Hormone Metabolization

Hormone metabolism in peripheral tissues serves three principal purposes:

• Activation:
  Some hormones require metabolic conversion to achieve their full biological potency. For example, thyroid hormones undergo activation steps to become biologically active. Other hormones are metabolized into more potent forms; testosterone (T), for instance, is converted into dihydrotestosterone (DHT), a more active androgen in specific tissues.
  
  

• Inactivation:
  Metabolic inactivation is essential for down regulating hormonal signals. A classic example is the conversion of cortisol to cortisone, an inactive glucocorticoid. Catecholamines are also rapidly inactivated through enzymatic degradation by monoamine oxidase (MAO) and catechol-O-methyltransferase (COMT), found in various tissues, ensuring proper neurotransmitter balance and preventing excessive accumulation.

• Clearance:
  Regardless of whether a hormone is activated or inactivated, metabolism ultimately prepares it for clearance and excretion. The specific pathways depend on the hormone’s biochemical structure and whether it circulates freely or is protein-bound.

  • Free Hormones:
    Free hormones are primarily metabolized and excreted by the liver and kidneys:

    • Peptide hormones are degraded through proteolysis, often by hormone-specific enzymes like insulin-degrading enzyme.

    • Steroid hormones and thyroid hormones undergo sequential phase I and phase II biotransformation reactions. Phase I modifications (e.g., hydroxylation) reduce hormonal activity, while phase II conjugations (e.g., sulfation, glucuronidation) enhance water solubility, promoting elimination via urine or bile.
      
      

  • Protein-bound Hormones:
    Hormones bound to carrier proteins can also be cleared through:

    • Carrier protein endocytosis:
      Some protein-bound hormones, such as steroid hormones, may enter cells through receptor-mediated endocytosis involving their carrier proteins—similar to cholesterol uptake via lipoproteins. After internalization and fusion with early lysosomes, these complexes are degraded, and their components excreted.
      
      

  • Receptor-bound Hormones (Clearance at the Action Site): After binding to their receptors and initiating cellular responses, hormones can be cleared by the target cell itself:

    • Cell surface receptors:
      Hormone-receptor complexes can undergo endocytosis, forming early endosomes. The complex can then be recycled back to the membrane (e.g., β₂-adrenergic receptors) or targeted for degradation (e.g., insulin receptors).

      Nuclear receptors:

      Hormones that bind intracellular receptors (such as steroid and thyroid hormones) may later dissociate, diffuse back into the extracellular space, or be transported out of the cell for systemic clearance like free or protein-bound hormones.