Annice Mukherjee

Does growth hormone cause cancer

The ability of GH, via its mediator peptide IGF‐1, to influence regulation of cellular growth has been the focus of much interest in recent years. In this review, we will explore the association between GH and cancer. Available experimental data support the suggestion that GH/IGF‐1 status may influence neoplastic tissue growth. Extensive epidemiological data exist that also support a link between GH/IGF‐1 status and cancer risk. Epidemiological studies of patients with acromegaly indicate an increased risk of colorectal cancer, although risk of other cancers is unproven, and a long‐term follow‐up study of children deficient in GH treated with pituitary‐derived GH has indicated an increased risk of colorectal cancer. Conversely, extensive studies of the outcome of GH replacement in childhood cancer survivors show no evidence of an excess of de novo cancers, and more recent surveillance of children and adults treated with GH has revealed no increase in observed cancer risk. However, given the experimental evidence that indicates GH/IGF‐1 provides an antiapoptotic environment that may favour survival of genetically damaged cells, longer‐term surveillance is necessary; over many years, even a subtle alteration in the environmental milieu in this direction, although not inducing cancer, could result in acceleration of carcinogenesis. Finally, even if GH/IGF‐1 therapy does result in a small increase in cancer risk compared to untreated patients with GH deficiency, it is likely that the eventual risk will be the same as the general population. Such a restoration to normality will need to be balanced against the known morbidity of untreated GH deficiency.

Impact of Growth Hormone Status on Body Composition and the Skeleton

Severe growth hormone (GH) deficiency (GHD) induces a well-defined clinical entity encompassing, amongst the most reported features, abnormalities of body composition, in particular increased fat mass, especially truncal, and reduced lean body mass. The results from virtually all treatment studies are in agreement that GH replacement improves the body composition profile of GHD patients by increasing lean body mass and reducing fat mass. More recently, the observations have been extended to adults with partial GHD, defined by a peak GH response to insulin-induced hypoglycaemia of 3–7 µg/l. These patients exhibit abnormalities of body composition similar in nature to those described in adults with severe GHD; these include an increase in total fat mass of around 3.5 kg and a reduction of lean body mass of around 5.5 kg. The increase in fat mass is predominantly distributed within the trunk. The degree of abnormality of body composition is intermediate between that of healthy subjects and that of adults with GHD. The impact of GH replacement on body composition in adults with GH insufficiency, although predictable, has not been formally documented. The skeleton is another biological endpoint affected by GH status: in adults with severe GHD, low bone mass has been reported using dual energy x-ray absorptiometry (DEXA) and other quantitative methodologies. The importance of low bone mass, in any clinical setting, is as a surrogate marker for the future risk of fracture. Several retrospective studies have documented an increased prevalence of fractures in untreated GHD adults. Hypopituitary adults with severe GHD have reduced markers of bone turnover which normalize with GH replacement, indicating that GH, directly or via induction of insulin-like growth factor-I, is intimately involved in skeletal modelling. Whilst the evidence that GH plays an important role in the acquisition of bone mass during adolescence and early adult life is impressive, the impact of GHD acquired later in adulthood is less clear. Recently we examined the relationship between bone mineral density (BMD) and age in 125 untreated adults with severe GHD using DEXA. A significant positive correlation was observed between BMD (z-scores) and age at all skeletal sites studied. Overall, few patients, except those aged less than 30 years, had significantly reduced bone mass (i.e. a BMD z-score of less than –2); correction of BMD to provide a pseudo-volumetric measure of BMD suggested that reduced stature of the younger patients may explain, at least in part, this higher frequency of subnormal BMD z-scores. Despite normal BMD, however, an increase in fracture prevalence may still be observed in elderly GHD adults as a consequence of increased falls related to muscle weakness and visual field defects.

Adult growth hormone replacement therapy and neuroimaging surveillance in brain tumour survivors.

Objective  Systematic collections of neuroimaging data are nonexistent in brain tumour survivors treated with adult growth hormone replacement therapy (AGHRT). We present our surveillance data.

A new sustained‐release preparation of human growth hormone and its pharmacokinetic, pharmacodynamic and safety profile

Objective  Adult GH replacement is currently given by daily subcutaneous (sc) injections. Recently, sustained‐release (SR) preparations of GH have been developed, the preparations being characterized by a dominant early release, resulting in supraphysiological early GH peaks, and a rapid decline thereafter. We present data on a new SR GH preparation.

The value of IGF1 estimation in adults with GH deficiency.

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.

Acquired prolactin deficiency indicates severe hypopituitarism in patients with disease of the hypothalamic–pituitary axis

objective  Prolactin deficiency has been the subject of many scientific studies, but there is a paucity of information regarding prolactin deficiency in humans. In this report, adults with disease of the hypothalamic–pituitary axis (HPA) were studied to determine the prevalence of severe acquired prolactin deficiency (APD) and the pathophysiological characteristics associated with it.

Pharmacological treatment of hypercortisolism.

Purpose of reviewTo consider the current status and types of drug therapy aimed at restoring eucortisolaemia in patients with Cushings syndrome. Recent findingsAdvances such as laparoscopic adrenalectomy modify the exact placing of drug therapy among the wide variety of therapies available to treat patients with Cushings syndrome because of different causes; nonetheless, it is now clear that hypercortisolism, per se, if present for any length of time, modifies the future prognosis of the patient, even after cure of the Cushings syndrome. Thus, early diagnosis and restoration of eucortisolsm are critical. There are three main types of drug therapy: steroidogenesis inhibitors, glucocorticoid antagonists and neuromodulatory compounds. Currently, steroidogenesis inhibitors such as metyrapone and ketaconazole are most commonly the first choice if drug therapy is to be used, but at least for the most common form of Cushings syndrome, Cushings disease, the neuromodulatory compounds such as cabergoline show potential. SummaryPharmacological therapy for Cushings syndrome remains critically important for normalizing cortisol levels while awaiting the impact of more definitive treatment.

Immune function in hypopituitarism: time to reconsider?

Hypopituitarism is not currently considered as a potential cause of immune disruption in humans. Accumulating data from in vitro and animal models support a role for the pituitary gland in immune regulation. Furthermore, the increased mortality risk noted in patients with adult hypopituitarism remains poorly explained and immune dysfunction could conceivably contribute to this observation. In a recent issue of Clinical & Experimental Immunology, we presented new data relating to immune status in adults with treated, severe hypopituitarism. We observed humoral immune deficiency in a significant proportion, despite stable pituitary replacement, including growth hormone (GH). This was especially evident in those with low pretreatment IGF‐I levels and appeared independent of anticonvulsant use or corticosteroid replacement. These observations require substantiation with future studies. In this short review, we summarize existing data relating to the effects of pituitary hormones on immune function and discuss potential clinical implications surrounding the hypothesis of immune dysregulation in severe hypopituitarism.

Acquired prolactin deficiency (APD) after treatment for Cushing's disease is a reliable marker of irreversible severe GHD but does not reflect disease status.

objective  We have previously reported that acquired prolactin deficiency (APD) is a marker for severe hypopituitarism and observed a high prevalence of APD in patients treated for Cushings disease. Recovery of GH secretion is recognized to occur in a proportion of patients treated for Cushings disease after the effects of glucocorticoid excess on GH secretion have subsided. The aim of this study was to investigate further the association between APD, treated Cushings disease and, in particular, to determine whether recovery of GH secretion may occur in these patients.

Skeletal requirements for optimal growth hormone replacement in the transitional years.

In addition to its well-established effects on linear growth in childhood and adolescence, growth hormone (GH) has both direct and indirect actions on bone remodelling and homeostasis. In this review, the discussion begins with the influence of childhood-onset growth hormone deficiency (CO-GHD) on bone mineral accretion. The limitations of methods of assessing bone mineral density (BMD) are highlighted and specific influential factors, which affect peak bone mass achievement and therefore skeletal health in later life, are evaluated.