SAT020 Is Testosterone The Male Sex Hormone Responsible For Increased Male Mortality In Melanoma? In-vitro Studies On Two Human Melanoma (BLM, 1205Lu) Cell Models

Disclosure: P. Ramaraj: None. Epidemiological data pointed to increased male mortality in melanoma and clinical studies pointed to better protection of menstruating females in melanoma than post-menopausal women and men of any age. Our in-vitro studies with progesterone (P) on human melanoma (BLM and 1205Lu) cell lines showed a significant decrease in cell growth along with a decrease in the secretion of proinflammatory cytokine IL-8 by these cells. These in-vitro studies correlated with the hormonal data which showed that progesterone levels in menstruating females ranged between 1000 - 1500 ng/dl, compared to post-menopausal women 20 - 100 ng/dl and men 27-90 ng/dl, suggesting low progesterone levels meant no protection in melanoma. This observation prompted us to hypothesize that lack of progesterone in males could be a cause for increased male mortality. This hypothesis also raised the question of the role of male sex hormones (AD-androstenedione and T-testosterone) in increased male mortality. In order to address these questions in-vitro experiments were planned. First, to indirectly induce endogenous IL-8 by pretreating the cells with endothelin and then adding steroid hormones (AD, T, P). Secondly, to add IL-8 directly to the cells and then add steroid hormones. Finally, to suppress endogenous IL-8 with curcumin and then add T to one set of cells and IL-8 + T to another set of cells. For the first experiment, the result was a marginal increase in cell growth (67%) in cells pretreated with endothelin followed by T-treatment compared to straight T-treated cells (60% cell growth) without endothelin pretreatment. For the second experiment, there was a slight increase in cell growth in IL-8-added cells, but it was not statistically significant. For the final experiment, the cells treated with IL-8 + T after curcumin pretreatment showed a partial restoration of cell growth (49%) compared to cells (40% cell growth) treated with plain T after curcumin treatment, suggesting T was not able to control or regulate IL-8 action like progesterone. These in-vitro experiments suggested that in males 2 reasons 1) a deficiency of progesterone and 2) inefficiency of T to control 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 leading to death. So, a situation arising out of male reproductive endocrine physiology could probably be responsible for increased male mortality in melanoma. Presentation: Saturday, June 17, 2023