12b. Neuroendocrinology of reproduction

Unit 12B: Neuroendocrinology of Reproduction (HPO Axis)

Learning Goals

By the end of this lesson, you should be able to:

• diagram the hypothalamic–pituitary–ovarian (HPO) axis and the route of portal circulation;
• explain GnRH pulsatility, the LH/FSH response, and ovarian feedback by oestrogen, progesterone, inhibin/activin/follistatin;
• map neuroendocrine events across the menstrual cycle, puberty, lactation, pregnancy, and menopause;
• recognise how prolactin, thyroid, adrenal, metabolic and stress signals modulate the axis;
• interpret common clinical patterns (FHA, PCOS, POI, hyperprolactinaemia) and justify investigations and first-line management.

1) Organisation of the HPO Axis

Anatomical tiers

1. Hypothalamus—mainly arcuate nucleus (ARC) and preoptic area neurons release GnRH (decapeptide) into the median eminence. Blood enters the hypophyseal portal system, carrying GnRH in pulses to the anterior pituitary.
2. Anterior pituitary (adenohypophysis)—gonadotrophs synthesize and secrete LH and FSH in response to each GnRH pulse.
3. Ovary—theca and granulosa cells produce oestrogens (E2), progesterone (P4), inhibin A/B, activin, follistatin. These feed back to both pituitary and hypothalamus.

Why pulsatile?
GnRH receptors desensitise with continuous exposure. Pulsatile GnRH (frequency + amplitude) is required to keep the pituitary responsive. Therapeutically, continuous GnRH agonists (after initial flare) suppress the axis and are used for endometriosis, fibroids, and IVF down-regulation.

The pulse generator—KNDy concept
A small network of Kisspeptin–Neurokinin B–Dynorphin (KNDy) neurons in the ARC acts as the intrinsic pacemaker:

• Kisspeptin strongly stimulates GnRH neurons (via KISS1R).
• Neurokinin B (NKB) provides excitatory synchrony among KNDy neurons.
• Dynorphin provides inhibitory tone, shaping inter-pulse interval.
  Oestrogen modulates KNDy activity—supporting negative feedback during most of the cycle and switching to positive feedback in the late follicular phase.

Additional neuromodulators

• GnIH (RFRP-3): inhibitory input to GnRH neurons (anti-gonadotropic).
• Leptin, insulin: metabolic signals that permit normal pulsatility.
• Cortisol and CRH: stress-related suppression.
• Dopamine: primary inhibitor of prolactin; indirectly supports GnRH by keeping prolactin in check.

2) Ovarian Hormones and Feedback Logic

Oestrogen (E2)

• Source: granulosa cells (aromatase converts thecal androgens to oestrogen).
• Low–moderate E2: negative feedback on GnRH and LH/FSH.
• Sustained high E2 for ~36 hours (late follicular phase): flips the system to positive feedback, causing the LH surge (and smaller FSH surge).

Progesterone (P4)

• Source: corpus luteum (post-ovulation); placenta later in pregnancy.
• Action: slows GnRH pulse frequency, stabilises endometrium, raises basal body temperature by ~0.3–0.5°C.

Inhibin/Activin/Follistatin

• Inhibin B (granulosa of small antral follicles) selectively suppresses FSH in early–mid follicular phase.
• Inhibin A (corpus luteum) suppresses FSH in luteal phase.
• Activin enhances FSH synthesis; follistatin binds activin, thus reducing FSH.

Summary table

3) Pulses, Frequencies and Cycle Dynamics

Early–mid follicular phase

• GnRH pulses: relatively fast (≈60–90 min).
• Pituitary bias: higher LH synthesis relative to FSH; FSH still sufficient to recruit a cohort of follicles.
• Selection: one follicle gains dominance via better FSH receptor expression, local IGFs, and decreased AMH locally.

Late follicular phase → Ovulation

• Dominant follicle raises E2 to sustained high levels; this sensitises GnRH neurons and pituitary to generate a mid-cycle LH surge.
• LH surge triggers:
  • oocyte meiosis I completion and ovulation,
  • luteinisation of granulosa/theca,
  • cumulus expansion and follicular rupture.

Luteal phase

• P4 slows GnRH pulses (e.g., 3–4 hourly) and reduces LH amplitude; FSH remains low due to inhibins.
• In absence of pregnancy, corpus luteum regresses → fall in P4/E2 → endometrial shedding; loss of negative feedback allows FSH rise to start the next cycle.

Arcuate vs preoptic control

• Arcuate KNDy drives pulsatile secretion throughout the cycle.
• Preoptic area contributes to the surge generation under sustained E2 conditions.

4) Neuroendocrinology Across Life Stages

Foetal and neonatal periods

• Transient activation (“mini-puberty”) after birth shows short-lived rises in LH/FSH/E2 that help reproductive tract maturation, then axis quiets under central inhibition.

Puberty

• Initiation requires adequate energy signals (leptin) and maturational changes in kisspeptin/NKB signalling.
• Pulsatility appears first at night, then daytime. Early cycles post-menarche are often anovulatory until positive feedback fully matures.

Reproductive years

• Stable interaction of pulses and feedback produces regular ovulatory cycles (typically 24–38 days).

Lactation

• Suckling inhibits tuberoinfundibular dopamine, increasing prolactin; prolactin suppresses GnRH pulses → lactational amenorrhoea. Oxytocin mediates milk ejection but does not drive the amenorrhoea.

Pregnancy

• hCG rescues the corpus luteum early; placenta later dominates E2/P4 production. High steroids keep GnRH/LH/FSH low. Pituitary lactotrophs hypertrophy, preparing for lactation.

Perimenopause and menopause

• Follicular depletion → low inhibin and E2 → high FSH/LH (FSH > LH). Thermoregulatory instability and KNDy neuron plasticity contribute to vasomotor symptoms.

5) Modifiers of the HPO Axis

Prolactin

• Chronic elevation (prolactinoma, hypothyroidism via ↑TRH, dopamine-antagonist drugs, chest wall lesions) inhibits GnRH → oligo/amenorrhoea, galactorrhoea, infertility.

Thyroid hormones

• Hypothyroidism: ↑TRH → ↑prolactin; cycles may be anovulatory/menorrhagic.
• Hyperthyroidism: oligomenorrhoea; fertility may be reduced until euthyroid.

Adrenal and stress

• Cortisol/CRH suppress GnRH pulsatility. Chronic stress, acute illness and excessive exercise can produce functional hypothalamic amenorrhoea (FHA).

Metabolic signals

• Leptin reflects energy sufficiency; insulin modulates ovarian steroidogenesis.
• Obesity: hyperinsulinaemia augments ovarian androgen production and lowers SHBG, contributing to PCOS.
• Under-nutrition: low leptin reduces GnRH pulse frequency (FHA).

Circadian and environmental factors

• Sleep deprivation, shift work and extreme endurance training alter pulse timing and can elongate cycles or cause anovulation.

6) Clinical Neuroendocrine Patterns

Functional Hypothalamic Amenorrhoea (FHA)

• Triggers: caloric deficit, stress, over-exercise.
• Labs: low/normal LH & FSH, low E2, normal prolactin/TSH; often low leptin.
• Management: restore energy balance, stress reduction; cyclic oestrogen–progestin for bone; fertility—with ovulation induction after lifestyle correction.

Hyperprolactinaemia

• Causes: micro/macroprolactinoma, hypothyroidism, antipsychotics, SSRIs, opioids.
• Features: amenorrhoea, galactorrhoea, headaches/visual symptoms (macroadenoma).
• Treatment: cabergoline preferred; treat hypothyroidism; pituitary MRI if marked elevation.

Polycystic Ovary Syndrome (PCOS)

• Neuroendocrine hallmark: relatively rapid pulses favour LH; hyperandrogenism and insulin resistance maintain follicular arrest.
• Labs: may show ↑LH/FSH ratio (not diagnostic), ↑testosterone; AMH often high.
• Treatment: lifestyle; letrozole for ovulation induction; metformin for metabolic indications; screen long-term cardiometabolic risk.

Primary Ovarian Insufficiency (POI)

• Age <40 with oligo/amenorrhoea, high FSH/LH and low E2.
• Aetiologies: autoimmune, genetic, iatrogenic.
• Management: hormone therapy for symptoms/bone; fertility via donor oocytes.

Thyroid disorders

• Correcting thyroid status often restores cycles.

Outflow obstruction vs neuroendocrine failure

• Primary amenorrhoea with cyclical pain suggests outflow obstruction (imperforate hymen, transverse septum), not HPO failure.

7) Investigations Based on Physiology

Baseline timing

• Day 2–5: FSH, LH, E2 (interpret with cycle phase).
• TSH, prolactin (fasting morning if possible) at any time.
• AMH: any day for ovarian reserve.
• Mid-luteal P4 (≈Day 21 for a 28-day cycle) confirms ovulation.

Dynamic tests (selected scenarios)

• GnRH stimulation: pituitary reserve (specialist use).
• Progesterone challenge: tests endometrial oestrogenisation and outflow.

Imaging

• Pelvic ultrasound for follicular tracking and PCOM morphology.
• Pituitary MRI for significant hyperprolactinaemia.
• Thyroid ultrasound only if nodules/goitre.

Pattern table

8) Therapeutic Principles

• Restore normal inputs: nutrition, sleep, stress control, balanced exercise.
• Cycle control and suppression: combined oral contraceptives; GnRH agonists/antagonists for endometriosis/fibroids (with add-back to protect bone).
• Ovulation induction: letrozole first-line in PCOS; gonadotropins with monitoring if required; hCG to trigger ovulation.
• Prolactin excess: cabergoline (dopamine agonist); surgery rarely needed.
• Thyroid: normalise TSH.
• POI: hormone therapy and early fertility counselling; screen bone health.
• Lactation: explain physiological amenorrhoea; advise contraception if pregnancy not desired.

9) Integrative Note

Though framed in modern physiology, the clinical goals resonate with Ayurvedic emphasis on ṛtuśuddhi (cycle regularity), ahara–vihara balance, and control of manasika nidāna (stress). Situations like atyāhāra-vyāyāma (over-exercise) and alpāhāra (caloric deficit) parallel FHA, while medoroga/prameha terrain reflects the metabolic drivers of PCOS. Use these parallels to counsel patients holistically while applying precise neuroendocrine diagnostics.

10) Key Take-Home Revision

• Pulsatile GnRH encodes pituitary output; continuous exposure suppresses LH/FSH.
• Sustained high oestrogen triggers LH surge and ovulation.
• Progesterone slows pulses and secures the luteal phase.
• Prolactin, thyroid, cortisol, leptin/insulin can derail the axis.
• Interpret labs with cycle phase and clinical context; treat the level of the lesion.

Assessment

A) MCQs (one best answer)

1. The neuronal peptide that most directly stimulates GnRH neurons at puberty is:
   A. Dynorphin B. Kisspeptin C. CRH D. Vasopressin
   Answer: B
2. Continuous administration of a GnRH agonist for several weeks will:
   A. Increase LH and FSH secretion
   B. Suppress LH and FSH secretion
   C. Selectively increase FSH
   D. Have no effect
   Answer: B
3. The immediate endocrine event that triggers ovulation is:
   A. FSH plateau due to inhibin B
   B. LH surge following sustained high oestrogen
   C. Sudden fall of progesterone
   D. Rise of prolactin
   Answer: B
4. In the early follicular phase, selective suppression of FSH is largely due to:
   A. Inhibin A B. Inhibin B C. Activin D. Follistatin
   Answer: B
5. The primary reason for lactational amenorrhoea is suppression of:
   A. Aromatase in granulosa cells
   B. GnRH pulsatility by high prolactin
   C. LH receptor expression on theca cells
   D. Oxytocin release
   Answer: B
6. A 22-year-old runner with BMI 17, stress, and amenorrhoea shows low/normal LH & FSH, low E2, normal TSH and prolactin. Most likely is:
   A. PCOS B. POI C. FHA D. Hyperprolactinaemia
   Answer: C
7. In PCOS, the GnRH pulse pattern is typically:
   A. Slow pulses favouring FSH
   B. Rapid pulses favouring LH
   C. Continuous non-pulsatile
   D. Absent
   Answer: B
8. Postmenopausal gonadotropin pattern is:
   A. Low FSH, low LH
   B. High FSH, high LH
   C. High FSH, low LH
   D. Low FSH, high LH
   Answer: B
9. Which statement about progesterone is correct?
   A. It speeds up GnRH pulses
   B. It lowers basal body temperature
   C. It slows GnRH pulses and stabilises the endometrium
   D. It triggers the LH surge
   Answer: C
10. The best single explanation for positive feedback in the late follicular phase is:
    A. High oestrogen increases KNDy dynorphin
    B. High oestrogen induces preoptic surge centre activation
    C. High progesterone drives GnRH surge
    D. Low inhibin A removes FSH inhibition
    Answer: B

B) Short Answer Questions (3–5 lines each)

1. Describe the KNDy neuron model of the GnRH pulse generator and the roles of kisspeptin, NKB and dynorphin.
2. Explain how sustained high oestrogen converts negative to positive feedback to produce the LH surge.
3. Outline the neuroendocrine basis of hyperprolactinaemic amenorrhoea and its first-line treatment.
4. List the baseline hormonal tests for secondary amenorrhoea and justify their timing.
5. Contrast the neuroendocrine profiles of FHA and POI.

C) Long Answer Questions

1. Describe the HPO axis in detail, including anatomical pathways, GnRH pulsatility, pituitary response, ovarian feedback (oestrogen, progesterone, inhibin/activin/follistatin), and the surge mechanism. Discuss how this physiology changes during puberty, lactation and menopause.
2. Discuss PCOS and hyperprolactinaemia as disorders of neuroendocrine control: pathophysiology, laboratory/ultrasound findings, differential diagnosis, and first-line evidence-based management.

D) Case-Based (OSCE-style)

A 28-year-old woman with oligomenorrhoea, acne and BMI 32 has Day-3 labs: FSH 5 IU/L, LH 11 IU/L, E2 normal, prolactin normal, TSH normal; total testosterone elevated; AMH high.

• a) Identify the most likely diagnosis and the underlying neuroendocrine disturbance.
• b) State first-line ovulation induction and why it is preferred.
• c) Name two long-term metabolic risks and how you will screen them.