HPG Axis and puberty

HPG Axis System Overview & Hierarchical Control

Hypothalamus → GnRH (pulsatile) → Pituitary → LH/FSH → Gonadal steroids → negative feedback.

Mechanism: Fine-tuned via steroid receptor signalling at multiple levels.

GnRH: Pulsatile Decapeptide & Functional Transport

10-aa peptide released into hypophyseal portal circulation; regulates pituitary gonadotrophs. Continuous GnRH shuts down the axis.

LH & FSH: Structure & Sex-Specific Actions

Heterodimeric glycoproteins with shared α-subunit.

LH: steroidogenesis (ovulation/testosterone)

FSH: follicle growth/testicular Sertoli cell activation → gametogenesis.

Steroidogenesis and Feedback Control

Oestradiol, progesterone, testosterone act on hypothalamus + pituitary (negative feedback) to regulate HPG output.

Kisspeptin Neurons: ARC & AVPV Pathways

Kisspeptin projections bind KISS1R on GnRH neurons → intracellular Ca²⁺ rise → GnRH release.

Kisspeptin: Master Switch for Puberty

Pubertal Gate Release Mechanism:

Role of Kisspeptin Mutation States

Inactivating mutations → absent puberty

Activating mutations → precocious puberty

Mechanism: Removes central GnRH inhibition present since early childhood.

Pulsatile Nature of GnRH & Gonadotrophins

Pulse frequency dictates hormonal outcome:

Slow pulses → ↑ FSH

Rapid pulses → ↑ LH

Mechanism: Differential β-subunit gene transcription.

Continuous GnRH Mechanism in Therapy

Continuous receptor binding → desensitisation → ↓ LH/FSH → ↓ gonadal steroids.

Used in precocious puberty, IVF, hormone-dependent cancers.

LH Pulses as Clinical Surrogate of GnRH Activity

Short half-life GnRH makes LH the measurable marker of pulsatile hypothalamic drive.

Adrenarche: Zona Reticularis

Maturation & DHEA/DHEAS

Age ~6–10. Androgen production induces pubic/axillary hair + skin oiliness.

Independently regulated from gonads.

Androgen Action on Pilosebaceous Units

Vellus → terminal hair conversion; sebaceous ↑ sebum → acne risk.

Silent Period → Reactivation by Kisspeptin Increase

Fetal HPG activity → postnatal quiescence → Kisspeptin-driven reactivation.

GnRH Pulse Maturation: Night-time to Circadian Pattern

In puberty → mostly nocturnal; adulthood → daytime pulses stable.

Gonadal Steroidogenesis & Gamete Maturity

FSH: Sertoli/granulosa → gamete development

LH: Leydig/theca → steroid output

Final output: fertility capacity.

Biphasic Oestrogen Action in Linear Growth & Fusion

Low E2 → growth acceleration

High E2 → epiphyseal fusion and end of height gain

Occurs in both sexes; earlier in females.

GH–IGF-1 Axis Synergy With Sex Steroids

E2 ↑ GH secretion → ↑ IGF-1 → bone expansion + mineralisation during puberty.

CNS-Driven Maturation as the Primary Pubertal Trigger

Exact neural mechanism unknown; change is intrinsic neurological development.

Metabolic Regulation: Leptin

Threshold for Puberty Initiation

Body fat ~17–18 percent required to trigger; ~22 percent to maintain cycles.

Leptin → stimulates Kisspeptin → activates GnRH.

Environmental/Nutritional Influences

Higher nutrition → earlier puberty

Anorexia/chronic illness → delayed puberty.

Consonance Principle: Order of Changes Always Preserved

Regardless of timing variability, the developmental sequence never changes.

Tanner Staging: Standard Monitoring of Pubertal Milestones

Stages 1–5 for genital/breast development and pubic hair.

Psychosocial Development During Puberty

Autonomy, sexual awareness, identity consolidation; risk-taking increases.

Central (GnRH-Dependent) Precocious Puberty Mechanism

↑ GnRH pulses → ↑ LH/FSH → ↑ sex steroids.

Consonance preserved; bone age advanced.

Treatment: continuous GnRH analogues.

Peripheral (GnRH-Independent) Precocious Puberty Mechanism

Sex steroids ↑ despite suppressed LH/FSH.

Loss of consonance → discordant development.

Examples: Testotoxicosis & McCune-Albright Syndrome

Testotoxicosis: constitutive LH receptor activation → Leydig steroidogenesis

McCune-Albright: activating cAMP pathway → autonomous hormone synthesis

Delayed Puberty Diagnostic Criteria

Girls: no secondary sex characteristics by 13, no menarche by 18

Boys: no testicular enlargement by 14

Constitutional Delay of Growth & Puberty (CDGP)

Most common cause (~90 percent).

Normal consonance; familial trait common; late but normal final height.

Hypogonadotropic Hypogonadism Mechanism

Low LH/FSH because of hypothalamic/pituitary failure.

Example: Kallmann syndrome (GnRH neuron migration defect).

Hypergonadotropic Hypogonadism Mechanism

High LH/FSH due to primary gonadal failure

Examples: Turner syndrome (XO), Klinefelter syndrome (XXY), post-viral gonadal injury.