Celina Franco

Effect of Surgery on Cardiovascular Risk Factors in Mild Primary Hyperparathyroidism

CONTEXT Mild primary hyperparathyroidism (pHPT) seems to have a good prognosis, and indications for active treatment (surgery) are widely discussed. The extraskeletal effects of PTH, such as insulin resistance, arterial hypertension, and cardiovascular (CV) risk, may however be reversible by operation. OBJECTIVE Our aim was to study biochemical markers of bone turnover, indices of the metabolic syndrome, and various risk markers for CV disease in patients with mild pHPT randomized to observation without surgery or operative treatment and followed for 2 yr. DESIGN/SETTING/PATIENTS A total of 116 patients (mean age, 63 +/- 8 yr; 19 men and 97 women) who on May 1, 2008, had performed the 2-yr visit in a randomized study on mild pHPT (serum calcium at baseline, 2.69 +/- 0.11 mmol/liter) and where frozen samples were available from baseline and follow-up participated in the study. RESULTS Calcium and PTH levels were normalized after surgery, and biochemical markers of bone turnover decreased by 35%, followed by a significant increase in BMD in the spine (2.7%; P < 0.01) and femoral neck (1.1%; P < 0.02) compared with the observation group. No significant differences were observed between the groups for blood pressure, markers of insulin resistance, detailed cholesterol metabolism, adipokines, or parameters of inflammation and CV surrogate markers. CONCLUSIONS We observed expected effects on biochemical markers of bone turnover and bone mass after surgical treatment of mild pHPT, with stable values in the group randomized to observation. For a variety of measures of the metabolic syndrome, adipokines, and CV risk factors, no benefit of operative treatment could be demonstrated. Neither did we observe any deleterious effects of conservative management in the 2-yr perspective.

Effect of surgery on cardiac structure and function in mild primary hyperparathyroidism

Context  The cardiovascular (CV) risk profile is worsened in primary hyperparathyroidism (PHPT), and CV mortality is related to serum calcium levels. It is unknown whether CV mortality is increased in the most common form of PHPT and whether the increased CV risk is reversible after surgery.

The GH/IGF-1 Axis in Obesity: Physiological and Pathological Aspects.

The cluster of cardiovascular risk factors-abdominal obesity, dyslipidaemia, insulin resistance and hypertension-has been recognized as the core of the metabolic syndrome. Adults with severe growth hormone (GH) deficiency have, to a large extent, features of the metabolic syndrome, and there is a strong inverse association between visceral fat accumulation and blunted GH secretion in adults. Hyposomatotropism in abdominal obesity has therefore been suggested to be of importance for its metabolic consequences. However, the underlying pathophysiological mechanisms are poorly understood. Prevalence of the metabolic syndrome is steadily increasing worldwide. Overnutrition and sedentary habits are the stigmata of modern society that predispose genetically susceptible individuals to develop central obesity and other features of the metabolic syndrome including glucose intolerance, hypertension and dyslipidemia. Although there are still no unified definitions of the syndrome, it is clear that this condition is associated with an increased risk for development of cardiovascular disease (CVD) and diabetes mellitus (DM). In this review, we discuss current evidence regarding alterations in the GH-IGF- 1 axis in abdominal obesity and its possible impact on other features of the metabolic syndrome.

Visceral obesity and the role of the somatotropic axis in the development of metabolic complications.

It is well recognized that aberrant fat localization such as visceral obesity rather than total body fat mass is a major risk factor for cardiovascular disease and type 2 diabetes mellitus. During recent decades, several studies have described a range of metabolic disturbances associated with abdominal obesity, including glucose intolerance, hyperinsulinaemia, insulin resistance, hypertension and dyslipoproteinaemia, now widely known as the metabolic syndrome. Several abnormalities in the hypothalamic-pituitary axis have been described associated with visceral obesity, suggesting a central neuroendocrine dysregulation including increased cortisol concentration and impaired gonadotropin and growth hormone (GH) secretion. Some steps in the chain of events in this theory still remain unclear, however, although these findings have introduced new therapeutic possibilities. These include therapy with sex steroids in both viscerally obese men and women, and several attempts to use GH to treat the endocrine abnormalities present in visceral obesity. The results of these studies are promising, but the therapies are still not recommended for general use.

Effects of 3-year GH replacement therapy on bone mineral density in younger and elderly adults with adult-onset GH deficiency

Objective Little is known of the effects of long-term GH replacement on bone mineral content (BMC) and bone mineral density (BMD) in elderly GH-deficient (GHD) adults. Design/patients/methods In this prospective, single-center, open-label study, the effects of 3-year GH replacement were determined in 45 GHD patients >65 years and in 45 younger control GHD patients with a mean age of 39.5 (s.e.m. 1.1) years. All patients had adult-onset disease and both groups were comparable in terms of number of anterior pituitary hormonal deficiencies, gender, body mass index, and waist:hip ratio. Results The mean maintenance dose of GH was 0.24 (0.02) mg/day in the elderly patients and 0.33 (0.02) mg/day in the younger GHD patients (P<0.01). The 3 years of GH replacement induced a marginal effect on total body BMC and BMD, whereas femur neck and lumbar (L2–L4) spine BMC and BMD increased in both the elderly and the younger patients. The treatment response in femur neck BMC was less marked in the elderly patients (P<0.05 vs younger group). However, this difference disappeared after correction for the lower dose of GH in the elderly patients using an analysis of covariance. There were no between-group differences in responsiveness in BMC or BMD at other skeletal locations. Conclusions This study shows that GH replacement increases lumbar (L2–L4) spine and femur neck BMD and BMC in younger as well as elderly GHD patients. This supports the notion that long-term GH replacement is also useful in elderly GHD patients.

The reduction in visceral fat mass in response to growth hormone is more marked in men than in oestrogen-deficient women

CONTEXT Women with severe growth hormone (GH) deficiency have a less marked response to GH replacement than men. This has mostly been attributed to the attenuating effects of oestrogen replacement therapy. OBJECTIVE To study gender related differences in the response to GH treatment in men and postmenopausal women. METHODS Fifteen men and 15 age- and BMI-matched women with abdominal obesity (mean age: 58; range 51-64 years) were treated for one year with similar doses (0.47 vs. 0.51 mg/day) of GH. All women were postmenopausal not receiving oestrogen treatment. Insulin sensitivity was assessed using a hyperinsulinemic euglycemic clamp and body composition by computed tomography (CT) scans and from total body potassium, K(40). RESULTS Men and women were comparable at baseline in terms of waist circumference, IGF-1 and lipid levels. After one year of GH treatment, there was a 18% reduction in visceral adipose tissue (VAT) in men and a 5% reduction in women (P=0.0001 men vs. women). Although the magnitude of the difference was small, men increased more in thigh muscle mass (P<0.0001 vs. women). A reduction in thigh intermuscular adipose tissue (IMAT) and diastolic blood pressure was seen only in men (both p<0.05 vs. baseline). A decrease in LDL cholesterol, and an increase in serum insulin, was observed only in women (both p<0.05 vs. baseline). CONCLUSION Low dose GH treatment reduced VAT more markedly in men as compared with women. As all women were postmenopausal and oestrogen-deficient, this gender difference in responsiveness was not due to an antagonistic effect of oestrogen on peripheral GH action.

P23 Effects of 3-year growth hormone (GH) replacement therapy on bone mineral density in younger and elderly adults with adult onset GH deficiency

Objective: Little is known of the effects of long-term GH replacement on bone mineral content (BMC) and bone mineral density (BMD) in elderly GH deficient (GHD) adults. Design/Patients/Methods: In this prospective, single-centre, open-label study, the effects of 3-year GH replacement were determined in 45 GHD patients above 65 years of age and in 45 younger control GHD patients with a mean age of 39.5 (SEM 1.1) years. All patients had adult onset disease and both groups were comparable in terms of number of anterior pituitary hormonal deficiencies, gender, body mass index (BMI), and waist:hip ratio. Results: The mean maintenance dose of GH was 0.24 (0.02) mg/day in the elderly patients and 0.33 (0.02) mg/day in the younger GHD patients (p<0.01). The three years of GH replacement induced a marginal effect on total body BMC and BMD whereas femur neck and lumbar (L2-L4) spine BMC and BMD increased in both the elderly and the younger patients. The treatment response in femur neck BMC was less marked in the elderly patients (p<0.05 vs. younger group). However, this difference disappeared after correction for the lower dose of GH in the elderly patients using an analysis of covariance. There were no between-group differences in responsiveness in BMC or BMD at other skeletal locations. Conclusions: This study shows that GH replacement increases lumbar (L2-L4) spine and femur neck BMD and BMC in younger as well as elderly GHD patients. This supports that long-term GH replacement is useful also in elderly GHD patients. Page 2 of 29