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GH treatment of childhood-onset adult GH deficiency: Results of a 2-year placebocontrolled trial
GRS '98 Abstracts
spine and femoral neck, total blood cholesterol and triglycerides levels in group (1) were significantly lower (P < 0.001) than in group (3). Parameters in group (2) were not significantly different from those of group (1) and (3) In conclusion, in patients with hypothalamo-pituitary diseases subjected to standard replacement therapy for adrenal, thyroid and gonad axes abnormalities in lipid metabolism and bone mineral density are positively associated to the severity of GH deficiency evaluated by GHRH+ARG as provocative test. O-18 G R O W T H H O R M O N E (GH) STATUS FOLLOWING CURE OF CUSHING'S DISEASE
NR Hughes, CA Lissett, and SM Shalet. NHS Christie Hospital, Manchester, UK. Treatment of Cushing's disease (CD) may consist of pituitary surgery and/or irradiation. Side effects of therapy include persistent deficits of one or more anterior pituitary hormones. Studies of GH status following treatment of CD are few and the incidence of persistent severe GH deficiency (GHD) is unknown. This situation is complicated by the fact that GH secretion is suppressed in the hypercortisolaemic state and for up to 1 year post-surgery, therefore long-term follow-up data are required. We studied GH status in 31 adults (age range 12-63 years, 6 males) with CD in remission: 13 treated with pituitary irradiation and 18 with pituitary surgery. Severe GHD was defined as a peak GH response of <9 mU/I to an ITT. 5/13 irradiated patients had severe GHD, at a median time of 95 months post-irradiation (20 Gy/8 fractions/9-12 days). During the first 24 months postsurgery 16/18 underwent GH studies and 10/16 proved to be severely GHD. Nine patients, seven of whom had been identified as severely GHD <24 months post-operatively, were studied >24 months post-operatively. Only 2/7 remained severely GHD at retest. Of the two patients not previously tested, neither was severely GHD. The incidence of severe GHD in patients tested >24 months post-surgery was 22%, however this cohort is biased as it contains a high proportion of patients previously identified as GHD who tend to be tested more frequently. It is more accurate to include in addition, patients identified as having normal GH secretory status <24 months post-surgery. This results in an overall incidence of persistent GHD after surgically induced remission of CD of only 13% (2/15). Furthermore, a n u m b e r of patients (70%) demonstrated recovery of GH secretory status >24 months post-surgically induced remission of CD. Definitive conclusions regarding GH status should be delayed for 24 rfionths post-surgery. O-19 GH TREATMENT OF C H I L D H O O D - O N S E T ADULT GH DEFICIENCY: RESULTS OF A 2-YEAR PLACEBOCONTROLLED T R I A L
LE Underwood ~, KM Attie 2, J Baptista 2, SD Chernausek 3, HJ Dean 4, ME Geffner 5, RW Gotlin~, MD Harbison 7, RL Hintz 8, MR Jenner 9, K Khoury 1~ A Lacroix ~1, SH LaFranchi 12, WV Moore 13, P Saenger ~4, JV Santiago ~5, F Szots ~6, DT WyattlL ~U No Carolina; 2Genentech, Inc; 3Children's, Cincinnati; 4Winnipeg; 5UCLA Med Ctr; 6Children's, Denver; 7Cornell Med Ctr; 8Stanford U; 9Children's, W Ontario; I~ Sherbrooke; HHotel-Dieu Montreal; 12Oregon HSU; ~3Children's, Kansas City; ~4Montefiore Med Ctr; ~St Louis Children's; ~6U Laval Ste-Foy; ~TChildren's, Milwaukee. This is a report of a double-blind, placebo-controlled study to assess the effects of 2 years of GH (Nutropin| Genentech) therapy in adults with childhood-onset GH deficiency. 64 subjects, treated with GH in childhood (off GH >1 year) and retested, were randomized into three groups: placebo, GH 12.5 gg/kg/day,
317
GH 25 gg/kg/day. Mean age was 24 years. The table below shows 0-24 month mean changes for body composition (DEXA), bone mineral density (BMD, DEXA), skin-fold thicknesses SFT), and echocardiogram. Comparisons were made for end-oftreatment vs baseline within if-test, */)<0.05) and between groups (ANCOVA): Strength, endurance and quality-of-life were not markedly abnormal at baseline and did not change significantly with treatment. Adverse events included edema (placebo: 5%, GH12.5: 15%, GH25: 30%). Elevated insulin levels occurred more commonly in GH-treated individuals with increased body mass index. Conclusions: GH treatment of childhood-onset adult GHD results in positive changes in body composition and bone density. These changes were dependent on dose and, for BMD, duration of therapy. [Funded by Genentech, Inc.]
Placebo
GH12.5
GH25
ANCOVA P-value 0.0013
Body %Fat
+1.4
-3.3
-6.8*
Trunk %Fat
+2.6
-3.8
-7,7"
0.0011
Body %Lean
-1.3
+3.4*
+6.6*
0.0017
Spine BMD (%change)
+1.3
+3.3*
+4.3*
NS
Sum SFT (ram)
+3.2
-6.1"
-12.4"
NS
+11.3
+10.4
+21.7"
NS
-0.5
-0.1
+2.4
NS
LV mass (g) %Fract. shortening
0 - 2 0 EFFECTS OF h G H REPLACEMENT ON C E R E B R A L METABOLISM IN ADULTS W I T H G R O W T H H O R M O N E DEFICIENCY
IC Cranston ~, PK Marsden ~, P CarroW, PH SonkseW, D RussellJonesL ~Dept of Medicine; 2Clinical PET Centre, UMDS St Thomas Hospital, London, UK. The beneficial effects of growth hormone (GH) replacement in GH-deficient adults on both quality of life, mood and cognitive functioning have been previously described. It is however unclear if these effects represent a direct central action of GH (perhaps via IGFI), or are secondary to the well-described peripheral effects of GH and the resulting improvements in systemic well-being. In order to determine this, we have studied 15 GH-deficient adults before and 3 months after growth hormone replacement (0.036 IU/kg/day) or placebo (randomized, doubleblind) using quantitative, dynamic cerebral positron emission tomography (PET). Regional cerebral metabolic rate for glucose (RCMRglu) was determined by comparison of arterial tracer disappearance (continuous on-line counting) with brain tracer uptake in 2 m m voxels measured by the PET scanner over 1 h (after the method of Sokoloff) after a 18 5 MBq intravenous bolus of the positron emittor 18-Fluoro-Deoxyglucose (18FDG) as a glucose tracer. Seven subjects received GH and six placebo, there were no significant baseline subject differences between the two groups. In both GHD groups, the baseline whole-brain CMRglu (0.304 _+0.014) was lower than that for previous nonGHD subjects (0.384 + 0.009 gmol/g/min) after placebo this fell still further to 0.275 _+0.017 ~mol/g/min P = NS vs baseline. In contrast, those receiving GH sustained a significant rise in whole-brain CMRglu from 0.285 _+0.020 at baseline to 0.319 _+ 0.021 gmol/g/min after GH P = 0.002. This effect was similar
spine and femoral neck, total blood cholesterol and triglycerides levels in group (1) were significantly lower (P < 0.001) than in group (3). Parameters in group (2) were not significantly different from those of group (1) and (3) In conclusion, in patients with hypothalamo-pituitary diseases subjected to standard replacement therapy for adrenal, thyroid and gonad axes abnormalities in lipid metabolism and bone mineral density are positively associated to the severity of GH deficiency evaluated by GHRH+ARG as provocative test. O-18 G R O W T H H O R M O N E (GH) STATUS FOLLOWING CURE OF CUSHING'S DISEASE
NR Hughes, CA Lissett, and SM Shalet. NHS Christie Hospital, Manchester, UK. Treatment of Cushing's disease (CD) may consist of pituitary surgery and/or irradiation. Side effects of therapy include persistent deficits of one or more anterior pituitary hormones. Studies of GH status following treatment of CD are few and the incidence of persistent severe GH deficiency (GHD) is unknown. This situation is complicated by the fact that GH secretion is suppressed in the hypercortisolaemic state and for up to 1 year post-surgery, therefore long-term follow-up data are required. We studied GH status in 31 adults (age range 12-63 years, 6 males) with CD in remission: 13 treated with pituitary irradiation and 18 with pituitary surgery. Severe GHD was defined as a peak GH response of <9 mU/I to an ITT. 5/13 irradiated patients had severe GHD, at a median time of 95 months post-irradiation (20 Gy/8 fractions/9-12 days). During the first 24 months postsurgery 16/18 underwent GH studies and 10/16 proved to be severely GHD. Nine patients, seven of whom had been identified as severely GHD <24 months post-operatively, were studied >24 months post-operatively. Only 2/7 remained severely GHD at retest. Of the two patients not previously tested, neither was severely GHD. The incidence of severe GHD in patients tested >24 months post-surgery was 22%, however this cohort is biased as it contains a high proportion of patients previously identified as GHD who tend to be tested more frequently. It is more accurate to include in addition, patients identified as having normal GH secretory status <24 months post-surgery. This results in an overall incidence of persistent GHD after surgically induced remission of CD of only 13% (2/15). Furthermore, a n u m b e r of patients (70%) demonstrated recovery of GH secretory status >24 months post-surgically induced remission of CD. Definitive conclusions regarding GH status should be delayed for 24 rfionths post-surgery. O-19 GH TREATMENT OF C H I L D H O O D - O N S E T ADULT GH DEFICIENCY: RESULTS OF A 2-YEAR PLACEBOCONTROLLED T R I A L
LE Underwood ~, KM Attie 2, J Baptista 2, SD Chernausek 3, HJ Dean 4, ME Geffner 5, RW Gotlin~, MD Harbison 7, RL Hintz 8, MR Jenner 9, K Khoury 1~ A Lacroix ~1, SH LaFranchi 12, WV Moore 13, P Saenger ~4, JV Santiago ~5, F Szots ~6, DT WyattlL ~U No Carolina; 2Genentech, Inc; 3Children's, Cincinnati; 4Winnipeg; 5UCLA Med Ctr; 6Children's, Denver; 7Cornell Med Ctr; 8Stanford U; 9Children's, W Ontario; I~ Sherbrooke; HHotel-Dieu Montreal; 12Oregon HSU; ~3Children's, Kansas City; ~4Montefiore Med Ctr; ~St Louis Children's; ~6U Laval Ste-Foy; ~TChildren's, Milwaukee. This is a report of a double-blind, placebo-controlled study to assess the effects of 2 years of GH (Nutropin| Genentech) therapy in adults with childhood-onset GH deficiency. 64 subjects, treated with GH in childhood (off GH >1 year) and retested, were randomized into three groups: placebo, GH 12.5 gg/kg/day,
317
GH 25 gg/kg/day. Mean age was 24 years. The table below shows 0-24 month mean changes for body composition (DEXA), bone mineral density (BMD, DEXA), skin-fold thicknesses SFT), and echocardiogram. Comparisons were made for end-oftreatment vs baseline within if-test, */)<0.05) and between groups (ANCOVA): Strength, endurance and quality-of-life were not markedly abnormal at baseline and did not change significantly with treatment. Adverse events included edema (placebo: 5%, GH12.5: 15%, GH25: 30%). Elevated insulin levels occurred more commonly in GH-treated individuals with increased body mass index. Conclusions: GH treatment of childhood-onset adult GHD results in positive changes in body composition and bone density. These changes were dependent on dose and, for BMD, duration of therapy. [Funded by Genentech, Inc.]
Placebo
GH12.5
GH25
ANCOVA P-value 0.0013
Body %Fat
+1.4
-3.3
-6.8*
Trunk %Fat
+2.6
-3.8
-7,7"
0.0011
Body %Lean
-1.3
+3.4*
+6.6*
0.0017
Spine BMD (%change)
+1.3
+3.3*
+4.3*
NS
Sum SFT (ram)
+3.2
-6.1"
-12.4"
NS
+11.3
+10.4
+21.7"
NS
-0.5
-0.1
+2.4
NS
LV mass (g) %Fract. shortening
0 - 2 0 EFFECTS OF h G H REPLACEMENT ON C E R E B R A L METABOLISM IN ADULTS W I T H G R O W T H H O R M O N E DEFICIENCY
IC Cranston ~, PK Marsden ~, P CarroW, PH SonkseW, D RussellJonesL ~Dept of Medicine; 2Clinical PET Centre, UMDS St Thomas Hospital, London, UK. The beneficial effects of growth hormone (GH) replacement in GH-deficient adults on both quality of life, mood and cognitive functioning have been previously described. It is however unclear if these effects represent a direct central action of GH (perhaps via IGFI), or are secondary to the well-described peripheral effects of GH and the resulting improvements in systemic well-being. In order to determine this, we have studied 15 GH-deficient adults before and 3 months after growth hormone replacement (0.036 IU/kg/day) or placebo (randomized, doubleblind) using quantitative, dynamic cerebral positron emission tomography (PET). Regional cerebral metabolic rate for glucose (RCMRglu) was determined by comparison of arterial tracer disappearance (continuous on-line counting) with brain tracer uptake in 2 m m voxels measured by the PET scanner over 1 h (after the method of Sokoloff) after a 18 5 MBq intravenous bolus of the positron emittor 18-Fluoro-Deoxyglucose (18FDG) as a glucose tracer. Seven subjects received GH and six placebo, there were no significant baseline subject differences between the two groups. In both GHD groups, the baseline whole-brain CMRglu (0.304 _+0.014) was lower than that for previous nonGHD subjects (0.384 + 0.009 gmol/g/min) after placebo this fell still further to 0.275 _+0.017 ~mol/g/min P = NS vs baseline. In contrast, those receiving GH sustained a significant rise in whole-brain CMRglu from 0.285 _+0.020 at baseline to 0.319 _+ 0.021 gmol/g/min after GH P = 0.002. This effect was similar