Chapter 4 / Steroid Hormones 49 4 Steroid Hormones Derek V. Henley, PhD, Jonathan Lindzey, PhD, and Kenneth S. Korach, PhD CONTENTS INTRODUCTION STEROID HORMONE SYNTHESIS MECHANISMS OF STEROID HORMONE ACTION STEROIDS AND DEVELOPMENT STEROIDS AND NORMAL PHYSIOLOGY STEROIDS AND PATHOPHYSIOLOGY CONCLUSION 1. INTRODUCTION Steroids are lipophilic molecules used as chemical of steroid synthesis, steroid hormone effects in normal messengers by organisms ranging in complexity from physiology, molecular and biochemical mechanisms water mold to humans. In vertebrates, steroids act on a of action of steroid hormones, and pathologic states wide range of tissues and influence many aspects of related to steroid hormone action. biology including sexual differentiation, reproductive physiology, osmoregulation, and intermediate metabo- 2. STEROID HORMONE SYNTHESIS lism. Major sites of steroid synthesis and secretion Steroid hormones are lipid molecules derived from include the ovaries, testes, adrenals, and placenta. a common cholesterol precursor (Cholestane, C27). Based on the distance of a target site from the site of There are four major classes of steroid hormones: synthesis and secretion, steroid hormones can be clas- progestins, androgens, estrogens, and corticoids, sified as either endocrine (distant target tissue), which contain 21, 19, 18, and 21 carbons, respectively. paracrine (neighboring cells), or autocrine (same cell) Steroid hormones are synthesized by dehydrogenases factors. When secreted into the environment, steroids and cytochrome P450 enzymes, which catalyze hydro- can also act as pheromones by conveying information xylation and dehydroxylation-oxidation reactions. to other organisms. Eukaryotic cytochromes P450 are membrane-bound Owing to the pervasive effects of steroids in verte- enzymes expressed in either the inner mitochondrial or brate biology, a number of pathologic states can occur endoplasmic reticulum membranes of steroid-synthe- because of problems related to steroid hormone action sizing tissues. A common and important rate-limiting (see Section 6). These disease states include cancer, step for the synthesis of all steroid hormones is cleav- steroid insensitivity, and abnormal steroid synthesis. age of the side chain from cholesterol (C27) to yield The purpose of this chapter is to provide an overview pregnenolone (C21), the common branch point for synthesis of progestins, corticoids, androgens, and, From: Endocrinology: Basic and Clinical Principles, Second Edition hence, estrogens (Fig. 1). Expression of the side-chain (S. Melmed and P. M. Conn, eds.) © Humana Press Inc., Totowa, NJ cleavage enzyme cytochrome P450scc (cytP450scc), 49 50 Part II / Hormone Secretion and Action Fig. 1. (A) Synthetic pathways and structures of major progestins and corticoids found in humans. Major enzymes involved in the synthesis are in boldface. which converts cholesterol to pregnenolone, is one of hormones from the anterior pituitary such as follicle- the unique features of steroidogenic cells that partici- stimulating hormone (FSH), luteinizing hormone (LH), pate in de novo steroid synthesis. and adrenocorticotropic hormone (ACTH). Mineralo- In vertebrates, the synthesis and secretion of gonadal corticoids are also regulated by ion concentrations and and adrenal steroid hormones are regulated by tropic circulating levels of angiotensin II. Common regulatory Chapter 4 / Steroid Hormones 51 Fig. 1. (B) Synthetic pathways and structures of major androgens and estrogens found in humans. Major enzymes involved in the synthesis are in boldface. mechanisms for steroid synthesis and release are nega- itary. The complex interplay among different compo- tive feedback loops in which elevated circulating levels nents of the hypothalamic-pituitary-gonad (HPG)/adre- of steroids suppress production of tropic hormones by nal (HPA) axes is an important feature of endocrine acting at specific sites in the brain and the anterior pitu- physiology and is discussed in Section 5. 52 Part II / Hormone Secretion and Action 2.1. Synthesis of Progesterone estrogen changes during the course of folliculogenesis Pregnenolone serves as a principal precursor to all during which, under the influence of LH, the thecal cells the other steroid hormones synthesized by the ovary, synthesize and secrete androstenedione and testoster- testes, or adrenals. It appears that the rate-limiting step one, which diffuse across the basement membrane and for the synthesis of progesterone is side-chain cleavage are subsequently aromatized to estrone and E2, respec- of cholesterol by P450scc. Pregnenolone is then con- tively, by the granulosa cells. The level of aromatase verted into progesterone by 3β-hydroxysteroid dehy- and, hence, estrogens produced in the granulosa cells is drogenase (3β-HSD). Thus, deficiencies in either under the control of FSH during midfollicular phases. P450scc or 3β-HSD have profound effects on the syn- Later in the cycle, the follicle/corpora lutea express thesis of all steroids. greater numbers of LH receptors and LH begins to regu- In the ovary, progesterone is produced at all stages of late E2 production. During pregnancy, the placenta uti- follicular development as an intermediate for androgen lizes androgen precursors from the fetal adrenal gland and estrogen synthesis but becomes a primary secretory and secretes large amounts of E2. In addition, in male product during the peri- and postovulatory (luteal) vertebrates, many target tissues such as pituitary cells phases. The synthesis of progesterone is under the con- and hypothalamic neurons convert circulating testoster- trol of FSH during the early stages of folliculogenesis one into E2. and, following acquisition of LH receptors, becomes 2.4. Synthesis of Corticoid sensitive to LH later in the ovarian cycle. The synthesis of progesterone by the corpus luteum is stimulated dur- Corticoids are divided into gluco- and mineralocor- ing early pregnancy by increasing levels of chorionic ticoid hormones. The predominant human glucocorti- gonadotropin. In addition, the placenta secretes high lev- coid, cortisol, is synthesized in the zona fasciculata of els of progesterone during pregnancy, although a differ- the adrenal cortex. The synthesis of cortisol involves α ent isozyme of 3β-HSD is involved in the synthesis. hydroxylations of progesterone at the 17 , 21 (CYP21), and 11β (CYP11B1) positions. The synthesis of cortisol 2.2. Synthesis of Androgen is under the control of an anterior pituitary hormone, Androgens are synthesized and secreted primarily by ACTH, and a negative feedback mechanism in which the Leydig cells of the testes, thecal cells of the ovary, elevated cortisol suppresses the release of ACTH (see and cells in the reticularis region of the adrenals. In most Section 5.2). tetrapod vertebrates, testosterone is the dominant circu- The dominant human mineralocorticoid is aldoster- lating androgen. Testicular synthesis and secretion of one, which is produced in the zona glomerulosa of the testosterone is stimulated by circulating LH, which adrenal. The synthesis of aldosterone involves the syn- upregulates the amount of 17α-hydroxylase:C-17,20- thesis of corticosterone and subsequent hydroxylation and lyase, a rate-limiting enzyme for conversion of C21 into oxidation at C18 to yield aldosterone. The synthesis of C19 steroids. Once taken up by target tissues, testoster- aldosterone is regulated directly by levels of potassium, one can be reduced by 5α-reductase to yield a more and indirectly by the effects of sodium levels and blood active androgen metabolite, 5α-dihydrotestosterone volume on levels of angiotensin II (see Section 5.2). (5α-DHT). Testosterone and androstenedione can also β 2.5. Serum-Binding Proteins be converted into estrogens such as 17 -estradiol (E2) or estrone through a process termed aromatization. Following synthesis, steroids are transported to their Aromatization is carried out by a cytochromeP450 target tissues through the bloodstream. The hydropho- aromatase enzyme that is expressed in the granulosa bic nature of steroid hormones results in low water solu- cells of the ovary, Leydig cells of the testes, and many bility; therefore, transport proteins, known as other tissues including the placenta, brain, pituitary, serum-binding proteins, help transport steroid hormones liver, and adipose tissue. Indeed, many of the effects of to their target tissues. This transport is accomplished circulating testosterone are owing to conversion into through the binding of steroid hormones to a specific α either 5 -DHT or E2 within target tissues. high-affinity ligand-binding domain (LBD) within the serum-binding proteins. Five serum-binding proteins 2.3. Synthesis of Estrogen have been identified: corticosteroid-binding globulin, Estrogens and progestins are synthesized and secreted retinol-binding protein, sex hormone–binding globulin primarily by maturing follicles, corpora lutea of ova- (SHBG), thyroxine-binding globulin, and vitamin D– ries, and the placenta during pregnancy. The predomi- binding protein. As indicated by their respective names, nant estrogen secreted is E2 and the predominant each serum-binding protein preferentially binds a progestin is progesterone. The profile of the synthesis of unique class of steroid hormones. Chapter 4 / Steroid Hormones 53 Table 1 Hormone Response Elements a Type of response element Sequence Gene Species • Estrogen GGTCAcagTGACC vitA2 Xenopus GGTCAcggTGGCC PS2 Human GGTCAnnnTGACC Consensus • Androgen AGAACAgcaAGTGCT PSA Human