Abnormalities In Growth And Puberty In Duchenne Muscular Dystrophy: Effects Of Corticosteroid Therapy Jarod Wong Developmental Endocrinology Research Group Division of Developmental Medicine Royal Hospital For Children Glasgow, UK

Acknowledgements Developmental Endocrinology Research Group Yorkhill -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 Collaborators Neuromuscular -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 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 GC Ahmed et al JPEM 1999, Crofton et al, JCEM,1998

Daily vs intermittent corticosteroid from Northstar Database 360 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 LH Bone 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 IBD Mason 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 3 months 12 months 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?