Steroids and Their Structure

Steroids

• Steroids are a class of chemical compounds vital in animal and plant biology. Examples include:
• Sterols
• Bile Acids
• Steroidal Hormones
• Steroids are widely used medicinally:
• Birth Control
• Hormone Replacement Therapy
• Inflammatory Conditions
• Cancer Treatment
• Most steroids have a common structural backbone:
• Steroid Backbone

Structure, Stereochemistry and Nomenclature of the Steroid Backbone

• The steroid backbone consists of four fused rings:
• Three Cyclohexane rings (A, B, C)
• One Cyclopentane ring (D)
• The numbering for steroid structures is unique.
• Groups above the plane of the molecule are in the β-position, while those below are in the α-position.

Steroid Synthesis

• All steroids are synthesized from cholesterol, which is synthesized from acetyl-CoA
• Estrogen, Progesterone, and Testosterone exist in both males and females, but in different amounts:
• Females primarily secrete Estrogens and Progesterone
• Males primarily produce Testosterone
• These differences in hormone production drive the development of distinct reproductive systems and physical characteristics between men and women.

Mechanism of Action

• Steroid hormones act by regulating tissue-specific gene expression and protein biosynthesis in target cells.
• They exhibit remarkable tissue specificity.
• Steroid hormone receptors in different tissues are responsible for this specificity.
• Steroid hormones act in a two-step process:
  1. They bind to nuclear membrane receptors inside the cell to form an activated hormone-receptor complex.
  2. The activated complex binds to DNA, triggering the expression of specific genes.

Adrenal Steroids

• The adrenal gland produces two types of hormones:
• Adrenal medulla: secretes catecholamines (primarily epinephrine)
• Adrenal cortex: secretes adrenal steroids (corticosteroids)
• Two main types of adrenal steroids are:
• Mineralocorticoid (MC): - Primarily aldosterone - Regulates salt and water balance
• Glucocorticoid (GC): - Primarily cortisol (hydrocortisone) - Regulates carbohydrate, lipid, and protein metabolism - Inhibits inflammation reactions - Suppresses immunity

Cortisol Production

• The secretion of cortisol is controlled by the hypothalamus (through corticotropin) and the pituitary gland (through adrenocorticotropic hormone (ACTH)).
• Cortisol and other glucocorticoids act as feedback inhibitors of both ACTH and corticotropin. This can lead to adrenal insufficiency when exogenous glucocorticoids are withdrawn.

Therapeutic Uses of Adrenal Steroids

• Treat adrenal insufficiency (Addison’s Disease)
• Manage rheumatoid diseases and allergic manifestations (e.g. severe asthma, rheumatoid arthritis, rheumatic fever)
• Suppress inflammation regardless of the cause.
• Important to note: Corticosteroids only provide palliative treatment and are not a cure.

Adverse Effects of Adrenal Steroids

• Salt and water retention (hypertension and Cushing’s Syndrome)
• Redistribution of body fat (Buffalo hump, Moon face)
• Enhanced lipolysis and increased triglycerides
• Inhibition of prostaglandins synthesis (can worsen peptic ulcers)
• Increased gluconeogenesis (leads to glucose intolerance)

Structure Activity Relationships for Corticosteroids

• Essential structural elements for activity:
• C=O at C3
• A double bond between C4 & C5
• Oxygen at C11 (C=O or OH)
• β-ketol side chain at C17
• Factors that increase glucocorticoid activity:
• α-CH3 groups at positions 6 and 16
• 9α-F group prevents metabolic oxidation and increases receptor dissociation
• 16α or β-CH3 blocks hydroxylation
• All trans (B/C and C/D) backbone
• 11β-OH
• Factors that decrease sodium retention:
• 16α-OH group
• Bulky substituents on the β-side of the molecule abolish gluconeogenic activity, while those on the α-side do not.

Systemic Glucocorticoids

• Cortisone:
• 11-keto analog of cortisol
• Orally active
• Used for replacement therapy in adrenocortical insufficiency
• Cortisol (Hydrocortisone):
• More potent and active
• Primarily inactivated by 11β-hydroxysteroid dehydrogenase type-1 (11β-HSD1) in the liver.
• Cortisone is inactivated by 11β-hydroxysteroid dehydrogenase type-2 (11β-HSD2) in the kidneys. This protects the mineralocorticoid receptor from glucocorticoids.

Synthetic Corticosteroids

• Many synthetic derivatives have been developed with modified structures to:
• Enhance anti-inflammatory activity while minimizing sodium and water retention.
• Predinsone and Prednisolone:
• Δ1-corticoids (dehydro derivatives of cortisone and hydrocortisone)
• 4 times the anti-inflammatory activity of their parent compounds.
• The increased potency of these Δ1-corticoids results from a change in ring-A geometry which increases receptor affinity.