Simonetta Vespucci is probably one of the most painted women of the Italian Renaissance, widely believed to have been used by painter Sandro Botticelli as his model for Venus, and who appears, transformed and idealised, across several of his most famous works.
She died in 1476, aged just 23, and for centuries, historians have assumed TB was to blame – it was common, it was often fatal, and it fitted the pattern of a young woman fading quickly.
But, writes Paolo Pozzilli in The Conversation, there could quite possibly be another reason altogether.
Pozzilli writes:
In 2019, my colleagues and I proposed a different explanation. We examined the portraits attributed to Botticelli alongside written descriptions from the period, looking for whether the same woman’s face changed in ways that might reflect an underlying illness.
What we found was a gradual shift in her features across multiple paintings – subtle changes to the jaw, the brow, the soft tissue of the face. These are the kinds of changes seen in patients with a pituitary adenoma, a tumour of the small gland at the base of the brain that controls hormone production.
Specifically, we suspected a tumour secreting both growth hormone and prolactin. Excess of these hormones can alter facial contours over time and, in some cases, cause unexpected lactation – and one allegorical figure in Botticelli’s work appears to depict exactly that symptom.
Our 2019 paper was cautious. We were not claiming proof – we were offering a plausible medical reading of the visual evidence, built by combining art history with clinical endocrinology.
Now, in a new paper published in Endocrinology, Diabetes and Metabolism, my team and I have gone further. We believe Simonetta’s death itself – sudden, rapid and dramatic according to contemporary accounts – is consistent with a specific medical emergency: pituitary tumour apoplexy.
Apoplexy occurs when a pituitary tumour bleeds or rapidly swells. It typically causes a sudden and severe headache, loss of vision, confusion, and a swift decline as the body’s hormonal regulation collapses.
We argue that this would explain something that tuberculosis alone struggles to account for: how a previously healthy young woman went from apparent wellness to death within a short period. Chronic infections such as TB usually cause a slower, more visible decline.
Three strands of evidence
Our case rests on three strands of evidence. First, the physical changes visible across the portraits: Botticelli painted her several times, from the 1470s through to the posthumous Birth of Venus (1482-1485), suggesting a tumour growing over months or years.
Second, the symptoms described in chronicles of her final illness (letters exchanged between Piero Vespucci and Lorenzo de’ Medici, describing her collapse at a ball and the headaches, hallucinations, vomiting and fever that followed), which align closely with the clinical presentation of apoplexy.
Third, two documented events in the months before her death – her collapse during vigorous dancing at a ball, and an alleged violent encounter with Alfonso II of Aragon, Duke of Calabria – that could plausibly have triggered a bleed or sudden tumour expansion.
None of this amounts to certainty. There is no tissue sample from 1476, no scan, no way to examine Simonetta directly, only paintings, letters, and clinical reasoning applied five centuries after the fact.
What we can say is that a tumour capable of slowly reshaping a person’s face is also capable, if it ruptures, of killing them quickly. Put together, the portraits and the historical record tell a more complete story than either can alone.
We hope this encourages both historians and medical professionals to look again at cases like Simonetta’s. Medical knowledge can sometimes answer questions that pure historical record cannot. And, in turn, historical puzzles can push medicine to think differently about how disease unfolds in the body over time.
Paolo Pozzilli – Honorary Professor of Diabetes and Clinical Research, Queen Mary University of London
Study details
Pituitary Tumour Apoplexy as Cause of Death of Simonetta Vespucci, the Venus by Botticelli
Domiziana Nardelli Dennis Black Anne Schafer, Paolo Pozzilli
Published in Endocrinology, Diabetes and Metabolism in June 2026
Abstract
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 hypothesise 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.
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