JC112 (Paediatrics) - Premature Puberty: Puberty & Related Disorders Flashcards
Hormonal changes that start onset of puberty
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
Describe the gonadal development during puberty
Under LH and FSH pulses:
1. Ovaries: follicular development, produce oestrogen for breast development, enlargement of uterus
- Testes: stimulate Sertoli cells, Leydig cells produce testosterone»_space; penile and scrotal development
- direct effect on growth plate, and indirect action by stimulation of growth hormone
Factors that modulate the onset of puberty
- Genetic factors
- Peripheral signs: intrauterine and postnatal growth, BMI and fat mass, insulin sensitivity, gonadal steroid levels
- Environmental signals: light, stress, environmental endocrine disruptors
Female puberty
- Age of puberty onset
- Signs of puberty onset
- Timing of secondary sexual characteristics
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
Male puberty
- Age of puberty onset
- Signs of puberty onset
- Timing of secondary sexual characteristics
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
Gynaecomastia in puberty
- Cause
- Progression of breast tissue in puberty
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
Definition of precocious puberty
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
Major causes of precocious puberty
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
Explain how primary hypothyroidism causes precocious puberty
Primary hypothyroidism»_space; Increase TSH acts as weak agonist on FSH receptors»_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
Effect of central precocious puberty on growth
accelerated bone maturation causes early fusion of bone plates
compromises final adult height
Central precocious puberty
- Effect on puberty development
- Common causes
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
Precocious pseudopuberty
- Definition
- Hormonal disturbances
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»_space; very high sex steroid concentrations despite low gonadotropins
Sex steroid disturbance:
Isolated high androgen
Isolated high oestrogen
Combined androgen and oestrogen production
Causes of androgen overproduction in precocious pseudopuberty
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
Causes of estrogen overproduction in precocious pseudopuberty
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)
Name 2 syndromes associated with precocious pseudopuberty
McCune-Albright syndrome (MAS)
Familial testotoxicosis/ familial male-limited precocious puberty (FMPP)
McCune-Albright syndrome
- Predominant gender
- Pathogenesis
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»_space; constitutive activation of adenylyl cyclase in multiple affected tissues: skin, bone, gonads
McCune-Albright syndrome
- Signs of sexual precocity in female and male
signs of sexual precocity
Female:
- Autonomously functioning luteinized follicular cysts of the ovaries»_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
McCune-Albright syndrome
Classical triad of symptoms and Diagnostic criteria
Diagnosis – >2 features present in classic triad:
- Irregularly-edged hyperpigmented macules/ café au lait spots
Characteristic features:
Jagged “coast of Maine” borders
Location respects midline of body (does not cross) - Polyostotic fibrous dysplasia (>1 bone is replaced by fibrous tissue»_space; weak bones, uneven growth, deformity)
- Multiple autonomous endocrinopathies:
- gonadotropin-independent sexual precocity (most common)
- Others: thyroid, adrenals, pituitary, parathyroids
Familial testotoxicosis/ familial male-limited precocious puberty (FMPP)
- Inheritance pattern
- Pathogenesis
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
Familial testotoxicosis/ familial male-limited precocious puberty (FMPP)
- Age of presentation
- Clinical presentation
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
Familial testotoxicosis/ familial male-limited precocious puberty (FMPP)
Hormonal disturbances
Investigations for confirmation of Dx
Treatment
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»_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
7 questions for formulating Ddx for abnormal puberty
- Onset of puberty
- Progression of clinical symptoms
- signs of exaggerated maturation: isosexual? Isolated sexual characteristics? Growth? Specific syndromal signs?
- Effects on predicted adult height/ Compromised final height?
- Psychological consequences
- Gonadotropin-dependent (precocious puberty) or independent cause (precocious pseudopuberty)
- Central precocious puberty: idiopathic or CNS lesion
Outline history taking questions for abnormal puberty
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
Effect of SGA on growth and development
SGA (small for gestational age)
more prone to precocious pubarche,
earlier onset of pubertal development and menarche
faster progression of puberty
Outline P/E for abnormal puberty and development
- Neurologic system (includes neurocutaneous markers, optic fundi, visual field)»_space; Central precocious puberty
- Endocrine system, thyroid examination (Primary hypothyroidism, Hyperprolactinemia, Adrenal hyperplasia/ tumor…)
- Tanner staging pubertal development – breast development, Testicle enlargement. Secondary sexual characteristics, signs of hyperandrogenism (virillization, oily skin, acne…)
- Scoliosis/ body asymmetry > imbalance in growth
- Growth chart*
6.
Growth chart patterns that suggest underlying pathologies
A rapid tempo of progression
Advanced development
Rapid linear growth
Advanced skeletal maturation
First-line investigations for abnormal puberty and development
- Hormonal profile: LH, FSH, oestradiol/testosterone, TFT, prolactin, β-hCG
- LHRH Test (Luteinizing Hormone Releasing Hormone)
- X-ray for bone age (bone maturation)
- MRI brain and pituitary gland with contrast - exclude CNS lesion
- 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) - Investigation for unilateral testicular enlargement: Imaging for androgen-producing tumour within the larger testis
- Investigation for bilateral testicular enlargement: Confirm CPP or FMPP
Ddx and confirmation tests for early pubarche only
early onset of pubic and axillary hair, acne
1) rapid growth and significantly advanced bone age»_space; 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)»_space; Idiopathic precocious puberty
- Prepubertal testosterone, Normal 17-OH-Progesterone, Pubertal level DHEAS
Ddx and confirmation tests for early thelarche (breast development) only
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»_space; Prepubertal / Low LH and FSH level + Pubertal/ high estradiol level
- Central precocious puberty»_space; Pubertal LH + FSH + Estradiol , Confirm with head MRI
Ddx and confirmation test for concurrent thelarche and pubarche
Central precocious puberty»_space; 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
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
Idiopathic precocious adrenarche
Interpret the following presentation:
- Pubarche only
- Rapid growth
- High testosterone, 17-OH- Progesterone and DHEAS
Most likely cause of precocious puberty
CAH, NCAH, adrenal tumor, exogenous androgen
Interpret the following profile:
- Thelarche only
- Normal growth
Most likely cause of precocious puberty
idiopathic precocious thelarche
Interpret the following profile:
- Thelarche only with rapid growth
- Prepubertal LH and FSH level
- Pubertal estradiol level
Most likely cause of precocious puberty
McCune-Albright syndrome
Exogenous source of estrogen
Interpret following profile:
- Thelarche only
- Rapid growth
- Pubertal LH and FSH
- Pubertal Estradiol level
Most likely cause of precocious puberty
Central precocious puberty
Interpret the following profile:
- Thelarche and pubarche present concurrently
- LH, FSH and Estradiol levels all at pubertal level
Most likely cause of precocious puberty
Central precocious puberty
Interpret following profile
Thelarche and pubarche
LH and FSH at prepubertal level
Estradiol and testosterone at pubertal level
Most likely cause of precocious puberty
Adrenal or ovarian tumor producing both estrogen and androgens
Ddx and confirmation test for Symmetrical, prepubertal-sized testicles in boys with precocious puberty
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
Ddx and confirmation test for asymmetrical testicular enlargement in boys
Functioning testicular tumor
- LH and FSH at prepubertal level
- Testosterone at pubertal level
- Confirm with testicular US
Ddx and confirmation test for symmetrical, pubertal-sized testes in boys
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
Interpret the following profile for ddx of precocious puberty
Symmetrical pubertal-sized testes
- LH and FSH at prepubertal level
- High hCG
- High testosterone
hCG-producing germ cell tumor
- LH and FSH at prepubertal level
- High hCG
- High testosterone
Interpret the following profile for ddx of precocious puberty
Symmetrical pubertal-sized testes
- LH and FSH at prepubertal level
- Undetectable hCG
- High testosterone
Familial testotoxicosis or McCune-Albright syndrome: autonomous testicle function
Interpret the following profile for ddx of precocious puberty
Symmetrical pubertal-sized testes
- Pubertal LH and FSH
- Suppressed/ undetectable hCG
- High testosterone
Central precocious puberty
Interpret the following profile for ddx of precocious puberty
asymmetrical testicular enlargement
- LH and FSH at prepubertal level
- Testosterone at pubertal level
Functioning testicular tumor
Interpret the following profile for ddx of precocious puberty
Symmetrical, prepubertal-sized testicles
- Prepubertal LH and FSH
- High testosterone
- 17-OH-progesterone
CAH, NCAH or adrenal tumor
Interpret the following profile for ddx of precocious puberty
Symmetrical, prepubertal-sized testicles
- Prepubertal LH and FSH
- Isolated high testosterone
Exogenous testosterone
central precocious puberty
- Indication for treatment
- Treatment option
- Route and timing of administration
- Benefit
Reasons for treatment:
- Preservation of adult height potential
- 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
Peripheral precocious puberty
- Indication for treatment
- Treatment option
- Benefit
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
Premature thelarche
- Definition
- S/S
- Progression
- Ix
- 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
Premature adrenarche/ pubarche:
- Definition
- Gender predominance
- Effect on growth
- S/S
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
Premature adrenarche/ pubarche:
Complication
Ix for ddx
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
exaggerated adrenarche
- Effect on growth
- S/S
- Complication
- Ix
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
Isolated premature menarche
- Definition
- Effect on growth
- S/S
menstruation without other signs of puberty in a young girl before 9 years of age
Effect:
- Menstruation may recur cyclically
- Transient ovarian activity»_space; Rise in oestrogenization»_space; accelerated bone maturation +/- breast development
S/S:
Foreign body
Local masses
McCune- Albright syndrome
Isolated premature menarche
Ix
Tx
Ix:
Inconsistent response to LHRH test
Functional ovarian cysts on UG pelvis
Tx:
Observe with close longitudinal follow-up
Stop puberty (rarely undertaken)
