6. The Two‑Cell, Two‑Gonadotropin Model

First principle: division of labour in the follicle

Estrogen synthesis requires two cells and two gonadotropins:

• LH → theca → androgens (the substrate).
• FSH → granulosa → aromatase → estradiol (the product).

FSH also drives follicular growth and rescues follicles from atresia, and mediates dominant‑follicle selection.

Prediction: where hyperandrogenism comes from

If LH drive is high (or aromatase is outpaced), theca androgen production rises faster than granulosa can aromatise it → hyperandrogenism + disordered folliculogenesis. This is the biochemical skeleton of PCOS (Concept 17): raised LH:FSH‑type drive, theca androgen excess, arrested follicles, anovulation.

Discriminators

• Ovarian androgen excess (theca) → predominantly testosterone.
• Adrenal androgen excess → predominantly DHEA‑S. This split localises hyperandrogenism at the bench (Concept 16).

Pitfalls

• Treating "estrogen" and "androgen" as separate systems — they are the same pathway: androgen is the obligatory precursor of estrogen. Block aromatase (letrozole) and you lower estrogen and raise FSH drive — the basis of ovulation induction.

Pearls

• 🎯 FSH → granulosa → estrogen; LH → theca → androgen. From this you can predict PCOS biochemistry and how letrozole works.
• 🩺 Aromatase inhibition (letrozole) is now first‑line ovulation induction in PCOS precisely because it exploits this loop.

Next → The two ovarian steroids drive everything downstream — how do I predict their effects? (Concept 7).