 0.01), LV mass index increased by 40% (P < 0.04) and isovolumetric relaxation time increased by 19% (P < 0.01), compared with patients with inactive acromegaly. These parameters were not different between well-controlled and cured patients. Using tissue Doppler imaging, the ratio between early and late diastolic velocity (E'/A' ratio) was decreased in active, compared with inactive acromegaly (0.75+/-0.07 versus 1.24+/-0.15; P < 0.01). This E'/A' ratio was considerably higher in cured, compared with octreotide-treated, patients (1.75+/-0.41 versus 1.05+/-0.1; P < 0.01). CONCLUSION: Diastolic function is persistently and significantly more impaired in acromegalic patients with long-term control by octreotide than in surgically cured patients, which points to biological effects of subtle abnormalities in growth hormone secretion. Criteria for strict biochemical control of acromegaly should thus be reconsidered.

Human longevity is characterised by high thyroid stimulating hormone secretion without altered energy metabolism.

Few studies have included subjects with the propensity to reach old age in good health, with the aim to disentangle mechanisms contributing to staying healthier for longer. The hypothalamic-pituitary-thyroid (HPT) axis maintains circulating levels of thyroid stimulating hormone (TSH) and thyroid hormone (TH) in an inverse relationship. Greater longevity has been associated with higher TSH and lower TH levels, but mechanisms underlying TSH/TH differences and longevity remain unknown. The HPT axis plays a pivotal role in growth, development and energy metabolism. We report that offspring of nonagenarians with at least one nonagenarian sibling have increased TSH secretion but similar bioactivity of TSH and similar TH levels compared to controls. Healthy offspring and spousal controls had similar resting metabolic rate and core body temperature. We propose that pleiotropic effects of the HPT axis may favour longevity without altering energy metabolism.

The influence of partial food deprivation on the quantity and source of triiodothyronine in several tissues of athyreotic thyroxine-maintained rats.

In the present study the influence of partial food deprivation (PFD) on the quantity and source of T3 [i.e. T3 derived from local T4 to T3 conversion (Lc T3 (T4] vs. plasma-derived T3] in several rat tissues was investigated. Two groups of athyroid rats on a synthetic diet received a continuous iv infusion consisting of T4 (1.0 microgram/100 g BW X day), [125I]T4, and [131I]T3 over a prolonged period. For one group of rats the daily food intake was restricted by one third to maintain constant BW during the infusion period. At isotopic equilibrium the mean plasma T3, T4, and TSH levels for control-fed rats were: 38 ng/dl, 5.1 micrograms/dl, and 470 ng/ml, respectively. The values for rats on PFD were T3: 22 ng/dl, T4: 4.8 micrograms/dl, TSH: less than 70 ng/ml. The [125I]T3 and [131I]T3 contents of whole homogenates from liver, kidney, thigh muscle, cerebral cortex, cerebellum, and anterior pituitary gland as well as the subcellular fractions from liver, kidney (nuclei, mitochondria, microsomes, and cytosol), and anterior pituitary gland (nuclei) were determined (after extraction in ethanol) by thin layer chromatography. The contribution of Lc T3(T4) and the total T3 levels in these tissue preparations could then be calculated. In the cerebral cortex, cerebellum, and anterior pituitary gland of PFD rats plasma-derived T3 as well as Lc T3(T4) was decreased. The total T3 level in the liver did not change under PFD, owing to an increase in Lc T3(T4). It is possible that the release of hepatic Lc T3(T4) into the blood stream was reduced. In neither group was there appreciable Lc T3(T4) in muscle. In contrast to the other tissues investigated, the [131I]T3 tissue-plasma ratio for muscle had increased under PFD, suggesting a higher uptake of T3. As a consequence, the T3 levels in the muscles of PFD rats did not differ from those in normally fed animals. For both groups of rats the contribution of Lc T3(T4) in hepatic nuclei was far lower than that found for the other hepatic cellular fractions. This would suggest that the hepatic nucleus preferentially takes up plasma-derived T3. In both control-fed and PFD rats the bulk of renal T3 appeared to be exchangeable with plasma T3. Hence the T3 levels in renal nuclei were reduced under PFD. The nuclear T3 levels in the anterior pituitaries from PFD rats were markedly decreased. Therefore it is likely that other factors determine TSH secretion under PFD.

The contribution of local thyroxine monodeiodination to intracellular 3,5, 3'-triiodothyronine in several tissues of hyperthyroid rats at isotopic equilibrium.

The local conversion of T4 as a source of intracellular T3 in several organs of both hypothyroid and euthyroid rats has recently been recognized to be an important phenomenon. In the present study the source and quantity of T3 in various peripheral tissues of hyperthyroid rats were investigated. Athyreotic rats received a continuous iv infusion of 3.5 micrograms T4/100 g BW X day over a prolonged period in order to attain hyperthyroid conditions. At the same time, the animals also received a continuous iv infusion of [125I]T4 and [131I]T3 until isotopic equilibrium was achieved. After the animals were bled and perfused, the source and quantity of T3 in various tissue homogenates and subcellular preparations of liver, kidney, and the anterior pituitary gland were analyzed. In spite of the elevated plasma T3 and T4 levels, the concentration of T3 in the cerebral cortex and cerebellum was within the normal range. The contribution of T3 derived from local T4 to T3 conversion [Lc T3(T4)] was rather low in both parts of the brain (cerebral cortex, 26%; cerebellum, 15%) when compared with values previously determined for euthyroid rats (cerebral cortex, 67%; cerebellum, 50%). It is concluded that in the cerebral cortex and cerebellum of hyperthyroid rats normal T3 concentrations were maintained by a compensatory decrease in the degree of Lc T3(T4). Whereas previous studies revealed that Lc T3(T4) contributes significantly to the T3 in the pituitary glands of both hypothyroid and euthyroid rats, this was not the case for the hyperthyroid animals; virtually all T3 was derived from plasma. The elevated plasma T3 levels caused an increased T3 content in both the homogenate and the nuclear fraction, leading to plasma TSH levels which were below the detection limit. It was found that the T3 in muscle was derived exclusively from plasma. Both the liver and kidney showed high concentrations of T3. Whereas Lc T3(T4) was the main source of T3 in the liver, it contributed only a minor fraction of the total T3 content in the kidney. In the liver Lc T3(T4) accounted for 50-53% of the T3 content in the mitochondrial and cytosolic fractions and about 64% in the microsomal fraction. In the kidney there was a small, but significant, amount of Lc T3(T4) in these subcellular fractions. In contrast, in the hepatic nuclei only 13% of the T3 was attributable to Lc T3(T4), whereas no Lc T3(T4) could be detected in the renal nuclei.

Concentrations of thyroxine and 3,5,3'-triiodothyronine at 34 different sites in euthyroid rats as determined by an isotopic equilibrium technique.

The present study was designed to assess the quantities of T4 and T3, and the source (i.e. plasma-derived vs. locally produced) of the latter iodothyronine, in various rat tissues. For this purpose, normal intact rats were brought to isotopic equilibrium by means of a continuous iv infusion of [125I]T4 and [131I]T3 for a prolonged period. At the end of the infusion period, the animals were bled and perfused. Either whole small organs or weighed portions of tissues were homogenized in saline. The iodothyronines were extracted with ethanol-ammonia and separated by TLC. The [125I]T3/[131I]T3 ratios for the tissue homogenates and plasma were determined, and the relative contribution of the T3 derived from local T4 to T3 conversion [abbreviated: Lc T3 (T4)] to the total T3 in a given tissue was calculated. The endogenous T4 and T3 levels in the various organs were computed from the known specific activities of the labeled iodothyronines. The concentration of T4 in plasma greatly exceeded that found for tissue. Among the tissues examined, the T4 concentration was highest in the liver and lowest in cerebral cortex and cerebellum. T3 (per gram) was most abundant in the kidney and anterior pituitary gland and least abundant in the testis, epididymis, and erythrocytes. In contrast to the other tissues investigated, the concentration of T3 in several regions of the brain and anterior pituitary gland either equalled or exceeded that of T4. Plasma exhibited by far the lowest T3/T4 ratio. For most of the organs investigated the contribution of Lc T3(T4) appeared to be low. On the other hand, in 15 tissues, including the central nervous system, the local production of T3 accounted for one fifth or more of the total T3 content. Although there were no regional differences between the total T3 levels in the brain, the relative contribution of Lc T3(T4) was 65% in the cerebral cortex and only 22% in the spinal cord. The variation in the source of T3 in the various parts of the central nervous system may be related to regional differences in T4 and T3 metabolism. The fact that the present study demonstrates that the relationship between circulating T3 and intracellular T3 varies from one organ to the next may be important for accurate interpretation of plasma T4 and T3 levels and for designing optimal thyroid hormone replacement therapy for patients with hypothyroidism.

Pulsatile thyrotropin release and thyroid function in acromegalics before and during subcutaneous octreotide infusion.

The pulsatile secretion of TSH was studied in eight patients with active acromegaly before treatment and after 1 month of therapy consisting of the sc infusion of 300 micrograms octreotide/day. Mean GH levels decreased from 37.1 +/- 7.2 to 5.2 +/- 1.4 mU/L (P = 0.002). Insulin-like growth factor-I levels decreased from 82.9 +/- 8.8 to 37.8 +/- 9.8 nmol/L (P less than 0.01) and normalized in five of the eight patients. In one patient TSH levels were undetectable before and during octreotide therapy. In the other seven patients, Cluster analysis revealed 11.9 +/- 0.8 pulses/24 h, with a mean pulse width of 81 +/- 4.6 min, a mean pulse height of 1.33 +/- 0.42 mU/L, and a mean pulse increment of 0.36 +/- 0.12 mU/L. During octreotide therapy these pulse parameters remained unchanged. Pulse height and amplitude increased significantly during the night (i.e. from 2000-0800 h) in both untreated and treated patients. The acrophase was unchanged by therapy. During therapy T3 levels decreased from 2.05 +/- 0.17 nmol/L to 1.44 +/- 0.08 nmol/L (P = 0.001), while rT3 levels increased from 0.14 +/- 0.02 nmol/L to 0.19 +/- 0.03 nmol/L (P less than 0.05). Plasma T4 levels remained unchanged. From these studies we conclude that the TSH pulse generator is unchanged in active acromegaly and apparently unaffected by chronic octreotide infusions.

Ten-year follow-up results of transsphenoidal microsurgery in acromegaly.

Fifty-nine acromegalic patients, transsphenoidally operated by a single neurosurgeon (H.v.D.) were followed for at least 10 yr to assess the late outcome of surgery. Mean follow-up was 16 +/- 0.4 yr (range, 10-22). Criteria for remission were a serum GH concentration below 2.5 microg/L, a normal glucose-suppressed GH (oral glucose tolerance test), and a normal serum insulin-like growth factor I (IGF-I) concentration. Mean serum GH concentration decreased from 59 +/- 8.7 microg/L to 5.6 +/- 1.4 microg/L after surgery. Early postoperative remission rates were 61% (GH, <2.5 microg/L), 67% (suppressed GH), and 60% (both GH <2.5 microg/L and suppressed GH). Early postoperative remission was significantly related to preoperative serum GH concentration (P: = 0.023), but not to tumor size. Of 36 patients with postoperative remission (GH, <2.5 microg/L), 9 patients received (prophylactic) radiotherapy for persistent paradoxical reaction to TRH or probable invasive tumor growth. All nine patients are in remission at the end of follow-up. Of the other 27 patients with postoperative remission, 5 (19%) developed recurrence, becoming evident within 5 yr in 4 patients and after 10 yr in 1 patient. Of these 27 patients, surgical remission rates at the end of follow-up are 78% (random GH, <2.5 microg/L), 73% (normal glucose-suppressed GH), 74% (normal IGF-I), and 65% (normal IGF-I and GH suppression). Of the patients with postoperative persistent disease, 18 patients were irradiated and 5 patients were followed without further treatment. Two of five nontreated patients had spontaneous normalization of GH concentration at the 6 months visit and remained in remission by surgery only. The long-term efficacy of multimodality treatment was evaluated after exclusion of the prophylactically irradiated patients. At the end of follow-up, 48% of patients had not required adjuvant therapy and the rest received radiotherapy (34%), octreotide (10%), or both (8%). Remission rates of multimodality therapy were 96% (serum GH, <2.5 microg/L) and 94% (normal serum IGF-I concentration). Remission rates of transsphenoidal surgery alone were 46% (serum GH, <2.5 microg/L), 44% (normal IGF-I concentration), 41% (suppressed serum GH), and 37% (normal serum IGF-I and suppressed GH). In this first report on separate 10 or more years results of transsphenoidal surgery for acromegaly, using strict criteria for remission, 19% of patients with postoperative remission developed recurrence. Nevertheless, about 40% of patients remain in remission after only surgical intervention, even after a mean follow-up of 16 yr.