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Peter J Trainer

Publications and source records attributed to Peter J Trainer.

At least 19 recordsLinked to original sources
PubMed2006

Gender, body weight, disease activity, and previous radiotherapy influence the response to pegvisomant.

CONTEXT/OBJECTIVE: To effectively normalize IGF-I in patients with acromegaly, various covariates may affect dosing and plasma concentrations of pegvisomant. We assessed whether sex, age, weight, and previous radiotherapy influence dosing of pegvisomant in patients with active disease. DESIGN: Data from 69 men and 49 women participating in multicenter, open-label trials of pegvisomant were retrospectively evaluated using multiple regression techniques. Sixty-nine subjects (39 men, 30 women) had undergone external beam pituitary radiotherapy. Serum IGF-I was at least 30% above age-related upper limit of normal in all patients at study entry. After a loading dose of pegvisomant (80 mg), patients were commenced on 10 mg/d. Pegvisomant dose was adjusted by 5 mg every eighth week until serum IGF-I was normalized. RESULTS: At baseline, men had significantly higher mean serum IGF-I levels than women despite similar GH levels. After treatment with pegvisomant, IGF-I levels were similar in men and women. A significant correlation between baseline GH, IGF-I, body weight, and the dose of pegvisomant required to normalize serum IGF-I was observed (all P < 0.001). Women required an average of 0.04 mg/kg more pegvisomant than men and a mean weight-corrected dose of 19.2 mg/d to normalize serum IGF-I [14.5 mg/d (men); P < 0.001]. Patients treated with radiotherapy required less pegvisomant to normalize serum IGF-I despite similar baseline GH/IGF-I levels (15.2 vs. 18.5 mg/d for no previous radiotherapy; P = 0.002). CONCLUSIONS: Sex, body weight, previous radiotherapy, and baseline GH/IGF-I influence the dose of pegvisomant required to normalize serum IGF-I in patients with active acromegaly.

Acromegaly↗
PubMed2006

Recent developments in the therapy of acromegaly.

Acromegaly, a condition due to growth hormone hypersecretion usually from a benign pituitary tumour, is associated with significant morbidity and mortality. Disease control leads to normalisation of life expectancy with a reduction in signs and symptoms. Treatment modalities include surgery, radiotherapy and medical management. Surgery is the primary treatment in most of the patients, with success rates of 61-91% reported for those with microadenomas who are operated on by a specialist pituitary surgeon; however, most patients have macroadenomas and, although benefiting from surgery, are not cured and require additional medical therapy. This review will focus on emerging concepts in the medical treatment of acromegaly.

Acromegaly↗
PubMed2006

The octreotide test dose is not a reliable predictor of the subsequent response to somatostatin analogue therapy in patients with acromegaly.

In many centres, a test dose (TD) of octreotide is administered before commencing somatostatin analogue therapy (SAT), although the merits of this procedure are uncertain. We have analysed the value of the GH response to a TD in predicting the efficacy of subsequent SAT in 47 patients with acromegaly (25 male, median age 51 years, range 20-82). The primary goal of SAT was a mean GH of < 5 mU/l. Median baseline GH was 19.3 mU/l (2.2-233 mU/l) and with the TD fell by 78% (35-98%) to a nadir of 4.2 mU/l (< 0.3-85 mU/l). Optimal predictive power was observed when GH fell to < 5 mU/l after the TD. With this criterion, the TD had a positive predictive value (PPV) of achieving the primary goal on SAT of 82% and a negative predictive value (NPV) of 50%. However, baseline GH was also highly predictive of the likelihood of successful SAT (GH < 5 mU/l). The GH response to the TD had PPV of 83% and NPV of 61% of normalising IGF-I on SAT. In summary, baseline GH and nadir after a TD are highly predictive of a good response to SAT; however, a poor response to a TD does not exclude an optimal response to SAT. Furthermore, failure to achieve biochemical control does not equate to no benefit, as biochemical improvement was seen in every patient; therefore, no patient should be deprived of octreotide therapy because of the result of a TD. In conclusion, our data indicate that the octreotide TD has no place in selecting patients for SAT.

Acromegaly↗
PubMed2005

Glucose homeostasis and safety in patients with acromegaly converted from long-acting octreotide to pegvisomant.

CONTEXT: In clinical practice, patients with acromegaly may be switched from therapy with long-acting somatostatin analogs to pegvisomant. The effect of changing therapies on glucose homeostasis and safety has not been reported. OBJECTIVES: The objectives of this study were to monitor changes in IGF-I levels, glycemic control, and safety, particularly liver function and tumor size. DESIGN: This was a multicenter, open-label, 32-wk trial study. SETTING: The study was performed at outpatient clinics. PATIENTS: Fifty-three patients with acromegaly previously treated with octreotide long-acting release (LAR) participated in this study. INTERVENTION: Pegvisomant (10 mg/d) was initiated 4 wk after the last dose of octreotide LAR and was adjusted based on serum IGF-I concentrations at wk 12, 20, and 28. MAIN OUTCOME MEASURES: The main outcome measures were changes in IGF-I, glycosylated hemoglobin A1c (HbA1c), fasting plasma glucose, and safety during the first 12 wk after conversion. RESULTS: At the end of pegvisomant treatment, IGF-I was normalized in 78% of patients. At wk 32, median fasting glucose concentration and HbA1c were reduced (-1.4 mmol/liter and -0.4%, respectively; both P < or = 0.0001) in the study population. Improvements in glycemic control occurred in patients with normal IGF-I concentrations at wk 4 [n = 15; fasting glucose, -1.7 mmol/liter (P < or = 0.0001); HbA1c -0.2% (P = 0.03)]. Decreases in fasting glucose and HbA1c levels were observed in patients with and without diabetes. HbA1c was reduced by more than 1.0% in patients with diabetes. Median pituitary tumor volume did not change, although tumor volume increased in two patients with macroadenomas. CONCLUSIONS: Conversion from octreotide LAR to pegvisomant was safe and well tolerated. Improved glycemic control indicates that pegvisomant should be considered in patients with acromegaly and diabetes.

Acromegaly↗
PubMed2005

Quality of life (QOL) in patients with acromegaly is severely impaired: use of a novel measure of QOL: acromegaly quality of life questionnaire.

Acromegaly Quality of Life Questionnaire (AcroQoL) is a new disease-generated quality of life (QOL) questionnaire comprising 22 questions covering physical and psychological aspects of acromegaly and subdivided into "appearance" and "personal relations" categories. We have performed a cross-sectional study of QOL in 80 patients [43 male (mean age, 54.2 yr; range, 20-84); median GH, 0.93ng/ml (range, <0.3 to 23.7); IGF-I, 333.1 ng/ml (range, 47.7-899)] with acromegaly. In addition to AcroQoL, patients completed three generic QOL questionnaires: Psychological General Well-Being Schedule (PGWBS), EuroQol, and a signs and symptoms score (SSS). All three generic questionnaires confirmed impairment in QOL [mean scores: PGWBS, 69.6; EuroQol, visual analog scale, 66.4 (range, 20-100) and utility index, 0.7 (range, -0.07 to 0.92); and SSS, 12 (range, 0-27)]. There was no correlation between biochemical control and any measure of QOL. AcroQoL (57.3%; range, 18.2-93.2) correlated with PGWBS (r = 0.73; P < 0.0001); and in patients with active disease, AcroQoL-physical dimension correlated with SSS (r = -0.67; P < 0.0003). In all questionnaires, prior radiotherapy was associated with impaired QOL. In conclusion, these data underline the marked impact that acromegaly has on patients' QOL and provide the first evidence validating AcroQoL against well-authenticated measures of QOL. This indicates the potential of AcroQoL as a patient-friendly measure of disease activity.

Acromegaly↗
PubMed2004

High levels of 150-kDa insulin-like growth factor binding protein three ternary complex in patients with acromegaly and the effect of pegvisomant-induced serum IGF-I normalization.

OBJECTIVE: To assess the effect of pegvisomant-induced serum insulin-like growth factor 1 (IGF-1) normalization on IGF binding proteins 1, 2, 3 (IGFBP-1, IGFBP-2 and IGFBP-3), total, non-bound (45 kDa) and 150-kDa ternary complex-associated IGFBP-3, and in vivo IGFBP-3 proteolysis in patients with active acromegaly. DESIGN: The above parameters were measured in 16 patients (median age 57 (range 27-78)) with active acromegaly (serum IGF-I at least 30% above the upper limit of an age-related reference range after washout) in a paired manner on samples obtained after washout and the first occurrence of serum IGF-I normalization during pegvisomant therapy (median dose 15 mg/day (10-40 mg)). RESULTS: Total IGFBP-3 and 150-kDa ternary complex-associated IGFBP-3 were significantly elevated in patients at baseline compared to controls ((mean+/-SEM) 4345+/-194 vs. 3456+/-159 microg/L, P<0.01 and 3908+/-160 va. 3042+/-149 microg/L, P<0.01, respectively), but no significant difference in 45-kDa IGFBP-3 or in vivo IGFBP-3 proteolysis was observed. Serum IGF-I normalization (699+/-76 to 242+/-28 microg/L, P<0.0001) was associated with a fall in total IGFBP-3 (4345+/-194 to 3283+/-160 microg/L, P<0.001) due to a reduction in 150-kDa ternary complex-associated IGFBP-3 (3908+/-160 to 3008+/-140 microg/L, P<0.0001). 45 kDa IGFBP-3 and in vivo IGFBP-3 proteolysis were unaffected by GH receptor blockade (326+/-13 to 330+/-18 microg/L, P=0.86; 30+/-3.5 to 30+/-3.9%, P=0.75, respectively). CONCLUSIONS: GH receptor blockade in patients with acromegaly lowers IGF-I and 150-kDa IGFBP-3 ternary complex formation. 50 kDa ternary complex formation (not in vivo IGFBP-3 proteolysis) is GH dependent and measurement of 150-kDa ternary complex-associated IGFBP-3 may provide useful information regarding treatment efficacy in patients with acromegaly.

Acromegaly↗
PubMed2004

The place of pegvisomant in the acromegaly treatment algorithm.

The disfiguring disease acromegaly results from hypersecretion of growth hormone (GH). The main goals of treatment for acromegaly include normalisation of biochemical markers of disease activity to restore normal life expectancy, amelioration of signs and symptoms of the disease, removal of the pituitary tumour without damaging the optic chiasm and other peripituitary structures, and preservation of pituitary function. Conventional options for treatment of acromegaly include surgery, radiotherapy (RT), and medical therapy with either dopamine agonists or somatostatin (SMS) analogues. The advent of the genetically engineered growth hormone analogue pegvisomant is unlikely to alter significantly the place of surgery and RT in the treatment algorithm for acromegaly biochemical control as determined based on serum IGF-I concentrations is achievable with pegvisomant in virtually all patients, and it will clearly become the drug of choice in patients partially or completely unresponsive to SMS analogues. Preliminary studies suggest improved insulin sensitivity for a given IGF-I with pegvisomant compared with SMS analogues; if these results are confirmed by results of future studies, such a metabolic advantage may encourage the use of pegvisomant.

Acromegaly↗
PubMed2004

Pitfalls in the diagnosis of acromegaly.

Acromegaly is a disfiguring and disabling illness which, when inadequately treated, reduces life expectancy. An implication of the ability to offer effective treatment is the increased onus on physicians of all sorts to ensure acromegaly is diagnosed and treated as early as possible. To this end, criteria for the diagnosis of acromegaly have been proposed in the consensus statement of Giustina et al. However, other data suggest that the proposed criteria are not rigorous enough and strict adherence to the guidelines would result in failure to diagnose a significant number of patients. A review of published experience suggests that the combination of a GH nadir during an oral glucose tolerance test of <0.25 microg/l plus a normal age-related insulin growth factor-I level makes the diagnosis of acromegaly extremely unlikely.

Acromegaly↗
PubMed2004

The challenges of reliance on insulin-like growth factor I in monitoring disease activity in patients with acromegaly.

Serum insulin-like growth factor I (IGF-I) is an important marker of disease activity in patients with acromegaly, and epidemiological data indicate control of circulating IGF-I in patients with acromegaly restores life expectancy to normal. Improvements in the quality of, and access to, IGF-I assays has encouraged monitoring of acromegaly with IGF-I, although circulating growth hormone (GH) and IGF-I values provide different information, so ideally both should be monitored. However, the introduction of the GH receptor antagonist pegvisomant poses new challenges. Pegvisomant binds with high affinity to GH receptors, thereby blocking the action of GH at the tissue level and rendering the hormone biologically inactive. This leaves IGF-I as the principal marker of disease activity. It is conceptually possible to induce a state of functional GH deficiency (GHD) with pegvisomant with IGF-I values within the normal range. With the goal of minimizing the risk of over-treatment and GHD, we have provided preliminary guidance on the target range for IGF-I in patients receiving pegvisomant based on the gender- and decade-based percentile ranges for IGF-I of adult patients with untreated GHD enrolled in the Pfizer International Metabolic Database (KIMS).

Acromegaly↗
PubMed2003

Medical treatment in acromegaly.

Acromegaly is a rare disabling disorder that results in premature death. The excess mortality and morbidity are the result of prolonged elevation of growth hormone (GH) and insulin-like growth factor-I (IGF-I) levels, and vigorous control of these improves well-being and restores life expectancy to normal. Recognition of the benefits of treatment has emphasised the need for optimal control of the GH/IGF-I axis. Transsphenoidal surgery is first-line therapy in the majority of patients; however, as most tumours are macroadenomas, cure rates are low. The role of radiotherapy is evolving and, although extremely effective at controlling tumour growth, it can take up to 15 years to control GH & IGF-I levels. In the interim, medical therapy is necessary. Dopamine agonists are inexpensive oral agents but, although most patients experience some benefit, GH and IGF-I levels are only normalised in around 35-40% of patients, and side effects are common. Somatostatin analogues are the gold standard of medical treatment. They can induce tumour shrinkage in a proportion of patients and can normalise the GH/IGF-I axis (at best) in approximately 65% of individuals; however, this leaves a significant cohort uncontrolled. The advent of the GH receptor antagonist pegvisomant provides the potential for IGF-I to be normalised in virtually every patient, but this novel form of therapy, which does not act on the pituitary, also raises many questions.

Acromegaly↗
PubMed2003

Metabolic effects of GH antagonism in patients with acromegaly.

Pegvisomant is a growth hormone (GH) receptor antagonist that represents a major advance in the treatment of acromegaly. Initial results with pegvisomant indicate this novel form of therapy to be the most effective treatment available for achieving biochemical disease control as ascertained by circulating IGF-I.

Acromegaly↗
PubMed2003

Seeking the optimal target range for insulin-like growth factor I during the treatment of adult growth hormone disorders.

Impaired GH activity at target tissues, occurring when GH action is blocked or during suboptimal GH replacement therapy, may result in a pathological state associated with lowering of IGF-I, but not GH levels. Such a state represents functional but not necessarily actual GH deficiency (GHD). The aim of this study was to identify a range of IGF-I values commensurate with GHD, which could be used to determine the risk of functional GHD during the treatment of adult GH disorders. Centrally measured baseline IGF-I data from the Kabi International Metabolic Study European GHD database were analyzed. Inclusion criteria were adult-onset GHD and two or more additional anterior pituitary hormone deficits. Adults with childhood-onset GHD and cured acromegaly were excluded. The cohort was stratified into six gender-based age ranges. Baseline IGF-I measurements from 376 females (median age, 48 yr; range, 21-77 yr) and 434 males (median age 52 yr; range 21-80 yr) were analyzed. Data were not normally distributed and are presented as medians (quartiles). The median serum IGF-I and IGF-I SDS in males were 94.0 microg/liter (64 and 141) and -1.52 (-2.53 and -0.456; n = 434). Both were significantly greater than the equivalent values of females, which were 73 microg/liter (46 and 103.5) and -2.30 (-3.28 and -1.328; n = 376; P < 0.0001 for both). Age and gender-related 90th and 95th percentiles for IGF-I SDS were determined to generate risk estimates for functional GHD, which, in conjunction with the clinical status of the patient, may be used to aid dose titration during treatment of GH disorders in adulthood.

Adult↗
PubMed2003

Optimizing control of acromegaly: integrating a growth hormone receptor antagonist into the treatment algorithm.

Acromegaly is associated with significant morbidities and a 2- to 3-fold increase in mortality because of the excessive metabolic action of GH and IGF-I, a marker of GH output. Reductions in morbidity correspond with decreases in IGF-I, and mortality is lowered following normalization of IGF-I or GH levels. Therefore, this has become an important end point. Current guidelines for the treatment of acromegaly have not considered recent advances in medical therapy, in particular, the place of pegvisomant, a GH receptor antagonist. Treatment goals include normalizing biochemical markers, controlling tumor mass, preserving pituitary function, and relieving signs and symptoms. Surgery reduces tumor volume and is considered first-line therapy. Radiation reduces tumor volume and GH and IGF-I levels, but the onset of action is slow and hypopituitarism typically develops. Therefore, pharmacotherapy is often used following surgery or as first-line therapy for nonresectable tumors. Dopamine agonists can be considered in patients exhibiting minimal disease or those with GH-prolactin-cosecreting tumors but will not achieve hormone normalization in most patients. Somatostatin analogs effectively suppress GH and IGF-I in most patients, but intolerance (e.g. diarrhea, cramping, gallstones) can occur. Pegvisomant, the newest therapeutic option, blocks GH action at peripheral receptors, normalizes IGF-I levels, reduces signs and symptoms, and corrects metabolic defects. Pegvisomant does not appear to affect tumor size and has few adverse effects. Pegvisomant is the most effective drug treatment for acromegaly in normalizing IGF-I and producing a clinical response; it is the preferred agent in patients resistant to or intolerant of somatostatin analogs.

Acromegaly↗
PubMed2003

Clinical use of pegvisomant for the treatment of acromegaly.

Understanding the mechanisms by which growth hormone (GH) interacts with its receptor has led to the design of compounds that function as GH receptor antagonists. One such compound has been conjugated to polyethylene glycol (PEG) to produce a drug, pegvisomant, which has been extensively investigated as a treatment for acromegaly. It was recently approved for clinical use in the US and will shortly be available on prescription in Europe. Studies have shown that the drug is able to normalize circulating levels of insulin-like growth factor-1 (IGF-1), the principal mediator of GH action, in 97% of patients with active acromegaly, as well as improve the symptoms and signs associated with GH excess. Serum IGF-1 levels have been used as the chief marker of efficacy of treatment with pegvisomant. The drug is able to achieve biochemical control in patients wholly or partially resistant to somatostatin analogs. Preliminary data suggests that pegvisomant may be a particularly suitable choice of medical therapy for patients with acromegaly and coexistent diabetes mellitus.

Acromegaly↗
PubMed2002

Current status and future opportunities for controlling acromegaly.

Growth-hormone (GH) secreting adenomas, including acromegaly, account for approximately one-sixth of all pituitary adenomas and are associated with mortality rates at least twice that of the general population. The ultimate goal of therapy for acromegaly is normalization of morbidity and mortality rates achieved through removal or reduction of the tumor mass and normalization of insulin-like growth factor I (IGF-I) levels. Previously published efficacy results of current treatment modalities (surgery, conventional radiation, and medical therapy with dopamine agonists and somatostatin analogs) are often difficult to compare because of the different criteria used to define cure (some of which are now considered inadequate). For each of these modalities, pooled data from a series of acromegaly studies were reviewed for rates of IGF-I normalization, a currently accepted definition of cure. The results showed overall cure rates of approximately 10% for bromocriptine, 34% for cabergoline, 36% for conventional radiation, 50-90% for surgery for microadenomas and less than 50% for macroadenomas, and 54-66% for octreotide. These cure rates based on IGF-I normalization are generally less than those reported for cure based solely on GH levels. Novel new therapies for acromegaly include the somatostatin analog, lanreotide, Gamma Knife radiosurgery, and pegvisomant, the first in its class of new GH receptor antagonists. Although it does not appear that Gamma Knife radiosurgery results in significantly higher cure rates or fewer complications, it does provide a notable improvement in delivery compared with conventional radiation. Early studies have reported IGF-I normalization in 48% of lanreotide-treated patients and up to 97% of pegvisomant-treated.

Acromegaly↗
PubMed2002

Corticosteroids and pregnancy.

Pregnancy results in major changes in the hypothalamo-pituitary-adrenal (HPA) axis, which in turn influence fetal growth and the timing of labor. From the beginning of the second trimester maternal cortisol secretion increases, and in late pregnancy the placenta, in large part mediated through corticotroph-releasing hormone, plays a crucial role in the regulation of the fetal HPA axis to ensure the synchronization of the various processes involved in parturition. Exposure of the fetus to excess glucocorticoid results in intrauterine growth failure and possibly "programs" the development of cardiovascular disease in adult life. Biochemical assessment of the HPA axis is complicated by the estrogen-induced elevation of circulating cortisol-binding globulin, resulting in misleadingly high circulating cortisol levels The hypercortisolemia of Cushing's syndrome causes infertility, but if pregnancy does occur it can result in increased morbidity and mortality in mother and fetus. However, the prospects of a successful pregnancy are greatly improved with control of hypercortisolemia by surgery and medical therapy with metyrapone. Hypoadrenalism can be difficult to diagnose during pregnancy but, once the diagnosis is made, with careful monitoring, dose adjustment as indicated, and parenteral cover for labor, a successful pregnancy should result.

Addison Disease↗