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 Pathologic Non-pathologic Hypogonadotrophic Hypergonadotrophic Pathologic Non-pathologic Transient Permanent

Girls (Ovarian failure) Turner syndrome, gonadal dysgenesis/agenesis 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

Girls Hypogonadotropic hypogonadism Congenital 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) 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: 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-independent GnRH-driven Peripheral Central Precocious pseudo True 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 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 Duration of condition Continues as adult sexual maturation Usually resolves after a few years, always by 8 years of age Prognosis for fertility 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