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Disorders of Early Sexual Maturation

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Concerns Raised by Precocious Puberty Possibly sinister underlying cause Psychologically unacceptable embarrassment of inappropriate early sexual changes, ... – PowerPoint PPT presentation

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Title: Disorders of Early Sexual Maturation


1
Disorders of Early Sexual Maturation
  • Assunta Albanese
  • St Georges Hospital
  • London

2
PUBERTY
  • Gonadal maturation with acquisition of secondary
    sexual characteristics and associated growth
    spurt
  • FERTILITY AND FINAL HEIGHT

3
Normal Puberty
  • GIRLS BOYS
  • - Thelarche - Testarche
  • - Pubarche - Pubarche
  • - Growth spurt - Growth spurt
  • - Menarche - Spermarche

4
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

5
Tanners Staging of Puberty in Girls
6
Tanners Staging of Puberty in Boys
7
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8
"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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10
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)

11
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

12
Central Precocious Puberty
  • 1 in 5000 children FgtM (x5-6)
  • Idiopathic
  • Secondary to CNS abnormalities
  • Congenital anomalies (hydrocephalus)
  • Tumours
  • Acquired (infections, surgery, irradiation)

13
Central Precocious Puberty
  • Sexual Dimorphism
  • Usually idiopathic in girls (90)
  • Almost always secondary to lesions in CNS in boys

14
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

15
Patterns of LH Secretion During Pubertal
Development
16
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

17
LH, FSH and E2 and Pubertal Stage in Girls
18
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

19
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20
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21
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

22
Variants of Precocious Sexual Maturation
  • Isolated premature thelarche and thelarche
    variants
  • Isolated menarche
  • Premature adrenarche

23
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

24
Sexual Spectrum
mixed characteristics
Isolated thelarche
Precocious puberty
25
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
26
Variants of Precocious Sexual Maturation
  • Isolated premature thelarche and thelarche
    variants
  • Isolated menarche
  • Premature adrenarche

27
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

28
Variants of Precocious Sexual Maturation
  • Isolated premature thelarche and thelarche
    variants
  • Isolated menarche
  • Premature adrenarche

29
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

30
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

31
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

32
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

33
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34
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

35
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36
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

37
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

38
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

39
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)

40
Evaluation of Premature Sexual Maturation
  • CLINICAL ASSESSMENT
  • History
  • Behavioural changes
  • Pubertal staging
  • Skin examination
  • Height measurement / Growth velocity
  • Bone age assessment

41
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

42
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

43
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

44
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


45
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

46
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

47
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)

48
  • Why treat precocious puberty?

49
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

50
Why treat precocious puberty?
  • To prevent psychosocial distress
  • To improve final height outcome

51
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

52
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

53
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
54
Treatment of Gonadotrophin Independent Precocious
Puberty in Male
  • Testolactone associated with Spironolactone
  • Ketoconazole
  • 3rd generation Aromatase inhibitors

55
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

56
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

57
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

58
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