Effects of testosterone, 17beta-estradiol, and downstream estrogens on cytokine secretion from human leukocytes in the presence and absence of cortisol.

Estrogens at physiological concentrations are thought to play an immune-stimulating role, whereas androgens have an anti-inflammatory impact. However, their role on cytokine secretion in the presence or absence of cortisol has not been investigated. Furthermore, the role of hydroxylated estrogens downstream of 17beta-estradiol (E2) on secretion of tumor necrosis factor (TNF) is not known. In this study on peripheral blood leukocytes of healthy male subjects, we scrutinized the influence of prior sex hormones (for 24 h) with and without later addition of cortisol (for another 24 h) on stimulated secretion of TNF, IL-2, IL-4, IL-6, IL-10, and interferon-gamma (IFN-gamma). E2 stabilized or increased immune stimuli-induced secretion of TNF, IL-2, IL-4, IL-6, IL-10, and IFNgamma in relation to testosterone. Testosterone, in contrast, inhibited (IL-2, IL-4, IL-10) or tended to inhibit stimulated secretion of these cytokines (TNF, IFNgamma). This effect of E2 was pronounced at a concentration of 10(-10) M (testosterone: 10(-7) M) in the presence of cortisol. E2 (10(-8) M, 10(-10) M) and testosterone (10(-7) M) did not change glucocorticoid receptor expression. The downstream estrogens 2OH-estradiol(one), 4OH-estradiol(one), and 16OH-estradiol(one) did not stimulate TNF secretion at 10(-10) M, but even inhibited its secretion at 10(-11) M. However, the combination of 16OH-estradiol(one) on one side and 2OH-estradiol(one) or 4OH-estradiol(one) on the other side markedly stimulated TNF secretion that was only observable in the presence of cortisol. In conclusion, at physiological concentrations, E2 and a combination of downstream estrogens stabilized or increased immune stimuli-induced TNF secretion. These effects are dependent on the presence of physiological concentrations of cortisol. This study underlines the proinflammatory role of E2, which is probably dependent on conversion to a proinflammatory cocktail of downstream estrogens and the presence of cortisol

Sex hormones and risk of liver tumor

The liver is morphologically and functionally modulated by sex hormones. Long-term use of oral contraceptives (OCs) and anabolic androgenic steroids (AASs) can induce both benign (hemangioma, adenoma, and focal nodular hyperplasia [FNH]) and malignant (hepatocellular carcinoma [HCC]) hepatocellular tumors. Hepatic adenomas (HAs) are rare, benign neoplasms usually occurring in young women, the development and the complications of which have been related to the strength of OCs and the duration of their use. HA incidence has fallen since the introduction of pills containing smaller amounts of estrogens. FNH is a benign lesion, most commonly seen in young women, which is thought to represent a local hyperplastic response of hepatocytes to a vascular abnormality. Because of the female predominance and the young age at onset, a role of female hormones has been suggested. Furthermore, a large proportion of women with FNH (50-75%) are OC users. Liver hemangiomas (LHs) are the most common benign liver tumors and are seen more commonly in young adult females. The female predilection and clinical observations of LH growth under conditions of estrogenic exposure suggest a possible role for estrogen in the pathogenesis of LHs. HCC has become one of the most widespread tumors in the world in recent years, representing the sixth leading cancer and the third most common cause of death from cancer. Apart from liver cirrhosis, numerous other factors responsible for its onset have been proposed: hepatitis infections from virus B (HBV) and C (HCV), alcohol, smoking, and aflatoxin. However, regardless of etiology, chronic liver diseases progress at unequal rates in the two sexes, with the major sequelae, such as cirrhosis and HCC, being more frequent in men than in women. These epidemiological data have prompted researchers to investigate the relationship between sex hormones and liver tumors. The human liver expresses estrogen and androgen receptors and experimentally both androgens and estrogens have been implicated in stimulating hepatocyte proliferation and may act as liver tumor inducers or promoters