Index

Endocrinology — MRCOG Part 1 Deep-Dive Study Guide

Examination Relevance: Foundation of reproductive physiology, menstrual cycle control, pregnancy endocrinology, and clinical disorders. Accounts for ~15–20% of MRCOG Part 1 questions.

Table of Contents

1. Hypothalamic-Pituitary Axis
2. Ovarian Steroidogenesis
3. Oestrogens
4. Progesterone
5. Androgens
6. Prolactin
7. Thyroid & Pregnancy
8. Adrenal Cortex
9. Calcium & Bone Metabolism
10. Carbohydrate Metabolism
11. Pancreatic & Gut Hormones
12. Pineal Gland
13. Clinical Correlations & Mnemonics

1. Hypothalamic-Pituitary Axis

1.1 Overview

The hypothalamic–pituitary axis is the master regulator of endocrine function. The hypothalamus integrates neural and endocrine signals and controls the pituitary gland, which in turn governs the thyroid, adrenal, gonadal, and growth axes.

Key Principle: The hypothalamus secretes releasing hormones (and one inhibiting hormone — dopamine/PIH) into the hypothalamo-hypophyseal portal venous system, which travel to the anterior pituitary (adenohypophysis) to regulate secretion of trophic hormones. The posterior pituitary (neurohypophysis) stores and releases hormones synthesised in the hypothalamus and transported via the hypothalamo-hypophyseal tract (axonal transport).

1.2 Hypothalamic Nuclei & Their Hormones

1.3 The GnRH Pulse Generator

Definition: The GnRH pulse generator is a network of ~1500–2000 KNDy neurons (Kisspeptin/Neurokinin B/Dynorphin) located primarily in the arcuate nucleus.

Mechanism:

• KNDy neurons co-express kisspeptin, neurokinin B (NKB), and dynorphin
• NKB stimulates kisspeptin release (positive autofeedback)
• Dynorphin inhibits kisspeptin release (negative autofeedback)
• Kisspeptin acts on KISS1R (GPR54) receptors on GnRH neurons to stimulate GnRH pulses
• This oscillatory system generates GnRH pulses every 60–120 minutes in the follicular phase and every 90–180 minutes in the luteal phase

Sexual dimorphism: Males have relatively constant GnRH pulse frequency; females have cyclical variation that drives the menstrual cycle.

Modulators of GnRH pulse frequency:

Clinical correlate — Hypothalamic amenorrhoea: Functional hypothalamic amenorrhoea (FHA) results from suppressed GnRH pulsatility due to stress, weight loss, or excessive exercise. Treatment involves restoring energy balance; kisspeptin analogues are being investigated therapeutically.

KNDy neuron developmental stages:

1. Infancy: GnRH pulse generator active (minipuberty)
2. Childhood: GnRH pulse generator quiescent (central restraint mediated by GABA/neurotransmitters)
3. Puberty: Reactivation of KNDy neurons → kisspeptin release → GnRH pulsatility restored → HPG axis activated
4. Adulthood: Functionally mature, cyclical in females
5. Menopause: Loss of ovarian feedback → high GnRH/LH/FSH

1.4 Pituitary Gland Anatomy

Location: Sella turcica of the sphenoid bone, inferior to the optic chiasm, connected to hypothalamus via pituitary stalk (infundibulum).

Dimensions: ~1.3 cm transverse × 1 cm AP × 0.5 cm vertical; weight ~0.5–1 g.

Lobes:

Pars intermedia: In humans, the pars intermedia is rudimentary but produces melanocyte-stimulating hormone (MSH) from POMC cleavage.

1.5 Hypothalamo-Hypophyseal Portal Venous System

Anatomy:

• Superior hypophyseal artery supplies the median eminence → forms primary capillary plexus
• Portal veins (long portal veins) travel down the pituitary stalk to the anterior pituitary
• Secondary capillary plexus bathes the anterior pituitary cells
• Releasing/inhibiting hormones enter the primary plexus and reach the anterior pituitary via the portal system
• Inferior hypophyseal artery supplies the posterior pituitary directly

Key fact: The portal system allows low concentrations of hypothalamic hormones to reach the anterior pituitary in high local concentrations without systemic dilution. This is the only portal system in the body connecting two capillary beds without passing through the heart.

Clinical correlate — Pituitary stalk transection: If the pituitary stalk is severed (e.g., trauma, post-surgery), the portal system is disrupted → loss of trophic hormone stimulation → anterior pituitary failure. Posterior pituitary dysfunction also occurs due to loss of hypothalamic-neurohypophyseal tract (DI may result). However, prolactin levels increase because tonic dopamine inhibition is lost.

1.6 Hypothalamo-Hypophyseal Tract (Neurohypophyseal Pathway)

Anatomy:

• Magnocellular neurons in the paraventricular (PVN) and supraoptic (SON) nuclei synthesise oxytocin and ADH
• These hormones are transported via axonal transport along the hypothalamo-hypophyseal tract through the pituitary stalk
• Stored in Herring bodies (axonal swellings) in the pars nervosa (posterior pituitary)
• Released directly into systemic circulation via the inferior hypophyseal artery

Stimuli for release:

1.7 Anterior Pituitary Cell Types

1.8 Hypothalamic & Pituitary Hormones — Detailed

1.8.1 Growth Hormone (GH)

• Structure: 191 amino acids, single-chain polypeptide
• Secretion: Pulsatile, highest during slow-wave sleep (stage 3–4 NREM)
• Regulation: GHRH (stimulates) ↔ Somatostatin/GHIH (inhibits)
• Actions: Direct (anti-insulin, lipolysis) + Indirect via IGF-1 (liver, bones → growth)
• IGF-1: Mediates many GH effects; synthesised in liver; negative feedback on GH
• Pregnancy: Placental GH variant replaces pituitary GH from ~15–20 weeks

1.8.2 Thyroid-Stimulating Hormone (TSH)

• Structure: α-subunit (common with FSH, LH, hCG) + β-subunit (specific)
• Regulation: TRH (stimulates) ↔ Somatostatin, Dopamine, T3/T4 negative feedback
• Pregnancy: hCG has weak TSH-agonist activity → transient gestational hyperthyroidism
• Diurnal rhythm: TSH peaks at night

1.8.3 Adrenocorticotrophic Hormone (ACTH)

• Structure: 39 amino acids, derived from POMC (pro-opiomelanocortin)
• POMC cleavage products: ACTH, β-lipotrophin, MSH, β-endorphin
• Regulation: CRH (stimulates) ↔ Cortisol (negative feedback)
• Circadian rhythm: High in early morning (peak ~6–8 am), low at midnight
• Stress response: Overrides circadian rhythm
• Pregnancy: Cortisol increases due to oestrogen-induced CBG rise + placental CRH

1.8.4 Follicle-Stimulating Hormone (FSH) & Luteinising Hormone (LH)

• Structure: α-subunit common to TSH, FSH, LH, hCG; β-subunit unique
• Regulation: GnRH (pulsatile) + oestrogen/progesterone/inhibin feedback
• GnRH pulse frequency differential:
• High frequency (~1 pulse/hour) → preferentially LH synthesis
• Low frequency (~1 pulse/3–4 hours) → preferentially FSH synthesis
• Inhibin B (from small antral follicles) → selectively inhibits FSH
• Activin → stimulates FSH synthesis
• Follistatin → binds activin → reduces FSH

1.8.5 Prolactin

• Structure: 198 amino acids, polypeptide
• Regulation: Tonic inhibition by dopamine (PIF) via D2 receptors; TRH stimulates
• Function: Lactation, suppression of GnRH (lactational amenorrhoea)
• Covered in depth in Section 6.

1.8.6 Melanocyte-Stimulating Hormone (MSH)

• Derived from POMC cleavage (ACTH also has MSH-like activity)
• Pregnancy: MSH increases → areolar hyperpigmentation, linea nigra, melasma (chloasma)
• Addison's disease: High ACTH → MSH activity → hyperpigmentation

1.8.7 Oxytocin & ADH (Vasopressin)

Oxytocin: - Structure: 9 amino acids (nonapeptide), synthesised in PVN - Actions: Uterine contraction (labour), milk ejection (let-down reflex) - Receptors: OTR (G-protein coupled, oxytocin receptors in myometrium and breast) - Ferguson reflex: Cervical/vaginal stretch → afferent signals → hypothalamus → oxytocin release → uterine contraction → further stretch → positive feedback - Suckling reflex: Nipple stimulation → hypothalamus → oxytocin release → milk ejection - Oestrogen: Upregulates oxytocin receptors in myometrium during pregnancy

ADH (Vasopressin): - Structure: 9 amino acids (nonapeptide, differs from oxytocin by 2 amino acids), synthesised in SON > PVN - Receptors: V1a (vascular smooth muscle → vasoconstriction), V1b (pituitary ACTH release), V2 (renal collecting duct → aquaporin-2 insertion → water reabsorption) - Actions: Antidiuresis (V2), vasoconstriction (V1a) - Stimuli: ↑ Plasma osmolality (even 1–2% change detected by osmoreceptors in OVLT), ↓ blood volume (detected by baroreceptors in carotid sinus/aortic arch), nausea, pain, stress - Diabetes insipidus: Central (ADH deficiency) vs Nephrogenic (ADH resistance)

1.9 Feedback Loops

Positive feedback (rare in endocrinology): - Oestradiol surge → stimulates GnRH/LH surge (mid-cycle ovulatory LH surge) - Oxytocin → during labour (Ferguson reflex) - CRH → in late pregnancy (placental CRH stimulates fetal ACTH → cortisol → lung maturation)

1.10 Pituitary Function Tests

1.10.1 Insulin Tolerance Test (ITT) — Gold Standard

1.10.2 TRH Test

• Procedure: IV TRH 200 μg; measure TSH at 0, 20, 60 min
• Normal: TSH rises >5 mU/L by 20 min
• Primary hypothyroidism: Exaggerated TSH response
• Secondary hypothyroidism (pituitary): Blunted/no response
• Tertiary hypothyroidism (hypothalamic): Delayed response (peak at 60 min)

1.10.3 GnRH Test

• Procedure: IV GnRH 100 μg; measure LH and FSH at 0, 20, 60 min
• Normal: LH rises 2–5× baseline within 20–30 min; FSH rises 1.5–2×
• Primary ovarian failure: Exaggerated LH/FSH response
• Hypogonadotrophic hypogonadism: Blunted response (but repeated GnRH can prime the pituitary)
• MRCOG note: Limited clinical utility; useful in differentiating pituitary vs hypothalamic causes of amenorrhoea

1.10.4 CRH Test

• Procedure: IV CRH 1 μg/kg; measure ACTH and cortisol at 0, 15, 30, 60, 90, 120 min
• Normal: ACTH peaks at 15–30 min; cortisol at 30–60 min
• Cushing's disease (pituitary ACTHoma): Exaggerated ACTH response
• Ectopic ACTH: No response
• Adrenal Cushing's: Suppressed ACTH, no response to CRH

1.10.5 GHRH-Arginine Test

• Procedure: IV GHRH 1 μg/kg + arginine 30 g over 30 min; measure GH
• Indication: Diagnosis of GH deficiency (safer alternative to ITT)
• Cut-off: GH <4.1 μg/L suggests severe GH deficiency (BMI-dependent cut-offs)

1.10.6 ACTH Stimulation Test (Short Synacthen Test)

• Procedure: IM/IV Synacthen (tetracosactide) 250 μg; measure cortisol at 0, 30, 60 min
• Normal: Cortisol >550 nmol/L at 30 or 60 min
• Primary adrenal insufficiency: No response (or <550)
• Secondary adrenal insufficiency: May have normal response if recent onset (adrenal not yet atrophied); blunted response if chronic
• MRCOG note: Preferred in pregnancy (safe alternative to ITT)

1.10.7 Water Deprivation Test

• Indication: Differentiating diabetes insipidus (DI) from primary polydipsia
• Procedure: Fluid restriction for 8 hours (or until 3–5% body weight loss); measure urine osmolality, plasma osmolality, ADH levels
• Normal: Urine osmolality >600 mOsm/kg, plasma osmolality <295 mOsm/kg
• Central DI: Low urine osmolality (<300) despite high plasma osmolality; responds to desmopressin
• Nephrogenic DI: Low urine osmolality; no response to desmopressin
• Primary polydipsia: Urine osmolality normalises (variable)

2. Ovarian Steroidogenesis

2.1 Overview

Ovarian steroidogenesis is the process by which the ovaries synthesise oestrogens, progesterone, and androgens from cholesterol. This occurs in a coordinated manner involving both theca cells and granulosa cells, regulated by LH and FSH respectively.

2.2 Cholesterol Source & Transport

• Source: LDL cholesterol (80%) + de novo synthesis from acetate (20%)
• Transport: LDL receptor-mediated endocytosis in theca and granulosa cells
• Rate-limiting step: Transfer of cholesterol from outer to inner mitochondrial membrane by StAR protein (Steroidogenic Acute Regulatory protein)
• StAR regulation: LH → cAMP-PKA pathway → StAR expression ↑

2.3 Steroidogenic Pathway (Complete)

Cholesterol (27C)
    │
    │ CYP11A1 (Desmolase/P450scc) — Side chain cleavage
    ▼
Pregnenolone (Δ⁵, 21C)
    │
    ├──▶ 3βHSD ──────────────────▶ Progesterone (Δ⁴, 21C)
    │                                    │
    │ CYP17A1 (17α-hydroxylase)          │ CYP17A1 (17α-hydroxylase)
    ▼                                    ▼
17-OH-Pregnenolone (Δ⁵)             17-OH-Progesterone (Δ⁴)
    │                                    │
    │ CYP17A1 (17,20-lyase)              │ CYP17A1 (17,20-lyase)
    ▼                                    ▼
Dehydroepiandrosterone (DHEA, Δ⁵)   Androstenedione (Δ⁴)
    │                                    │
    │ 3βHSD                              │ 17βHSD (17β-hydroxysteroid dehydrogenase)
    ▼                                    ▼
Androstenedione (Δ⁴)                Testosterone (Δ⁴, 19C)
    │                                    │
    │ Aromatase (CYP19A1)                 │ Aromatase (CYP19A1)
    ▼                                    ▼
Oestrone (E1)                       Oestradiol (E2)

Key enzymes:

Δ⁴ vs Δ⁵ pathway: - Δ⁵ pathway (preferred in humans): Pregnenolone → 17-OH-pregnenolone → DHEA → androstenedione - Δ⁴ pathway: Pregnenolone → progesterone → 17-OH-progesterone → androstenedione - The two pathways converge at androstenedione

2.4 The Two-Cell Two-Gonadotrophin Model

This is the central paradigm of ovarian oestrogen synthesis:

        Theca Cell                          Granulosa Cell
    (LH receptor)                       (FSH receptor)
          │                                    │
     Cholesterol                            Androstenedione
          │                                        │
          │ LH                                    │ FSH
          ▼                                        ▼
    Pregnenolone ──▶ Progesterone              Aromatase (CYP19A1)
          │                                        │
          ▼                                        ▼
    17-OH-Pregnenolone ──▶ 17-OH-Progesterone    Oestrone + Oestradiol
          │
          ▼
    DHEA ──▶ Androstenedione ────────────────────────────▶
                      │                                   │
                      │ Diffuses across                    │
                      │ basement membrane                  │
                      └───────────────────────────────────┘

Detailed Mechanism:

1. Theca interna cells (outer layer of the follicle):
2. Express LH receptors
3. LH activates cAMP-PKA pathway → StAR expression → cholesterol transport → steroidogenesis
4. Theca cells have high CYP17A1 activity (17α-hydroxylase and 17,20-lyase)
5. Produce androstenedione and testosterone

6. These androgens diffuse across the basement membrane to granulosa cells

7. Granulosa cells (inner layer, around the oocyte):

8. Express FSH receptors (and later LH receptors in the dominant follicle)
9. FSH activates cAMP-PKA pathway → induces aromatase (CYP19A1) expression
10. Granulosa cells lack CYP17A1 (cannot synthesise androgens from cholesterol directly)
11. Convert theca-derived androgens to oestrogens via aromatase
12. FSH also induces: LH receptor expression, inhibin production, antral cavity formation

Follicular phase dynamics:

Dominant follicle selection: - The follicle with the highest FSH sensitivity (most FSH receptors) produces the most oestrogen - Oestrogen + FSH upregulate LH receptors on granulosa cells (exclusive to dominant follicle) - Smaller follicles are less responsive to FSH and undergo atresia - INHIBIN B from granulosa cells selectively inhibits FSH → further reduces growth of subordinate follicles

Luteal phase shift: - After ovulation, granulosa and theca cells luteinise → corpus luteum - LH maintains the corpus luteum - The corpus luteum produces primarily progesterone (via Δ⁴ pathway) and oestradiol - CYP17A1 expression decreases in the luteinised granulosa cells → shift from oestrogen to progesterone production - If no pregnancy → luteolysis at ~day 24 (due to prostaglandin F2α, loss of LH support) - If pregnancy → hCG from syncytiotrophoblast rescues corpus luteum (maintains progesterone until luteal-placental shift at 8–10 weeks)

2.5 Oestrogen Synthesis in Pregnancy — The Fetoplacental Unit

This is a classic MRCOG topic. Oestrogen production in pregnancy involves cooperation among three compartments: maternal, fetal, and placental.

    MATERNAL                    FETAL                      PLACENTAL
    Compartment                 Compartment                Compartment
                              (Adrenal → Liver)
                                 │
    Cholesterol (maternal) ──▶ Pregnenolone ──▶ DHEA-S
                                 │
                                 │ Fetal adrenal zone     DHEA-S → Androstenedione → Testosterone
                                 │ (fetal zone, 80% of    │
                                 │ fetal adrenal cortex)   │
                                 ▼                        │
                           16-OH-DHEA-S ◀─────────────────│── DHEA-S
                           (fetal liver)                  │
                                 │                        │
                                 └───────────────────────▶│ Aromatase
                                                          │
                                                          ▼
                                                     Oestriol (E3)
                                                     (90% of pregnancy oestrogens)

Key concepts:

• Placenta lacks CYP17A1: Cannot convert progesterone/pregnenolone to androgens directly
• Placenta has high aromatase (CYP19A1): Converts fetal and maternal androgens to oestrogens
• Fetal adrenal zone (fetal zone): Produces massive amounts of DHEA-S (dehydroepiandrosterone sulphate)
• Fetal liver: 16α-hydroxylates DHEA-S to 16-OH-DHEA-S
• Placenta: Converts 16-OH-DHEA-S → oestriol (E3)

Oestrogen types in pregnancy:

Clinical correlate — Smith-Lemli-Opitz syndrome: - Defect in cholesterol synthesis (7-dehydrocholesterol reductase deficiency) - Low oestriol levels on maternal serum screening (since DHEA-S cannot be synthesised from cholesterol) - Associated with fetal growth restriction, dysmorphic features, intellectual disability

Clinical correlate — Placental sulphatase deficiency (X-linked ichthyosis): - Defect in steroid sulphatase (STS) enzyme - Cannot convert DHEA-S to DHEA (desulphation required for aromatase) - Very low oestriol levels - Male fetus (X-linked recessive) - Associated with ichthyosis vulgaris, failure of cervical ripening (prolonged labour, often requires CS) - No adverse fetal outcome (oestriol has minimal role in fetal well-being beyond this)

Oestriol as a marker in prenatal screening: - Part of quadruple test (AFP, hCG, uE3, inhibin A) for Down syndrome screening - Low uE3 is associated with trisomy 18 and 21 - Low uE3 also in: anencephaly (absent fetal adrenal), Smith-Lemli-Opitz, placental sulphatase deficiency

2.6 Regulation of Steroidogenesis

Short-term regulation (minutes–hours): - LH/hCG → LH receptor → Gs → cAMP → PKA → StAR phosphorylation → increased cholesterol transport → increased steroidogenesis - StAR protein is rate-limiting for acute steroidogenesis

Long-term regulation (hours–days): - LH/FSH upregulate steroidogenic enzyme gene transcription (CYP17A1, CYP19A1, HSD3B2) - FSH induces aromatase; LH induces CYP17A1 - Insulin/IGF-1 synergise with LH to enhance steroidogenesis (relevant in PCOS)

2.7 Extra-Ovarian Steroidogenesis

Aromatisation outside the ovary: - Adipose tissue (significant source in postmenopausal women: androstenedione → oestrone) - Breast tissue (local oestrogen production in breast cancer) - Bone, brain, skin, placenta

Adrenal androgen production: - Zona reticularis → DHEA, DHEA-S, androstenedione - DHEA-S is the most abundant circulating steroid (mainly adrenal origin in females) - Adrenarche: Onset of DHEA-S production at ~age 6–8 (independent of HPG axis)

3. Oestrogens

3.1 Types, Potency & Sources

Oestradiol ↔ Oestrone interconversion: - Reversible via 17βHSD types 1 and 2 - Type 1 (HSD17B1): Favours E2 production (ovary, breast) - Type 2 (HSD17B2): Favours E1 production (endometrium, placenta) - This is a local regulatory mechanism

Oestrogen synthesis in menopause: - Ovaries cease producing oestradiol - Main source: Adipose tissue aromatisation of adrenal androstenedione → oestrone - Adipose aromatase activity increases with age and obesity - Higher oestrone levels in obese postmenopausal women → increased risk of endometrial cancer (unopposed oestrogen)

3.2 Oestrogen Transport & Metabolism

Transport in blood: - 65% bound to SHBG (sex hormone-binding globulin, with high affinity) - 30% bound to albumin (low affinity) - ~2–5% free (biologically active)

SHBG regulation:

Clinical correlate: In PCOS, high insulin → low SHBG → increased free testosterone → clinical hyperandrogenism (even with normal total testosterone).

Metabolism: - Liver: Conjugation with glucuronide and sulphate (CYP450 hydroxylation, then conjugation) - Enterohepatic circulation: Conjugated oestrogens excreted in bile → deconjugated by gut bacteria → reabsorbed → recirculated - CLINICAL RELEVANCE: Antibiotics reduce enterohepatic circulation → may reduce OCP efficacy - Urinary excretion: Oestrone glucuronide and oestriol glucuronide

3.3 Mechanism of Action

3.3.1 Nuclear Receptors — ERα and ERβ

Receptor structure (nuclear receptors): - N-terminal A/B domain (AF-1 — ligand-independent activation) - C domain (DNA-binding domain — zinc fingers) - D domain (hinge region) - E/F domain (ligand-binding domain + AF-2 — ligand-dependent activation)

3.3.2 Genomic vs Non-Genomic Actions

Oestrogen Response Elements (ERE): Specific DNA sequences (GGTCAnnnTGACC) where oestrogen-ER complex binds.

Coactivators: SRC-1, AIB1 (amplified in breast cancer), TIF2, CBP/p300.

3.4 Physiological Actions of Oestrogen

3.4.1 Female Reproductive Tract

Cervical mucus changes — clinical relevance: - Pre-ovulatory (oestrogen-dominant): Spinnbarkeit ≥8–10 cm, ferning (palm leaf pattern) on microscopy - Post-ovulatory (progesterone-dominant): Thick, scanty, cellular, no ferning - Post-coital test (PCT): Assesses cervical mucus interaction with sperm - MRCOG note: Ferning is due to NaCl crystallisation in mucus; destroyed by progesterone

3.4.2 Breast Development (Thelarche)

• Ductal elongation and branching (oestrogen + GH/IGF-1)
• Stromal growth (fat deposition, connective tissue)
• Areolar enlargement and pigmentation
• Nipple development
• Oestrogen + progesterone + prolactin are required for complete lobuloalveolar development

3.4.3 Bone

• Promotes epiphyseal closure (in high doses, terminates growth at puberty)
• Inhibits osteoclast activity → decreased bone resorption
• Stimulates osteoblasts (via IGF-1)
• Maintains bone density — loss at menopause (1–3% per year for 5–10 years)
• Mechanism: Oestrogen induces osteoclast apoptosis via FasL/Fas signalling; reduces RANKL production
• MRCOG note: Oestrogen deficiency (menopause, hypothalamic amenorrhoea, hyperprolactinaemia) → bone loss. This is why HRT prevents postmenopausal osteoporosis.

3.4.4 Cardiovascular System

• Vasodilation: NO-mediated (endothelial ERα → eNOS activation)
• Lipid profile: ↓ LDL, ↑ HDL, ↓ Lp(a) (but ↑ triglycerides)
• Anti-atherosclerotic (in premenopausal women)
• Pro-thrombotic (increases coagulation factors VII, VIII, X, fibrinogen; decreases antithrombin III and protein S)
• Venous thromboembolism risk increases with OCP and HRT (especially oral route, first-pass hepatic effect)

3.4.5 Coagulation & Haemostasis

Clinical correlate — OCP and VTE: - Risk increases with oestrogen dose - Second-generation (levonorgestrel) < Third-generation (gestodene, desogestrel) < Fourth-generation (drospirenone) - Progestogen-only preparations have minimal/no increased VTE risk - Transdermal oestrogen has less effect on coagulation factors (no first-pass hepatic effect)

3.4.6 Fluid & Electrolyte Balance

• Sodium and water retention (mild — oestrogen ↑ renin substrate → angiotensinogen → aldosterone)
• Contributes to premenstrual fluid retention
• Responsible for increased blood volume in pregnancy (oestrogen + aldosterone + RAAS activation)

3.4.7 Central Nervous System

• Neuroprotective (promotes synaptic plasticity, reduces Aβ accumulation)
• Mood and cognition (modulates serotonin, dopamine, noradrenaline systems)
• Thermoregulation: Oestrogen withdrawal (menopause) → hot flushes (instability of hypothalamic thermoregulatory centre)
• Libido: Oestrogen maintains libido (but testosterone is more directly linked)
• Memory: Verbal memory improved by oestrogen; controversial effects on Alzheimer's risk

3.4.8 Skin & Connective Tissue

• Increases skin thickness and collagen content
• Promotes wound healing
• Sebum production: Oestrogen ↓ sebum (androgens ↑ sebum)
• Melanin: Oestrogen + MSH → increased pigmentation (areola, linea nigra, melasma)

3.5 Clinical Applications — Selective Oestrogen Receptor Modulators (SERMs)

Clomiphene citrate mechanism (must know for MRCOG): - Mixed oestrogen agonist/antagonist - Antagonises oestrogen receptors in the hypothalamus (blocks negative feedback) - ↑ GnRH pulse frequency → ↑ FSH and LH → follicular recruitment - Also has anti-oestrogenic effects on cervical mucus and endometrium (may impair fertility even while inducing ovulation)

Aromatase inhibitors: - Anastrozole, Letrozole, Exemestane - Block peripheral conversion of androgens to oestrogens - Used in: Breast cancer (postmenopausal), ovulation induction (off-label, but effective in PCOS) - No endometrial effects (unlike tamoxifen) - Less VTE risk than tamoxifen

3.6 Oestrogen & the Menstrual Cycle

Follicular phase: - Low E2 at menses → feedback inhibition removed → FSH rise - Follicle growth → E2 rises slowly at first, then rapidly - Threshold theory: E2 >200 pg/mL for ≥50 hours → positive feedback at pituitary - Positive feedback: E2 surge → ↑ GnRH sensitivity → LH surge (also FSH surge) - LH surge triggers ovulation ~36 hours later

Luteal phase: - E2 second peak (from corpus luteum, along with progesterone) - High E2 + P4 → negative feedback on LH/FSH - If no pregnancy → luteolysis → E2 and P4 fall → menstruation → FSH rises again

Menstrual cycle E2 levels:

4. Progesterone

4.1 Overview

Progesterone is the key hormone of the luteal phase and pregnancy. It prepares the endometrium for implantation, maintains pregnancy, and has multiple systemic effects.

4.2 Sources

Luteal-placental shift: - Before 8 weeks: Corpus luteum essential for progesterone production - At 8–10 weeks: Placental progesterone production becomes sufficient to maintain pregnancy - After 10–12 weeks: Ovariectomy does NOT cause abortion - hCG rescues the corpus luteum and stimulates placental progesterone synthesis

4.3 Structure & Classification

• 21-carbon steroid (pregnane skeleton)
• Δ⁴,3-keto configuration (4-pregnene-3,20-dione)
• Precursor: Cholesterol → pregnenolone → progesterone (via 3βHSD)
• Progestins: Synthetic compounds with progestogenic activity (progesterone analogues)

4.4 Transport & Metabolism

• 48% bound to CBG (corticosteroid-binding globulin) — also called transcortin
• 50% bound to albumin
• ~2% free
• Half-life: ~5–10 minutes (very short — metabolised rapidly)
• Metabolism: Liver (CYP450 reduction) → pregnanediol → glucuronide conjugation → urinary excretion
• Urinary pregnanediol: Historical marker of ovulation; now replaced by serum progesterone

4.5 Progesterone Receptors

PR isoforms distribution: - Endometrium: PR-A predominant - Breast: PR-B predominant (PR-B promotes proliferation) - Myometrium: PR-A > PR-B (but ratio changes at term)

Ligand-dependent vs independent activation: - Classical: Progesterone binds PR → nuclear translocation → dimerisation → PRE binding - Ligand-independent: cAMP, growth factors can activate PR via phosphorylation

Progesterone Response Elements (PRE): Specific DNA sequences in target gene promoters.

4.6 Physiological Actions of Progesterone

4.6.1 Endometrium

Noyes criteria for endometrial dating (classic, now supplemented by molecular markers):

4.6.2 Myometrium

• Quiescence (anti-oestrogenic effect):
• ↓ Myometrial contractility
• ↓ Gap junction formation (downregulates connexin-43)
• ↓ Oxytocin receptors
• ↑ BKCa channels (large-conductance calcium-activated potassium channels) → membrane hyperpolarisation
• ↑ β-adrenergic receptor expression
• "Progesterone block" theory: High progesterone maintains uterine quiescence throughout pregnancy; at term, progesterone withdrawal (functional, not necessarily serum level) → increased contractility → labour onset

Functional progesterone withdrawal at term: - Controversial mechanism: Changes in PR-A/PR-B ratio (increased PR-A relative to PR-B → reduced PR-B-mediated quiescence) - Metabolism: Local metabolism of progesterone (17α-hydroxylase, 20α-HSD) reduces effective progesterone in myometrial cells - Decidual activation: Progesterone suppresses decidual activation; functional withdrawal lifts suppression → prostaglandin production → contractions

4.6.3 Cervix

• Cervical ripening prevention:
• Thick, viscous, cellular mucus (ferning absent, spinnbarkeit <1 cm)
• Closure of cervical canal
• Maintains cervical length
• At term: Functional progesterone withdrawal → cervical ripening (collagen breakdown, increased water content, softening)

4.6.4 Breast

• Lobuloalveolar development:
• Ductal branching (with oestrogen)
• Development of secretory alveoli
• Acinar formation
• Lactation:
• Prolactin stimulates milk production
• Progesterone inhibits lactogenesis (high levels during pregnancy suppress milk production)
• After placental delivery (progesterone falls dramatically) → lactogenesis begins (day 2–3 postpartum)

4.6.5 Thermogenic Effect

• Basal body temperature (BBT) rise of 0.3–0.5°C in luteal phase
• Mechanism: Progesterone acts on hypothalamic thermoregulatory centre (preoptic area)
• Clinical use: BBT charting for ovulation detection (temperature shift indicates ovulation has occurred)
• MRCOG note: The BBT rise is a retrospective indicator of ovulation — it confirms ovulation occurred but cannot predict it

4.6.6 Respiratory System

• Respiratory stimulation:
• ↑ Chemosensitivity to CO₂ (increases sensitivity of medullary chemoreceptors)
• ↑ Minute ventilation (↑ tidal volume more than rate)
• ↓ PaCO₂ (↓ arterial pCO₂ by 8–10 mmHg in pregnancy — normal pregnancy PaCO₂ ~30–32 mmHg)
• ↓ Serum bicarbonate (compensated respiratory alkalosis)
• Clinical correlate: Dyspnoea of pregnancy is partly due to progesterone-driven hyperventilation

4.6.7 Immunomodulation in Pregnancy

• Th2 shift: Progesterone promotes Th2-dominant immune response (humoral, anti-inflammatory) and suppresses Th1 response (cell-mediated, pro-inflammatory)
• Uterine NK cells: Progesterone modulates uNK cell function
• Progesterone-induced blocking factor (PIBF): — Produced by lymphocytes in response to progesterone; mediates immunomodulatory effects; inhibits NK cell activity; promotes Th2 cytokines
• Treg cells: Progesterone promotes regulatory T cell expansion
• Clinical correlate: Progesterone supplementation may reduce preterm birth risk in women with short cervix (mechanism: immunomodulation + myometrial quiescence)

4.6.8 Other Effects

4.7 Progestins (Synthetic Progestogens)

Pharmacological differences: - Binding affinities: Vary for PR, AR, ER, GR, MR - Androgenic progestins (norethisterone, levonorgestrel) → negate beneficial HDL effect of oestrogen - Anti-androgenic progestins (cyproterone acetate, drospirenone) → beneficial in hyperandrogenic states - Drospirenone: Also has anti-mineralocorticoid activity (natriuretic, may cause hyperkalaemia in predisposed)

4.8 Progesterone in Clinical Practice

Luteal phase support (IVF): - Micronised progesterone vaginal pessaries (most common), IM progesterone, or oral dydrogesterone - Started from oocyte retrieval day or embryo transfer day - Continued until 10–12 weeks (luteal-placental shift)

Threatened miscarriage: - Controversial — current evidence shows no benefit in sporadic threatened miscarriage - May benefit women with recurrent miscarriage (especially if luteal phase defect)

Preterm birth prevention: - Short cervix (<25 mm) on mid-trimester scan: Vaginal progesterone reduces preterm birth risk by ~45% - Previous preterm birth: Weekly IM 17α-hydroxyprogesterone caproate (17-OHPC) from 16–36 weeks (controversial efficacy)

HRT: - In women with uterus: Combined oestrogen + progestogen to prevent endometrial hyperplasia/cancer - Continuous combined (for postmenopausal women >1 year since LMP) - Cyclical sequential (for perimenopausal women)

5. Androgens

5.1 Types & Relative Potency

5.2 Androgen Synthesis

Ovarian synthesis (covered in Section 2): - Theca interna cells (LH-dependent) - Androstenedione and testosterone produced - Diffuse to granulosa cells → aromatised to oestrogens

Adrenal androgen synthesis: - Zona reticularis (LH-independent; regulated by ACTH, but also other factors — e.g., insulin, IGF-1) - Cortisol pathway diverges at 17,20-lyase step to produce DHEA and androstenedione - Adrenarche: Onset at ~6–8 years of age (increasing DHEA-S); independent of HPG axis; unique to humans and great apes - DHEA-S is the major adrenal androgen (half-life ~10 hours, longer than any other steroid → stable marker)

Peripheral conversion: - Androstenedione → Testosterone (17βHSD in adipose, skin, liver) - Testosterone → DHT (5α-reductase type 2 in genital skin, prostate; type 1 in sebaceous glands, liver) - Androstenedione → Oestrone (aromatase in adipose) - DHEA-S → DHEA (sulphatase in multiple tissues)

5.3 Transport

Calculating free testosterone: - Free androgen index (FAI) = Total Testosterone (nmol/L) / SHBG (nmol/L) × 100 - Normal FAI in women: <4.5% - FAI is a better marker of hyperandrogenism than total testosterone alone

Other methods: - Free testosterone by equilibrium dialysis (gold standard but expensive) - Calculated free testosterone (Vermeulen formula — uses total T, SHBG, albumin)

5.4 Androgen Receptors

• AR is a nuclear receptor (NR3C4) on X chromosome (Xq11-12)
• Structure: N-terminal domain (most variable, contains polyglutamine repeat — CAG repeats), DBD, LBD
• CAG repeat length: Inverse correlation with AR sensitivity
• Fewer repeats (<19) → increased AR sensitivity → increased risk of hirsutism, PCOS, prostate cancer
• More repeats (>40) → Kennedy's disease (spinal and bulbar muscular atrophy)
• Ligand: Testosterone and DHT both bind; DHT has 2–5× higher affinity and dissociates slower
• Mechanism: Ligand binding → nuclear translocation → dimerisation → ARE binding → transcription of androgen-responsive genes

5.5 Physiological Actions of Androgens in Females

Androgen-dependent hair growth: - Non-androgen dependent hair: Scalp hair, eyebrows, eyelashes - Androgen-dependent hair: Pubic, axillary, beard, chest, back, external auditory meatus, nasal passages - Pilosebaceous unit: Androgen stimulates terminal hair growth and sebaceous gland activity - Male pattern baldness (androgenetic alopecia): Androgen-induced miniaturisation of scalp hair follicles (genetic predisposition)

5.6 Female Androgen Excess

5.6.1 Polycystic Ovary Syndrome (PCOS)

Diagnosis (Rotterdam 2003) — 2 out of 3: 1. Oligo/anovulation (menstrual irregularity) 2. Clinical/biochemical hyperandrogenism 3. Polycystic ovaries on ultrasound (≥12 follicles 2–9 mm per ovary, or ovarian volume >10 mL)

PCOS phenotypes:

Pathophysiology of hyperandrogenism in PCOS: - ↑ LH pulse frequency and amplitude (by GnRH pulse generator) → ↑ LH:FSH ratio (>2:1) - ↑ LH → theca cell hyperstimulation → ↑ androgen production - Insulin resistance → compensatory hyperinsulinaemia → acts on: - Ovarian theca cells (via insulin receptor + IGF-1R) → ↑ androgen synthesis - Liver → ↓ SHBG → ↑ free testosterone - Adrenals → ↑ DHEA-S production - ↓ FSH (due to increased oestrone from peripheral aromatisation of androgens) → impaired follicular maturation → anovulation

PCOS — Key investigations: - Total testosterone, SHBG, FAI - 17-OHP (to exclude 21-OH CAH — check early follicular phase, fasting AM) - DHEA-S (adrenal contribution) - LH, FSH (LH:FSH ratio) - Fasting glucose, insulin, HOMA-IR - Lipid profile (↑ TG, ↓ HDL) - Pelvic ultrasound

5.6.2 Congenital Adrenal Hyperplasia (CAH)

21-Hydroxylase deficiency (95% of CAH cases):

Diagnosis: - Basal 17-OHP (measured in early follicular phase, AM): >30 nmol/L is diagnostic of classic CAH - ACTH stimulation test: 17-OHP >30 nmol/L at 60 min suggests non-classic CAH - CYP21A2 gene sequencing

Treatment: - Glucocorticoid replacement (hydrocortisone or dexamethasone) - Mineralocorticoid if salt-wasting (fludrocortisone) - Prenatal treatment: Dexamethasone to mother (starting ≤9 weeks) to prevent genital ambiguity in affected female fetuses (controversial — limited to clinical trials)

5.6.3 Cushing's Syndrome

Endogenous hypercortisolism: - ACTH-dependent (80%): Cushing's disease (pituitary ACTHoma, 70%), ectopic ACTH (10%) - ACTH-independent (20%): Adrenal adenoma/carcinoma, bilateral adrenal hyperplasia

Androgen excess in Cushing's: - Adrenal carcinoma: High DHEA-S (>40 μmol/L) + virilisation - Cushing's disease: Mild androgen excess (ACTH stimulates adrenal androgens) - Ectopic ACTH: Can cause high androgens

5.6.4 Androgen-Secreting Tumours

Ovarian: - Sertoli-Leydig cell tumour: Highly androgenic; produces testosterone (often >7 nmol/L); rapid onset virilisation - Hilus cell tumour: hilar Leydig cell hyperplasia; testosterone excess - Lipoid cell tumour - Signs: Rapid onset (<1 year) of hirsutism, virilisation (deepening voice, clitoromegaly, alopecia, increased muscle mass)

Adrenal: - Adrenocortical carcinoma: DHEA-S >40 μmol/L; often co-secrete cortisol - Adrenal adenoma: Rarely produces androgens alone

Red flags for androgen-secreting tumour: - Rapid onset (<1 year) - Total testosterone >5–7 nmol/L - DHEA-S >18 μmol/L (>650 μg/dL) - Virilisation (clitoromegaly, voice change, male-pattern balding) - Palpable pelvic/adrenal mass

5.6.5 Idiopathic Hirsutism

• Hirsutism with normal ovulatory cycles, normal androgen levels, normal 17-OHP
• Increased 5α-reductase activity in skin → increased local DHT production
• Increased peripheral sensitivity to normal androgen levels
• Treatment: Focus on cosmetic + anti-androgens (if desired)

5.7 Anti-Androgen Therapies

Note: Anti-androgens are contraindicated in pregnancy (risk of feminisation of male fetus); advise reliable contraception.

5.8 Androgens & the Menstrual Cycle

Normal cycle changes: - Testosterone and androstenedione peak at mid-cycle (LH surge stimulates theca cell androgen production) - Small mid-luteal rise (corpus luteum produces some androgens) - No major clinical significance

5.9 Androgens in Menopause

• Ovarian androgen production (androstenedione, testosterone) declines by ~50% after menopause
• Adrenal DHEA-S declines with age (adrenopause)
• Net result: Decreased androgen levels
• Some women experience androgen insufficiency syndrome (decreased libido, fatigue, bone loss)
• Testosterone replacement in selected postmenopausal women (weak evidence, not routinely recommended)

6. Prolactin

6.1 Overview

Prolactin is a 198-amino acid polypeptide hormone synthesised and secreted by lactotrophs of the anterior pituitary. It is unique among anterior pituitary hormones in being under tonic inhibition by the hypothalamus, primarily by dopamine.

6.2 Structure

• 198 amino acids (23 kDa major form)
• Prolactin family: Several molecular forms (little PRL 23 kDa — most active; big PRL 50 kDa; big-big PRL 150 kDa)
• Macroprolactin: PRL bound to IgG (usually PRL autoantibodies) → high molecular weight → decreased renal clearance → elevated serum PRL but low bioactivity
• Clinical importance: Macroprolactinaemia accounts for ~15–25% of cases of hyperprolactinaemia
• Diagnosis: PEG precipitation (macroprolactin precipitated, free PRL measured in supernatant)
• No treatment needed (no risk of hypogonadism, no tumour)

Homology: Prolactin shares structural homology with growth hormone and human placental lactogen (hPL) — all derived from a common ancestral gene.

6.3 Regulation of Prolactin Secretion

6.3.1 Inhibitory Control (Dominant)

Dopamine tone: Lactotrophs are under tonic, continuous dopamine inhibition. When the pituitary stalk is severed, prolactin levels rise (loss of dopamine inhibition) while all other pituitary hormones fall (loss of releasing hormones).

6.3.2 Stimulatory Control

Prolactin-releasing factors (PRFs): - TRH (strongest known PRF) - VIP (vasoactive intestinal peptide) - Oxytocin (minor) - Possibly: PRL-releasing peptide (PrRP)

6.4 Physiological Actions

6.4.1 Lactation

Suckling reflex pathway: 1. Nipple stimulation → afferent sensory nerves (T4–T6 spinal nerves) 2. Spinal cord → hypothalamus 3. ↓ Dopamine (TIDA neurons) + ↑ PRF → ↑ Prolactin release 4. Suckling also → ↑ Oxytocin (from PVN) → milk ejection

Lactational amenorrhoea: - Suckling-induced hyperprolactinaemia → ↑ dopamine in hypothalamic portal blood (short-loop feedback) → ↓ GnRH pulsatility → ↓ LH/FSH → anovulation → amenorrhoea - 98% contraceptive efficacy in first 6 months if exclusively breastfeeding and amenorrhoeic (LAM — Lactational Amenorrhoea Method) - Mechanism: Prolactin suppresses kisspeptin expression in the arcuate nucleus → ↓ GnRH

6.4.2 Reproductive Function

• Inhibits GnRH (via kisspeptin suppression) → hypogonadotrophic hypogonadism
• Inhibits gonadotrophin secretion
• Inhibits steroidogenesis (direct effect on ovary: ↓ luteal function, ↓ oestrogen/progesterone)

6.4.3 Other Actions

6.5 Hyperprolactinaemia

Definition: Serum prolactin >480–500 mU/L (≈24 ng/mL) in women (lower in men: >300 mU/L).

6.5.1 Causes

Stalk effect: Large non-prolactin pituitary tumours (GH-, ACTH-, gonadotroph-, or TSH-secreting, also non-functioning) compress the pituitary stalk → disrupt dopamine transport → mild hyperprolactinaemia (usually <3000 mU/L or <100 ng/mL). Prolactinomas typically produce higher levels (>5000 mU/L).

6.5.2 Clinical Features

Galactorrhoea: More common in women with high oestrogen background (premenopausal); uncommon in postmenopausal women (low oestrogen). Not all women with hyperprolactinaemia have galactorrhoea, and not all galactorrhoea is due to hyperprolactinaemia.

6.5.3 Investigation

1. Serum prolactin level:
2. Single morning sample (fasting, at least 1–2 hours after waking, avoid exercise/breast exam)
3. If mild elevation, repeat ×2–3 (stress can cause transient elevation)
4. Prolactin >5000 mU/L (≈200 ng/mL) → strongly suggestive of prolactinoma
5. Prolactin >10,000 mU/L → almost certainly macroprolactinoma

6. Prolactin <3000 mU/L + normal MRI → consider idiopathic, stalk effect, drugs, macroprolactin

7. Exclude secondary causes:

8. β-hCG (rule out pregnancy)
9. TFTs (hypothyroidism)
10. Renal function, LFTs
11. Drug history (including OTC, herbal, psychiatric meds)

12. Macroprolactin screen (PEG precipitation) if asymptomatic with mild elevation

13. Pituitary MRI:

14. Indicated if prolactin significantly elevated or symptoms suggest mass effect
15. Microprolactinoma: <10 mm

16. Macroprolactinoma: ≥10 mm (risk of visual compromise)

17. Visual field testing:

18. All macroprolactinomas (bitemporal hemianopia risk)
19. Microprolactinoma if suprasellar extension

6.5.4 Management

General principles: - Dopamine agonists are first-line treatment (medical therapy only — surgery rarely needed) - Bromocriptine (first generation) or Cabergoline (second generation, preferred) - Goal: Normalise prolactin → restore gonadal function → reduce tumour size

Cabergoline vs Bromocriptine:

Management algorithm: 1. Microprolactinoma: - Asymptomatic, no infertility, normal oestrogen → observe (no treatment required) - Symptomatic (hypogonadism, infertility, galactorrhoea) → cabergoline - Once PRL normalised and menses restored → can try pregnancy

1. Macroprolactinoma:
2. Cabergoline (titrate to normalise PRL and shrink tumour)
3. Monitor visual fields
4. ~60–80% tumour shrinkage on cabergoline

5. Trans-sphenoidal surgery if: resistance to DA therapy, apoplexy, visual failure despite medical therapy, CSF leak on treatment

6. Pregnancy:

7. Microprolactinoma: Withdraw DA once pregnant (low risk of tumour enlargement — <3%)

8. Macroprolactinoma: Significant risk of tumour enlargement (~15–30% in pregnancy); continue DA (cabergoline is safe in pregnancy — large cohort data suggest no increased congenital anomalies) or consider surgery pre-conception

9. Drug-induced:

10. Withdraw offending drug if possible (replace antipsychotic with one less likely to raise PRL — e.g., aripiprazole, quetiapine)
11. If must continue → add dopamine agonist (low dose — risk of psychosis exacerbation with high doses)

Adverse effects of dopamine agonists: - Nausea, vomiting, postural hypotension, dizziness, headache, nasal congestion - Impulse control disorders: Pathological gambling, hypersexuality, compulsive shopping (more with cabergoline — rare but important counselling point) - Valvular heart disease: Cabergoline at high doses (used in Parkinson's disease) → fibrotic valvulopathy; at standard PRL doses (0.5–2 mg/week), risk is negligible

6.6 Hypoprolactinaemia

• Rare — usually iatrogenic (over-treatment with dopamine agonists)
• Syndrome: Absence of postpartum lactation (can be a sign of Sheehan's syndrome)
• Sheehan's syndrome: Postpartum haemorrhage → pituitary necrosis → panhypopituitarism (including prolactin deficiency → failure of lactation)

6.7 Pituitary Apoplexy vs Sheehan's Syndrome

Note: Pituitary apoplexy is an endocrine emergency — high-dose IV hydrocortisone must be given immediately before imaging/surgery.

7. Thyroid & Pregnancy

7.1 Overview

Pregnancy causes profound changes in thyroid physiology. Understanding these changes is essential for MRCOG as thyroid disorders are common in women of reproductive age and have significant implications for pregnancy outcomes.

7.2 Physiological Changes in Pregnancy

7.2.1 Thyroid Binding Globulin (TBG)

• Oestrogen ↑ hepatic TBG synthesis
• TBG doubles by 6–8 weeks → stable thereafter
• ↑ TBG → ↑ total T4/T3 (but free T4/T3 remain normal)
• Clinical implication: Measure free T4 (not total T4) in pregnancy; total T4 is unreliable

7.2.2 Thyroid Volume

• Increases by 10–30% in pregnancy
• Due to: Increased blood flow, mild hyperplasia (hCG stimulation, relative iodine deficiency)
• Palpable goitre in ~15% of pregnant women (iodine-sufficient areas); higher in iodine-deficient regions

7.2.3 hCG Effect

• hCG has weak TSH-agonist activity (structural homology of α-subunits)
• Peak hCG at 8–12 weeks → stimulates TSH receptor → ↑ T4/T3 → ↓ TSH (negative feedback)
• Transient gestational hyperthyroidism: Physiological suppression of TSH at 10–12 weeks
• In ~1–2% of pregnancies, hCG stimulates TSH receptor excessively → gestational transient thyrotoxicosis
• Hyperemesis gravidarum: Severe vomiting associated with high hCG → transient hyperthyroidism, resolves by 18–20 weeks

Thyroid function changes by trimester:

7.2.4 Iodine Metabolism

• Renal iodide clearance increases (↑ GFR + increased iodide loss)
• Placenta: Actively transports iodide to fetus (fetal thyroid develops at 10–12 weeks)
• Iodine requirements: Increase from 100–150 μg/day to 250 μg/day in pregnancy
• Iodine deficiency in pregnancy → maternal goitre, fetal hypothyroidism → cretinism (if severe)
• WHO recommends universal salt iodisation

7.3 Thyroid Function Tests in Pregnancy — Interpretation

Trimester-specific reference ranges are essential (pregnancy alters TSH and FT4).

Optimal TSH in pregnancy: 0.4–2.5 mU/L (first trimester), 0.4–3.0 mU/L (second trimester), 0.4–3.5 mU/L (third trimester) — based on ATA guidelines.

7.4 Screening for Thyroid Disease in Pregnancy

Current UK guidance (NICE): - Do not routinely screen all pregnant women for thyroid disease - Offer screening to high-risk groups: - Type 1 diabetes - Other autoimmune disorders (SLE, Sjögren's, coeliac disease) - Previous thyroid disease/premature ovarian insufficiency - Family history of thyroid disease - Goitre - Symptoms of thyroid dysfunction

Screening test: TSH ± free T4 ± TPO antibodies

7.5 Hyperthyroidism in Pregnancy

7.5.1 Aetiology

Graves' disease in pregnancy: - First trimester: May worsen (immune rebound from pregnancy immunosuppression? Actually Graves' often improves due to pregnancy-induced immunosuppression and decreased TSI titres) - Second/third trimester: Usually improves (↑ TBG and decreased TSI? Actually pregnancy is immunosuppressive → TSI titres fall) - Postpartum: Worsens significantly (immune rebound after delivery) → highest risk period for Graves' flare

7.5.2 Diagnosis

• Suppressed TSH (<0.1 mU/L) + elevated free T4 (with or without elevated free T3)
• TSH receptor antibodies (TRAb/TSI): >95% sensitive/specific for Graves'
• TPO antibodies: May also be positive but TRAb is diagnostic

Differentiating Graves' from gestational transient hyperthyroidism:

7.5.3 Treatment

Goals: Maintain free T4 at upper-normal range (or slightly above upper-normal) to avoid fetal hypothyroidism.

First trimester — Propylthiouracil (PTU): - PTU 50–100 mg TDS (max 300–400 mg/day) - Why PTU? Methimazole/carbimazole teratogenicity risk in first trimester - Methimazole embryopathy: Aplasia cutis congenita (scalp defect), choanal atresia, oesophageal atresia, dysmorphic facies - PTU risk: Hepatotoxicity (rare but severe — FDA black box warning) - Switch to carbimazole after 16 weeks (PTU hepatotoxicity risk increases with continued use)

Second/third trimester — Carbimazole: - CBZ 10–20 mg daily (max 40 mg/day) - Adjust to keep free T4 at upper normal range (aim for TSH suppressed — don't target normal TSH as it takes weeks to recover)

β-blockers: - Propranolol 20–40 mg TDS (or atenolol) for symptom control - Used 1st trimester only or briefly when needed - Long-term use associated with fetal growth restriction

Monitoring: - Free T4 (every 2–4 weeks until stable, then monthly) - TSH is unreliable early — may remain suppressed for months after treatment - TRAb titres: Check by 24–28 weeks (high TRAb → risk of fetal/neonatal hyperthyroidism)

Do NOT use radioactive iodine in pregnancy (absolute contraindication — ablates fetal thyroid).

Surgery: - Subtotal/Total thyroidectomy in pregnancy - Indications: Failed medical therapy, severe allergy to both PTU and CBZ, large goitre with compression, suspected malignancy - Best performed in second trimester (organogenesis complete, uterus not yet large) - Risk: Hypoparathyroidism (if parathyroids removed), recurrent laryngeal nerve injury

7.5.4 Fetal/Neonatal Hyperthyroidism

• Due to transplacental passage of TSI (TRAb) — occurs in ~1–5% of women with Graves' (past or present)
• Risk correlates with high TRAb titres (>3× ULN or >5 IU/L)
• Fetal effects: Tachycardia (>160 bpm sustained), growth restriction, goitre (visible on US), hydrops
• Neonatal effects: Hyperkinesis, irritability, goitre, exophthalmos, feeding problems, cardiac failure
• Can occur even after maternal thyroidectomy (if TRAb remains elevated)
• Treatment: Methimazole crosses placenta; treat mother with carbimazole to control fetal hyperthyroidism
• Neonatal monitoring: Cord blood TFTs at birth; thyroid dysfunction usually resolves in 3–12 weeks (as maternal TRAb cleared)

7.6 Hypothyroidism in Pregnancy

7.6.1 Aetiology

7.6.2 Diagnosis

• Elevated TSH + low free T4
• Subclinical hypothyroidism: Elevated TSH (>2.5 mU/L) with normal free T4
• TPO antibodies: Positive in ~90% of Hashimoto's; indicate increased risk of progression to overt hypothyroidism

7.6.3 Maternal & Fetal Consequences

Critical window: The fetal brain depends entirely on maternal T4 for the first 10–12 weeks (before fetal thyroid function begins). After 12 weeks, the fetal thyroid produces T4 but still relies on maternal iodine supply.

Maternal T4 requirement in pregnancy: - Pre-existing hypothyroidism: Levothyroxine dose typically increases by 30–50% (average 45%) - Increase at confirmation of pregnancy: Immediately increase levothyroxine dose by 30% (e.g., 2 extra tablets per week) and check TSH within 4–6 weeks - Monitoring: TSH every 4–6 weeks in first half of pregnancy; aim for TSH <2.5 mU/L in first trimester, <3.0 in second/third

7.6.4 Management

Target TSH: <2.5 mU/L first trimester; <3.0 mU/L second/third trimester.

Pre-existing hypothyroidism: 1. Advise preconception optimisation — TSH <2.5 mU/L before pregnancy 2. On positive pregnancy test → increase levothyroxine by 30–50% immediately (don't wait for TSH) 3. Check TSH every 4–6 weeks, adjust dose by 25–50 μg increments 4. Most women need a dose increase by 8–12 weeks 5. After delivery → reduce to pre-pregnancy dose (check TSH at 6 weeks postpartum)

Newly diagnosed in pregnancy: - Start levothyroxine 1.6–2.0 μg/kg/day (or 100–150 μg daily) - Severe/severe symptoms: Start at full dose - Mild/moderate: Start at 50–100 μg and titrate up - Monitor TSH every 4–6 weeks

Subclinical hypothyroidism in pregnancy: - Controversial — current evidence does not clearly show benefit of treatment for maternal or fetal outcomes - ATA guidelines suggest treatment if TPO-positive + TSH >2.5 mU/L - NICE/UK: Not recommended to routinely treat subclinical hypothyroidism in pregnancy - Professional bodies disagree — ACOG is against universal screening/treatment; ATA/Endocrine Society are in favour of targeted screening

7.6.5 Levothyroxine Absorption

7.7 Postpartum Thyroiditis

• Prevalence: ~5–10% of women
• Autoimmune: Anti-TPO antibodies (strongly associated)
• Classic biphasic course:
• Transient thyrotoxicosis (1–4 months postpartum) — destructive thyroiditis (not increased synthesis)
• Transient hypothyroidism (4–8 months postpartum)
• Euthyroid (by 12 months postpartum) — in most women
• Not all women have both phases: Some only have thyrotoxicosis; others only hypothyroidism
• Diagnosis: Low uptake on radioactive iodine scan (differentiates from Graves' where uptake is high) — but RAI is contraindicated if breastfeeding
• Thyrotoxic phase: Symptomatic treatment (β-blockers only — no PTU/CBZ as this is destructive, not synthetic)
• Hypothyroid phase: Levothyroxine if symptomatic or trying to conceive
• Long-term: ~20–30% develop permanent hypothyroidism (higher risk with high TPO titres, multiparity)
• Recurrence risk: ~70% in subsequent pregnancies

Distinguishing postpartum thyroiditis from Graves' disease:

7.8 Thyroid Nodules & Cancer in Pregnancy

• Incidence: Thyroid nodules found in ~3–10% of pregnant women
• Evaluation: Ultrasound + FNA if suspicious (>1 cm, solid, hypoechoic, microcalcifications)
• FNA is safe in pregnancy (no radiation)
• Differentiated thyroid cancer (papillary, follicular):
• Usually slow-growing — surgery can be deferred until postpartum
• If rapid growth or metastatic → surgery in second trimester
• Radioactive iodine contraindicated in pregnancy and breastfeeding
• Medullary thyroid cancer: More aggressive → may require surgery in pregnancy

7.9 Fetal Thyroid Function

Development timeline: - Week 10–12: Fetal thyroid begins to concentrate iodine - Week 18–20: Fetal thyroid responds to TSH - Week 20–24: Fetal T3/T4 reach measurable levels - Term: Fetal T4 ~70% of maternal levels; fetal T3 very low (majority of T3 is produced locally from T4)

Placental transfer: - Maternal T4 crosses placenta in small amounts (critical in first trimester) - TSH does NOT cross placenta - TRAb (TSI) crosses placenta — can cause fetal/neonatal hyperthyroidism - PTU/Carbimazole cross placenta (can treat fetal hyperthyroidism) - Iodine crosses placenta — excess iodine can cause fetal goitre/hypothyroidism

7.10 Key MRCOG Pearls — Thyroid

8. Adrenal Cortex

8.1 Overview

The adrenal cortex is the outer layer of the adrenal gland and produces three classes of steroid hormones: glucocorticoids (cortisol), mineralocorticoids (aldosterone), and androgens (DHEA, DHEA-S). It is histologically and functionally divided into three zones.

8.2 Zonal Anatomy

Why can't the zona glomerulosa make cortisol? - Lacks CYP17A1 (17α-hydroxylase) — cannot convert pregnenolone to 17-OH-pregnenolone - Has aldosterone synthase (CYP11B2) which zona fasciculata/ reticularis lack

Why can't the zona fasciculata/reticularis make aldosterone? - Lack CYP11B2 (aldosterone synthase) - Have 11β-hydroxylase (CYP11B1) instead → produces cortisol

8.3 Steroidogenic Pathways in the Adrenal Cortex

                        Cholesterol
                            │
                        CYP11A1 (Desmolase)
                            ▼
                       Pregnenolone
                            │
              ┌─────────────┼──────────────┐
              │ (ZF/ZR)     │ (ZG)         │
           CYP17A1          HSD3B2         │
              ▼              ▼             │
        17-OH-Pregnenolone  Progesterone   │
              │              │             │ (ZG)
           CYP17A1           │             │
        (17,20-lyase)        │             │
              ▼              ▼             ▼
            DHEA ←────── Androstenedione
              │ (ZR)       │ (ZF)          │ (ZG)
              │            │               │
           SULT2A1        CYP21A2         CYP21A2
              ▼            ▼               ▼
            DHEA-S    11-Deoxycortisol  11-Deoxycorticosterone
                         │ (ZF)            │ (ZG)
                      CYP11B1            CYP11B2
                         ▼                 ▼
                       Cortisol          Corticosterone
                                            │ (ZG)
                                         CYP11B2
                                            ▼
                                        Aldosterone

Key adrenal enzymes:

8.4 Cortisol

8.4.1 Synthesis & Secretion

• Produced in zona fasciculata
• Pathway: Cholesterol → Pregnenolone → Progesterone → 17-OH-Progesterone → 11-Deoxycortisol → Cortisol
• Rate-limiting step: StAR-mediated cholesterol transport
• Regulated by ACTH (from anterior pituitary via POMC)
• Circadian rhythm: Highest ~6–8 AM (peak), lowest ~midnight (nadir)
• Secretory bursts: Episodic (ultradian rhythm superimposed on circadian)
• Stress: Overrides circadian rhythm (cortisol can rise 10×)

8.4.2 Transport

• 90% bound to CBG (corticosteroid-binding globulin / transcortin)
• 5% bound to albumin
• ~5% free (biologically active)

CBG changes: - ↑ by oestrogen (pregnancy, OCP) → ↑ total cortisol but free cortisol normal - ↓ by inflammation, sepsis, liver disease, nephrotic syndrome - In pregnancy: Total cortisol rises 2–3× (due to CBG increase), but free cortisol increases 1.5–2× (because CBG saturates → more free)

8.4.3 Metabolism

• Liver: Reduction (CYP450) → tetrahydrocortisol + tetrahydrocortisone → glucuronide conjugation
• Kidney: Urinary excretion
• Urinary free cortisol (UFC): Measures unbound cortisol excretion; used to screen for Cushing's
• Half-life: ~60–90 minutes

8.4.4 Physiological Actions

MRCOG key concept — Cortisol in pregnancy: - Total cortisol rises 2–3× (due to CBG increase) - Free cortisol rises 1.5–2× (physiological hypercortisolism of pregnancy) - Placental CRH is produced and increases exponentially in the third trimester - Placental CRH stimulates fetal ACTH → fetal cortisol → lung maturation - Circadian rhythm: Preserved in pregnancy (though blunted)

8.5 Aldosterone

8.5.1 Synthesis & Secretion

• Produced in zona glomerulosa
• Final step: 11-Deoxycorticosterone → Corticosterone → Aldosterone (via CYP11B2 — aldosterone synthase)
• Regulated by:
• Renin-Angiotensin-Aldosterone System (RAAS): ↓ Renal perfusion pressure → ↑ Renin → Angiotensin I → ACE → Angiotensin II → ZG (AT1R) → ↑ Aldosterone
• Plasma K⁺: Directly stimulates aldosterone (even small ↑ of 0.3–0.5 mmol/L)
• ACTH: Acute stimulator (minor)
• Na⁺: ↓ Na⁺ → ↑ renin → ↑ aldosterone

RAAS cascade:

↓ Renal perfusion / ↓ Na⁺
        │
    Renin (from JG cells of kidney)
        │
    Angiotensinogen (liver)
        │
        ▼
    Angiotensin I (inactive)
        │
    ACE (lung, endothelium)
        │
        ▼
    Angiotensin II
        │
    ├── Zona glomerulosa → ↑ Aldosterone → ↑ Na⁺ reabsorption → ↑ K⁺ excretion → ↑ H⁺ excretion
    ├── Vascular smooth muscle → Vasoconstriction (↑ BP)
    ├── Brain → ↑ Thirst, ↑ ADH
    ├── Adrenal medulla → ↑ Catecholamines
    └── Kidney → ↑ Tubular Na⁺ reabsorption

8.5.2 Actions

Net effect: Na⁺ retention, K⁺ loss, metabolic alkalosis.

Aldosterone in pregnancy: - Renin activity increases (due to ↑ arterial compliance, ↓ systemic vascular resistance, ↑ prostacyclin) - Angiotensin II increases (but vascular sensitivity is reduced — requires higher doses to cause pressor response) - Aldosterone rises 3–5x in pregnancy - Net effect: Na⁺ and water retention → increased plasma volume (40–50%)

Preeclampsia connection: - Impaired RAAS adaptation in preeclampsia - Lower renin and aldosterone relative to normal pregnancy - Increased sensitivity to angiotensin II (infusion test used historically as screening — no longer used)

8.6 Adrenal Androgens (DHEA & DHEA-S)

• Produced in zona reticularis
• DHEA-S is the most abundant circulating steroid (plasma levels ~5–15 μmol/L in reproductive-age women)
• DHEA-S has a long half-life (~10 hours) → stable marker of adrenal androgen production

Regulation: - ACTH stimulates DHEA-S production (parallels cortisol response to ACTH) - Adrenarche: Rising DHEA-S at age 6–8 (independent of HPG axis) - Adrenopause: Declining DHEA-S with age (from peak at age 20–30 → 10–20% by age 70)

Actions: - Weak androgen (most effects from conversion to more potent androgens in peripheral tissues) - Precursor for testosterone and oestrogen in peripheral tissues - Role in female libido, bone density, immune function (still debated)

8.7 Adrenal Function Tests

8.8 Cushing's Syndrome in Pregnancy

8.8.1 Aetiology

8.8.2 Diagnosis in Pregnancy

Challenges: - Normal pregnancy causes physiological hypercortisolism (↑ total and free cortisol) - False positives on dexamethasone suppression test (pregnancy reduces pituitary sensitivity to dexamethasone) - UFC rises in pregnancy (2–3× normal) — upper limit of normal in third trimester is ~3× non-pregnant

Diagnostic approach: - UFC: >3× upper limit of normal is suspicious - Overnight dexamethasone suppression: Low specificity in pregnancy - Midnight salivary cortisol: Less affected by pregnancy; elevated in Cushing's - CRH stimulation + IPSS (inferior petrosal sinus sampling): Can be done in pregnancy (but with radiation protection)

8.8.3 Maternal & Fetal Risks

8.8.4 Treatment in Pregnancy

• First-line: Surgical removal of adenoma (transsphenoidal for Cushing's disease; laparoscopic adrenalectomy for adrenal adenoma)
• Second trimester is optimal for surgery
• Medical therapy (if surgery not possible): Metapyrone (11β-hydroxylase inhibitor) — limited safety data
• Untreated: High maternal-fetal morbidity

8.9 Addison's Disease (Primary Adrenal Insufficiency)

8.9.1 Aetiology

Autoimmune Polyglandular Syndromes (APS):

8.9.2 Clinical Features

Laboratory findings: - Hyponatraemia (aldosterone deficiency → Na⁺ wasting + ADH excess) - Hyperkalaemia (aldosterone deficiency → K⁺ retention) - Metabolic acidosis (mild — due to ↓ NH₃ production) - Hypoglycaemia (fasting) - Lymphocytosis, eosinophilia (loss of cortisol-induced suppression) - Cortisol: Low (AM <140 nmol/L) - ACTH: Very high (>100 pg/mL) — primary adrenal insufficiency - Renin: Elevated (aldosterone deficiency) - Aldosterone: Low - Anti-21-hydroxylase antibodies: Positive in autoimmune disease

8.9.3 Diagnosis

Short Synacthen Test (SST) — diagnostic: - Synacthen (ACTH₁₋₂₄) 250 μg IM/IV - Cortisol at 0, 30, 60 min - Normal: Peak cortisol >550 nmol/L (or rise >200 nmol/L) - Addison's: Peak <550 (or no significant rise)

Differentiating primary and secondary adrenal insufficiency:

8.9.4 Addison's in Pregnancy

Pregnancy effects: - Improvement: Many women require lower glucocorticoid doses in pregnancy (due to increased placental 11β-HSD2 activity that converts maternal cortisol to cortisone, reducing free cortisol, but CBG increases total cortisol) - Actually most stable: Dose adjustments often not needed, but stress doses required for labour/delivery - Risk: Adrenal crisis if stress doses not given

Management: - Continue usual hydrocortisone dose (10–20 mg AM, 5–10 mg PM) - Stress dosing: - Labour: Hydrocortisone 50 mg IV q6h (or 100 mg bolus then 200 mg/24h infusion) - Caesarean section: Hydrocortisone 100 mg IV pre-op, then 50 mg q6h × 24h, then taper to usual dose - Fever/infection: Double dose for duration of illness - Fludrocortisone (mineralocorticoid): Continue same dose (aldosterone levels regulated by RAAS, which increases in pregnancy) - Fetal outcomes: Generally good with careful management

Adrenal crisis in pregnancy — emergency management: 1. IV fluids (0.9% saline, 1 L fast, then 4–6 L/24h) 2. Hydrocortisone 100 mg IV bolus → 100 mg q6h × 24h → taper 3. Treat precipitating cause (infection, bleeding, etc.) 4. Monitor glucose, K⁺, BP

8.10 Congenital Adrenal Hyperplasia (CAH)

Already covered in detail in Section 5.6.2. Key points for review:

• 21-hydroxylase deficiency accounts for 95% of CAH
• Classic salt-wasting (↓ aldosterone + ↓ cortisol + ↑ androgens)
• Classic simple virilising (↓ cortisol + ↑ androgens, normal aldosterone)
• Non-classic (mild ↑ androgens, normal cortisol)
• 17-OHP is diagnostic marker
• Prenatal dexamethasone: Controversial; given to mother to suppress fetal ACTH → ↓ virilisation in affected female fetuses
• MRCOG focus: Understanding CAH is important for prenatal counselling, managing pregnancy in women with CAH, and differentiating from PCOS

8.11 Key MRCOG Pearls — Adrenal

9. Calcium & Bone Metabolism

9.1 Overview

Calcium homeostasis involves a complex interplay between parathyroid hormone (PTH), vitamin D, and calcitonin. Pregnancy and lactation place significant demands on calcium metabolism, with the fetal skeleton requiring ~30 g of calcium.

9.2 Calcium Physiology

Body calcium distribution: - 99% in bone and teeth (as hydroxyapatite crystals) - 1% in extracellular fluid and soft tissues - Total body calcium: ~1 kg (women) to ~1.2 kg (men)

Blood calcium fractions: - Ionised (free) calcium: 50% — biologically active - Albumin-bound: 40% — inactive but rapidly exchangeable - Complexed (with citrate, phosphate, bicarbonate): 10%

Corrected calcium (for low albumin):

Corrected Ca²⁺ (mmol/L) = Measured Ca²⁺ + 0.02 × (40 - Albumin in g/L)

Or: Corrected Ca²⁺ = Measured Ca²⁺ + (Albumin deficit) × 0.02

MRCOG note: In pregnancy, albumin falls (haemodilution) → total calcium falls but ionised calcium remains normal — always interpret with albumin correction or measure ionised Ca²⁺.

9.3 Parathyroid Hormone (PTH)

9.3.1 Structure & Synthesis

• 84 amino acid polypeptide
• Synthesised in chief cells of parathyroid glands (4 glands: 2 superior, 2 inferior — behind thyroid)
• Derived from pre-pro-PTH → pro-PTH → PTH (stored in secretory granules)
• Half-life: ~4 minutes

9.3.2 Regulation

Calcium-Sensing Receptor (CaSR): - G-protein coupled receptor - On parathyroid chief cells (and renal tubules, C-cells, bone, brain) - Allosteric modulator: Cinacalcet (calcimimetic) — enhances CaSR sensitivity → ↓ PTH - Activating mutation: Familial hypocalciuric hypercalcaemia (FHH) — ↓ PTH, ↓ Ca²⁺ excretion - Inactivating mutation: Neonatal severe hyperparathyroidism (NSHPT) — ↑ PTH, hypercalcaemia

9.3.3 Actions

Net effect of PTH: ↑ Serum Ca²⁺, ↓ Serum PO₄³⁻.

9.4 Vitamin D

9.4.1 Synthesis & Metabolism

7-Dehydrocholesterol (skin)
        │
        │ UV-B (sunlight, 290–315 nm)
        ▼
Cholecalciferol (Vitamin D₃)
        │
        │ 25-hydroxylase (CYP2R1 — liver)
        ▼
Calcifediol — 25-Hydroxyvitamin D₃ [25(OH)D₃]
        │
        │ 1α-hydroxylase (CYP27B1 — kidney)  ← regulated by PTH, ↓ Ca²⁺, ↓ PO₄³⁻
        ▼
Calcitriol — 1,25-Dihydroxyvitamin D₃ [1,25(OH)₂D₃]  ← active form
        │
        │ 24α-hydroxylase (CYP24A1 — target tissues)
        ▼
Calcitroic acid (inactive — excreted)

Vitamin D₂ (Ergocalciferol): Plant-derived, identical metabolism to D₃.

Measurement: - 25(OH)D (calcifediol): Best measure of vitamin D status (half-life ~2–3 weeks; reflects stores) - 1,25(OH)₂D (calcitriol): Not a good measure of stores (half-life ~4–6 hours; tightly regulated) - Normal in vitamin D deficiency (compensatory ↑ PTH → ↑ 1α-hydroxylase) - Low only in severe/severe renal disease

9.4.2 Actions

Vitamin D deficiency: - Defined as 25(OH)D <25 nmol/L (UK); <50 nmol/L (US/Endocrine Society) - Pregnancy: Associated with: preeclampsia (weak), gestational diabetes, low neonatal vitamin D stores, neonatal hypocalcaemia - Screening: Not universal in UK; consider in high-risk groups (dark skin, covered skin, obesity, malabsorption) - Supplementation: All pregnant women should take 400 IU/day (10 μg); high-risk groups need 1000–2000 IU/day

9.4.3 1α-Hydroxylase Regulation

9.5 Calcitonin

• Produced by C-cells (parafollicular cells) of the thyroid
• 32 amino acid polypeptide
• Stimulus: ↑ Plasma Ca²⁺
• Action:
• ↓ Osteoclast activity (inhibits bone resorption)
• ↑ Renal Ca²⁺ excretion
• Physiological role: Minor in humans (thyroidectomy does not cause hypercalcaemia; calcitonin's role is more important in fetal bone development and during pregnancy/lactation)
• Pharmacological use: Paget's disease of bone, hypercalcaemia (pamidronate is preferred now)

9.6 Calcium Metabolism in Pregnancy

9.6.1 Maternal Adaptations

9.6.2 Fetal Calcium Requirements

• Total fetal Ca accretion: ~30 g (80% in third trimester)
• Daily Ca transfer in third trimester: ~300 mg/day
• Placental Ca transport: Active (against gradient — fetal Ca²⁺ is higher than maternal)
• TRPV6 Ca channel (syncytiotrophoblast)
• Calbindin-D9k, D28k (intracellular binding)
• PMCA3 (Ca²⁺-ATPase) at fetal-facing membrane
• PTHrP from fetal parathyroids and placenta is key regulator of placental Ca transport
• Fetal Ca²⁺: 0.25–0.5 mmol/L higher than maternal

9.6.3 Parathyroid Hormone-Related Peptide (PTHrP)

• 141 amino acid protein
• Shares N-terminal homology with PTH (binds same receptor — PTHR1)
• Sources in pregnancy:
• Placenta (syncytiotrophoblast)
• Fetal parathyroid glands
• Maternal breast (lactation)
• Decidua
• Functions:
• Regulates placental Ca transport
• Modulates maternal calcium metabolism
• Promotes milk Ca secretion (lactation)
• Involved in fetal bone development
• Pathological: Can cause hypercalcaemia of malignancy (some tumours secrete PTHrP)

9.7 Calcium Metabolism in Lactation

Clinical pearl: Lactation-associated bone loss is transient and not associated with increased fracture risk. It is reversible with weaning.

9.8 Hypercalcaemia in Pregnancy

Causes: - Primary hyperparathyroidism (most common cause): Parathyroid adenoma (80–85%), hyperplasia (15–20%), carcinoma (<1%) - Familial hypocalciuric hypercalcaemia (FHH): Benign, no treatment needed - Malignancy: PTHrP, bone metastases - Granulomatous disease: Sarcoidosis (↑ 1,25(OH)₂D₃) - Drugs: Thiazides, calcium, vitamin D excess - Milk-alkali syndrome: Calcium + antacids

Maternal effects: Nephrolithiasis, pancreatitis, hyperemesis, hypertension, preeclampsia, confusion Fetal effects: Neonatal hypocalcaemia (suppression of fetal parathyroids), IUGR, preterm birth, stillbirth

Management: - Mild (Ca <2.85 mmol/L): Conservative (hydration, low Ca diet — monitor) - Moderate-severe: Surgery (parathyroidectomy) in second trimester (preferred) - Medical: IV fluids, calcitonin, bisphosphonates (limited safety data — avoid if possible)

9.9 Hypocalcaemia in Pregnancy

Causes: - Hypoparathyroidism (post-surgical most common; also autoimmune) - Vitamin D deficiency (common in high-risk groups) - Renal failure - Acute pancreatitis - Pseudohypoparathyroidism (PTH resistance) - Magnesium deficiency (Mg required for PTH secretion)

Symptoms: Paraesthesia (perioral, fingertips), muscle cramps, tetany (Chvostek's sign, Trousseau's sign), seizures, prolonged QT interval

Management: - Oral calcium + active vitamin D (calcitriol — bypasses need for renal 1α-hydroxylase) - PTH replacement not available

9.10 Osteoporosis & Pregnancy

• Pregnancy-associated osteoporosis: Rare (presents with back pain, vertebral fracture in third trimester or postpartum)
• Mechanism: Uncertain; possibly related to PTHrP, low oestrogen, genetic predisposition
• Management: Supportive (analgesia, breastfeeding cessation, calcium + vitamin D), bisphosphonates after pregnancy (teratogenic — avoid in pregnancy)

10. Carbohydrate Metabolism

10.1 Overview

Carbohydrate metabolism in pregnancy is characterised by progressive insulin resistance driven by placental hormones. This is an adaptive physiological phenomenon designed to ensure that the fetus receives a constant supply of glucose. In women whose pancreatic β-cells cannot compensate adequately, gestational diabetes mellitus (GDM) develops.

10.2 Normal Glucose Homeostasis

10.2.1 Key Hormones

The Incretin Effect: - Oral glucose load produces 2–3× greater insulin response than IV glucose matched for blood glucose level - This is the incretin effect — mediated by GLP-1 and GIP - Clinical correlate: The incretin effect is blunted in type 2 diabetes and GDM

10.2.2 The Pancreatic Islet

Islet of Langerhans:
    ┌─────────────────────────────┐
    │  Core: β-cells (~60-70%)   │ — Insulin, Amylin
    │  Periphery:                 │
    │    α-cells (~20%)          │ — Glucagon
    │    δ-cells (~5-10%)       │ — Somatostatin
    │    PP cells (~1%)         │ — Pancreatic polypeptide
    │    ε-cells (<1%)          │ — Ghrelin
    └─────────────────────────────┘

Insulin synthesis: - Preproinsulin → Proinsulin (cleaved in ER) - Proinsulin → Insulin + C-peptide (cleaved in secretory granules) - C-peptide measurement: Marker of endogenous insulin secretion (useful in differentiating type 1 from type 2 DM; not affected by exogenous insulin)

Insulin secretion: - Glucose → GLUT2 transporter → glycolysis → ↑ ATP/ADP ratio → closes K_ATP channels (SUR1/Kir6.2) → depolarisation → opens voltage-gated Ca²⁺ channels → Ca²⁺ influx → exocytosis of insulin granules - Biphasic response: - First phase: Rapid (within minutes) — release of stored, docked granules - Second phase: Prolonged (minutes to hours) — synthesis and release of new granules - Loss of first-phase insulin response is an early defect in type 2 diabetes and GDM

10.3 Pregnancy as a Diabetogenic State

10.3.1 The Hormonal Milieu

Pregnancy hormones that cause insulin resistance:

10.3.2 Adaptations to Insulin Resistance

Normal glucose values in pregnancy: - Fasting: <5.1 mmol/L (WHO 2013 criteria for GDM diagnosis) - 1-hour post 75g OGTT: <10.0 mmol/L - 2-hour post 75g OGTT: <8.5 mmol/L

10.3.3 β-cell Compensation

Normal pregnancy requires: - ↑ β-cell mass (proliferation, hypertrophy — prolactin and hPL drive this) - ↑ Insulin synthesis per cell - ↑ Glucose sensitivity (lower threshold for insulin secretion) - Enhanced incretin effect

Failed compensation → GDM: - Insufficient β-cell mass expansion - Impaired glucose sensing - Reduced first-phase insulin response - Underlying genetic susceptibility (similar to type 2 diabetes risk genes) - Pre-existing insulin resistance (obesity, PCOS, family history)

10.4 Gestational Diabetes Mellitus (GDM)

10.4.1 Definition & Diagnosis

GDM: Carbohydrate intolerance of variable severity with onset or first recognition during pregnancy (does not exclude pre-existing diabetes).

Screening and diagnosis:

NICE risk factors for GDM: - BMI >30 kg/m² - Previous GDM - Family history of diabetes (first-degree relative) - Previous macrosomic baby (>4.5 kg) - Ethnicity: South Asian, Black Caribbean, Middle Eastern - Age >40 years - Polycystic ovary syndrome

Timing of OGTT: - 24–28 weeks (insulin resistance peaks in third trimester) - Early OGTT (<20 weeks) if previous GDM or high risk

10.4.2 Pathophysiology

GDM is primarily due to:

1. Chronic insulin resistance (pre-existing, often subclinical) — exacerbated by pregnancy
2. β-cell dysfunction — inability to increase insulin secretion sufficiently to compensate for insulin resistance

Risk factors for β-cell dysfunction: - Genetics (TCF7L2, KCNJ11, etc. — overlapping with type 2 diabetes) - Reduced β-cell mass (low birth weight, poor nutrition in utero) - Chronic insulin resistance (obesity, PCOS) - Inflammatory milieu (TNF-α, IL-6, CRP)

Placental contribution: - ↑ hPL, cortisol, prolactin, GH-V - ↑ Leptin (from placenta) - ↓ Adiponectin (insulin-sensitising — reduced in GDM) - ↑ Inflammatory cytokines from placenta

10.4.3 Maternal & Fetal Risks

Macrosomia: - Pederson's hypothesis: Maternal hyperglycaemia → fetal hyperglycaemia → fetal β-cell hyperplasia → fetal hyperinsulinaemia → anabolic effects (↑ fat, ↑ protein, ↑ glycogen) → macrosomia - Fetal hyperinsulinaemia also: ↓ Surfactant → RDS; ↓ Glucose after delivery → neonatal hypoglycaemia (within 2–4 hours of birth — screen cord blood and 2h) - Insulin doesn't cross placenta; glucose crosses by facilitated diffusion (GLUT1, 3 in placenta)

Long-term programming (Barker hypothesis / DOHaD): - Offspring of GDM mothers have increased risk of obesity, type 2 diabetes, metabolic syndrome in later life - Epigenetic programming in utero

10.4.4 Management

Lifestyle modification (first-line): - Diet: Carbohydrate-controlled (complex > simple), low glycaemic index - Exercise: 30 min moderate intensity ≥5×/week (↓ insulin resistance) - Self-monitoring of blood glucose (SMBG): Fasting + 1h (or 2h) postprandial

Glycaemic targets: - Fasting: <5.3 mmol/L - 1h postprandial: <7.8 mmol/L - 2h postprandial: <6.4 mmol/L

Pharmacotherapy (if targets not met in 1–2 weeks):

Metformin vs Insulin: - Metformin is non-inferior to insulin for pregnancy outcomes (MiG trial) - Fewer episodes of hypoglycaemia, less weight gain - Concern: Metformin crosses placenta → potential for long-term epigenetic effects? (MiG TOFU follow-up showed no difference in offspring body composition at 2, 7, 9 years — reassuring) - UK NICE: Metformin is first-line pharmacological treatment for GDM

Fetal monitoring: - Ultrasound: Growth scans every 4 weeks (assess for macrosomia; but US is poor at predicting macrosomia — sensitivity ~50%) - Fetal well-being: Kick charts, CTG if indicated (not routine)

Delivery: - Timing: Most guidelines: Offer induction of labour at 38–39 weeks if well-controlled (but NICE says wait until 40+6 if no complications) - Vaginal delivery possible unless estimated fetal weight >4–4.5 kg (consider CS) - Intrapartum glucose management: Maintain 4–7 mmol/L (insulin sliding scale if needed) - Neonatal monitoring: Blood glucose at 2–4 hours (screen for hypoglycaemia)

Postpartum: - Stop metformin/insulin immediately after delivery (insulin resistance resolves quickly) - OGTT at 6–12 weeks postpartum: Screen for type 2 diabetes - Annual HbA1c or 3-yearly OGTT thereafter - Lifestyle advice to reduce type 2 diabetes risk (weight loss, diet, exercise) - Contraception counselling: Progestogen-only may be preferred (less metabolic effect than OCP)

10.5 Pre-Existing Diabetes in Pregnancy

10.5.1 Preconception Care

Risk of congenital anomalies in diabetes: | Malformation | Odds Ratio (vs non-diabetic) | |---|---| | Caudal regression syndrome | 200–300× (rare but specific) | | Neural tube defects | 3–5× | | Congenital heart disease | 3–5× | | Renal anomalies | 3–5× | | GI atresias | — |

St. Vincent Declaration (1989): Target to bring pregnancy outcomes in women with diabetes to those of non-diabetic women. Not yet fully achieved.

10.5.2 Management in Pregnancy

Glycaemic control: - Capillary glucose targets: Fasting <5.3, 1h <7.8, 2h <6.4 (same as GDM) - HbA1c: Check monthly (but less reliable in pregnancy due to haemodilution and reduced Hb lifespan; also iron deficiency may falsely elevate) - Insulin requirements: Increase progressively (up to 2–3× prepregnancy dose by third trimester)

Increased risks (compared to GDM): - Preeclampsia (↑ 2–4×) — low-dose aspirin from 12 weeks - Proliferative retinopathy (may worsen if rapid improvement of glucose or with pregnancy-induced hypertension) - Diabetic nephropathy (may worsen; risk of preeclampsia, preterm birth, IUGR) - Preterm delivery (40–50%) - Macrosomia (even with good glycaemic control — diabetes-specific factors: lipids, maternal genetics) - Stillbirth (risk peaks after 38 weeks → elective delivery at 38–39 weeks)

10.5.3 Diabetic Ketoacidosis (DKA) in Pregnancy

• More dangerous and occurs at lower glucose levels (euglycaemic DKA is possible — glucose may be <11 mmol/L)
• Precipitants: Infection, missed insulin doses, vomiting (hyperemesis), steroids for fetal lung maturity, tocolysis (β-mimetics)
• Pathophysiology: Combination of insulin deficiency + ↑ counter-regulatory hormones → ↑ lipolysis → ↑ FFA → ketogenesis → metabolic acidosis
• Fetal effects: Uteroplacental insufficiency (maternal acidosis → ↓ fetal O₂ delivery); fetal acidosis; fetal death; preterm labour
• Management: Aggressive IV fluids (1L 0.9% saline in first hour), IV insulin infusion (0.1 U/kg/h), correct K⁺, identify/treat precipitant, fetal monitoring

10.5.4 Postpartum

• Insulin requirements drop dramatically (back to prepregnancy level within 24–48 hours)
• Breastfeeding: Safe; encouraged (↓ future diabetes risk in both mother and child)
• Contraception: POP, implant (etonogestrel), IUS, copper IUD — all safe. Low-dose OCP acceptable if no vascular disease

10.6 Key MRCOG Pearls — Carbohydrate Metabolism

11. Pancreatic & Gut Hormones

11.1 Overview

The pancreas and gastrointestinal tract produce a wide array of hormones that regulate glucose metabolism, satiety, and energy balance. Understanding these hormones is increasingly relevant to obstetrics and gynaecology, particularly in the context of GDM, PCOS, and obesity.

11.2 Pancreatic Hormones

11.2.1 Insulin

• Structure: 51 amino acids (A chain 21aa, B chain 30aa — linked by 2 disulphide bridges)
• Synthesis: Preproinsulin (ER) → Proinsulin (Golgi) → Insulin + C-peptide (secretory granules)
• Secretion: Biphasic (see Section 10.2.2)
• Receptor: Insulin receptor (tyrosine kinase — IR-A, IR-B isoforms)
• Downstream signalling: IRS-1 → PI3K → AKT (glucose transport, glycogen synthesis, cell growth); also MAPK pathway

Insulin actions: - Muscle/fat: ↑ GLUT4 translocation → ↑ glucose uptake - Liver: ↑ Glycogenesis, ↓ Gluconeogenesis, ↓ Glycogenolysis - Adipose: ↑ Lipogenesis, ↓ Lipolysis - General: ↑ Protein synthesis, cell growth and proliferation

Amylin (Islet Amyloid Polypeptide — IAPP): - Co-secreted with insulin from β-cells - Slows gastric emptying, suppresses glucagon, promotes satiety - Amyloid deposits in type 2 diabetes → β-cell dysfunction

11.2.2 Glucagon

• Structure: 29 amino acids (derived from proglucagon)
• Synthesis: α-cells; proglucagon cleaved to glucagon in α-cells (but to GLP-1 in L-cells)
• Secretion: Inhibited by glucose, insulin, somatostatin; stimulated by hypoglycaemia, amino acids, catecholamines, exercise
• Receptor: Glucagon receptor (GPCR — Gs → cAMP)
• Actions:
• Liver: ↑ Glycogenolysis, ↑ Gluconeogenesis, ↑ Ketogenesis
• Adipose: ↑ Lipolysis
• Net: Hyperglycaemic (prevents hypoglycaemia)
• Also: ↑ Inotropic/chronotropic cardiac effects

11.2.3 Somatostatin

• Structure: 14 and 28 amino acid forms (SST-14, SST-28)
• Synthesis: δ-cells (pancreas), also hypothalamus, gut (D-cells)
• Receptor: 5 subtypes (SSTR1–5)
• Action: Paracrine inhibitor — ↓ insulin, ↓ glucagon, ↓ GH, ↓ TSH, ↓ gastrin, ↓ secretin, ↓ CCK, ↓ VIP, ↓ GIP, ↓ GLP-1
• Net: Inhibitory modulator of endocrine/exocrine function
• Somatostatin analogues: Octreotide, Lanreotide (used in acromegaly, neuroendocrine tumours)

11.2.4 Pancreatic Polypeptide (PP)

• 36 amino acids
• Synthesis: PP cells (γ-cells) — islet periphery
• Secretion: ↑ by food (especially protein), vagal stimulation; ↓ by somatostatin
• Action: Inhibits exocrine pancreatic secretion, regulates gastric motility
• Clinical: Low levels in type 2 diabetes; high levels in PP-secreting tumours (rare)

11.3 Gut Hormones (Incretins & Others)

11.3.1 GLP-1 (Glucagon-Like Peptide-1)

11.3.2 GIP (Glucose-Dependent Insulinotropic Peptide)

Incretin effect in GDM: - GLP-1 and GIP responses are blunted in women with GDM - This contributes to reduced insulin secretion - DPP-4 activity is unchanged in pregnancy

11.3.3 Ghrelin

11.3.4 Leptin

11.3.5 Adiponectin

11.3.6 Resistin

11.3.7 Visfatin (NAMPT)

11.3.8 Irisin

11.4 Summary of Adipokines in GDM & PCOS

12. Pineal Gland

12.1 Overview

The pineal gland (epiphysis cerebri) is a small endocrine gland located in the epithalamus near the centre of the brain. It secretes melatonin, which regulates circadian rhythms and has roles in sleep, reproduction, and seasonal timing.

12.2 Anatomy

• Location: Attached to the roof of the third ventricle via the pineal stalk
• Size: ~5–8 mm in humans
• Composition: Pinealocytes (main secretory cells), glial cells (astrocytes, microglia)
• Blood supply: Posterior choroidal arteries
• Calcification: Pineal calcification increases with age — visible on CT; no known functional significance
• Innervation: Sympathetic (postganglionic fibres from superior cervical ganglion — noradrenergic)

12.3 Melatonin Synthesis

Tryptophan (essential amino acid)
    │
    │ Tryptophan hydroxylase
    ▼
5-Hydroxytryptophan
    │
    │ AADC (aromatic L-amino acid decarboxylase)
    ▼
Serotonin (5-HT)
    │
    │ AANAT (arylalkylamine N-acetyltransferase) — RATE-LIMITING STEP
    ▼
N-Acetylserotonin
    │
    │ HIOMT (hydroxyindole-O-methyltransferase)
    ▼
Melatonin (N-acetyl-5-methoxytryptamine)

Regulation of melatonin synthesis: - Light: Retinal photoreceptors (intrinsically photosensitive retinal ganglion cells — ipRGCs containing melanopsin) → retino-hypothalamic tract → suprachiasmatic nucleus (SCN) → superior cervical ganglion → pineal - Light → INHIBITS melatonin (AANAT activity ↓) - Darkness → STIMULATES melatonin (AANAT activity ↑) - Noradrenaline (from SNS) → β₁-adrenergic receptors (pinealocytes) → cAMP → ↑ AANAT transcription → ↑ melatonin

12.4 Melatonin Actions

12.5 Melatonin & the Menstrual Cycle

• Normal menstrual cycle: Melatonin levels are relatively stable (slight increase in luteal phase? — controversial)
• Nocturnal melatonin may be altered in women with luteal phase deficiency
• PCOS: Reduced nocturnal melatonin peak? (inconsistent evidence)
• Menopause: Melatonin decreases with age (but also reduced by oestrogen decline? complex)

12.6 Melatonin in Pregnancy

Melatonin and labour: - Melatonin receptors (MT1, MT2) are present in human myometrium - Melatonin potentiates oxytocin-induced contractions (via MT1/MT2 receptors → ↑ Ca²⁺ sensitisation?) - Nocturnal onset of labour in many mammals; some human data suggest increased spontaneous labour at night - Clinical correlate: Melatonin may be involved in timing of parturition — the "labour clock" hypothesis

12.7 Melatonin & Breastfeeding

• Melatonin levels in breast milk show circadian variation (high at night, low during the day)
• Night-time feeds may help entrain infant circadian rhythms
• Melatonin in formula milk: Absent — may contribute to disrupted sleep patterns in formula-fed infants

12.8 Clinical Applications

12.9 Melatonin Agonists & Antagonists

12.10 Key MRCOG Points — Pineal

13. Clinical Correlations & Mnemonics

13.1 MRCOG High-Yield Clinical Scenarios

Scenario 1: Secondary Amenorrhoea in a 28-Year-Old

History: 28-year-old woman, 6 months amenorrhoea, galactorrhoea, no pregnancy, no OCP, on no medications.

Differential: 1. Pregnancy (always exclude first) 2. Hyperprolactinaemia 3. PCOS 4. Hypothalamic amenorrhoea 5. Premature ovarian insufficiency (POI) 6. Thyroid dysfunction

Investigations: - β-hCG (pregnancy) - Prolactin - FSH, LH - Oestradiol - TSH, free T4 - Testosterone, SHBG

Key discriminator: - High prolactin + galactorrhoea: Think prolactinoma, hypothyroidism, drug-induced - High FSH + low oestradiol: Think POI - Normal/low FSH + low oestradiol: Think hypothalamic/pituitary cause - ↑ LH:FSH ratio ( >2) + ↑ testosterone + PCO on US: Think PCOS

Scenario 2: Hirsutism in a 22-Year-Old

History: Progressive hirsutism over 2 years, irregular menses, BMI 28.

Differential: 1. PCOS (most common) 2. Non-classic CAH 3. Idiopathic hirsutism 4. Cushing's syndrome (rare) 5. Androgen-secreting tumour (rare — rapid onset)

Investigations: - Total testosterone, SHBG, FAI - 17-OHP (early follicular, AM fasting) - DHEA-S - LH, FSH - Pelvic ultrasound (PCO morphology) - ACTH stimulation test if 17-OHP borderline

Key discriminator: - ↑ 17-OHP (>30 nmol/L) → CAH - ↑ Testosterone + ↑ DHEA-S → adrenal source - ↑ Testosterone + normal DHEA-S → ovarian source - Rapid onset + severe virilisation → tumour (US/MRI)

Scenario 3: Thyroid Mass in a 30-Year-Old Pregnant Woman

History: 16 weeks pregnant, anterior neck swelling, no symptoms.

Investigations: - TSH, free T4, TPO antibodies - Neck ultrasound (US is safe in pregnancy) - No RAI scan or uptake in pregnancy - FNA if suspicious features (>1 cm, solid, hypoechoic, microcalcifications)

Management: - Benign: Observe (surgery after delivery if needed) - Suspicious/malignant: Surgery in second trimester - Differentiated thyroid cancer is slow-growing; surgery can usually wait until postpartum

Scenario 4: Hypertensive Crisis in a 35-Year-Old — Cushing's or Conn's?

History: Hypertension, hypokalaemia, weakness, buffalo hump, easy bruising.

Investigations: - Overnight dexamethasone suppression test → Cushing's (AM cortisol >50 nmol/L) - Aldosterone:renin ratio → Conn's (>30 with aldosterone >500 pmol/L) - ACTH, DHEA-S - CT/MRI adrenal

Key discriminator: - Hypokalaemia + alkalosis + hypertension + suppressed renin → Conn's - + Cushingoid features → Consider ACTH-dependent Cushing's or Carney's

Scenario 5: Severe Postpartum Haemorrhage Followed by Failure of Lactation

History: PPH (2 L blood loss), now day 5 postpartum: no milk production, extreme fatigue, hypotension.

Diagnosis: Sheehan's syndrome (postpartum pituitary necrosis)

Key features: - Failure of lactation (first sign — prolactin deficiency) - Loss of axillary/pubic hair (ACTH deficiency → androgen deficiency) - Hypotension (ACTH → cortisol deficiency) - Hypoglycaemia - Amenorrhoea (FSH/LH deficiency)

Investigation: - Low prolactin (key diagnostic feature) - Low cortisol, low ACTH - Low FSH/LH, low oestrogen - Pituitary MRI: Empty sella (or partially empty)

Management: Hormone replacement - Hydrocortisone (first — before levothyroxine) - Levothyroxine (then) - Sex steroid replacement

Never give thyroxine before cortisol in panhypopituitarism → could precipitate adrenal crisis (thyroxine increases cortisol metabolism).

13.2 Mnemonics

Hypothalamic Hormones

"Go To TRH ("Go to T-R-H") — CRH is not Good, GHRH"

Anterior Pituitary Hormones

"FLAT PEG" — the six anterior pituitary hormones: - FSH - LH - ACTH - TSH - Prolactin - Endorphins (POMC) - GH

Pituitary Hormones: Neurohypophysis

"A-O" — ADH and Oxytocin

Steroidogenesis — Enzyme Sequence

"17-20 lyase adds is; 21 for cortisol; 11 for final"

Cholesterol → ║CYP11A1║ → Pregnenolone → ║3βHSD║ → Progesterone
                                                      │
                                              ║CYP21A2║ → 11-Deoxycorticosterone (DOC)
                                                      │
                                              ║CYP11B1║ → Corticosterone
                                                      │
                                              ║CYP11B2║ → Aldosterone

Alternative mnemonics:

"CCCP-4-Me" For the four steps of the TCA cycle (okay, not relevant — try instead):

Androgen synthesis: 1. Cholesterol → Pregnenolone → 17-OH-Pregnenolone → DHEA (C/P/17/D) 2. Progesterone → 17-OH-P → Androstenedione → Testosterone (P/17/A/T)

Or: "Find All Oestrogens, Neatly" - Follicle → Theca → Androstenedione → Oestrone → No, E2 is Oestradiol!

The Two-Cell Two-Gonadotrophin Model

"Theca Takes LH — Give Androgens. Granulosa Gets FSH — Converts Androgens to Oestrogens"

Or: "Theca T-L-H → Makes Androgens. Granulosa F-S-H → Makes Oestrogens"

Contraindications to ITT

"I SHED" - Ischaemic heart disease - Seizures (epilepsy) - Hypopituitarism (baseline cortisol <100) - Elderly - Drugs (propranolol)

Causes of Hyperprolactinaemia

"PHOTOGRAPHY" (sounds like photography): - Prolactinoma - Hypothyroidism - OCP/Oestrogen - Tumours (stalk effect) - Other (stress, sleep, exercise) - Galactorrhoea - Renal failure - Antipsychotics, antidepressants - Pregnancy - Herbal (some supplements) - Y? (Idiopathic)

"PALM-COIN" (simpler): - Physiological (pregnancy, lactation, stress, exercise, sleep, nipple stimulation, sex) - Anti-psychotics/antiemetics - Lactotroph adenoma - Macroprolactin - Chest wall trauma - Oestrogen (OCP) - Idiopathic - Neurogenic (stalk compression, hypothalamic tumours)

Addison's Clinical Features

"Addison's: A-D-D-I-S-O-N" - Addison's - Dark skin (hyperpigmentation) - Diarrhoea - Infection risk - Salt craving - Overwhelming weakness - Na⁺ low (hyponatraemia), K⁺ high (hyperkalaemia)

Or: "Great Like Fred" - Glucocorticoid deficiency - Low blood pressure - Fatigue - + Salt craving, Hyperpigmentation

Hypothalamic Amenorrhoea

"RAMEN" — Causes: - Relative energy deficiency - Athletic (excessive exercise) - Malnutrition / low weight - Emotional stress - No — Negative energy balance

GDM Risk Factors

"BIG MAC" + "SOUTH ASIAN" - BMI >30 - In previous GDM - Grandmother (family history of DM) - Macrosomic baby previously (>4.5 kg) - Age >40 - Child of South Asian / Black Caribbean / Middle Eastern ethnicity

Sheehan's vs Apoplexy

"Sheehan's is Slow; Apoplexy is Acute"

CAH Types & Enzymes

"21: Salt, Sex, Stress. 11: Blood pressure up, Boy looks like girl"

Oestrogen Effects

"FAB 5" — F: FSH/LH regulation A: Anabolism B: Bone protection 5: (Endometrial proliferation, cervical mucus, breast ductal growth, vaginal epithelium, lipid profile)

Actually:

"4 B's and 2 C's" — Oestrogen actions: - Breast (ductal growth) - Bone (maintenance) - Brain (cognition, mood) - Blood flow (NO-mediated vasodilation) - Cervical mucus (spinnbarkeit) - Coagulation (↑ clotting factors)

13.3 Summary of Key Endocrine Values in Pregnancy

13.4 Quick Reference: Hormones That Cross the Placenta

13.5 Quick Reference: Diabetogenic Hormones in Pregnancy

13.6 Final MRCOG Exam Tips — Endocrinology

1. Know your feedback loops cold: Long, short, ultra-short. Be able to predict what happens if a peripheral gland fails vs pituitary fails.

2. Two-cell two-gonadotrophin model: Could be asked in multiple formats — draw it, explain it, predict what happens with LH deficiency/FSH deficiency.

3. Fetoplacental unit oestrogen synthesis: Why doesn't the placenta make oestradiol directly? (Answer: lacks CYP17A1). What enzyme deficiencies cause low oestriol? (Sulphatase, Smith-Lemli-Opitz).

4. Prolactin is under tonic inhibition: Stalk transection → prolactin ↑, everything else ↓.

5. Thyroid in pregnancy: TBG doubles due to oestrogen. TSH suppressed at 10–12 weeks due to hCG. Free T4 is what matters.

6. Dose adjustments: Levothyroxine ↑ 30–50%, insulin ↑ up to 2–3×, hydrocortisone stress doses in labour.

7. Which drugs cross placenta: Metformin crosses, insulin doesn't, glyburide doesn't.

8. Calcium: Total calcium falls (albumin ↓) but ionised is normal. PTHrP is the key player in pregnancy/lactation.

9. Adrenal crisis in pregnancy: Fluids + hydrocortisone IV immediately.

10. Melatonin: Minor topic — know circadian rhythm role, synthesis (tryptophan → serotonin → melatonin), and that human reproduction is non-seasonal (pineal not essential for fertility).

End of Document — Endocrinology for MRCOG Part 1

Last updated: May 2026

Key: This document covers the complete MRCOG Part 1 endocrinology syllabus. Focus on understanding feedback loops, the two-cell model, fetoplacental steroidogenesis, and pregnancy adaptations. These form the foundation of clinical questions.