Precocious Puberty – Long journey of gyn&obs

A SEVEN YEAR OLD GIRL IS BROUGHT TO THE CLINIC BECAUSE SHE HAS BEEN HAVING REGULAR MONTHLY BLEEDS FOR THE LAST 2 MONTHS DURATION.

WHAT IS THE WORKING DIAGNOSIS?

Precocious puberty

WHAT IS THE Definition OF ABOVE CONDITION?

Development of pubertal maturation (secondary sexual characteristics) before the age of 8 years.

WHAT IS THE ICNIDENCE OF ABOVE CONDITION?

Incidence: 1:5000 to 1:10000, with the female-to-male ratio being approximately 10:1.

WHAT ARE THE MAIN TYPES OF ABOVE CONDITION?

Central, true or gonadotrophin-dependent
- Peripheral, pseudo or gonadotrophin-independeny
  - Can be isosexual or heterosexual.
    - Isosexual – secondary sexual characteristics that are appropriate for the child’s sex
    - Heterosexual/contrasexual – secondary sexual characteristics are contrary to the phenotypic sex, i.e. there is virilisation in girls
- Isolated variants: precocious thelarche, pubarche or menarch

WHAT ARE THE CAUSES FOR ABOVE CONDITION?

HOW WILL YOU EVALUATE THIS GIRL? (Referral to a paediatric endocrinologist)

History

Age at onset, sequence and progression of pubertal changes (SSCs and their pattern of progression). Take detailed history to determine if the pattern of endocrine change is the same as in normal puberty.
Any history of recent rapid growth
Family history (25% of cases) – parents’ age and height at onset of puberty; age of menarche in mother.
Symptoms suggesting possible CNS dysfunction – headache, visual impairment, or seizures.
Social history –history of adoption, child abuse, or sexual abuse.
Exogenous sex steroid exposure in food, drug / cosmetics (steroid creams, oestrogen, anabolic hormone)

Examination

Height & weight measurement plotted using age specific growth chart – increased growth velocity; may precede the onset of pubertal manifestations.
BMI
Presence of dysmorphic features in multisystem syndromes.
Eye examination: Visual fields and fundoscopy (in intracranial tumours, injury)
Hyper-pigmented skin lesions in neurofibromatosis or McCune–Albright syndrome (café-au-lait)
Stage of pubertal development (Tanner staging): Breast /pubic hair development.
- Pubic hair results from the effects of androgens, which may be produced by ovaries in central PP.
- Pubic hair in the absence of breast development is suggestive of adrenal disorders, premature pubarche, or exposure to androgens.
Focal motor deficits in intracranial tumours, injury.
Abdominal examination
Examination of external genitalia
Signs of virilization (hirsutism, clitoromegaly)

HOW WILL YOU INVESTIGATE THIS GIRL?

Biochemical investigations

Serum LH levels (baseline)
- Poorly discriminates prepubertal and early pubertal levels.
- Values > 0.3–0.4 iu/l suggests central PP (high specificity and low sensitivity).
- However, if levels of LH are not clearly elevated, it needs to be confirmed with a stimulation test.
Serum FSH levels (baseline)
- Not useful, as varies little throughout pubertal development.
Estradiol levels
- Elevated levels suggest oestrogen production or exposure.
- Markedly elevated levels (> 100 pg/ml) suggest ovarian cyst/tumour.
- Highly variable and has a low sensitivity in discriminating early pubertal and prepubertal levels.
- Levels can be normal in progressive central PP.
GnRH stimulation test (↑↑↑ LH and ↑ FSH)
Testosterone levels
- Elevated levels suggest adrenal disorder.
Adrenal steroids – 17 oh progesterone, DHES & androstenedione (raised in CAH and adrenal tumours)
ACTH stimulation test (to identify steroid synthesis defects, e.g. Congenital adrenal hyperplasia)
Free thyroxine and thyroid-stimulating hormone – to rule out primary hypothyroidism.
Serum prolactin levels (may be raised in chronic hypothyroidism, Mccune–albright syndrome or prolactinomas or point towards pituitary stalk compression)
Urinary steroid profile (to identify and quantify excess adrenal androgens)
Genetic testing, e.g., neurofibromatosis type 1.

Imaging

Left wrist x-ray for bone age – It is generally greater than their chronological age (2years).
Cranial magnetic resonance imaging/computed tomography – in all cases of progressive central PP, determine whether a hypothalamic lesion is present.
Pelvic ultrasound (size, shape of uterus, endometrial thickness and ovarian morphology)
- Uterine changes due to oestrogen exposure such as uterine size & shape (pear); endometrial echo.
- Uterine volume > 2.0 ml – 89% sensitivity and specificity.
- Ovarian cysts/tumours; the multicystic ovary is a classic feature of early puberty.
CT or MRI of the adrenals (adrenal masses)
Skeletal survey/bone scan (mc’cune–albright syndrome)

what is the reason for Central precocious puberty?

Premature activation of the HPG axis

what is the gold standard test to confirm the diagnosis of cpp?

GnRH stimulation test

how will you perform and interpreat the result?

Measuring LH or FSH levels sequentially 30-60 minutes after GnRH stimulation at 100mcg or GnRHa

In healthy pubertal children the LH response exceeds the FSH response.

In prepubertal children and in thelarche variant, FSH response exceeds LH response.

CPP, GnRH stimulation shows a pubertal response with LH predominance (LH: FSH ratio >1). Peak LH levels vary, depending on the specific assay used, but values of >8 iu/l are usually considered diagnostic of CPP.

Suppressed peak LH level with elevated sex steroid levels indicates peripheral PP.

what are the other investigation findings expected In Central pp?

The bone age – advanced, often by more than 2 years.
A uterine volume >2 ml or length >34 mm, a pear-shaped uterus and endometrial thickening
Baseline serum gonadotrophins may be raised.
Estradiol levels
- Variable
- Not very reliable in the diagnosis of precocious puberty.
Elevated prolactin levels
- Rarely seen in girls with CPP (hyperprolactinaemia is seen more commonly in association with delayed puberty)
- Present usually prolactinoma or non-functioning pituitary adenomas à by stalk compression, resulting in interference with dopamine major inhibitor of prolactin secretion transport from the hypothalamus.
MRI of the brain (or computed tomography [CT] if MRI is unavailable)
- Progressive CPP to exclude a central nervous system lesion.

how will you treat cpp?

Majority of CPP(74%) – no apparent cause is found
Important to look for evidence of any underlying disorder.
Rx of the underlying cause varies with the type of central nervous system lesion involved.
- Intracerebral tumours – require resection, rarely causes regression of pubertal changes.
- Non-progressive central lesions – hypothalamic hamartomas – usually Rx conservatively.
- Slowly progressive forms of idiopathic CPP may not require Rx & observation is acceptable

The goal of treatment is to:

Halt or cause regression of secondary sexual characteristics
Prevent early menarche
Retard skeletal maturation and improve final height
Avoid psychosocial/behavioural sequelae.

Gonadotrophin-releasing hormone analogues (GnRHa)

Mainstay of treatment
Continuous stimulation of pituitary à short period of pubertal stimulationà down-regulation of GnRH receptors à pituitary desensitization à reduced gonadotrophin synthesis.
During initial gonadotrophin flare, a transient withdrawal bleed may occur, especially those well established in puberty.
Preparations:
- Rapid-acting or long-term depot preparations.
- The long- acting preparations
  - Leuprorelin, triptorelin and goserelin à SC /IM every 3–4 weeks or as a long-acting depot at 10 to 12 weekly intervals.
  - An implant – histrelin (effective for 1 year)
- Short-acting intranasal preparations – nafarelin for daily administration à less efficient & significant difficulties with compliance à limit them substantially as a first-line Rx
Experts from Europe, the USA and Canada concluded
- Efficacy of GnRHa in increasing adult height is undisputed only in girls <6 years old with early-onset CPP.
- Only modest improvement in final height in girls aged 6–8 years.
- Does not improve final height in girls beyond 8 years of age
So aim of treatment with GnRH after 8years is aimed solely at controlling psychosocial consequences or delaying menarche should be carefully considered and the decision to treat must be made on an individual basis. (further data needed)

Monitoring of response to treatment

Growth and anthropometric measurement
Assessment of pubertal progression
Bone age at regular intervals
Tanner staging
A suppressed LH response to GnRH testing indicates that the therapy is having the desired effect and can be used to evaluate treatment efficacy.

Treatment period

Treatment usually stopped when it is time for normal puberty to begin.
Decision to discontinue Rx should be taken jointly by endocrinologist, the child and the parents.
The suppression of puberty seems to be reversible on cessation of treatment and reproductive function seems to be unaffected.
Pubertal manifestations generally reappear within months of GnRHa treatment being stopped, with a mean time to menarche of 16 months

Adverse effects

Headaches
Hot flushes
Mood swings
Injection site reactions such as rashes, bruising
Sterile abscess formation
Long-term – polycystic ovary syndrome
Adult bone mineral density appears not to be adversely affected by childhood GnRHa therapy

what are the investigation findings expected In Peripheral precocious puberty?

Bone age – usually advanced except in hypothyroidism.
Baseline FSH and LH – in the prepubertal range.
GnRH (LHRH) testing – relatively flat gonadotrophin response.
Serum estradiol: very high levels may be associated with ovarian cysts or tumours.
Serum 17-hydroxyprogesterone and other androgens (testosterone, androstenedione, dehydroepiandrosterone (DHEA) and dehydroepiandrosterone sulphate (DHEAS) is indicated.
- If an adrenal cause is suspected
- Serum 17-hydroxyprogesterone levels are elevated in adrenal enzymatic defects (21-hydroxylase deficiency [classic CAH]) and occasionally with adrenal tumours.
- Serum DHEAS – produced in adrenals – a marker of androgen-producing adrenal tumours and adrenal enzymatic defects.
Urinary steroid profile & ACTH stimulation test – identifying adrenal steroid synthesis defects
Urinary17-ketosteroid levels can be very high in girls with adrenal tumours.
TFTs – low free T4 and markedly elevated TSH – severe primary hypothyroidism.
Serum prolactin levels
- May be increased in some girls with mccune–Albright syndrome (due to the association with prolactin-secreting pituitary adenomas)
- Chronic hypothyroidism (probably because of enhanced TRH secretion, stimulating prolactin release).
Pelvic ultrasound and adrenal CT – look for a gonadal or adrenal tumour.
A skeletal survey and bone scan may identify the characteristic bony abnormalities of polyostotic fibrous dysplasia in McCune–Albright syndrome