PUBERTAL
DISORDERS
Prof. Dr. Oya Ercan
Early

Timing
Delayed
DELAYED PUBERTY
Delayed Puberty *
Girls >13 years ( menarche >15 )
 Boys >14 years

*No sign
DELAYED PUBERTY
HYPOGONADISM
Hypogonadotrophic
Pathologic
Transient
Non-pathologic
Permanent
Hypergonadotrophic
Girls
Hypergonadodotrophic hypogonadism
(Ovarian failure)


Turner syndrome, gonadal dysgenesis/agenesis
Autoimmune ovarian failure
Type 1: Addison’s, hypoparathyroidism, mucocutaneous candidiasis
Type 2: Addison’s, autoimmune thyroid disease, Type 1 DM
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Mutations in gonadotrophin and gonadotrophin
receptor genes
Galactosemia
Irradiation
Chemotherapy
Infectious disease (Malaria, mumps, shigella, varicella)
Enzyme deficiency
Girls
Hypogonadotropic hypogonadism


Constitutional delay
Permanent hypogonadotropic hypogonadism
Congenital
Acquired
Tumors (craniopharyngioma)
Others CNS lesions: Travma, surgery, infections,
infiltrative diseases
Temporary hypogonadotropic hypogonadism
(secondary causes)

Excessive emotional stres
Unusual physical activity
Inadequate nutritional state
Chronic disease
Systemic illness
BOYS
Hypergonadotrophic Hypogonadism
(Testicular failure)

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Klinefelter and Multiple X Syndromes
Anorchia
Bilateral Cryptorchidism with Dysgenetic Testes
Torsion (bilateral)
Travma
Infection ( mumps, coxsackie )
Chemotoxicity
Irradiation
Inactivating Mutations of LH and its receptor
BOYS
Hypogonadotrophic Hypogonadism
1- Without a permanent defect
Constitutional delay of growth and development
Systemic illness
Crohn disease
Poorly controlled DM
Systemic therapy for chronic conditions
2- Permanent defect
Isolated gonadotrophin deficiency
Multiple Pituitary Hormone Deficiency
Congenital.
Acquired
Tumors, travma, irradiation, surgery, infections,
infiltrative disorders
Congenital Isolated
Hypogonadotrophic Hypogonadism
(IHH)
Absent, incomplete or arrested
isosexual development
 Low gonadotrophins and sex
hormones
 Absence of systemic disease,
syndromic malformations, nutritional
deprivation and other functional or
anatomic pituitary abnormalities

Inactivating Mutations in
Genes Responsible For:
Differentiation and development of GnRH
synthesizing neuron
NROB1 or DAX1, CHD7, FGFR 1, FGF8
 Migration of neurons that synthesize and
secrete GnRH
 Synthesis, release and action of GnRH
 Synthesis, secretion of Gn’s

Migration of GnRH-synthesizing
Nerve Cells
KAL-1 ®
 FGFR 1
 FGF 8
 NELF
 PROK 2
 PROKR 2 ®


Loss of function mutations in these
genes associated with abnormalities
of olfaction (anosmia, hyposmia)
-Kallmann syndrome-
New Modulators of GnRH
Synthesis and Secretion (2009)

Products of TAC3 and TACR3
Prof. Kemal Topaloğlu
-Reproductive function might recover after
adolescence in both males and females
These are subjects with CDGD in the
families of many patients with IHH
(CDGP=CDGD : Absence of micropenis and
crypthorchidism, endogenous initiation of
sexual maturation by age 18 yr )
 These aberrations of pubertal timing are
varying clinical manifestations of a broad
phenotypic expression of disordered
regulation of GnRH pulse generation.

Investigation of Delayed
Puberty

For practical purposes , the complete
absence of signs of puberty after 14
years requires investigation.

Growth rate, rate of epiphyseal
maturation and rate of advance in
sexual maturation have all to be
considered in order to attempt to
separate those children with abnormal
endocrine function from those with
constitutional delay of growth and
puberty.

Pelvic ultrasound assessment
Unfortunately, there is no
equivalent examination in males. Ovarian
maturation continues throughout childhood
and as the ovarian morphology reflects
pulsatile Gn secretion, this examination can
be used to distinguish constitutional delay
from complete hypogonadotrophic
hypogonadism. The examination may also be
useful in the diagnosis of Turner’s syndrome
and gonadal dysgenesis.

Serum sex steroid measurements:
These have little use in the
investigation of delayed puberty. In order to
be useful, serum testosterone in males in
early puberty needs to be measured from
samples in the early hours of the morning
although in girls in early puberty,
measurement of serum estradiol during the
daytime is more appropriate than the
measurement of testosterone in boys.

Serum gonadotrophin measurements:
Basal serum Gn is useful in the
diagnosis of gonadal failure. After the
age of 10 years, both LH and FSH
concentrations are markedly elevated in
gonadal failure.
GnRH Test
GnRH test has no use in the
investigation of delayed puberty. Such
a test is inappropriate in that Gn
release is tested at the pituitary rather
than the hypothalamic level.
 Spontaneous Gn secretion


hCG Test:
Serum testosterone concentrations
before and after hCG offers a method of
distinguishing between constitutional
delay of growth and puberty and
complete hypogonadotrophic
hypogonadism in the majority of cases.

Serum prolactin:
Prolactinomata are a rare cause
of delayed puberty. However, this
diagnosis will be missed unless serum
PRL measurements is undertaken.

Neuroradiology:
Tms of the hypothalamo-pituitary
region may present as an evolving
endocrinopathy of which the loss of Gn
and GH are early in the sequence of the
development of panhypopituitarism.
Chromosomes: Turner syndrome
 GI function:

red cell folate
anti-gliadin ab
coeliac
anti-endomysium ab
inflammatory bowel disease:
radiology ,endoscopy
CDGP:

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Stature reduced for chronological age
but appropriate for pubertal
development and bone maturation.
Family history of delayed puberty
Much more common in boys than girls
Idiopathic Hypogonadotrophic
Hypogonadism:
Normal height
 Arrested epiphyseal maturation at
approximately 13 years
 (+) anosmia (Kallmann’s syndrome)
 Colour blindness
 Cryptorchidism
boys
 micropenis

Sex steroids in boys and girls
 hCG in boys


Not less than 2 years (puberty
induction)
EARLY PUBERTY
Classification
GnRH-dependent
GnRH-driven
Central
True
GnRH-independent
Peripheral
Precocious pseudo
puberty
Early Puberty

Normal Consonance
Idiopathic central precocious puberty
Central precocious puberty secondary to
Hypothalamo-pituitary tumours and infections
Raised intracranial pressure
Cranial irradiation
Gonadotrophin-independent precocious
puberty(Testotoxicosis)

Loss of consonance (pseudopuberty)
Hypothalamo-pituitary endocrinopathy
Cushing’s Disease
Adrenal Disorders
Cushing’s syndrome
Congenital adrenal hyperplasia
Primary tumours
Gonadal Disorders
Primary tumours
Mc Cune- Albright syndrome
Primary Hypothyroidism
Isolated Premature Thelarche
Etiology
FEATURES
CENTRAL
PRECOCİOUS
PUBERTY
THELARCHE
Age of onset
< 8 years
< 2 years
Pubic and axillary hair
Progressive
development
Absent
Menses
As in normal puberty
Usually absent
Skeletal maturation
Advanced
Appropriate
Growth velocity
Accelerated
Normal
Growth prognosis
Compromised
Normal
Duration of condition
Continues as adult
sexual maturation
Usually resolves after a
few years, always by 8
years of age
Prognosis for fertility
Normal
May be compromised
Breast development
Progressive
development
Minor (Usually B2 or B3
cycling at approximately
6 week intervals
Mc Cune-Albright Syndrome
Activating mis-sense mutation in the gene
for the α subunit of Gs.
 Mosaic distribution of cells with mutation
 Polyostotic fibrous dysplasia
 Café au lait spots
 Endocrinopathy
gonads
adrenal cortex
thyroid
pituitary gland
parathyroid gland
“G protein stimulation as if trophic hormones
were present.”

Testotoxicosis

Activating mutation of the LH receptor