Glucocorticoids represent an enigmatic dilemma relative to their effects on GH secretion. In vitro data demonstrate glucocorticoids directly stimulate GH release from the anterior pituitary (68), and regulate pituitary GH gene expression by augmenting GH gene transcription and by an increase in GHRH receptor number (7). In vivo, glucocorticoids appear to blunt endogenous and stimulated GH secretion (68). The proposed mechanisms by which glucocorticoids effect this dual role in the regulation of GH secretion include: 1) facilitating GH secretion by enhancing pituitary somatotrope responsiveness to GHRH by increasing cAMP (68) and increasing somatotrope GHRH receptor number (69); and 2) inhibiting GH release by stimulating hypothalamic SRIF release through glucocorticoid-enhanced ^-adrenergic receptor responsivity (7).

The in vivo effects of increased glucocorticoid concentrations is to blunt GH secretion in physiologic systems. Through the use of a variety of pharmacologic stimuli, investigators have attempted to identify which agent(s) can reverse glucocorticoid-induced inhibition of GHRH-induced GH secretion. Despite their utility as potent GH secretogogues, dopaminergic agonists (bromocriptine, apomorphine) have no effect on glucocorticoid-inhibition of GH release (68). Short-term (12 h) and long-term (4 d)

exposure to dexamethasone blunts GHRH-induced GH secretion, whereas subjects with Cushings syndrome, and acromegalic individuals receiving steroids, have a blunted GH response to GHRH (68).

Corticosteroid therapy longer than 48 h in duration blunts the effect of insulin on GH secretion, whereas acute administration of glucocorticoids in normal volunteers leads to a normal response. Thus, the duration of exposure to steroids was influential on the subsequent GH response (68). Arginine stimulates GH secretion by inhibiting SRIF release (70). In the presence of glucocorticoids, arginine has had a variable effect on GH secretion, suggesting that either arginine and corticosteroids have a common site of action or arginine-induced GH secretion is unaffected by glucocorticoids (68).

Blunted GHRH-induced GH secretion in Cushing syndrome subjects was not affected by the addition of pyridostigmine, whereas others have demonstrated partial restoration of GH secretion in healthy volunteers receiving dexamethasone and children on chronic glucocorticoid therapy (68). Clonidine appears to partially restore and propranolol augments GHRH-induced GH secretion following dexamethasone administration (71). Glucocorticoid exposure increases ß-adrenergic receptor number on SRIF-neurons (72). Propranolol therapy inhibits SRIF release, whereas clonidine, a postsynaptic (a2) receptor agonist is only able to influence a partial GH response in the presence of glucocorticoid (68).

GABAergic (gamma-aminobutyric acid) agonists (baclofen) influence GH release through the dual mechanism of enhanced GHRH tone and inhibition of SRIF (68). Patients suffering from depression associated with hypercortisolism demonstrated blunting of GH response to GHRH following baclofen (a structural analog of GABA) administration (73). Prolonged hypercortisolism appears to blunt this GABAergic mechanism of GH release.

Although there are numerous studies of in vivo glucocorticoid inhibited-GH release, there remain conflicting reports of augmented GH secretion in the presence of steroids. One report demonstrated a change in the pattern of GH secretion (a reversal of the ultradian rhythm), but the total amount of GH secreted was unchanged (74). In another study, there was an increase in GH pulse frequency and mass per GH burst and an overall increase of two and a half times the amount of GH release (75). These stimulatory effects on GH secretion were duration-dependent (short-term) and independent of the dose or the type of steroid used (76,77).

Significantly, from a pediatric perspective, the hallmark of endogenous or exogenous glucocorticoid excess in children is growth failure as a result of inhibition of GH secretion and IGF-1 production, protein catabolism, and the direct effect of glucocorticoid on bone. Glucocorticoids inhibit IGF-1 bioactivity, both following acute and chronic administration of glucocorticoids and in the absence of measurable reductions in IGF-1 concentrations (78). The reduction in IGF-1 activity is a result of increases in circulating IGF inhibitors, a common finding following steroid therapy (79).

A study of nine children with chronic renal failure and short stature (>2 SD below mean for age) treated with recombinant hGH following renal transplantation demonstrated improvement in growth velocity after 12 mo of therapy; however, all subjects were receiving either alternate-day or low-dose glucocorticoid immunosuppression (80). Anecdotal reports of exogenous GH therapy in subjects receiving chronic daily glucocor-ticoid immunosuppression have not demonstrated improvement in linear growth and this therapy has the theoretical disadvantage of worsening carbohydrate intolerance and antagonizing the therapeutic benefit of glucocorticoid-mediated immunosuppression.

A report of 83 slow-growing subjects receiving corticosteroid therapy for a variety of disorders (post-transplant, inflammatory disease, asthma, other) under the auspices of the National Cooperative Growth Study, revealed a doubling of growth velocity in the first 2 yr of therapy. There were 16 adverse events, but only 6 related to GH therapy (transplant rejection [2], slipped capital femoral epiphysis [1], diabetes mellitus [1], irritability [1], musculoskeletal [1]) (81). Presently, the short-term benefits of exogenous GH therapy must be weighed against the unknown long-term benefits on final height and potential adverse outcomes.

Supplements For Diabetics

Supplements For Diabetics

All you need is a proper diet of fresh fruits and vegetables and get plenty of exercise and you'll be fine. Ever heard those words from your doctor? If that's all heshe recommends then you're missing out an important ingredient for health that he's not telling you. Fact is that you can adhere to the strictest diet, watch everything you eat and get the exercise of amarathon runner and still come down with diabetic complications. Diet, exercise and standard drug treatments simply aren't enough to help keep your diabetes under control.

Get My Free Ebook

Post a comment