Biosynthesis and degradation of steroid hormones

Introduction to Steroid Hormones

• Steroid hormones are a group of hormones derived from cholesterol.
• They are lipophilic (fat-soluble), allowing them to pass through cell membranes and bind to intracellular receptors.
• Main categories include:
  • Glucocorticoids (e.g., cortisol)
  • Mineralocorticoids (e.g., aldosterone)
  • Sex hormones (e.g., estrogen, testosterone)
  • Progestogens (e.g., progesterone)

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Biosynthesis of Steroid Hormones

a. Cholesterol as a Precursor

• Cholesterol is the starting material for all steroid hormones.
• Location of synthesis: Mainly occurs in the adrenal glands, gonads (testes and ovaries), and placenta.

b. Step-by-Step Pathway of Steroid Hormone Synthesis

1. Cholesterol Conversion to Pregnenolone
   • Cholesterol is converted to pregnenolone via the action of cytochrome P450scc (side-chain cleavage enzyme) in the mitochondria.
   • Pregnenolone is the precursor to all steroid hormones.
2. Formation of Progestogens (e.g., Progesterone)
   • Pregnenolone is converted into progesterone in the gonads and adrenal glands.
3. Formation of Glucocorticoids (e.g., Cortisol)
   • Progesterone can be further converted into 11-deoxycortisol and eventually into cortisol by a series of enzyme-mediated reactions in the adrenal cortex.
   • Cortisol is important for stress response, metabolism, and immune function.
4. Formation of Mineralocorticoids (e.g., Aldosterone)
   • Pregnenolone can be converted into progesterone, which is then converted into 11-deoxycorticosterone, followed by aldosterone.
   • Aldosterone regulates salt balance, blood pressure, and fluid balance.
5. Formation of Androgens (e.g., Testosterone)
   • Pregnenolone and progesterone are converted into androgens (e.g., testosterone) in the gonads.
   • Testosterone is important for male secondary sexual characteristics and reproductive function.
6. Formation of Estrogens (e.g., Estradiol)
   • Androgens (e.g., testosterone) are converted into estrogens (e.g., estradiol) by the enzyme aromatase.
   • Estradiol is a key estrogen involved in female reproductive health, menstrual cycles, and pregnancy.

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Regulation of Steroid Hormone Biosynthesis

• Hormonal Regulation:
  • ACTH (Adrenocorticotropic hormone) stimulates cortisol production in the adrenal glands.
  • LH (Luteinizing hormone) and FSH (Follicle-stimulating hormone) regulate steroidogenesis in the gonads.
  • Angiotensin II and ACTH influence aldosterone production in the adrenal glands.
• Feedback Mechanisms:
  • Negative feedback: High levels of cortisol, aldosterone, or sex hormones inhibit the release of stimulating hormones like ACTH and LH/FSH from the pituitary.

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Degradation of Steroid Hormones

a. Inactivation and Metabolism

• Steroid hormones are inactivated primarily in the liver and then excreted in urine or bile.
• Conjugation with sulfate or glucuronide groups (via sulfotransferase or glucuronosyltransferase enzymes) makes them more water-soluble for excretion.

b. Breakdown Pathways

1. Cortisol:
   • Cortisol is metabolized in the liver into cortisone, an inactive form.
   • The conversion is catalyzed by the enzyme 11β-hydroxysteroid dehydrogenase.
2. Sex Hormones:
   • Testosterone and estradiol are metabolized to inactive compounds like androstenedione or estrone.
   • These metabolites are conjugated with glucuronic acid or sulfate for excretion.
3. Aldosterone:
   • Aldosterone is converted into inactive forms such as tetrahydroaldosterone, which is excreted in urine.

c. Excretion

• After conjugation, the steroid hormones are excreted either via the urinary system or bile, which can then be eliminated in feces.

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Clinical Significance

a. Disorders in Steroid Biosynthesis

• Congenital Adrenal Hyperplasia (CAH): A genetic disorder that results in a deficiency of enzymes in the steroidogenesis pathway, leading to abnormal levels of adrenal hormones.
• Cushing's Syndrome: Overproduction of cortisol, often due to tumors in the adrenal glands or pituitary.
• Addison's Disease: Insufficient production of cortisol and aldosterone, leading to fatigue, muscle weakness, and low blood pressure.

b. Steroid Hormone Therapy

• Corticosteroids: Synthetic glucocorticoids like prednisone are used to treat inflammatory diseases, autoimmune disorders, and adrenal insufficiency.
• Sex Hormone Replacement Therapy: Estrogen or testosterone therapy is used in cases of menopause, hypogonadism, or transgender hormone therapy.