Paediatrics JC112: Premature Puberty: Puberty And Related Disorders Flashcards
Normal puberty development
- ***Kisspeptins from hypothalamus bind to GPCR called GPR54 on hypothalamic neurons —> secrete GnRH
Puberty onset:
- Central process with activation of GnRH pulse generator
—> Episodic ↑ GnRH
—> Anterior pituitary to secrete pulses of FSH + LH (Gonadotropins)
—> Ovaries: Follicular development + Estrogen secretion / Testes: Stimulation of Sertoli cells + Testosterone secretion
(***Revision: Initiation of puberty: ↑ in Pulsatile LH release)
Onset of puberty also modulated by:
1. Genetic factors
- Peripheral signs
- intrauterine / postnatal growth
- BMI + fat mass
- insulin sensitivity
- gonadal steroid levels - Environmental signals
- light
- stress
- environmental endocrine disruptors
Estrogen:
- **breast development
- enlargements of uterus
- **direct effect on growth plate + indirect stimulation of GH
—> sexual maturation + growth spurt
Testosterone:
- **penile + scrotal development
- **direct effect on growth plate + indirect stimulation of GH
—> sexual maturation + growth spurt
Hypothalamic-pituitary-gonadal axis
- Gonadotropin release controlled by GnRH
- Selective -ve feedback inhibition of Gonadal steroids at pituitary + hypothalamic levels
Prepuberty:
- Low + Infrequent GnRH pulse
- Low FSH / LH
Puberty:
- ↑ **Amplitude + **Frequency of GnRH pulse
- Suppression of GnRH pulse with ***long-acting GnRH analogue (Leuprolide) in treatment of precocious puberty —> Suppression of FSH / LH
***Normal pubertal development in girls
- Puberty starts in both sexes around ***11 yo
- More evident in girls ∵ breast development + onset of growth spurt
Breast development:
- caused by **Estrogen
- may be **unilateral for several months
Pubic + Axillary hair growth:
- caused by ***Adrenal androgens (but stage of breast development usually correlates well with stage of pubic hair development)
Growth:
- accelerates as breast development starts
- peak height velocity attained 6-9 months after Breast Tanner stage 2
Menarche:
- **2-2.5 years after breast budding (B2)
- first menstrual bleeding are **anovulatory
- time from menarche to regular cycling ~3 years
- average girl will grow for another 6-7cm after menarche
Mean ages based on Tanner stages for breast development (B), pubic hair (P)
- **Breast buds (B2): 10.1 (but urban Chinese may have earlier breast development than currently used norms)
- **Sparse pubic hair (P2): 11.2
- Darker, coarser pubic hair growth (P3): 12.2
- **Growth spurt: 12.2
- **Menarche: 12.7
- Adult pubic hair type / quantity (P5): 14
- Mature breast (B5): 14
記: Breast bud —> Pubic hair —> Growth spurt —> Menarche
***Normal pubertal development in boys
Testicular development:
- 1st sign of puberty: **↑ Testicular volume to 4ml (∵ enlargement of Sertoli cells rather than Leydig cells)
- Growth of penis / genitalia correlate well with pubic hair development (∵ **both regulated by Androgen (vs female: estrogen regulate breast while adrenal androgen regulate pubic hair))
- Spermatogenesis histologically from **11-15 years
- Sperm found in early morning urine at mean of 13.3 years
- Ejaculation occurs by mean of **13.5 years
- Adult morphology, motility, concentration of sperm not found until bone age advances to 17 years but immature-appearing boys can be fertile
Prader orchidometer (一抽珠):
- determine testicular volume
Growth spurt:
- peak during **mid-puberty
- mean **13.5 years (testicular volume 10-12ml)
Breast:
- enlargement common during early puberty ∵ ↑ Estrogen production by ***aromatisation of testosterone before testosterone achieves concentrations that can oppose estrogen
- breast tissue often regress within 2 years
- occasionally gynaecomastia remains permanent in normal, often obese boys and frequently in pathological conditions e.g. Klinefelter syndrome / Partial androgen resistance, in which effective amount of bioactive testosterone is reduced
(But some studies have found that pubertal onset in urban Chinese boys is earlier than currently used norms)
記: Testes / Penis —> Spermatogenesis / Ejaculation —> Growth spurt
Precocious puberty
Definition: Onset of puberty at younger age than expected for normal population (>2 SD earlier than population mean)
- pubertal signs before **8 yo for girls / **9 yo for boys have been considered precocious classically
LWPES:
- recommend lowering age cutoff: <7 in white girls, <6 in black girls
- pubertal onset should be evaluated if:
—> unusual rapid pubertal progression resulting in bone age **advancement by >2 years + **predicted height <150 cm / >2 CD below genetic target height
—> S/S of a CNS lesion
—> behaviour-based factors suggesting the child’s emotional state adversely affected by early puberty and potential early menses
Sexual development in girls <8 / boys <9:
- Thorough history + P/E
- ***Bone age
- Close longitudinal follow up
- Necessity for / type of treatment will usually require input from specialist
- NOT all organic etiologies / normal variants require treatment
Causes:
1. Central (Hypothalamic / Pituitary)
2. Adrenal / Ovarian
NOT all presentations of precocious puberty are TRUE precocious puberty
- Can be Variations of normal puberty development
- 50-60% only 1 secondary sexual characteristic shows premature development
—> Isolated premature thelarche (breast development)
—> Isolated premature adrenarche (i.e. pubic hair)
—> Isolated premature menarche (rarer)
Ethology should be sought + Monitoring to prevent precocious onset of puberty
Adrenal / Ovarian cause of precocious puberty
- 10%
- Autonomous hyperproduction of estrogen —> **Precocious pseudopuberty **independent of gonadotropin activation
Hyperestrogenism:
- may have exogenous cause e.g. environmental chemical pollutants in air, water, food chain —> endocrine disruptors (***xenoestrogens)
- xenoestrogens have a chemical structure that mimic actions of natural estrogens by stimulating activity of target tissues
Variations of normal puberty development
- Premature thelarche
- Premature adrenarche / pubarche
- Isolated premature menarche
- Premature thelarche
- Isolated breast development in girls 2-7 yo
- Bilateral in 50% cases, unilateral, asymmetric (less frequently)
- Volume varies: 60% B2, 30% B3, 10% B4
- Breast often **tender, palpation **painful
- No discharge
- If persistent / marked thelarche —> **LHRH test (LHRH = GnRH) —> LHRH test show predominant **FSH response
- Bone maturation ***rarely accelerated
- Progression characterised by fluctuation over time: spontaneous remission / persistence / aggravation of breast volume (evoke possibility of pubertal onset)
- 30-60% regress within average 18 months
- Usually do ***NOT require any treatment
Precocious puberty vs Genital crisis of newborn (whose breast development associated with strong estrogenisation / even milk production may last for first 18 months of life)
- Premature adrenarche / pubarche
- Appearance of pubic hair <8
- more commonly in girls than boys
- usually isolated but occasionally axillary hair observed
- clinical exam to detect other signs of ***hyperandrogenism: acne, abnormal perspiration, clitoral hypertrophy
- growth velocity / bone age maturation usually only slightly accelerated
Investigations:
- **Androgen workup (Testosterone, 17-OH progesterone, DHEAS) +/- **Synacthen test —> to exclude **CAH (Synacthen test: show **high level of 17-OH progesterone but low level of cortisol / aldosterone)
- most situations: maturation of adrenal function that precedes puberty is accelerated / early (reason remains unknown)
Exaggerated adrenarche:
- extreme type of premature adrenarche
- girls with subtle androgen excess (e.g. significant bone age advancement but not clitoromegaly) / insulin resistance (e.g. central adiposity / acanthosis nigricans)
- often with **slightly advanced onset of true puberty, but **height potential not compromised
- adrenal steroid levels in mid / late-pubertal range
- testosterone not exceeding lower end of adult female range
- still ***unclear whether Premature adrenarche is a normal variant
—> ∵ advanced onset of normal zona reticularis development / early manifestation of steroidogenic dysregulation of PCOS with ↑ cardiometabolic risk factors
Prognosis:
- premature pubarche carries 15-20% risk of developing ***PCOS (∵ androgen excess) (esp. in exaggerated adrenache)
Management:
- girls with premature adrenarche should be ***followed through puberty
- Isolated premature menarche
Menstruation without other signs of puberty in a young girl before 9 yo
- **poorly defined / understood
- **etiology often unknown
- must exclude foreign body, local masses, ***McCune-Albright syndrome
- transient ovarian activity has been observed
Clinical features:
1. Menstruation isolated / associated with breast development, with **inconsistent response to LHRH test + frequent presence of functional ovarian cysts
2. Menstruation may recur cyclically
—> ↑ estrogenisation ↑ risk of **accelerated bone maturation
Management:
- Treatment to stop puberty often discussed but rarely undertaken
- ***Observe + close longitudinal follow up
Primary hypothyroidism and Precocious puberty
- TSH ↑ —> weak agonist at FSH receptor —> ***ovarian stimulation with isolated breast development in girls
- Boys: ***testicular enlargement without other secondary sexual characteristics may occur
- No pubertal progression in majority of cases
- **Delayed bone age with **poor growth velocity
- Excellent prognosis with reversal of puberty once treatment started but final height may be affected if diagnosis delayed / if normal puberty progresses at early age
Pathological causes of Precocious puberty
- Central precocious puberty (CPP)
- Precocious pseudopuberty
- Central precocious puberty (CPP)
- Caused by Hypothalamus / Pituitary problems
- Only 10-20% of presentations of precocious puberty
- **Must exclude CNS tumour (esp. in **boys)
- Progresses rapidly —> **accelerated bone maturation —> early fusion of bone plates —> **compromising final adult height
- Isosexual premature pubertal development but with pubertal changes ***appropriate for sex of the child (e.g. sex budding in girls / testicular enlargement in boys)
- results from activation of HPG axis at an ***earlier age
Etiology:
1. Idiopathic (>=80% in girls, 10% in boys)
2. **Tumours arising in suprasellar region, with / without **pituitary hormonal deficiencies (usually anterior) (most concerning)
3. Benign hypothalamic hamartoma (classic triad: Gelastic seizures, Precocious puberty, Developmental delay) (most common cause of CPP in very young child)
4. Others
- **Cranial irradiation
- **Hyperprolactinaemia
- **Previous meningoencephalitis
- **Major head trauma
Investigations:
- need to exclude underlying CNS lesion
***2. Precocious pseudopuberty
- Gonadal / Adrenal sex steroid secretion **not resulting from activation of HPG axis (i.e. **pituitary-independent / ***peripheral in origin)
- Loss of normal feedback
- **Sex steroid concentrations can be very high + **Low gonadotropins
- Can involve isolated androgen / isolated estrogen / combined androgen + estrogen production
Causes:
1. Androgen overproduction in girls
- Ovarian arrhenblastomas
- Ovarian hyperthecosis
- Androgen overproduction in boys
- **Leydig cell tumours
- **McCune-Albright syndrome
- ***Familial testotoxicosis - Androgen overproduction in girls + boys
- **Non-classical (Late-onset) congenital adrenal hyperplasia (CAH)
- Androgen-secreting **adrenal tumours - Estrogen overproduction in girls
- Ovarian cysts
- **Granulosa cell tumours
- **McCune-Albright syndrome - Estrogen overproduction in boys
- ***Sertoli cell tumours
***McCune-Albright syndrome
記: Absent LH response to GnRH —> 自動放Estrogen / Testosterone
Multisystem disorder of both boys + girls (but much more commonly in girls)
Triad of:
1. Irregularly edged hyperpigmented macules / **Cafe au lait spots with **“coast of Maine” jagged borders, location **not cross midline of body (vs coast of California in Neurofibromatosis)
2. **Polyostotic fibrous dysplasia (bone is replaced by fibrous tissue —> weak bone, uneven growth)
3. **Multiple autonomous endocrinopathies
- most commonly **gonadotropin-independent sexual precocity
- other endocrine involvement: thyroid, adrenals, pituitary, parathyroids
—> ***>=2 of above features should be present for diagnosis
Pathogenesis:
- Sporadic condition ∵ somatic activating missense mutation in gene encoding α subunit of G-protein that stimulate cAMP production
—> Mutation occurs early in embryogenesis (somatic / postzygotic instead of germ cell in origin)
—> Failure of phosphorylation from GTP to GDP
—> ***constitutive activation of Adenylyl cyclase in multiple affected tissues
- Mutation can occur in skin, bones, liver (cholestasis), heart (arrhythmias), GI tract
Sexual precocity in girls:
- caused by **autonomously functioning luteinised follicular cysts of ovaries
- multiple follicular cysts (with an occasional large solitary cyst may be present)
- estrogen production is associated with a **prepubertal pattern of LH secretion with ***absent LH response to GnRH
- later GnRH-dependent puberty ensues with ovulatory cycles
Sexual precocity in boys:
- rare in boys with MAS
- but when it occurs it is associated with ***asymmetric enlargement of testes + signs of sexual precocity
Familial testotoxicosis / Familial male-limited precocious puberty (FMPP)
記: LH自動activate —> 放Testosterone
- Rare familial condition
- **Gonadotropin-independent precocious puberty **only in boys
- often presenting at 2-5 yo with accelerated growth, early secondary sexual characteristics, reduced adult height
- Testes: only ***little ↑ in size
- Biopsy: ***Leydig cell hyperplasia
Treatment:
- ***Androgen-receptor blocking agents (Ketoconazole) / Aromatase inhibitors
Inheritance:
- **AD inheritance only in males
- associated with a number of **constitutively activating mutations of LH receptor, mostly in transmembrane domain of receptor
Clinical features:
- FMPP associated with **premature Leydig + Germinal cell maturation
- Virilisation with **very high concentrations of Testosterone + ***enlargement of Testes to early / mid-pubertal range (although smaller than expected in relation to stage of penile growth)
Investigations:
- Extensive lab evaluation to localise source of testosterone secretion to testes
- **Testicular biopsy: premature maturation of Leydig cells + Spermatogenic elements
- Unstimulated gonadotropin concentrations are **prepubertal with **minimal response to GnRH stimulation
- **Lack of usual pubertal pattern of LH pulsatility
- But fertility, a normal pattern of LH secretion, response to GnRH are demonstrated in adulthood
Evaluation of abnormal puberty
- Onset of puberty before 7 in girls / 9 in boys
- Any rapid tempo of pubertal progression?
- ***Any biological / radiographic signs of exaggerated maturation?
- ***Predicted adult height affected? ((sum of parents height +/- 13) / 2) (+13 for boys, -13 for girls)
- Any psychological consequences?
- ***Gonadotropin-dependent / independent?
- Any cafe au lait patches, bony deformity, other endocrinopathies?
- If CPP, is it due to tumour / idiopathic?
History taking in Precocious puberty
- Birth history
- ***SGA (more prone to precocious pubarche, earlier onset of pubertal development and menarche and faster progression of puberty than children born AGA) - Past medical history
- **past x-rays
- **brain trauma
- ***neonatal infection of CNS - Family history
- **precocious puberty
- **mid-parental height - Precise timing + Sequence of pubertal milestones
- Impact on psychological health / wellbeing
P/E in Precocious puberty
- ***Neurologic examination
- Optic fundi
- Visual field - ***Thyroid exam
- ***Stages of pubertal development - Tanner stages
- Neurocutaneous markers
- Scoliosis / body asymmetry
- ***Assessment of growth chart (for subtle changes in growth velocity)
Tanner stages of pubertal maturation
Breast
1: Prepubertal
2: ***Breast budding
3: Continued enlargement of both breast + areola without separation of their contours
4: Areola, nipple form a secondary mound projecting above breast contour
5: Adult shape, areola and nipple recessed to breast contour
Pubic hair
1: Prepubertal
2: ***Sparse growth
3: Additional darkening + coarsening of hair, spreading over pubic symphysis
4: Adult in character but confined to suprapubic area in males / females
5: Adult in distribution with spread to medial thighs in males / females, may extend to lower abdomen in males
Male genitalia
1: Prepubertal
2: **Enlargement of testes + scrotum, **penis remain prepubertal, thinning + reddening of scrotal skin
3: Further growth / enlargement of testes, scrotum, penis
4: Pigmentation of scrotal skin, maturation of glans
5: Testes, scrotum, penis are adult in size, shape
Findings suggestive of pathology
- Rapid tempo of progression
- Advanced development
- Rapid linear growth
- Advanced skeletal maturation
***Investigations of Precocious puberty
- ***Hormonal profile
- LH, FSH
- Estradiol / Testosterone
- TFT
- Prolactin
- β-hCG - ***X-ray for bone age / maturation
- ***LHRH test (if LH rise to pubertal level —> GnRH-dependent precocity (i.e. CPP))
- Pelvic USG in girls
- ***MRI contrast brain + pituitary
- exclude CNS lesion
- esp. in boys (∵ only 10% of CPP is idiopathic)
If Peripheral cause suspected:
1. USG pelvis + **adrenals
2. Measurement of **17-OH progesterone, **DHEAS, **Testosterone (esp. in girls with virilisation to screen for non-classical CAH)
3. **24-hour urine steroid profile
4. ACTH stimulation test (occasionally to assess adrenal function)
5. **24-hour urine free cortisol (if suspicious of Cushing syndrome)
Boys:
- if only 1 testis enlarged —> Radiological search for **androgen-producing tumour within larger testis is **mandatory
- if both testes enlarged —> Etiology most likely central, but FMPP must also be considered
***Diagnostic algorithm of precocious puberty in girls
Pubarche only
1. Rapid growth + Advanced BA
—> ↑ Testosterone, ↑ 17-OHP, ↑ DHEAS, Adrenal USG, Ovarian USG
—> **CAH / NCAH / **Adrenal tumour / ***Exogenous source of androgen
- Normal growth rate, mildly advanced BA
—> Normal Testosterone, 17-OHP, DHEAS
—> Idiopathic precocious puberty
Thelarche only
1. Normal growth rate + non-advanced BA
—> Idiopathic precocious puberty
- Rapid growth + significantly advanced BA
—> Prepubertal LH, FSH but Pubertal Estradiol —> **MAS / Exogenous source of Estrogen
—> Pubertal LH, FSH, Estradiol —> **CPP
Thelarche + Pubarche
—> Pubertal LH, FSH, Estradiol —> **CPP
—> Prepubertal LH, FSH but Pubertal Estradiol, Testosterone —> Adrenal / Ovarian tumour producing **both Estrogen + Androgen
