steroid hormones

Section 1: Aims of the Lecture (Page 1)

By the end of this lecture, students will be able to:

• Understand the biosynthetic origins of steroidal sex hormones.

• Describe the mechanism of receptor binding and subsequent gene expression.

• Identify these steroidal ligands and the biosynthetic pathway as potential drug targets.

Section 2: Steroid Structures – Biosynthetic Origins (Page 2)

• Steroid biosynthesis was introduced in Year 1 as part of triterpene biosynthesis.

• Squalene is cyclised to give lanosterol in mammals.

• Lanosterol is then converted to cholesterol.

• Cholesterol is the key intermediate in the synthesis of all mammalian steroidal hormone molecules.

• Understanding their biosynthesis and structure has aided the design of hormonally-related drugs (e.g., agonists, antagonists, enzyme inhibitors).

Section 3: Overview of Sterol Biosynthesis (Page 3)

The conversion of squalene to cholesterol involves several key enzymatic steps:

Image Description (Page 3): Detailed chemical schemes showing the cyclisation of squalene to lanosterol and the subsequent demethylation and reduction steps leading to cholesterol.

Section 4: Steroid Structure (Page 4)

• Steroids share a common core structure: the cyclopentanoperhydrophenanthrene ring system.

• This consists of:

  • Three cyclohexane rings (A, B, C) in a phenanthrene arrangement.

  • One cyclopentane ring (D).

Image Description (Page 4): A diagram of the basic steroid nucleus with the rings labelled A, B, C, and D, and the carbon atoms numbered according to standard steroid nomenclature.

PART 2: STEROID HORMONE RECEPTORS AND MECHANISM OF ACTION

Section 5: General Principles of Receptor Binding (Page 5)

• The Endocrine System: Steroid hormones are secreted into the bloodstream and carried to distant organs where they exert their effects.

• Binding Characteristics:

  • Steroids bind to their receptors with high affinity and specificity.

  • Blood concentrations of steroid hormones are normally in the nanomolar (nM) range.

  • Despite low concentration and the presence of many other biomolecules, only the correct ligand must bind and trigger a response.

• Nature of Binding:

  • Non-covalent binding via multiple types of interactions (hydrogen bonds, van der Waals, hydrophobic interactions).

  • Importance of 3D shape – both ligand and receptor have complementary shapes.

  • Large complementary surfaces between the ligand and receptor.

• Cross-reactivity: At high ligand concentrations, they may bind to non-target receptors, leading to off-target effects.

Section 6: Steroidal Receptors – General Properties (Page 6)

• Ligand Binding Effects: Very often, ligand binding causes receptors to:

  • Change shape (conformational change).

  • Aggregate with other proteins.

  • Dimerise (bind with another ligand/receptor complex).

  • Change location (e.g., migrate to the nucleus).

• Receptor Location: Receptors may be found within cell membranes (for some peptide hormones) or in the cytoplasm (for steroid hormones).

• Modulation of Sensitivity: The action of steroid hormones can modulate sensitivity to the same or other hormones by:

  • Increased/decreased receptor synthesis.

  • Receptor internalisation.

  • Degradation.

  • Phosphorylation.

Section 7: Mechanism of Action of Steroidal Sex Hormones (Page 7)

This is the classic genomic pathway of steroid hormone action.

• Receptor Structure: Comparisons between steroid hormone receptors show the HRE binding region to be highly conserved.

• Zinc Fingers: These receptors contain structures described as "zinc fingers" that bind to DNA. Mutations in the zinc fingers change HRE specificity.

PART 3: ESTROGENS

Section 8: Estrogen Structure (Page 8)

• Key Structural Features:

  • Aromatic A ring (phenolic).

  • No methyl group at C-10 (characteristic of estrogens).

  • 3-hydroxyl group (phenolic OH) on the A ring.

  • 17β-hydroxyl group (or ketone) on the D ring.

Image Description (Page 8): The chemical structure of estradiol, the primary estrogen, highlighting the aromatic A ring and the hydroxyl groups at positions 3 and 17.

Section 9: Estrogen Activity (Page 9)

• Physiological Effects:

  • Coordinate systemic responses during the ovulatory cycle.

  • Mediate development of secondary female sexual characteristics.

• Pathological Role: Estrogens may drive the progression of some tumours (e.g., breast cancer).

• Therapeutic Use: Synthetic estrogenic agonists and antagonists have been produced and are licensed for use in:

  • Fertility control (contraceptives).

  • Hormone replacement therapy (HRT) .

  • Cancer chemotherapy (e.g., treating hormone-dependent cancers).

PART 4: PROGESTOGENS

Section 10: Progestogens (Page 10)

• Structure: Progesterone has a similar steroid nucleus but lacks the aromatic A ring of estrogens. It has a ketone at C-3 and a methyl ketone side chain at C-17.

• Relationship with Estrogens: Progestogens have complementary roles with estrogens.

• Receptor Expression: Progesterone receptors are in low abundance in the absence of estrogens (estrogen upregulates progesterone receptor expression).

• Key Roles:

  • Regulation of the menstrual cycle.

  • Maintenance of pregnancy (progesterone is crucial for sustaining the endometrium).

Image Description (Page 10): The chemical structure of progesterone.

PART 5: BIOSYNTHESIS OF FEMALE SEX HORMONES

Section 11: Female Sex Hormone Biosynthesis (Page 11)

• Starting Material: Cholesterol (C27) is the precursor.

• Rate-Limiting Step: The conversion of cholesterol to pregnenolone by the enzyme P450scc (side-chain cleavage enzyme) is the slowest (rate-limiting) step in steroidogenesis.

• Pathway: Cholesterol → Pregnenolone → Progesterone → ... → Androgens → Estrogens (via aromatase).

• Transport in Bloodstream:

  • Steroids in the bloodstream may be free (unbound) or bound to globulin proteins.

  • Estrogens bind to sex hormone-binding globulin (SHBG) .

  • Progesterone binds to corticosteroid-binding globulin (CBG) .

• Active Concentration: The biologically active concentration is the free (unbound) steroid.

• Feedback Control: Hormone molecules control globulin concentration, and hence free steroid concentration (a regulatory mechanism).

PART 6: ESTROGEN RECEPTOR BINDING AND MODULATION

Section 12: Estrogen Receptor Binding and Cellular Effects (Page 12)

• Receptor Activation: Estrogens bind to receptors and activate HREs as described in Section 7.

• Cell-Specific Effects: The actual proteins synthesised depend on the specific transcription factors also present in the cell (explains tissue-specific effects of estrogens).

• General Effects:

  • Estrogens: Increase cellular proliferation.

  • Progestins: Decrease cellular growth and increase cellular differentiation.

• Requirements for Tissue Responsiveness: For a tissue to be affected by a steroid, three conditions must be met:

  1. The cells must express the receptor.

  2. Genes with the correct HRE must be present in the DNA.

  3. Appropriate transcription factors/proteins must be present.

Section 13: Phytoestrogens (Page 13)

• Definition: Non-steroidal compounds of plant origin displaying oestrogenic properties.

• Mechanism: They bind to the oestrogen receptor and stimulate an oestrogenic response (they are agonists, but usually much weaker than endogenous estradiol).

• Therapeutic Effects: They are believed to:

  • Counter the effects of menopause (reduce hot flushes).

  • Protect against stroke and heart attack.

  • Help prevent osteoporosis.

  • Lessen the risk of breast and uterine cancer.

Section 14: Antiestrogens – Tamoxifen as a Key Example (Page 14)

• Definition: Antiestrogens are oestrogen receptor antagonists.

• Key Example: Tamoxifen.

• Clinical Use: Used to treat hormone-dependent breast cancer (by blocking the stimulatory effects of estradiol on cancer cell growth).

• Mechanism: Tamoxifen and its active metabolites (e.g., endoxifen) inhibit the binding of estrogens to the estrogen receptor (ER) .

• SERM Properties: Tamoxifen is a Selective Estrogen Receptor Modulator (SERM) – it acts as an antagonist in breast tissue but as a partial agonist in other tissues (e.g., bone, endometrium).

Exercise (Page 14): Examine the structures of oestrogen agonists (estradiol) and antagonists (tamoxifen) and relate their key structural features to their activity/function.

Image Description (Page 14): Chemical structures of estradiol and tamoxifen side-by-side for comparison.

PART 7: ANDROGENS

Section 15: Androgens (Pages 15-16)

15.1. General Principles (Page 15):

• Androgens act via similar ligand-receptor processes as seen with estrogens.

• Testosterone is the most important endogenous androgen.

• Distribution: Found predominantly in males but also in females.

15.2. Physiological Effects:

15.3. Pathological Role: Androgens can also promote tumour progression (e.g., prostate cancer).

Image Description (Page 15): The chemical structure of testosterone.

15.4. Androgen Transport and Metabolism (Page 16):

• Transport: Androgens can bind to sex hormone-binding globulin (SHBG) .

• Tissue-Specific Activation: In the prostate, testosterone is converted to 5α-dihydrotestosterone (DHT) by the enzyme 5α-reductase. DHT has greater receptor affinity than testosterone and is a more potent androgen.

• Therapeutic Use: Synthetic agonists and antagonists of testosterone have been identified and are used to treat:

  • Hormone imbalances.

  • As part of cancer chemotherapies (e.g., GnRH agonists to reduce testosterone in prostate cancer).

• Abuse: Androgens have been (and continue to be) abused to promote increase in muscle mass (anabolic steroid abuse).

PART 8: READING REFERENCES

Section 16: Recommended Reading (Page 17)

• Dewick, Medicinal Natural Products, 3rd edition, Chapter 5, pg 247-306 – for detailed steroid biosynthesis and chemistry.

• Rang and Dale's Pharmacology, Chapter 26 – for pharmacology of steroid hormones and their receptors.

SUMMARY TABLE: KEY STEROID HORMONES AND THEIR PROPERTIES