Guide Steroid and Sterol Hormone Action

Metabolic profiling of cholesterol and sex steroid hormones to monitor urological diseases

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Steroid hormone

The H-PPT specifically retains phospholipids by Lewis acid—base interactions between the zirconia-coated silica particles bonded to the stationary phase and the phosphate group of the phospholipids, which provides simple yet rapid selective removal of interference Bylda et al.

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The horizontal blue, orange, and red lines represent the approximate positions of the POPC choline, phosphate, and ester moieties, respectively. Darin sollte mind. This specific configuration of functional groups imposes a vertical orientation i. All Rights Reserved. If available, experimental values were taken from the literature Figure 6 , triangles or determined by ITC in this study Figure 6 , circles.

Bead-assisted liquid—liquid extraction via the addition of methanol and then centrifugation can be achieved simultaneously with pulverization, extraction and protein precipitation Son et al. Samples were then loaded into H-PPT cartridges and eluted three times with 0.

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The matrix background such as proteins and phospholipids was easily removed and finally hair sterols were collected. Silylation is the most widely used derivatization reaction in steroid analysis, and trimethylsilyl TMS derivatization is extensively used for most functional groups on steroid backbone, including aliphatic and phenolic alcohols, and carbonyl and amine groups.

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Most steroids were monitored using their molecular ions as base peaks. Cholesterol and cholesterol precursors have a hydroxyl group at the C-3 position, and OHCs have two polar functional groups: one is a hydroxyl group at the C-3 position and the other is a hydroxyl or ketone group at the C-4, C-7, C, C, C, C or C position. These results may provide useful information about the chemical structures of cholesterol and its metabolites.

Mixed derivatization is performed to improve physical and chemical properties and mass spectral characteristics. The spectra of flophemesyl derivatives generally display intense molecular ions under electron impact ionization, resulting in enhanced chromatographic selectivity and mass spectral information with sensitive detection Choi et al. Recently, the enhanced GC—MS analytical selectivity and sensitivity were allowed for quantitative analysis of estrogen metabolites in urine samples obtained from the postmenopausal female patients with osteoporosis Moon et al.

It was successfully achieved by two-phase extractive ethoxycarbonylation EOC and subsequent pentafluoropropionyl PFP derivatization. In case of estrogen profiling, the ultra-sensitive LC—MS analytical method has been conducted with a novel chemical derivatization procedure, which formed analytes as pre-ionized N -methyl pyridiniumsulfonyl NMPS derivatives Wang et al. Furthermore, only single enzymes are estimated at a single time Spiehler , Hsing et al.

In contrast, mass spectrometry-based quantification has better reproducibility and generates multi-targeted profiling analysis Cho et al. Several mass spectrometric methods for the measurement of steroids and sterols from various biological matrices have been proposed, coupled to GC Ahmida et al.

The LC—MS methods based on electrospray and atmospheric pressure chemical ionization techniques have been conducted with a good sensitivity and chromatographic resolution of estrogens Falk et al. However, the method often requires sample derivatization with dansyl chloride Falk et al. In particular, GC—MS with electron impact ionization is used widely for the measurement of steroid hormones with good analytical efficiencies as well as structural information.

In , the simultaneous quantification of hair steroids, including androgens, progestins, corticoids and sterols by GC—MS method in selected ion monitoring SIM mode, was successfully validated to evaluate the concentrations of individual steroids as well as the activities of the enzymes responsible for steroidogenesis in hair follicles and sebaceous glands Jung et al. This can synthesize many steroids from cholesterol or locally convert circulating steroids with a range of metabolic enzymes Chen et al.

Steroid hormone

In previous studies, it successfully achieved good chromatographic properties for the analysis of lipid molecules including cholesterols Jung et al. Results showed that lower bleeding achieved results in better detectability with a short analytical run compared with a fused silica GC column. All analytes were successfully separated and detected without any interference within a min chromatographic run. With the same pathological events, the biochemical mechanism of male pattern baldness MPB was clearly confirmed with hair steroid analysis Choi et al.

In addition to the androgen actions, the cortisol metabolic alteration can be monitored as a biochemical marker of chronic stress, which is an excessive symptom that causes cumulative negative impacts on health outcomes Lee et al. The detection of cortisol in biological fluids, even saliva, has still been questionable. The increased levels of hair cortisol were observed in childhood obesity, which were also linked to long-term activation of HPA axis Veldhorst et al.

Recently, our research team was able to successfully establish the analytical method for the profiling of cholesterol precursors and metabolites e. In the laboratory setting, we have observed that high circulating cholesterol in blood could be associated with high levels of androgens and hair loss in male mice Fig. No weight changes or liver function or dysfunction was observed. Levels of cholesterol and androgen were increased in all mice of high-cholesterol group five out of five mice.

Interestingly, three out of five mice in high-cholesterol group showed hair loss Fig.

Figure 3 Download Figure Download figure as PowerPoint slide High cholesterol, high sex steroids and hair loss were observed in mice with chronic high-cholesterol diet. Line within the value represents the median. In particular, the metabolic ratios of testosterone:DHEA and DHT:testosterone in PC group tended to increase against the other two groups, whereas a metabolic ration of testosterone:epitestosterone was significantly increased in MPB group Fig.

This is in accordance with our previous findings Manenschijn et al. These results suggest that the altered metabolic ratios of androgens combined with the higher levels of androgens might serve as the potential biomarkers for PC and MPB. Figure 4 Download Figure Download figure as PowerPoint slide Metabolic ratios of hair androgens in patients with prostate cancer and male pattern baldness compared with healthy control subjects. PC and BPH are characterized by alterations of steroidogenic genes, which are important in synthesis of androgens from cholesterol, or genes converting adrenal androgens to DHT or DHT to inactive metabolites.

In this short review article, we summarized these cholesterol and sex steroid metabolic pathways during progression of PC and BPH. Both synthesis and metabolism of sex steroids with intracrine or paracrine actions are expressed locally in skin, which serve as a target for various steroid hormones including cholesterol Slominski Hair as the adnexal structure of the skin contains the entire biochemical apparatus necessary for the production of steroid hormones either from precursors of systemic origin or, alternatively, through the conversion of steroid precursors.

Thus, hair metabolomics could therefore be a promising technique for the retrospective assessment of physiological changes in many clinical events including urological diseases. Figure 5 shows important lipid metabolites that our laboratory has successfully established, with the optimized quantitative analysis methods to measure cholesterol and sex steroid hormones for monitoring, using hair metabolomics.

The substrate for estrogen biosynthesis in the fetoplacental unit is dehydroepiandrosterone sulfate DHEAS which is obtained from the fetomaternal bloodstream see ref. The reactions shown in Fig. The gene encoding human aromatase cytochrome P has been cloned recently and its expression has been shown to be regulated by tissue-specific promoters 8. A number of endocrine disorders can be attributed to specific enzyme defects. Thus, inability to secrete normal levels of adrenals steroids may result in congenital adrenal hyperplasia CAH following hyperstimulation by ACTH the negative steroid feed-back controlling adrenal activity being lost.

In the majority of cases, this syndrome is due to hydroxylase deficiency, and is associated with increased adrenal androgen secretion and partial virilization in girls 5. Less common adrenal enzyme deficiencies involve either hydroxylase with a possible increase in mineralocorticoid levels or hydroxylase aldosterone may be deficient with normal levels of cortisol.

It is generally assumed that steroids are released into the blood circulation as soon as they are formed, i.

Secretion rates are therefore directly related to the biosynthetic activity of the gland and to the blood flow rate. Because of their lipophilic properties, free steroid molecules are only sparingly soluble in water. In biological fluids, they are usually found either in a conjugated form, i. In the plasma, unconjugated steroids are found mostly bound to carrier proteins 6. Apart from the two functions mentioned above, the major roles of plasma binding proteins seem to be a to act as a " buffer " or reservoir for active hormones because of the non-covalent nature of the binding, protein-bound steroids are released into the plasma in free form as soon as the free concentration drops according to the law of mass action and b to protect the hormone from peripheral metabolism notably by liver enzymes and increase the half-life of biologically active forms.

Because steroids are lipophilic, they diffuse easily through the cell membranes, and therefore have a very large distribution volume. In their target tissues, steroids are concentrated by an uptake mechanism which relies on their binding to intracellular proteins or " receptors ", see below.

High concentration of steroids are also found in adipose tissue, although this is not a target for hormone action. In the human male, adipose tissue contains aromatase activity, and seems to be the main source of androgen-derived estrogens found in the circulation.

But most of the peripheral metabolism occurs in the liver and to some extent in the kidneys, which are the major sites of hormone inactivation and elimination, or catabolism see below. Steroids have both short- and long-term effects. Long-term effects lasting from hours to days usually involve interaction of the hormone with a specific intracellular steroid-binding protein called a receptor. The steroid-receptor complex binds to hormone-responsive elements on the chromatin and regulates gene transcription Steroid receptor genes are only expressed in target tissues, where their presence determines accumulation of the hormone in the cell nucleus and facilitates steroid entry into the target cell by the law of mass action.

This mode of cellular action is generally referred to as a genomic action. Non-genomic action, on the other hand, is any mode of action for which gene transcription is not directly implicated, e. In contrast to the genomic effects, non-genomic effects require the continued presence of the hormone. Some of these effects may involve specific receptors located on the cell membrane For certain classes of hormones and particular target tissues, steroids must be converted in situ to an active form before they can interact with their specific receptor s.

This metabolic activation step is either an absolute prerequisite or a way of achieving a range of complex effects which involve interaction with more than one type of receptor. Two examples are shown in Fig. The two main classes of hormones for which metabolic activation has been shown to play a role are the progestins and the androgens, but catecholestrogens 2- or 4-OH derivatives of estrogens may also constitute another class of biologically active compounds resulting from target organ metabolism.

When conversion of the circulating hormone is required for its action, the original compound is sometime called a prehormone. Enzymes involved in metabolic activation usually catalyse irreversible conversion steps and are often rate-limiting for steroid action, i. Steroid metabolism in target tissues may be critical for determining both the specificity and the magnitude of hormone effects. The biological activity of a steroid molecule depends on its ability to interact with a specific binding site on the corresponding receptor. In most cases, biological activity can be directly correlated with binding affinity.

The affinity usually characterised by the binding constant KD, which is the molar concentration required to saturate half of the available binding sites of a steroid for its specific receptor is dependent upon the presence or absence of particular functional groups and the overall three-dimensional structure of the molecule.

Stereoisomerism may play an important role in this respect: molecules with the same chemical composition but a different spatial orientation of their substituents at critical points e. Isomerisation can therefore lead either to inactivation or to a change in the specific biological properties of the original molecule.

The importance of even minor changes in the structure of a steroid molecule for its biological activity explains why target tissue metabolism may play such a critical role in modulating hormone action at the cell level. Since the activity of most enzymes is regulated by a number of factors in particular hormonal factors related to the endocrine status , and since this activity is often rate-limiting for steroid action, target tissue metabolism provides an additional degree of control over steroid hormone action.

It should be mentioned here that target tissue metabolism is not limited to the local production of active metabolites: inactivation can also occur within the target cell, and this mechanism can contribute to the regulation of the intracellular concentration of biologically active molecules. Thus, the hormonal " micro environment " of a steroid-target cell is determined by a complex interplay between activating and inactivating mechanisms.

Various disorders can result from a genetic defect in target tissue metabolism. The best known example is male pseudohermaphroditism i. This type of androgen resistance syndrome results notably in an abnormal sexual differentiation of the male genitalia. Inactivation refers to the metabolic conversion of a biologically active compound into an inactive one.

Inactivation can occur at various stages of hormone action. Peripheral inactivation e. Moreover, if a hormone is to act as a " chemical signal ", its half-life in the circulation must be limited, so that any change in secretion rate is immediately reflected by a change in its plasma concentration particularly when secretion rates are decreased. But hormone inactivation can also occur in target tissues, notably after the hormone has triggered the relevant biological effects in order to ensure termination of hormone action.