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?