Association of periodontal disease with sex hormones levels among men; an analysis of NHANES III data

Background. The purpose of this study was to investigate the association of periodontal disease with sex hormones. If periodontal disease is associated with abnormal levels of sex hormones this may indicate a link between periodontal disease and prostate cancer. ^ Methods. All participants were derived from the third National Health and Nutrition Examination survey (NHANES III) data. For the purpose of our study, serum samples for hormones measurements such as testosterone, free testosterone, estradiol, free estradiol and sex hormone binding globulin (SHBG) and periodontal examination data were available for 1,101 of these men. ^ Results. After adjusting for known risk factors, periodontal disease was significantly associated with sex hormones as testosterone, free testosterone, estradiol and free estradiol. The association of periodontal disease and sex hormone levels were not significantly different between ethnicity groups. ^ Discussion. The results indicate the need for further study of periodontal disease and serum levels of testosterone, free testosterone, estradiol and free estradiol in men.^

Regulation of sex hormone dependent growth by a serum borne inhibitor

This thesis project focused on understanding the basic process controlling cell proliferation in sex-steroid hormone dependent cancers. The availability of inculture models using cloned cell lines offers the greatest advantage for studying the control of this event. Incubation of cloned sex-hormone sensitive cells in medium containing increasing concentrations of sex-hormone stripped serum, results in a dose dependent growth inhibition; this inhibition is reversed by the addition of physiological concentrations of steroid hormones. The mechanisms explaining this phenomenon are not yet fully understood, but different theories propose the existence in serum of a sex hormone binding protein with growth inhibitory properties. We were able to identify a protein that specifically binds sex hormones in rat and horse serum with affinities 10-fold lower to the ones observed with the classic sex-hormone binding globulin (SHBG) in humans. Purification of this protein on a large scale Lowed a more detailed analysis. The putative sex-hormone binding protein has an apparent molecular weight of 386 KDa. SDS-PAGE with commassie staining of the purified product, displayed a pattern non-characteristic of SMG, but all bands cross-reacted with a commercial anti-SMG antibody in western analysis. Titrations of the purified product on cell proliferation assays using sex-hormone dependent lines, resulted in a dose dependent growth inhibition. This inhibition was reversed by the addition of sex hormones. Our results indicate that we have identified and purified a sex-hormone binding protein in serum with characteristics similar to SHBG and with cell growth inhibitory properties. ^

The relationship between rheumatoid arthritis and reproductive function

There is growing support for the theory that an interaction between the immune and reproductive/endocrine systems underlies the pathogenesis of autoimmune rheumatic diseases. Most of the recent evidence derives from studies of sex hormones and pregnancy in women with systemic lupus. Other than an ameliorative effect of pregnancy, little is known about reproductive factors in relation to rheumatoid arthritis. To elucidate the relationship, a population-based retrospective study was undertaken. Included were 378 female residents of Olmsted County, Minnesota diagnosed with rheumatoid arthritis between 1950 and 1982 (cases) and 325 arthritis-free, married female controls matched to the 324 married cases on birth-year, age at first marriage, and duration of Olmsted County residency. Information of reproductive factors was extracted from the medical records system maintained by the Mayo Clinic.^ Cases had lower fertility rates compared with the female population of Minnesota (rate ratio = 0.86, 95% confidence interval (CI)= 0.80-0.92). Fertility was significantly reduced even prior to the onset of rheumatoid factor positive arthritis. Restricting the comparison to married Olmsted County residents did not alter the results. Further adjustments for time not at risk of conception using survival analysis and proportional hazards modeling only intensified the fertility reduction in the married cases compared with controls. Nulligravidity was more common among cases than controls (odds ratio = 3.16, CI = 1.61-6.20). Independent of fertility, pregnancy had a protective effect against rheumatoid arthritis (odds ratio = 0.31, CI = 0.11-0.89), which was dramatically reversed in the 12 months postpartum (odds ratio = 4.67, CI = 1.50-14.47). Cases were younger at menopause than controls (p $<$ 0.01).^ Small but statistically insignificant associations were observed between rheumatoid arthritis and the following factors: increased frequency of complaints to a physician of infertility; increased frequency of spontaneous abortion, premature birth, and congenital malformations following arthritis onset; and increased prevalence of menopause at arthritis onset. Cases did not differ from controls on age at menarche, duration of pregnancy, or birth weight.^ The findings provide further support for the involvement of the reproductive/endocrine systems in the pathogenesis of autoimmune rheumatic disease. The search for biological mechanisms should be intensified. ^

17-beta estradiol and progesterone-induced alterations in human type-1/type-2 cytokine balance and the role of costimulatory and apoptotic mechanisms

Evidence suggests that sex-based differences in immune function may predispose women to numerous hypersensitivity conditions such as Systemic lupus erythematosus (SLE), Hashimoto's thyroiditis and asthma. To date, the exact mechanisms of sexual dimorphism in immunity are not fully characterized but sex hormones such as 17-β estradiol (E2) and progesterone (PR) are believed to be involved. Since E2 and PR may modulate the production of critical regulatory cytokines, we sought to characterize their effects on the in vitro human type-1/type-2 cytokine balance. We hypothesized that E2 and/or PR vary cytokine production and influence costimulatory molecule expression and apoptosis. We first described the effect of E2 and/or PR on type-1 (IFN-γ and IL-12) and type-2 (IL-4 and IL-10) cytokine production by human peripheral blood mononuclear cells (PBMC) treated with various T-lymphocyte and monocyte stimuli. E2 and/or PR were each used at concentrations similar to those found at the maternal-fetal interface during pregnancy. At this dose, E2 increased IFN-γ and IL-12 production and PR decreased IFN-γ production and tended to increase IL-4 production. Furthermore, the combination of E2+PR decreased IL-12 production. This suggests that E2 shifts the type-1/type-2 cytokine balance towards a type-1 response and that PR and E2+PR shift the balance towards a type-2 response. Next, we used intracellular cytokine detection to demonstrate that E2 and/or PR are capable of altering cytokine production of CD3+ T-cells and the CD3+CD4+ and CD3+CD8+ subsets. In addition, we used the H9 T-lymphocyte cell line and the THP-1 monocyte cell line to show that E2 and/or PR can induce cytokine effects in both T-cells and monocytes independent of their interaction. Lastly, we determined the effect of E2 and/or PR on costimulatory molecule expression and apoptosis as potential mechanisms for the cytokine-induced alterations. E2 increased and PR decreased CD80 expression on THP-1 cells and PR and E2+PR decreased CD28 expression in PBMC and Jurkat cells. Furthermore, E2, PR and E2+PR increased Fas-mediated apoptosis in Jurkat cells and E2 increased FasL expression on THP-1 cells. Thus, E2 and/or PR may alter the cytokine balance by modulating the CD28/CD80 costimulatory pathway and apoptosis. ^

ISOELECTRIC FOCUSING STUDIES OF STEROID BINDING PROTEINS

Steroid binding proteins are an obvious choice in the search for genetic factors in plasma that might predispose to upper body obesity, a risk factor for non-insulin dependent diabetes and cardiovascular disease. The two steroid binding proteins studied by isoelectric focusing were sex hormone binding globulin (SHBG), the transport protein for sex hormones and corticosteroid binding globulin (CBG), the transport protein for corticosteroids. Auto-radiography and immunoblotting on polyacrylamide gels were used to detect polymorphism in SHBG. Immunoblotting on agarose gels was used to visualize corticosteroid binding globulin. SHBG showed similar structural variation in American Caucasians, American Blacks and Canadian Indians. Two alleles (1, 2) were hypothesized with highly polymorphic frequencies in all three ethnic groups. CBG was not found to be polymorphic, but two variants were found in Caucasian male twins and in a Black individual. The finding of a good assay and a polymorphic system for SHBG are the first steps for additional studies into disease associations. ^

Adenovirus-36 infection and obesity related hormones in children

Obesity has a complex, multi-factorial etiology. Infectious agents have recently emerged as a possible contributor to the current obesity epidemic. Seven viruses have demonstrated an association with obesity in animals; however, Adenovirus-36 (Ad-36) is the only known virus associated with obesity in humans. The primary aim of this research was to determine the association between Ad-36 infection and the expression of obesity related hormones in children. Additionally, this study proposed to compare the mean three year change in the level of obesity related hormones between Ad-36 positive and negative children. This study utilized pilot data collected from 98 children at baseline and year three of the Project Heartbeat! cohort. Fasting serum samples were analyzed for the concentration of adiponectin, insulin and leptin. The crude analysis uncovered Ad-36 positive children had significantly lower mean concentrations of insulin (p=0.039) and leptin (p=0.038) at baseline compared to Ad-36 negative children. The results of the adjusted analysis indicated the leptin association with Ad-36 infection at baseline was statistically significant even after controlling for age, sex, ethnicity, and BMI percentile. The longitudinal evaluation revealed individuals with a history of Ad-36 infection experienced a larger mean decrease in adiponectin, a larger mean increase in leptin, and a smaller mean increase in insulin levels over a three year period compared to individuals without a history of infection. These results suggest Ad-36 infection may produce changes in hormone expression. The only statistically significant findings in the crude and adjusted longitudinal analysis occurred at baseline when the children were younger, suggesting physical changes that occur during sexual maturation may mask or enhance Ad-36 induced changes in hormone expression. Furthermore, the longitudinal analysis revealed the duration and course of Ad-36 infection may influence changes in the expression of obesity-related hormones. Taken together, the results of this pilot study are suggestive of an association between Ad-36 infection and the expression of obesity-related hormones.^