Precocity and Sex hormones

From US data, by age 7 10% of white girls and 23% of black girls have started puberty.  Rates are probably lower in Europe.  Likely that dietary changes (in particular, increasing adiposity) have driven this change over time to earlier puberty in girls.

Red flags:

  • boys (much more likely to be a serious underlying issue) with changes before age 9.
  • Unilateral testicular enlargement.
  • clitoromegaly (ie virilizing, so excess androgens)
  • Rapidly increasing height (increase across 1 space typical for precocious puberty)
  • Vaginal bleeding before age 8 (consider tumours etc)
  • Polydipsia, polyuria incl bed wetting (pituitary pathology)
  • Headaches, visual disturbance similarly
  • History of CNS disease eg head trauma, meningitis

For a girl, pubertal developmental that follows the normal pattern before the age of 8 is considered abnormal. Where no serious cause suspected, usually idiopathic gonadotrophin dependent – common, slow to progress, no treatment required usually.  Often mothers had the same.

Obesity contributes as a result of raised oestrogen levels, and increased aromatisation of androgens.  But obesity can also give appearance of breast development.

Note puberty lines on RCPCH growth charts, for starting puberty (girls 8), delayed beginning (girls 13, boys 14) and completing (girls 16, boys 17).  Delayed completion (especially menses) also needs investigation.  Also a shaded triangle for short boys and girls during this time, to remind that probably ok if puberty not yet started, but potentially a problem if nearly completing.

Differential is:

  • Central precocious puberty – therefore pubertal development associated with growth spurt, behaviour changes (“moods like a teenager”), acne, odour, vaginal discharge/bleed. LH/FSH should be raised (less than 3.5iU/L in prepubertal) but unless random levels very high needs GnRH testing (shows high responses viz 2-3x baseline). The majority are idiopathic but MRI brain should be done to rule out central lesion.
  • Thelarche=breast bud development. Usually the first sign of puberty, but premature thelarche often seen. Due to high oestradiol or rising sensitivity. Common in babies, then another peak in infants/preschool. Breast only, often just one: clinical diagnosis if normal growth, most regress within 1-2 yrs. Older girls less likely to regress. Sometimes fluctuating.
  • Variant thelarche – a significant minority of girls with premature thelarche will progress to precocious puberty, another group show advanced bone age and accelerated height velocity but these do not seem to be the ones who get precocious puberty.
  • Peripheral precocity ie hormone secreting tumours – tend to produce asynchronous pubertal milestones (eg virilization, penile enlargement without testicular enlargement, extensive pubic hair, or menarche without breast buds).
  • Premature adrenarche – ie adrenal hormones moderately raised but normal pre-pubertal FSH/LH with low oestrogens. Due to increased sensitivity to ACTH, zona reticularis in adrenal gland develops, producing steroid enzymes.
    • Best thought of as extreme end of normal.  But slight risk of obesity and insulin resistance, and possibly mood disorder and PCOS.
    • Principally androgen effects viz pubic/axillary hair development, +/- acne/sweating/odour. In girls, true puberty (ie with gonadal oestrogens) follows soon after, but the two can be distinct (Turners get one but not the other, Addisons may get more of the other). Bone age should not be advanced, although the child may be taller than expected. Androstenedione, precursor of both oestrogen and testosterone, is most sensitive (but can be adrenal OR ovarian), DHEA and DHEAS will also go up as precursors to androstenedione.  Do urinary steroid profile for completeness and to exclude congenital adrenal hyperplasia (CAH) – might need ACTH stimulation test to exclude late onset CAH. If progresses, then might be true precocious puberty after all. Some suggestion that premature adrenarche is related to intrauterine environment (eg SGA) and obesity, and may lead on to polycystic ovarian syndrome.
  • Premature menarche – usually benign! Not well understood, ?transient upregulation of ovarian activity, ?exogenous steroids. Observe.
  • Else Mccune Albright – sporadic genetic disease.  Unilateral cafe au lait spots, facial asymmetry, fibrous dysplasia of bones (?nerve compression). Periods appear early, even before development of breasts and pubic hair! May cause premature puberty in boys but less of a feature. Thyroid, adrenal abnormalities (Cushings) and acromegaly sometimes seen too.

So do:

  • Pubertal assessment – Tanner scale.  For obese children, lipomastia can look like breast development but will not be firm tissue under areola (lying child supine may help).  In boys, pubertal development with small (<4cm) testes means gonadotrophin independent.
  • FSH/LH, prolactin (normal is 0-500)
  • Oestradiol (not great sensitivity in girls, v high levels suggest tumour), testosterone (good sensitivity in boys)
  • DHEAS, Androstenedione, 17-OH progesterone, urinary steroid profile
  • Bone age – advanced by obesity, CAH.

Can be hard for parents to discuss! Check if they are worried about social issues (ie sexualisation).  Then pelvic USS, MRI adrenals, brain, LHRH test as appropriate. Else monitor progression and growth.

GnRH treatment can be discussed to prevent premature fusion of epiphyses and thus to preserve adult height potential.  Some families are concerned about the psychosocial impact of early puberty.  If untreated, menarche commences at mean 4.5 years, so not much different from mean age (12.3) in population.  And actually untreated children have similar height to those treated (but selection bias).  GnRH treatment is monthly or 3 monthly injections to postpone periods.

Virilizing in girls(clitoromegaly) can be due to –

  • CAH (mild needs no rx, leads to polycystic)
  • exaggerated adrenarche (“adrenal puberty”- tall, no breast/menarche, ?pubic hair)
  • tumour (v rapid changes)

Virilising in boys: true precocious (v rarely brain tumour), adrenarche, adrenal/testic tumour.

Functional ovarian hyperandrogenism (FOH), with obesity, hirsutism, acne, LH:FSH >3, irregular menses in perimenarcheal girls. Pelvic ultrasound exams are usually normal.

[BMJ 2020;368:l6597]