Volume 6, Issue 1

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder. Worse prognostic factors in ALS are: (a) advanced age, (b) bulbar onset, and (c) short time between onset and diagnosis. Progesterone (PROG) has been associated with neuroprotective and promyelinating activities in injury, ischemia and degeneration of the central and peripheral nervous system. Cortisol is connected to the response to stress situations and could contribute to neuronal damage. The goals of this study were: (i) to investigate whether PROG levels are modified by ALS prognostic factors and (ii) to determine whether cortisol follows the same pattern. We determined serum steroid levels in 27 patients with sporadic ALS (sALS) and 21 controls. Both steroid hormones showed significantly increased levels in ALS patients versus controls (mean±SEM: PROG ALS vs. control: 0.54±0.05 vs. 0.39±0.04 ng/mL, p<0.05; cortisol ALS vs. control: 17.02±1.60 vs. 11.83±1.38 μg/dL, p<0.05). 1 A trend towards higher levels of PROG were demonstrated in spinal onset patients compared with bulbar onset (p=0.07), positive correlation with survival time (R Rho =0.43, p=0.04) and a trend towards significance with time to diagnosis (R Rho =0.36, p=0.06). These correlations have not been demonstrated for cortisol. Elevated serum steroid levels in sALS were probably due to hyperfunction of the hypothalamic-pituitary-adrenal axis. However, only PROG correlated with better prognostic factors. Future studies will determine if the different behavior of PROG and cortisol relate to any particular role they might play during the course of this motor neuron degenerative disease. 1 Conversion factors from conventional units to SI units: Progesterone ng/mL to nmol/L=3.18 Cortisol μg/dL to nmol/L=27.59

The aim of this review is to describe the associations between circulating plasma estrogens and prostate cancer (PCa). We recall the origins of estrogens, which derive from the aromatization of androgens, but also by sulfatase hydrolysis of estrone sulfate (E1-S), the main circulating plasma estrogen. We evoke that the carcinogenic effects of estrogens were demonstrated in the rat and murine prostate when estrogens and androgens were simultaneously administered to them. We also describe estrogen proliferative activity and the genotoxicity of estrogen-hydroxylated metabolites with the formation of DNA adducts. We report published aromatase and CYP1B1 polymorphisms found in men with PCa. We published a bibliography on the relation between PCa and prostate inflammation, as well as the possible role of obesity in the aggressiveness of PCa. In this review, we provide an exhaustive list of assays carried out in subjects at high risk for PCa compared with Caucasians, showing that higher estrogen levels were found in the plasma of these subjects at high risk for PCa. Plasma estrone was the estrogen for which plasma concentration was highest in subjects of African descent. We recall the links observed between plasma estrogens, particularly E1-S, and PCa aggressiveness. Finally, we describe assays for determining hydroxylated estrogens and DNA adducts in the urine of men with PCa. We insist on the importance of the technology employed in estrogen measurement and propose the use of mass spectrometry methods to carry out estrogen assays, in order to decrease variability in the results of plasma estrogen assays.

Objectives: Progestogens influence mammary gland development and probably breast cancer tumorigenesis by regulating a broad spectrum of physiological processes. We investigated receptor membrane-initiated actions of progestogens in MCF-7 breast cancer cells overexpressing progesterone receptor membrane component 1 (PGRMC1). Design: MCF-7 cells were stably transfected with PGRMC1 expression plasmid (MCF-7/PGRMC1-3HA) and overexpression of PGRMC1 was verified by immune fluorescent analysis and Western blot. To test the effects of progestogens on cell proliferation, MCF-7 and MCF-7/PGRMC1-3HA cells were stimulated with a membrane-impermeable progesterone: BSA-fluorescein-isothiocyanate conjugate (P4-BSA-FITC), unconjugated progesterone (P4), medroxyprogesterone acetate (MPA), norethisterone (NET) and drospirenone (DRSP). Furthermore, reverse phase protein technology was applied to identify modified downstream signaling. Results: Progesterone did not elicit any proliferative effect on MCF-7/PGRMC1-3HA cells. By contrast, P4-BSA-FITC, DRSP, MPA and NET significantly triggered proliferation of MCF-7/PGRMC1-3HA cells, the effect being more pronounced for NET. Almost no effect of progestogens on proliferation was observed in MCF-7 cells. In MCF-7/PGRMC1-3HA cells, expression of Erk1/2 was significantly reduced by 40% compared to MCF-7 cells. Conclusions: Our data indicate that PGRMC1 mediates a progestogen-dependent proliferative signal in MCF-7 cells. Of significant interest is that progesterone and synthetic progestins that are used for hormone therapy are different in their proliferative effects on MCF-7 and MCF-7/PGRMC1-3HA cells. Progesterone appears to act neutrally, whereas MPA, NET and DRSP trigger proliferation and thus might increase breast cancer risk. The data presented are very important in terms of the positive results of progestogens and breast cancer risk in clinical studies so far.

Background: Testosterone administration to hypogonadal men improves the metabolic syndrome. This study analyzed whether age, serum testosterone, body mass index/waist circumference, increment in testosterone values and C-reactive protein (CRP) predicted the outcome of testosterone administration. Materials and methods: A total of 110 mainly elderly men, aged between 18 and 83 years (mean±SD=59.6±8.0) with baseline serum testosterone of 5.8–12.1 nmol/L (mean±SD=9.3±1.7) (n>14.0 nmol/L), received parenteral testosterone undecanoate whereupon serum testosterone normalized between 3 and 24 months. Results: (i) The lower the baseline testosterone, the stronger the decreases in waist size and triglycerides. (ii) The greater the increment in serum testosterone, the stronger the decreases in low-density lipoprotein (LDL) cholesterol, triglycerides and glucose. (iii) Older age was associated with stronger beneficial effects on waist size, glucose and all lipids, but a small negative effect on high-density lipoprotein cholesterol. (iv) Obese men and men with the largest waist circumference showed the strongest declines over 2 years in weight, waist circumference and body mass index (BMI), and also in total cholesterol, triglycerides and glucose. Baseline BMI predicted a stronger decline in LDL cholesterol, but a smaller decline in CRP levels. (v) Higher baseline CRP predicted larger declines in levels of triglycerides, glucose and CRP. (vi) In the multivariate model, age, BMI and CRP were independent predictors of the strongest benefit of testosterone treatment on the metabolic syndrome. Conclusions: Older men, particularly when obese with chronic low-grade inflammation benefited most of normalizing their testosterone levels, preferably if they reached mid-normal reference values.

Background: Human 17β-hydroxysteroid dehydrogenase type 1 (17β-HSD1) acts at a pre-receptor level. It catalyzes NADPH-dependent reduction of the weak estrogen estrone into the most potent estrogen estradiol, which exerts its proliferative effects via estrogen receptors. Overexpression of 17β-HSD1 in estrogen-responsive tissues is related to the development of hormone-dependent diseases, such as breast cancer and endometriosis. 17β-HSD1 thus represents an attractive target for development of new drugs. Methods: We designed and synthesized a series of 3-, 5- and 6-phenyl indole derivatives as mimetics of the steroid substrate estrone. All of these compounds were evaluated for inhibition of recombinant human 17β-HSD1 from Escherichia coli , at concentrations of 0.6 μM and 6.0 μM. Results: Among 14 indole derivatives, compound 9 was an initial hit inhibitor of 17β-HSD1, with moderate inhibition (64% at 6 μM). Molecular docking into the crystal structure of 17β-HSD1 (1A27) revealed that this 5-phenyl indole derivative binds to 17β-HSD1 similarly to co-crystalized E2. Compound 9 forms two H-bonds with 17β-HSD1: one between the indole nitrogen and His222, and the second between the phenolic OH group and catalytic Tyr155. Conclusions: The indole scaffold is one of the possible starting points for the design of substrate mimetics of the steroid substrate estrone. Our study shows that these 6- and, especially, 5-phenol indole derivatives can act as moderate inhibitors of 17β-HSD1. Based on inhibition assays and docking simulations, we can infer further improvements of the 5-phenol indole derivatives that might result in better inhibition profiles.