🧠 PART 1 — BIG PICTURE: STEROIDS vs PROSTAGLANDINS

Core Concept

Both are lipid hormones, but fundamentally different in:

In pregnancy, these must coordinate precisely to regulate myometrial contraction timing.

🧠 PART 2 — STEROID HORMONES

2.1 Classification

Steroids are divided into:

• Corticosteroids → adrenal cortex
• Gonadal steroids → ovary or testis

All derived from cholesterol.

2.2 Cholesterol Sources (4 Major)

Steroidogenic cells obtain cholesterol from:

1. De novo synthesis (from acetate)
2. Plasma membrane
3. Intracellular lipid droplets (cholesteryl esters)
4. Plasma LDL cholesterol

All must ultimately reach mitochondria.

2.3 Rate-Limiting Step in Steroidogenesis

Critical Reaction

Cholesterol (27C) → Pregnenolone (21C)

Enzyme:

CYP11A1 (P450scc)

Located in inner mitochondrial membrane facing matrix

⚠️ Important implication:

Cholesterol must cross aqueous intermembrane space.

2.4 Cholesterol Transport Machinery

Requires:

• StAR protein
• Mitochondrial peripheral benzodiazepine receptor
• Voltage-dependent anion channel activation → Cl⁻ efflux
• Membrane apposition

Hormones that increase StAR:

• LH
• FSH
• hCG
• ACTH

2.5 Clinical Correlation — Lipoid Congenital Adrenal Hyperplasia

Failure of StAR → no cholesterol entry into mitochondria

Consequences:

• Accumulation of cholesteryl esters in adrenal cortex
• No corticosteroid synthesis
• Usually lethal in utero
• If born:
• Poor lung inflation (no fetal glucocorticoids)
• Salt-wasting crisis (no aldosterone)

🧠 PART 3 — STEROIDOGENIC ENZYMES

Two enzyme classes only:

3.1 CYP Enzymes

Functions:

• Hydroxylation → increase solubility
• Some act as lyases:
• CYP11A1
• CYP17A

Mechanism:

• Requires NADPH
• Electron transfer via:
• Ferredoxin reductase
• Ferredoxin
• To haem centre

3.2 HSD Enzymes

Types:

• 3β-HSD
• 17β-HSD

Functions:

• Oxidoreductases (short-chain alcohol dehydrogenases)
• Modify alcohol/ketone groups

3β-HSD

• Converts:
• Pregnenolone → Progesterone
• DHEA → Androstenedione
• Acts as Δ5 → Δ4 isomerase

Double bond shifts:

C5–6 → C4–5

17β-HSD

• Reduces C17 ketone
• Converts:
• Androstenedione → Testosterone
• Estrone → Estradiol

🧠 PART 4 — TISSUE-SPECIFIC STEROIDOGENESIS

Pathway depends entirely on enzyme expression pattern.

4.1 Testis Leydig Cells

Enzymes:

• CYP11A1
• CYP17A
• 3β-HSD
• 17β-HSD

Product:

→ Testosterone

4.2 Ovarian Theca Cells

Enzymes:

• CYP11A1
• CYP17A
• 3β-HSD

Product:

→ Androstenedione

4.3 Ovarian Granulosa Cells

FSH induces:

• Aromatase (CYP19)

Converts:

Androstenedione → Estrone → Estradiol (via 17β-HSD)

4.4 Corpus Luteum

Expresses:

• CYP11A1
• 3β-HSD
• CYP17A
• CYP19
• 17β-HSD

Produces:

• Progesterone
• Estradiol

🧠 PART 5 — PLACENTA AS “INCOMPLETE ENDOCRINE GLAND”

Key missing enzyme:

CYP17A

Thus placenta cannot convert progestogens → androgens.

Estrogen production requires:

• Fetal adrenal gland
• Maternal liver
• Placenta

Important fetal steroid:

16α-hydroxyandrostenedione

→ Aromatised in placenta

→ Estriol

Estriol = Marker of fetal adrenal function

🧠 PART 6 — STEROID METABOLISM & CLEARANCE

Peripheral metabolism:

• Skin
• Bone
• Adipose tissue

Examples:

• Testosterone → DHT (5α-reductase 2) → genital virilisation
• Testosterone → Estradiol (CYP19) → epiphyseal closure

Clearance (Liver, 2-Step)

Step 1:

CYP or HSD create polar OH groups

Step 2:

Conjugation by:

• Glucuronyltransferases
• Sulphotransferases

→ Excretion in urine/faeces

🧠 PART 7 — STEROID HORMONE ACTION

7.1 Receptors

Five steroid receptors exist.

All share four domains:

1. Ligand-binding domain
2. DNA-binding domain (zinc fingers)
3. Dimerisation domain
4. Transactivation domains

7.2 Mechanism

Ligand binding →

Receptor activation →

Dimer formation (homo/hetero) →

DNA binding at response elements →

Recruit co-regulators

7.3 Co-regulators

Co-repressors

• Recruit histone deacetylase
• Condense DNA
• Repress transcription

Coactivators

• Recruit histone acetyltransferase
• Open chromatin
• Increase transcription

Speed

Slow:

6 hours → days

Because genomic

🧠 PART 8 — PROSTAGLANDINS

8.1 Substrate: Arachidonic Acid

Stored in membrane phospholipids.

Liberated by:

Phospholipase A2

Inhibited by:

Lipocortin

(which is upregulated by glucocorticoids)

8.2 COX Enzymes

Arachidonate → PG G2 → PG H2

Two forms:

• COX-1 (constitutive)
• COX-2 (inducible)

Inhibited by:

NSAIDs (indometacin, aspirin)

8.3 Prostaglandin Synthases

PGH2 → converted to:

• PGD2
• PGE2
• PGF2α
• PGI2 (prostacyclin)

8.4 Inactivation

15-hydroxyprostaglandin dehydrogenase

Oxidises 15-OH → ketone

Highly expressed in lungs

→ 65% inactivated per pulmonary pass

Result:

Short-lived, local action only

🧠 PART 9 — PROSTAGLANDIN ACTION

Despite lipid nature → act via:

GPCR (cell surface)

PGF2α

Receptor:

F-prostanoid receptor

Pathway:

PLC → IP3 → ↑Ca²⁺

PGE2

Four receptor subtypes

Pathway:

↑ cAMP → activate PKA

Opposing actions often due to different signalling.

Speed:

Seconds–minutes

Acts via modifying pre-existing proteins.

🧠 PART 10 — REGULATION OF MYOMETRIAL CONTRACTILITY

Yin–Yang balance.

10.1 Contractants

• Oxytocin (originates from uterus, not posterior pituitary)
• PGF2α

Mechanism:

Receptor → PLC → IP3 → ↑Ca²⁺

Activates:

• Myosin light chain kinase
• Ca²⁺/calmodulin kinase

Positive Feedback Loop

Oxytocin → ↑ prostaglandins

PGF2α → ↑ oxytocin receptors

Amplification loop.

Steroid Modulation

Estradiol & Cortisol increase:

• Oxytocin expression
• Oxytocin receptor
• F-prostanoid receptor
• Prostaglandin enzymes

10.2 Relaxants (Anticontractants)

Work via:

• cAMP
• cGMP

Cause:

Dephosphorylation of myosin light chain

Major Relaxant

Progesterone

Actions:

• Decreases oxytocin synthesis
• Decreases prostaglandin action
• Increases cAMP
• Decreases gap junction formation

Uses both genomic + rapid non-genomic mechanisms.

Other Relaxants

• Nitric oxide (may act independent of cGMP)
• Relaxin → ↑ cAMP
• Prostacyclin → ↑ cAMP

🧠 PART 11 — TERM LABOUR SWITCH

At term:

Placental progesterone output declines

↓ Progesterone : Estradiol ratio

Shift:

Relaxant dominance → Contractant dominance

Labour begins.