PUBERTY

Division of Endocrinology
Dept of Child Health FMUI-CMGH
 Learning Objectives

Physiology of puberty
H-P-G axis
Hormonal changes
Physical changes
Somatic changes
Secondary sexual characteristics (Tanner
staging)
Schedule of puberty
 INTRODUCTION
Puberty
Transition period HHOORRM
GROWTHMOONNAALL
LH, FSH, SEX STEROID
HORMONE DHEAS
between childhood
to adult
Maturation of
reproductive PPHHYYSSIICCAALL
GROWTH REPRODUCTIVE ORGAN

organs and SPURT SECONDARY SEX

attainment of
fertility
MM AATTUURREE
Termination of FINAL
FERTILITY
linear growth HEIGHT
 Introduction

Onset
Female : 8-13 years old
Male : 9.5-13.5 years old
Basic changes
neuroendocrine : gonadotropin, sex steroid, and GH
biologic/physical : linear growth, body composition,
reproductive organs
 Introduction
Reactivation of GnRH secretion -
Hypothesis
Height & weight ratio (nutritional
factors).
Maturation of hypothalamus .
CNS neurotransmitter output .
Onset of adrenal androgen activity
 Gene & HPG Axis

Gene Loss-of-Function Phenotype

GPR54 (G-protein coupled Hypogonadotropic hypogonadism
receptor 54)

KAL-1 (Kallmanns X-linked Kallmanns syndrome:

syndrome 1) hypogonadotropic hypogonadism

SFI (steroidogenic factor 1) Sex reversal and adrenal insufficiency

DAX1 (DSS-AHC critical Hypogonadotropic hypogonadism and
region on the X chromosome adrenal insufficiency
1)
 Gene & HPG axis

Gene Loss-of-Function Phenotype

GNRHR (gonadotropin- Hypogonadotropic hypogonadism;
releasing hormone
receptor)

FGFR1 (fibroblast growth Autosomal dominant Kallmanns

factor receptor 1) syndrome: hypogonadotropic
hypogonadism;

LEP (leptin) Hypogonadotropic hypogonadism and

obesity

LEPR (leptin receptor) Hypogonadotropic hypogonadism and

obesity
 Nutritional theory

Weight gain & %age body fat prerequisite

to puberty critical weight for activation
of HPG axis
47-48 kg / 17% fat
Slightly obese ( 30% ideal BW) begin puberty
earlier
>30% fat delayed puberty
 Gonadostat Hypothesis
Prepubertal:
negative feedback
regulation of FSH /
LH secretion low
threshold &
sensitive to low
levels of steroids
Puberty: sensitivity

gonadotrophins &
sex steroids
 Hormonal changes at
puberty
Adrenarche (mini puberty)
2-3 yrs before gonadarche age 6 - 8 yrs
cortex adrenal activity adrenal
androgens production (DHEA, DHEAS &
androstenedione) pubic and axillary hair
Gonadarche
Pulsatile GnRH secretion leads to stimulation
of FSH/LH activation of gonad sex
steroids & completion of gametogenesis
maturation reproductive organs
Hormonal changes at
puberty
Prepubertal
LH/FSH levels low
insufficient to initiate
gonadal function
Onset of puberty
activity GnRH pulse
generator
frequency & amplitude
GnRH pulses, especially
during sleep progressive
LH/FSH initiate gonadal
function
nocturnal gonadotropin
pulses (onset) daytime
gonadotropin pulses
 Normal pubertal
development
Boys Girls

Onset (yrs)
12.5 11.5
(9.5-13.5) (8-13)

1st sign of puberty Testes volume Breast budding

( 4ml)

Max growth velocity (cm/yr) 10.3 9.0

(Tanner III-IV) (Tanner II-III)

Duration of puberty (yrs) 3.2 1.8 2.4 1.1

 Percentage body fat
Tanner Stage % body fat
Girls
Tanner I 15.7
Tanner II 18.9
Tanner III 21.6
Tanner IV 26.7
Tanner V unchange

Boys
Tanner I 14.3
Tanner II 11.2
Tanner III Unchanged
Tanner IV Unchanged
Tanner V Unchanged
 SOMATIC CHANGES

Pubarche: development of pubic hair

Thelarche: development of breast in females
Gynecomastia: development of breast tissue in
males
Menarche: first menstruation
Female puberty
Female hormonal changes
LH surge initiates
1st ovarian cycle
not sufficient for
ovulation during
1st cycle
estrogen levels in
blood increase, due
to growing follicles
Estrogen induces
somatic changes
Female hormonal changes
Estrogen induces
secondary sex
characteristics:
growth of pelvis
deposit of subcutaneous fat
growth of internal
reproductive organs,
external genitalia
androgen release by
adrenal glands increases
> growth of pubic hair,
lowering of voice, growth
of bone, increased
secretion from sebaceous
glands
 Tanner staging (girls)
Stage
Stage11
Prepubertal;
Prepubertal;no
nobreast
breasttissue
tissue(M1)
(M1)
None (P1)
None (P1)
Stage
Stage22
Areolar
Areolarenlargement
enlargementwith
withbreast
breastbud
bud(M2)
(M2)
AAfew darker hairs along labia (P2)
few darker hairs along labia (P2)
Stage
Stage33
Enlargement
Enlargementof
ofbreast
breast&&areola
areolaas
assingle
singlemound
mound(M3)
(M3)
Curly pigmented hairs across pubes (P3
Curly pigmented hairs across pubes (P3
Stage
Stage44
Projection
Projectionof
ofareola
areolaabove
abovebreast
breastas
asdouble
doublemound
mound(M4)
(M4)
Small adult configuration (P4)
Small adult configuration (P4)

Stage
Stage55
Mature
Matureadult
adultbreast
breastwith
withsingle
singlecontour
contour(M5)
(M5)
Adult pubic hair distribution (P5)
Adult pubic hair distribution (P5)
Sequence of Sexual Maturation

Age
Event
(years)
Thelarche 10-11
Pubarche 10.5-11.5
Growth Spurt 11-12
Menarche 11.5-13
Adult Breast
12.5-15
Development
Adult Sexual Hair 13.5-16
LH, FSH and E2 - PUBERTAL
STAGE
SECONDARY SEXUAL CHARACTERISTIC
HORMONAL CHANGES CHANGES (TANNER STAGE)

1 2 3 4 5
Female Puberty landmark
Breast budding
1st sign of puberty
Menarche
2 yrs > onset of
puberty
Ovulation-
2 yrs > menarche
Growth spurt
early Tanner stage
Final Height -
Puberty in males
Male hormonal changes
LH and FSH release
increases ~10 yrs. of
age
spermatogenesis;
androgen secretion
adrenals also secrete
androgens
androgens initiate
growth of reproductive
organs (e.g. prostate,
penis), other male
characteristics (facial
hair, growth of larynx
voice changes)
LH, FSH and Testosterone and
PUBERTAL STAGE
Tanner staging (Boys)
Male Puberty Landmark
Testes enlargement

1st sign of puberty
Spermache
Wet dream
Age 12-14 yrs
Growth spurt
late Tanner stage
Final Height
Age 18 20 yrs
 CONCLUSION
Puberty progress in
a orderly schedule
Reproductive
function & adult
height is attained
at end of puberty
PRECOCIOUS
PRECOCIOUS
PUBERTY
PUBERTY
 INTRODUCTION
Epidemiology
Frequency : girls > boys
Girls: most have a benign central cause
Boys: 50% pathologic peripheral cause.
all boys with precocious puberty should
undergo detailed investigation, but in girls
additional investigation can be based on the
clinical impression
 Precocious Puberty
Definition
Appearance of
secondary sexual
characteristics : boys <
9 years and girls < 8
years old (- 2SD)
Sex steroid
Estrogen: female
Testosterone:male
 Classification
GnRH dependent (central) :
premature reactivation hypothalamus-
pituitary-gonad axis increased gonadotropin
increased sex steroids (dependent)
Usually idiopathic
GnRH independent (peripheral):
autonomous sex steroid secretion,
depressing the hypothalamus-pituitary-gonad
axis
Usually pathologic
 Classification
Variant
premature thelarche
premature adrenarche
gynecomastia
 Etiology GDPP
idiopathic
CNS
tumor
non-tumor: post infection, radiation, trauma,
congenital
iatrogenic
Delayed diagnosis of GIPP
 Clinical manifestation GDPP
Always isosexual
Normal sequence of puberty
Hormonal profile: increased gonadotropin
and sex steroid
 Etiology GIPP - male
Isosexual
adrenal: tumor, CAH
testes : cell Leydig tumor, familial
testotoxicosis
gonadotropin-secreting tumor:
non CNS: hepatoma, germinoma, teratoma
CNS: germinoma, adenoma (LH secreting)
heterosexual
Increased peripheral aromatization
Etiology GIPP - female

Isosexual)
McCune Albright
Severe hypothyroid
heterosexual
adrenal: tumor,
CAH
tumor ovarium:
arrhenoblastoma
Mc Cune Albright
Syndrome

Trias
Precocious puberty /
endocrine hyperactivity
Fibrodysplasia
Caf au lait
 Clinical manifestation GIPP
Isosexual or heterosexual (late onset
CAH, tumor adrenal)
Disconcordant of sexual characteristics
(testes volume inappropriate with
pubertal stage - smaller)
Low or normal gonadotropin and
increased sex steroid
Benign Premature Adrenarche
self-limited condition occurring before six
years of age
characterized by the appearance of pubic
and no further secondary sexual
development.
normal growth patterns
Benign Premature Adrenarche
Normal bone age
Slight elevation of serum DHEA
Normal adrenal steroid hormone levels
Normal sex hormone levels
ACTH stimulation test: to exclude late-
onset CAH
GnRH test: prepubertal pattern
Normal imaging studies
No specific treatment required
 Premature Adrenarche
Excude virilization
clitoral enlargement, advanced bone age,
acne, rapid growth, and voice change.
rapid progression
If virilization present
measure testosterone, 17-OHP and DHEA
USG: adrenal or ovarian tumor
17-OHP or DHEA: CAH
 Benign Premature
Thelarche
Normal growth rate and bone age
Normal levels of gonadotropins and
estradiol
USG: normal ovaries, prepubertal uterus
Usually resolves spontaneously and
requires no treatment
re-evaluation at intervals of 6-12 months
to ensure that premaure thelarche is not
the beginning of isosexual precocious
puberty
 Gynecomastia
Breast enlargement in males
common in teenage years, lasting 2 years
differentiate with obese boys
lipomastia
no mammae disk
Pathological causes must be sought
 Pubertal Gynecomastia
Incidence: 50-60% of boys during early
adolescence
breast tissue usually asymmetric and
often tender.
If history and physical examination,
including palpation of the testicles, are
unremarkable, reassurance and periodic
reevaluation are all that is necessary.
Most cases resolve in one to two years.
 Gynecomastia
Drugs
sex steroids, hCG,
psychoactive
(phenotiazine),
antituberculosis,
testosterone antagonist
(ketoconazole, cimetidine,
spironolactone)
Malnutrition
Idiopathic (most
common)
Tumor producing
disease
hepatoma, adrenal, testes,
LH and hCG producing
 Pubertal Gynecomastia
Familial gynecomastia
X-linked recessive trait or a sex-limited
dominant trait
unless associated with hypogonadism no
further evaluation in an otherwise normal boy
If severe, gynecomastia cosmetic surgery.
Pathologic gynecomastia
Klinefelter's syndrome: high risk for breast
cancer
prolactin-secreting adenomata
 Pubertal Gynecomastia
Pathologic gynecomastia
hormone-secreting tumors (testes, hepatoma),
cirrhosis, hypo- and hyperthyroidism.
Drug induced (marijuana, phenothiazines,
opiates, amphetamines, digitalis, estrogens,
ketoconazole, spironolactone, isoniazid,
tricyclic antidepressants, cimetidine, etc).
If worsens and associated with
psychologic morbidity bromocriptine,
tamoxifen
reduction mammoplasty rarely indicated.
 Diagnostic work up
Gonadotropin dependent or independent?
Etiology?
 Hypothalamu
Hypothalamu
ss
GnRH

(-) Pituitar
Pituitar
yy
LH/FSH

Gonad
Gonad

E2 or T

H-P-G
H-P-G axis
axis
 Hypothalam
Hypothalam
us
us
GnRH
Primary
(-) Pituitar
Pituitar
yy
LH/FSH

Gonad
Gonad

Sex steroid
H-P-G
H-P-G axis
axis in
in GDPP
GDPP
 Hypothalamu
Hypothalamu
ss
GnRH

(-) Pituitar
Pituitar
yy
LH/FSH

Gonad
Gonad
Extra Gonadal
Extra Gonadal

RY
A
R IM
P
Sex steroid

H-P-G axis in GIPP

 Diagnostic work up
History
age of onset, progressivity, family history,
growth, symptoms extragonadal cause
(adrenal), CNS complaints, gelactic
laughter (hamartoma), previous history:
encephalitis, meningitis TB
Physical examination
pubertal stage, signs of virilisation,
height, testes size (small indicative of
perpheral cause), CNS signs, skin (acne,
caf au lait),
 Diagnostic work up
Laboratory
gonadotropin, HCG, 17-OHProgesterone
(CAH), cortisol (Cushing syndrome,
adrenal tumor)
Imaging
Bone age, pelvic ultrasound, skull x-ray,
CT/MRI, bone survey (McCune Albright),
 Therapy
According to the etiology
GDPP idiopathic: GnRH agonis
GIPP : medroxy-progesteron,
ketoconazole, dll
Variant: observation
 Prognosis
According to etiology
GDPP idiopathic: GnRH agonis
Final height = potential genetic height
Preserved fertility
Psychosocial minimal, regression of
secondary sex
GIPP : medical
Potential genetic height
Regression of secondary sex
 Conclusion
Not all pubertal disorders are
pathologic
Early increase of sex steroid should be
thoroughly investigated
GnRH agonist = drug of choice for
GDPP
PUBERTAS TERLAMBAT
 Definisi
Pubertas terlambat bila tidak adanya
tanda-tanda pubertas
laki-laki pada usia 14 tahun
perempuan pada usia 13 tahun
Klasifikasi
hipergonadotropik hipogonadism
hipogonadotropik hipogonadism
 Definisi
Ammenorrhoe primer
Ammenorrhoe sekunder
 hipogonadis
Hipergonadotro
m
pik
Hipotalamus LHRH

Hipofisis LH/FSH

(-)
Target Organ
(gonad) Primary defect

Sex Steroid
 Hipergonadotropik
hipogonadism
Dengan kelainan kromosom
Dysgenesis gonad
Sindrom Turner
Pure gonadal dysgenesis
Sindrom Klinefelter
Androgen Insensitivity Syndrome *
 Hipergonadotropik
hipogonadism
Tanpa kelainan kromosom
kongenital
gangguan biosintesis steroid adrenal
(P450c17,P450scc,3HSD) dan gonad (17-KS,
P450 aromatase)
anorchia, ovary resistant syndrome, LH
resistance
didapat
radiasi, chemotherapy, proses autoimun
 hipogonadis
Hipogonadotro
m
pik
Hipotalamus LHRH

Primary defect

Hipofisis LH/FSH

(-)
Target Organ
(gonad)

Sex Steroid
 Hipogonadotropik
hipogonadism
Constitutional delay
Kelainan Susunan Syaraf Pusat
Tumor (craniopharyngioma, germinoma, optic
glioma, histiocytosis X)
Struktural (mid line defect)
Sindrom Kallmann
hipopituitarism idiopathic
pasca tindakan (radiasi, khemoterapi
inflamasi, infiltrasi - hemosiderosis)
 Hipogonadotropik
hipogonadism
Penyakit kronis
endokrin, malnutrisi/anorexia nervosa,
kelainan sistemik
Aktivitas fisik berlebihan
Sindrom-sindrom
Prader-Willi; Laurence-Moon-Biedl
 Tatalaksana
Anamnesis
Pemeriksaan fisik
Pemeriksaan penunjang
Terapi
 Anamnesis
Riwayat perkembangan pubertas di
dalam keluarga
Data pertumbuhan & perkembangan
Riwayat penyakit/pengobatan dahulu
Fungsi penciuman
 Pemeriksaan fisik
Pemeriksaan fisik secara umum
Pemeriksaan neurologis (funduskopi) d
Antropometri (TB, BB, rasio segmen atas
dan bawah, rentang lengan)
Status pubertas
Stigmata suatu sindrom (pendek, obese,
retardasi mental, webbed neck dll)
 Pemeriksaan Penunjang
Pencitraan:
usia tulang, CT scan/MRI kepala & USG
genitalia interna (atas indikasi),
Hormonal (basal/ uji GnRH)
LH,FSH,Prolactin, Estrogen atau testosterone
Dan lain-lain
analisis kromosom (atas indikasi)
uji fungsi penciuman
THANK
THANK YOU
YOU