Abstract 5287: Is testosterone the male sex hormone responsible for increased male mortality in melanoma? In-vitro studies based on human melanoma (BLM) cell model

Abstract

Abstract Clinical studies showed that menstruating females were better protected in melanoma than post-menopausal women and men of any age. But, these studies did not correlate with the steroid status of females. Our in-vitro study with progesterone (P), a female sex hormone showed significant inhibition of human melanoma cell growth. A literature survey showed that progesterone levels ranged between 1000-1500 ng/dl in menstruating females compared to post-menopausal women (20-100 ng/dl) and men (27-90 ng/dl), suggesting increased progesterone levels could offer protection to the menstruating females. Moreover, Elisarray showed that progesterone action was mediated by specific suppression of proinflammatory cytokine IL-8. So, it was proposed that a low level of progesterone in males leading to non-suppression of IL-8 in melanoma, could be responsible for increased melanoma cell growth and male mortality. This hypothesis prompted us to check the effect of male sex hormones androstenedione (AD) and testosterone (T) on melanoma cell growth and IL-8 secretion. Both AD and T decreased IL-8 secretion along with a decrease in cell growth. However, when progesterone was added along with androgens, there was a significant decrease in cell growth and in IL-8 secretion. This raised the question of why male mortality was high when androgens also decreased cell growth and IL-8 secretion. In order to address this question, it was decided to induce endogenous IL-8 in melanoma cells by pre-incubating with endothelin (50ng/ml) and then add steroids. AD and P individually decreased IL-8 secretion and in combination significantly decreased IL-8 secretion and cell growth even in endothelin pretreated cells when compared to their respective control cells. But, T was not able to suppress endogenous IL-8 induced by endothelin and in fact, cell growth also was slightly increased compared to straight T-treated cells. Conclusion: So, in males 2 reasons 1) a deficiency of progesterone and 2) inefficiency of T to suppress endogenous IL-8 could possibly result in increased IL-8 levels. This increased IL-8 level in males could lead to increased cell growth and metastasis in melanoma (IL-8 had already been shown to stimulate melanoma cell growth and metastasis by us and others) leading to death. So, a situation arising out of male reproductive endocrine physiology could probably be responsible for increased male mortality in melanoma. Citation Format: Pandurangan Ramaraj. Is testosterone the male sex hormone responsible for increased male mortality in melanoma? In-vitro studies based on human melanoma (BLM) cell model. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5287.