A Comprehensive Endocrine Description of Kennedy’s Disease Revealing Androgen Insensitivity Linked to CAG Repeat Length

Abstract

Our study aims to provide a comprehensive view of the endocrine features in Kennedy's disease (KD). Twenty-two men with KD underwent detailed endocrine investigations. Clinical signs of partial androgen resistance were present in more than 80% of the patients, with gynecomastia being the most prominent. Gynecomastia was postpubertal but appeared before muscular weakness in most cases. Thirteen patients had alteration of testicular exocrine function. Hormonal profile of partial androgen resistance was present in 86% of the patients, with an elevated testosterone level in 68%. Androgen insensitivity seems to appear later in life in KD, similar to the development of neurological signs. Although we confirm the previously reported correlation between the CAG repeat length and the early onset of the neurological disease, we describe a significant correlation between repeat length and the age of onset of gynecomastia as well as biological indexes of androgen insensitivity. This is supported by numerous in vitro data correlating variations in the CAG tract with androgen receptor activity; the longer the CAG repeats, the weaker the receptor transactivation. Ours is the first study to show such a clear and prominent pattern of androgen insensitivity in KD. In clinical practice, KD patients are often misdiagnosed as having amyotrophic lateral sclerosis. Careful examination of the endocrine component could avoid such a deleterious misdiagnosis.

Non-neural phenotype of spinal and bulbar muscular atrophy: results from a large cohort of Italian patients

“…According to the International Prostate Symptom Score (IPSS), 23 lower urinary tract symptoms (LUTS) were classified as mild (IPSS 0-7), moderate (8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19) and severe (>19) (see online supplementary material). Seven patients reporting severe LUTS (IPSS>19) were further characterised by prostate volume analysis by transabdominal ultrasonography 24 and videourodynamic evaluation performed according to the International Continence Society (ICS) recommendations.…”

“…The majority of patients show endocrine dysfunctions mainly consisting of partial androgen insensitivity 23 12 These include gynaecomastia, testicular atrophy, erectile dysfunction (ED) and decreased fertility. Abdominal obesity, dyslipidemia and glucose intolerance are also detected in some patients.…”

Efficacy and safety of dutasteride in patients with spinal and bulbar muscular atrophy: a randomised placebo-controlled trial

“…There is currently no effective treatment. In addition to bulbar and extremity muscle weakness, SBMA patients may have manifestations of androgen insensitivity 2. The cause of SBMA is a repeat expansion in the androgen receptor (AR) gene that causes a toxic gain of function in the AR protein and leads to a loss of spinal and bulbar motor neurons 3…”

Male patients with partial androgen insensitivity syndrome: a longitudinal follow-up of growth, reproductive hormones and the development of gynaecomastia

“…Decreased signalling activity of the AR may also result in gynaecomastia. Trinucleotide CAG repeat expansions in exon 1 of the AR gene (CAGn>38) results in decreased AR signalling, and is responsible for Kennedy's disease, in which gynaecomastia is a very frequent symptom 9. Kennedy's disease is mainly characterised by neuromuscular problems (the disease is also termed X-linked spinal and bulbar muscle dystrophy) which normally manifest themselves in patients aged 40–50 years, but onset in adolescence and young adulthood has also been reported.…”