Paediatrics JC112: Premature Puberty: Puberty And Related Disorders

Question 1

Normal puberty development

Answer 1

• ***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

2. Peripheral signs
   - intrauterine / postnatal growth
   - BMI + fat mass
   - insulin sensitivity
   - gonadal steroid levels
3. 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

Question 2

Hypothalamic-pituitary-gonadal axis

Answer 2

• 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

Question 3

***Normal pubertal development in girls

Answer 3

• 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

Question 4

***Normal pubertal development in boys

Answer 4

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

Question 5

Precocious puberty

Answer 5

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

Question 6

NOT all presentations of precocious puberty are TRUE precocious puberty

Answer 6

• 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

Question 7

Adrenal / Ovarian cause of precocious puberty

Answer 7

• 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

Question 8

Variations of normal puberty development

Answer 8

1. Premature thelarche
2. Premature adrenarche / pubarche
3. Isolated premature menarche

Question 9

1. Premature thelarche

Answer 9

• 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)

Question 10

2. Premature adrenarche / pubarche

Answer 10

• 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

Question 11

3. Isolated premature menarche

Answer 11

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

Question 12

Primary hypothyroidism and Precocious puberty

Answer 12

• 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

Question 13

Pathological causes of Precocious puberty

Answer 13

1. Central precocious puberty (CPP)
2. Precocious pseudopuberty

Question 14

1. Central precocious puberty (CPP)

Answer 14

• 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

Question 15

***2. Precocious pseudopuberty

Answer 15

• 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

2. Androgen overproduction in boys
   - **Leydig cell tumours
   - **McCune-Albright syndrome
   - ***Familial testotoxicosis
3. Androgen overproduction in girls + boys
   - **Non-classical (Late-onset) congenital adrenal hyperplasia (CAH)
   - Androgen-secreting **adrenal tumours
4. Estrogen overproduction in girls
   - Ovarian cysts
   - **Granulosa cell tumours
   - **McCune-Albright syndrome
5. Estrogen overproduction in boys
   - ***Sertoli cell tumours

Question 16

***McCune-Albright syndrome

Answer 16

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

Question 17

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

Answer 17

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

Question 18

Evaluation of abnormal puberty

Answer 18

1. Onset of puberty before 7 in girls / 9 in boys
2. Any rapid tempo of pubertal progression?
3. ***Any biological / radiographic signs of exaggerated maturation?
4. ***Predicted adult height affected? ((sum of parents height +/- 13) / 2) (+13 for boys, -13 for girls)
5. Any psychological consequences?
6. ***Gonadotropin-dependent / independent?
7. Any cafe au lait patches, bony deformity, other endocrinopathies?
8. If CPP, is it due to tumour / idiopathic?

Question 19

History taking in Precocious puberty

Answer 19

1. Birth history
   - ***SGA (more prone to precocious pubarche, earlier onset of pubertal development and menarche and faster progression of puberty than children born AGA)
2. Past medical history
   - **past x-rays
   - **brain trauma
   - ***neonatal infection of CNS
3. Family history
   - **precocious puberty
   - **mid-parental height
4. Precise timing + Sequence of pubertal milestones
5. Impact on psychological health / wellbeing

Question 20

P/E in Precocious puberty

Answer 20

1. ***Neurologic examination
   - Optic fundi
   - Visual field
2. ***Thyroid exam
3. ***Stages of pubertal development - Tanner stages
4. Neurocutaneous markers
5. Scoliosis / body asymmetry
6. ***Assessment of growth chart (for subtle changes in growth velocity)

Question 21

Tanner stages of pubertal maturation

Answer 21

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

Question 22

Findings suggestive of pathology

Answer 22

1. Rapid tempo of progression
2. Advanced development
3. Rapid linear growth
4. Advanced skeletal maturation

Question 23

***Investigations of Precocious puberty

Answer 23

1. ***Hormonal profile
   - LH, FSH
   - Estradiol / Testosterone
   - TFT
   - Prolactin
   - β-hCG
2. ***X-ray for bone age / maturation
3. ***LHRH test (if LH rise to pubertal level —> GnRH-dependent precocity (i.e. CPP))
4. Pelvic USG in girls
5. ***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

Question 24

***Diagnostic algorithm of precocious puberty in girls

Answer 24

Pubarche only
1. Rapid growth + Advanced BA
—> ↑ Testosterone, ↑ 17-OHP, ↑ DHEAS, Adrenal USG, Ovarian USG
—> **CAH / NCAH / **Adrenal tumour / ***Exogenous source of androgen

2. 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

2. 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

Question 25

***Diagnostic algorithm of precocious puberty in boys

Answer 25

Symmetrical prepubertal-sized testes (說明Testosterone由其他地方製造)
1. Prepubertal LH + FSH, ↑ Testosterone, ↑ 17-OHP
—> **CAH / NCAH / **Adrenal tumour

2. Prepubertal LH + FSH, ↑ Testosterone
   —> Exogenous source of testosterone

Asymmetrical testes
—> Pre-pubertal LH + FSH, Pubertal Testosterone
—> Testicular etiology
—> ***Functioning testicular tumour

Symmetrical pubertal-sized testes
1. Pubertal LH + FSH, undetectable hCG, ↑ Testosterone
—> CPP

2. Prepubertal LH + FSH, ↑ hCG, ↑ Testosterone
   —> hCG producing germ cell tumour
3. Prepubertal LH + FSH, undetectable hCG, ↑ Testosterone
   —> **FMPP / **MAS

Question 26

***Treatment of precocious puberty

Answer 26

Depend on whether Central vs Peripheral precocious puberty

CPP:
- Reasons: Preservation of adult height potential + Psychological difficulties with early puberty + menarche
- Not all cases require treatment
- **GnRH analogues
—> provide constant serum level of GnRH activity
—> **override pulsatility of endogenous GnRH
—> Depot IM ***Leuprolide acetate once every 4 weeks

Outcome:
- adult height preservation esp. in girls <6 yo with greatest ↑ in adult height after treatment
- those between 6-8 yo form a more heterogeneous group
—> some with very rapid / advanced puberty may benefit
—> many with slowly progressive puberty yield a normal height outcome without treatment
- little utility to treat girls >8 yo for purpose of ↑ adult height

Peripheral:
- Depends on cause
1. Surgical removal of tumours +/- Chemo +/- RT as indicated
2. Large ovarian cyts: Drainage under USG guidance
3. Exogenous estrogens / androgens: uncovered + eliminated
4. Non-classical CAH: Exogenous glucocorticoid
5. GnRH analogue may be needed in addition to any of above if CPP concomitantly starts at early age

Question 27

Delayed puberty and Hypogonadism (SpC Revision)

Answer 27

Delayed puberty:
- Temporary delay in sexual maturation is not uncommon
- Most common cause of delayed puberty is ***constitutional delay in growth and puberty, with slower tempo than usual
- Usually resolves with time leading to normal development, optimum final height and fertility

Refer for assessment if:
1. Delayed puberty
- No sign of puberty in girls >13 yo / boys >14 yo

2. Pubertal arrest
   - >4 years have passed between initial breast development and menarche in girls / between onset and completion of genital development in boys

Goal of assessment:
- To determine whether the delay is just a lag in normal pubertal maturation or an abnormality
that must be investigated

Causes:
1. Constitutional delay in growth and puberty
2. Secondary / Functional hypogonadotropic hypogonadism (as a result of chronic illness / malnutrition)
3. Primary hypogonadotropic hypogonadism
4. Hypergonadotropic hypogonadism

Evaluation:
History taking:
1. Perinatal history
2. Family history (parental height, ages of pubertal milestones)
3. Growth history
4. Chronic illness
5. Previous treatment / surgery
6. Medications
7. Other hormonal deficiency / excess
8. Sense of smell (Kallmann syndrome)
9. Abnormal eating pattern
10. Excessive exercise

P/E:
1. Present + Past heights, weights (with pubertal staging)
2. Body proportion (estimation of upper + lower body segments)
3. Midline facial defects
4. Dysmorphic features (suggestive of a syndrome)
5. Neurological examination
6. Evidence of underlying / associated condition (e.g. Hypothyroidism, Galactorrhoea)

Investigations:
1. Bone age
2. Biochemical tests
- Screen for occult disease
- Gonadotropins, Estradiol, Testosterone
- Morning cortisol, TFT, Prolactin
- Karyotype (if elevated gonadotropins)
- Anti-ovarian Ab
3. GnRH test / Combined pituitary stimulation test
4. hCG stimulation test (assess testicular Leydig cell function in boys)
5. MRI brain (for hypogonadotropic hypogonadism)
6. Pelvic / Scrotal USG
7. Surgical exploration for gonadal tissue

Question 28

Delayed sexual development and hypogonadism in girls

Answer 28

1. Delayed sexual development
   - Lack of any breast development by 13 yo in girls
   or
   - >4 years have passed between initial breast development and menarche
2. Primary amenorrhoea
   - Absence of menarche by 14 years in girls with absent secondary sexual characteristics
   or
   - In girls who develop secondary sexual characteristics but fail to achieve menarche by 16 yo
3. Secondary amenorrhoea
   - Absence of menstruation for 3-6 months in women who have menstruated before

Question 29

Delayed sexual development and hypogonadism in boys

Answer 29

• Sexual development is delayed if no testicular enlargement by 14 years
  or
• > 4 years between onset and completion of genital development

Question 30

Constitutional delay in growth and puberty

Answer 30

• Delayed growth in healthy children who also manifest pubertal delay with a delayed bone age
• Often familial and more common in boys
• Accounts for about 60% of pubertal delay in boys and 30% in girls
• Typically with normal length and weight at birth and growing normally for a few years before a fall in growth centiles
• This is then followed by a normal childhood growth velocity and the child continues to grow along a low percentile curve with delayed puberty
• Spontaneous puberty occurs, allowing the child to become a normal adult

Investigations:
1. Blood will show Prepubertal LH, FSH, Estradiol / Testosterone
2. GnRH stimulation test show Prepubertal response
—> ∴ making it difficult to distinguish from a pathological gonadotropin deficiency unless a structural / biochemical abnormality of hypothalamic-pituitary axis is found

Treatment:
- Very occasionally a short low dose testosterone / estrogen treatment may be required when the child experiences serious psychological difficulties and low self-esteem relating to his / her short stature and physically infantile aspect

Question 31

Functional hypogonadotropic hypogonadism

Answer 31

• Chronic illness may have a significant impact on normal sexual development
• Children may not develop secondary sexual characteristics until the condition is identified + well-controlled —> reversible hypogonadism
• Pubertal delay usually accompanied by a delay in growth + an absent / blunted pubertal growth chart
• Extent to which growth and pubertal development are affected depends on:
  1. Type of disease
  2. Age at onset of illness
  3. Duration + Severity of illness

Causes:
1. Underlying chronic illness (GI, Cardiac, Renal, Respiratory, Anaemia, Endocrine (Hypothyroidism, Hyperprolactinaemia, Hypercortisolaemia), Psychiatric)
2. Recurrent infections
3. Prolonged medical treatment requiring glucocorticoids
4. Excessive emotional stress
5. Intense physical activity
6. Inadequate nutritional state

Treatment:
1. Depend on underlying condition
2. Sex steroid replacement (when treatment unavailable / unsuccessful for underlying condition)

Question 32

Primary hypogonadotropic hypogonadism

Answer 32

• Lack of any clinical manifestation of puberty by 13 years in girls / 14 years in boys, along with persistence of low LH + FSH levels

Congenital vs Acquired forms:
Congenital deficiency states:
- Isolated gonadotropin deficiency
- Effects on multiple levels of HPG axis (e.g. Adrenal hypoplasia congenita)
- Certain genetic syndromes
1. Prader-Willi syndrome
2. Noonan syndrome
3. CHARGE syndrome
4. Bardet-Biedl syndrome
5. Others

Acquired deficiency:
- From disorders affecting the brain e.g. tumours, malformations, head trauma, surgery, radiation, infections, infiltrative diseases
1. Suprasellar / Sellar solid tumour
- Craniopharyngioma most common in children
2. Trauma / Surgery / Radiation
3. Infiltration
- Hypophysitis
—> Lymphocytic
—> Granulomatous
—> Histiocytosis X
—> Wegener
—> Sarcoidosis
4. Infectious
- Meningoencephalitis

Question 33

Hypergonadotropic hypogonadism

Answer 33

• Elevated LH + FSH levels with delayed sexual development are indicative of a primary defect in gonadal function
• Hypothalamic-pituitary component of pubertal signaling has been activated through lack of -ve feedback normally exerted by sex steroids

Causes:
1. Congenital
- Chromosomal (Turner syndrome, Klinefelter syndrome)
- Ovarian / Gonadal dysgenesis
- LH / FSH resistance
- Other causes of primary ovarian failure (Autoimmune, Metabolic, PCOS, Anorchia, Cryptorchidism)

2. Acquired
   - RT / Chemo / Surgery (esp. orchidopexy for very highly placed testes) —> all result in gonadal failure

Question 34

Treatment of Permanent hypogonadism

Answer 34

Males:
- Reduced BMD, alterations in body composition, effects on mood, aggression, cognitive, sexual function, several factors important in CVS risk
1. Hormonal replacement
- Replacement of testosterone in a stepwise fashion —> mimic normal physiology
- IM long-acting testosterone esters monthly

2. GnRH therapy
   - Sex steroid alone will not be sufficient to initiate spermatogenesis in Hypogonadotropic hypogonadism
   - Pump-administered
   - Induce fertility (assuming intact pituitary gland)
3. Parenteral combination of Gonadotropin
   - hCG + recombinant FSH
   - If pituitary non-functioning

Females:
1. Hormonal replacement therapy
2. Pulsatile GnRH (to induce gonadotropin secretion) / Exogenous gonadotropin
- Current treatment of choice if fertility is desired