Lecture
#16: Adrenal Steroid Hormones and Their Synthesis
I. INTRODUCTION
1. The adrenal cortex arises from coelomic mesoderm in the genital ridge of the embryo. (Fig. 15.1)
2. Like the gonads, it secretes steroid hormones (= 2nd gonads).
3. Steroid secreting cells are filled with lipid droplets and mitochondria.
4. Steroid secreting cells contain conspicuous smooth endoplasmic reticulum.
5. Functional zonation of the adrenal cortex: (Fig. 15.2) (see histology of the adrenal gland)
a. zona glomerulosa secretes mineralocorticoids. [mineralocorticoid]
b. zona fasciculata secretes glucocorticoids.
c. zona reticularis secretes androgens.
6. May want to recall that the cortex is supplied by a portal system from adrenal medulla.
7. Adrenal cortex and medulla both respond in different ways to help maintain homeostasis during times of physiological and psychological stress.
II. STEROID NOMENCLATURE
1. Numbering the steroid rings (Fig. 15.4) (comes from cholesterol).
2. Terms used in steroid nomenclature: (Table 15.1)
a. pregnane, androstane, & estrane: pregn-ene..., pregn-diene..., pregn-triene.
b. hydroxyl groups designated by hydroxy-, or -ol.
c. ketone groups designated by oxy-, keto-, or -one.
d. aldehyde groups designated by -al.
3. Study the systematic names of vertebrate steroids. (Table 15.2).
III. BASIC SYNTHETIC PATHWAY OF STEROIDS (Fig. 15.3)
1. Cholesterol is the precursor for all adrenal and gonadal steroid hormones.
2. Cholesterol is derived primarily by uptake from plasma cholesterol, rather than synthesis.
3. Low-density lipoproteins (LDLs) are principal cholesterol transporters in plasma.
4. Cholesterol is converted to pregnenolone by cytochrome P450scc in mitochondria.
(cytochrome P450scc enzyme is part of the "desmolase" system)
5. In smooth ER, 3ß-OH steroid dehydrogenase and isomerase convert pregnenolone to progesterone.
a. aldosterone production: [aldosterone] (note that zona glomerulosa lacks a 17a -hydroxylase)
(1) 21-hydroxylase converts progesterone to 11-deoxycorticosterone.
(2) 11ß-hydroxylase converts 11-deoxycorticosterone to corticosterone.
(3) 18-hydroxylase & 18-OH-dehydrogenase (i.e., aldosterone synthase) create aldosterone.
b. cortisol production: (zona fasiculata has 17a -hydroxylase).
(1) 17a -hydroxylase converts progesterone to 17a -hydroxyprogesterone.
(2) 21-hydroxylase converts 17a -hydroxyprogesterone to 11-deoxycortisol.
(3) 11ß-hydroxylase
converts 11-deoxycortisol to cortisol.
c.
androgen
production (zona reticularis
has 17b-hydroxysteroid dehydrogenase to form testosterone.
IV. ALDOSTERONE PRODUCTION (regulated by angiotensin II)
1. Renin secretion is stimulated by one or more of the following mechanisms:
a. baroreceptor hypothesis: if blood volume or renal perfusion pressure drops, juxtaglomerular cells act as baroreceptors and begin secreting renin.
b. macula densa hypothesis: if distal tubule Na+ drops, macula densa cells stimulate juxtaglomerular cells to secrete renin.
c. norepinephrine from sympathetic nerves: stimulates JG cells to secrete renin.
2. Renin acts on Angiotensinogen from liver to form angiotensin I (Ang-I) (Fig. A) (or, see Fig. 15.8).
3. Angiotensin converting enzyme (ACE) from lung & kidney endothelial cells converts Ang-I to Ang-II.
4. Ang-II acts on zona glomerulosa cells to produce cAMP, PLC, IP3/DAG, & Ca++. (see Fig. 15.20).
5. This leads to the transcription/translation of 18-hydroxylase (and 18-OH-dehydrogenase).
6. Secreted aldosterone circulates to distal convoluted tubule to resorb renal Na++ and H2O.
7. Ang-II also stimulates heart rate and vasoconstriction, thus elevating blood pressure.)
8. It also acts to retain body fluids and to maintain blood pressure.
B. RELATIONSHIP BETWEEN RENIN/ANGIOTENSIN/KININ SYSTEM (Fig. 15.11)
1. Kallikrein (from kidneys and other sources) converts prorenin to renin.
2. Kallikrein also converts kininogen into bradykinin.
3. Bradykinin (BK) is a potent smooth muscle relaxant and vasodilator (increases blood)
4. Thus, BK keeps blood flowing to the kidney glomeruli while AngII causes vasoconstriction elsewhere.
5. Thus, ACE activates AngII, but inactivates BK (when away from the kidney, where it is necessary to have vasoconstriction rather than vasodilation.)
6. So, it appears that kallikrein/bradykinin function to help maintain a normal renal blood flow.
V. CORTICOSTEROID SYNTHESIS AND ACTION
A. GLUCOCORTICOID PRODUCTION (cortisol) (regulated by pituitary ACTH)
1. ACTH acts on membrane receptors to stimulate cAMP and protein kinases. (Fig. 15.7)
2. This leads to the production of P450scc (i.e., Cyp11A1) in zona fasciculata & 17a-hydroxylase.
3. ACTH also stimulates IGF-II, causing hypertrophy and hyperplasia of cortex.
1. Examples of actions:
a. cortisol at chronic high levels has a catabolic effect on muscle and adipose.
b. cortisol promotes anabolic gluconeogenesis and glycogen storage in liver.
c. cortisol suppresses all phases of inflammatory and allergic reactions.
d. cortisol suppresses lymph node activity and immune response, causing atrophy.
2. Chronic cortisol secretion under stress leads to muscle wasting, hyperglycemia, atrophy of the immune system, vascular derangements, gastrointestinal ulceration. (Hans Selye)
VI. ADRENAL ANDROGEN PRODUCTION (dehydroepiandrosterone = DHEA)
1. ACTH also stimulates adrenal androgen production.
2. ACTH promotes the zona reticularis to produce 17a-hydroxylase (i.e., 17,20-lyase, or Cyp17A1).
3. ACTIONS:
a. Generally stimulates male sex characteristics, and contribute to female puberty.
b. Excess androgens in female cause facial and chest hair, small breasts, enlarged clitoris, muscle development and some baldness.
c. May cause more aggressive female sexual contacts and amplify responsiveness to males.
VII. ATRIAL NATRIURETIC FACTOR (ANF, or ANP) (Atriopeptin)
1. First forms as a 126-AA precursor that becomes 28-AA ANF (in heart and hypothalamus).
2. If there is too great a blood volume, atrial cardiocytes produce ANF.
3. ANF promotes diuresis and natriuresis [diuresis] [natriuresis] by:
a. inhibiting renin secretion.
b. inhibiting aldosterone production by glomerulosa cells.
c. inhibiting vasopressin (i.e., antidiuretic hormone) secretion from the pituitary.