7.4 Steroid hormones and their effects on metabolism

Steroid hormones, derived from cholesterol, play a crucial role in regulating metabolism. These lipid-soluble molecules, including glucocorticoids and sex hormones, cross cell membranes to interact with intracellular receptors, influencing gene expression and cellular function.

Steroid hormones impact various metabolic processes, from glucose regulation to protein synthesis. Their effects on metabolism are far-reaching, influencing stress responses, reproductive function, and overall homeostasis. Understanding steroid hormone action is key to grasping metabolic regulation in health and disease.

Steroid hormone structure and synthesis

Chemical structure and classification

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• Steroid hormones consist of lipid-soluble molecules derived from cholesterol
• Four-ring core structure characterizes steroid hormones (three cyclohexane rings and one cyclopentane ring)
• Major classes of steroid hormones include glucocorticoids, mineralocorticoids, androgens, estrogens, and progestogens
• Each class has distinct modifications to the basic steroid nucleus (cortisol, aldosterone, testosterone, estradiol, progesterone)

Steroidogenesis process

• Steroidogenesis occurs primarily in the adrenal cortex and gonads
• Series of enzymatic reactions modify the cholesterol precursor
• Key enzymes involved cytochrome P450 enzymes (CYPs) and hydroxysteroid dehydrogenases (HSDs)
  • CYPs catalyze hydroxylation reactions
  • HSDs catalyze oxidation-reduction reactions
• Rate-limiting step involves cholesterol transport from outer to inner mitochondrial membrane
  • Mediated by steroidogenic acute regulatory protein (StAR)
• Interconnected synthesis pathways allow for complex regulation of hormone production
  • Intermediate products serve as precursors for multiple hormone types

Steroid hormone action on cells

Intracellular receptor mechanism

• Lipophilic nature of steroid hormones allows them to cross cell membranes
• Interact with intracellular receptors belonging to the nuclear receptor superfamily
• Steroid hormone-receptor complex undergoes conformational change
  • Exposes DNA-binding domains
  • Reveals nuclear localization signals
• Activated hormone-receptor complexes translocate to the nucleus
• Bind to specific DNA sequences called hormone response elements (HREs)
  • Located in promoter regions of target genes
• Binding to HREs can activate or repress gene transcription
  • Depends on specific hormone and target gene

Modulation of transcriptional effects

• Steroid hormone receptors interact with coactivator or corepressor proteins
• Further modulates their transcriptional effects
• Duration and magnitude of steroid hormone action regulated by various factors
  • Receptor availability
  • Hormone metabolism
  • Negative feedback mechanisms

Non-genomic effects

• Some steroid hormones exert rapid, non-genomic effects
• Occurs through membrane-associated receptors
• Interacts with other signaling pathways (cAMP, calcium signaling)

Steroid hormone effects on metabolism

Glucocorticoid effects

• Promote gluconeogenesis in the liver
• Increase protein catabolism in muscle and other tissues
• Enhance lipolysis in adipose tissue
• Modulate insulin sensitivity (often decrease insulin sensitivity)

Mineralocorticoid effects

• Regulate electrolyte balance and blood pressure
• Promote sodium reabsorption in kidneys
• Enhance potassium excretion in kidneys

Sex steroid effects

• Androgens promote muscle protein synthesis
• Estrogens affect lipid metabolism and bone density
• Both influence protein anabolism

Metabolic enzyme modulation

• Steroid hormones alter activity of key metabolic enzymes
• Use both genomic and non-genomic mechanisms
• Changes flux through various metabolic pathways (glycolysis, gluconeogenesis, fatty acid synthesis)

Tissue-specific responses

• Different organs respond differently to the same hormone
• Steroid hormones influence tissue sensitivity to other hormones (insulin)
• Indirectly affect metabolic processes through hormone interactions

Chronic exposure effects

• High levels of certain steroid hormones lead to metabolic imbalances
• Can cause insulin resistance
• May alter lipid profiles (increased triglycerides, decreased HDL cholesterol)

Steroid hormones in homeostasis

Stress response regulation

• Glucocorticoids mediate "fight or flight" reaction
• Mobilize energy resources during stress (glucose, fatty acids)

Endocrine axes

• Hypothalamic-pituitary-adrenal (HPA) axis regulates glucocorticoid production
• Hypothalamic-pituitary-gonadal (HPG) axis controls sex steroid production
• Both axes maintain homeostasis through feedback mechanisms

Glucose regulation

• Glucocorticoids oppose insulin actions
• Promote glucose production during fasting states
• Help maintain blood glucose levels within normal range

Electrolyte and blood pressure balance

• Mineralocorticoids essential for electrolyte homeostasis
• Regulate blood pressure through effects on renal sodium and potassium handling

Reproductive function and secondary characteristics

• Sex steroids regulate reproductive processes (gametogenesis, menstrual cycle)
• Influence development of secondary sexual characteristics
• Affect bone density, muscle mass, and fat distribution

Endocrine system interactions

• Steroid hormones interact with other endocrine systems
• Coordinate with thyroid and growth hormone axes
• Ensure overall metabolic regulation

Circadian rhythm influence

• Cortisol secretion follows a circadian pattern
• Helps synchronize physiological processes with sleep-wake cycle
• Coordinates daily activities and metabolic functions

Steroid hormone imbalances and disorders

Cushing's syndrome

• Characterized by excess glucocorticoids
• Leads to central obesity and insulin resistance
• Alters glucose metabolism
• Increases risk of type 2 diabetes

Addison's disease

• Results from adrenal insufficiency
• Causes hypoglycemia and electrolyte imbalances
• Leads to weight loss due to inadequate glucocorticoid and mineralocorticoid production

Aldosterone disorders

• Hyperaldosteronism causes hypertension and hypokalemia
• Hypoaldosteronism results in hypotension and hyperkalemia
• Both affect cardiovascular health

Polycystic ovary syndrome (PCOS)

• Associated with androgen excess in women
• Leads to insulin resistance and obesity
• Increases risk of metabolic syndrome

Hypogonadism

• Occurs in both males and females
• Results in altered body composition
• Decreases bone density
• Changes lipid metabolism
• Increases cardiovascular risk

Congenital adrenal hyperplasia

• Caused by enzymatic defects in steroid hormone synthesis
• Leads to various metabolic disturbances
• Specific effects depend on the enzyme affected (21-hydroxylase deficiency, 11β-hydroxylase deficiency)

Exogenous steroid use

• Hormone replacement therapy can affect metabolism
• Performance-enhancing drugs have significant metabolic consequences
• May alter glucose tolerance and lipid profiles
• Can lead to long-term health risks (cardiovascular disease, osteoporosis)