Pituitary Tumour Apoplexy as Cause of Death of Simonetta Vespucci, the <i>Venus</i> by Botticelli

INTRODUCTION: Simonetta Vespucci is the model for the world-renowned Venus painted by Sandro Botticelli at the end of the XV Century. Her unexpected death at the age of 23 remained a mystery for more than 500 years, until we proposed in 2019 that she probably suffered from a pituitary adenoma. METHODS: We now hypothesize with further evidence from historical descriptions of her last days that an expansion of the adenoma was the cause of her premature death, aged twenty-three. RESULTS: Our hypothesis is supported by three elements: (1) tumour characteristics; (2) symptoms presented during her last days; and (3) the historical records of two potential precipitating events. CONCLUSIONS: We conclude that Simonetta Vespucci, the Venus by Botticelli, died as a consequence of a rapidly expanding pituitary adenoma causing tumour apoplexy, thereby making this endocrine emergency the likeliest cause of her death.