Dataset Information

Is ongoing testosterone required after pubertal induction in Duchenne muscular dystrophy?

ABSTRACT: Glucocorticoids (GC) reduce inflammation and preserve muscle function in boys with Duchenne muscular dystrophy (DMD) but cause pubertal delay. Pubertal induction with testosterone is recommended but longer-term outcome is unknown.

Objective

To assess hypothalamic-pituitary-gonadal axis, muscle volume and function 5 years after pubertal induction.

Methods

A prospective observational follow-up of a clinical study was conducted. 15 GC-treated males with DMD were treated with incremental testosterone for 2 years (end of regimen +2y) then evaluated at +2.5y and +5y (final follow-up~ 3 years after last injection). Data collected included testicular volume (TV), gonadotrophin, testosterone, inhibin B, muscle function and limb muscle MRI.

Results

Participants were 18.7 years (SD 1.6) at final follow-up and had been on GC for 11.2 years (SD 2.2). Testosterone levels were similar at +2.5y (8.6nmol/l (SD 3.4) and 5y (11.0 nmol/l (SD 6.1). TV increased from 2.8 mls (SD 0.9) at +2y to 7.1 mls (SD 1.8) then 10.6 mls (SD 3.5) at +2.5y and +5.0y(p<0.001). Inhibin B levels increased from 55.6 pg/ml (SD 47.0) at baseline to 158.2 pg/ml (SD 87.6), p=0.004 at 5y but remained lower than reference values (mean 305 pg/ml). Muscle contractile bulk decreased.

Interpretation

Pubertal induction with testosterone in DMD is associated with HPG axis activation and ongoing increases in Inhibin B, TV and testosterone concentrations. Some patients have normal levels which is promising regarding future fertility. Given the beneficial impact of testosterone on bone health, muscle and wellbeing, monitoring testosterone levels in this population and supplementation of sub-optimal levels is important.

SUBMITTER: Wood CL

PROVIDER: S-EPMC10620460 | biostudies-literature | 2023 Sep

REPOSITORIES: biostudies-literature

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Publications

Is ongoing testosterone required after pubertal induction in Duchenne muscular dystrophy?

Wood Claire L CL Hollingsworth Kieren G KG Bokaie Edrina E Hughes Eric E Muni-Lofra Robert R Mayhew Anna A Mitchell Rod T RT Guglieri Michela M McElvaney Joseph J Cheetham Timothy D TD Straub Volker V

Endocrine connections 20231026 12

Glucocorticoids (GC) reduce inflammation and preserve muscle function in boys with Duchenne muscular dystrophy (DMD) but cause pubertal delay. Pubertal induction with testosterone is recommended but longer-term outcome is unknown.<h4>Objective</h4>To assess hypothalamic-pituitary-gonadal axis, muscle volume and function 5 years after pubertal induction.<h4>Methods</h4>A prospective observational follow-up of a clinical study was conducted. 15 GC-treated males with DMD were treated with increment ...[more]

PMID: 37768006

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Project description:BackgroundAdolescents with DMD treated with chronic high dose GC therapy typically have profound pubertal delay. Testosterone, the main circulating androgen in men, promotes virilisation and growth with associated accrual of fat-free muscle mass and bone mineral content. Testosterone therapy is routinely used to mimic the normal stages of pubertal development in patients with hypogonadotrophic hypogonadism, androgen deficiency secondary to testicular disease and in constitutional delay of growth and puberty (CDGP). Improved life expectancy in DMD has meant that more adolescents are eligible for testosterone supplementation but there is little objective data regarding the impact of this treatment on muscle structure and function, bone integrity and overall well-being.MethodsThis is a single centre observational clinical trial (NCT02571205) that aims to follow the progress of 15 adolescents with Duchenne muscular dystrophy and delayed puberty as they are managed with incremental testosterone therapy to induce puberty. Subjects will all be treated with a steadily increasing dose of testosterone administered by injection every 4 weeks and data will be collected to help us determine the effectiveness and tolerability of the described treatment regimen. We will use the data to explore the effects of testosterone on pubertal development, growth, muscle strength and function, bone mineral density, body composition with a detailed record of any adverse events. We will also carry out interviews to explore the boys' views on the tolerability of the regimen. The study will last for 27 months in total for each participant.DiscussionOur experience has indicated that testosterone treatment in adolescents with DMD is liked and well tolerated but we have not collected objective data on a specific treatment regimen and there is no current consensus. Testosterone supplementation is not part of the standard of care of pubertal delay in DMD but inclusion in future protocols may be appropriate depending on the results of this trial.Trial registrationEudraCT Number: 2015-003195-68. Research Registry & References: Clinical trials.gov- NCT02571205 (registered 8/10/15).

Project description:Abstract Delayed puberty is almost universal in patients with Duchenne muscular dystrophy (DMD) treated with pharmacological doses of glucocorticoid. We have demonstrated wide variation in terms of how delayed puberty is managed and set out to evaluate the efficacy of exogenous testosterone on a range of endpoints. This was a single centre clinical trial (NCT02571205) of 15 adolescents with DMD and delayed puberty (12-16 years) treated with an increasing dose of Sustanon 250 starting at 0.2 mls up to a maximum of 1ml every 4 weeks for 2 years. We assessed a range of endpoints including pubertal status, gonadal function, bone turnover markers as well as adverse events (AEs). All 15 patients completed 27 months of follow-up. All were pre-pubertal at baseline with a testicular volume (TV) less than 4mls. Baseline testosterone levels were <2nmol/l. 27 months later (3 months after the last testosterone injection) the mean testicular volume was 3.3 mls (range 1.5-6mls), Tanner stage G4P4 (range G4P4-G5P5) with a mean testosterone of 10.4 nmol/l (1.9-21.8). Mean FSH was 9.1 IU/L (range 1.8-38.3) and mean LH 8.6 IU/L(range <0.5-25.1). By 9-12 months after the last injection there was evidence of endogenous testosterone production with a mean testicular volume of 8mls (4.75-10) and mean testosterone of 11.6nmol/l (5.1-19.1). There were no change in mean P1NP or CTX levels during the study but RANKL decreased from 515.0 pmol/l (227.1) at baseline to 308.2 pmol/l (214.7) after 24 months of testosterone. Qualitative interviews/treatment satisfaction questionnaire responses were encouraging with no significant AEs attributed to testosterone therapy and all patients either ‘satisfied’ or ‘very/extremely satisfied’ with their treatment. 2 patients chose to stop testosterone injections at 18 months because of concerns about potential effects on mobility. They continued to progress through puberty. Testosterone treatment is not part of DMD standard care but this regimen appears to be effective and well-tolerated. By 1 year after cessation of the regimen there is evidence of endogenous testosterone production. Continuing data is required in terms of longer term gonadal function and effects on muscle function and skeletal integrity also require detailed scrutiny.

Project description:Dystrophinopathies cover a spectrum of rare progressive X-linked muscle diseases, arising from DMD mutations. They are among the most common pediatric muscular dystrophies, being Duchenne muscular dystrophy (DMD) the most severe form. Despite the fact that there is still no cure for these serious diseases, unprecedented advances are being made for the development of therapies for DMD. Some of which are already conditionally approved: exon skipping and premature stop codon read-through. The present work aimed to characterize the mutational spectrum of DMD in an Argentinian cohort, to identify candidates for available pharmacogenetic treatments and finally, to conduct a comparative analysis of the Latin American (LA) frequencies of mutations amenable for available DMD therapies. We studied 400 patients with clinical diagnosis of dystrophinopathy, implementing a diagnostic molecular algorithm including: MLPA/PCR/Sanger/Exome and bioinformatics. We also performed a meta-analysis of LA's metrics for DMD available therapies. The employed algorithm resulted effective for the achievement of differential diagnosis, reaching a detection rate of 97%. Because of this, corticosteroid treatment was correctly indicated and validated in 371 patients with genetic confirmation of dystrophinopathy. Also, 20 were eligible for exon skipping of exon 51, 21 for exon 53, 12 for exon 45 and another 70 for premature stop codon read-through therapy. We determined that 87.5% of DMD patients will restore the reading frame with the skipping of only one exon. Regarding nonsense variants, UGA turned out to be the most frequent premature stop codon observed (47%). According to the meta-analysis, only four LA countries (Argentina, Brazil, Colombia and Mexico) provide the complete molecular algorithm for dystrophinopathies. We observed different relations among the available targets for exon skipping in the analyzed populations, but a more even proportion of nonsense variants (∼40%). In conclusion, this manuscript describes the theragnosis carried out in Argentinian dystrophinopathy patients. The implemented molecular algorithm proved to be efficient for the achievement of differential diagnosis, which plays a crucial role in patient management, determination of the standard of care and genetic counseling. Finally, this work contributes with the international efforts to characterize the frequencies and variants in LA, pillars of drug development and theragnosis.

Dataset Information

Is ongoing testosterone required after pubertal induction in Duchenne muscular dystrophy?

Objective

Methods

Results

Interpretation

Publications

Is ongoing testosterone required after pubertal induction in Duchenne muscular dystrophy?

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