Background: Neuroendocrine tumors (NET) are malignant neoplasms that can be associated with specific hormonal syndromes. We describe a novel syndrome of postmenopausal vaginal bleeding and ovarian estradiol overproduction due to an ovarian NET localization.

Methods: A clinical workup was performed for 2 index patients with ovarian metastases of small bowel neuroendocrine tumors and symptoms of postmenopausal vaginal bleeding. Ovarian tissue was collected after oophorectomy, cultured ex vivo and incubated with anti-hormonal and antitumoral drugs. Electronic medical records were screened for postmenopausal patients with ovarian NET localizations and similar symptoms that presented in our center between 1991 and 2023.

Results: In the index patients, clinically significant ovarian estrogen production was demonstrated by a combination of ovarian vein sampling and normalization of circulating estrogen levels after oophorectomy. Ex vivo and in vivo endocrine tests were unable to identify the paracrine mechanism of ovarian estradiol overproduction by NET cells, although a link with gonadotrophins was observed in one case. A retrospective analysis revealed that 21% of postmenopausal patients with an ovarian NET localization reported symptoms of vaginal blood loss.

Conclusions: Together, these findings support the presence of a novel NET-associated hormonal syndrome, which is presumably caused by paracrine effects of infiltrating NET cells on ovarian steroidogenesis.