Key content
 Precocious puberty is defined as the development of secondary sexual characteristics before the age of 8 years in girls. It is divided into central (gonadotrophin-dependent) precocious puberty and
peripheral (gonadotrophin-independent) precocious puberty.
 Variants of premature sexual development include isolated premature thelarche, premature pubarche and isolated premature menarche (menstruation without other signs of puberty).
 Possible consequences of precocious puberty include short adult stature due to premature epiphyseal closure and psychosocial problems.
 Gonadotrophin-releasing hormone analogues are the mainstay of treatment for central precocious puberty.
 Treatment options vary for peripheral precocious puberty,depending on the underlying aetiology. These include aromatase inhibitors, anti-estrogens, anti-androgens and tumour resection.
 Combined consultation with or referral to a paediatric endocrinologist is indicated in all cases.
Learning objectives
 To be aware of the normal development and milestones of puberty.
 To understand the aetiology and diagnostic evaluation of the girl with precocious puberty.
 To be aware of treatment modalities and multidisciplinary management.
Ethical issues
 Should children with precocious puberty and severe brain dysfunction be given contraception and treated for behavioural
problems on parental request?
Keywords GnRH analogues / McCune–Albright syndrome /precocious puberty / premature menarche

Introduction

The physiology of normal puberty

Clinical stages of puberty

Timing of puberty

Classification

Causes of premature sexual development in girls
Central precocious puberty
• Idiopathic
• Central nervous system pathology/lesion
◦ Hypothalamic hamartoma
◦ Tumour: astrocytoma, glioma, craniopharyngioma,
pituitary adenoma
◦ Congenital disorder: hydrocephalus, myelomeningocele,
arachnoid cyst
◦ Acquired: central nervous system irradiation, post head
trauma, post infection: encephalitis/meningitis,
chemotherapy
• Secondary to peripheral precocious puberty
Peripheral precocious puberty
• Ovarian cause
◦ Estrogen-secreting: granulosa cell tumour, functional
ovarian cyst
◦ Androgen-secreting: Sertoli–Leydig cell tumour,
arrhenoblastoma (contrasexual)
• Adrenal cause
◦ Congenital adrenal hyperplasia (contrasexual)
◦ Cushing syndrome (contrasexual)
◦ Neoplasm: estrogen or androgen-secreting
adenoma/carcinoma (isosexual or contrasexual)
• Exogenous sex hormones: e.g. oral contraceptives, skin
cream, anabolic steroid
• McCune–Albright syndrome
• Severe longstanding hypothyroidism
Variants of normal pubertal development
• Premature thelarche/thelarche variant
• Isolated premature menarche
• Premature pubarche/adrenarche (contrasexual)

Evaluation of the child with premature sexual development
History
• Age of onset, sequence and progression of pubertal changes
• Family history: timing of onset of puberty in mother and siblings
• Neurological symptoms
• Exogenous sex steroid exposure in food, drugs or cosmetics
(e.g. steroid creams, estrogen, anabolic steroids)
• Social history: history of adoption or child sexual abuse
Clinical examination
• Height and weight measurements plotted using age-specific
growth charts
• Body mass index
• Pubertal Tanner staging
• Neurological examination
• Examination of eyes including visual fields and fundoscopy
• Skin lesions (e.g. caf´e au lait spots)
• Abdominal examination
• Examination of external genitalia
• Signs of virilisation: clitoromegaly, deepening of voice, hirsutism
Biochemical investigations
• Serum LH and FSH levels (baseline)
• GnRH (LHRH) stimulation test (LH and FSH)
• Estradiol/testosterone levels
• Adrenal steroids, e.g. 17 OH progesterone,
dehydroepiandrosterone sulphate and androstenedione (raised
in congenital adrenal hyperplasia and adrenal tumours)
• Adrenocorticotrophic hormone stimulation test (to identify
steroid synthesis defects, e.g. congenital adrenal hyperplasia)
• Free thyroxine and thyroid-stimulating hormone
• 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)
Imaging
• Left wrist X-ray for bone age
• Cranial magnetic resonance imaging/computed tomography
(CT)
• CT adrenals (adrenal masses)
• Pelvic ultrasound (size, shape of uterus, endometrial thickness
and ovarian morphology)
• Skeletal survey/bone scan (McCune–Albright syndrome)

 

Treatment of peripheral precocious puberty
Aetiology Treatment
Hypothyroidism Replacement of thyroxine
Exogenous source of steroids Discontination of the source of sex
steroids
Classic form of congenital
adrenal hyperplasia
Glucocorticoid treatment, usually
with mineralocorticoid
replacement (hydrocortisone with
fludrocortisone)
Non-classical congenital
adrenal hyperplasia
Treatment with hydrocortisone
alone to allow attainment of
normal adult height
Adrenal and ovarian tumours Surgical treatment or chemotherapy
or radiotherapy depending on the
tumour
McCune–Albright syndrome Suppresson of gonadal
steroidogenesis with aromatase
inhibitors (which inhibit synthesis
of estrogen): first (testolactone),
second and third-generation
(anastrazole, letrozole) available
Secondary CPP (following
prolonged steroid exposure
in McCune–Albright
syndrome, congenital
adrenal hyperplasia)
Adjunctive GnRHa therapy23
Other drugs used in the
treatment of peripheral
precocious puberty
Treatment Mode of action
Progestational agents (e.g.
medroxyprogesterone
acetate)
Cause suppression of gonadotrophin
release and block gonadal
steroidogenesis24
Selective estrogen receptor
modulators (e.g.
tamoxifen)
Cause estrogen receptor blockade
Antifungal agents (e.g.
ketoconazole)
Block enzymes in steroid biosynthesis
Antiandrogens (e.g.
spironolactone,
cyproterone acetate)
Act by competing with testosterone
for its receptor in peripheral
tissues. Cyproterone has an
additional progestational action at
the pituitary level, partially
suppressing gonadotrophin
secretion