Steroid hormones excess

Aldosterone (183) is one of the key steroid hormones involved in regulation of the body s mineral and fluid balance. Excess levels of this steroid quickly lead to marked retention of sodium chloride, water and, often as a consequence, hypertension. The aldosterone antagonist spironolactone (184) has proven of great clinical value in blocking the effects... 

The cholesterol required for biosynthesis of the steroid hormones is obtained from various sources, it is either taken up as a constituent of LDL lipoproteins (see p. 278) into the hormone-synthesizing glandular cells, or synthesized by glandular cells themselves from acetyl-CoA (see p. 172). Excess cholesterol is stored in the form of fatty acid esters in lipid droplets. Hydrolysis allows rapid mobilization of the cholesterol from this reserve again. 

The adrenal cortex produces in excess of 50 steroid hormones, which can be divided into 3 classes ... 

Severe consequences can occur from defective syn- thesis of a steroid hormone, as is the case in several metabolic diseases. Patients who have 21-hydroxylase deficiency are unable to convert progesterone to aldosterone and cortisol. Instead the progesterone is directed to an excess production of testosterone. In the female, this results in masculinization and hirsutism (growth of hair). In the male, premature masculinization occurs. If the disease is diagnosed before the first birthday, the patient can be treated with the missing steroid hormones, which in turn suppress the synthesis of excess progesterone and, as a consequence, testosterone via feedback mechanisms. 

The step-by-step synthesis of the steroid hormones pregnenolone and progesterone from cholesterol (C27) was presented in chapter 20 (see fig 20.22). Note that pregneno-lone (C2i) and progesterone (table 20.4) (C2 ) are intermediates in the biosynthesis of all of the major adrenal steroids, including cortisol (C2i), corticosterone (C21), and aldosterone (C21). The same two compounds are intermediates in the synthesis of the gonadal steroid hormones, testosterone (C,9) and 17/3-estradiol (CI8). Because the synthesis of all these hormones follows a common pathway, a defect in the activity or amount of an enzyme along that pathway can lead to both a deficiency in the hormones beyond the affected step and an excess of the hormones, or metabolites, prior to that step. 

The excessive production of thyroid hormone in Graves disease is associated with an enlarged thyroid gland, but in this case a circulating immunoglobulin that mimics the activity of thyroid stimulating hormone (TSH) is implicated. Finally, we saw in an earlier section how an inappropriate steroid hormone may be secreted in excessive amounts when specific enzymes in the adrenal steroid biosynthetic pathway are present at inadequate levels. 

The final chapter in part 5, chapter 20, Metabolism of Cholesterol, deals with the synthesis of cholesterol and some of its derivatives, the steroid hormones and the bile acids. This chapter considers the structure, function and metabolism of these molecules. Also, the health-related concerns associated with cholesterol excess are addressed. 

Cholesterol is a vital component of the human body. It stabilizes cell membranes and is the precursor of bile acids, vitamin D, and steroid hormones. The body s cells can synthesize cholesterol when needed, but excess cholesterol cannot be broken down and must be excreted from the body through the bile into the small intestine. When imbalances occur, cholesterol can accumulate in the gallbladder promoting gallstone formation. Cholesterol accumulation in the bloodstream (hypercholesterolemia) can cause atherosclerotic plaques to form within artery walls. 

UGT activity is modulated by various hormones. Excess thyroid hormone and ethinyl oestradiol (but not other oral contraceptives) inhibit bilirubin glucuronidation. In contrast, the combination of progestational and oestrogenic steroids results in increased enzyme activity. Bihrubin glucuronidation can also be inhibited by certain antibiotics (e.g. novobiocin or gentamicin, at serum concentrations exceeding therapeutic levels) and by chronic hepatitis, advanced cirrhosis and Wilson s disease. 

D3. Danowski, T. S., Rodnan, G. P., Sarver, M. E., and Moses, C., Hydrocortisone and/or desiccated thyroid in physiologic dosage. XII. Effects of thyroid hormone excesses on urinary solutes and steroids. Metab., Clin. ExpU. 13, 729-738 (1964). 

FIGURE 18-6 Chemical structures of major sterols and cholesterol derivatives. The major sterols in animals (cholesterol), fungi (ergosterol), and plants (stigmasterol) differ slightly in structure, but all serve as key components of cellular membranes. Cholesterol is stored as cholesteryl esters in which a fatty acyl chain (R = hydrocarbon portion of fatty acid) is esterified to the hydroxyl group. Excess cholesterol is converted by liver cells into bile acids (e.g., deoxycholic acid), which are secreted into the bile. Specialized endocrine cells synthesize steroid hormones (e.g., testosterone) from cholesterol, and photochemical and enzymatic reactions in the skin and kidneys produce vitamin D. 

The mechanism by which immune suppression is brought about is not well understood, although it has been suggested that important mediators of T-cell suppression include the steroid hormones such as cortisol, soluble IL-2 receptor, trauma-derived peptides, and acute phase proteins (C35, El, H28, 06, R18, S30, T7, T13). It is also possible that the impaired PMN and macrophage functions observed in trauma patients are not entirely the result of suppression but may be the result of excessive activation and depletion of functional cells from the circulation. 

The glycogen store normally present in liver also plays a role in elimination of poisons such as carbon tetrachloride, chloroform, p-aminobenzoic acid, sulfanilamide, alcohol, arsenic, and bacterial poisons (10, 26, 28, 32, 51, 60, 61, 75) It probably plays a role also in regulating steroid hormone metabolism and in eliminating excess sex hormones. The elimination of substances that otherwise would be carcinogenic may turn out to involve the liver and liver glycogen (62, page 14). 

Excess cholesterol can also be metabolized to CE. ACAT is the ER enzyme that catalyzes the esterification of cellular sterols with fatty acids. In vivo, ACAT plays an important physiological role in intestinal absorption of dietary cholesterol, in intestinal and hepatic lipoprotein assembly, in transformation of macrophages into CE laden foam cells, and in control of the cellular free cholesterol pool that serves as substrate for bile acid and steroid hormone formation. ACAT is an allosteric enzyme, thought to be regulated by an ER cholesterol pool that is in equilibrium with the pool that regulates cholesterol biosynthesis. ACAT is activated more effectively by oxysterols than by cholesterol itself, likely due to differences in their solubility. As the fatty acyl donor, ACAT prefers endogenously synthesized, monounsaturated fatty acyl-CoA. 

Some antifungal drugs such as ketoconazole (see Chapter 48) inhibit CYPs and thereby block the synthesis of steroid hormones, including testosterone and cortisol. Because they may induce adrenal insufficiency and are associated with hepatotoxicity, these drugs generally are not used to inhibit androgen synthesis, but sometimes are employed in cases of glucocorticoid excess. 

Cholesterol A lipid substance that we both make and take in via our diet. Important component of membranes, lipoproteins, etc. but in excessive levels contributes to atherosclerotic plaques. Precursor of steroid hormones. 

With the help of vasopressin, a healthy person can vary the intake of water widely and yet preserve a stable overall concentration of substances in the blood. But sometimes the water level of the body gets dangerously low, from not drinking enough water or excessive water loss caused by diarrhea or excessive perspiration. Under such circumstances, the adrenal gland secretes the steroid hormone aldosterone. At the kidneys, aldosterone... 

On the basis of studies of the effect of excessive doses of vitamin A on culture bones and on the tail of Xenopus laevis, a theory has been put forward suggesting that vitamin A acts by rupturing lysosomes and by releasing hydrolytic enzymes in the media. In vitro experiments done in Dingle s laboratory [112, 113] and in De Duve s laboratory [114], where the hydrolases were released under the influence of vitamin A, are often called upon to support this theory. This theory meets with a number of serious objections (1) the release of a large number of hydrolases can hardly be reconciled with the effect of the vitamin on mucus synthesis and steroid hormone biosynthesis and (2) the experiments done in vivo on the Xenopus laevis were carried out with doses of vitamin A that killed 30% of the larvae, so that much of the effect may be due to necrosis rather than to a specific effect of the vitamin. Similar objections can be made with respect to experiments done in vitro with organ culture. The validity of the interpretation of an effect of vitamin A on the isolated particles is discussed in more detail in the section on cellular necrosis. 

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