Effect of oral phosphate and alendronate on bone mineral density when given as adjunctive therapy to growth hormone replacement in adult growth hormone deficiency.

BACKGROUND: Adult GH deficiency (AGHD) is associated with osteoporosis, which occurs as the result of reduced sensitivity of the bone and kidney to the effect of PTH. AIM: The aim of the study was to examine the effect of oral phosphate and alendronate therapy on PTH sensitivity, bone turnover, and bone mineral density (BMD) in AGHD patients. METHODS: Forty-four AGHD patients were hospitalized for 24 h, and half-hourly blood and 3-hourly urine samples were collected for PTH, nephrogenous cAMP (marker of renal PTH activity), procollagen type-I amino-terminal propeptide, and type-I collagen ß C-telopeptide. Patients were randomized to one of six groups: patients who were previously naive to GH were randomized to receive GH replacement (GHR) alone, GHR+alendronate, or GHR+phosphate-sandoz, whereas patients already receiving GHR were randomized to continue GHR alone, GHR+alendronate, or GHR+phosphate-sandoz. Study visits were repeated after 1, 3, 6, and 12 months in the previously GH-naive group and after 12 months in the previously GH-replaced group. BMD was measured at 0 and 12 months. RESULTS: Patients receiving GHR+phosphate had greater increases in nephrogenous cAMP and bone markers than patients receiving GHR alone (P < 0.01), and this was associated with greater increases in BMD (P < 0.01). In the GHR+alendronate groups, type-I collagen ß C-telopeptide decreased (P < 0.001), and BMD increases were greater than in those receiving GHR alone (P < 0.05). The greatest increases in BMD were seen in patients receiving GHR+phosphate. CONCLUSIONS: Phosphate and alendronate therapy given in combination with GHR confer advantage in terms of BMD increase. Phosphate appears to exert its effect by increasing PTH target-organ action, whereas alendronate acts primarily through reduction in bone resorption.

Correlation of serum-adjusted calcium with ionized calcium over a 24-h period in patients with adult growth hormone deficiency before and after growth hormone replacement.

BACKGROUND: Difficulties associated with measuring ionized calcium in clinical practice have led to the use of total calcium, with or without adjustment for albumin concentration, as an estimate of calcium metabolism. We examined the correlation between ionized and total/adjusted calcium over a 24-h period in patients with adult growth hormone deficiency (AGHD), a group of patients with previously reported alterations in calcium metabolism. METHODS: Four patients with AGHD were consented to the study. They were hospitalized for 24 h where half-hourly blood samples were collected for ionized calcium, total calcium, albumin and creatinine, before and one month after the commencement of growth hormone replacement. Total calcium concentration was adjusted for serum albumin. RESULTS: Strong correlations were found between ionized calcium and adjusted calcium (r(2) = 0.840 and 0.766 for visits 1 and 2, respectively, P < 0.001), and between ionized calcium and total calcium (r(2) = 0.828 and 0.731 for visits 1 and 2, respectively, P < 0.001). Correlations remained significant during the day (ionized versus adjusted calcium: r(2) = 0.847 and 0.780 for visits 1 and 2, respectively; ionized versus total calcium: r(2) = 0.860 and 0.792 for visits 1 and 2, respectively, all P < 0.001) and at night (ionized versus adjusted calcium: r(2) = 0.831 and 0.802 for visits 1 and 2, respectively; ionized versus total calcium: r(2) = 0.767 and 0.722 for visits 1 and 2, respectively, all P < 0.001). CONCLUSION: The results of our study suggest that total calcium and serum-adjusted calcium can be used in place of ionized calcium as a reliable indicator of calcium metabolism over a 24-h period in patients with AGHD.

Endocrine evaluation of pituitary tumours.

This paper aims to provide a framework for understanding the investigations and management of pituitary adenomas from an endocrinologists viewpoint. The commonest problems, as well as the more controversial issues, are discussed and relevant, interesting papers on the topic are highlighted.

The circadian rhythm of osteoprotegerin and its association with parathyroid hormone secretion.

BACKGROUND: Osteoclast resorptive activity, which is known to demonstrate circadian rhythmicity, is regulated by various endocrine hormones and cytokines. PTH suppresses osteoprotegerin (OPG), a regulator of osteoclast activity that has recently been shown to have a circadian rhythm in healthy controls. We studied the differences in the relationship between PTH, OPG, and type I collagen C-telopeptide (betaCTX) over a 24-h period in premenopausal women, elderly postmenopausal women, and elderly men. METHODS: Hourly peripheral venous blood samples were obtained from 18 healthy non-osteoporotic volunteers: premenopausal women (n = 6; mean age, 30.2 +/- 2.2 yr), postmenopausal women (n = 6; mean age, 68.2 +/- 2.6 yr), and elderly men (n = 6; mean age, 68.2 +/- 2.3 yr). Plasma PTH (1-84), OPG, betaCTX, and calcium were measured on all samples. Cosinor analysis was performed to analyze the circadian rhythm parameters. Cross-correlation analysis was used to determine the relationship between the time series of the variables. RESULTS: The 24-h mean PTH, OPG, and betaCTX concentrations were significantly higher in postmenopausal women as compared with premenopausal women and elderly men (P < 0.001). Significant circadian rhythms were observed for PTH (P < 0.05), OPG (P < 0.05), and betaCTX (P < 0.001) in all subjects. PTH secretion was characterized by two peaks in premenopausal women and elderly men and by a sustained increase in PTH concentration in postmenopausal women. OPG secretion was circadian with a daytime increase and nocturnal decrease, and a greater percent decrease in OPG secretion was observed in the postmenopausal women between 1600 and 2400 h. OPG secretion was inversely related to PTH (r = -0.4) and betaCTX (r = -0.6) secretion over a 24-h period. CONCLUSION: This report confirms a circadian rhythm for circulating OPG. The nocturnal decline in circulating OPG is greater in postmenopausal women as compared with premenopausal women and elderly men. Altered PTH secretion may contribute to the OPG secretory pattern in postmenopausal women resulting in increased nocturnal bone resorption.

Effect of active acromegaly and its treatment on parathyroid circadian rhythmicity and parathyroid target-organ sensitivity.

CONTEXT: Patients with active acromegaly have increased bone turnover and skeletal abnormalities. Biochemical cure of acromegaly may represent a functional GH-deficient state and result in cortical bone loss. Reduced PTH target-organ sensitivity occurs in adult GH deficiency and may underlie the associated development of osteoporosis. OBJECTIVE: We examined the effect of active and treated acromegaly on PTH concentration and target-organ sensitivity. PATIENTS: Ten active acromegalic subjects (GH nadir > 0.3 mug/liter after 75-g oral glucose load and IGF-I above age-related reference range) and 10 matched controls participated in the study. DESIGN: Half-hourly blood and 3-h urine samples were collected on patients and controls for 24 h. Samples were analyzed for PTH, calcium (Ca), nephrogenous cAMP (NcAMP, a marker of PTH renal activity), beta C-telopeptide (bone resorption marker), and procollagen type-I amino-terminal propeptide (bone formation marker). Serum calcium was adjusted for albumin (ACa). Eight acromegalic subjects who achieved biochemical cure (GH nadir < 0.3 mug/liter after 75-g oral glucose load and IGF-I within reference range) after standard surgical and/or medical treatment reattended and the protocol repeated. RESULTS: Active acromegalic subjects had higher 24-h mean PTH, NcAMP, ACa, urine Ca, beta C-telopeptide, and procollagen type I amino-terminal propeptide (P < 0.05), compared with controls. Twenty-four-hour mean PTH increased (P < 0.001) in the acromegalic subjects after treatment, whereas NcAMP and ACa decreased (P < 0.05). CONCLUSION: Increased bone turnover associated with active acromegaly may result from increased PTH concentration and action. Biochemical cure of acromegaly results in reduced PTH target-organ sensitivity indicated by increased PTH with decreased NcAMP and ACa concentrations. PTH target-organ sensitivity does not appear to return to normal after successful treatment of acromegaly in the short term and may reflect functional GH deficiency.

Growth hormone replacement is important for the restoration of parathyroid hormone sensitivity and improvement in bone metabolism in older adult growth hormone-deficient patients.

Alterations in PTH circadian rhythm and PTH target-organ sensitivity exist in adult GH-deficient (AGHD) patients and may underlie the pathogenesis of AGHD-related osteoporosis. GH replacement (GHR) results in increased bone mineral density, but its benefit in AGHD patients over 60 yr old has been debated. To examine the effect of age on changes in PTH circadian rhythm and target-organ sensitivity after GHR, we recruited 22 AGHD patients (12 were <60 yr of age, and 10 were >60 yr of age). Half-hourly blood samples were collected for PTH, calcium, phosphate, nephrogenous cAMP (marker of renal PTH activity), type-I collagenbeta C-telopeptide (bone resorption marker), and procollagen type-I amino-terminal propeptide (bone formation marker) before and after 1, 3, 6, and 12 months of treatment with GHR. Significant PTH circadian rhythms were present in both age groups throughout the study. After GHR, PTH decreased and nephrogenous cAMP, adjusted calcium, and bone turnover markers increased in both groups, suggesting increased PTH target-organ sensitivity. In younger patients, the changes were significant after 1 month of GHR, but, in older patients, the changes were delayed until 3 months, with maximal changes at 12 months. Older AGHD patients derive benefit from GHR in terms of improvement in PTH sensitivity and bone metabolism. Their response appears delayed and may explain why previous studies have not shown a positive effect of GHR on bone mineral density in older AGHD patients.

Gender variation in PTH sensitivity and rhythmicity following growth hormone replacement in adult growth hormone-deficient patients.

BACKGROUND: Adult GH deficiency (AGHD) is associated with osteoporosis and reduced bone turnover; factors improved by GH replacement (GHR), with men gaining greater benefit than women. Reduction in sensitivity of bone and kidney to the effects of PTH may underlie AGHD changes in bone turnover. We determined the gender difference in PTH target-organ sensitivity following GHR in AGHD patients. DESIGN, PATIENTS AND MEASUREMENTS: Twenty AGHD patients (10 men) were admitted to hospital before and after GHR initiation. Half-hourly blood samples were collected for PTH, calcium, nephrogenous cyclic AMP (NcAMP, marker of PTH activity), type-I collagen C-telopeptide (CTX, bone resorption marker) and procollagen type-I amino-terminal propeptide (PINP, bone formation marker). RESULTS: The 24-h mean PTH concentration decreased in both genders (P < 0.001), with maximal changes seen 6 and 12 months following GHR in men and women, respectively. Increases in 24-h mean NcAMP (P < 0.05), calcium (P < 0.001) and bone turnover markers (P < 0.001) occurred in both genders following GHR, with maximal changes at 1 month in men, but at 3 months for NcAMP, calcium and CTX and 12 months for PINP in women. Maximal NcAMP increase was higher in men (P = 0.009). CONCLUSIONS: Following GHR, PTH target-organ sensitivity increased in both genders, demonstrated by simultaneous reduction in PTH concentration and increase in NcAMP, calcium and bone turnover. In women, improvement in renal PTH sensitivity was delayed and reduced, and changes in bone turnover were delayed, with increase in bone resorption preceding bone formation. Both factors may contribute to the reduced bone mineral density (BMD) response to GHR observed in women.

Incidence of sight-threatening retinopathy in Type 1 diabetes in a systematic screening programme.

AIM: To measure the cumulative incidence of any retinopathy, maculopathy and sight-threatening diabetic retinopathy (STDR), and calculate optimal screening intervals by retinopathy grade at baseline for patients with Type 1 diabetes attending an established systematic retinal screening programme. METHODS: All patients with Type 1 diabetes registered with enrolled general practitioners, excluding only those attending an ophthalmologist, were studied if retinopathy data was available at baseline and at least one further screen event. Screening utilized non-stereoscopic 3-field mydriatic photography and modified Wisconsin grading. STDR was defined as moderate pre-proliferative retinopathy or greater and/or significant maculopathy in any eye. RESULTS: Patients (n=501) underwent 2742 screen events. Cumulative incidence of STDR in patients without baseline retinopathy was 0.3% (95% CI 0.0-0.9) at 1 year, rising to 3.9% (1.4-5.4) at 5 years. Rates of progression to STDR in patients with background and mild pre-proliferative retinopathy at 1 year were 3.6% (0.5-6.6) and 13.5% (4.2-22.7), respectively. Progression to STDR was greater in patients with a higher grade of baseline retinopathy (P=0.001) or a longer disease duration (P=0.003). For a 95% likelihood of remaining free of STDR, mean screening intervals by baseline status were: no retinopathy 5.7 (95% CI 3.5-7.6) years, background 1.3 (0.4-2.0) years and mild pre-proliferative 0.4 (0-0.8) years. CONCLUSIONS: Screening at 2-3 year intervals, rather than annually, for patients without retinopathy in Type 1 diabetes is feasible because of the low risk of progression to STDR, and may result in significant cost savings for a screening programme. Patients with higher grades of retinopathy require screening at least annually or more frequent.

Ambulatory photographic screening for diabetic retinopathy in nursing homes.

PURPOSE: To evaluate the feasibility and cost of screening for diabetic eye disease in homebound nursing home residents not attending a systematic screening programme. METHODS: Postal survey identification of residents with diabetes in all nursing homes in Liverpool. An ophthalmologist and nurse performed Bailey-Lovie logmar visual acuity (VA), portable slit-lamp examination, fundus photography, and subjective assessment of ability to cooperate with treatment in a sample of homes. Modified Wisconsin photographic grading was performed. Screen-positive patients were invited to a dedicated assessment clinic. Sight-threatening diabetic eye disease (STED) was defined as any of: moderate preproliferative retinopathy or worse, circinate maculopathy, or exudate within 1 disc diameter of fixation. RESULTS: A total of 54 (78%) nursing homes responded reporting 199/2427 (8.2%) residents with diabetes. Of these, 64/80 (80%) residents in 17 homes were examined: VA possible in 50 (78%); slit-lamp examination in 56 (88%); gradable photographs in at least one eye in 34 (53%); STED in 12 (35%) patients. In all, 35 (70%) patients had Snellen-equivalent VA worse than 6/12 in the better eye, of whom 13 (26%) were worse than 6/60. Of 29 screen positive patients, 12 attended the assessment clinic: one was unable to cooperate outside the home; 11 continue under ophthalmic review, four for previously undetected STED of which one listed for laser photocoagulation. Total cost pound 16,980; cost per screen event pound 60.30. CONCLUSIONS: Systematic eye screening in homebound patients with diabetes detects disease but follow-up and treatment is only feasible in a small proportion and at high cost. Alternative targeted assessment is recommended.

Effects of adult growth hormone deficiency and growth hormone replacement on circadian rhythmicity.

In health, growth hormone (GH) is secreted in a circadian rhythm with superimposed pulsatility. Temporal fluctuations of hormone concentrations are essential for physiological action, and loss of diurnal rhythm is important in the development of disease. GH feedback occurs through the hypothalamus and involves neuropeptides such as somatostatin, GH-releasing hormone, GH-releasing peptides and neuropeptide Y. In addition, the same neuropeptides are involved in the regulation of other hormone axes and biological systems, thus, establishing a link through which regulation by GH may occur. Clinical features of adult growth hormone deficiency (AGHD) include abnormal body composition, reduction in quality of life, osteoporosis and increased risk of cardiovascular mortality. In health, many of the factors which regulate these features demonstrate circadian rhythmicity and pulsatility. Furthermore, AGHD is associated with abnormalities in the periodic variation of such controlling factors. GH replacement therapy, administered in the form of timed, intermittent subcutaneous injections, results in improvement of many of the clinical effects of AGHD, and is associated with normalization of the temporal fluctuations. Currently, there remains scope for further investigation of the effects of AGHD and subsequent GHR on the circadian rhythmicity of many hormones and systems; and additional studies are required to understand the physiological significance of the changes observed to date.

Gender variation in leptin circadian rhythm and pulsatility in adult growth hormone deficiency: effects of growth hormone replacement.

OBJECTIVES: Adult growth hormone deficiency (AGHD) is characterized by obesity and associated with increased leptin concentration and decreased leptin pulsatility. Growth hormone replacement (GHR) results in a decrease in leptin concentration and increase in leptin pulsatility, followed by reduction in body fat mass (BFM). In both health and AGHD, women exhibit relatively higher leptin concentrations compared to men. The effect of gender on leptin rhythm and pulse parameters in AGHD is yet to be defined and the gender difference in the response of leptin secretory pattern to GHR has not been determined. Therefore the aim of this study was to evaluate the effect of gender on circadian and pulse parameters of leptin secretion in AGHD, and examine the gender variation in response of these parameters to GHR. STUDY DESIGN: A prospective, open treatment design study to determine the effect of gender on leptin rhythm and pulse parameters in untreated and treated AGHD. GH was commenced at a daily dose of 0.5 IU, and titrated up by increments of 0.25 IU at 2-weekly intervals to achieve and maintain IGF-I SDs between the median and upper end of the age-related reference range. PATIENTS: Twelve patients (six men, six women) with severe AGHD following pituitary surgery, defined as peak GH response < 9 mU/l to provocative testing were studied. All patients required additional pituitary replacement hormones following pituitary surgery and were on optimal doses at recruitment. MEASUREMENTS: Plasma leptin was measured at half-hourly intervals for 24 h, before and 1 month after initiation of GHR. Cosinor analysis was used to determine the circadian rhythm parameters: MESOR (rhythm-adjusted mean), acrophase and amplitude; and ULTRA algorithm used for pulse analysis. Body composition was measured using bioelectrical impedance. RESULTS: BFM was higher in women than men at both visits (P < 0.05), but there was no significant change in BFM in either gender following 1 month of GHR. Women had a higher mean 24-h leptin concentration, MESOR, circadian amplitude and pulse amplitude, both before and after GHR (P < 0.05). Following treatment, mean leptin concentration and MESOR decreased significantly in both men and women (P < 0.05), with no significant difference in percentage change between the genders. Pulse frequency increased and duration decreased significantly after GHR in both groups, without any significant gender difference. IGF-I and IGF SDs were similar in both genders at baseline (P = 0.93). However, after 1 month GHR, the increase in both measurements was greater in men than women (P = 0.005) and men had significantly higher IGF-I and IGF SDs than women (P = 0.01). CONCLUSIONS: As in healthy individuals, leptin levels were higher in women with AGHD than men, both prior to and after GHR. Decline in leptin concentrations and increase in leptin pulsatility following 1 month of GH treatment were similar in both genders. Changes in leptin secretory parameters appeared to occur without any significant decrease in BFM, suggesting a regulatory role for GH. Additionally, the action of GH on leptin secretory pattern does not appear to be mediated by IGF-I. Our data suggest that changes in leptin concentration and rhythm parameters following GHR are independent of gender.

Parathyroid hormone secretory pattern, circulating activity, and effect on bone turnover in adult growth hormone deficiency.

Adult growth hormone deficiency (AGHD) is associated with osteoporosis. Reports have associated parathyroid hormone (PTH) circadian rhythm abnormalities with osteoporosis. Furthermore, there is evidence of relative PTH insensitivity in AGHD patients. Factors regulating PTH circadian rhythm are not fully understood. There is evidence that serum phosphate is a likely determinant of PTH rhythm. The aim of this study was to investigate PTH circadian rhythm and its circulating activity and association with bone turnover in untreated AGHD patients compared to healthy individuals. We sampled peripheral venous blood at 30-min and urine at 3-h intervals during the day over a 24-h period from 1400 h in 14 untreated AGHD patients (7 M, 7 W; mean age, 49.5 +/- 10.7 years) and 14 age (48.6 +/- 11.4 years; P = NS) and gender-matched controls. Cosinor analysis was performed to analyze rhythm parameters. Cross-correlational analysis was used to determine the relationship between variables. Serum PTH (1-84), phosphate, total calcium, urea, creatinine, albumin, type I collagen C-telopeptides (CT(x)), a bone resorption marker, and procollagen type I amino-terminal propeptide (PINP), a bone formation marker, were measured on all samples. Nephrogenous cyclic adenosine monophosphate (NcAMP), which reflects the renal activity of PTH, was calculated from plasma and urinary cAMP. Urinary calcium and phosphate were measured on all urine samples. Significant circadian rhythms were observed for serum PTH, phosphate, CT(x), and PINP in AGHD and healthy subjects (P < 0.001). No significant rhythm was observed for serum-adjusted calcium. PTH MESOR (rhythm-adjusted mean) was significantly higher (P < 0.05), whereas the MESOR values for phosphate, CT(x) (P < 0.05), and PINP (P < 0.001) were lower in AGHD patients than in controls. AGHD patients had significantly lower 24-h NcAMP (P < 0.001) and higher urinary calcium excretion (P < 0.05). Maximum cross-correlation between PTH and phosphate (r = 0.75) was observed when PTH was lagged by 1.5 h in healthy individuals, suggesting that changes in phosphate precede changes in PTH concentration. PTH/CT(x) and PTH/PINP showed maximum correlation when CT(x) (r = 0.68) and PINP (r = 0.71) were lagged by 3 h. In AGHD patients, compared to controls the maximum correlation between PTH/phosphate (r = 0.88, P = 0.007), PTH/CTx (r = 0.61, P = 0.027), and PTH/PINP (r = 0.65, P = 0.028) was observed when the lag time was reduced by 1.5 h in all variables, with changes in PTH and phosphate occurring at concurrent time points. Our data suggest decreased end-organ sensitivity to the effects of PTH in AGHD patients, resulting in a significantly lower NcAMP, low bone turnover, and higher calcium excretion in the presence of significantly higher PTH concentrations. We have also demonstrated that changes in serum phosphate precede those of PTH, which in turn precede changes in bone resorption and formation in healthy individuals. This relationship was altered in AGHD patients. These results suggest a possible role for GH in regulating PTH secretion and the bone remodeling process.

Current status of screening for diabetic retinopathy in the UK.

This article reviews the current status of retinopathy screening schemes in the UK. There is evidence that high-quality diabetic retinopathy screening schemes are in existence but provision is patchy. Many health authorities have ad hoc screening programmes reaching only about 60% of patients, with unacceptable or undocumented efficacy and minimal quality control. Several models of screening are currently in use with the current preferred option being camera-based screening. Digital imaging systems offer the best prospects for image acquisition, although at present evidence of adequate effectiveness only exists for 35 mm film-based systems. The final report of the National Diabetic Retinopathy Screening Programme commissioned by the UK National Screening Committee for inclusion into the national service framework for diabetes, is thus eagerly awaited and should set standards for screening programmes, in order to improve the care of all those with diabetes. Quality assurance will be the main driver in the immediate future of improvements in screening programmes. Research data will provide the evidence to refine techniques and set targets in the longer term, with the emphasis on cost-effectiveness and quality of life.

The role of somatostatin receptor scintigraphy in the management of pituitary tumours.

The detection of functioning neuroendocrine tissue bearing somatostatin receptors has been facilitated to a large extent by the availability of radiolabelled octreotide scanning with 111In octreotide. This review discusses the possible role for somatostatin receptor scintigraphy (SRS) in the evaluation of pituitary adenomas.

Circadian and ultradian rhythm and leptin pulsatility in adult GH deficiency: effects of GH replacement.

Leptin contributes to the regulation of body weight in healthy individuals and is secreted by adipocytes in a diurnal pattern, with superimposed pulsatility. The circulating leptin concentration is increased in both normally obese and untreated adult GH deficiency, a syndrome characterized by increased adiposity. Leptin circadian rhythm is preserved in adult GH deficiency patients; however, an ultradian rhythm and pulsatility has previously not been reported. Alterations in plasma leptin concentration in obese individuals and adult GH deficiency patients after GH replacement have been attributed to changes in body fat mass. In our present study leptin circadian and ultradian rhythm, leptin pulsatility and its relationship with body fat mass were examined in 12 adult GH deficiency patients (6 men) before and 1 month after GH replacement. All subjects with adult GH deficiency had hypopituitarism subsequent to pituitary surgery and were stabilized on conventional pituitary hormone replacement. Plasma leptin was measured over 24 h at 30-min intervals, and changes in body composition were recorded using bioelectrical impedance. The 24-h mean leptin concentration decreased from 2.04 +/- 0.04 nmol/liter in untreated adult GH deficiency patients to 1.64 +/- 0.03 nmol/liter after 1 month of GH replacement (P < 0.0001). Before GH replacement, patients demonstrated a significant mean leptin circadian rhythm (P < 0.001), with a mesor of 2.05 +/- 0.03 nmol/liter and a superimposed ultradian frequency of 2.0 +/- 0.1 cycles/d. After GH replacement, the circadian rhythm was preserved (P < 0.001), but mesor decreased to 1.65 +/- 0.01 nmol/liter (P < 0.0001), and leptin ultradian frequency increased to 16.0 +/-0.2 cycles/d (P < 0.0001). Pulse analysis (ULTRA) revealed 3.1 +/- 0.9 pulses/24 h in untreated adult GH deficiency patients, which significantly increased to 9.9 +/- 2.2 pulses/24 h after 1 month of GH replacement (P < 0.001). There was no significant change in body mass index or body fat mass after 1 month of GH replacement. The body fat percentage significantly reduced from 36.5 +/- 2.8% to 35.5 +/- 2.7% after 1 month of GH replacement (P < 0.05). This change in body fat percentage was explained by a significant increase in lean body mass, from 56.2 +/- 2.8 kg at baseline to 57.4 +/- 2.7 kg after 1 month (P < 0.05). A significant correlation was observed between plasma leptin and body fat percentage at baseline and 1 month after GH replacement (both, r = 0.7; P < 0.01) in the absence of a significant correlation between leptin and body fat mass before and after GH replacement (P = 0.13 and P = 0.11, respectively). Thus, untreated adult GH deficiency is associated with elevated 24-h leptin concentration, preserved circadian rhythm, and decreased pulsatility. The secretory pattern is restored after GH replacement, with a significant reduction in the 24-h mean leptin concentration, maintenance of circadian rhythm, and increased pulsatility. This GH-induced change in the leptin secretory pattern precedes significant changes in body fat mass and may therefore be independent of changes in adipose tissue. Restoration of leptin pulsatility may be of clinical benefit, and our data could lead to novel approaches for leptin manipulation in the future.

Body composition and quality of life in adults with growth hormone deficiency; effects of low-dose growth hormone replacement.

OBJECTIVE: Adult growth hormone deficiency (AGHD) is characterized by abnormalities in body composition and a poor perceived quality of life (QoL). Weight-based high-dose growth hormone replacement (GHR) results in improvements in body composition and QoL in AGHD. However, a high patient percentage reported side-effects on high-dose GHR resulting in a high rate of patient withdrawal from growth hormone (GH) treatment. High-dose GH therapy also leads to supraphysiological serum insulin-like growth factor-I (IGF-I) concentrations that have been associated with breast and prostate cancer, raising major concerns over the use of such high-dose GH regimen in AGHD. The aim of this study was to assess the effects of low-dose growth hormone replacement (GHR) on body composition and QoL as early as 1 and 3 months. STUDY DESIGN: A prospective, open treatment design study to determine the early effects of low-dose GH administration on body composition and QoL. GH was initiated at a daily dose of 0.4-0.5 IU, and titrated up to achieve and maintain IGF-I standard deviation score (IGF-I SDS) between the median and upper end of the age-related reference range. PATIENTS: Forty-six, post-pituitary surgery, severe AGHD patients (22 women), defined as peak GH response < 9 mU/l to provocative testing. The mean age was 50.4 years (range 26-72). Forty-three patients required additional pituitary replacement hormones following pituitary surgery and were on optimal doses at recruitment. MEASUREMENTS: Body composition and QoL were assessed prior to GHR and subsequently at 1 and 3 months after initiating GHR. Body mass index (BMI) and waist hip ratio (WHR) were calculated from measurements of height, weight, and waist and hip circumference, respectively. Bioelectrical impedance analysis (BIA) was used to determine body fat and lean body mass. QoL was assessed using the disease-specific 'QoL-assessment of growth hormone deficiency in adults (QoL-AGHDA)' questionnaire. Serum IGF-I was measured at each visit to assess the adequacy of GHR. RESULTS: IGF-I and IGF-I SDS increased significantly at 1 and 3 months (P < 0.001) after commencing GHR. The increase in IGF-I (P < 0.05) and IGF-I SDS (P < 0.01) was significant between 1 and 3 months in the absence of any significant increase in GH dose (P = ns) during this period. Eighty-five per cent of patients achieved IGF-I SDS levels between median and upper end of the age-related reference range after 3 months of GHR, and no side-effects were reported during this period. There was a significant reduction in body fat percentage (BFP) from 36.1 +/- 9.1% at baseline to 34.9 +/- 9.3% (P < 0.01) at 1 month and 34.1 +/- 9.2% (P < 0.001) at 3 months. Body fat mass (BFM) reduced from 32.8 +/- 13.6 kg at baseline to 31.9 +/- 13.9 kg at 1 month (P < 0.05) and 31.1 +/- 13.6 kg at 3 months (P < 0.001). These changes in BFP and BFM occurred in the absence of any significant change in BMI and WHR (P = ns). Lean body mass (LBM) was 55.9 +/- 11.1 kg at baseline and increased to 57.1 +/- 11.3 kg after 1 month (P < 0.01) and to 57.6 +/- 11.5 kg (P < 0.001) after 3 months of GHR. Significant improvement was observed in the perceived QoL with the AGHD assessment scores reducing from 13.3 +/- 6.4 to 11.5 +/- 6.6 within 1 month (P < 0.01) and 10.0 +/- 6.6 at 3 months (P < 0.001). There was no significant correlation between improvement in QoL and changes in body fat percentage (r = 0.01 at 1 month and r = 0.12 at 3 months, P = ns) or IGF-I levels (r = 0.04 and r = 0.003, P = ns at 1 and 3 months, respectively). The improvement in body composition and QoL was significant between 1 and 3 months. CONCLUSIONS: Low-dose GHR improves body composition and QoL as early as 1 month after commencement and the beneficial effects continue at 3 months. Most importantly, these changes occur in the absence of side-effects. We therefore suggest the use of low-dose GH therapy, maintaining IGF-I between the median and upper end of the age-related reference range, for the treatment of AGHD.

Beta blocker prescribing differences in patients with and without diabetes following a first myocardial infarction.

AIMS: To document the prescribed usage of beta blockers in patients with and without diabetes mellitus discharged from hospital following a first myocardial infarction. METHODS: All patients with diabetes and a group of patients matched for age and sex without diabetes, admitted with a documented first myocardial infarction during the period 1995-1999 at the Royal Liverpool University Hospital, Liverpool, UK were audited. RESULTS: Data were available on 201 patients with diabetes and 199 patients without diabetes. No significant differences existed between the diabetic and non-diabetic groups for age and sex. Twenty-three per cent of patients with diabetes were prescribed a beta blocker compared to 52% of non-diabetic patients (P < 0.01). Patients with diabetes had a higher frequency of perceived contraindications than patients without diabetes (36 vs. 27%, P < 0.001). Thirty-five per cent of patients with diabetes and 18% of non-diabetic patients had no contraindication to the use of beta blocker but were not prescribed one (P < 0.001). CONCLUSIONS: Although beta blockers can provide useful benefits in patients with diabetes following a myocardial infarction, this study suggests that a significant proportion of patients with diabetes and without a contraindication to treatment are still not receiving beta blockers after myocardial infarction.

Responding to the challenge of diabetic nephropathy: the historic evolution of detection, prevention and management.

Diabetic nephropathy remains a leading cause of end-stage renal disease (ESRD) in western societies, accounting for about 40% of all patients beginning renal replacement therapy. Patients with type 2 diabetes comprise the largest and fastest growing single disease group requiring renal replacement therapy. In addition to the high risk of progression to ESRD, diabetic nephropathy is associated with a very high risk of cardiovascular (CV) morbidity and mortality, which is not abolished by dialysis or renal transplantation. Over the past two decades there have been major advances in our attempts to understand the risk factors for development and progression of diabetic renal dysfunction, that have resulted in better characterisation of the natural history of this serious complication. Effective antihypertensive treatment and aggressive management of CV risk factors have helped improve the prognosis of patients with overt diabetic nephropathy, particularly those with type 1 diabetes. However, for the larger proportion of patients with type 2 diabetes, the renal and CV prognoses are still poor. Recently, more focus has been placed on treating diabetic patients early in order to prevent future organ damage. Microalbuminuria is an important intermediary end-point that correlates strongly with CV mortality in all people with diabetes as well as progression to ESRD in people with type 1 diabetes. We can now identify patients at high risk early in the natural history of their disease. Clinical trials have uniformly shown that in the early disease history of diabetes, achievement of both tight glucose control, eg, HbA1c <7%, and tight blood pressure control eg, blood pressure <140/80 mm Hg, substantially reduces CV events and progression of nephropathy. In latter stages of diabetes, tight blood pressure control has a relatively greater impact on CV risk reduction as compared to tight glucose control. The challenge for the practising physician, however, is to maximally utilise the available modalities of treatment to prevent progression to overt nephropathy and reduce the associated high risk of CV morbidity and mortality. In the early 21st century, the patient with type 2 diabetes will need to be the specific focus for use of these preventive treatment modalities due to the geometric risk in the international incidence of this disease.

Prevalence of diabetic eye disease in an inner city population: the Liverpool Diabetic Eye Study.

PURPOSE: To measure the population prevalence of diabetic eye disease in an inner city setting. METHODS: As part of a systematic screening programme all adult diabetic patients in four general practices were invited to attend for slit-lamp biomicroscopy by a retinal specialist. Data on non-attenders were available from community-based photography. RESULTS: Of 395 diabetic patients identified, 326 attended biomicroscopy with photographic data available on a further 31, giving a 90% compliance rate. Point prevalence of diabetes in the target population was 12.4/ 1000. Demographic data included: mean age 60 years (range 13-92 years); type of control: type I 49, type II insulin-requiring (IR) 40, type II non-insulin-requiring (NIR) 268. Prevalences were as follows: any retinopathy: of all diabetic patients 33.6%, type I 36.7%, type II IR 45.0%, type II NIR 31.3%; proliferative/ advanced: all 1.1%, type I 2.0%, type II IR 0, type II NIR 1.1%; clinically significant macular oedema: all 6.4%, type I 2.3%, type II IR 16.2%, type II NIR 5.7%. The percentage of patients with retinopathy requiring follow-up by an opthalmologist was 4.5%, and 9.2% had macular exudates within 1 disc diameter of fixation or significant circinate maculopathy. Sight-threatening diabetic eye disease (STED) was found in 13.4%. A visual acuity of < or = 6/24 in the better eye occurred in 12 (3.4%) patients and of < or = 6/60 in the better eye in 3 (0.8%). CONCLUSIONS: Compared with previous population studies, prevalences appear to have declined in type I, but remain high in type II diabetic patients and especially in those requiring insulin.