192. Puberty

Question 1

Define puberty. What are its biochemical changes?

How does puberty occur over the lifespan?

Fetus vs. Neonate vs. Childhood vs. Adrenarche vs Adolescence

Answer 1

P: maturation of HPG axis
Changes: pulsatile GnRH secretion (hypothalamus) = more amp and freq, initially at night
pulsatile LH/FSH secretion (pituitary) = more amp and freq, initially at night, diurnal rhythm lost as puberty progresses
more E or T = gonadarche: beginning of gonad maturation

Fetus: GnRH neurons migrate with olfactory placode and secrete GnRH as fetus; levels fall late in gestation due to rising CNS inhibition
Neonate: Subclinical Neonatal Mini-Puberty: NORMAL, may have presence of LH/FSH + E/T from 3-4mo until 1 yo; eventually stopped by growing CNS inhibition
Childhood: high levels of CNS inhibition prevent puberty
Adrenarche: adrenal maturation begins usually at or before puberty (independent) as CNS inhibition falls

Puberty: pulsatile GnRH secretion during sleep as CNS inhibition falls, then increased pit sensitivity (pulsatile LH/FSH), then increased gonadal sensitivity, then amplification (more feedback, move from diurnal pulse to continuous)

Question 2

Timing of Puberty

• kisspeptin: location, fx, effect of mutation
• neurokinin B (TAC3): location, effect of mutation
• MRKN3: fx, effect of mutation
• what regulates the HPG axis (4 hormones, 2 other things)
• what genes stimulate pubertal onset? Which inhibit?

Answer 2

Kisspeptin: hypothalamic gatekeeper released from Arc nucleus

• levels increase at pubertal onset (advances pubertal timing)
• activates KISS1R (GPR54): increases LH/FSH Receptor
• GPR54 knockout mice: normal GnRH neurons but hypogonadotropic hypogonadism (no LH/FSH/puberty)

NKB (TAC3): acts upstream to release kisspeptin

• mutations: initial hypogonadism, then reversed in adulthood
• only important for onset of puberty not reproduction (normal spermatogenesis/reproduction)

MRKN3: inhibits puberty during childhood
- mutations: only inherited from paternal allele (maternal imprinting) - causes precocious puberty (disinhibition)

HPG Axis:
T (-fb) and E (-/+ fb)
ghrelin and leptin (need high leptin to enter puberty)
sleep: need sleep for pulsatile GnRH and puberty onset
EE: need adequate fat mass available (leptin) to enter puberty

Stimulate: KAL1/ANOS (gene tells GnRH neurons to migrate with olfactory placode and make GnRH), leptin, kisspeptin, GPR54, NKB, EE
Inhibit: GABA, MRKN3

Question 3

Define:

• Puberty
• Adrenarche
• Pubarche
• Menarche

what are the typical labs for prepubertal, adrenarchal, and pubertal stages?

Answer 3

Puberty = gonadarche: growth + maturation of gonads, reproductive capability, maturation of HPG axis, high GnRH, FSH, LH, T/E
Adrenarche = maturation of HPA axis, increase in adrenal androgens (DHEA, DHEA-S, androstenedione), INDEPENDENT OF PUBERTY - happen at similar times but NOT RELATED
Pubarche = presence of pubic hair
Menarche = presence of menses

Labs:
Prepubertal: LOW - fsh, lh, e, t, dhea-s (need ultrasensitive labs to detect low dhea-s)
Adrenarchal: higher dhea-s
Pubertal: HIGH - fsh, lh, e, t + DHEA-S higher than in adrenarche

Question 4

What is the first sign of central puberty in girls and in boys?
What are other signs of puberty? signs of testosterone?

Answer 4

Boys: testes enlargement
Girls: breast development (thelarche)

Other signs: linear growth, voice change, facial hair, menarche
Testosterone (adrenarche or puberty): pubic hair, axillary hair, acne, body odor (adrenal in girls, adrenal + pubertal in males)

Question 5

Puberty in Girls:

• when is avg onset
• when is menarche
• when is peak growth rate
• tanner staging for breasts and pubic hair

Answer 5

Avg onset: 10 (8-13)
Menarche: 12 (1-4 years after thelarche; at B4)
Peak growth: B2-B3

B1: prepubertal
B2: breast buds
B3: breast elevation
B4: areolar mound
B5: adult contour

Ph1: prepubertal
Ph2: long straight hair
Ph3: long curly hair
Ph4: enters pubis
Ph5: spreads to thighs

Question 6

Puberty in Boys:

• when is avg onset
• when is gynecomastia
• when is voice change
• when is peak growth rate
• when is spermarche
• when is facial hair
• tanner staging for tests and pubic hair

Answer 6

Avg onset: 11.5 (9-15) later than girls
Gynecomastia: T2-T3 (resolves in 2-3years)
Voice Change: T3-T4
Peak Growth: T4 (later than girls)
Spermarche: T3-T4
Facial Hair: T4-T5

G1 - prepubertal (4mL)
G2 - scrotum enlarges, reddening
G3 - scrotum enlarges, penile growth
G4 - further scrotal/penile growth, darkening of scrotum
G5 - adult stage (25mL)

Ph1 - prepubertal
Ph2 - long straight
Ph3 - long curly
Ph4 - spread to pubis
Ph5 - spread to thighs

Question 7

What are 4 variations of normal puberty?

What are the two categories of abnormal puberty and how are they defined?

Answer 7

1. Premature thelarche - before age 7-8 girls
2. Premature pubarche - pubic hair before 8 girls and 9 boys
3. Premature adrenarche - high adrenal androgens
4. Constitutional delay of puberty - late bloomers
5. Precocious puberty (<7-8 girls, <9 boys)
6. Delayed (>13 girls, >15 boys, or >4yrs from puberty onset to menarche or full testicular enlargement)

Question 8

Precocious Puberty

• central vs. peripheral: causes and labs
• what is McCune-Albright Syndrome?

Answer 8

CPP: GnRH dependent = HIGH LH/FSH, HIGH T/E
causes: idiopathic (most common, F>M), CNS abnormality (acquired: infection surgery trauma, congenital, tumor, chronic exposure to sex steroids)

PPP: GnRH independent = LOW LH/FSH, HIGH T/E
causes: genetic (LH-R activating mutation, McAS), tumors (adrenal, ovarian, testicular), other (hypothyroidism, exogenous sex steroids

McCune-Albright Syndrome: TRIAD of PPP (episodic ovarian cysts in girls), cafe-au-lait spots, polyostotic fibrous dysplasia (bone dysplasia)
- also can have hyperfx of other hormones - TSH, GH, ACTH

Question 9

Delayed Puberty

• central vs. peripheral: causes and labs
• what is Kallmann Syndrome?
• what is Klinefelter Syndrome

Answer 9

CDP: central, hypothalmic-pit = LOW LH/FSH, LOW E/T
cause: acquired (autoimmune, irradiation, tumor), congenital (Kallmann, CN2 hypoplasia = pit deficiencies), malnutrition (anorexia), excessive exercise, chronic illness, endocrinopathies (hyperPRL, Cushing Syndrome = high other hormones suppress LH/FSH)
AKA: HYPOgonadotrophic Hypogonadism

PDP: primary gonadal = VERY HIGH LH/FSH, LOW E/T
cause: acquired (autoimmune, chemotx, irradiation, torsion, mumps), congenital (Klinefelter Syndrome = gonadal dysgenesis, Turner syndrome)
AKA: HYPERgonadotrophic Hypogonadism

Kallmann: failure of GnRH neuron and olfactory placode migration - X-LINKED mutation in KAL1/ANOS gene (or AD), causing anosmia, coloboma, synkinesis (mirror image movements), hearing loss, single kidney