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S.M. SHALET

Pituitary adenomas are uncommon in childhood (Zimmerman, 1969). The majority of pituitary adenomas are benign hormonally active tumours arising from the 5 hormonal secreting cell types of the adenohypophysis (Asa and Kovacs, 1983). With the availability of modern immunohistochemical techniques it is apparent that only 25% of pituitary adenomas are non-functioning.

In paediatric practice the important hormonally active adenomas are GH (gigantism), prolactin and ACTH (Cushing's disease). Both functional and non-functional pituitary tumours may be associated with hypopituitarism resulting from compression of the normal pituitary tissue or from tumour interfering with transport and synthesis of hypothalamic releasing hormones. This may lead to impaired growth, hypothyroidism, hypoadrenalism and failure of normal pubertal development.

Gigantism

The excessive secretion of GH before fusion of the epiphyses leads to gigantism. After fusion it produces the typical features of acromegaly. In nearly all cases, gigantism results from a pituitary tumour. Some tumours are mixed and

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S M Shalet

In the UK, through the use of a forced economic model, endocrinologists are in the curious position of offering GH replacement to some patients with severe GH deficiency (GHD) but withholding it from other patients with even more severe GHD. This approach is counter-intuitive to endocrine practice in treating endocrine deficiency states. For all other endocrine deficiencies, one would opt for treating those with the most severe biochemical evidence of deficiency first. If this endocrine approach was applied to adult GH replacement in an era of rationing, one would start with the GHD patients with a pathologically low IGF1 level. Given that the prevalence of subnormal IGF1 levels in a GHD population is age-dependent, this would result in GH replacement being offered to more young adult onset (AO) GHD and childhood onset GHD adults, and less often to middle-aged and elderly AO GHD adults. This in itself has the added advantage that the skeletal benefits appear more real in the former cohort of patients.

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A Mukherjee and S M Shalet

The GH/IGF1 system, like other endocrine systems, is dynamic and its activity changes with age and sexual maturation, and is influenced by body composition and other factors. A normal level of IGF1 does not exclude a diagnosis of GH deficiency (GHD) in adults, and the usefulness of IGF1 in the diagnosis of adult GHD has historically been confusing and contentious. The regulation of IGF1 secretion in adults is complex, and is not solely dependent on GH status with factors recognized to influence IGF1 status in patients with GHD including age, gender, exogenous estrogen therapy, prolactin status, and severity of GHD. The usefulness of IGF1 for monitoring treatment of GH disorders in adulthood is now widely accepted, especially as GH-dosing regimens for GHD have evolved from weight-based dosing (associated with overtreatment and side effects) to individualized dose–titration strategies, which maintain IGF1 within target limits. Sub-optimal replacement therapy may be associated with morbidity and mortality risk from a continuing state of functional GHD. Conversely, avoiding iatrogenic biochemical acromegaly is clearly important and other potential safety issues may be associated with a persistently high IGF1. Analysis and interpretation of IGF1 status therefore represent a useful diagnostic tool especially in the younger adult patients with severe GHD and an essential measurement for monitoring GH replacement in all adults with GHD. High-quality, method-specific reference ranges for IGF1 and a high degree of methodological consistency in the assay are essential for reliable comparison of results.

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I. M. Golland, C. A. Vaughan-Williams, S. M. Shalet, I. Laing, and M. Elstein

Abstract.

To investigate the effects of medical treatment of endometriosis on concentrations of insulin and glucagon in comparison with those of androgens, 12 nonobese women with minimal endometriosis were randomly allocated to receive treatment with either danazol or the gonadotropin-releasing hormone analogue, goserelin. In subjects treated with danazol, mean (sd) summed serum insulin (1.08 (0.22) nmol/l pretreatment; 3.00 (1.50) nmol/l after treatment, p<0.05) and summed plasma glucagon (94 (21) pmol/l pretreatment; 238 (113) pmol/l after treatment, p<0.05) responses to oral glucose administration increased significantly, but remained unchanged in subjects treated with goserelin. In the danazol-treated group, the mean free testosterone index increased from 3.3 (1.6) to 13.3 (4.2) (p<0.01), but there was no correlation between either glucagon or insulin and free testosterone index. In the goserelin-treated subjects, however, there was no change in mean free testosterone indices (pretreatment 3.6 (1.0), post-treatment 3.9 (1.8). Thus, the increase in free testosterone index induced by danazol treatment is not responsible for the concomitant development of hyperinsulinaemia and hyperglucagonaemia.

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P E Clayton, R C Cuneo, A Juul, J P Monson, S M Shalet, and M Tauber

The European Society for Paediatric Endocrinology held a consensus workshop in Manchester, UK in December 2003 to discuss issues relating to the care of GH-treated patients in the transition from paediatric to adult life. Clinicians experienced in the care of paediatric and adult patients on GH treatment, from a wide range of countries, as well as medical representatives from the pharmaceutical manufacturers of GH participated.

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I. A. MacFarlane, C. G. Beardwell, S. M. Shalet, Gill Ainslie, and Elaine Rankin

Abstract.

Twelve patients with pituitary adenomas and increased serum concentration of the glycoprotein hormone α-subunit were studied. Eight patients were acromegalic and one had a FSH1 producing tumour. The adenomas in 9 patients had undergone subtotal operative removal and/or external irradiation but no patient was studied within 3 months of these treatments.

Many of the acromegalic patients, with moderately elevated α-levels, showed marked increases in α-concentration after TRH and/or LRH, compared with controls. The non-acromegalic patients, with the highest α-levels, showed poor responses to releasing hormones. These results suggest that excessive α-subunit secretion in acromegalic patients is often under hypothalamic control whereas in non-acromegalic patients it is often autonomous.

Seven patients, 4 with acromegaly, were then given oral bromocriptine, 5 mg over 3 h. There was a significant fall in log mean α-level at 4 and 5 h (P < 0.02). Six patients took bromocriptine for 1–2 months. Log mean α-concentration was significantly reduced at the end of treatment (P < 0.02) and then recovered to basal levels after stopping treatment for one week. α-Subunit hypersecretion in some patients with pituitary adenomas is therefore modulated by dopaminergic control mechanisms.

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S. M. Shalet, C. G. Beardwell, I. A. MacFarlane, P. H. Morris Jones, and D. Pearson

ABSTRACT

Hypothalamic-pituitary function was assessed in 20 adult subjects who were treated with cerebral irradiation for brain tumours during childhood between 8 and 32 years earlier. Nine patients showed impaired growth hormone (GH) responses to hypoglycaemia, of whom, 7 are below the third centile for standing height. All GH deficient subjects received more than 2950 rads to the hypothalamic-pituitary axis with a maximum dose of approximately 5000 rads being used in one case.

Three subjects have an elevated basal serum thyroid stimulating hormone (TSH) level and 2 of these show an exaggerated TSH response to thyrotrophin releasing hormone (TRH) but no patient was clinically or biochemically hypothyroid. The rest of hypothalamic-pituitary function was essentially normal.

This study shows that multiple pituitary hormone deficiencies do not develop with time when the radiation dose is below a critical level. Thus it appears that there is a gradation of radiation damage to the hypothalamic-pituitary axis which is dependent primarily on the dose received rather than the time interval after radiotherapy.