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Abnormalities In Growth And Puberty In Duchenne Muscular Dystrophy:
Effects Of Corticosteroid Therapy
Jarod WongDevelopmental Endocrinology Research GroupDivision of Developmental MedicineRoyal Hospital For ChildrenGlasgow, [email protected]
1882 1914 19711451
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Acknowledgements
Developmental Endocrinology Research GroupYorkhill-F Ahmed-S Joseph-A Mason-L Lucaccioni-M McMillan-J McNeilly
- Roslin-C Farquharson-V MacRae-T Mushtaq (previous)
- University of Glasgow-C McComb-J Foster
CollaboratorsNeuromuscular-I Horrocks, M Di Marco, J Dunne, S Joseph (Glasgow)-V Straub, C Woods (Newcastle)
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Plan
1- Normal growth and puberty
2- Growth and short stature in DMD
3- Corticosteroid and poor growth
4- Corticosteroid and delayed puberty
5- Strategies for promoting growth
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Normal Growth And Puberty
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Bone accrual parallels linear growth
Puberty leads to changes in bone and body composition
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ICP model of growth
In utero: Maternal/placental factors
Infancy: Nutrition
Childhood: Growth hormone
Puberty: Growth hormone + sex steroid
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GH-IGF1 Axis
Growth hormone
IGF-1
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Growth Plate
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Puberty And Growth Velocity In Boys
Majority healthy boys enter puberty by age 11-12 years
Peak height velocity 14 years
True delayed puberty in boys: no signs of puberty > 14 years
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Testosterone-↑ growth, ↑ GH-↑ hair, ↑ genital size-↑ muscle
↑ testes size
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ICP model of growth and chronic disease
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Bone Growth Parallels Linear Growth
Rate of bone accrual Rate of linear growth
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Importance of growth & puberty for bone development
40-50% total bone mass for life accumulated during puberty
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Importance of puberty for muscle development
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Growth And Short Stature In DMD
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Poor growth in DMD predates the use of CS
0 years 5 years 10 years Eiholzer et al Eur J Pediatr 1988
Nagel BH et al Acta Paediatr 1999
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Reasons for poor growth in DMD before CS
Unclear
Contiguous gene deletion
Intrinsic abnormality in DMD bone and growth plate
Subtle abnormality of GH secretion/GH resistance
Chronic inflammation- effects on growth factors and growth plate
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Corticosteroid And Poor Growth In DMD
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Bone Turnover In ALL
Growth rate lower leg
Bone formation
Bone resorption
High dose GC GCAhmed et al JPEM 1999, Crofton et al, JCEM,1998
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Daily vs intermittent corticosteroid from Northstar Database360 DMD
Mean 4 years treatment
-1.8 SD -0.7 SD +1.5 SD +2.0 SD
Ricotti V et al J Neurol Neurosurg Psychiatry 2013
At age 10 years, boys with daily Deflazacort were 7 cm shorter than untreated At age 15 years, boys with daily Deflazacort were 21 cm shorter than untreated
Biggar WD et al Neuromuscul Disord 2006
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Corticosteroid And Delayed Puberty/Hypogonadism In DMD
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Delayed Puberty In DMD
6 out of 12 boys (50%) > 14 years with DMD treated with deflazacort no signs of puberty (Dooley JM et al Pediatr Neurol 2013)
4 out of 4 boys (100%) with DMD treated with alternate day Prednisolone had delayed puberty and 3 required testosterone treatment (Merlini L et al Muscle Nerve 2012)
43 out of 44 boys (98%) aged > 13 years (31 boys > 14 years) with DMD treated with daily steroid were pre-pubertal (Bianchi ML et al Neuromuscul Disord 2011)
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Strategies To Promote Growth In DMD
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Challenges In Clinical Practice
1- Accurate measurement in wheel chair bound boys
Arm span / segmental growth Sitting height Measurement during DXA
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Challenges In Clinical Practice
2- Assessment of puberty in adolescents with DMD
Accurate measurement of testes Self assessment charts
Bloods/ dynamic stimulation test
Urinary LHBone age x ray
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GH-IGF1 Axis
Growth hormone
IGF-1
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Growth Hormone In DMD
Rutter M et al Neuromuscul Disord 2012
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Unanswered questions about use of rhGH-Dose-Long term effects on linear growth-Other benefits – bone and muscle-Adverse events: glucose homeostasis and insulin resistance
Possible role of rhIGF1-Ongoing trial in USA-Efficacy-Adverse events: hypoglycaemia-GH+ IGF1
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Pubertal Induction In Chronic Disease
Testosterone therapy in boys with IBDMason A et al Horm Res 2011
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Testosterone Therapy In DMD
Duration of treatment, dose, route of administration
No published study on effects on growth
May lead to progression in puberty but little or no growth
Accurate measurement
Other effects: bone and muscle
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Testosterone In Other Muscular Dystrophy
Testosterone Placebo Testosterone Placebo
3 months 12 monthskg kg
Lean Mass
Testosterone: Myotonic dystophy (n,7), limb girdle dystrophy (n,1), fascioscapulohumeral dystrophy (n, 1)
Placebo: Myotonic dystophy (n, 4) Welle S et al JCEM 1992
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Testosterone In DMD
14 DMD treated with testosterone for delayed puberty
8 treated till attained adult secondary sexual characteristics
(Mean 3.1 years)
6 still undergoing treatment
5/8 had testosterone measurements at adult maturity-4/5 (80%) low testosterone level at adult maturity (off testosterone)
6/8 testes examined at adult maturity- 6/6 (100%) testes small (< 5ml) at adult maturity
Wood C et al In press
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Alternative Therapies For DMD
1. Selective glucocorticoid receptor modulator
2. Anti-cytokine therapy
3. Others
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Endocrine Aspects of Muscular Dystrophy
1. Bone health and fractures
2. Growth
3. Puberty and hypogonadism
4. Weight gain and type 2 diabetes mellitus
5. Secondary adrenal insufficiency **
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Summary
1- Short stature common in boys with DMD.
2- Delayed puberty/ hypogonadism common in DMD and is due to prolonged use of corticosteroid but may be part of the condition itself.
3- Measurement of height and assessment of puberty should be routinely performed in the clinic but is challenging.
4- Improving growth and puberty in DMD may have extended benefits beyond improving stature itself.
5- Close clinical and research collaborations between the neuromuscular team and endocrinologists are needed.
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Recommendations for the clinic
Regular measurement of height even in wheel chair bound boys
Attention to puberty from 12 years onwards-Examination (by paediatric endocrinologist)-Biochemistry (blood or urine)-Bone age
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Questions?