A dose titration model for recombinant GH substitution aiming at normal plasma concentrations of IGF-I in hypopituitary adults

Abstract

Objective: To evaluate a dose titration model for recombinant human GH substitution in adult patients with GH deficiency, aiming at normal plasma levels of IGF-I. Design and methods: Eighteen patients participated and a start dose of 0.17 mg GH/day was used except by two men who started with 0.33 mg/day. To demonstrate a clear GH effect the patients were first titrated, with steps of 0.17 mg GH/day every 6 -8 weeks, to IGF-I levels in the upper range of age-adjusted reference values. The GH dose was then reduced 1 dose step and kept for a further 6 months. For comparison we investigated 17 healthy control subjects. Results: Plasma IGF-I was increased after 2 weeks on the start dose and did not increase further for up to 8 weeks. Women had significantly lower GH sensitivity than men measured as net increment of IGF-I on the start dose of GH. GH sensitivity was not changed by age. The plasma IGF-I levels increased from 76:3^47:0 (S.D.) to 237^97 mg=l at the end of the study ðP , 0:001Þ; and similar IGF-I levels were obtained in both sexes. The maintenance median GH dose was 0.33 mg/day in males and 0.83 mg/day in females ðP ¼ 0:017Þ: The GH dose correlated negatively with age in both sexes. Body weight, very low density triglycerides, lipoprotein(a) (Lp(a)), and fasting insulin increased, whereas insulin sensitivity index (QUICKI) decreased significantly. In comparison with the controls, the patients had lower fasting blood glucose, fasting insulin and Lp(a) levels at baseline, but these differences disappeared after GH substitution. The two groups had equal insulin sensitivity (QUICKI), but 2 h oral glucose tolerance test values of blood glucose and insulin were significantly higher in the patients at the end of the study. Conclusions: In conclusion our data suggest that the starting dose of GH substitution and the dose titration steps should be individualised according to GH sensitivity (gender) and the IGF-I level aimed for (age). The reduced insulin sensitivity induced by GH substitution could be viewed as a normalisation if compared with control subjects.

Growth hormone substitution titrated to obtain IGF-I levels in the physiological range in hypopituitary adults: effects upon dynamic strength, endurance and EMG

“…However, a study of mice found that over-expression of IGF-I could increase both muscle strength and muscle mass (Barton-Davis et al 1998). Another alternative explanation is that there are metabolic changes at the carbohydrate level, since we have previously reported that insulin and blood glucose levels both increased in patients after GH substitution (Ekman et al 2002). However, we could not find any relationship between changes in IGF-I and insulin or blood glucose in the GHtreated group.…”

“…Patients and control subjects both did the same muscle tests on biomechanical output and EMG at baseline and at the last visit in the study. The GH titration procedure is described in detail elsewhere (Ekman et al 2002).…”

Persisting effects on fasting glucose levels and insulin sensitivity after 6 months of discontinuation of a very low‐dose GH therapy in adults with severe GH deficiency

“…We have recently reported that, in contrast to the standard GH replacement dose (SGH) titrated to normalize serum IGF‐I levels, 15–17 fixed administration of a very low GH dose (LGH) (0·1 mg/day) decreased fasting glucose levels and improved insulin sensitivity without modifying body composition in severely GH‐deficient adults 18 . The mechanism/s responsible for the glucose‐lowering effects of the LGH, however, remain unclear.…”

The Effect of Gender and Age on Growth Hormone Replacement in Growth Hormone-Deficient Patients

“…The waist/hip ratio was not influenced by the age at onset of GHD, severity of hypopituitarism, or gonadal status [15]. There are conflicting reports on the effect; the waist/hip ratio was found to be unchanged [14,18] or decreased in both genders with more pronounced changes in men [15], while no significant difference was found in the sum of skinfold thicknesses during short-term (6-month) replacement [18].…”

“…Men lose more body fat than women [10,15 ± 19] and a similar trend has been seen in the improvement of bone mineral density (BMD) [4,13, 20 ± 27]. GH secretion is also known to depend on the age, but the change of GH sensitivity by age was not proven after short-term administration of GH [14]. On the other hand, the BMD increase was found to be more marked in young than in old patients in the lumbar spine, the femoral neck and in the trochanter regions after long-term GH substitution [27].…”