Growth Hormone Withdrawal in Obese Premenopausal Women
Growth Hormone Withdrawal in Obese Premenopausal Women
Fifty women completed the 6-month randomized trial (n = 28 in GH, n = 22 in placebo group), and thirty-nine women completed the subsequent 6-month period after GH withdrawal (n = 21 in GH, n = 18 in placebo group). At baseline, the mean age of the subjects was 36 ± 0·8 years, mean BMI was 34·9 ± 0·6 kg/m (range 25·1–49·7 kg/m), mean waist circumference was 109·6 ± 1·4 cm, and mean IGF-I SDS was −1·7 ± 0·05.
Mean IGF-I and SDS levels are shown in Fig. 2. At baseline, IGF-I and SDS levels were comparable between the two groups. At 6 months, mean IGF-I was 265 ± 23·0 μg/l (P < 0·0001) and SDS was –0·1 ± 0·3 (P < 0·0001). At 12 months (6 months after GH withdrawal), both absolute levels of IGF-I and IGF-I SDS were comparable to pretreatment levels, with no evidence of suppression of the GH axis. At 12 months, mean IGF-I was 138 ± 10 μg/l in the GH group and 107 ± 7 μg/l in the placebo group (P = 0·11) with a mean SDS −1·7 ± 0·1 in the GH group and −2·0 ± 0·1 in the placebo group (P = 0·11).
(Enlarge Image)
Figure 2.
Mean IGF-I (panel a) and IGF-I SDS (panel b) levels (± SEM) in women randomized to growth hormone (solid diamonds) or placebo (open diamonds) for the first 6 months, followed by 6-month withdrawal of study medication. P by repeated measures anova between the two groups.
Following 6 months of GH withdrawal, body composition parameters that had improved with GH (decrease in TAT, SAT, trunk fat, and increase in thigh muscle and lean mass in GH vs placebo) returned to baseline levels at 12 months (P > 0·05). TAT (P = 0·05), SAT (P = 0·01), total fat (P = 0·001), trunk fat (P < 0·001) and trunk/extremity fat (P = 0·03) increased at the 12-month visit compared to the 6-month visit. There was no significant change in IMCL, IHL, VAT and BMI during the 6-month treatment and 6-month withdrawal periods in the GH group vs placebo (P = 0·2–0·9). BMI, thigh muscle area, TAT and trunk fat over the 12-month period (first 6 months receiving GH vs placebo and subsequent 6 months receiving no study drug) are shown in Fig. 3.
(Enlarge Image)
Figure 3.
Mean body mass index (panel a), thigh muscle cross-sectional area (panel b), total abdominal adipose tissue (panel c) and trunk fat (panel d) (±SEM) in women randomized to growth hormone (solid diamonds) or placebo (open diamonds) for the first 6 months, followed by 6-month withdrawal of study medication. P by repeated measures anova between the two groups.
Following 6 months of GH withdrawal, cardiovascular risk markers which had decreased following 6 months of GH treatment compared with placebo, increased compared with the 6-month visit: tPA (P = 0·01), apoB (P = 0·002), LDL (P = 0·05). All cardiovascular risk marker outcome measures that had improved with GH returned to pretreatment levels at 12 months by repeated-measures analysis of variance (P > 0·05). hsCRP and apoB are shown in Fig. 4. There was no significant change in serum cholesterol, triglycerides and carotid IMT, during the 6-month treatment and 6-month withdrawal periods in the GH group vs placebo (P = 0·1– 0·9).
(Enlarge Image)
Figure 4.
Mean high-sensitivity C-reactive protein (panel a) and apolipoprotein B (panel b) (±SEM) in women randomized to growth hormone (solid diamonds) or placebo (open diamonds) for the first 6 months, followed by 6-month withdrawal of study medication. P by repeated measures anova between the two groups.
GH administration was associated with an increase in fasting and 2-h OGTT glucose compared with placebo during 6 months of GH administration with four subjects having 2-h OGTT glucose levels >11·1 mmol/l. Three of these subjects underwent follow-up OGTTs at 9 months, which demonstrated normalization of glucose levels. The fourth subject followed up with her primary care physician regarding the elevated glucose. No subjects had fasting glucose levels ≥7·0 mmol/l at any point during the study. All glucose parameters that had increased with GH returned to pre-treatment levels at 12 months by repeated-measures analysis of variance (P > 0·05). Fasting glucose and 2-h OGTT glucose are shown in Fig. 5.
(Enlarge Image)
Figure 5.
Mean fasting glucose (panel a) and 120-min oral glucose tolerance test glucose (panel b) levels (±SEM) in women randomized to growth hormone (solid diamonds) or placebo (open diamonds) for the first six months, followed by 6-month withdrawal of study medication. P by repeated measures anova between the two groups
Results
Subjects
Fifty women completed the 6-month randomized trial (n = 28 in GH, n = 22 in placebo group), and thirty-nine women completed the subsequent 6-month period after GH withdrawal (n = 21 in GH, n = 18 in placebo group). At baseline, the mean age of the subjects was 36 ± 0·8 years, mean BMI was 34·9 ± 0·6 kg/m (range 25·1–49·7 kg/m), mean waist circumference was 109·6 ± 1·4 cm, and mean IGF-I SDS was −1·7 ± 0·05.
GH dosing and IGF-I levels
Mean IGF-I and SDS levels are shown in Fig. 2. At baseline, IGF-I and SDS levels were comparable between the two groups. At 6 months, mean IGF-I was 265 ± 23·0 μg/l (P < 0·0001) and SDS was –0·1 ± 0·3 (P < 0·0001). At 12 months (6 months after GH withdrawal), both absolute levels of IGF-I and IGF-I SDS were comparable to pretreatment levels, with no evidence of suppression of the GH axis. At 12 months, mean IGF-I was 138 ± 10 μg/l in the GH group and 107 ± 7 μg/l in the placebo group (P = 0·11) with a mean SDS −1·7 ± 0·1 in the GH group and −2·0 ± 0·1 in the placebo group (P = 0·11).
(Enlarge Image)
Figure 2.
Mean IGF-I (panel a) and IGF-I SDS (panel b) levels (± SEM) in women randomized to growth hormone (solid diamonds) or placebo (open diamonds) for the first 6 months, followed by 6-month withdrawal of study medication. P by repeated measures anova between the two groups.
Body Composition
Following 6 months of GH withdrawal, body composition parameters that had improved with GH (decrease in TAT, SAT, trunk fat, and increase in thigh muscle and lean mass in GH vs placebo) returned to baseline levels at 12 months (P > 0·05). TAT (P = 0·05), SAT (P = 0·01), total fat (P = 0·001), trunk fat (P < 0·001) and trunk/extremity fat (P = 0·03) increased at the 12-month visit compared to the 6-month visit. There was no significant change in IMCL, IHL, VAT and BMI during the 6-month treatment and 6-month withdrawal periods in the GH group vs placebo (P = 0·2–0·9). BMI, thigh muscle area, TAT and trunk fat over the 12-month period (first 6 months receiving GH vs placebo and subsequent 6 months receiving no study drug) are shown in Fig. 3.
(Enlarge Image)
Figure 3.
Mean body mass index (panel a), thigh muscle cross-sectional area (panel b), total abdominal adipose tissue (panel c) and trunk fat (panel d) (±SEM) in women randomized to growth hormone (solid diamonds) or placebo (open diamonds) for the first 6 months, followed by 6-month withdrawal of study medication. P by repeated measures anova between the two groups.
Cardiovascular Risk Markers
Following 6 months of GH withdrawal, cardiovascular risk markers which had decreased following 6 months of GH treatment compared with placebo, increased compared with the 6-month visit: tPA (P = 0·01), apoB (P = 0·002), LDL (P = 0·05). All cardiovascular risk marker outcome measures that had improved with GH returned to pretreatment levels at 12 months by repeated-measures analysis of variance (P > 0·05). hsCRP and apoB are shown in Fig. 4. There was no significant change in serum cholesterol, triglycerides and carotid IMT, during the 6-month treatment and 6-month withdrawal periods in the GH group vs placebo (P = 0·1– 0·9).
(Enlarge Image)
Figure 4.
Mean high-sensitivity C-reactive protein (panel a) and apolipoprotein B (panel b) (±SEM) in women randomized to growth hormone (solid diamonds) or placebo (open diamonds) for the first 6 months, followed by 6-month withdrawal of study medication. P by repeated measures anova between the two groups.
Glucose Parameters
GH administration was associated with an increase in fasting and 2-h OGTT glucose compared with placebo during 6 months of GH administration with four subjects having 2-h OGTT glucose levels >11·1 mmol/l. Three of these subjects underwent follow-up OGTTs at 9 months, which demonstrated normalization of glucose levels. The fourth subject followed up with her primary care physician regarding the elevated glucose. No subjects had fasting glucose levels ≥7·0 mmol/l at any point during the study. All glucose parameters that had increased with GH returned to pre-treatment levels at 12 months by repeated-measures analysis of variance (P > 0·05). Fasting glucose and 2-h OGTT glucose are shown in Fig. 5.
(Enlarge Image)
Figure 5.
Mean fasting glucose (panel a) and 120-min oral glucose tolerance test glucose (panel b) levels (±SEM) in women randomized to growth hormone (solid diamonds) or placebo (open diamonds) for the first six months, followed by 6-month withdrawal of study medication. P by repeated measures anova between the two groups
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