Puberty - Particulars Pertaining to
Precocity
Plus - points on plasticizers, poultry as possible
perpetrators
Genna W. Klein, M.D.
Molly Center for Children with Diabetes and
Endocrine Disorders
DISCLOSURES
• No disclosures
• No specific off label medication
GOALS OF THIS SESSION
• 1) recognize the timing and events that occur in
normal and abnormal puberty in boys and girls, with
specifics regarding when to refer
• 2) understand the differences among forms of
complete and incomplete precocious puberty as well
as the evaluation and possible treatments of these
• 3) recognize and discuss posited associations
between certain exposures and
puberty timing.
ROADMAP
• Definitions/mechanisms
• Clinical findings
• Link between puberty and growth
• Growth chart review
• Perturbations to normal timing
• Delay
• Precocity
• Is there a rising incidence? Why?
• Throughout talk
When to refer
A ‘GROWING’ PROBLEM?
• Up to 52% of referrals to pediatric
endocrinologist were for growth or pubertal
problem
•
•
•
•
Short stature
Puberty
Tall stature
Pituitary disorder
• Thyroid: add another 7%
• Obesity: add another 6%
J Paediatr Child Health. 2010 Jun;46(6):304-9
MORE ON THIS LATER
ADOLESCENCE – WHO
DEFINITION
• “The period in human growth and development that
occurs after childhood and before adulthood, from
ages 10 to19.”
• “ critical transition in the life span
characterized by a tremendous pace in growth and
change
second only to that of infancy.”
• “ onset of puberty mark[s] the passage from
childhood to adolescence.”
ADOLESCENCE – WHO
DEFINITION
• “ Duration and defining characteristics of this
period may vary across time, cultures, and
socioeconomic situations. This period has seen many
changes over the past century namely the earlier
onset of puberty, later age of marriage, urbanization,
global communication, and changing sexual
attitudes and behaviors.”
PUBERTY - DEFINITION
• Puberty is biological process whereby sexual
and physical characteristics mature
• Sexual maturation of HypothalamicPituitary-Gonadal (HPG) axis that culminates
in adult-type hormone profiles (levels and
feedback) that are required for reproduction.
H
P
X
Endocrine Axes
H
P
X
PUBERTY DEMONSTRATES NEUROENDOCRINOLOGY AT ITS FINEST
• For puberty to occur, there must be an
organized interplay of:
• Peripheral hormones
• Central transmitters (inhibitory and stimulatory as
well as timed release of inhibitory processes)
• Changing sensitivities of receptors to their ligands
under hormonal influence
• Changing feedback loops
PUBERTY ONSET – DEFINITION
BY CLINICAL SIGNS
• Girls – first sign in most is breast budding (‘thelarche’)
• Boys – first sign in most is testicular enlargement to
> 3 ml and scrotal thinning
• These are the physical findings that occur after the
reactivation of the HPG axis to promote ‘gonadarche’.
• ‘Adrenarche’ is the result of a separate re-awakening
of the HPA (adrenal) axis.
• 10-15% of normal children can have adrenarche as their
first sign
SEPARATE PARALLEL HP AXES
“Gonadarche”
Glutamate, NKB,
Kisspeptins,
Leptin
GABA
“Adrenarche”
?
• We don’t fully know what
sparks the reactivation of
the HPG axis to initiate these
changes
• Somatic growth, body fat mass,
diet, stress, circadian rhythm,
gonadal steroids, energy
expenditure, olfactory cues
• More on the roles of this
neuronal network later.
PROBLEMS WITH PUBERTY
• Timing
• Too early?
• Too late?
• Too fast?
will go through growth chart
• Inappropriate height gain? We
mini workshop if time permits
• Incomplete or puberty variant?
• Failure to progress?
PUBERTY - TIMING
• Puberty normally begins between the ages of 8 and
13 years in girls and 9 and 14 years in boys
• Biochemical changes representing the reactivation
of the HPG and HPA axes begin prior to the onset of
physical changes
ACTIVATION
OF HPG
AXIS FROM
FETUS TO
CHILDHOOD
TO
PUBERTY
AND ADULT
LIFE
Bourvattier, 2012
GnRH PULSE GENERATOR
AND SERUM LH BY TIME
OF DAY
Courtesy Medscape
A WORD ABOUT PUBERTAL
HORMONE LEVELS
• At very early stages of pubertal development,
serum levels of pubertal hormones can be
equivalent to prepubertal levels.
• Assays that have high sensitivity at the very
low concentrations are necessary to discern
no puberty from early puberty
• Time of day is important due to the onset of puberty being
marked by irregular and infrequent, yet effective pulsatility
mostly at night while asleep AM clinic values will be more
likely to be measurable
GnRH PULSE GENERATOR
AND SERUM LH BY TIME
OF DAY
Courtesy Medscape
SERUM LH BY TIME OF DAY
Courtesy Medscape
A WORD ABOUT PUBERTAL
HORMONE LEVELS
As Tanner stage increases, and as gonadal volume increases,
serum sex hormone concentrations also do increase, however
there is much overlap in these levels and levels of measured
hormones do not correlate to clinical stage of development
SEQUENCE OF PUBERTAL
EVENTS
SEQUENCE OF PUBERTAL
EVENTS
DELAYED PUBERTY - DEFINITION
• Boys – no testicular enlargement by the age of 14
(some sources 13)
• Girls – no breast development by thirteen (some
sources 12) or no menarche by sixteen or more than
3 (some sources 4) years between breasts and
menses
GROWTH AND
PUBERTY
• Peak Height
Velocity is earlier in
girls than boys
PRECOCIOUS PUBERTY DEFINITION
• Despite discussions of earlier timing of
puberty start, pediatric endocrinologists
continue to use the same definition:
• Any secondary sexual changes that occur
prior to age 8 in a girl or age 9 in a boy.
PRECOCIOUS PUBERTY
PARTICULARS
• Definition of range of normal puberty
• Is there really a shift to earlier onset? – more on this later
• Are there factors responsible for this earlier start?
• Evaluation of puberty –Are the findings consistent
with pubertal changes?
Enter expert opinion regarding
whether early age is significant or
• Are these findings of concern?
normal forwith
ethnicity,
family, etc.
• Are these findings progressive or associated
other
markers of rapid development?
• Is treatment warranted?
• Is treatment likely to be beneficial?
TREATMENT
• Treatment is warranted depending on the
cause as well as the likelihood that treatment
will benefit.
• If cause is a tumor, obvious.
• If cause is idiopathic, reasons to treat CPP
• Final height likely to be impaired
• Psychologically not ready
• In a non-classical CAH
• Above reasons
GNRH PULSE GENERATOR
AND SERUM LH BY
TIME OF DAY
Courtesy Medscape
EVALUATION OF PRECOCIOUS
PUBERTY - HISTORY
• Onset, age, sex, characteristics, tempo, exposures
• Growth pattern
• Past medical history
• Birthweight (SGA), catch up growth, medical problems and treatments
(neuro, oncologic), dental development, international adoption
• Milestones/development
• Medications
• Rx (valproate)
• Family history
• Parent/sib heights and puberty
EVALUATION OF PRECOCIOUS
PUBERTY - PHYSICAL
• General
• Signs of virilization in girls, feminization in boys
• Skin – generalized hypertrichosis, CAL macules,
hyperpigmentation, EENT – fundi
• Thyroid
• Abdominal masses
ARE THE PHYSICAL FINDINGS
CONSISTENT WITH TRUE SIGNS OF
HORMONAL STIMULATION?
• If referred for pubic hair: is it fine vellus hair in the pubic
region vs. androgen dependent hair?
• If referred for breast development: is it glandular or fatty?
• Are there other signs of estrogenization?
• If the findings ARE consistent, how do we categorize and
evaluate the child further?
• Are there signs present those of estrogenization,
androgenization or both?
EVALUATION OF PUBERTAL STAGE
- PHYSICAL
• Puberty (Girl) - estrogenization
• Breasts
• By inspection (nipple/areolar changes, mound) and palpation
(discs of tissue subareolarly, admixed with fatty tissue)
• Vaginal mucosa color change and elongation of labia
minora
• Note loss of the abundant vasculature of the prepubertal
hymen, change from red mucosa prepubertally to pastel pink,
moist mucosa of the estrogenized vagina and thickening of
tissue, and slight white vaginal secretions
ESTROGENIZATION OF VULVA
http://www.austinurogynecology.com/labiaplasty/
TANNER STAGES –
FEMALE
EVALUATION OF PUBERTY PHYSICAL
• Puberty (Boy) – ‘testosteronization’
• Scrotal thinning
• Testicular enlargement
TANNER STAGES – MALE GENITALIA
EVALUATION OF PUBERTY PHYSICAL
• Puberty (Both) - adrenarche
•
•
•
•
•
Acne
Axillary odor
Oily skin
Axillary hair
Pubic hair
TANNER STAGES – MALE AND
FEMALE
A WORD ABOUT GYNECOMASTIA
• Pubertal gynecomastia is a very common
phenomenon, occurring in up to 50% of
pubertal boys.
• Can be tender, can be asymmetric
• Typically lasts up to a year, sometimes longer
• In boys with obesity, or in boys with syndromes with
low endogenous testosterone (47 XXY), will persist
• Prepubertal gynecomastia should always be
investigated
Testosterone
Estradiol
Adult Male
Early/Mid puberty Male
47 XXY
ARE THE PHYSICAL FINDINGS
CONSISTENT WITH TRUE SIGNS OF
HORMONAL STIMULATION?
• If the findings ARE consistent, how do we categorize and
evaluate the child further?
• Growth velocity increased?
• Lab tests (baseline and under stimulated conditions)
• Imaging
•
•
•
Bone age to determine skeletal maturity
Ultrasound
MRI pituitary
DEFINITIONS RELATED TO
PRECOCITY
• Central precocious puberty (PP) – aka “True
PP” aka gonadotropin dependent PP
•
More common and more likely benign in girls
(idiopathic) in girls
•
Much more critical to evaluate in BOYs (tumor)
• Peripheral precocious puberty – aka
gonadotropin independent precocious
puberty
•
Can jumpstart CPP
Grumbach, Horm Res, 2002
MORE DEFINITIONS RELATED
TO PRECOCITY
• Variations of puberty development
• premature thelarche
• premature adrenarche
• premature isolated menarche
ARE THE FINDINGS CONSISTENT
WITH VARIANTS, INCOMPLETE
PUBERTY OR COMPLETE PUBERTY?
• Difficult to determine in one office visit window.
2
2
History sometimes helps.
• Only hair in a girl but no breast budding or vaginal
discharge
>3
2
• Breast buds in a girl 6 mo – 2 years of age
• Boy with axillary hair but testicles 1-2 cc and
symmetric (central cause ruled out)
>3
>3
• CAVEAT – height velocity not increased
“Gonadarche”
“Adrenarche”
Glutamate, NKB,
Kisspeptins,
Leptin
GABA
BENIGN PREMATURE
THELARCHE OF INFANCY
• CAVEAT – height velocity not increased
Consultant for pediatrics, Volume 11, Aug. 2012
Cannot
stress the
importance
of accurate
graphing
on a growth
chart
GROWTH AND PUBERTY
CANNOT BE UNTANGLED
• Part of your evaluation is the review of the
Growth curve – review for height acceleration, BMI
• Caution in the age of EMR
• Not always measured/plotted well
• Cannot superimpose parental heights
• Often points from other clinics/other equipment cannot be
extracted.
• Accurate measurement and GRAPHING is very
important
Measure correctly and
carefully
FRANKFURT PLANE
PLOT
CAREFULLY
AND NEATLY
SO THAT IT
IS A TOOL TO
DETERMINE
THE
GROWTH
VELOCITY
www.cdc.gov/growthcharts
PLOT
CAREFULLY
AND NEATLY
SO THAT IT
IS A TOOL TO
DETERMINE
THE
GROWTH
VELOCITY
www.cdc.gov/growthcharts
PLOT
CAREFULLY
AND NEATLY
SO THAT IT
IS A TOOL TO
DETERMINE
THE
GROWTH
VELOCITY
www.cdc.gov/growthcharts
Growth velocity is the key
in
cm
Stature
in
62
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180
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cm
160
155
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145
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95
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-3 SDS
-4 SDS
-5 SDS
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10 11 12 13 14 15 16 17 18 19
Age (y)
20
76
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97
75
25
1.88
1.28
0.67
0.00
-0.67
-1.28
-1.88
-2.25