Elevated Plasma Levels of the Novel Hormone INSL3 in a Woman with Metastatic Ovarian Cancer

Abstract

Ovarian cancer is the most lethal gynecologic cancer and the fifth cause of cancer death in women (1). Most patients present at an advanced stage with poor survival while at early stages the long-term survival rate is close to 90% (2). There is no effective method for early diagnosis through serum markers or other means. The most common biomarker for ovarian cancer is CA 125 but it lacks sensitivity and specificity as it is elevated also in other benign and malignant clinical conditions (2).Insulin-like peptide-3 (INSL3), a recently identified member of the insulin superfamily, is synthesized in testicular Leydig cells and, although to a much lesser extent, in the theca cells of the ovary (3). A specific immunoassay for its measurement in plasma has been developed recently and it has been demonstrated that this peptide is secreted almost exclusively by Leydig cells in men, and that the plasma levels in premenopausal women are 6 to 13-fold lower than those in men (4).We recently observed a 34-year-old woman who was admitted in our clinic for dyspnea. A bilateral, poorly differentiated papillary serous ovarian carcinoma was diagnosed in April 2004 with distant metastatses (FIGO stage IV). After diagnosis the patient received chemotherapy and then underwent surgical removal of the ovaries, uterus, fallopian tubes, breasts, omentum, peritoneum, spleen, and abdominal lymph nodes, which were all sites of metastatic invasion. On admission, the patient was severely dyspneic with respiratory acidosis and bilateral pleural effusion (cytologically proven as malignant); thoracic CT scan revealed multiple metastatic lesions in the lungs and pleuras. The patient died a few days after admission.In this patient CA 125 plasma levels were highly elevated. Using a specific enzymatic immunoassay we evaluated INSL3 plasma levels, which were 35-fold higher than those found in healthy premenopausal women (Tab. I). Plasma concentrations of INSL3 were determined in duplicate using an enzymatic immunoassay specific for human INSL3 (Phoenix Pharmaceuticals, Inc., Belmont, CA, USA). The lower detection limit of this assay is 10 pg/mL, with intra-and interassay variations of <5% and <14%, respectively.For the present study, premenopausal women were recruited among female partners of infertile couples attending our clinic because of male factor infertility; the women were healthy and had normal ovarian function. Postmenopausal women were recruited among patients admitted to our clinic because of emergencies pertaining to internal medicine. Male subjects were recruited among a group of young subjects attending our clinic because of left varicocele with normal testicular function. All subjects gave their informed consent for INSL3 plasma level evaluation (Tab. I).The elevated INSL3 plasma levels found in this ovariectomized patient with metastatic serous ovarian cancer suggest that during malignant transformation cancer cells acquired the ability to secrete this hormone, whose production in adult healthy women is negligible.To the best of our ...

INSL3 has tumor‐promoting activity in thyroid cancer

“…If one assumed the presence of an RXFP2 gene product in thyroid cells as suggested by our PCR and promoter experiments, the activation of endogenous RXFP2 would only be feasible through INSL3 derived from the systemic circulation. Detectable INSL3 serum levels have so far been reported in early postnatal boys, postpubertal men, pregnant women, or a woman with metastatic ovarian cancer 33–37. Although speculative at this stage, the fact that thyroid disease is up to 3 times more frequent in women and blunted during pregnancy may suggest a potential involvement of systemic INSL3 as a protective factor in the normal thyroid gland.…”

Identification and Validation of a Hypoxia-Immune-Based Prognostic mRNA Signature for Oral Squamous Cell Carcinoma

“…The tumor-promoting effect of INSL3 in cancer has also been widely addressed. The plasma level of INSL3 was found to be raised in an individual with metastatic ovarian cancer [32]. Other reports highlight the potential role of INSL3 as a marker of human testicular Leydig cell tumors [33].…”

Identification and Validation of a Hypoxia-Immune-Based Prognostic mRNA Signature for Oral Squamous Cell Carcinoma

“…e tumor-promoting effect of INSL3 in cancer has also been widely addressed. e plasma level of INSL3 was found to be raised in an individual with metastatic ovarian cancer [42]. Other reports highlight the potential role of INSL3 as a marker of human testicular Leydig cell tumors [43].…”