Disorders of Puberty

PE Clayton

Endocrine Science Research Group
University of Manchester

Summer School 15-18 July 2003
University of Manchester, Hulme Hall, Manchester, UK

Recognition of an abnormality in the timing or progression of puberty requires an understanding of the process of normal puberty (physical, hormonal and psychological) and the range of variation around that normal process. Over previous decades, the onsets of puberty and specific events such as menarche have occurred at ever earlier ages. In Europe this trend seemed to have slowed, and in some countries even reversed. However in the last 5 years or so, there has been some data indicating that the onset of puberty in girls is occurring at ages that overlap our classic definitions of early and precocious puberty (see below). It is notable that definition of early breast development is difficult in overweight/obese girls. As there has been a marked shift in the weight distribution of prepubertal children, this may be biasing the downward trend in pubertal onset.

Early puberty in girls – Attainment of Breast stage 2 <9 years
Precocious puberty in girls – Attainment of B2 <8 years

Early puberty in boys – Attainment of Genital Stage 2 (Testicular volume ?4mls)
Precocious puberty in boys – Attainment of G2/TV ?4mls

There are a number of variants of the normal pubertal process that appear to be benign processes that do not require treatment, but may need differentiation from abnormality. These include:

Premature Thelarche – Isolated breast development between 6 months and 2 years without other features of a full precocious puberty. This condition may however be associated later with a relatively early onset of normal puberty.

Thelarche variant – Breast development associated with some ovarian and uterine development, but without all the features of a full precocious puberty. Again this condition may be associated with a relatively early onset of normal puberty.

Isolated menstrual blood loss in an otherwise prepubertal girl – this phenomenon is occasionally encountered with one or two menstrual bleeds. Such an episode raises concern about the differential diagnosis, which includes local lesions and abuse.

Adrenarche – This is a normal event in mid-childhood with a surge in adrenal androgen excretion. In some it manifests as the premature appearance of pubic and/or axillary hair. If this occurs before the age of 6 years, a pathological cause is likely, such as simple virilising (SV) adrenal hyperplasia.

Abnormality in the timing of Puberty

Too Early

Precocious puberty (as defined above) in either sex requires endocrine assessment to establish aetiology (central versus peripheral, idiopathic versus underlying pathology) and to consider whether treatment is required.

Central Precocious Puberty – Pathological Causes
• Associated with non-specific brain injury eg cerebral palsy/mental retardation, autism
• CNS lesions
o Hypothalamic hamartoma
o Other hypothalamic tumours – germinoma, glioma
o Cranial irradiation for CNS tumours distant from the hp axis
o Hydrocephalus
o Septo-optic dysplasia
o Head injury
• Secondary to peripheral precocious puberty
o SV congenital adrenal hyperplasia

Peripheral Precocious Puberty –
In boys – Signs of virilisation in the absence of bilateral testicular enlargement
• SV CAH
• Adrenal adenoma/carcinoma
• Rare - Pituitary Cushing’s
• Rare - testicular tumours (Leydig/Sertoli)

In girls – Signs predominantly of oestrogenisation ie breast development and menstrual activity
• McCune Albright syndrome
• Rare oestrogen-secreting ovarian cysts/tumours
• Exogenous oestrogen cream prescribed for other purposes

In both sexes – Signs of virilisation/excess androgen (May include pubic/axillary/body hair growth, acne, aggression, increased muscle & strength)
• SV CAH in boy, Non-classical CAH in girl
• Adrenal androgen secreting tumour

Treatment of Central PP: GnRH analogue eg Goserelin as the monthly or 3 monthly depot preparations. NB Frequency of injections may need to be increased to fully suppress CPP.

Treatment of Peripheral PP: Treat underlying cause. For McCune Albright, anti-oestrogen (eg cyproterone acetate) &/or an aromatase inhibitor

Too Late/Absent

Definitions for delayed puberty are not as rigidly defined as those for early puberty. However the following criteria can be applied:

For girls – failure of breast development (B2) by age 13 years, and following on from this, failure of menarche by age 15 years
For boys – failure of genital/ testicular development by age 14 years

In addition, the failure to progress smoothly through puberty, ie very slow breast/genital development or arrest of development, is abnormal and should trigger the search for an underlying cause.

• Constitutional delay in growth and puberty – Commonest disorder, predominantly presenting in boys, often a family history, will resolve spontaneously but the most distressed can be treated with short courses of testosterone (boys) or oestrogen (girls)
• Gonadotrophin deficiency:
o Primary/isolated – Kallmann syndrome
o Secondary – As part of congenital or acquired hypopituitarism
Anorexia nervosa, overtraining
Thalassaemia
Chronic disease – Atopy, Inflammatory bowel disease, chronic
renal failure
• Gonadal failure
o Chromosomal – 45X & variants, 47XXY and variants
o Testicular/ovarian failure eg
? Anorchia, vanishing testes, damage post-orchidopexy/torsion
? Chemotherapy/radiotherapy damage
? Autoimmune ovarian failure (usually seen after puberty started)

Puberty can be induced by sex steroids, starting at low doses (eg 2?g ethinyloestradiol/day, testosterone 50mg im monthly, testoerone undeconoate 40mg alternate days) and building upto adult replacement doses over 3-4 years.

In some conditions, the gonadal axis may recover, eg with recovery of anorexia. In those with gonadotrophin deficiency, consideration may be given to achievement of fertility at the appropriate time with exogenous gonadotrophins.

The opinions expressed in this paper are those of the speaker and do not necessarily reflect the views of the Society

Revised: 30-Oct-2006