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黑色素瘤是一种致命的皮肤癌，占皮肤癌的不到2%，但却导致75%的皮肤癌死亡[1]。太阳紫外线被认为是90%的黑色素瘤发病率的罪魁祸首，只有10%的黑色素瘤在家族中遗传。流行病学研究表明，男性的死亡率高于女性。目前的靶向治疗和免疫治疗伴随着严重的副作用，如内分泌病和其他过敏和自身免疫疾病[4,5]。这种情况要求在开发任何治疗方法之前必须了解这种疾病的基本性质。在这个关键时刻，类固醇对黑素瘤生长[6]的体外和体内影响的研究为这种疾病的性质提供了基础。

皮肤不仅是人体最大的器官，也是分泌各种激素的内分泌腺[7,8]。皮肤有类似的下丘脑、垂体和肾上腺轴，产生POMC、ACTH和糖皮质激素类固醇生成[9]。研究表明，皮肤中激素的局部产生不仅影响局部，而且影响全身。此外，皮肤也是产生睾丸素和雌激素等性激素的场所。性类固醇，如孕酮、雌激素和雄激素是健康皮肤所必需的。事实上，在皮肤中产生黑色素的黑素细胞是受垂体[8]分泌的黑素细胞刺激激素(MSH)的影响。因此，这些观察结果提出了一个问题，黑色素瘤是否像乳腺癌、子宫内膜癌和前列腺癌一样是一种依赖激素的癌症。到目前为止，来自太阳的紫外线和其他辐射被认为是黑色素瘤的主要原因，但激素不是这种疾病的原因。然而，各种体外实验表明类固醇激素降低了黑色素瘤细胞的生长[12,13]。我们的实验室还发现，女性激素孕酮在体外可以显著抑制黑色素瘤细胞的生长[14,15]。 Other researchers , Fang et al. [16] from China also showed the effect of progesterone on melanoma cell growth in-vitro. Later the study was repeated by Moroni et al. [17] from Italy using progesterone concentration up to 1000 µM and showed the inhibition of melanoma cell growth. Earlier Kanda and Watanbe [18] from Japan also demonstrated the inhibitory effect of progesterone on melanoma cell growth. So, these in-vitro studies suggested that progesterone might regulate melanoma cell growth. This raised the question whether there were in-vivo evidences for the effect of progesterone on melanoma. To that end, previous clinical studies showed that menstruating females were better protected in melanoma than post-menopausal women and men of any age [19,20]. But these clinical studies were not correlated with steroid status in females and did not demonstrate any direct effect of steroids on melanoma cells. In addition, there were in-vivo experiments with small animals where steroids were used to treat melanoma [21,22]. So, in-vitro and in-vivo studies suggested that melanoma could be a hormone responsive cancer, where hormones were needed for survival in melanoma. Progesterone could be the steroid hormone protecting menstruating females in melanoma, as progesterone level peaked in menstruating females between 1000 – 1500 ng/dL [23]. Whereas, progesterone level in post-menopausal women ranged between 20 – 100 ng/dL [23]. Further, epidemiological data showed that mortality rate was higher in males than in females [3]. Progesterone level in males ranged between 27 – 90 ng/dl and its function were not known in males. So, the two groups which were not protected in melanoma had low progesterone level in circulation. But this observation could be a mere coincidence between progesterone and melanoma growth. A valid biochemical evidence mediated by a biomolecule is needed to make the connection between, progesterone and melanoma growth. In this context, our further in-vitro research revealed that progesterone action was mediated by a specific suppression of pro-inflammatory cytokine IL-8 [24]. When IL-8 level was decreased, melanoma cell growth was decreased. There were several in-vitro and in-vivo studies connecting IL-8 level with melanoma growth such as IL-8 acting as an autocrine growth factor for melanoma cell growth and IL-8 conditional expression increased melanoma growth and metastasis in a mouse model [25,26].

总之，体外和体内动物研究以及临床和流行病学研究表明，黑色素瘤可能是一种激素(孕激素)反应性癌症，孕激素的作用是通过抑制促炎细胞因子IL-8介导的。反过来，IL-8被证明可以调节黑色素瘤细胞的生长。因此，IL-8可能是孕酮对黑色素瘤生长作用的中介分子，为以往临床发现的月经期女性(孕酮峰值为1000-1500 ng/dL)在黑色素瘤中得到更好的保护提供了生化基础。了解黑素瘤的这一基本性质对于开发黑素瘤的未来治疗方法非常重要。

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