Hypopituitarism

Regardless of adequate hormonal replacement therapy including growth hormone (GH) replacement therapy, hypopituitary patients (HPs) continue to gain weight, and up to one-half of HPs develop obesity. Among these, many report numerous failed weight loss attempts. Long-term studies have revealed that adults with conventionally treated hypopituitarism have increased total and cardiovascular mortality rates. The high prevalence of obesity and cardiovascular risk factors in hypopituitarism necessitates effective weight loss management in these patients. The objective of a study by Mersebach et al. was to investigate the combined effect of sibutramine, diet, and exercise in obese HPs and match simple obese controls. Secondarily, the researchers aimed to evaluate the impact of weight loss on the lipid and glucose profiles.

In this open-label prospective intervention study, 14 obese nondiabetic HPs (nine women and five men, 27 to 57 years old) and 14 simple obese nondiabetic controls (nine women and five men, 29 to 56 years old) were allocated to an 11-month combined treatment regimen of sibutramine, diet, and increased exercise. Patients and controls were matched for age, sex, and BMI. All HPs had multiple pituitary hormone deficiencies, due mainly to a pituitary adenoma. Ten patients had undergone surgical hypophysectomy, and one patient had received radiotherapy. The mean duration of pituitary disease was 15 (range 5 to 30) years.

The initial dose of sibutramine was 10 mg every morning. The dose was increased to 15 mg in the case of weight loss below 2 kg per month (six patients, seven healthy controls). The subjects were evaluated by a research team and a dietitian at baseline (0 months) and monthly for the first five months and thereafter every second month for the following six months. The subjects were prescribed a 600 kcal/d deficit diet based on a macronutrient content of 15% protein and <30% fat. A skilled dietitian provided dietary guidance using the educational dietary counseling system, Eat for Life, based on color-coded isoenergetic interchangeable units to ensure compliance in reducing both the energy and fat intake. The subjects were encouraged to fill out a counter diary daily for the first three months and thereafter by request. In addition, all participants were encouraged to complete 30 min extra walking daily. Data on three components of physical activity (work, sports, and other leisure-time activities) were obtained from the Baecke questionnaire, which was completed by the subjects at each visit. Body weight, body composition, blood pressure (BP), and heart rate were assessed at all visits. Laboratory investigations were performed at 0 and 4 months.

All enrolled participants (n = 28) completed the first four-month regimen. Six simple obese and four HPs were excluded before study end. The reasons for discontinuation were: increase in BP (n = 1; HP = 1), unexpected pregnancy (n = 1; simple obese = 1), lack of efficacy (n = 1; HP = 1), protocol violation (n = 2; simple obese = 1 and HP = 1), and unknown reason (n = 5; simple obese = 4 and HP = 1). Sibutramine was discontinued in one control due to achievement of a normal BMI (25 kg/[m.sup.2]) after 7 months of treatment.

After the first month of treatment, the initial weight loss was 4.5 [+ or -] 2.0 kg in HPs compared with 4.3 (+ or -]1.1) kg in controls [not statistically significant (NS)]. The relative weight loss was 3.9 [+ or -] 1.7% and 4.0 [+ or -] 0.9% of baseline body weight in HPs and controls, respectively (NS). Weight loss was more rapid during the first four months of treatment than during the rest of the period, but was evident at all time-points during the study compared with baseline. At 4 months, 86% (n = 12) of HPs had lost over 5% weight, and one-half(n = 7) had lost > 10% weight. At study end-point, 90% (n = 9) of HPs had achieved >5% weight loss, and 60% (n = 6) had lost over 10% weight. A total of 10% to 14% of HPs lost <5% weight. The relative number of controls who achieved a 5% and 10% weight loss, respectively, was not significantly different from that found in patients. The relative FM was reduced by 7.0 [+ or -] 2.5% and 9.0 [+ or -] 3.0% in HPs and controls, respectively (NS). Both groups achieved significant improvements in truncal, abdominal, and leg FM. Consistently, waist and hip circumferences were significantly reduced in both patients and controls. Overall, the changes in anthropometric indices, body composition, and regional distribution were not significantly different between HPs and simple obese.

This study demonstrated that HPs were not resistant to weight loss therapy, and almost all achieved at least a 5% weight loss and 60% experienced more than a 10% weight loss within 11 months on the management program. The application of a centrally acting drug such as sibutramine that restrains the reuptake of noradrenaline and serotonin may have normalized the impaired sympathoadrenal function of HPs and facilitated weight loss. In this study, ~10% to 14% of HPs lost <5% weight at study end-points, implying that they were nonresponders. In HPs, the initial weight loss after the first month of treatment significantly predicted the total weight loss. Achievement of an initial weight loss above 1% or 1 kg was associated with >5% weight loss at month 4. However, one HP, despite minimal initial weight loss of <1%, subsequently managed a satisfactory weight loss of >7%. It was observed that obese HPs with a longer duration of pituitary disease achieved a more minor weight loss than those with a shorter disease period before intervention. It is possible that long-term duration of pituitary disease may cause severe obesity that is more resistant to intervention.

Weight loss associated with sibutramine and diet was accompanied by improved metabolic risk factors. The decline in leptin, triglyceride, and fasting glucose was consistent with the extent of weight loss. In conclusion, sibutramine in conjunction with diet and exercise significantly reduced weight by 5% to 10% of pretreatment body weight in obese HPs, similar to what was obtained in simple obese. Weight loss resulted predominantly from loss of fat, rather than lean tissue. The weight loss was predicted by pretreatment weight, duration of pituitary disease, and duration of GH replacement therapy. The sibutramine-induced weight loss was accompanied by reduced waist circumference and improvements in lipids and glucose. HPs exhibited the same favorable changes in anthropometric indices, body composition, regional distribution, lipids, and glucose as controls. Modest weight loss has a beneficial effect on most risk factors of type 2 diabetes or cardiovascular disease, but the long-term effect needs to be established.

H Mersebach, M Klose, O Svendsen, A Astrup, U Feldt-Rasmussen. Combined dietary and pharmacological weight Management in Obese Hypopituitary Patients. Obes Res 12:1835-1843 (November 2004) [Correspondence:Henriette Mersebach, Department of Endocrinology, PE 2131, Copenhagen University Hospital 9, Blegdamsvej DK-2100 Copenhagen O, Denmark. E-mail: Mersebach@dadlnet.dk]

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