CHAPTER 31 Adrenal Physiology
What is the weight of a normal adult adrenal gland?
5 g.
Embryologically, does the adrenal arise from a single structure? Describe the process.
No, the adrenal cortex and medulla are derived from embryologically distinct structures. The cortex develops from embryonic mesoderm and the medulla from embryonic neureoectoderm. The hormonal secretions of each have different actions. Regulation of cortical and medullary secretions are independent of each other.
Describe the functional relationship between the adrenal cortex and medulla.
Despite their anatomic proximity, there is virtually no functional relationship between the adrenal cortex and medulla.
In patients with renal ectopia or agenesis, where does the ipsilateral adrenal gland lie?
It lies in its normal orthotopic position. Since the adrenal gland and the kidney are of different embryologic origins, their migrations to their final anatomic positions take place independently.
What percentage of the adrenal gland is made up of the adrenal cortex?
The cortex constitutes 90% of the gland.
What are the 3 zones of the adrenal cortex?
Zona glomerulosa lies immediately beneath the capsule of the gland, the zona fasciculata is the middle zone and is the largest portion of the cortex, and the zona reticularis is the innermost zone.
Is there a functional significance between the anatomic zonations of the adrenal gland?
Yes, each anatomic zone is also a functional zone. Aldosterone is produced exclusively in the zona glomerulosa. Cortisol is produced in the two inner zones, zona fasciculata and the zona reticularis. Adrenal androgens are produced in the inner cortical zone, the zona reticularis.
What are the building blocks of adrenal hormones?
Adrenal cells are capable of synthesizing cholesterol de novo, but most of the adrenal cholesterol used for steroidogenesis is derived from circulating lipoproteins and in particular from low-density lipoproteins (LDL).
What is the first step in the production of adrenal steroid hormones?
The first step is the production of pregnenolone from cholesterol via 2 hydroxylations followed by cleavage of the cholesterol side chain. Pregnenolone has no known biologic activity, but it is an intermediate in the production of all the biologically active steroid hormones.
How are adrenal hormones stored?
Adrenal hormones are steroid hormones, and as all biologic steroid hormones, adrenal hormones are not stored but are secreted immediately upon synthesis. The rate of steroid hormone secretion can be controlled by regulation of synthesis.
Are active forms of adrenal hormones free or bound in serum?
Only the free hormone is biologically active; however, all steroid hormones are largely protein-bound when they circulate in plasma. Because of the limited solubility of steroid hormones in water, protein binding acts to increase the amount of hormone that can circulate in the blood. Since the protein-bound fraction of hormone is relatively resistant to metabolism, protein binding also increases the plasma half-life of steroid hormones.
Adrenal androgen production is limited by what factors?
Many steroid compounds can be synthesized by the adrenal cortex; however, the enzymes required for the production of testosterone and estrogen are found in low concentration in the cortical cells. Consequently, androgens are normally produced in only very small quantities.
Does the androgen precursor dehydroepiandrosterone (DHEA) have any androgenic activity in males?
Only minimal; DHEA is secreted in large quantities by the adrenal cortex in males. DHEA has much less activity than testosterone, and in males, the overall effect of DHEA as an androgen is negligible. In females, both DHEA and androstenedione may be converted to testosterone at extra-adrenal sites, thus it has more androgenic activity in females.
What stimulates adrenal androgen production?
Adrenocorticotropic hormone (ACTH) influences adrenal androgen production and seems to be the primary stimulus. However, it is clearly not the only factor, as evidenced by dissociation of ACTH and adrenal androgen production during events such as puberty and stress. Other regulators are not completely delineated, but it appears to be independent of gonadotropins.
What are the principal androgens produced by the adrenal glands?
Dehydroepiandrosterone (DHEA), dehydroepiandrosterone sulfate (DHEAS), and androstenedione are the principal androgens produced by the adrenals.
How substantial is adrenal androgen production compared to total androgen production?
The major androgen products of the adrenals are weak in their androgen effect. They are converted to more potent androgens, testosterone, and dihydrotestosterone in peripheral tissues. Even so, adrenal androgens contribute 5% to 10% of the production rate of testosterone in an adult male, making a negligible contribution compared to testicular production. The proportion of adrenal androgen production is substantially higher in females (40%-60%). However, overall adrenal androgen production is rarely physiologically important in the natural state and is only clinically apparent in disease states of overproduction, such as congenital adrenal hyperplasia.
How does ketoconazole affect adrenal androgen production?
It inhibits the cytochrome P-450–dependent enzymes (CYP) important for steroidogenesis. Therefore, the conversion of cholesterol to pregnenolone is shut down, inhibiting production of testicular and adrenal androgens, as well as cortisol.
True/False: Ketoconazole is a specific CYP inhibitor.
False. Ketoconazole is a nonspecific CYP inhibitor that only weakly inhibits relevant enzymes at high doses. The dose-escalation required for effective CYP inhibition limits the widespread use of ketoconazole secondary to considerable patient intolerance.
Which CYP enzyme has been implicated in the promotion of hormone-resistance in advanced prostate cancer?
CYP17. Intratumoral overexpression of CYP17 has been implicated in the development of resistance to castration.
Describe the role of adrenal androgens in the promotion of castrate-resistant prostate cancer (CRPC).
In castrate prostate tumor tissues, levels of DHEA, DHEAS, and 5-androstenediol far exceed the concentrations of testosterone and dihydrotestosterone. These precursor adrenal androgens have been shown to activate both the wild-type and mutant androgen receptors (ARs).
What is the mechanism of action of abiraterone acetate?
Abiraterone acetate is a potent, selective inhibitor of CYP17, 17α-hydroxylase, and C17, 20-lyase.
What are the side effects of abiraterone acetate, and why do these side effects occur?
Side effects of abiraterone acetate include hypokalemia, hypertension, and fluid overload. The disruption of 17α-hydroxylase results in increased in deoxycorticosterone (10-fold) and corticosterone (40-fold). These changes result in secondary mineralocorticoid excess and the aforementioned symptoms.
How does one manage the side effects of abiraterone acetate?
Coadministration with prednisone avoids development of side effects by reducing ACTH secretion and thereby reducing production of downstream mineralocorticoid production. Alternatively, the addition of eplerenone, a specific mineralocorticoid receptor antagonist, is effective in controlling secondary mineralocorticoid excess associated with the administration of abiraterone acetate.
Describe the differences between traditional antiandrogens (flutamide, bicalutamide) and enzalutamide.
Traditional antiandrogens have low binding affinity for the AR, and in many cases, exhibit partial agonism resulting clinically in PSA declines upon withdrawal of these medications. Enzalutamide has a higher affinity for the AR than does bicalutamide and prevents nuclear translocation, DNA binding, and coactivator recruitment. Finally, enzalutamide has no demonstrable agonist activity.
There are 5 enzymes involved in the conversion of cholesterol to cortisol. What are the consequences of deficiencies of these enzymes and what disease state does this produce?
This family of disorders is known as congenital adrenal hyperplasia. In general, steroidogenesis is shunted to increased production of androgens in favor of cortisol and mineralocorticoid. The characteristic manifestations depend upon the enzyme affected, but typically include virilization of females and can include life-threatening salt-wasting due to lack of mineralocorticoid.
What tests are used to distinguish adrenal tumors in women with hirsutism?
Serum testosterone and DHEA.
What is the most important mineralocorticoid produced by the adrenal cortex?
Aldosterone, although produced in small quantities, is the most physiologically important mineralocorticoid. Other mineralocorticoids such as 11-deoxycorticosterone (DOC) have both glucocorticoid and mineralocorticoid properties, but are secreted in such small quantities that they are physiologically unimportant.
What is the half-life of plasma aldosterone?
Twenty to thirty minutes.
What is the most significant regulator of aldosterone secretion?
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