abnormalities in growth and puberty in duchenne muscular dystrophy: effects of corticosteroid...
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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, UKjarod.wong@glasgow.ac.uk
1882 1914 19711451
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)
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
Normal Growth And Puberty
Bone accrual parallels linear growth
Puberty leads to changes in bone and body composition
ICP model of growth
In utero: Maternal/placental factors
Infancy: Nutrition
Childhood: Growth hormone
Puberty: Growth hormone + sex steroid
GH-IGF1 Axis
Growth hormone
IGF-1
Growth Plate
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
Testosterone-↑ growth, ↑ GH-↑ hair, ↑ genital size-↑ muscle
↑ testes size
ICP model of growth and chronic disease
Bone Growth Parallels Linear Growth
Rate of bone accrual Rate of linear growth
Importance of growth & puberty for bone development
40-50% total bone mass for life accumulated during puberty
Importance of puberty for muscle development
Growth And Short Stature In DMD
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
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
Corticosteroid And Poor Growth In DMD
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
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
Corticosteroid And Delayed Puberty/Hypogonadism In DMD
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)
Strategies To Promote Growth In DMD
Challenges In Clinical Practice
1- Accurate measurement in wheel chair bound boys
Arm span / segmental growth Sitting height Measurement during DXA
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
GH-IGF1 Axis
Growth hormone
IGF-1
Growth Hormone In DMD
Rutter M et al Neuromuscul Disord 2012
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
Pubertal Induction In Chronic Disease
Testosterone therapy in boys with IBDMason A et al Horm Res 2011
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
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
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
Alternative Therapies For DMD
1. Selective glucocorticoid receptor modulator
2. Anti-cytokine therapy
3. Others
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 **
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.
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
Questions?
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