Disorders of Early Sexual Maturation

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Disorders of Early Sexual Maturation

• Assunta Albanese
• St Georges Hospital
• London

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PUBERTY

• Gonadal maturation with acquisition of secondary
  sexual characteristics and associated growth
  spurt
• FERTILITY AND FINAL HEIGHT

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Normal Puberty

• GIRLS BOYS
• - Thelarche - Testarche
• - Pubarche - Pubarche
• - Growth spurt - Growth spurt
• - Menarche - Spermarche

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PUBERTY

• Average age of onset
• 11.4 years in girls
• 12.0 years in boys
• First signs of pubertal maturation
• breast budding in girls
• increase in testicular volume in boys

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Tanners Staging of Puberty in Girls
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Tanners Staging of Puberty in Boys
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"Consonance" of Puberty

• Close relationship between secondary sexual
  characteristics and pubertal growth spurt
• In girls the pubertal growth spurt occurs early
  in puberty (B2-3)
• In boys the pubertal growth spurt occurs late in
  puberty (G3-4 10 ml testicular volume)

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Classification of Premature Sexual Maturation

• Gonadotrophin-Dependent (True Precocious
  Puberty)
• Gonadotrophin-Independent (Pseudo Precocious
  Puberty)
• Variants of Precocious Sexual Maturation
  (Premature thelarche / adrenarche isolated
  menarche)

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Gonadotrophin-Dependent

• Precocious Puberty
• Onset of puberty before
• 8 yrs in girls
• 9 yrs in boys
• Early Puberty
• Onset of puberty between
• 8 - 9 yrs in girls
• 9 - 10 yrs in boys
• Primary Hypothyroidism

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Central Precocious Puberty

• 1 in 5000 children FgtM (x5-6)
• Idiopathic
• Secondary to CNS abnormalities
• Congenital anomalies (hydrocephalus)
• Tumours
• Acquired (infections, surgery, irradiation)

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Central Precocious Puberty

• Sexual Dimorphism
• Usually idiopathic in girls (90)
• Almost always secondary to lesions in CNS in boys

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Central Precocious/Early Puberty

• Pulsatile gonadotrophin secretion, especially
  overnight
• High LH FSH ratio
• Gonadal activation with sex steroid production
• Development of secondary sexual characteristics
• Normal "Consonance"
• Bone age acceleration
• Final height impairment

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Patterns of LH Secretion During Pubertal
Development
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Central Precocious/Early Puberty

• Pulsatile gonadotrophin secretion, especially
  overnight
• High LH FSH ratio
• Gonadal activation with sex steroid production
• Development of secondary sexual characteristics
• Normal "Consonance"
• Bone age acceleration
• Final height impairment

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LH, FSH and E2 and Pubertal Stage in Girls
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Central Precocious/Early Puberty

• Pulsatile gonadotrophin secretion, especially
  overnight
• High LH FSH ratio
• Gonadal activation with sex steroid production
• Development of secondary sexual characteristics
• Normal "Consonance"
• Bone age acceleration
• Final height impairment

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Primary Hypothyroidism

• Loss of "Consonance" between sexual maturation
  and growth spurt
• Absence of pubertal growth spurt
• Isolated breast development in girls
• Isolated testicular enlargement, with inadequate
  virilization

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Variants of Precocious Sexual Maturation

• Isolated premature thelarche and thelarche
  variants
• Isolated menarche
• Premature adrenarche

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Isolated Premature Thelarche

• Isolated cyclic breast enlargement
• Absence of other signs of puberty
• Absence of behavioural problems
• Normal growth and bone maturation
• Predominant FSH pulsatility
• Development of follicular ovarian cysts

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Sexual Spectrum
mixed characteristics
Isolated thelarche
Precocious puberty
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Spectrum Of Sexual Development Between Isolated
Premature Thelarche and CPP
Unsustained central precocious
puberty Intermediate sexual precocity Slowly
progressive variant of sexual precocious
puberty Thelarche variant Exaggerated
thelarche INTERMEDIATE CONDITIONS
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Variants of Precocious Sexual Maturation

• Isolated premature thelarche and thelarche
  variants
• Isolated menarche
• Premature adrenarche

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Isolated Menarche

• Absence of other signs of sexual maturation
• Menses can occur regularly for several yrs and
  then stop
• Puberty usually occurs at a normal time
• All causes of premature oestrogen secretion and
  local causes of vaginal bleeding must be excluded
• Due to ? increased sensitivity of endometrium to
  oestrogens
• Secondary to oestrogen production from a
  follicular cyst

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Variants of Precocious Sexual Maturation

• Isolated premature thelarche and thelarche
  variants
• Isolated menarche
• Premature adrenarche

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Premature Adrenarche (Pubarche)

• Usually begins at around 6-8 years of age
• Early appearance of pubic hair, with or without
  axillary hair
• Puberty usually occurs at a normal time
• Slight growth spurt and advance in bone
  maturation
• Final height prognosis is not compromised

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Premature Adrenarche

• Increased adrenal production of sex hormones
• Links with PCOS and hyperinsulinism in older age
• Clitoral virilization in girls and phallic
  enlargement in boys together with excessive bone
  age maturation should suggest excessive
  production of sex hormones due to CAH or an
  adrenal tumour

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Gonadotrophin-independent

• Sex steroid production from gonads or adrenal
  gland or exogenous source
• Suppressed LH and FSH levels
• Secondary sexual characteristics or virilization
  without testicular enlargement in boy
• Growth acceleration
• Bone age acceleration with final height impairment

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Gonadotrophin-independent

• Adrenal disorders
• Tumours secreting sex steroids
• Congenital adrenal hyperplasia
• Gonadal disorders
• Ovarian cyst/tumours secreting sex steroids
• Leydig cell tumour
• Exogenous sex steroids
• McCune-Albright Syndrome
• Testotoxicosis

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McCune - Albright Syndrome

• Fibrous dysplasia of skull and long bone
• "Cafe-au lait" patches with serrated edges
• Autonomous endocrine overactivity
• Precocious puberty
• Hyperthyroidism
• Hypercortisolism
• Pituitary adenomas secreting GH/ PRL
• Hyperparathyroidism

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McCune - Albright Syndrome

• PPP most common presenting feature
• autonomous, gonadotropin-independent ovarian
  function
• large ovarian cysts? ??E2 secretion
• Acute breast enlargement
• sudden onset of vaginal bleeding from cyst
  resolution and ?E2
• Natural history sporadic and unpredictable
• Concerns Continued 2o sexual development, freq.
  menstrual bleeds, ?GV and early fusion of
  epiphyses

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McCune - Albright Syndrome

• Gene mutation for the a-subunit of the G protein,
  which stimulate cAMP formation
• Activation of receptors that operate with a
  cAMP-dependent mechanism
• The somatic mutation occurs early in embriogenesis

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Testotoxicosis

• Occurs in boys, Familial, Autosomic Dominant
• Normal "Consonance" between sexual maturation and
  growth spurt
• Extreme degree of virilization compared to the
  testicular enlargement
• Prepubertal values of FSH and LH
• Failure to respond to GnRH analogue treatment
• Due to a mutation of LH receptor with constant
  activation of the G protein even without ligand

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Investigation of Premature Sexual Maturation

• The purpose of investigating precocious puberty
  is to distinguish between
• conditions that are benign (isolated thelarche or
  premature adrenarche)
• and
• those that require treatment (adrenal/gonadal
  adrenal tumours, CAH, central precocious puberty)

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Evaluation of Premature Sexual Maturation

• CLINICAL ASSESSMENT
• History
• Behavioural changes
• Pubertal staging
• Skin examination
• Height measurement / Growth velocity
• Bone age assessment

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Investigation in Suspected CPP

• Basal gonadotrophins
• Basal oestradiol in girls and testosterone
• GnRH stimulation test
• (Spontaneous overnight LH profile)
• TFT
• Pelvic USS in girls
• Neuroradiological imaging

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Gn-RH Stimulation Test

• LH and FSH response to Gn-RH
• LH predominance or
• a peak LH to FSH ratio of more than 0.66 or
• a LH peak more than 5 IU/L
• consistent with central activation of puberty

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Diagnostic Value of Pelvic USS

• Depend on experience of examiner!
• Size and shape of uterus and ovarian volume and
  appearance are a indicator of the degree of
  pubertal development

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Main Findings on Pelvic USS

• Ovarian enlargement with a volume more than 2 ml
• Larger bilateral ovarian cysts (gt 9 mls)
• Uterine length greater than 3.5 cm
• Fundus to cervix ratio of more than 1
• Endometrium thickness
• ARE INDICATIVE OF EARLY PUBERTY

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Investigations in Isolated Premature Thelarche

• In girls with breast development only, without
  acceleration of growth or bone age advancement
• Regular clinical follow-up to monitor growth
  velocity
• Investigation required only if precocious puberty
  is suspected

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Investigations in Isolated Adrenarche

• In children with early pubic/axillary hair and
  mild growth acceleration and bone age
  advancement
• Clinical monitoring
• 24 hour urine steroid profile
• Adrenal androgens and 17-OH P

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Investigations in Adrenarche

• Extensive and progressive virilization, as well
  as young age, requires investigation
• Urinary steroid profile (CAH/adrenal tumour)
• Basal A4, DHEA-S, 17-OH-P, Testosterone
• ACTH stimulation test (CAH)
• Dexamethasone suppression test (adrenal tumour)
• Adrenal imaging (adrenal tumour)

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• Why treat precocious puberty?

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Concerns Raised by Precocious Puberty

• Possibly sinister underlying cause
• Psychologically unacceptable embarrassment of
  inappropriate early sexual changes, excessively
  tall stature, early onset of periods in girls,
  vulnerability of young girls
• Long term sequelae short stature

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Why treat precocious puberty?

• To prevent psychosocial distress
• To improve final height outcome

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GnRH agonists

• Act like endogenous GnRH, with long term
  occupation of GnRH receptors leading to a
  desensitisation of the pituitary and lack of
  response to endogenous GnRH
• Depot formulations are available

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GnRH agonists

• Initial stimulatory effect may occur before
  inhibitory action
• Incomplete suppression is suggested by the
  persistence of behavioural problems, progression
  of sexual maturation, growth and bone maturation
  acceleration

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GnRH agonists

• Treatment with GnRHa can improve final height
• Height gain is positively correlated with
• Duration and height SDS for CA at the start of Rx
• Height gain is negatively correlated with
• Age at onset of puberty and at beginning of Rx
• Final height prediction based on BA overestimates
  final height

Discontinuation of treatment should be
individualised
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Treatment of Gonadotrophin Independent Precocious
Puberty in Male

• Testolactone associated with Spironolactone
• Ketoconazole
• 3rd generation Aromatase inhibitors

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Conclusions

• A good understanding of normal puberty is
  necessary to fully assess disorders of early
  sexual maturation
• Precocious puberty is not a single entity
• The commonest disorders of precocious puberty are
  idiopathic
• Physical exam, growth chart and bone age are
  important diagnostic tools

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Conclusions

• GnRH analogs are the therapy of choice for CPP
• GnRH analogs suppress elevated gonadotrophin and
  sex steroid levels, rates of linear growth and
  skeletal maturation associated with CPP and
  improve FH
• GnRH analogs are ineffective for
  gonadotrophin-independent precocious puberty

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Conclusions Testotoxicosis and McCune - Albright
Syndrome

• Rare conditions clinically heterogenous
• Activating mutation of Gsa gain of function
• Management PPP difficult ? mixed, sub-optimal
  response to date

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