Three-year experience with access to nationally funded growth hormone (GH) replacement for GH-deficient adults.

OBJECTIVE: Treatment of growth hormone (GH)-deficient adults with GH has been shown to improve a range of metabolic abnormalities and enhance quality of life. However, the results of access to nationally funded treatment have not been reported. DESIGN: Retrospective case series auditing nationally funded treatment of defined GH-deficient adults in New Zealand, with carefully designed entry and exit criteria overseen by a panel of endocrinologists. PATIENTS: Applications for 201 patients were assessed and 191 approved for funded treatment over the initial 3 years since inception. The majority had GH deficiency following treatment of pituitary adenomas or tumours adjacent to the pituitary. RESULTS: After an initial 9-month treatment period using serum IGF-I measurements to adjust GH dosing, all patients reported a significant improvement in quality of life (QoL) score on the QoL-AGHDA(®) instrument (baseline (95%CI) 19 (18-21), 9 months 6 (5-7.5)), and mean serum IGF-I SD scores rose from -3 to zero. Mean waist circumference decreased significantly by 2.8 ± 0.6 cm. The mean maintenance GH dose after 9 months of treatment was 0.39 mg/day. After 3 years, 17% of patients had stopped treatment, and all of the remaining patients maintained the improvements seen at 9 months of treatment. CONCLUSION: Carefully designed access to nationally funded GH replacement in GH-deficient adults was associated with a significant improvement in quality of life over a 3-year period with mean daily GH doses lower than in the majority of previously reported studies.

Comparison of two low-dose calcium infusion schedules for localization of insulinomas by selective pancreatic arterial injection with hepatic venous sampling for insulin.

OBJECTIVE: Localization of small insulinomas may be difficult. Selective pancreatic arterial injection of calcium with hepatic venous insulin measurement (SACST) has been used for this purpose, but can rarely cause hypoglycaemia. Two low-dose concentrations of calcium, 0·25 and 0·1 of the usual concentration used for the test, have been compared for sensitivity of localization and safety. DESIGN: Selective pancreatic arterial injection of calcium with hepatic venous insulin measurement was performed at calcium concentrations of 0·0025 (Protocol A) and 0·00625 (Protocol B) mEq calcium per kg. The standard concentration is 0·025 mEq/kg. PATIENTS: Twenty one successive patients with biochemical evidence of insulinoma were studied. RESULTS: Using surgical localization as the gold standard, Protocol A had a sensitivity of 91% and Protocol B 75% for correct localization. The false-positive localization rate was 16%. No hypoglycaemia was observed. These results compare favourably with published data using the standard calcium concentration. Selective pancreatic arterial injection of calcium with hepatic venous insulin measurement was superior to localization by noninvasive imaging; in seven cases, SACST was correct when conventional imaging was negative (five) or false positive (two). CONCLUSION: Low concentrations of calcium are effective and safe when performing SACST for localization of insulinoma.

A meta-analysis of the effect of lowering serum levels of GH and IGF-I on mortality in acromegaly.

OBJECTIVE: Formal studies of acromegaly have found increased mortality associated with the disorder, although reduction of serum levels of GH and IGF-I by treatment appears to improve survival. A meta-analysis of mortality studies in acromegaly has thus been performed to assess the effect of lowering serum GH and IGF-I on survival. DESIGN AND METHODS: Medline was searched for studies under 'acromegaly', 'mortality' and 'cause of death' (1965-2008), and abstracts of recent meetings of the US Endocrine Society were hand searched. Studies were restricted to those presenting mortality data according to serum GH and IGF-I at last follow-up, and with mortality expressed as a standardized mortality ratio (SMR). RESULTS: Patients with random serum GH <2.5 microg/l following treatment, mostly measured by standard RIA, had mortality close to expected levels (SMR 1.1, 95% confidence interval (CI) 0.9-1.4) compared with an SMR of 1.9 (95% CI 1.5-2.4) for those with final GH >2.5 microg/l. Similarly, a normal serum IGF-I for age and sex at last follow-up after treatment was associated with an SMR of 1.1 (95% CI 0.9-1.4) compared with an SMR of 2.5 (95% CI 1.6-4.0) for those with continued IGF-I elevation. There was a significant trend for reduced mortality in series reporting frequent use of somatostatin analogues and in studies reporting high (>70%) rates of biochemical remission after treatment. CONCLUSIONS: Clinicians treating acromegalic patients should aim for random serum GH <2.5 microg/l measured by RIA (probably <1 microg/l measured by modern sensitive immunoassay) and normal serum IGF-I values, to restore the elevated mortality of the condition to normal levels.

Excess mortality in acromegaly.

BACKGROUND: Increased production of growth hormone (GH) and insulin-like growth factor-I (IGF-I) in patients with acromegaly is associated with a twofold increase in mortality compared with the general population. The range of standardised mortality rates in various studies ranges from 1.2 to 3.6. PREDICTORS OF MORTALITY: Multivariate analysis has indicated that post-treatment serum GH levels and, in a number of studies, serum IGF-I levels are the most powerful predictors of outcome. Normal IGF-I concentrations and random GH levels <2.5 microg/l measured by polyclonal radioimmunoassay result in optimal outcome. Other factors adversely influencing mortality include hypertension and a long interval between onset of the disorder and diagnosis. CONCLUSIONS: Analysis of recent reports suggests that adoption of treatment guidelines with appropriate post-treatment target ranges for GH and IGF-I, together with the availability of newer methods to control GH oversecretion, has significantly improved patient outcomes.

Serum IGF-I levels are similar in Samoan, Maori and European populations despite differences in body composition.

OBJECTIVE: To determine if serum IGF-I concentrations are similar in healthy adult subjects from the Samoan, Maori and European populations in New Zealand. DESIGN: Serum IGF-I concentration was measured in 75 healthy adults, aged 18-50 years, of Samoan (n=23), Maori (n=22) and European (n=30) descent. Body composition was assessed using standard anthropomorphic measures. In addition all subjects had body composition assessed by Dual energy X-ray absorptiometry (DXA). RESULTS: Weight, body mass index (BMI), and fat mass were significantly greater in Maori and Samoan subjects than European subjects (ANOVA p=0.006, p=0.0003, p=0.03, respectively). However, serum IGF-I concentration was similar between the groups (European 186.8 SEM 14.9 microg/l, Maori 204.8 SEM 17.1 microg/l, Samoan 180.0 SEM 17.5 microg/l, p=0.58). IGF-I levels were similar between ethnic groups after adjustment (ANCOVA) for age, sex or BMI (p=0.5) or age, sex and fat mass (p=0.44). In multivariate analysis the only independent predictor of IGF-I was age (p<0.001) and explained 22% of the variance in IGF-I level. CONCLUSIONS: Serum IGF-I concentrations were similar in Maori, Samoan and European population groups in New Zealand, despite significant differences in anthropomorphic variables and body composition.

An unusual cause of hyperinsulinaemic hypoglycaemia syndrome.

Endogenous hyperinsulinism as a cause for hypoglycaemia can be attributed to a number of different causes including insulinoma, sulphonylurea drugs and the newly described disorder non-insulinoma pancreatogenous hypoglycaemia (NIPH). The calcium stimulation test is increasingly used as a method for not only localizing insulinoma but also for distinguishing the above entities. We describe a case in which felonious sulphonylurea administration was used to mimic either an insulinoma or NIPH. Importantly, this case demonstrates that, contrary to previous reports, the insulin response to calcium stimulation in such cases may be uniformly positive and should alert the physician to possible surreptitious sulphonylurea ingestion.

Long-term treatment outcome in acromegaly.

A number of groups have developed guidelines to indicate whether an individual with acromegaly has been cured by treatment. However, studies to date do not provide a robust definition of biochemical remission of the disorder based on correlation with long-term outcome. Available data suggest that those with a random serum growth hormone (GH) level of <2.5 microg/l, or a glucose-suppressed GH level of <1 microg/l following treatment have mortality figures indistinguishable from the general population. However, the confidence limits for these mortality estimates are quite wide. It remains possible that growth hormone levels lower than 1 microg/l for random samples, or even lower when using ultrasensitive GH assays, may indicate superior outcome, but this remains to be confirmed. There are limited data relating serum insulin-like growth factor-I (IGF-I) levels to outcome, although normalisation of serum IGF-I clearly improves outcome compared with continued elevation of measurements after treatment. Current evidence suggests that a post-treatment random serum GH <2.5 microg/l and a normal serum IGF-I value defines biochemical cure. Available data suggest that achieving similar growth hormone levels after treatment also reduces the prevalence of chronic complications of the disorder, which is subsequently reflected in improved mortality.

Effect of breast surgery on serum levels of insulin-like growth factors (IGF-I, IGF-II, and IGF binding protein-3) in women with benign and malignant breast lesions.

BACKGROUND: There is evidence that insulin-like growth factors play a role in the development of breast cancer. Antiestrogens reduce circulating levels of IGF-I, but the influence of other breast cancer treatments, including surgery, is unknown and is investigated in this study. METHODS: Circulating serum concentrations of IGF-I, IGF-II, and IGF binding protein-3 (IGFBP-3) were measured before and after breast surgery in 31 patients with breast cancer and 12 controls with benign breast lesions. Serum albumin was measured as a marker of the nonspecific metabolic effect of surgery. RESULTS: Serum IGF-I, IGF-II, IGFBP-3, and albumin fell 24 hours after surgery for breast cancer but largely normalized again over the next 7 days. The fall in IGF-I and IGFBP-3 was not significant when the change in serum albumin was used as a covariate, suggesting a nonspecific effect of surgery. However, the reduction in IGF-II remained significant when adjusted for albumin and was greater after lumpectomy of malignant tumors (-8 +/- 2%) compared with benign disease (2 +/- 2%, P = .001). The fall in IGF-II was significantly related to the size of the removed tumor. CONCLUSIONS: Breast cancer may directly influence the serum concentration of IGF-II, possibly by direct tumor production.

Comparison of an LH-RH analogue (Goeserelin acetate, 'Zoladex') with combined androgen blockade in advanced prostate cancer: final survival results of an international multicentre randomized-trial. International Prostate Cancer Study Group.

OBJECTIVE: The aim of this study was to compare the effects of the nonsteroidal antiandrogen flutamide plus the LH-RH analogue goserelin acetate (combined androgen blockade [CAB]) with goserelin acetate alone in patients with advanced prostate cancer. The original analyses at 25 and 56 months of follow-up have been reported previously, and here we report the final survival analysis after 10 years of follow-up. METHODS: 589 patients with advanced prostate cancer (55% with metastatic [M1] and 45% with locally advanced [M0] disease) were randomized to receive goserelin acetate 3.6 mg either alone or in combination with flutamide (250 mg three times daily). RESULTS: A total of 583 patients were included in the analysis. There was a small, but nonsignificant, benefit for CAB compared with goserelin acetate alone in all patients with respect to survival (hazard ratio 0.88, 95% CI 0.73, 1.06). Subgroup analysis of M0 and M1 patients showed similar results (M0: hazard ratio 0.92, 95% CI 0.68, 1.25; M1: hazard ratio 0.85, 95% CI 0.66, 1. 08). The treatment effect was not significantly different for M0 and M1 patients (p = 0.685). CONCLUSIONS: In this large randomized trial containing significant numbers of M0 patients, after 10 years there was a small but nonsignificant benefit for CAB over castration alone.

Height-related risk factors for prostate cancer.

Previous studies have reported that adult height is positively associated with the risk of prostate cancer. The authors carried out a population-based case-control study involving 317 prostate cancer cases and 480 controls to further investigate the possibility that height is more strongly associated with advanced, compared with localized forms of this disease. Since the inherited endocrine factors, which in part determine height attained during the growing years, may influence the risk of familial prostate cancer later in life, the relationship with height was also investigated for familial versus sporadic prostate cancers. Adult height was not related to the risk of localized prostate cancer, but there was a moderate positive association between increasing height and the risk of advanced cancer (relative risk (RR) = 1.62; 95% confidence interval (CI) 0.97-2.73, upper versus lowest quartile, P-trend = 0.07). Height was more strongly associated with the risk of prostate cancer in men with a positive family history compared with those reporting a negative family history. The RR of advanced prostate cancer for men in the upper height quartile with a positive family history was 7.41 (95% CI 1.68-32.67, P-trend = 0.02) compared with a reference group comprised of men in the shortest height quartile with a negative family history. Serum insulin-like growth factor-1 levels did not correlate with height amongst men with familial or sporadic prostate cancers. These findings provide evidence for the existence of growth-related risk factors for prostate cancer, particularly for advanced and familial forms of this disease. The possible existence of inherited mechanisms affecting both somatic and tumour growth deserves further investigation.

Serum levels of insulin-like growth factor binding protein-3 in benign and malignant breast disease.

BACKGROUND: The insulin-like growth factors IGF-I and IGF-II and their major binding protein IGFBP-3 influence the growth of breast cancer cells in vitro. Some benign non-breast tumours appear to be associated with increased serum IGFBP-3 levels which would tend to reduce bioactive-free IGF concentrations. The present study investigates whether this pattern also occurs in neoplastic breast disease. METHODS: Serum IGF-I, IGF-II and IGFBP-3 were measured by specific radioassay in 12 women with benign breast disease, 31 patients with breast cancer and in age-matched controls. RESULTS: The mean (+/-SD) serum IGFBP-3 concentration was higher in benign breast disease (3.6+/-0.7 mg/L) than in controls (2.7+/-0.6 mg/L) or in breast cancer patients (2.7+/-0.5 mg/L) (P = 0.001). Serum IGF-I and IGF-II levels were not significantly different among the groups. However, the index of free unbound IGF measured as the molar ratio of IGF-I plus IGF-II divided by IGFBP-3 was significantly lower in benign breast disease than in the other subjects. CONCLUSIONS: Either the production or clearance of IGFBP-3 is altered in benign breast disease so that there is less free IGF available to cells. This may serve to protect against malignant transformation in patients with benign breast disorders.

Epidemiology of acromegaly.

Acromegaly is a consequence of chronic growth hormone (GH) excess, due in the majority of cases to a GH-secreting pituitary adenoma, and occurring with a population prevalence of 60 per million and an incidence of 3-4 per million per year. Males and females appear to be equally affected with an average age of presentation of 44 years. Younger patients may have more aggressive tumours and higher GH concentrations. There is co-existent hyperprolactinaemia in about one third of cases, and a variable proportion of [figure: see text] tumours appear to have activating mutations of the gsp gene or other genetic abnormalities. Acute complications such as carpal tunnel syndrome, sweating and obstructive sleep apnoea are usually readily reversible with treatment of the condition, but chronic complications such as hypertension, diabetes and heart disease are less readily corrected and post-treatment GH levels of < 2.5 ug/L (5 mU/L) are needed to achieve the prevalence found in the general community. Such 'curative' levels of GH are achieved in only about 50% of patients with current therapies, and as a result there is an ongoing excess of patients with chronic complications of acromegaly leading to increased morbidity and mortality from the disorder, with observed-to-expected mortality ratios ranging from 1.6-3.3 and only approaching unity in those with growth hormone levels < 2.5 ug/L following treatment. Prognostic factors include in some studies the presence of diabetes and [table: see text] hypertension prior to diagnosis as well as measures of exposure to excessive growth hormone derived from the product of preoperative serum GH and the time from first symptoms to treatment. Overall, however, the most important prognostic variable appears to be the serum GH concentration achieved by treatment, with an increasing consensus that this needs to be < 2.5 ug/L (5 mU/L) to achieve cure of the condition.

Characteristics of the menstrual cycle at the time of surgery for breast cancer.

Hormone measurements during the menstrual cycle were assessed in six premenopausal women undergoing breast cancer surgery and ten controls to determine whether the stress of diagnosis and surgery influenced cycle characteristics. There was hormonal evidence for normal ovulation in all cancer and control women, although the length of the luteal phase of the cycle was prolonged because of a delay in menstruation in two cancer patients. The timing of surgery in the cycle did not influence the hormonal data. The hormonal characteristics of the menstrual cycle thus appear to be normally preserved in women during the month in which breast cancer surgery is performed.

Seasonal variation in the secretion of mammotrophic hormones in normal women and women with previous breast cancer.

Hormones such as melatonin whose serum concentrations vary seasonally have been previously implicated in the growth of breast cancer. The present study was undertaken to identify possible seasonal variation in a range of mammotrophic hormones which could exert a chronobiologic influence in women with breast tumours. Fifteen premenopausal women with a history of previous breast cancer (BC subjects) and 10 control women underwent 2-hourly serum sampling for 24 h at both summer and winter solstice for measurement of melatonin, growth hormone (GH), insulin-like growth factor-I (IGF-I), cortisol, prolactin and thyrotrophin (TSH). Hormone secretion at the different seasons was compared by measuring the area under the 24 h serum hormone concentration x time curves and by time series analysis of summer-to-winter differences in hormone concentration. Control women had significantly higher GH and IGF-I levels in summer compared to winter and significantly higher cortisol secretion in winter than summer. In contrast, BC women had no significant seasonal difference in IGF-I concentrations and had a reversal of the normal seasonal pattern of melatonin secretion, although seasonal changes in GH production were similar to controls. Prolactin and TSH showed no significant summer/winter variation in either group. Thus, seasonal variations in hormone secretion seen in normal women were, with exception of GH, absent or reversed in women with a previous history of breast cancer. As a result these individuals may be exposed to an asynchronous hormonal stimulus which could influence tumour growth. These changes could reflect a constitutional abnormality in BC women or may have been induced by the previous breast tumour.

Overall survival from breast cancer in women pregnant or lactating at or after diagnosis. Auckland Breast Cancer Study Group.

The effect of concurrent or subsequent pregnancy or lactation has been studied in women with breast cancer to determine if these variables influence prognosis. Information was collected from 382 women potentially capable of bearing children, aged less than 45 years, in the Auckland Breast Cancer Study Group data file, a consecutive series of women diagnosed with breast cancer from 1976 to 1985, with a median follow-up of 10.2 years. The prevalence of both pregnancy at diagnosis and lactation at diagnosis was 2.6%. The incidence of pregnancy subsequent to diagnosis was 3.9%. Women pregnant at the time of breast cancer diagnosis had significantly more advanced disease than non-pregnant patients, and there was a similar trend for women lactating at diagnosis. Overall survival in these women was poor compared with the non-pregnant and non-lactating groups; only 2 of 10 pregnant patients and 0 of 10 lactating patients survived more than 12 years. The adverse outcome for women lactating at diagnosis of their breast cancer persisted despite allowance for nodal status, tumour size and age. However, survival was similar between pregnant and non-pregnant patients when these variables were taken into account. No significant differences in survival were found between those women who had pregnancies subsequent to diagnosis of breast cancer and breast cancer patients who did not become pregnant.

Survival of women with node negative breast cancer in the Auckland region.

AIMS: To assess the effect of prognostic factors on overall survival from node negative breast cancer. METHODS: Information was collected on 1138 node negative breast cancer patients in the Auckland region, diagnosed between 1976 and 1985. Prognostic variables investigated included oestrogen (ER) and progesterone (PR) receptor status, tumour grade, tumour size, body mass index, lactation history and parity. The effects of these variables on overall survival were assessed separately in pre and postmenopausal groups. RESULTS: Over a median follow up time of 10.2 years, improved survival was seen in premenopausal women with PR+ status (p = 0.0007), ER+ status (p = 0.03), positive lactational history (p = 0.03) and low tumour grade (p = 0.04). In postmenopausal women, only ER+ status (p = 0.01) and PR+ status (p = 0.02) were associated with improved survival. Multivariate analysis suggested that positive PR status combined with tumour size provided the best prognostic discrimination in premenopausal women, whereas ER status was the dominant prognostic variable in postmenopausal patients. CONCLUSIONS: For premenopausal node negative women, progesterone receptor status, considered either alone, or together with tumour size, provides the best prognostic prediction of survival. By comparison, oestrogen receptor status is the most important predictor of overall survival in postmenopausal women.