Part 1 Science Notes
MRCOG Part 1
Biochemistry
Biochemistry for MRCOG Part 1
Steroid Hormone Biosynthesis
All steroid hormones derive from cholesterol. The rate-limiting step is transport of cholesterol into the mitochondrion by StAR (steroidogenic acute regulatory protein), followed by side-chain cleavage to pregnenolone by CYP11A1 (desmolase).
| Enzyme | Converts | Deficiency effect |
|---|---|---|
| CYP11A1 (desmolase) | Cholesterol → pregnenolone | Complete steroid failure |
| 3β-HSD | Pregnenolone → progesterone | Salt-wasting CAH, ambiguous genitalia in both sexes |
| CYP17 (17α-hydroxylase) | Pregnenolone → 17-OH-pregnenolone | Hypertension, hypokalaemia, absent puberty |
| CYP21A2 (21-hydroxylase) | 17-OH-progesterone → 11-deoxycortisol | ~90–95% of CAH; salt-wasting, virilisation |
| CYP11B1 (11β-hydroxylase) | 11-deoxycortisol → cortisol | Hypertension with virilisation |
| Aromatase (CYP19) | Androgens → oestrogens | Maternal and fetal virilisation; no oestrogen |
| 5α-reductase | Testosterone → DHT | 46,XY DSD with normal testosterone |
Two-cell two-gonadotrophin model. LH acts on theca cells to produce androstenedione; FSH acts on granulosa cells, where aromatase converts it to oestradiol. Granulosa cells lack CYP17, so they cannot make androgen themselves; theca cells lack aromatase.
Placental Steroidogenesis
The fetoplacental unit is a functional whole because neither part is complete alone:
- The placenta lacks CYP17, so it cannot make androgen from progesterone. It relies on fetal adrenal DHEAS.
- The fetal adrenal lacks 3β-HSD in the fetal zone, so it cannot make progesterone. It relies on placental progesterone.
- Fetal DHEAS is 16α-hydroxylated in the fetal liver, then aromatised by the placenta to oestriol — which is why maternal oestriol reflects fetal wellbeing, and why it is low in fetal demise, anencephaly (no fetal adrenal) and placental sulfatase deficiency.
Carbohydrate Metabolism in Pregnancy
Pregnancy is a diabetogenic state. Human placental lactogen (hPL), progesterone, cortisol and prolactin drive peripheral insulin resistance, which rises through the second and third trimesters. The teleology is fetal glucose supply: maternal resistance spares glucose for placental transfer.
- Glucose crosses by facilitated diffusion (GLUT1), down a gradient — so fetal glucose tracks maternal.
- Insulin does not cross the placenta. Fetal hyperinsulinaemia in maternal diabetes is fetal in origin, and is what drives macrosomia and neonatal hypoglycaemia.
- Fasting glucose falls in early pregnancy (expanded volume, fetal uptake), while post-prandial excursions rise.
- Accelerated starvation: fasting ketogenesis is faster in pregnancy, which is why prolonged fasting produces ketosis sooner.
Lipids
Total cholesterol and triglycerides both rise substantially through pregnancy — a physiological hyperlipidaemia, not a pathological one. Free fatty acids are the preferred maternal fuel in late pregnancy, sparing glucose for the fetus.
Amino Acid and Protein Handling
Amino acids cross the placenta by active transport against a gradient, so fetal concentrations exceed maternal. Maternal serum albumin falls (dilution), which matters clinically: total calcium falls with it while ionised calcium is unchanged, so a low total calcium in pregnancy needs no treatment.
Enzymes and Markers
| Marker | Behaviour in normal pregnancy |
|---|---|
| Alkaline phosphatase | Rises 2–4×, placental isoenzyme — a rise is not liver disease |
| ALT / AST | Unchanged; a rise is always pathological |
| Albumin | Falls |
| Urea, creatinine | Fall (increased GFR) |
| Fibrinogen | Rises markedly |
| TSH | Falls in first trimester (hCG cross-reactivity at the TSH receptor) |
| Total T4/T3 | Rise (increased thyroid-binding globulin); free levels near-normal |
Vitamins and Cofactors
- Folate is required for one-carbon transfer in thymidylate and methionine synthesis. Deficiency causes megaloblastic anaemia and neural tube defects.
- Vitamin B12 is a cofactor for methionine synthase and methylmalonyl-CoA mutase. B12 deficiency traps folate as methyltetrahydrofolate — the "folate trap" — so giving folate alone can correct the anaemia while the neurological damage progresses.
- Iron absorption increases in pregnancy; ferritin is the best storage marker but is an acute-phase reactant and rises with inflammation.
High-Yield Exam Points
- 21-hydroxylase deficiency is ~90–95% of congenital adrenal hyperplasia; the accumulating substrate is 17-hydroxyprogesterone, which is the screening test.
- Granulosa cells have aromatase and no CYP17; theca cells have CYP17 and no aromatase. Every question about the two-cell model turns on this.
- Placental sulfatase deficiency gives low oestriol with a normal fetus.
- A raised alkaline phosphatase in pregnancy is placental until proven otherwise; a raised ALT never is.
- Insulin does not cross the placenta; glucose does, by facilitated diffusion.
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