JC112 (Paediatrics) - Premature Puberty: Puberty & Related Disorders

Question 1

Hormonal changes that start onset of puberty

Answer 1

Kisspeptins from hypothalamus bind to GPR54 (GPCR) on the hypothalamic neurons to secrete GnRH
Activation of hypothalamic-pituitary-gonadal axis:
- frequency and amplitude of hypothalamic GnRH pulses increases at onset of puberty
- gonadotrophs in anterior pituitary secrete pulses of gonadotrophin (LH, FSH)
- Gonads stimulated

Question 2

Describe the gonadal development during puberty

Answer 2

Under LH and FSH pulses:
1. Ovaries: follicular development, produce oestrogen for breast development, enlargement of uterus

2. Testes: stimulate Sertoli cells, Leydig cells produce testosterone&raquo_space; penile and scrotal development
3. direct effect on growth plate, and indirect action by stimulation of growth hormone

Question 3

Factors that modulate the onset of puberty

Answer 3

1. Genetic factors
2. Peripheral signs: intrauterine and postnatal growth, BMI and fat mass, insulin sensitivity, gonadal steroid levels
3. Environmental signals: light, stress, environmental endocrine disruptors

Question 4

Female puberty

• Age of puberty onset
• Signs of puberty onset
• Timing of secondary sexual characteristics

Answer 4

Age of onset: 11 years old (same for both sex)

Signs:

• Breast development
• Public and axillary hair (simultaneous with breast growth)
• Menarche

Timing:

• 10.1 years: Breast budding
• 11.2 years: Pubic hair growth
• 12.2 years: Growth spurt (9 months after tanner stage 2 breast development)
• 12.7 years: Menarche (2 years after breast budding)
• 14 years: Mature breasts

Question 5

Male puberty

• Age of puberty onset
• Signs of puberty onset
• Timing of secondary sexual characteristics

Answer 5

Age of onset - 11 years old (same for both sex)

Signs of puberty onset

• Increase testicular volume to 4mL first
• Growth of penis and genitalia simultaneously with pubic hair
• Breast enlargement

Timing:
11-15 years: histological spermatogenesis
13.5 years: ejaculation occurs, peak growth spurt, corresponding to testicular volume of 10-12 ml
17 years (bone age): sperm with adult morphology, motility and concentration

Question 6

Gynaecomastia in puberty

• Cause
• Progression of breast tissue in puberty

Answer 6

Cause: High oestrogen production by aromatization of testosterone before testosterone achieves concentrations that can oppose the oestrogen

Progression:

• Breast tissue often regresses within 2 years
• Gynaecomastia remains permanent in obese boys, or conditions e.g. Klinefelter syndrome, Partial androgen resistance

Question 7

Definition of precocious puberty

Answer 7

Onset of puberty at a younger age than expected for the normal population (i.e. >2 SDs earlier than population mean)

If sexual development in:
 Girls younger than 8 years
 Boys younger than 9 years

Adjusted age cut-off for ethnicity:
<7 years in white girls
<6 years in black girls

Question 8

Major causes of precocious puberty

Answer 8

Isolated premature sexual characteristic

• Primary hypothyroidism
• Precocious pseudopuberty

Central precocious puberty

• Idiopathic
• CNS lesions: most commonly Benign Hypothalamic Hamartoma
• Suprasellar tumors
• Other CNS lesions…etc

Peripheral precocious puberty

• Autonomous hyperproduction of estrogen/ androgens (e.g. Testicular or ovarian tumors)
• Exogenous hyperestrogenism/ androgens
• Congenital adrenal hyperplasia, Non-classical Adrenal hyperplasia, Androgen-producing tumors

Question 9

Explain how primary hypothyroidism causes precocious puberty

Answer 9

Primary hypothyroidism&raquo_space; Increase TSH acts as weak agonist on FSH receptors&raquo_space; abnormal pattern of gonadotropin secretion:

 In girls: ovarian stimulation  isolated breast development
 In boys: testicular enlargement without other secondary sexual characteristics
 No pubertal progression in majority of cases
 Delayed bone age with poor growth velocity

Question 10

Effect of central precocious puberty on growth

Answer 10

accelerated bone maturation causes early fusion of bone plates
compromises final adult height

Question 11

Central precocious puberty

• Effect on puberty development
• Common causes

Answer 11

Effect on puberty development:
- Activation of HPG axis at an earlier age, causing isosexual pubertal development (e.g. breast budding in girls, testicular enlargement in boys)

Idiopathic in girls (>80%)

CNS lesions in boys (>80%):

• benign hypothalamic hamartoma (Most common)
• Suprasellar tumors
• Previous meningoencephalitis
• Major head trauma
• Neurofibromatosis
• Hyperprolactinemia
• Activating mutation of GPR54, the GPCR mediating effects of kisspeptin

Question 12

Precocious pseudopuberty

• Definition
• Hormonal disturbances

Answer 12

Definition: Gonadal/ adrenal sex steroid secretion not resulting from activation of HPG axis, i.e.
 Pituitary independent or Peripheral production

Hormonal disturbance: Loss of normal feedback&raquo_space; very high sex steroid concentrations despite low gonadotropins
Sex steroid disturbance:
 Isolated high androgen
 Isolated high oestrogen
 Combined androgen and oestrogen production

Question 13

Causes of androgen overproduction in precocious pseudopuberty

Answer 13

Girls:
 Ovarian arrhenoblastomas
 Ovarian hyperthecosis

Boys:  
 Leydig cell tumors
 hCG-secreting tumors (e.g. hepatoblastomas, germ cell tumors
 McCune-Albright syndrome
 Familial testotoxicosis

Both sex: 
 Nonclassical (late- onset) adrenal hyperplasia
 Androgen- secreting adrenal tumors
 Generalized glucocorticoid resistance
 Cushing syndrome 
 Exogenous anabolic steroid abuse

Question 14

Causes of estrogen overproduction in precocious pseudopuberty

Answer 14

Girls: 
 Ovarian cysts
 Ovarian granulosa cell tumors
 Sertoli-Leydig cell tumors (isolated or as part of Peutz- Jeghers syndrome)
 McCune- Albright syndrome

Boys:
 Adrenal tumors
 Sertoli cell tumors (usually part of Peutz- Jeghers syndrome)

Question 15

Name 2 syndromes associated with precocious pseudopuberty

Answer 15

McCune-Albright syndrome (MAS)

Familial testotoxicosis/ familial male-limited precocious puberty (FMPP)

Question 16

McCune-Albright syndrome

• Predominant gender
• Pathogenesis

Answer 16

multisystem disorder, predominantly female

Pathogenesis:
sporadic somatic mutation (missense) in the gene encoding the α-subunit of the G- protein that stimulates cAMP production:
- Mutation occurs early in embryogenesis
- Failure of phosphorylation of GTP to GDP&raquo_space; constitutive activation of adenylyl cyclase in multiple affected tissues: skin, bone, gonads

Question 17

McCune-Albright syndrome

• Signs of sexual precocity in female and male

Answer 17

signs of sexual precocity

Female:
- Autonomously functioning luteinized follicular cysts of the ovaries&raquo_space; estrogen production
- Pre-pubertal LH secretion with absent LH response to GnRH
- Precocious thelarche
Ix: USG in girls – multiple follicular cysts with an occasional large solitary cyst

Male:
- asymmetric enlargement of the testes

Question 18

McCune-Albright syndrome

Classical triad of symptoms and Diagnostic criteria

Answer 18

Diagnosis – >2 features present in classic triad:

1. Irregularly-edged hyperpigmented macules/ café au lait spots
   Characteristic features:
    Jagged “coast of Maine” borders
    Location respects midline of body (does not cross)
2. Polyostotic fibrous dysplasia (>1 bone is replaced by fibrous tissue&raquo_space; weak bones, uneven growth, deformity)
3. Multiple autonomous endocrinopathies:
   - gonadotropin-independent sexual precocity (most common)
   - Others: thyroid, adrenals, pituitary, parathyroids

Question 19

Familial testotoxicosis/ familial male-limited precocious puberty (FMPP)

• Inheritance pattern
• Pathogenesis

Answer 19

Inheritance: autosomal dominant inheritance, but only phenotypic in boys

Pathogenesis:
constitutively activating mutations of LH receptor
» premature Leydig and germinal cell maturation
» gonadotropin-independent precocious puberty

Question 20

Familial testotoxicosis/ familial male-limited precocious puberty (FMPP)

• Age of presentation
• Clinical presentation

Answer 20

gonadotropin-independent precocious puberty:

• present at 2-5 years
• Accelerated growth
• Early secondary sexual characteristics: Virilization and Mild enlargement of testesto early-/ mid-pubertal range
• Reduced adult height

Question 21

Familial testotoxicosis/ familial male-limited precocious puberty (FMPP)

Hormonal disturbances
Investigations for confirmation of Dx
Treatment

Answer 21

Testosterone levels:
 Very high concentrations
 Source of secretion localized to testes

Gonadotropin levels
 In childhood: unstimulated/ prepubertal concentrations with minimal response to GnRH stimulation
 In puberty: lack of the usual pattern of LH pulsatility
 In adulthood: normal pattern of LH secretion and response to GnRH&raquo_space; fertile

Testicular biopsy: premature maturation of Leydig cell (hyperplasia), spermatogenic elements
Hormone profile: High Testosterone, Pre-pubertal/ low gonadotrophins, Low hCG

Tx: Androgen-receptor-blocking agents (ketoconazole); or Aromatase inhibitors

Question 22

7 questions for formulating Ddx for abnormal puberty

Answer 22

1. Onset of puberty
2. Progression of clinical symptoms
3. signs of exaggerated maturation: isosexual? Isolated sexual characteristics? Growth? Specific syndromal signs?
4. Effects on predicted adult height/ Compromised final height?
5. Psychological consequences
6. Gonadotropin-dependent (precocious puberty) or independent cause (precocious pseudopuberty)
7. Central precocious puberty: idiopathic or CNS lesion

Question 23

Outline history taking questions for abnormal puberty

Answer 23

Presentation:
- Isosexual development? Adrenarche/ Pubarche/ Thelarche/ Testicular enlargement?
- Growth and final adult height potential

Birth history – SGA (small for gestational age** major risk factor), birth complications

Past medical history:

• past X-rays,
• brain trauma,
• neonatal meningoencephalitis
• Brain tumors (e.g. hypothalamic, suprasellar, prolactinoma…)

Family history:

• History of precocious puberty
• Check mid-parental height

Pubertal milestones (precise timing and sequence)

Impact on psychological health/ wellbeing

Question 24

Effect of SGA on growth and development

Answer 24

SGA (small for gestational age)

more prone to precocious pubarche,
earlier onset of pubertal development and menarche
faster progression of puberty

Question 25

Outline P/E for abnormal puberty and development

Answer 25

1. Neurologic system (includes neurocutaneous markers, optic fundi, visual field) >> Central precocious puberty 2. Endocrine system, thyroid examination (Primary hypothyroidism, Hyperprolactinemia, Adrenal hyperplasia/ tumor…) 3. Tanner staging pubertal development – breast development, Testicle enlargement. Secondary sexual characteristics, signs of hyperandrogenism (virillization, oily skin, acne…) 4. Scoliosis/ body asymmetry > imbalance in growth 5. Growth chart* 6.

Question 26

Growth chart patterns that suggest underlying pathologies

Answer 26

 A rapid tempo of progression  Advanced development  Rapid linear growth  Advanced skeletal maturation

Question 27

First-line investigations for abnormal puberty and development

Answer 27

1. Hormonal profile: LH, FSH, oestradiol/testosterone, TFT, prolactin, β-hCG 2. LHRH Test (Luteinizing Hormone Releasing Hormone) 3. X-ray for bone age (bone maturation) 4. MRI brain and pituitary gland with contrast - exclude CNS lesion 5. Investigations for peripheral causes; - USG pelvis (girls) and adrenals - Measure 17OHP, DHEAS and testosterone (screen for non-classical congenital adrenal hyperplasia) - ACTH stimulation test - 24 hour urine free cortisol (Cushing's syndrome) 6. Investigation for unilateral testicular enlargement: Imaging for androgen-producing tumour within the larger testis 7. Investigation for bilateral testicular enlargement: Confirm CPP or FMPP

Question 28

Ddx and confirmation tests for early pubarche only | early onset of pubic and axillary hair, acne

Answer 28

1) **rapid growth** and significantly **advanced bone age** >> Confirm **CAH, Non-classical AH, Adrenal tumor, Exogenous androgens** - **High Testosterone, High 17-OH- progesterone, High DHEAS** - **Adrenal and ovarian ultrasound** 2) **normal growth rate** and mildly advanced bone age (5-7 years) >> **Idiopathic precocious puberty** - **Prepubertal testosterone, Normal 17-OH-Progesterone, Pubertal level DHEAS**

Question 29

Ddx and confirmation tests for early thelarche (breast development) only

Answer 29

**Normal growth rate** and non-advanced bone age (birth- 3 years) >> **Idiopathic precocious thelarche** **Rapid growth** and significantly advanced BA - **McCune-Albright syndrome** or **exogenous estrogen** >> **Prepubertal / Low LH and FSH level + Pubertal/ high estradiol level** - **Central precocious puberty** >> **Pubertal LH + FSH + Estradiol** , Confirm with head MRI

Question 30

Ddx and confirmation test for concurrent thelarche and pubarche

Answer 30

**Central precocious puberty** >> **Pubertal LH and FSH and estradiol level**, confirm with **brain MRI** **Peripheral precocious puberty**: **Adrenal or ovarian tumor** producing estrogen and androgen - **Pre-pubertal LH and FSH level + Pubertal Estradiol and testosterone** - Confirm with **Adrenal and ovarian ultrasound**

Question 31

Interpret the following presentation: Pubarche only with normal growth rate Pre-pubertal testosterone level Normal 17-OH-Progesterone Pubertal DHEAS level Most likely cause of precocious puberty

Answer 31

Idiopathic precocious adrenarche

Question 32

Interpret the following presentation: - Pubarche only - Rapid growth - High testosterone, 17-OH- Progesterone and DHEAS Most likely cause of precocious puberty

Answer 32

CAH, NCAH, adrenal tumor, exogenous androgen

Question 33

Interpret the following profile: - Thelarche only - Normal growth Most likely cause of precocious puberty

Answer 33

idiopathic precocious thelarche

Question 34

Interpret the following profile: - Thelarche only with rapid growth - Prepubertal LH and FSH level - Pubertal estradiol level Most likely cause of precocious puberty

Answer 34

McCune-Albright syndrome Exogenous source of estrogen

Question 35

Interpret following profile: - Thelarche only - Rapid growth - Pubertal LH and FSH - Pubertal Estradiol level Most likely cause of precocious puberty

Answer 35

Central precocious puberty

Question 36

Interpret the following profile: - Thelarche and pubarche present concurrently - LH, FSH and Estradiol levels all at pubertal level Most likely cause of precocious puberty

Answer 36

Central precocious puberty

Question 37

Interpret following profile Thelarche and pubarche LH and FSH at prepubertal level Estradiol and testosterone at pubertal level Most likely cause of precocious puberty

Answer 37

Adrenal or ovarian tumor producing both estrogen and androgens

Question 38

Ddx and confirmation test for Symmetrical, prepubertal-sized testicles in boys with precocious puberty

Answer 38

Extra-testicular, gonadotropin- independent etiologies: CAH, NCAH or adrenal tumor: - Prepubertal LH and FSH - High testosterone, 17-OHP, DHEAS - Confirm with adrenal ultrasound Exogenous testosterone - Prepubertal LH and FSH - Isolated high testosterone

Question 39

Ddx and confirmation test for asymmetrical testicular enlargement in boys

Answer 39

Functioning testicular tumor - LH and FSH at prepubertal level - Testosterone at pubertal level - Confirm with testicular US

Question 40

Ddx and confirmation test for symmetrical, pubertal-sized testes in boys

Answer 40

Gonadotropin mediated: 1) Central precocious puberty - Pubertal LH and FSH - Suppressed/ undetectable hCG - High testosterone - Confirm with Head MRI 2) hCG-producing germ cell tumor - LH and FSH at prepubertal level - High hCG - High testosterone 3) Familial testotoxicosis or McCune-Albright syndrome: autonomous testicle function - LH and FSH at prepubertal level - Undetectable hCG - High testosterone

Question 41

Interpret the following profile for ddx of precocious puberty Symmetrical pubertal-sized testes - LH and FSH at prepubertal level - High hCG - High testosterone

Answer 41

hCG-producing germ cell tumor - LH and FSH at prepubertal level - High hCG - High testosterone

Question 42

Interpret the following profile for ddx of precocious puberty Symmetrical pubertal-sized testes - LH and FSH at prepubertal level - Undetectable hCG - High testosterone

Answer 42

Familial testotoxicosis or McCune-Albright syndrome: autonomous testicle function

Question 43

Interpret the following profile for ddx of precocious puberty Symmetrical pubertal-sized testes - Pubertal LH and FSH - Suppressed/ undetectable hCG - High testosterone

Answer 43

Central precocious puberty

Question 44

Interpret the following profile for ddx of precocious puberty asymmetrical testicular enlargement - LH and FSH at prepubertal level - Testosterone at pubertal level

Answer 44

Functioning testicular tumor

Question 45

Interpret the following profile for ddx of precocious puberty Symmetrical, prepubertal-sized testicles - Prepubertal LH and FSH - High testosterone - 17-OH-progesterone

Answer 45

CAH, NCAH or adrenal tumor

Question 46

Interpret the following profile for ddx of precocious puberty Symmetrical, prepubertal-sized testicles - Prepubertal LH and FSH - Isolated high testosterone

Answer 46

Exogenous testosterone

Question 47

central precocious puberty - Indication for treatment - Treatment option - Route and timing of administration - Benefit

Answer 47

Reasons for treatment: 1. Preservation of adult height potential 2. Psychological difficulties with early puberty and menarche Option: GnRH analogues (leuprolide acetate) - Provides constant serum levels of GnRH activity and overrides pulsatility of endogenous GnRH IM injection once every 4 weeks Benefit in preserving/ increasing adult height

Question 48

Peripheral precocious puberty - Indication for treatment - Treatment option - Benefit

Answer 48

Indication: depends on cause  **Ovarian/ Adrenal Tumours**: surgical removal ± chemotherapy and/or radiation therapy  **Ovarian cysts**: drainage under USG guidance  **Exogenous oestrogens/ androgens**: uncover and eliminate  Non-classical CAH: exogenous glucocorticoid Additional GnRH agonist if central puberty starts concomitantly

Question 49

Premature thelarche - Definition - S/S - Progression - Ix

Answer 49

- isolated breast development in girls between 2-7 years S/S: - 50% bilateral - Volume: **Tanner stage B2, B3** - **Tender breasts** - No discharge (c.f. genital crisis of newborn with milk production) Progression: - Spontaneous remission over 18 months - Persistent - Aggravate breast development with increased bone maturation Ix for persistent thelarche: **LHRH test – predominant FSH response**

Question 50

Premature adrenarche/ pubarche: - Definition - Gender predominance - Effect on growth - S/S

Answer 50

appearance of **pubic hair before 8 years old** More common in girls Effect: Slight increase Growth velocity and bone age maturation **Significant Maturation of adrenal function** S/S of hyperandrogenism: - **acne, abnormal perspiration, clitoral hypertrophy, oily skin**

Question 51

Premature adrenarche/ pubarche: Complication Ix for ddx

Answer 51

Complication: - **PCOS** (20% risk) - Exaggerated adrenarche: presents as subtle androgen excess and **insulin resistance (central adiposity, acanthosis nigricans)** Ix to Exclude congenital adrenal hyperplasia: - Androgen work-up: **high testosterone, high 17-OH-P, high DHEA** - **synacthen test: Low cortisol**

Question 52

exaggerated adrenarche - Effect on growth - S/S - Complication - Ix

Answer 52

Growth: Slightly advanced onset of true puberty **Height potential not compromised** S/S: Subtle androgen excess: **significant bone age advancement but not clitoromegaly** **Insulin resistance (central adiposity, acanthosis nigricans)** Complications - **PCOS** Ix: **Adrenal steroid levels - mid to late pubertal range/ high** Testosterone: under adult female range

Question 53

Isolated premature menarche - Definition - Effect on growth - S/S

Answer 53

menstruation without other signs of puberty in a young girl before 9 years of age Effect: - Menstruation may recur cyclically - Transient ovarian activity >> Rise in oestrogenization >> accelerated bone maturation +/- breast development S/S:  Foreign body  Local masses  McCune- Albright syndrome

Question 54

Isolated premature menarche Ix Tx

Answer 54

Ix:  **Inconsistent response to LHRH test**  **Functional ovarian cysts on UG pelvis** Tx:  Observe with close **longitudinal follow-up**  Stop puberty (rarely undertaken)