192b - Puberty

Question 1

GPR54 knockout mice have which clinical finding?

A. Central precocious puberty.
B. Delayed puberty in females.
C. Gonadotropin independent precocious puberty.
D. Hypogonadotropic hypogonadism

Answer 1

D. Hypogonadotropic hypogonadism

GPR54 is necessary to initiate puberty (activated by kisspeptin)

No kisspeptin also results in hypogonadotropic hypogonadism

Question 2

What defines precocious and delayed puberty in:

• People with ovaries:
• People with testes:

Answer 2

Ages refer to *onset* of puberty

• People with ovaries: Thelarche
  
  • Precocious: < 8 years old (or 7, in African American populations)
  • Delayed: > 13 years, or >4 years between onset of thelarche and menses
• People with testes: Testicular growth
  
  • Precocious: < 9 years
  • Delayed: > 15 years, or >4 yeasrs between onset of testicular growth and full testicular maturation

Question 3

A 16 year old girl had thelarche at age 11 years, but has not had menses yet.

Is this delayed puberty?

Answer 3

Yes

• Onset of thelarche at a normal age, but >4 years since onset of thelarche without menses

Question 4

As children approach adolescence, GnRH secretion increases.

When are secretions highest?

Are they continuous or pulsatile?

Answer 4

Highest during sleep

Pulsatile

Continuosu GnRH secretion, even if high, will suppress LH/FSH

Question 5

What is the peripheral “permissive hormone” that allows puberty to happen?

Answer 5

Leptin

• Signals to the hypothalamus that there is adequate fat/energy for puberty
  
  • Allows the NKB -> kisspeptin -> GPR54 pathway to initiate puberty
• Promotes gonadotropin synthesis

Question 6

What is the first sign of central puberty in:

• People with ovaries:
• People with testes:

Answer 6

• People with ovaries: thelarche (breast development)
• People with testes: testicular enlargement

Question 7

List 3 congenital causes of hypergonadotropic hypogonadism

Answer 7

• Klinefelter syndrome (XXY)
• Turner syndrome (XO)
• Gonadal dysgenesis

In all 3 cases, GnRH, LH, FSH will be high - but there is not gonadal response; low sex steroids feed back centrally -> continued increased LH/FSH

Question 8

In puberty, pubic hair, axillary hair, acne, and body odor ususally result from increased levels of what hormone?

What is the source of this hormone in people with ovaries vs. people with testes?

Answer 8

Testosterone

• People with ovaries: adrenal testosterone
• People with testes: gonadal testosterone

Question 9

A 7 year old girl presents with concern for early puberty. She has had some acne + body odor and pubic hair for the last 6 months. No growth spurt.

PE: Tanner 1 breast tissue, Tanner 3 pubic hair, axillary hair present

Is this precocious puberty?

What would you expect labs to show? (general)

Answer 9

Not precocious puberty

Signs point to increased testosterone, but not increased estradiol

=> suspect premature adrenarche

• LH/FSH: low
• Estradiol: low
• DHEA-S: high

DHEA-S is a marker of adrenal testosterone production

Question 10

What is the role of NKB (aka TAC3) in puberty?

Answer 10

NKB regulates kisspeptin release - important for the onset of puberty

(and kisspeptin activates GPR54 -> puberty)

Mutation in NKB -> hypogonadotrypic hypogonadism, then reversal in adultood (not important for reproduction

Question 11

What is the effect of a mutation in the ANOS1 gene?

Answer 11

Kallman syndrome: hypogonadotripic hypogonadism + anosmia

• ANOS1 (aka KAL1) tells GnRH neurons to migrate with the olfactory placode
• Mutation -> Failure to migrate -> Kallman syndrome

Question 12

During which periods of childhood ar LH, FSH, and sex steroids elevated?

Answer 12

• Fetal life (subclinical neonatal mini-puberty)
• Infancy (mini-puberty of infancy)
• Puberty

Question 13

An 8 year old Caucasian girl presents with breast development, left greater than right, over the past year. Her mother had menarche at 15 years and her father remembers pubertal timing being normal. Examination reveals left breast is Tanner Stage 2 and right is Tanner stage 3.

What would be your evaluation and next step?

Answer 13

This is premature thelarche

Asymmetric growth is common, but breast development beofre age 8 (7 in African-American girls) is considered premature

Evaluate for precocious puberty (measure LH/FSH, sex steroids)

I’m not really sure if you would treat precocious puberty? But evaluating for the cause may reveal other endocrine abnormalities, which may require intervention?

Question 14

What is the role of kisspeptin in puberty?

Answer 14

kisspeptin activates GPR54, causing initiation of puberty

Note: kisspeptin is regulated by NKB (aka TAC3)

• Missing either kisspeptin or GPR54 -> hypogonadotropic hypogonadism*
• Missing NKB -> hypogonadotropic hypogonadism THEN reversal in adulthood (important for puberty, not reproduction)*

Question 15

What is pubarchy?

Answer 15

Pesence of pubic hair

Question 16

What is the “classic” triad of findings in McCune Albright syndrome?

Answer 16

• Peripheral precocious puberty (in 85% of people w/ ovaries and in 10-15% of people w/ testes)
  
  • Low LH/FSH, high sex steroids
• Cafe-au-lait spots
• Polyostotic fibrous dysplasia

Caused my a mutation in GNAS1 gene; moasaicism -> varible presentation

Question 17

Answer 17

This is not delayed puberty

Would count as “constitiuttional delay of puberty”

Reassure and observe

(normal range = 9-15 years old for people with testes)

Question 18

How does grhelin impact puberty?

Answer 18

Ghrenlin is a semi-inhibitory signal of puberty

• In male rats, ghrelin delayed puberty
• Female rats needed higher doses of ghrelin to delay puberty

Basically, grhelin is the “I’m hungry, not enough energy” hormone - in combination with low leptin, signals will inhibit puberty

Question 19

What is the role of MKRN3 in puberty?

Answer 19

MKRN3 prevents puberty during childhood

Loss of MKRN3 -> precocious puberty if mutation is in the paternally inherited allele

(maternal imprinting)

Question 20

Elevation of what substance can differentiate pubarche from adrenarche in people with testes?

Answer 20

Adrenarche = elevated DHEA-S

• Adrenarche and pubarche may present similarly (body odor, pubic hair, elevated testosterone)
• Elevated DHEA-S confirms that the source of testosterone is the adrenal glands, not the gonads

Question 21

What Tanner stage signals the start of puberty/

Answer 21

Tanner 2