Hypothalamic-pituitary-ovarian axis
Gonadotrophins and the hypothalamic–pituitary–ovarian axis
Pulsatile GnRH from the hypothalamus drives FSH and LH, which make the ovary grow a follicle and secrete oestradiol, inhibin and progesterone; these feed back to switch the axis up or down. CPSP asks about pulse frequency, positive and negative feedback, the two-cell model, and how to read FSH and LH in amenorrhoea, PCOS, menopause and ovulation induction.
GnRH
- A decapeptide from neurones of the arcuate nucleus and preoptic area, carried to the anterior pituitary in hypophyseal portal veins (far higher concentration than in peripheral blood). Kisspeptin drives the GnRH neurones.
- Half-life only a few minutes; it must be pulsatile. GnRH acts on gonadotrophs (basophils) through Gq, phospholipase C, IP3 and DAG.
| GnRH pulse frequency | Result |
|---|---|
| Fast (about hourly, late follicular) | Favours LH |
| Slow (every 3–4 hours, mid-luteal) | Favours FSH; slowing is caused by progesterone |
| Persistently fast (PCOS) | High LH:FSH ratio |
| Continuous | Receptor down-regulation and suppression |
- GnRH agonists (leuprorelin, goserelin) have a D-amino acid substitution that resists breakdown and binds more strongly: an initial flare (pain may worsen for about 10 days), then desensitisation, low oestradiol and amenorrhoea. Long use needs add-back HRT to protect bone.
- GnRH antagonists block the receptor at once, without a flare.
FSH and LH
- Glycoproteins sharing an alpha subunit with TSH and hCG; the beta subunit gives specificity (assays target it). Both act through Gs and cAMP.
- Two-cell, two-gonadotrophin model:
| Cell | Hormone acting | Product |
|---|---|---|
| Theca | LH | Androgens (androstenedione) from cholesterol |
| Granulosa | FSH | Aromatase converts theca androgen to oestradiol; also inhibin and AMH |
- FSH induces LH receptors on granulosa cells of the dominant follicle, so only it can respond to the LH surge.
- Follicle growth is gonadotrophin-independent until the early antral stage (about 2–5 mm); on a GnRH agonist follicles stop at that size.
- The LH surge luteinises granulosa cells: oestradiol dips and progesterone starts to rise before the follicle ruptures.
Feedback
| Signal | Effect |
|---|---|
| Low or moderate oestradiol | Negative feedback on FSH and LH |
| High oestradiol sustained for about 2 days | Positive feedback: LH surge |
| Progesterone with oestrogen (luteal) | Negative; slows GnRH pulses |
| Inhibin B (granulosa, follicular phase) | Selectively suppresses FSH |
| Inhibin A (corpus luteum, luteal phase) | Selectively suppresses FSH |
| Activin (pituitary, granulosa) | Raises FSH beta synthesis; neutralised by follistatin |
| AMH (granulosa of small follicles) | Marker of ovarian reserve; stable through the cycle |
- In the last 2–3 days of a cycle without pregnancy, luteolysis lowers oestradiol and inhibin A, so FSH rises and recruits the next cohort.
- In pregnancy, high placental oestrogen and progesterone suppress FSH and LH, so no follicles mature. The combined pill works the same way: oestrogen suppresses FSH (no follicle above about 5 mm) and progestogen prevents the LH surge.
- Early follicular (day 2–3) FSH is measured because steroid and inhibin feedback is lowest then.
- In the late reproductive years, fewer follicles make less inhibin B, so FSH rises alone while LH and oestradiol are still normal. After menopause both FSH and LH are high (postmenopausal urine was the source of hMG).
Reading the hormone pattern
| Pattern | Causes |
|---|---|
| Low FSH, LH and oestradiol (hypogonadotrophic) | Stress, weight loss, heavy exercise, low leptin, opioids (methadone), hyperprolactinaemia, Cushing syndrome, Kallmann syndrome (with anosmia), Sheehan syndrome, stalk section (low FSH and LH, high prolactin) |
| High FSH and LH, low oestradiol (hypergonadotrophic) | Ovarian failure, Turner syndrome (45,X) with streak ovaries |
| High FSH but normal AMH and many antral follicles | Inactivating FSH receptor mutation (resistant ovary) |
| High LH:FSH, high androgens, high insulin | Polycystic ovary syndrome |
| High LH with high testosterone in a 46,XY girl | Androgen insensitivity: the hypothalamus and pituitary cannot sense testosterone |
- GnRH test: after a week of pulsatile priming, a normal LH and FSH response places the defect in the hypothalamus; no response means the pituitary.
Ovulation induction and IVF
- Clomiphene blocks hypothalamic oestrogen receptors, so the brain senses low oestrogen and raises GnRH and FSH. It causes hot flushes, and its anti-oestrogen effect can thin the endometrium and thicken cervical mucus, so women may ovulate yet not conceive.
- FSH injections bypass the feedback that normally selects one follicle: the main risks are multiple pregnancy and ovarian hyperstimulation.
- In IVF, a GnRH agonist trigger (in an antagonist cycle) produces a short endogenous LH surge, lowering hyperstimulation risk compared with long-acting hCG. After pituitary suppression the corpus luteum gets little LH, so luteal progesterone support is given.
- Hypopituitary women need exogenous FSH and LH (hMG), then hCG; hypothalamic amenorrhoea responds best to pulsatile GnRH every 60–90 minutes.
- Inhibin is the tumour marker for granulosa cell tumours.
The male axis
- LH acts on Leydig cells to make testosterone; FSH acts on Sertoli cells to make androgen-binding protein and inhibin B, which suppresses FSH.
Remember Fast pulses make LH, slow pulses make FSH; inhibin hits FSH only.
Exam trap Low-dose oestradiol inhibits LH, but a sustained high level triggers the LH surge: same hormone, opposite effect.
Exam trap A raised FSH with normal LH and periods in a woman in her forties reflects falling inhibin B, not established menopause.
Test yourself on this topic
5 of the 41 questions in our bank on this topic. Choose an answer to see why every option is right or wrong.
Natural GnRH is a decapeptide with a plasma half-life of only a few minutes, whereas leuprorelin and goserelin act for hours to weeks. Which structural change underlies the longer action of these agonists?
Answer: D-amino acid substitution at position 6
In native GnRH the bond between positions 6 (glycine) and 7 is the main site cleaved by peptidases. Agonists replace glycine-6 with a bulky D-amino acid and often modify the C-terminal position 10 (ethylamide). This resists enzymatic breakdown and stabilises the active shape, raising receptor affinity and prolonging half-life. Depot formulations (implants, microspheres) then release the drug steadily, producing the continuous stimulation that down-regulates the receptor.
GnRH agonist design
- Native GnRH: decapeptide, minutes
- Position 6: D-amino acid
- Position 10: ethylamide
- Result: resistant to peptidases
Remember Change position 6 and the peptide lasts.
Exam trap Long action plus depot release gives continuous exposure, which is why agonists suppress.
Why the other options are wrong
- Addition of a steroid side chain GnRH analogues are peptides, not steroids.
- Conversion to a cyclic glycoprotein They remain small linear peptides.
- Removal of the pyroglutamate end The pyroglutamate end is kept.
- Coupling to an albumin carrier Not how standard agonists are made.
A 17-year-old girl with primary amenorrhoea, normal breasts and absent pubic hair has a 46,XY karyotype and intra-abdominal testes. Her serum testosterone is in the high male range. Why is her LH also raised?
Answer: Androgen feedback on LH is lost
In complete androgen insensitivity the androgen receptor does not work. Testosterone normally inhibits LH secretion partly by acting on androgen receptors in the hypothalamus and pituitary; without that feedback, LH rises and drives the Leydig cells to make even more testosterone. Some testosterone is aromatised to oestradiol, which produces breast development. Sertoli cells function and make AMH and inhibin, so Müllerian structures are absent.
AIS hormone pattern
- Androgen receptor non-functional
- No feedback on LH
- LH high, testosterone high
- Aromatised oestradiol: breasts
Remember Hormone present, receptor absent, feedback lost.
Exam trap High testosterone with high LH points to receptor resistance, not deficiency.
Why the other options are wrong
- Her testes secrete an LH-like hormone Testes do not secrete LH.
- Oestradiol stimulates LH continuously Oestradiol is not continuously stimulating LH here.
- Inhibin is absent from her testes Sertoli cells make inhibin normally.
- She has an LH-secreting pituitary adenoma No adenoma is needed to explain this.
A woman at high risk of hyperstimulation is in an IVF cycle using a GnRH antagonist. Instead of hCG, the final egg maturation is triggered with a single dose of a GnRH agonist. Why does this lower her risk of OHSS?
Answer: It produces only a short endogenous LH surge
Because the antagonist only competitively blocks GnRH receptors, a dose of agonist can displace it and release the pituitary's stored LH and FSH. This produces a surge that lasts about 24–36 hours, enough to complete oocyte maturation, but LH has a short half-life. hCG, in contrast, has a half-life of over a day and keeps stimulating the corpora lutea and VEGF release for days. The short surge leads to early luteolysis and much less OHSS, though the luteal phase then needs support.
Agonist trigger
- Displaces antagonist
- Releases own LH surge
- LH is short-acting
- Less corpus luteum drive and VEGF
Remember Short LH surge, short risk.
Exam trap An agonist trigger works only in antagonist cycles; after a long agonist protocol the pituitary is already down-regulated.
Why the other options are wrong
- It blocks VEGF receptors in the ovary It has no direct anti-VEGF action.
- It destroys excess follicles directly It does not destroy follicles.
- It lowers oestradiol by inhibiting aromatase GnRH agonists do not inhibit aromatase.
- It prevents luteinisation of granulosa cells Granulosa cells still luteinise; luteal support is needed later.
A pituitary biopsy is stained with routine dyes. Which cells of the pars distalis secrete LH and FSH?
Answer: Basophils
In the anterior pituitary the chromophil cells are acidophils, which make growth hormone and prolactin, and basophils, which make the glycoprotein hormones and ACTH: FSH, LH, TSH and ACTH. Gonadotrophs are basophils and often make both LH and FSH. Chromophobes stain poorly and are mostly resting or degranulated cells. Pituicytes are glial cells of the posterior pituitary.
Anterior pituitary cells
- Acidophils: GH, prolactin
- Basophils: FSH, LH, TSH, ACTH
- Chromophobes: resting cells
- Gonadotroph makes both LH and FSH
Remember Glycoprotein hormones live in basophils.
Exam trap ACTH is not a glycoprotein but is still made by basophils.
Why the other options are wrong
- Acidophils Make growth hormone and prolactin.
- Chromophobes Poorly staining resting or degranulated cells.
- Pituicytes Glial cells of the neurohypophysis.
- Folliculostellate cells Supporting cells, not hormone-secreting.
A 23-year-old woman has secondary amenorrhoea with FSH of 65 IU/L and low oestradiol, suggesting ovarian failure. However, her serum AMH is normal and ultrasound shows many small antral follicles. Karyotype is 46,XX. What is the most likely mechanism?
Answer: Inactivating FSH receptor mutation
In resistant (insensitive) ovary syndrome the follicles are present, as shown by normal AMH and antral follicles on scan, but they cannot respond to FSH. Inactivating mutations of the FSH receptor, or blocking antibodies to it, are the usual causes. Without FSH action no follicle matures, so oestradiol and inhibin stay low and FSH rises to menopausal levels. True premature ovarian insufficiency from autoimmunity, Turner syndrome or FMR1 premutation shows depleted follicles and low AMH.
Resistant ovary syndrome
- FSH very high
- AMH normal; follicles present
- Cause: FSH receptor defect
- Differs from POI: follicles not lost
Remember Follicles present but deaf to FSH.
Exam trap High FSH alone does not prove follicles are gone; check AMH and antral follicle count.
Why the other options are wrong
- Autoimmune destruction of follicles Would deplete follicles and lower AMH.
- Accelerated follicle atresia from 45,X Karyotype is normal.
- FMR1 premutation Associated with follicle depletion and low AMH.
- Hypothalamic GnRH deficiency Would give low, not high, FSH.
Where this sits in the CPSP syllabus
- Obstetrics & Gynaecology, Paper 2: Reproduction, pregnancy and labour, Gonadotrophins and the hypothalamic-pituitary-ovarian axis
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