Delayed Puberty: Clinical Practice

The
n e w e ng l a n d j o u r na l
of
m e dic i n e
clinical practice
Delayed Puberty
Mark R. Palmert, M.D., Ph.D., and Leo Dunkel, M.D., Ph.D.
This Journal feature begins with a case vignette highlighting a common clinical problem.
Evidence supporting various strategies is then presented, followed by a review of formal guidelines,
when they exist. The article ends with the authors clinical recommendations.
A 14-year-old boy with an unremarkable medical history presents because of lack

of pubertal development. He has always been relatively short, but his growth velocity
is slowing as compared with that of his peers. His height is 146 cm (57.5 in., <3rd
percentile for age), and his weight is 37 kg (82 lb, 3rd percentile). His father, who is
168 cm (66.1 in.) tall, continued to grow until his second year in college; his mother is
153 cm (60.2 in.) tall and began menstruating at the age of 14.0 years. The patients
target height on the basis of the parental heights is 167 cm (65.8 in.). The physical
examination reveals Tanner stage 1 pubic hair and prepubertal-sized testes. How
should the boy be evaluated and treated?
The Cl inic a l Probl em

Puberty leads to sexual maturation and reproductive capability. It requires an intact
hypothalamicpituitarygonadal (HPG) axis and is heralded by the reemergence of
gonadotropin-releasing hormone (GnRH) secretion from its relative quiescence
during childhood. GnRH stimulates the secretion of luteinizing hormone and follicle-stimulating hormone (FSH), which then stimulate gonadal maturation and
sex-steroid production. Much is known about components of the HPG axis, but the
factors that trigger pubertal onset remain elusive. It is not understood why one boy
begins puberty at the age of 10 years and another at the age of 14 years.
Delayed puberty is defined as the absence of testicular enlargement in boys or
breast development in girls at an age that is 2 to 2.5 SD later than the population
mean (traditionally, the age of 14 years in boys and 13 years in girls). However,
because of a downward trend in pubertal timing in the United States1-3 and other
countries4,5 and differences in pubertal timing among racial and ethnic groups,
some observers have advocated for updated definitions with younger age cutoffs
for the general population or perhaps for particular countries or racial or ethnic
groups. Development of pubic hair is usually not considered in the definition because pubarche may result from maturation of the adrenal glands (adrenarche),
and the onset of pubic hair can be independent of HPG-axis activation.
Late puberty can affect psychosocial well-being, and patients, families, and
practitioners are often concerned that it may affect adult stature. Adult height can
be affected but on average is only slightly below the genetic target.6 Many adolescents present with delayed puberty combined with relative familial short stature,
compounding these concerns and leading to more subspecialty referrals than either condition alone.
Delayed puberty in boys usually represents an extreme of the normal spectrum
of pubertal timing, a developmental pattern referred to as constitutional delay of
growth and puberty (CDGP). In one large series, approximately 65% of boys and
30% of girls with delayed puberty had CDGP.7 However, because the data were
From the Division of Endocrinology, the

Hospital for Sick Children, and the Departments of Pediatrics and Physiology,
University of Toronto both in Toronto
(M.R.P.); and the Centre for Endocrinology, William Harvey Research Institute,
Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London (L.D.). Address
reprint requests to Dr. Palmert at the
Hospital for Sick Children, 555 University
Ave., Toronto, ON M5G 1X8, Canada, or
at [email protected]; or to Dr.
Dunkel at the Centre for Endocrinology,
William Harvey Research Institute, Barts
and the London School of Medicine and
Dentistry, Queen Mary University of London, Charterhouse Sq., London EC1M
6BQ, United Kingdom, or at l.dunkel@
qmul.ac.uk.
N Engl J Med 2012;366:443-53.
Copyright 2012 Massachusetts Medical Society.
An audio version
of this article
is available at
NEJM.org
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443
The
of
m e dic i n e
key clinical points
delayed puberty
Delayed puberty is diagnosed when there is no testicular enlargement in boys or breast development in girls at an age
that is 2 to 2.5 SD later than the mean age at which these events occur in the population (traditionally, 14 years in boys
and 13 years in girls).
Constitutional delay of growth and puberty (CDGP) is the single most common cause of delayed puberty in both sexes,
but it can be diagnosed only after underlying conditions have been ruled out.
The cause of CDGP is unknown, but most patients with CDGP have a family history of delayed puberty.
Management of CDGP may involve expectant observation or therapy with low-dose sex steroids.
When treatment is given, the goals are to induce the appearance of secondary sexual characteristics or the acceleration
of growth and to mitigate psychosocial difficulties associated with pubertal delay and short stature.
The routine use of growth hormone, anabolic steroids, or aromatase inhibitors is not currently recommended.
obtained from a tertiary referral center, these

percentages may underestimate the frequency of
CDGP encountered by primary care providers.
The evaluation and treatment of boys with CDGP
is the main focus of this review, but consideration is given to other causes of delayed puberty
and issues specific to girls.
Although CDGP represents the single most
common cause of delayed puberty in both sexes,
it can be diagnosed only after underlying conditions have been ruled out. The differential diagnosis of CDGP can be divided into three main
categories7: hypergonadotropic hypogonadism
(characterized by elevated levels of luteinizing
hormone and FSH owing to the lack of negative
feedback from the gonads), permanent hypogonadotropic hypogonadism (characterized by low
levels of luteinizing hormone and FSH owing to
hypothalamic or pituitary disorders), and transient
hypogonadotropic hypogonadism (functional hypogonadotropic hypogonadism), in which pubertal delay is caused by delayed maturation of the
HPG axis secondary to an underlying condition
(Table 1, and Table 1 in the Supplementary Appendix, available with the full text of this article
at NEJM.org).
The cause of CDGP is unknown, but it has a
strong genetic basis. It has been estimated that
50 to 80% of variation in the timing of puberty
in humans is due to genetic factors,8 and 50 to
75% of patients with CDGP have a family history of delayed puberty.9,10 The inheritance of
CDGP is variable but most often is consistent
with an autosomal dominant pattern, with or
without complete penetrance. CDGP is not sexspecific and is characterized by either relatively
444
delayed development among family members

(e.g., the average age at menarche among mothers is 14.3 years, as compared with a mean of
12.7 years among controls9) or evidence of true
CDGP. The investigation of patients with the
Kallmann syndrome and isolated hypogonadotropic hypogonadism has led to the identification of genes that play critical roles in the development and regulation of the HPG axis, but
mutations that have been identified in such
genes do not cause CDGP, except in rare instances.11,12 However, the genes causing 60 to
70% of cases of the Kallmann syndrome and
isolated hypogonadotropic hypogonadism remain unknown.13 Loci have also been identified that are associated with the age of menarche in the general population,14-18 but these
particular loci have likewise not been associated with CDGP.19
S t r ategie s a nd E v idence
First-Line Evaluation
Ruling Out Underlying Disorders
The aim of initial evaluation is to rule out

underlying disorders causing delayed puberty
(Table 2, and Table 2 in the Supplementary Appendix).20-28 Pubertal development is assessed
clinically and biochemically, providing information that is important for counseling and
predicting further pubertal development. Eventual normal progression of puberty verifies the
diagnosis of CDGP, whereas absent or slow
development or cessation of development after
onset is consistent with permanent hypogo
nadism.

clinical pr actice
Table 1. Frequency and Common Causes of Delayed Puberty Other Than Constitutional Delay of Growth and Puberty.*
Delayed Puberty
Hypergonadotropic
Hypogonadism
Permanent Hypogonadotropic
Hypogonadism
Functional Hypogonadotropic
Hypogonadism
Frequency (%)
Boys
510
10
20
Girls
25
20
20
Common causes
Turners syndrome, gonadal dysgen- Tumors or infiltrative diseases of the Systemic illness (inflammatory bowel
esis, chemotherapy or radiation
central nervous system, GnRH
disease, celiac disease, anorexia
therapy
deficiency (isolated hypogonadonervosa or bulimia), hypothyroidtropic hypogonadism, Kallmanns
ism, excessive exercise
syndrome), combined pituitaryhormone deficiency, chemotherapy or radiation therapy
* For a more comprehensive listing of causes of delayed puberty, see Table 1 in the Supplementary Appendix. GnRH denotes gonadotropinreleasing hormone.
Family History
A family history, including childhood growth

patterns and age at pubertal onset of the parents,
should be obtained. Delayed puberty in a parent
or sibling followed by spontaneous onset of puberty suggests CDGP. However, if pubertal development was induced by sex steroids in family
members, isolated hypogonadotropic hypogonadism is also possible, since reversal of hypogonadism is noted after the discontinuation of sex steroids in about 10% of patients with isolated
hypogonadotropic hypogonadism.29,30
Patients and their parents should be questioned about a history or symptoms of chronic
disease, with emphasis on specific disorders (e.g.,
celiac disease, thyroid disease, and anorexia) that
may cause temporary delay of puberty (functional
hypogonadotropic hypogonadism), as well as
medication use, nutritional status, and psychosocial functioning. Delayed cognitive development associated with obesity or dysmorphic
features may suggest an underlying genetic syndrome. Bilateral cryptorchidism or a small penis
at birth and hyposmia or anosmia may suggest
hypogonadotropic hypogonadism. A history of
chemotherapy or radiotherapy may indicate primary gonadal failure (Fig. 1).
have an increased likelihood of having an underlying condition delaying HPG-axis activation.

Conversely, in boys, unlike girls, being overweight
can be associated with later pubertal development.20,21 The most widely used pubertal rating
system is Tanner staging31,32 (Fig. 3). In boys, the
presence of Tanner stage 2 genitalia marks the
onset of pubertal development and is characterized by enlargement of the scrotum and testes
and by a change in the texture and color of the
scrotal skin. Testicular volume should be measured, with a volume of more than 3 ml indicating
the initiation of central puberty. In patients with
CDGP, both adrenarche and hormonal activation
of the gonads often occur later than average, but
in isolated hypogonadotropic hypogonadism,
adrenarche usually occurs at a normal age.7,33
Bone-Age Radiography
The bone age should be reviewed by a practitioner who is experienced in interpreting such radiographs. A delay in bone age is characteristic
but not diagnostic of CDGP and also may occur
in patients with chronic illness, hypogonadotropic hypogonadism, or gonadal failure. Adult
height prediction is an important part of counseling if short stature is a component of the presentation, and practitioners should be aware that
Physical Examination
the BayleyPinneau tables overestimate adult
Previous height and weight measurements should height in patients with CDGP if bone age is debe obtained and plotted so that longitudinal layed by more than 2 years (Table 2, and Table 2
growth can be carefully assessed (Fig. 2). Delayed in the Supplementary Appendix).
puberty is often associated with short stature
and slow growth for age although the height and Hormone Measurements and Brain Imaging
growth rate are within the prepubertal normal Pubertal onset is characterized by the accentuarange. Children who are underweight for height tion of diurnal secretion of gonadotropin and

445
The
testosterone (in boys) and estrogen (in girls) before apparent phenotypic changes. Basal levels of
luteinizing hormone and FSH are low in patients
with CDGP or hypogonadotropic hypogonadism,
whereas such levels are usually elevated in those
with gonadal failure. Serum levels of insulin-like
growth factor 1 (IGF-1) can be helpful in the
evaluation of growth hormone deficiency but
must be interpreted carefully because levels are
often low for chronologic age but within the normal range for bone age. Thyroid-function tests
are routinely obtained. Brain magnetic resonance
imaging (MRI) is indicated when there are signs
or symptoms to suggest a lesion in the central
nervous system. Otherwise, although some clini-
of
m e dic i n e
cians routinely perform brain imaging, a reasonable strategy is to defer such evaluation until the
age of 15 years, at which point many patients with
CDGP will have spontaneously begun puberty and
will require no further evaluation. Full neuro
endocrine testing is warranted in patients with
hypothalamicpituitary tumors causing hypogonadotropic hypogonadism, since they may have
additional pituitary-hormone deficiencies.
Second-Line Evaluation
Most patients will not have an apparent alternative cause for delayed puberty on initial evaluation, suggesting CDGP as the likely diagnosis.
However, no test can reliably distinguish CDGP
Table 2. Investigations for Delayed Puberty.*

Variable
Interpretation
First-line
Growth rate
In early adolescence in both sexes, an annual growth rate of less than 3 cm is suggestive of a disease specifically inhibiting growth (e.g., growth hormone deficiency, hypercortisolism, and hypothyroidism), but such rates can also be seen in CDGP. Boys with delayed puberty who are
overweight tend to have height and predicted adult height consistent with their genetic height
potential.20,21
Tanner stages
In girls, Tanner stage 2 breast development is usually the first physical marker of puberty. In boys,
a testicular volume of >3 ml is a more reliable indicator of the onset of puberty than Tanner
stage 2 genital development.
Testis volume in boys
A testicular volume of >3 ml (2.5 cm in length) indicates central puberty. Most healthy boys with a
testicular volume of 3 ml will have a further increase in testicular volume or pubic-hair stage, or
both, at repeated examination 6 mo later.22
Bone age
A bone-age delay of >2 yr has arbitrarily been used as a criterion for CDGP but is nonspecific. A
bone-age delay of 4 years has been associated with a mean overprediction of adult height of
8 cm. In children with short stature who have no bone-age delay, adult height is usually underestimated by the BayleyPinneau tables.23
Biochemical analyses
To rule out chronic disorders, common tests include complete blood count, erythrocyte sedimentation rate, creatinine, electrolytes, bicarbonate, alkaline phosphatase, albumin, thyrotropin, and
free thyroxine. Additional testing may be necessary on the basis of family history and symptoms
and signs, including screening for celiac disease and inflammatory bowel disease.
Serum luteinizing hormone
At low levels, values obtained on immunochemiluminometric (ICMA) assays are at least 50% lower
than those obtained on immunofluorometric (IFMA) assays.24 Values of <0.1 IU per liter are
not specific for hypogonadotropic hypogonadism. Values of >0.2 IU per liter on ICMA or >0.6 IU
per liter on IFMA are specific but not sensitive for the initiation of central puberty; some adolescents in early puberty have lower values.24 In delayed puberty, elevated values suggest primary
hypogonadism. In general, luteinizing hormone is a better marker of pubertal initiation than
follicle-stimulating hormone.
Serum follicle-stimulating hormone
At low levels, values obtained on ICMA are approximately 50% lower than those obtained on IFMA.
Values of <0.2 IU per liter on ICMA or <1.0 IU per liter on IFMA suggest hypogonadotropic hypogonadism but are not diagnostic.24,25 In delayed puberty, a value above the upper limit of the
normal range for the assay is a sensitive and specific marker of primary gonadal failure.
Serum insulin-like growth factor 1
Measurement is used to screen for growth hormone deficiency. An increase in the level during followup or during or after treatment with sex steroids makes the diagnosis of growth hormone deficiency less likely. Growth hormone provocation tests are needed to diagnose growth hormone
deficiency.
Serum testosterone in boys
A morning value of 20 ng per deciliter (0.7 nmol per liter) often predicts the appearance of pubertal
signs within 12 to 15 mo.26
446

clinical pr actice
Table 2. (Continued.)
Variable
Interpretation
Second-line
Gonadotropin-releasing hormone test A predominant response of luteinizing hormone over follicle-stimulating hormone after stimulation
or peak luteinizing hormone levels of 5 to 8 IU per liter (depending on the assay) suggests the
onset of central puberty. However, patients with CDGP or hypogonadotropic hypogonadism
may have a prepubertal response.
Human chorionic gonadotropin test
Peak testosterone levels are lower in patients with hypogonadotropic hypogonadism than in those
with CDGP.27
Serum inhibin B
Prepubertal boys with a baseline inhibin B level of >35 pg per milliliter have a higher likelihood of
CDGP.28 In boys, unmeasurable inhibin B indicates primary germinal failure.
Serum prolactin
Elevated levels may indicate hypothalamicpituitary tumors causing hypogonadotropic hypogonadism. In such cases, additional pituitary-hormone deficiencies may be present. Measurement of
macroprolactin (a physiologically inactive form of prolactin) is recommended in patients with
unexplained hyperprolactinemia.
Brain magnetic resonance imaging
Imaging is performed to rule out underlying disorders of the central nervous system. Imaging in
patients with the Kallmann syndrome commonly shows olfactory-bulb and sulcus aplasia or
hypoplasia and thus may help differentiate the Kallmann syndrome from hypogonadotropic
hypogonadism in patients with an apparently normal or difficult-to-evaluate sense of smell.
Genetic testing
Genotyping for known monogenic causes is currently a research procedure and not warranted in
routine clinical practice.
* For a more comprehensive listing of investigations, see Table 2 in the Supplementary Appendix. CDGP denotes constitutional delay of
growth and puberty.
These tests are used to try to differentiate CDGP from isolated hypogonadotropic hypogonadism. However, validation in larger, independent
studies is needed before the use of such tests can be fully endorsed. Often, clinical follow-up is needed to confirm the diagnosis; no endogenous puberty by the age of 18 years is diagnostic of isolated hypogonadotropic hypogonadism.
from isolated hypogonadotropic hypogonadism,

so the diagnosis of CDGP cannot be made with
certitude. Observation usually resolves this conundrum; isolated hypogonadotropic hypogonadism
is diagnosed if endogenous puberty has not begun by the age of 18 years. Several tests have
been proposed to distinguish CDGP from isolated
hypogonadotropic hypogonadism (Table 2, and
Table 2 in the Supplementary Appendix). If basal
gonadotropin levels are inconclusive, stimulation
by GnRH or a GnRH agonist may be helpful.24,25
Stimulated levels of luteinizing hormone in the
pubertal range indicate that the HPG axis has
been reactivated and that secondary sexual development is likely to occur within 1 year. However,
the GnRH test alone often cannot differentiate
CDGP from isolated hypogonadotropic hypogonadism because prepubertal values may be observed in isolated hypogonadotropic hypogonadism or in patients with CDGP in whom the HPG
axis has not yet been activated. Recent data suggest that baseline levels of inhibin B may facilitate discrimination between these conditions,28
but replication is needed before this or other
tests can be routinely adopted.
Growth hormone secretion in the basal state,

as well as after provocative testing, may be decreased in patients with CDGP. If concern about
growth is sufficient to warrant stimulation testing of growth hormone, sex-steroid priming with
estrogen or testosterone is necessary for reliable
results in patients with delayed puberty; estrogen stimulates endogenous growth-hormone secretion, and sex-steroid priming facilitates separation of true growth hormone deficiency from
the physiologic low growth hormone secretion
that stems from low estrogen levels. If a patient
has a normal growth rate, growth hormone
provocation testing is not necessary, whereas low
IGF-1 levels together with reduced growth velocity warrant testing.
Treatment
Patients with CDGP
The options for management of CDGP include

expectant observation or therapy with low-dose
testosterone (in boys) or estrogen (in girls) (Table
3, and Table 3 in the Supplementary Appendix).
If puberty has started, clinically or biochemically, and stature is not a major concern, reassur-

447
The
of
m e dic i n e
Delayed Puberty
First-Line
Evaluation
Family history of delayed puberty

History of chronic disease, cryptorchidism, anosmia,
anorexia, radiotherapy, or chemotherapy
First-line investigations: growth rate, Tanner stage,
testis volume
Tests: biochemical analyses, bone-age radiography,
basal serum LH, FSH, IGF-1, thyrotropin, free
thyroxine, and testosterone (in boys)
Low or normal serum LH and

FSH for early Tanner stages
Working
Diagnosis
Second-Line
Evaluation
(if CDGP is
not evident)
Growth rate in prepubertal

range
Growth rate below prepubertal

range
GnRH deficiency or CDGP

(65% of boys, 30% of girls)
Functional hypogonadotropic
hypogonadism (secondary
to a chronic disease, anorexia)
Permanent hypogonadotropic
hypogonadism or hypopituitarism (10% of boys, 20%
of girls)
Hypergonadotropic hypogonadism
Examine further for chronic

disease: MRI, prolactin
Examine further for underlying cause:

karyotype, serum inhibin B (in boys)
GnRH test
hCG stimulation test
Serum inhibin B
Olfactory-function test
Genetic testing
MRI
Second-Line
Diagnosis
Intervention
448
Elevated FSH
Follow up
Evaluate the need for the
induction of secondary
sex characteristics
Low BMI
Normal BMI
High BMI
GI disorder
Underfeeding
Anorexia
Hypothyreosis
Hyperprolactinemia
GH deficiency
Multiple pituitary hormone deficiency
Glucocorticoid excess
(iatrogenic,
Cushings disease)
Hypothyroidism
Treat underlying cause
Treat with sex steroids

clinical pr actice
Age (yr)
72
70
68
66
64
62
60
58
56
54
52
n engl j med 366;5
50
48
46
44
42
40
38
10
11 12 13 14 15 16
17 18
190
19 20
cm
165
95 190
90 185
75
180
50
175
25
170
10
5 165
160
160
155
155
150
150
185
180
175
170
in
76
74
72
70
68
66
64
60
145
140
105 230
100 220
135
95
130
125
90
120
115
75
95 210
90 200
85
80
75
110
50
105
100
25
95
10
5
70
190
180
170
160
150
65 140
60 130
90
34
85
50 110
32
80
45 100
40 90
35
35
30
30
25
25
20
20
15
15
10
kg
10
kg
30
70
60
50
40
30
lb
Target
height
62
36
80
Weight
ance with realistic adult height prediction is frequently sufficient. If therapy is initiated, it is
usually to assuage psychosocial difficulties that
may derive from negative interactions with peers,
decreased self-esteem, and anxiety about growth
rate or body habitus.
Numerous studies of treatment of CDGP in
boys have been reported. Although some randomized, controlled trials have been performed with
small numbers of subjects, studies have been
largely observational and have involved treatment with short courses of low-dose androgens.34-36 The data suggest that treatment leads
to increased growth velocity and sexual maturation and positively affects psychosocial well-being,
without significant side effects, rapid advancement of bone age, or reduced adult height.
Similar data are not available for girls, but similar outcomes are likely as long as therapy is initiated with appropriately low doses of estrogen.
For a subset of patients with CDGP, short
stature can be more worrisome than delayed
puberty, and indeed CDGP is considered by some
observers to be a subgroup of idiopathic short
stature. Although the Food and Drug Administration has approved the use of growth hormone
for the treatment of idiopathic short stature and
height that is 2.25 SD below average for age, this
therapy has at best a modest effect on adult
height in adolescents with CDGP, and its use in
CDGP is not recommended.
In boys with CDGP and short stature, another
potential therapeutic approach is aromatase inhibition, but this treatment requires further study
before it should be incorporated into routine
practice.37,38 Aromatase inhibitors block the conversion of androgens to estrogens; because estrogen is the predominant hormone needed for
epiphyseal closure, the use of aromatase inhibi-
Stature
74
cm
10
11 12 13 14 15 16
17 18
Weight
in
76
Stature
Figure 1 (facing page). Algorithm for the Evaluation

of a Patient with Delayed Puberty.
Percentages of patients with delayed puberty with various conditions are from Sedlmeyer and Palmert.7 Percentages do not add up to 100% because of rounding and
because a small percentage of patients have disorders
that cannot be classified with the use of this algorithm.
BMI denotes body-mass index, CDGP constitutional delay
of growth and puberty, FSH follicle-stimulating hormone,
GH growth hormone, GI gastrointestinal, GnRH gonadotropin-releasing hormone, hCG human chorionic gonadotropin, IGF-1 insulin-like growth factor 1, LH luteinizing
hormone, and MRI magnetic resonance imaging.
55 120
80
70
60
50
40
30
lb
19 20
Age (yr)
Figure 2. Linear Growth in Delayed Puberty.

In children with delayed puberty (data points), linear growth progresses
with a normal preadolescent height velocity (>3 cm per year). Height relative to that of peers (height percentile) may decrease slightly before the
usual adolescent age range, but this effect is accentuated when the child
with delayed puberty does not undergo a growth spurt in concert with his
or her peers. Consequently, the height percentile decreases in the early teenage years. In children with constitutional delay of growth and puberty, a late
growth spurt will facilitate subsequent catch-up growth, but adult heights
are often slightly shorter than expected on the basis of parental heights.
tors could prolong linear growth and potentially

increase adult height. In controlled trials in boys
with short stature or delayed puberty, aromatase
inhibitors delayed bone maturation and appeared
to increase adult height.37,38 However, the amount
of height gained as well as the optimal timing,
dose, and duration of therapy with aromatase
inhibitors remain uncertain.39 Moreover, potentially adverse effects, especially impaired development of trabecular bone and vertebral-body
deformities, which were observed in boys with
idiopathic short stature who were treated with
letrozole,40 must be considered.
nejm.org
february 2, 2012

449
The
m e dic i n e
Permanent Hypogonadism
Breast Development and Pubic Hair
Stage 1
of
In boys and girls with hypogonadotropic hypogonadism, initial sex-steroid therapy is the
same as that for CDGP, but doses are gradually
increased to full adult replacement levels during
a period of approximately 3 years (Table 3). In
hypogonadotropic hypogonadism, exogenous
testosterone does not induce testicular growth
or spermatogenesis and exogenous estrogen
does not induce ovulation, and the induction of
fertility in both sexes requires treatment with
pulsatile GnRH42-45 or exogenous gonadotropins.44 In girls with hypogonadotropic hypogonadism, treatment with estrogen needs to be
combined with progestin for endometrial cycling.
Stage 2
A r e a s of Uncer ta in t y
Stage 1
Stage 2
Genital Development and Pubic Hair

Stage 1
Stage 2
Figure 3. Tanner Stages in the Assessment of Delayed

Puberty.
Delayed puberty is often associated with short stature
and slow growth for age although the growth rate is
within the prepubertal normal range. Physical markers
of puberty can also be delayed. In girls (Panel A), breast
development from Tanner stage 1 (preadolescent) to
stage 2 (appearance of the breast bud) should traditionally take place between 8 and 13 years of age, and
in boys the development of genital Tanner stage 1 (preadolescent) to stage 2 (enlargement of the testes and
scrotum and change in the texture and reddening of the
scrotal skin) should take place between 9 and 14 years.
Recent data regarding earlier timing of puberty suggest
that these traditional age cutoffs should be adjusted
downward, but new age ranges have not yet been defined.
450
n engl j med 366;5
Further research is needed to establish appropriate age cutoffs for delayed puberty in different racial and ethnic groups and to better understand the physiological basis of CDGP.
Suggested causes of CDGP include increased total energy expenditure46 and increased insulin
sensitivity,47 but no definitive cause has been
identified. Studies should carefully assess the
psychosocial distress among children with delayed puberty, whether this distress has longterm sequelae, and what effect sex-steroid supplementation has on these outcomes. It remains
unclear whether adult bone mass is adversely
affected by pubertal delay48 and whether this
represents a medical reason to initiate sex-steroid
replacement. Distinguishing between CDGP and
isolated hypogonadotropic hypogonadism remains difficult in many cases, and further assessment of the role of inhibin B or other markers for this purpose is needed. Randomized trials
are needed to compare different estrogen formulations, routes of administration (oral vs.
transdermal), and drug regimens to determine
optimal therapy for girls with delayed puberty.
Studies are needed to identify genes that cause
CDGP, which would also elucidate factors that
regulate the timing of puberty.
Guidel ine s
To our knowledge, there are no recent guidelines
regarding the evaluation and treatment of CDGP.
nejm.org
february 2, 2012

No data available on intramuscular injection

No data available
Undecanoate
Transdermal preparations
Side Effects and Cautions
Usually necessary only if estrogen treatment continues longer than

12 mo
Added to induce endometrial cycling after 1218 mo of estrogen therapy (later if estrogen dose is increased slowly, sooner if breakthrough bleeding occurs)
Initial dose, 5 g per kilogram of body weight daily; increase to 10 g Natural estrogen, may be preferable to synthetic estrogens; transderper kilogram daily after 612 mo
mal route may have advantages over oral administration
Overnight patch: initial dose, 3.16.2 g per 24 hr (one-eighth to one- No data on dose equivalent between estradiol patches and gel
fourth of 25-g 24-hr patch); increase by 3.16.2 g per 24 hr every
available in younger patients
6 mo
Initial dose, 0.1625 mg daily for 612 mo with subsequent adjustment Not estradiol precursors; use is questioned as not being physiological
to 0.325 mg daily; dose depends on formulation
and because of reports of increased cardiovascular risks in postmenopausal women
Liver toxicity, increased levels of some plasma-binding proteins, potentially greater risk of thromboembolism and arterial hypertension
than with natural estrogens
Not yet approved for this indication; after onset of puberty, may increase gonadotropin secretion and circulating testosterone levels41
Decreased level of high-density lipoprotein cholesterol, erythrocytosis,
vertebral deformities40
Less potent than letrozole
Local irritation; applied topically at bedtime; after application, must

avoid close skin contact with others
Erythrocytosis, weight gain, prostate hyperplasia; high doses can

cause premature epiphyseal closure; not for use in boys with
a bone age of <10 yr
All administered by intramuscular injection; local side effects: pain,
erythema, inflammatory reaction, and sterile abscess; priapism
can occur in patients with sickle cell disease; longer duration of
effect for testosterone enanthate than propionate
* For further discussion of these agents and of treatment of permanent hypogonadism, see Table 3 in the Supplementary Appendix.
Testosterone undecanoate tablets or anabolic steroids are not recommended for the induction of secondary sexual characteristics.
Progestin
Various options (usually oral)
Conjugated equine estrogens
Transdermal patch
17-Estradiol
Oral
Estrogen
Ethinyl estradiol (component
of contraceptive pills)
Initial dose, 2 g daily; increase to 5 g daily after 612 mo; lowerdose pills available in Europe
1.0 mg daily
Oral anastozole
Girls
2.5 mg daily
Oral letrozole
Aromatase inhibitors
Not recommended before 14 yr of age; initial dose, 50100 mg every

4 wk for 3 to 6 mo; repeated treatment with 25-to-50-mg increment in dose (not exceeding 100 mg)
In Children with CDGP
Enanthate, cypionate, and propionate
Testosterone
Boys
Drug and Formulation
Table 3. Medications for the Treatment of Constitutional Delay of Growth and Puberty (CDGP).*
clinical pr actice

451
The
C onclusions a nd
R ec om mendat ions
The patient in the vignette has delayed puberty.
Given that he is male and has a family history of
late pubertal development, CDGP is the most likely diagnosis. Before making this diagnosis, a careful evaluation is required to rule out other causes;
this is especially true among young women, in
whom underlying disorders are more common.
In CDGP, in which pubertal delay is transient,
the decision regarding whether to treat should
be made by the patient; the goal of therapy,
when used, is to induce the acceleration of secondary sexual characteristics or growth and to
mitigate psychosocial difficulties. For boys who
elect to be treated, we initiate monthly intramuscular injections of 50 mg of testosterone ester
for 3 to 6 months; this regimen can be repeated
for another 3 to 6 months with dose escalation
(Table 3). If spontaneous puberty has not occurred
after 1 year, other diagnoses, such as permanent
of
m e dic i n e
hypogonadotropic hypogonadism, should be reconsidered, and MRI of the brain is indicated.

We believe that when CDGP is treated, therapy
should be with testosterone alone, even if stature
is a prominent concern. We do not use growth
hormone or anabolic steroids for delayed puberty, nor do we recommend aromatase inhibitors for this indication, pending more data from
randomized trials.
Dr. Palmert reports receiving funding as a member of the
Hvidre Study of Childhood Diabetes, which is supported by
Novo Nordisk; payment for lectures at the 2011 Japanese Endocrine Society Meeting and the 2011 Asahikawa Winter Conference on Molecular Medicine with support from Japan Chemical
Research Pharmaceuticals; and payment for participating in a
symposium sponsored by Sandoz at the 2011 Annual Meeting of
the European Society of Pediatric Endocrinology, as well as for a
Grand Rounds lecture at McGill University sponsored by Eli Lilly.
Dr. Dunkel reports receiving lecture fees from Pfizer and payment for participating in a symposium sponsored by Sandoz at
the 2011 Annual Meeting of the European Society of Pediatric
Endocrinology. No other potential conflict of interest relevant to
this article was reported.
Disclosure forms provided by the authors are available with
the full text of this article at NEJM.org.
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Delayed Puberty: Clinical Practice

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What is delayed puberty?

What is delayed puberty?

What are the causes of delayed puberty?

What are the causes of delayed puberty?

The

A 14-year-old boy with an unremarkable medical history presents because of lack

The Cl inic a l Probl em

From the Division of Endocrinology, the

n engl j med 366;5 nejm.org february 2, 2012

The New England Journal of Medicine

key clinical points

obtained from a tertiary referral center, these

delayed development among family members

Ruling Out Underlying Disorders

The aim of initial evaluation is to rule out

n engl j med 366;5 nejm.org february 2, 2012

The New England Journal of Medicine

A family history, including childhood growth

have an increased likelihood of having an underlying condition delaying HPG-axis activation.

The New England Journal of Medicine

Table 2. Investigations for Delayed Puberty.*

Testis volume in boys

Serum luteinizing hormone

Serum follicle-stimulating hormone

Serum insulin-like growth factor 1

Serum testosterone in boys

n engl j med 366;5 nejm.org february 2, 2012

The New England Journal of Medicine

Brain magnetic resonance imaging

from isolated hypogonadotropic hypogonadism,

Growth hormone secretion in the basal state,

Patients with CDGP

The options for management of CDGP include

n engl j med 366;5 nejm.org february 2, 2012

The New England Journal of Medicine

Family history of delayed puberty

Low or normal serum LH and

Growth rate in prepubertal

Growth rate below prepubertal

GnRH deficiency or CDGP

Examine further for chronic

Examine further for underlying cause:

Treat underlying cause

Treat with sex steroids

n engl j med 366;5 nejm.org february 2, 2012

The New England Journal of Medicine

n engl j med 366;5

Figure 1 (facing page). Algorithm for the Evaluation

Figure 2. Linear Growth in Delayed Puberty.

tors could prolong linear growth and potentially

The New England Journal of Medicine

Breast Development and Pubic Hair

Genital Development and Pubic Hair

Figure 3. Tanner Stages in the Assessment of Delayed

n engl j med 366;5

The New England Journal of Medicine

No data available on intramuscular injection

Side Effects and Cautions

Usually necessary only if estrogen treatment continues longer than