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Structures of Steroid Hormones
Page 894 21.1— Overview Steroid hormones in the human include cortisol as the major glucocorticoid or antistress hormone, aldosterone as an important regulator of Na+ uptake, and the sex and progestational hormones. Sex hormones are 17b estradiol in females and testosterone in males. Progesterone is the major progestational hormone. Testosterone is reduced in some target tissues to dihydrotestosterone, a higher affinity ligand for the androgen receptor. Vitamin D3 is converted to the steroid hormone, dihydroxy vitamin D3. Genes in the steroid receptor supergene family include retinoic acid receptors and thyroid hormone receptor, although the ligands for these additional receptors are not derivatives of cholesterol. Retinoic acid and thyroid hormone, however, have sixmembered ring structures that could be considered to resemble the A ring of a steroid. Figure 21.1 The steroid nucleus. Steroidal structure will be reviewed with the synthesis and inactivation of steroid hormones. Regulation of synthesis of steroid hormones is reviewed with respect to the renin–angiotensin system for aldosterone, the gonadotropes, especially folliclestimulating hormone for 17b estradiol, and the vitamin D3 mechanism. Steroid hormone transport is reviewed with respect to the transporting proteins in blood. A general model for steroid hormone action at the cellular level is presented with information on receptor activation and regulation of receptor levels. Specific examples of steroid hormone action for programmed cell death and for stress are presented. Finally, the roles of steroid hormone receptors as transcriptional transactivators and repressors are reviewed. 21.2— Structures of Steroid Hormones Steroid hormones are derived in specific tissues in the body and are divided into two classes: the sex and progestational hormones, and the adrenal hormones. They are synthesized from cholesterol and all of these hormones pass through the required intermediate, 5pregnenolone. The structure of steroid hormones is related to the cyclopentanoperhydrophenanthrene nucleus. The numbering of the cyclopentanoperhydrophenanthrene ring system and the lettering of the rings is presented in Figure 21.1. The ring system of the steroid hormones is stable and not catabolized by mammalian cells. Conversion of active hormones to less active or inactive forms involves alteration of ring substituents rather than the ring structure itself. The parental precursor of the steroid is cholesterol, shown in Figure 21.2. The biosynthesis of cholesterol is given on p. 410. The major steroid hormones of humans and their actions are shown in Table 21.1. Many of these hormones are similar in gross structure, although the specific receptor for each hormone is able to distinguish the cognate ligand. In the cases of cortisol and aldosterone, however, there is overlap in the ability of each specific receptor to bind both ligands. Thus the availability and concen Figure 21.2 Structure of cholesterol. Page 895 TABLE 21.1 Major Steroid Hormones of Humans Hormone Structure Secretion Signala Secretion from Functions Corpus luteum LH Maintains (with estradiol) the uterine endometrium for implantation; differentiation factor for mammary glands Ovarian follicle; corpus luteum; (Sertoli cell) FSH Female: regulates gondotropin secretion in ovarian cycle (see Chapter 20); maintains (with progesterone) uterine endometrium; differentiation of mammary gland. Male: negative feedback inhibitor of Leydig cell synthesis of testosterone Leydig cells of testis; (adrenal gland); ovary LH Male: after conversion to dihydrotestosterone, production of sperm proteins in Sertoli cells; secondary sex characteristics (in some tissues testosterone is active hormone) Reticularis cells ACTH Various protective effects; weak androgen; can be converted to estrogen; no receptor yet found; inhibitor of G6PDH: regulates NAD+ coenzymes Fasciculata cells ACTH Stress adaptation through various cellular phenotypic expressions; slight elevation of liver glycogen; killing effect on certain T cells in high doses; elevates blood pressure; sodium uptake in luminal epithelia Glomerulosa cells of adrenal cortex Angiotensin II/III Causes sodium ion uptake via conductance channel; occurs in high levels during stress; raises blood pressure; fluid volume increased Vitamin D arises in skin cells after irradiation and then successive hydroxylations occur in liver and kidney to yield active form of hormone PTH (stimulates Facilitates Ca2+ and phosphate absorption by kidney proximal tubule intestinal epithelial cells; induces intracellular hydroxylation system) calciumbinding protein Progesterone 17bEstradiol Testosterone Dehydroepian drosterone Cortisol Aldosterone 1,25Dihydroxy vitamin D3 a LH, luteinizing hormone; FSH, folliclestimulating hormone; ACTH, adrenocorticotropic hormone; PTH, parathyroid hormone.