Differential Action of Glycoprotein Hormones: Significance in Cancer Progression

Growth of multicellular organisms depends on maintenance of proper balance between proliferation and differentiation. Any disturbance in this balance in animal cells can lead to cancer. Experimental evidence is provided to conclude with special reference to the action of follicle-stimulating hormone (FSH) on Sertoli cells, and luteinizing hormone (LH) on Leydig cells that these hormones exert a differential action on their target cells, i.e., stimulate proliferation when the cells are in an undifferentiated state which is the situation with cancer cells and promote only functional parameters when the cell are fully differentiated. Hormones and growth factors play a key role in cell proliferation, differentiation, and apoptosis. There is a growing body of evidence that various tumors express some hormones at high levels as well as their cognate receptors indicating the possibility of a role in progression of cancer. Hormones such as LH, FSH, and thyroid-stimulating hormone have been reported to stimulate cell proliferation and act as tumor promoter in a variety of hormone-dependent cancers including gonads, lung, thyroid, uterus, breast, prostate, etc. This review summarizes evidence to conclude that these hormones are produced by some cancer tissues to promote their own growth. Also an attempt is made to explain the significance of the differential action of hormones in progression of cancer with special reference to prostate cancer.

Halogen Bonding Controls the Regioselectivity of the Deiodination of Thyroid Hormones and their Sulfate Analogues

The type1 iodothyronine deiodinase (1D-1) in liver and kidney converts the L-thyroxine (T4), a prohormone, by outer-ring (5) deiodination to biologically active 3,3,5-triiodothyronine (T3) or by inner-ring (5) deiodination to inactive 3,3,5-triiodothronine (rT3). Sulfate conjugation is an important step in the irreversible inactivation of thyroid hormones. While sulfate conjugation of the phenolic hydroxyl group stimulates the 5-deiodination of T4 and T3, it blocks the 5-deiodination of T4. We show that thyroxine sulfate (T4S) undergoes faster deiodination as compared to the parent thyroid hormone T4 by synthetic selenium compounds. It is also shown that ID-3 mimics, which are remarkably selective to the inner-ring deiodination of T4 and T3, changes the selectivity completely when T4S is used as a substrate. From the theoretical investigations, it is observed that the strength of halogen bonding increases upon sulfate conjugation, which leads to a change in the regioselectivity of ID-3 mimics towards the deiodination of T4S. It has been shown that these mimics perform both the 5- and 5-ring deiodinations by an identical mechanism.

Remarkable Effect of Chalcogen Substitution on an Enzyme Mimetic for Deiodination of Thyroid Hormones

Iodothyronine deiodinases are selenoenzymes which regulate the thyroid hormone homeostasis by catalyzing the regioselective deiodination of thyroxine (T4). Synthetic deiodinase mimetics are important not only to understand the mechanism of enzyme catalysis, but also to develop therapeutic agents as abnormal thyroid hormone levels have implications in different diseases, such as hypoxia, myocardial infarction, critical illness, neuronal ischemia, tissue injury, and cancer. Described herein is that the replacement of sulfur/selenium atoms in a series of deiodinase mimetics by tellurium remarkably alters the reactivity as well as regioselectivity toward T4. The tellurium compounds reported in this paper represent the first examples of deiodinase mimetics which mediate sequential deiodination of T4 to produce all the hormone derivatives including T0 under physiologically relevant conditions.

The survey of sexual maturity in Mugil cephalus so measuring sex hormones and histologic studies

In this study the process of female gray mullet brooders was carried out by using histological study and masurment of sex steroids. Results of histological studies showed that oocyte of gray mullet brooders in Gomishan Rearing Center conditions of develop to the end of yolk globule stage. The results were observed with oocyte in chromatin nucleolar stage (first stage) with means of diameter of 20 p m, in August, perinucleolar stage (second stage) in September with mean diameter of 87 p m, yolk vesicle stage (third stage) in October with mean diameter 200 p m and yolk granules stage (forth stage) from October to November with average diameter of 180 — 650 p m. For the reason of stopping oocyte develop at the end of fourth stage, hormonal induction to final oocyte maturation and ovulation was used. For this purpose, carp pituitary , HCG and LRH-A2 with different combinations were used in two stages, second injection was used 24 hours after first injection. 15 females brooders were divided in 5 groups, different hormonal combinations were injected to four groups and to fifth group as control, only saline, was injected. The process of female brooder rippening in hormonal induction was studied via masurment of sex steroids including 17 a - hydroxy progestrone, estradio1-17)6 and testosterone. Blood samples were collected from caudal vein during first injection, 24, 30 and 48 hours after the first injection. At the same time, for distinguishing histological changes the sample has been attained from the gonads Sex stroid fluctuation patterns in different brooder groups that injected hormon were similar, however hormonal composition had similar effects. All brooder that their oocyte in the beginning of hormonal injection were At the end of fourth stage with oocyte diameter average of 600 p m received to final maturation and ovulation. The brooder that its oocytes were At the begining or mid-fourth stage did not show ovulation but hormonal induction caused oocyte develop at the beginning of fifth stage. Study of 17-hydroxy progestrone fluctuation showed that the maximum level of this steroid (0.347 ng/ml) measured 30 hours after the first injection and was significantly higher (p< 0.05) than those of control group. So, 17-hydroxy progestrone is probably precursor of maturation inducing steroid (MIS). However the maximum level of that observed was coincident with germinal vesicle breakdown, oil droplets coalescence and dissolution of yolk granuls The maximum levels of esteradiol— 17/0 and testosterone (3.778 and 16.801ng/ml,respectively) in spawned brooders,were observed 24 hours after the first injection. levels of those steroids were significantly higher (p<0.05) than control group. Maximum level of sex steroids in the brooders that did not spawn to the end of treatment was observed with more delay than those in spawned brooders. Therefor maximum level of 17a-hydroxy progestrone (0.264 ng/ml) in those brooders observed in fourth sampling time and the maximum levels of estradio1-17a and testosterone (2.944 and 18.993 ng/ml, respectivly)observed in third sampling time that was significantly higher (p<0.05) than those of control group. For the study of stress effect on brooders during the hormonal induction, level of cortisol was measured in every sampling time. level of cortisol had high fluctuation that showed handling level and stress effect on brooders. However maximum level of cortisol in majority of brooders was dominant in third sampling time that was coincident with final maturation.

Transport of anti-sperm monoclonal IGA and IGC into murine male and female genital tracts from blood - Effect of sex hormones

Ab levels in the genital tract may be important in fertility and in preventing sexually transmitted diseases, In this study, I-125-labeled polymer or monomer mAb IgA (C4pIgA or C4mIgA) and IgC2b (C4IgC) to murine lactate dehydrogenase C4 and a polymer mAb IgA (npIgA) not cross-reacting with mouse sperm were intravenously injected into BALB/c mice, and the relative distribution of these Abs was determined. Polymer IgA was transported much more efficiently into the genital tract, trachea, and duodenum of both sexes than C4IgG and C4 mIgA (p < 0.01), The transport of polymer IgA (C4pIgA and npIgA) into the male genital tract greatly increased following orchiectomy (p < 0.01); this change was not affected by testosterone, suggesting that the unknown regulatory factor(s) from the testis may suppress polymer IgA transport, However, the transport of polymer IgA into female genital tissues was significantly decreased by ovariectomy (p < 0.01); this decline can be rectified by P-estradiol but not progesterone treatment, suggesting that estradiol may stimulate polymer IgA transport, Furthermore, the transport of C4IgG into tissues of the Fallopian tubes and the uterus was significantly decreased by treatment with progesterone (p < 0.01). Together, these findings indicate that serum polymer IgA can be transported selectively into the genital tracts of both sexes, that this transport is strongly under the control of gonads, and that transport of Ige into the Fallopian tubes and uterus is downregulated by progesterone.

Circulating immunoglobulin A- and immunoglobulin G-secreting hybridoma cells in peripheral blood preferably migrate to female genital tracts. The role of sex hormones

Antigen-specific circulating immunoglobulin-secreting cells (ISC) migrate to various secondary and tertiary lymphoid tissues. To understand the migration of the cells into the genital tract and its regulation by sex hormones, spleen-derived SG2 hybridoma cells secreting immunoglobulin G2b (IgG2b) and Peyer's patch-derived PA4 hybridoma cells secreting polymer IgA were labelled with (3) H-TdR, and intravenously injected into syngeneic mice of both sexes. Using flow cytometry, surface molecular markers of plasma cells, CD38 and CD138, and adhesion molecules, CD49d, CD162, and CD11a were found to be positive in SG2 and PA4 cells, but CD62L, alpha4beta7 and CD44 were not expressed on these cells. The relative distribution indexes (RDIs) of the cells in genital tract and other tissues were measured. The means of RDIs of SG2 and PA4 cells in female genital tissues were 6.5 and 4.5 times as many as the means in male genital tissues, respectively. The treatment of ovariectomized mice with beta-oestradiol significantly increased the RDIs of PA4 cells in cervix and vagina, but decreased the RDIs of SG2 cells in vagina, horn of uterus, uterus and rectum (P <0.05). Progesterone treatment increased the RDIs of PA4 cells in vagina and rectum (P <0.05). The treatment with testosterone significantly increased the RDIs of SG2 and PA4 cells in epididymis and accessory sex glands (P <0.05). These results demonstrate that the female genital tract is the preferable site for the migration of circulating hybridoma cells to the male genital tract, and sex hormones play an important role in regulation of the migration of circulating ISC to genital tracts.

Migration of mouse antibody-secreting hybridoma cells from blood to genital tract and its regulation by sex hormones are associated with the differential expression patterns of adhesion molecules and chemokines in the tract rather than in the antibody-secreting cells

To understand better the molecular mechanisms of differential migration of antibody-secreting cells (ASCs) into mouse genital tracts, and regulation by sex hormones, surface markers, hormone receptors and adhesion molecules in mouse SG2 and PA4 hybridoma cells, respectively, secreting IgG2b and polymeric IgA antibody were detected by flow cytometry or RT-PCR. Semiquantitative RT-PCR was also used for measuring mRNA expression of adhesion molecules and chemokines (VCAM-1, ICAM-1, P-selectin, JAM-1 and CXCL12) in genital tracts of various adult mouse groups. The mRNAs of androgen receptor, estrogen receptor beta and CXCR4 were expressed in the ASCs. Sex hormones had no effect on expression of these molecules in ASCs. Except for VCAM-1, mRNA of all examined genes was expressed in normal mouse genital tracts. The mean of relative amounts of ICAM-1 and CXCL12 mRNA in all examined organs of females were higher (2.1- and 1.9-fold) than those in males. After orchiectomy or ovariectomy, the expression of ICAM-1, CXCL12 and P-selectin mRNA in the examined organs increased, except JAM-1 in male and CXCL12 in female. Sex hormone treatment recovered the changes to normal levels of mRNA expression in many examined genital tissues. In combination with our previous work, preferential migration of ASCs into female genital tract and regulation of migration by sex hormones are associated with expression patterns of adhesion molecules and chemokines in genital tract rather than in ASCs. (C) 2006 Elsevier Ireland Ltd. All rights reserved.

Changes in plasma thyroid hormones and cortisol levels in crucian carp (Carassius auratus) exposed to the extracted microcystins

The endocrine response of crucian carp injected intraperitoneally with extracted microcystins (MC) was investigated in this study. Fish were injected intraperitoneally either with 0.75% NaCl (control) and Microcystis extract corresponding to 150 and 600 mu g microcystins per kg body weight. The plasma levels of triiodothyronine (T-3), thyroxine (T-4), free triiodothyronine (FT3), free thyroxine (FT4), and cortisol were determined at 0, 1, 3, 12, 24. and 48 h post-administration of MC-containing extract. Treated fish displayed abnormal behaviors, Such as a startle response and disoriented swimming, as well as changes in ventilation rates. Plasma cortisol concentrations of fish in both dose groups significantly increased after administration of extracted MC and remained high throughout the experiment, which suggested that MC elicited a stress response in treated fish. The profiles of cortisol changes in treated fish appeared to be dose dependent, indicating that fish in the high dose group experienced greater MC-incluced disturbance. Mortality occurred after 12 h in the high dose group. Plasma levels of T-4, T-3, FT4, and FT3 did not vary significantly between the control fish. In contrast to this, fish exposed to MC-containing extract showed significant declines in T-3, FT4, and FT3 levels in a dose-depenclent manner throughout the experiment. Plasma T4 levels, however, did not vary significantly in the low dose group, whereas they decreased significantly it 48 h post injection in the high dose group. This study demonstrates that administration of microcystins-containing extract causes a stress response and reduces the plasma levels of thyroid hormones in crucian carp. These results illustrate that microcystins exerted potent effects on the endocrine system of crucian carp, through activating their hypothalamus-pituitary- interrenal axis and disturbing thyroid function. (c) 2008 Elsevier Ltd. All rights reserved.

Determination of sexual hormones in liquid cosmetics by polymer monolith microextraction coupled with high performance liquid chromatography

A method was presented for the determination of testosterone, methyltestosterone and progesterone in liquid cosmetics by coupling polymer monolith microextraction (PMME) to high performance liquid chromatography with UV detection. A poly (methacrylic acid-ethylene glycol dimethacrylate) monolithic capillary column was selected as the extraction medium, which showed high extraction capacity towards these compounds. To achieve optimum extraction performance, several parameters relating to PMME were investigated, including extraction flow rate and pH value, inorganic salt and organic phase concentration of the sample matrix. By simple dilution with phosphate solution and filtering, the sample solution then could be directly injected into the device for extraction. The limits of detection of testosterone, methyltestosterone and progesterone were calculated to be 2, 3, 2, 8 and 4.6 mu g/L. Good linearity was achieved in the range of 10 to 1000 mu g/L with a linear coefficient. r value above 0. 996. Excellent method reproducibility was found by intra- and inter-day precisions, yielding the relative standard deviations of < 7. 7 % and < 7. 5 %, respectively. Recovery for them in the real samples was between 83% and 119%.

Serum concentrations of gonadotropins and steroid hormones of Neophocaena phocaenoides asiaeorientalis in middle and lower regions of the Yangtze River

As a relatively isolated and unique freshwater population, the Yangtze finless porpoise (Neophocaena phocaenoides asiaeorientalis) is the most endangered subpopulation of this species. The objective of this study was to improve our understanding of their reproductive endocrinology by measuring (radioimmunoassay) serum concentrations of FSH, LH, estradiol (E-2), progesterone (P-4) and testosterone (T-2) in free-ranging animals. Blood samples were collected from 66 Yangtze finless porpoises (41 males and 25 females) captured in the middle and lower reaches of the Yangtze River. Based on significant variation of serum T-2 concentrations in males with body length (BL) > 138 cm, we inferred that they were mature; in these animals, there were significant seasonal variations in serum T-2 concentrations, with the highest concentrations in March and April (502.0 +/- 319.8 ng/dL, mean +/- S.D.) and the lowest in December (79.4 +/- 83.2 ng/dL). Serum T-2 concentrations positively correlated with serum concentrations of LH and weakly correlated with serum concentrations of E-2, whereas there was a significant negative correlation between serum LH and FSH concentrations in males > 138 cm. The smallest apparently pregnant female porpoise had a BL of 130 cm. Serum P-4 concentrations ranged from 13.2 to 112.4 ng/mL (43.9 +/- 28.3 ng/mL) in pregnant females, and fluctuated under 1.0 ng/mL in non-pregnant females with BL > 130 cm. Serum LH concentrations were significantly higher in non-pregnant females > 130 cm versus those females < 130 cm. To our knowledge, this is the first study of endocrine-related maturity and seasonal breeding characteristics of the Yangtze finless porpoise. (c) 2006 Elsevier Inc. All rights reserved.

Characterization of basal pseudopod-like processes in ileal and colonic PYY cells.

The peptide tyrosine tyrosine (PYY) is produced and secreted from L cells of the gastrointestinal mucosa. To study the anatomy and function of PYY-secreting L cells, we developed a transgenic PYY-green fluorescent protein mouse model. PYY-containing cells exhibited green fluorescence under UV light and were immunoreactive to antibodies against PYY and GLP-1 (glucagon-like peptide-1, an incretin hormone also secreted by L cells). PYY-GFP cells from 15 μm thick sections were imaged using confocal laser scanning microscopy and three-dimensionally (3D) reconstructed. Results revealed unique details of the anatomical differences between ileal and colonic PYY-GFP cells. In ileal villi, the apical portion of PYY cells makes minimal contact with the lumen of the gut. Long pseudopod-like basal processes extend from these cells and form an interface between the mucosal epithelium and the lamina propria. Some basal processes are up to 50 μm in length. Multiple processes can be seen protruding from one cell and these often have a terminus resembling a synapse that appears to interact with neighboring cells. In colonic crypts, PYY-GFP cells adopt a spindle-like shape and weave in between epithelial cells, while maintaining contact with the lumen and lamina propria. In both tissues, cytoplasmic granules containing the hormones PYY and GLP-1 are confined to the base of the cell, often filling the basal process. The anatomical arrangement of these structures suggests a dual function as a dock for receptors to survey absorbed nutrients and as a launching platform for hormone secretion in a paracrine fashion.