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Spinal and bulbar muscular atrophy (SBMA; MIM 313200) is an X linked late onset motor neurone disease characterised by slowly progressive proximal and bulbar muscle weakness, muscle atrophy, postural hand tremor, gynecomastia, and endocrine disturbances that include signs of partial androgen resistance. SBMA is caused by the expansion of a trinucleotide CAG repeat in the first exon of the androgen receptor (AR) gene encoding a polyglutamine stretch.1
Recently, Katsuno et al2 reported that leuprorelin, a lutenising hormone releasing hormone (LHRH) agonist that reduces the level of testosterone release from the testis, rescued motor dysfunction and nuclear accumulation of mutant ARs in a male transgenic mouse model of SBMA. This result indicates that ligand dependent nuclear translocation of mutant ARs containing expanded polyglutamine is the main source of the pathogenesis of SBMA, and that leuprorelin suppresses this translocation. We read this report with great interest, because we followed up a patient with SBMA, who has been administered leuprorelin for 5 years to treat his coexisting prostate cancer.
A 75 year old male noticed bilateral finger tremor at age 57. At age 63, he noticed weakness in his arms. He was admitted to our hospital in December 1991, when he was 64 years old. On initial examination, he had bilateral gynecomastia. Neurological examinations revealed facial weakness and lingual atrophy with fasciculations. Mild muscular atrophy was observed in the proximal parts of the upper extremities. Muscle strength was approximately in the range of 3/5 to 4/5 in the proximal parts, and 5/5 in the distal parts of the upper extremities. Fasciculations were observed in upper and lower extremities. Deep tendon reflexes were either lost or markedly diminished. Babinski signs were absent. Laboratory examinations revealed that the serum creatine kinase (CK) level increased to 803 IU/l (normal range 43–239 IU/l). LH (5.9 IU/L; normal range 1.8–5.2 IU/L) and follicle stimulating hormone (20.5 IU/L; normal range 2.9–8.2 IU/L) levels were elevated. After his informed consent was obtained, high molecular weight genomic DNA was extracted from peripheral leucocytes of the patient according to standard protocols. Genetic analysis of the AR gene was performed and the expansion of a CAG repeat (45 repeats) in exon 1 of the AR gene was identified, leading to a diagnosis of SBMA.
At age 67, he developed weakness in the legs, and noticed difficulty in climbing up stairs or standing up from a chair. Serum CK levels gradually increased to 1717 IU/l at age 70. In January 1998, when he was 71 years old, he was diagnosed as having prostate cancer, and was intramuscularly injected with 3.75 mg of leuprorelin every 28 days, because leuprorelin inhibits production of testosterone and dihydrotestosterone (DHT), which enhances the growth of prostate cancer cells. One month after the start of treatment, he noticed that his gait disturbance was rapidly exacerbated; however, the gait disturbance returned to the level before the start of treatment by April 1998. After the episode of transient exacerbation, his muscle weakness and atrophy exhibited no apparent deterioration to date. On the contrary, an improved muscle strength was recorded in the neck flexor, biceps brachii, and quadriceps femoris muscles. Furthermore, serum CK levels gradually decreased from 1717 IU/L to 834 IU/L after the leuprorelin treatment (see fig 1). Levels of LH (<0.6 IU/L) or testosterone (<0.1 IU/L; normal range 1.2–8.0 IU/L) were decreased by the leuprorelin injections.
The experience of a 5 year follow up of this patient treated with leuprorelin is highly indicative of the following. Firstly, leuprorelin treatment induced a transient deterioration of the motor function in humans, as demonstrated in a transgenic mouse model of SBMA.2 Secondly, after the initial transient deterioration, long term stabilisation of the motor function was obtained. Finally, leuprorelin treatment was effective even when the treatment was started in the advanced stage of the disease, although the patient’s muscle weakness and atrophy have not completely disappeared. These findings provide grounds for the proposal made by Katsuno et al2 that leuprorelin is a promising candidate for the treatment of SBMA.
At least nine neurodegenerative diseases are known to be caused by expanded CAG repeats. SBMA is unique among these diseases because the disease protein, AR, has a specific ligand, testosterone. It has been demonstrated that the nuclear translocation of ARs is solely dependent on testosterone. Recently, a transgenic mouse model carrying full length AR containing 97 glutamine repeats has been generated, and this model showed progressive muscular atrophy and weakness.3 These phenotypes were markedly pronounced in male transgenic mice, which were significantly rescued by castration. Female transgenic mice exhibited only a few manifestations that markedly deteriorated with testosterone administration. Furthermore, in a Drosophila model of SBMA, it has been demonstrated that androgen agonists induce nuclear translocation of the mutant ARs and toxicity.4 Taken together, this raises the possibility that blockade of nuclear translocation of the mutant ARs by hormonal intervention can provide therapeutic benefits in SBMA.
LHRH agonists including leuprorelin have been used for the treatment of prostate cancer. These drugs eventually inhibit LH production, which in turn inhibits production of testosterone and DHT, on which growth of prostate cancer cells depend. The alleviation or improvement of muscular weakness and decrease in the serum CK level in our patient may be due to the anti-androgen effects of leuprorelin. Interestingly, he noticed rapid exacerbation of gait disturbance one month after the administration of leuprorelin. It has been demonstrated that when LHRH agonists are administered continuously, the pituitary gland is initially stimulated, but after 5−12 days, the pituitary gland becomes desensitised and stops releasing LH.5 When that occurs, the testes stop releasing testosterone. During the period of the initial stimulation, more LH is released, consequently there is a surge in the secretion of testosterone and DHT from the testes (so called “androgen surge”). It is reasonable that administration of leuprorelin causes a transient exacerbation of muscle weakness in patients with SBMA due to the transient androgen surge.
In conclusion, we report the beneficial effect of leuprorelin on SBMA. Our current experience warrants further investigations to determine whether leuprorelin may be of benefit for the treatment of SBMA in humans.
Competing interests: none