GROWTH AND PUBERTY

Disorders of puberty

Whats new ?
Genes associated with autosomal hypogonadotrophic
hypogonadism are being characterized

Cristina Traggiai
Richard Stanhope

morning and then declines during the day. The factors that regulate
the hypothalamopituitarygonadal axis and modulate the timing
of puberty remain unknown, but it is clear that some regulation
is under genetic control.2

Definition
Disorders of pubertal development (Figure 1)

Puberty is defined as the acquisition of secondary sexual characteristics (development of breasts, genitalia and pubic and axillary
hair, and increase in testicular volume) associated with a growth
spurt and resulting in the attainment of reproductive function. It
usually lasts 34 years.1 There is usually a relationship between
the attainment of secondary sexual characteristics and the onset of
growth acceleration at an early stage in girls; in contrast, in boys,
this occurs at genitalia stage 3/4. Although girls enter puberty at
an earlier chronological age than boys, their onset of fertility is
usually later. The first 1 or 2 years after menarche involve anovulatory cycles associated with irregular and often painful periods;
in boys, spermatogenesis begins at Tanner stage 3. When there
are discrepancies (loss of consonance or harmony) between the
timing of different aspects of maturation, an endocrine disorder
should be suspected.
Precocious puberty is defined as development of sexual characteristics before the age of 8 years in girls or 9 years in boys.
Delayed puberty is diagnosed when there is no breast development by 13.4 years of age in a girl or no testicular enlargement by
14 years in a boy.

Isolated premature thelarche is a common, benign disorder. Girls

usually present with breast development before the age of 2 years,
with no other signs of puberty. There is no pubic hair development,
and growth and bone age are normal. The condition resolves after
a few years and requires no treatment.3
Premature adrenarche is characterized by precocious development of sexual hair (pubic, axillary or both) before 8 years in girls
or 9 years in boys, with no other signs of sexual maturation. The
condition is more common in girls than in boys and in black than
in white racial groups. It requires no treatment.4
Isolated premature menarche comprises cyclical uterine withdrawal bleeding with no other signs of sexual maturation. There
do not appear to be any long-term sequelae in either puberty or
fertility.5
Precocious puberty: it is important to distinguish gonadotrophindependent precocious puberty (CPP) from gonadotrophinindependent precocious puberty (GIPP), because this determines
investigations and treatment. Idiopathic CPP occurs in 74% of
girls and 60% of boys; boys are more likely to have an occult
intracranial tumour. Management is discussed below.6,7 GIPP is
characterized by pubertal sex steroid concentrations in the presence of prepubertal or suppressed gonadotrophins. In patients
with GIPP, particularly those without a family history, disorders
of the gonad or adrenal gland and autonomous secretion of sex
hormones by tumour should be excluded.8

Endocrinology of puberty
The endocrine events of puberty start many years before the
onset of phenotypic puberty. Luteinizing hormone (LH) secretion
results from both increased secretion of gonadotrophin-releasing
hormone (GnRH) from the hypothalamus and increased pituitary
responsiveness to GnRH. The nocturnal increase in serum LH
is sleep dependent; LH concentration then gradually changes to
the adult pattern of one pulse approximately every 90 minutes
throughout day and night. In girls, peak oestrogen secretion is
during the morning, probably as a consequence of aromatase
induction; in boys, testosterone starts increasing after the first
nocturnal pulse of LH, reaches a peak in the early hours of the

Cristina Traggiai is in the Department of Paediatrics at Gaslini Hospital,

Genoa, Italy. She trained in London, UK. Her research interest is
paediatric endocrinology. Conflicts of interest: none declared.

Constitutional delay of growth and puberty is the most common

condition presenting to paediatric endocrinologists. It is characterized by short stature (growth deceleration occurs from about
2 years of age), delayed puberty and delayed epiphyseal maturation. There is often a family history, and the predicted height for
the child is in the appropriate range for the parental heights. The
clinical features of the condition are usually sufficient for clinical
diagnosis. In girls, karyotyping is essential. Constitutional delay
may be treated for psychological reasons.9

Richard Stanhope is Consultant Paediatric Endocrinologist at

Great Ormond Street Hospital and the Middlesex Hospital, London, UK.
He qualified from St Bartholomews Hospital, London. His main research
interests are disorders of puberty, suprasellar tumours and psychosocial
short stature. Conflicts of interest: none declared.

Hypogonadotrophic hypogonadism: it is often difficult to distinguish hypogonadotrophic hypogonadism from constitutional delay
of growth and puberty, particularly in the early teenage years.
However, children with hypogonadotrophic hypogonadism are
taller and grow at a faster rate. Features of Kallmanns syndrome

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GROWTH AND PUBERTY

gations are required. In girls, thyroid function and karyotype are

determined and treatment then offered if necessary. Assessment is
required before treatment in those who present with dysmorphic
features or a family history of the problem.11

Classification of disorders of pubertal development

Premature sexual maturation
Premature thelarche
Isolated premature thelarche classical, non-classical
(atypical)
Slowly progressive precocious puberty
(thelarche variant, exaggerated thelarche)
Isolated premature menarche
Premature adrenarche
Precocious puberty
Gonadotrophin-dependent
Gonadotrophin-independent McCuneAlbright
syndrome, testotoxicosis
Pubertal delay
Constitutional growth and pubertal delay
Secondary to chronic illness
Hypogonadotrophic hypogonadism defect in the
hypothalamopituitary region, secondary to radiotherapy/
chemotherapy
Hypergonadotrophic hypogonadism secondary to gonadal
failure (Turners syndrome), secondary to radiotherapy/
chemotherapy

Management
Precocious puberty: CPP is treated with a GnRH agonist, which
has the paradoxical action of inducing down-regulation of pituitary
GnRH receptors and desensitization of pituitary gonadotrophs,
with suppression of spontaneous and stimulated pituitary
gonadotrophin secretion. Immediate recovery of the hypothalamopituitarygonadal axis is seen at the end of treatment.12
GIPP is treated with drugs that suppress gonadal steroidogenesis, such as cyproterone acetate, ketoconazole (a steroid
biosynthesis inhibitor), spironolactone (an anti-androgen) and
testolactone (an aromatase inhibitor).12
Delayed puberty is treated for psychological reasons. In boys,
treatment options include depot testosterone (if induction of a
growth spurt and pubertal development is required) and low-dose
anabolic steroid (if virilization is not required). In girls, a course
of oestrogens is required for at least 6 months.13

REFERENCES
1 Tanner J M. Growth at adolescence. Oxford: Blackwell, 1962.
2 Plant T M. Neurobiological bases underlying the control of the onset
of puberty in the rhesus monkey: a representative higher primate.
Front Neuroendocrinol 2001; 22: 10739.
3 Stanhope R, Brook C G D. Thelarche variant: a new syndrome of
precocious sexual maturation? Acta Endocrinol (Copenh) 1990; 123:
4816.
4 Ibanez L, Dimartino-Nardi J, Potau N et al. Premature adrenarche
normal variant or forerunner of adult disease? Endocr Rev 2000; 21:
67196.
5 Murran D, Dewhurst J, Grant D B. Premature menarche: a follow-up
study. Arch Dis Child 1983; 58: 1423.
6 Cisternino M, Arrigo T, Pasquino A M et al. Etiology and age incidence
of precocious puberty in girls: a multicentric study. J Pediatr
Endocrinol Metab 2000; 13: 695701.
7 De Sanctis V, Corrias A, Rizzo V et al. Etiology of central precocious
puberty in males: the results of the Italian Study Group for
Physiopathology of Puberty. J Pediatr Endocrinol Metab 2000; 13:
68793.
8 Traggiai C, Stanhope R. Disorders of pubertal development. Best Pract
Res Clin Obstet Gynaecol 2003; 17: 4156.
9 Traggiai C, Stanhope R. Delayed puberty. Best Pract Res Clin
Endocrinol Metab 2002; 16: 13951.
10 Chemaitilly W, Trivin C, Adan L et al. Central precocious puberty:
clinical and laboratory features. Clin Endocrinol (Oxf) 2001; 54:
28994.
11 Albanese A, Stanhope R. Investigation of delayed puberty. Clin
Endocrinol 1995; 43: 10510.
12 Tato L, Savage M O, Antoniazzi F et al. Optimal therapy of pubertal
disorders in precocious/early puberty. J Pediatr Endocrinol Metab
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13 Stanhope R, Preece M A. Management of constitutional delay of
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such as anosmia, disturbance of colour vision and dyskinesis may

suggest the diagnosis, as may non-enlargement of testicular volume
during exogenous testosterone therapy or growth deceleration after
stopping testosterone.
In children with hypogonadotrophic hypogonadism, puberty
should be induced at an average age and the dose of sex steroids
gradually increased to mimic the normal progress of puberty. This
is important for psychological reasons in both sexes, and also to
induce normal nipple/breast morphology in girls.
Pubertal delay secondary to chronic illness: most chronic illnesses result in pubertal delay if they are of sufficient severity
and duration, and improved treatment of such conditions has
increased life expectancy.
Reduced growth rate and pubertal delay has been reported in
children with conditions that start in the prepubertal period.
In diseases that start during puberty, pubertal development
may stop or regress.
In some cases, therapy has caused pubertal delay. For example,
corticosteroids can delay growth and epiphyseal and pubertal
maturation in children with severe asthma.

Investigations and diagnosis

Precocious puberty is diagnosed using auxological parameters
(increased growth velocity, advanced bone age), the LH-releasing
hormone test (peak LH) and pelvic ultrasonography (increased
uterine volume and endometrial thickness).10
Delayed puberty is diagnosed on the basis of the history, auxological data and physical examination. Boys with delayed puberty
usually require treatment; if they do not respond, further investi-

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2005 The Medicine Publishing Company Ltd