G. Michael Besser

Long-term treatment of acromegaly with pegvisomant, a growth hormone receptor antagonist

BACKGROUND Pegvisomant is a new growth hormone receptor antagonist that improves symptoms and normalises insulin-like growth factor-1 (IGF-1) in a high proportion of patients with acromegaly treated for up to 12 weeks. We assessed the effects of pegvisomant in 160 patients with acromegaly treated for an average of 425 days. METHODS Treatment efficacy was assessed by measuring changes in tumour volume by magnetic resonance imaging, and serum growth hormone and IGF-1 concentrations in 152 patients who received pegvisomant by daily subcutaneous injection for up to 18 months. The safety analysis included 160 patients some of whom received weekly injections and are excluded from the efficacy analysis. FINDINGS Mean serum IGF-1 concentrations fell by at least 50%: 467 mg/L (SE 24), 526 mg/L (29), and 523 mg/L (40) in patients treated for 6, 12 and 18 months, respectively (p<0.001), whereas growth hormone increased by 12.5 mg/L (2.1), 12.5 mg/L (3.0), and 14.2 mg/L (5.7) (p<0.001). Of the patients treated for 12 months or more, 87 of 90 (97%) achieved a normal serum IGF-1 concentration. In patients withdrawn from pegvisomant (n=45), serum growth hormone concentrations were 8.0 mg/L (2.5) at baseline, rose to 15.2 mg/L (2.4) on drug, and fell back within 30 days of withdrawal to 8.3 mg/L (2.7). Antibodies to growth hormone were detected in 27 (16.9%) of patients, but no tachyphylaxis was seen. Serum insulin and glucose concentrations were significantly decreased (p<0.05). Two patients experienced progressive growth of their pituitary tumours, and two other patients had increased alanine and asparate aminotransferase concentrations requiring withdrawal from treatment. Mean pituitary tumour volume in 131 patients followed for a mean of 11.46 months (0.70) decreased by 0.033 cm(3) (0.057; p=0.353). INTERPRETATION Pegvisomant is an effective medical treatment for acromegaly.

AIP Mutation in Pituitary Adenomas in the 18th Century and Today

Gigantism results when a growth hormone-secreting pituitary adenoma is present before epiphyseal fusion. In 1909, when Harvey Cushing examined the skeleton of an Irish patient who lived from 1761 to 1783, he noted an enlarged pituitary fossa. We extracted DNA from the patients teeth and identified a germline mutation in the aryl hydrocarbon-interacting protein gene (AIP). Four contemporary Northern Irish families who presented with gigantism, acromegaly, or prolactinoma have the same mutation and haplotype associated with the mutated gene. Using coalescent theory, we infer that these persons share a common ancestor who lived about 57 to 66 generations earlier.

Sustained reduction in circulating cholesterol in adult hypopituitary patients given low dose titrated growth hormone replacement therapy: a two year study

To study the effects of short (6 months) and longer‐term (up to 24 months) growth hormone (GH) replacement therapy using a dose titration regimen, on lipid and glucose metabolism in GH‐deficient, hypopituitary adults.

ACTH and α-MSH inhibit leptin expression and secretion in 3T3-L1 adipocytes: model for a central–peripheral melanocortin-leptin pathway ☆

Leptin is the 167 amino-acid protein product of the Lep (obese) gene that is released predominantly from adipose tissue and circulates at levels related to the amount of fat. Leptin expression is hormonally regulated: insulin and glucocorticoids are stimulators, while inhibitors include beta-adrenergic agonists and testosterone. Recently, adenylate cyclase-coupled melanocortin receptors have been identified in murine adipose tissue, the 3T3-L1 adipocyte cell line, and in human fat tissue. These studies prompted us to evaluate the effects of pro-opiomelanocortin (POMC)-derived peptides on leptin production and expression in 3T3-L1 adipocytes in culture. 3T3-L1 pre-adipocytes differentiated by the insulin/indomethacin (I/I) method produced leptin at levels that were two times higher than those obtained in cells differentiated by the more traditional insulin/dexamethasone/isobutylmethylxanthine (I/D/M) method. By RT-PCR studies, 3T3-L1 cells expressed both the melanocortin 2 receptors (MC2-R) and melanocortin 5 receptors (MC5-R) isoforms of the melanocortin receptor at an early stage of differentiation. When I/I differentiated 3T3-L1 adipocytes were incubated with different concentrations of dibutyryl cAMP (db-cAMP) or POMC-derived peptides (ACTH and alpha-MSH), ACTH and alpha-MSH stimulated cAMP production after 30 min (2-fold increase) associated with a dose-dependent inhibition of leptin secretion (ACTHz.Gt;alpha-MSH; IC(50)=3.2+/-0.4 SE and 36+/-5 nM, respectively), maximal after 3 h of incubation (30% inhibition). In addition, 100 nM ACTH and alpha-MSH induced a 60% reduction in leptin expression by RT-PCR. Incubation of cells with 0.5 mM db-cAMP led to a more prominent inhibition of leptin expression and secretion (up to 80% at 1 and 24 h, respectively). The ACTH and alpha-MSH inhibitory effects on leptin secretion were mediated by activation of the MC2-R and MC5-R and were reversed by the MC-R antagonists ACTH(11-24) and ACTH(7-38). In summary, we have shown that POMC-peptides are potent inhibitors of leptin expression and production in 3T3-L1 adipocytes. The finding of ACTH/alpha-MSH receptor-induced inhibition of leptin production and expression in adipocytes support the possibility that there is a control mechanism for modulation of adipose tissue function via a melanocortin-leptin axis.

Differential stimulation of corticol and dehydropiandrosterone levels by food in obese and normal subjects: relation to body fat distribution

BACKGROUND It has been previously shown that food intake elevates circulating ACTH and cortisol levels, but no report has been published regarding the changes in circulating dehydroepiandrosterone (DHEA). DHEA was originally described as a weak androgen, but more recently it has been associated with a wide range of metabolic functions. In addition, previous studies have described a hyper‐responsive hypothalamo‐pituitary‐adrenal axis in obese subjects in response to various stimuli, but the specific response to food has not been studied.

Modulation of Cortisol Metabolism during Treatment of Acromegaly Is Independent of Body Composition and Insulin Sensitivity

Objectives: The set point of cortisol-cortisone conversion is shifted in the direction of cortisone by the inhibition of the activity of 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) during adult GH replacement and in active acromegaly. Additionally, both fat mass and insulin may modulate 11β-HSD1 and are both influenced by changes in GH status. This study examined the relative direct contribution of GH/IGF1 in modulating cortisol metabolism. Methods: Overall cortisol/cortisone conversion (ratio of urine 11-hydroxy-/11-oxo-cortisol metabolites; Fm/Em), insulin sensitivity (homeostatic model assessment; HOMA %S) and fat mass (DXA) were examined in parallel in 6 patients (mean age 53 years, range 42–76; 4 males, 2 females) with previously untreated active acromegaly during 6 months of therapy with Sandostatin® LAR® (20–30 mg i.m. 4 weekly). All but 1 patient had normal ACTH reserve. Results: At baseline, Pearson correlation demonstrated an inverse relationship between serum GH (mean of a 5-point day curve) and Fm/Em (r = –0.83, p = 0.04) and a trend towards an inverse relationship between HOMA %S and Fm/Em (r = –0.79, p = 0.06) but no other patterns were evident. During the course of treatment, serum GH decreased from 9.9 ± 6.4 (mean ± SD) to 3.5 ± 3.1 ng/ml (p < 0.01) and serum IGF-1 from 785 ± 268 to 431 ± 156 ng/ml (p < 0.005). Fm/Em increased from 0.52 ± 0.1 to 0.75 ± 0.08 (p < 0.03) consistent with increased 11β-HSD1 activity. There were no significant changes in truncal fat percentage (33.0 ± 9.0 vs. 33.0 ± 8.2) or insulin sensitivity (HOMA %S: 37.1 ± 8.6 vs. 52.8 ± 33.7). Conclusions: Modulation of cortisol metabolism during treatment of active acromegaly is dependent on changes in GH/IGF-1 status and is not influenced by any individual change in body composition or insulin sensitivity.

The effect of an opiate antagonist on the hormonal changes induced by hexarelin.

OBJECTIVE Growth hormone‐releasing peptides (GHRPs) stimulate growth hormone (GH) release in vitro and in vivo in animals and in humans. GHRPs were developed by modification of the structure of met‐enkephalln but GHRP‐6 does not activate opioid receptors in animal studies. These agents may well have diagnostic and/or long‐term therapeutic potential in the future so their effects on opioid receptors need to be clarified in humans as well. Hexarelin is a recently developed six amino acid residue GHRP.

The release of leptin and its effect on hormone release from human pituitary adenomas

BACKGROUND Leptin is the protein product of the obese gene, known to play an important role in body energy balance. The leptin receptor exists in numerous isoforms, the long isoform being the major form involved in signal transduction. Leptin expression has recently been demonstrated in the human pituitary, both in normal tissue and in pituitary adenomas. The long isoform of the leptin receptor has also been shown to be present in pituitary adenomas; however, contrasting results have been obtained regarding its expression in the normal human pituitary.

Cyclic prednisolone therapy for male infertility associated with autoantibodies to spermatozoa

Seventy-six subfertile men with significant titers of antisperm antibodies were treated with a new corticosteroid regimen, consisting of prednisolone, 40 mg daily, rising to 80 mg daily if antibody titers did not fall, given from days 1 to 10 of the partners menstrual cycle, for up to nine cycles. Twenty-five (33%) of the partners became pregnant during a treatment cycle, more than twice the expected incidence without treatment. No serious complications occurred, although one half of the patients had transient minor side effects. This regimen appears to be encouraging and suitable for further assessment in a prospective controlled trial.

Clinical use of a growth hormone receptor antagonist in the treatment of acromegaly

The elucidation of the mechanisms by which growth hormone (GH) interacts with its receptor has facilitated the design of compounds that function as GH-receptor antagonists. One such compound, B2036, has been conjugated to polyethylene glycol to produce a drug, pegvisomant, that has a powerful ability to lower circulating concentrations of insulin-like growth factor I (IGF-I), the principal mediator of GH action, in patients with acromegaly and to improve the symptoms and signs associated with GH excess. This article describes the mechanism of action of GH-receptor antagonists, reviews the preclinical and clinical data on the use of pegvisomant and discusses some of the challenges that lie ahead in judging the efficacy of a treatment that, unlike established therapies for acromegaly, does not aim to modify the underlying cause of acromegaly, namely excess GH secretion, but aims to lower serum IGF-I levels to normal.