Adrenal Cortical Hormones and Steroid Hormones

Adrenal Cortical Hormones

Steroid Hormones

  • The adrenal cortex consists of three different zones, each responsible for the production of different classes of steroid hormones: C21, C19, and C18 hormones.
Zones of the Adrenal Cortex

  1. Zona Glomerulosa (Outermost Layer)

    • Produces C21 steroids, also known as mineralocorticoids.
    • These hormones are responsible for regulating water and electrolyte balance.

  2. Zona Fasciculata (Middle Layer)

    • Primarily produces glucocorticoids, with less production of adrenal androgens and estrogens.

  3. Zona Reticularis (Innermost Layer)

    • Produces C19 androgens and C18 estrogens.
Historical Context
  • Cortisone
    • Isolated by Tadeus Reichstein, structure identified by Edward Kendall. In 1948, Philip Hench demonstrated its efficacy in treating rheumatoid arthritis.
    • All three were awarded the Nobel Prize in 1950.

Synthesis of Steroid Hormones

  1. Cholesterol Conversion

    • Cholesterol undergoes action by desmolase, resulting in the cleavage of a 6-carbon unit, forming pregnenolone (C21 steroid). (Figure 46.1)
    • Pregnenolone is a common precursor for all steroid hormones and its synthesis is regulated by Adrenocorticotropic Hormone (ACTH), which is considered the rate-limiting step for all steroid hormone synthesis.

  2. Formation of Progesterone

    • From pregnenolone, progesterone is formed via two enzymatic steps: a keto group is created via 3-beta-ol-dehydrogenase, and the double bond shifts to A4. (Figure 46.2)

  3. Conversion to Other Hormones

    • Progesterone is subsequently transformed into glucocorticoids (Figure 46.2), mineralocorticoids (Figure 46.3), and sex steroids (Figure 46.4).

  4. Major Hormones

    • Major adrenal glucocorticoids: Cortisol, cortisone, and corticosterone (in that order).
    • Primary mineralocorticoid: Aldosterone, with 11-deoxycorticosterone and corticosterone exhibiting significant mineralocorticoid activity.

  5. Role of Hydroxylation

    • Hormone synthesis is facilitated by hydroxylation reactions, carried out by hydroxylases which are mono-oxygenases.
    • All enzymes in these processes are NADPH-dependent and are summarized in Figure 46.5.

  6. ACTH's Role in Hormone Synthesis

    • ACTH boosts steroid hormone production by activating desmolase, thereby increasing pregnenolone availability.

Secretion of Adrenal Hormones

  1. Control of Secretion

    • The secretion of all adrenocortical hormones is governed by ACTH.

  2. Diurnal Variation

    • Cortisol secretion varies diurnally, peaking early in the morning and minimizing at night.
    • This secretion pattern reflects the pulsatile release of ACTH from the anterior pituitary under the influence of Corticotropin-Releasing Factor (CRF).

  3. Negative Feedback Mechanism

    • Cortisol exerts negative feedback on the secretion of ACTH, stabilizing levels within a homeostatic range.

  4. Impact on Aldosterone

    • ACTH triggers increased secretion of aldosterone, which is also influenced by body position; levels rise in an upright posture and drop when lying down.

  5. Mechanism of Action

    • Steroid hormones act via intracellular messengers, enhancing transcription rates of specific genes.

Transport and Metabolism of Steroid Hormones

  1. Binding in Blood

    • Approximately 70% of cortisol in blood is bound to cortisol-binding globulin (CBG) or transcortin.
    • About 20% binds to albumin, while the remainder exists as free cortisol, which is the biologically active form.
    • The half-life of cortisol is around 2 hours.

  2. Liver Metabolism

    • Steroid hormones undergo metabolism and inactivation, mainly in the liver through processes of reduction and conjugation.
    • C21 steroids are reduced to tetrahydro derivatives before being excreted as glucuronides or sulfates in urine.

Urinary Steroids

  1. Classification of Urinary Steroids

    • Urinary steroids can be categorized into 17-ketosteroids and 17-hydroxy steroids, noting that these urinary bodies originate from adrenal steroids and androgens from the gonads.
    • The 11-oxygenation index serves as an indicator of adrenal steroid production, as 11-hydroxylation is unique to the adrenal cortex.

  2. Testing and Measurement

    • Zimmerman reaction is employed to estimate 17-ketosteroids, wherein the 17-keto group reacts with metadinitrobenzene, resulting in a purple coloration.
    • 17-hydroxy steroids, directly derived from adrenal steroids (glucocorticoids and mineralocorticoids), are assessed through the Porter-Silber reaction.
    • 17-ketogenic steroids include all compounds featuring a keto or hydroxyl group at the 17th carbon position.

Biological Effects of Glucocorticoids

  1. Cortisol Levels Measurement

    • Plasma cortisol levels can be determined via methods such as radio-immunoassay (RIA), enzyme-linked immunosorbent assay (ELISA), or chemiluminescent immunoassay (CLIA).
    • Normal ranges are 5-25 micrograms/dL at 9 AM and 2-5 micrograms/dL around 10 PM.

  2. Assessment of Urinary Free Cortisol

    • The free fraction of cortisol in plasma indicates biological activity; its measurement in urine provides insight into adrenal function. High levels suggest hyperfunction, whereas low levels indicate hypoactivity.

  3. Plasma ACTH Levels

    • In cases of hyperadrenalism, ACTH levels are suppressed; inversely, high ACTH levels occur during hypo-adrenalism or conditions like Cushing's disease. Elevated ACTH may result from ectopic ACTH secretion.

  4. Metabolic Effects

    • Glucocorticoids mainly influence glucose metabolism. A summary of effects is presented in Table 46.1.