HPG Axis and puberty

HPG Axis System Overview

The HPG axis (Hypothalamic–Pituitary–Gonadal axis) is a top-down hormonal control system that regulates sexual development, puberty, gamete production, and sex steroid levels through hierarchical signalling and negative feedback.

Step-by-step definition

1. Hypothalamus releases GnRH in a pulsatile manner.

2. Pituitary gland responds to GnRH by releasing LH and FSH.

3. Gonads (testes or ovaries) respond to LH/FSH by:

   • Producing sex steroids (testosterone, oestrogen, progesterone)

   • Producing gametes (sperm or oocytes)

4. Sex steroids feed back negatively to the hypothalamus and pituitary to regulate output.

Why pulsatile GnRH matters:

Continuous GnRH would switch the system off; pulses keep the axis active and tunable.

HPG axis

A) Hypothalamus (top of the diagram)

• Produces GnRH (a peptide hormone).

• GnRH release is pulsatile.

• Kisspeptin stimulates GnRH neurons (important for puberty onset).

• Red “minus” symbols show negative feedback from sex steroids.

B) Pituitary (middle)

• Responds to GnRH by releasing LH and FSH (glycoprotein hormones).

• LH and FSH are the output signals to the gonads.

C) Gonads (bottom)

• In testes:

  • LH → Leydig cells → testosterone

  • FSH → Sertoli cells → spermatogenesis + inhibin

• In ovaries:

  • LH → theca cells → androgen production

  • FSH → granulosa cells → oestrogen production + follicle development

D) Steroid hormones and feedback

• Testosterone, oestrogen, progesterone:

  • Act on target tissues

  • Feed back to both hypothalamus and pituitary

• This feedback:

  • Reduces GnRH

  • Reduces LH/FSH

  • Prevents hormone overproduction

GnRH pathway

1) GnRH neurons (top of the diagram)

• These neurons live in the hypothalamus.

• They release GnRH.

• GnRH release is pulsatile (short bursts).

Important:

• Kisspeptin neurons stimulate GnRH neurons.

• Kisspeptin is what helps switch puberty on.

2) GnRH does NOT go to the whole body

• GnRH is released into a local capillary network at the base of the hypothalamus.

• This is called the hypothalamo-hypophyseal portal system.

Why this exists:

• GnRH would be diluted and broken down if released into general circulation.

• The portal system delivers GnRH directly and efficiently to the pituitary.

3) GnRH reaches the anterior pituitary

• GnRH travels down the infundibulum (the pituitary stalk).

• It reaches the anterior pituitary only.

• It binds GnRH receptors on gonadotroph cells.

Key cell to remember:

• Gonadotrophs = LH + FSH producers

4) Pituitary response

• Gonadotroph cells release:

  • LH

  • FSH

These are released into normal bloodstream.

5) LH and FSH go to the gonads

• LH and FSH travel via circulation to:

  • Testes or ovaries

• They stimulate:

  • Sex steroid production

  • Gamete production

Gonadotrophin hormones

Heterodimeric glycoproteins with shared α-subunit but different b subunits

LH: steroidogenesis (ovulation/testosterone)

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

Pulse frequency dictates hormonal outcome:

Slow pulses → ↑ FSH

Rapid pulses → ↑ LH

Mechanism: Differential β-subunit gene transcription.

Puberty

Puberty is the transition from a non-reproductive state to a reproductive state, driven mainly by sex steroids.

A) Changes common to puberty

• Growth spurt

• Epiphyseal plate closure

• Skin changes (acne, oiliness)

• Pubic and axillary hair (androgen-dependent)

B) Male puberty (testosterone-driven)

Main hormone: Testosterone

Effects shown on the slide:

• Increased muscle mass and strength

• Shoulder broadening

• Facial and body hair

• Voice deepening (larynx growth)

• Adam’s apple prominence

• Penile and testicular growth

C) Female puberty (oestrogen-driven)

Main hormone: Oestrogen

Effects shown on the slide:

• Breast development (thelarche)

• Hip widening

• Increased subcutaneous fat

• Female pattern pubic/axillary hair

• Growth spurt followed by epiphyseal closure

• Softer skin and higher-pitched voice

How the two slides connect (this is the exam logic)

• Adrenarche explains:

• Pubic/axillary hair

• Acne

• Gonadarche explains:

• Breast development

• Voice deepening

• Muscle mass

• Fertility

You need both for normal puberty.

Puberty happens because two different hormone systems switch on, and they are independent but combine to produce puberty.

A) Adrenarche

What it is:

Adrenarche = maturation of the adrenal glands.

Hormones involved:

• Adrenal androgens (DHEA, DHEAS, some testosterone-like effects)

What it causes:

• Pubic hair

• Axillary hair

• Body odour

• Acne

This is called pubarche.

Important:

• Adrenarche is NOT driven by the HPG axis

• It can happen even if the gonads are not working

B) Gonadarche

What it is:

Gonadarche = activation of the HPG axis.

Hormones involved:

• GnRH (hypothalamus)

• LH and FSH (pituitary)

• Sex steroids from gonads (testosterone or oestrogen)

What it causes:

• Gonadal growth

• Sex steroid production

• Secondary sexual characteristics

• Fertility

Important:

• Gonadarche usually follows adrenarche

• It is essential for true reproductive puberty

Continuous GnRH Mechanism in Therapy

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

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

Androgens and PSUs

Androgens act on hair + skin

Androgens act on pilosebaceous units (PSUs), causing:

• Increased sebum production

• Transformation of fine hair into thicker hair

• Development of acne, pubic hair, axillary hair, and facial hair

What a pilosebaceous unit (PSU) is

A PSU is a functional skin unit made of:

• Hair follicle

• Hair shaft

• Sebaceous (oil) gland

• Arrector pili muscle

Function:

• Produces sebum

• Sebum travels along the hair shaft to the skin surface

Types of PSUs in the diagram

1) Sebaceous PSUs (acne pathway)

• Have large sebaceous glands

• Highly androgen-sensitive

• Androgens → ↑ sebum production

• Excess sebum blocks pores ± infection

Result:

• Acne

2) Vellus PSUs (starting point)

• Produce fine, soft vellus hair

• Cover most of the body

• Androgen exposure can change them

They can differentiate into:

3) Terminal PSUs (beard/facial hair)

• Under high androgen exposure

• Vellus hair → terminal hair

• Thick, coarse, pigmented hair

• Seen in:

• Beard

• Moustache

• Chest (in males)

4) Apocrine PSUs (pubic & axillary hair)

• Found in:

• Armpits

• Groin

• Under androgen influence:

• Form pubic and axillary hair

• Act as scent glands

Why this matters in puberty and disease

• Adrenarche:

• Androgens → pubic & axillary hair + acne

• CAH:

• Excess androgens → early pubic hair + acne

• AIS:

• Androgens present but receptors don’t work → reduced body hair

LH Pulses as Clinical Surrogate of GnRH Activity

We can’t measure GnRH directly, so we use LH pulses as a stand-in.

Why we can’t measure GnRH

• GnRH is released in tiny pulses

• It has an extremely short half-life (minutes)

• It travels only in the portal circulation

• It is rapidly degraded

So in blood tests, GnRH is basically invisible.

2) What GnRH does instead

• Every time the hypothalamus releases a GnRH pulse,

• The pituitary responds by releasing an LH pulse.

Important:

• This happens one-to-one.

• No GnRH pulse → no LH pulse.

3) Why LH is useful

• LH lasts longer in the blood than GnRH.

• LH enters the systemic circulation.

• We can measure LH repeatedly with blood samples.

So:

• LH pulse frequency and size reflect GnRH pulse activity.

LH pulses = surrogate marker

• GnRH activity = real driver

Epiphyseal fusion

• Epiphyses are the rounded ends of long bones that start separate from the shaft and fuse with age.

• When puberty begins, low levels of oestrogen (from reactivation of the HPG axis) stimulate rapid linear growth (growth spurt).

• As puberty progresses, rising oestrogen levels cause the growth plates to close (epiphyseal fusion).

• Once fusion occurs, longitudinal bone growth stops.

• Fusion happens earlier in females than males, which is why females typically stop growing sooner.

• Early puberty:

  • Adrenal androgens are noticeable (hair, acne)

• Later puberty:

  • Gonadal steroids dominate (breasts, voice, muscle)

• This is shift in visible effects, not suppression of HPA activity

Silent Period → Reactivation by Kisspeptin Increase

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

Consonance

Puberty doesn’t always happen at the same age for everyone,

• Central Precocious puberty: Precocious puberty is the onset of secondary sexual characteristics before age 8 in girls and before age 9 in boys, due to EARLY activation of pubertal hormone pathways.

Peripheral Precocious puberty:

• Cause: Sex steroids produced independently of the HPG axis

• Sources:

  • Adrenal (e.g. CAH)

  • Ovarian/testicular tumours

  • Exogenous hormones

Features:

• Abnormal or incomplete pubertal sequence

• LH/FSH are low

What “consonance” means

• Pubertal changes occur in a smooth, ordered sequence.

• One change does not skip ahead of another.

• A child may start earlier or later, or progress faster or slower, but the sequence stays the same.

Think: same order, different clocks.

Boys: typical order of changes

1. Growth of testes and scrotum (first true sign of puberty)

2. Penile lengthening

3. Pubic hair growth

4. Growth spurt

5. Voice deepening

6. Change in body shape (more muscle, broader shoulders)

7. Underarm and facial hair

Key point:

• Testicular enlargement always comes first

• Facial hair comes late, never early

Girls: typical order of changes

1. Breast budding (thelarche) – first sign

2. Pubic hair growth

3. Growth spurt

4. First period (menarche) – occurs after the growth spurt

5. Underarm hair growth

6. Change in body shape (hips widen, fat redistribution)

7. Adult breast size

Key point:

• Menarche is not the start of puberty

• It happens after several other changes

Why this matters clinically

• If the order is abnormal, think pathology (e.g. precocious puberty, endocrine disorders).

• If the order is normal but timing is early/late, this can still be normal variation.

Tanner scale of pubertal development

The Tanner scale is a clinical staging system (Stages I–V) used to describe physical pubertal development, based on external genitalia/breast development and pubic hair, not age.

Stage I: Pre-pubertal

Stage II: Puberty begins

Stage III: Progressive pubertal development

Stage IV: Advanced pubertal development

Stage V: Adult sexual maturity

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.

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.

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

Pubertal delay

What “pubertal delay” means

Definition:

• Boys: no secondary sexual characteristics by 14 years

• Girls: no secondary sexual characteristics by 13 years, or no menarche by 18 years

Causes of pubertal delay (3 main groups)

1) Constitutional delay

(most common)

What it is:

• A normal variant — puberty happens late but normally.

Key features:

• Affects growth and puberty

• ~90% of pubertal delay cases

• Much more common in boys

• Often familial

• Can be worsened by chronic illness (e.g. diabetes, cystic fibrosis)

Hormones:

• HPG axis intact, just late to activate

Outcome:

• Normal adult height and sexual development

2) Hypogonadotrophic hypogonadism

(Low LH and FSH)

Problem location:

• Hypothalamus or pituitary

Mechanism:

• GnRH or gonadotrophin deficiency → gonads not stimulated

Causes:

• Kallmann syndrome (failed GnRH neuron migration)

• Hypopituitarism

• Long-term opioid or glucocorticoid use

• Other genetic causes

Hormones:

• Low LH/FSH

• Low sex steroids

3)

Hypergonadotrophic hypogonadism

(High LH and FSH)

Problem location:

• Gonads themselves

Mechanism:

• Gonads fail → low sex steroids

• Loss of negative feedback → high LH/FSH

Causes:

• Gonadal dysgenesis

• Turner syndrome (XO)

• Klinefelter syndrome (XXY)

• Acquired gonadal damage (e.g. mumps)

Hormones:

• High LH/FSH

• Low sex steroids