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S W J Lamberts

Acromegaly is a chronic, slowly developing disease characterized by progressive disfigurement and disability (Melmed 1990). The disfigurement of the face occurs insidiously in most patients and develops only slowly, so that very often the disorder is diagnosed only when a new physician replaces the usual doctor and sees the patient for the first time, and/or when photographs of the patient taken over a number of years are collected together (Molitch 1992).

Apart from the cosmetic changes, a multitude of complaints interfere with normal daily working life in most patients. In addition, complications related to the cardiovascular and respiratory systems, and to tumour formation (Table 1), often cause premature death if not effectively treated (Lamberts 1992, Wass 1994). Mortality risk in acromegalic patients is probably two to three times that of healthy people (Alexander et al. 1980).

Pathogenesis and diagnosis

The clinical syndrome of acromegaly is caused in virtually all patients

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S W J Lamberts and S Melmed

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S. W. J. LAMBERTS and J. C. BIRKENHÄGER

Department of Medicine III and Clinical Endocrinology, University Hospital 'Dijkzigt', Erasmus University, Rotterdam, The Netherlands

(Received 16 February 1976)

The role of catecholamines in modulating the secretion of adrenocorticotrophin (ACTH) has been investigated by numerous workers with conflicting results (van Loon, 1973). In some of these studies l-DOPA has been used, which induces the production of adrenaline and noradrenaline in addition to that of dopamine. Recently 2-bromo-α-ergocryptine became available; this drug seems to be a more specific activator of the dopaminergic pathways in the central nervous system (Corrodi, Fuxe, Hökfelt, Lidbrink & Ungerstedt, 1973). On the basis of a recent observation, that the daily administration of 0·05 mg ergotamine to rats bearing ACTH-secreting pituitary tumours inhibited tumour growth and reversed adrenal enlargement (Macleod & Lehmeyer, 1973), we investigated the effect of bromocriptine on plasma ACTH levels in seven patients with pituitary-dependent Cushing's syndrome (one with a pituitary tumour) and four

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R. Oosterom, T. Verleun, and S. W. J. Lamberts

ABSTRACT

Growth hormone-secreting human pituitary adenoma cells in long-term culture show a decline in GH secretion. We investigated the effects of dexamethasone on GH production and on the responsiveness of the adenoma cells to various drugs. Twenty-four-hour GH secretion by cultures from seven acromegalics was consistently stimulated by 100 nM-dexamethasone. In four out of seven cultures the effect of dexamethasone occurred within 24 h. After 3 weeks in culture the decline in GH secretion by control cultures was over 90%, while in dexamethasone-treated cultures this was limited to less than 50%. The effect of dexamethasone was dose-dependent over a range of 1 nmol/l to 10 μmol/l. Dexamethasone stimulated not only GH secretion (fivefold), but also GH content (twofold). Cycloheximide and actinomycin D blocked the stimulatory effect of dexamethasone on GH secretion, the latter irreversibly. After 4 days of treatment with 100 nm-dexamethasone, the relative effects of somatostatin, prostaglandin E1, bromocriptine and thyrotrophin releasing hormone were the same in treated and untreated cultures. However, the response to synthetic GH releasing factor (GRF) was greatly enhanced by pretreatment of adenoma cells with dexamethasone (100 and 5 nmol/l). Cells unresponsive to small concentrations of GRF could be stimulated effectively by GRF after pretreatment with dexamethasone.

In conclusion, dexamethasone prevents the decline in GH production as seen in control cultures, possibly by stimulation of DNA transcription. Furthermore, the response to GRF is greatly enhanced in the presence of dexamethasone, while the relative effects of other direct GH stimulatory and inhibitory compounds seem to be unchanged.

J. Endocr. (1984) 100, 353–360

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A J van der Lely, W W de Herder, J A M J L Janssen, and S W J Lamberts

We have studied the physiological and clinical relevance of measurements of serum total and free IGF-I and IGF-binding protein-3 (IGFBP-3) in 57 previously untreated patients with active acromegaly (32 males, 25 females; mean age 47 years) as compared with sex- and age-matched normal healthy controls. Serum total and free IGF-I, but not IGFBP-3, are suitable biochemical parameters for screening for acromegaly. In acromegalics, the mean 24 h serum GH, total IGF-I and IGFBP-3 levels tend to decrease with age. However, in our series of patients, mean 24 h serum GH levels, IGFBP-3, total and free IGF-I do not correlate with disease activity in acromegaly.

Journal of Endocrinology (1997) 155, S9–S13

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S. W. J. Lamberts, E. G. Bons, P. Uitterlinden, and W. H. Hackeng

Cyproheptadine and its metabolite desmethylcyproheptadine were shown to suppress directly the release of adrenocorticotrophin (ACTH) and β-lipotrophin/β-endorphin activity from the neurointermediate lobe of the pituitary gland incubated in vitro. Neither compound affected the release of ACTH from the anterior pituitary gland. Serotonin stimulated the release of ACTH and β-lipotrophin/β-endorphin activity from the neurointermediate lobe, but did not influence the (desmethyl)cyproheptadine-mediated inhibition of hormone release.

These results indicate that serotonin and cyproheptadine affect hormone release by the neurointermediate lobe by a direct action. The effect of cyproheptadine, however, might not be exerted by a serotonin receptor.

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M. DE QUIJADA, H. A. T. TIMMERMANS, and S. W. J. LAMBERTS

The effect of administering the antioestrogenic drug, tamoxifen, on the growth of the pituitary tumour 7315a in the rat was studied. This tumour is induced by the administration of oestrogen. When administered early after the implantation of the tumour, tamoxifen prevented its growth completely but when treatment was delayed until a later stage of its development, 20 μg tamoxifen/100 g body wt each day for 7–12 days stopped further tumour growth, while 200 μ/100 g body wt each day reduced the size of the tumours. These effects of tamoxifen on tumour growth were accompanied by a decrease in the level of prolactin in the circulation, if the treatment was started at an early stage of tumour development and if the high dose of tamoxifen was administered. Bromocriptine either when given alone or together with tamoxifen was unable to inhibit growth and secretion of prolactin by these rat pituitary tumours. The high plasma concentrations of prolactin in the tumour-bearing rats are known to produce atrophy of the pituitary gland of the host and to decrease the synthesis and release of prolactin. Despite the inhibitory effect of tamoxifen on both tumour size and plasma levels of prolactin, the ability of the pituitary glands of these animals to synthesize prolactin remained suppressed. It was concluded that tamoxifen has a dual effect on this model of a transplantable pituitary tumour that secretes prolactin in the rat; it prevents and/or inhibits tumour growth and it has an inhibitory effect on the synthesis of prolactin by the pituitary gland.

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S. W. J. Lamberts, T. Verleun, E. G. Bons, P. Uitterlinden, and R. Oosterom

The effects of cyproheptadine, desmethylcyproheptadine, serotonin, γ-amino-butyric acid (GABA) and sodium valproate were studied on ACTH secretion by cultured non-enzymatically dispersed pituitary tumour cells from three patients with Nelson's syndrome. Cyproheptadine (1–10 μmol/l) and desmethylcyproheptadine (1–10 μmol/l) suppressed ACTH secretion significantly (P <0·01), while serotonin (10 μmol/l) did not have a direct effect. Serotonin was also not able to reverse the (desmethyl)cyproheptadine-mediated inhibition of ACTH release. Sodium valproate and GABA did not exert a direct effect on hormone release by these cultured pituitary tumour cells. It is suggested that cyproheptadine-mediated inhibition of ACTH release in Nelson's syndrome might be effected by a direct non-serotonin-related effect on the pituitary tumour, while sodium valproate suppresses ACTH release by a suprahypophysial action.

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A. Tsatsoulis, K. Mavroudis, J. Frost, A. Lambert, S. M. Shalet, and W. R. Robertson

ABSTRACT

The degree of stability in vitro of bioactive and immunoreactive LH in human blood, plasma and serum was examined. Bioactivity and immunoreactivity of LH were assayed by the dispersed mouse Leydig cell assay and by standard radioimmunoassay respectively, using the same reference preparation (first international reference preparation for human pituitary LH 68/40 for immunoassay).

Bioactive and immunoreactive LH were stable in blood and plasma at 22 °C for up to 4 and 24 h respectively, and in blood at 4 °C for up to 24 h. There was no loss of biological or immunological LH activity in plasma which had been either snap-frozen and stored at −70 °C, allowed to freeze at −20 °C and stored at that temperature or kept at 4 °C for 24 h and then stored at − 70 °C. Likewise, the levels of LH in plasma and serum which had been stored at either − 20 or − 70 °C and then thawed and refrozen up to four times remained unchanged. In addition, the biological and immunological activity of LH was not affected after vortexing samples of plasma or serum for up to 60 s. Bioactive LH was also stable in plasma samples after prolonged storage (up to 9 months) at either −70 or −20 °C.

We conclude that LH bioactivity and immunoreactivity are stable in blood and plasma following a variety of treatments commonly experienced during normal handling of a blood sample after venepuncture.

J. Endocr. (1988) 117, 139–145

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R P Stolk, S W J Lamberts, F H de Jong, H A P Pols, and D E Grobbee

Abstract

To investigate the role of cortisol in the etiology of insulin resistance in men and women, we examined 218 healthy non-hospitalized elderly, selected from the Rotterdam Study. Free cortisol was assessed by the ratio of fasting serum cortisol over corticosteroid-binding globulin (CBG), and insulin resistance was estimated by the fasting insulin level. CBG was higher in women and decreased with age. In both men and women, the early morning free cortisol level showed no association with age or waist/hip ratio. In men, an inverse association between cortisol and body mass index was observed. In women, higher cortisol levels were associated with increased insulin levels; an increase of 9·7 mU/l insulin per unit cortisol/CBG (s.e. 3·9, P=0·01). The association did not change after adjustment for age, body mass index or waist/hip ratio. The results of this study in elderly subjects suggest that in women cortisol may be implicated in the age-associated insulin resistance.

Journal of Endocrinology (1996) 149, 313–318