Simonetta Vespucci died in Florence on the night of April 26, 1476. She was 23 years old. For more than five centuries, the official cause of her death was tuberculosis.
A study published June 12, 2026, in the journal Endocrinology, Diabetes & Metabolism proposes a different explanation: a tumor in the pituitary gland that triggered an acute hemorrhage, a medical emergency known as pituitary apoplexy.
The research was led by Domiziana Nardelli, an otolaryngology resident at the Università Campus Bio-Medico di Roma, alongside Paolo Pozzilli, a professor of clinical research at Queen Mary University of London, and colleagues from the University of California.
The same team had argued in 2019 that Vespucci may have suffered from a pituitary adenoma, based on visible changes in her facial features across multiple Botticelli portraits.
The new study adds evidence from documents of the period and concludes that it was the growth of that tumor — not a lung infection — that killed her.
A Muse Painted Five Times
Simonetta Cattaneo was born around 1453 in the Ligurian region of Italy. In 1469, she married Marco Vespucci, a member of a Florentine banking family related to the explorer Amerigo Vespucci.
In Florence, she was quickly drawn into the inner circle of the Medici court. The humanist Poliziano called her la Sans Par — “the incomparable” — and she was close to Lorenzo and Giuliano de’ Medici, though the precise nature of those ties has long been debated by historians.
Sandro Botticelli, a devoted admirer and close friend, painted her five times. He is widely believed to have used her as the model for the face of Venus in The Birth of Venus.
When she died, her body was laid out fully clothed with her face uncovered — an honor reserved for the most distinguished figures of Renaissance Florence — and she was buried in the church of Ognissanti.
In 1510, near the end of his own life, Botticelli asked to be buried at the foot of her tomb.
What the Researchers Found
The team reconstructed Vespucci’s final days from correspondence between Piero Vespucci and Lorenzo de’ Medici.
According to those letters, she collapsed during a dance and spent her final hours in a darkened room, suffering from severe headaches, hallucinations, vomiting, and high fever.
For the study’s authors, that clinical picture is consistent with pituitary apoplexy — an episode in which a pituitary tumor hemorrhages or expands suddenly, potentially causing vision loss, confusion, and rapid hormonal collapse.
The researchers point to two events in the months before her death that may have triggered the tumor’s hemorrhage.
One was the physical strain of the dance during which she collapsed. The other was an encounter with Alfonso II of Aragon, Duke of Calabria, that some contemporary accounts describe as a violent assault. The authors themselves acknowledge that the historical accuracy of that account remains uncertain.
What the Portraits May Have Unknowingly Captured
To support their hypothesis, the team applied a deep-learning facial recognition algorithm to five Botticelli portraits of Vespucci. The goal was to identify changes in her facial features consistent with the gradual growth of a tumor.
According to Pozzilli, Botticelli’s Allegory of a Woman depicts Vespucci in a nursing pose, even though the historical record indicates she had no children. The team interprets this detail as a possible visual sign of a prolactin- and growth hormone-secreting adenoma.
The study also raises the possibility that the slight cast in Venus’s eyes in The Birth of Venus — celebrated for centuries as a mark of beauty and modesty — may have the same explanation. Pozzilli is preparing a new paper focused specifically on that detail.
The authors are careful to acknowledge the limits of their work. No tissue, no X-ray, no direct examination of Vespucci is possible 550 years after her death.
The entire reconstruction rests on paintings, letters, and clinical reasoning applied five centuries after the fact — which makes the diagnosis a compelling hypothesis, but not a medical certainty.
