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 Hypergonadotrophic

Pathologic Non-pathologic

Transient Permanent

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 Mutations in gonadotrophin and gonadotrophin

receptor genes Galactosemia Irradiation Chemotherapy Infectious disease (Malaria, mumps, shigella, varicella) Enzyme deficiency

GirlsHypogonadotropic 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

BOYSHypergonadotrophic Hypogonadism(Testicular failure) 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

BOYSHypogonadotrophic Hypogonadism1- Without a permanent defect Constitutional delay of growth and development Systemic illness Crohn disease Poorly controlled DM Systemic therapy for chronic conditions2- 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 neuronNROB1 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: 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-independentGnRH-driven PeripheralCentral Precocious pseudoTrue puberty

Early Puberty

Normal Consonance

Idiopathic central precocious pubertyCentral 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 HypothyroidismIsolated Premature Thelarche

EtiologyFEATURES 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