Assistant Professor and Consultant Paediatric Endocrinologist Abnormal Puberty Dr. Amir Babiker MBBS (U of K), FRCPCH (UK), CCT (UK), MSc Endocrinology and Diabetes (UK) Assistant Professor and Consultant Paediatric Endocrinologist  Program Director, Paediatric Endocrinology Fellowships at King Saud University King Saud University (KSU) and King Saud University Medical City (KSUMC) Riyadh, Saudi Arabia

Overview • Physiology of normal puberty • Pubertal assessment • Early puberty: Causes Diagnosis management • Delayed puberty:

Timing of puberty

Incomplete Puberty Premature thelarche Premature Adrenarche Premature menarche

CAUSES OF CPP Idiopathic (F>>M) Organic CNS disruption: Tumours of the hypothalamic-pituitary region Post head injury / meningitis Neurofibromatosis Williams syndrome Prematurity / Cerebral Palsy Hydrocephalus Post cranial surgery or radiotherapy Hypothyroidism Priming

Precocious pseudopuberty in females Isosexual (feminizing) conditions McCune – Albright syndrome Autonomous ovarian cyst Ovarian tumors Feminizing adrenocortical tumor Exogenous estrogens Heterosexual (masculinizing) Congenital adrenal hyperplasia Adrenal tumor Ovarian tumor Glucocorticoid receptor defect Exogenous androgens.

Precocious pseudopuberty in males Isosexual (Virilizing) Congenital adrenal hyperplasia Adrenocortical tumor Leydig cell tumor Familial male precocious puberty HCG secreting tumor Teratoma Heterosexual Feminizing adrenocortical tumor Exogenous estrogens

Causes of Pseudo-Precocious Puberty Sex steroids from the adrenal: • Congenital adrenal hyperplasia • Adrenal tumour • Premature adrenarche (<8-9 yr) • Cushing’s Syndrome Sex steroids from the gonad: • Ovarian tumour, cysts • McCune-Albright Syndrome • Testotoxicosis • HCG – secreting (germ cell) tumours Exposure to exogenous steroids

Assessment History: timing, Family history, associated symptoms Physical examination: •Cutaneous lesions e.g neurofibromatosis, McCune Albright syndrome • CNS examination - Fundi Auxology: Pubertal staging (Tanner) + size of testes Height, weight, MPH, growth velocity Bone age

Investigations Endocrine tests: • Testosterone / oestradiol • LH / FSH • Adrenal androgens (DHEA-S, androstenedione) • 17 –OH progesterone ± synacthen test • β HCG • GnRH test (central or pseudo-precocious) Radiology: • Pelvic ultrasound • MRI hypothalamic – pituitary region DNA analysis: • For known genetic disorders (testotoxicosis, McCune Albright Syndrome)

The goals of treatment for CPP Improvement of adult height Prevention of social and psychological problems. Treatment of Pseudopuberty – by treating the cause (e.g adrenal tumour or CAH)

Delayed puberty/Pubertal failure

classification 1. Central (Hypogonadotrophic Hypogonadism) Physiological central delay and true GnRH /gonadotrophin deficiency 2. Peripheral (Hypergonadotrophic Hypogonadism) Primary gonadal failure

Hypogonadotrophic hypogonadism Constitutional delay of puberty Chronic illness/systemic disease Malnutrition (including anorexia nervosa, Dieting, over-exercise) Hypothyroidism Impaired H-P axis: Tumours H-P axis Congenital: SOD, Genetic defects Acquired : CNS Radiotherapy/trauma

Hypergonadotrophic hypogonadism: Girls • Gonadal dysgenesis/Turner’s syndrome • Autoimmune ovarian failure • Gonadal failure following chemotherapy or abdominal irradiation, Toxic damage (iron overload) • 46 XY DSD including CAIS • PCOS

Hypergonadotrophic hypogonadism: Boys Testicular damage: cryptoorchidism, orchidopexy, torsion Bilateral anorchia Syndromes: Noonans’s, P-W S, L-M-B-B S Gonadal dysgenesis: Klinefelter’s syndrome, other XY aneuploidy, XO / XY Gonadal failure following chemotherapy or testicular irradiation

When should you investigate? Delay of more than 2-3 standard deviations from the mean age of pubertal onset. Delayed : no sexual maturity by 14 years in boys & 13 years in girls. Absence of menarche by 16 years of age, or within 5 years of pubertal onset. Pubertal development begins, but progression stalls, the duration of a given characteristic is longer than expected

Assessment Careful History : Anosmia, galactorrhea, hypothyroidism Excessive exercise Chronic illness or psychiatric disease. Family history. Physical examination: Growth parameters. Sexual maturity. Stigmata of congenital syndromes. Chronic illness, Fundal examination

CONSTITUTIONAL DELAY Constitutional delay explains 90-95 % of pubertal delay. It is a normal variant that results from persistence of the prepubertal hypogonadotropic state. Boys present more often than girls. It may be superimposed on constitutional short stature.

CDP More than 60% of patients have positive family history. Findings on physical examination are unremarkable. Delayed bone age that is consistent with the pubertal maturation. Sexual maturity & final height are not affected.

BILATERAL GONADAL FAILURE Uncommon. Markedly elevated serum gonadotropins. Congenital : –Turner Syndrome –Klinefelter Syndrome Other congenital & acquired causes are rare.

OTHER CONGENITAL syndromes Androgen Resistance. Prader-Willi Syndrome. Laurence-Moon & Bardet-Biedl Syndrome. Noonan Syndrome. Vanishing Testes Syndrome Resistant Ovaries Syndrome.

Delayed PUBERTY & GROWTH

Investigations

Other INVESTIGATIONS Chromosomal analysis. Screen for occult chronic: CBC, ESR First morning urinary testosterone

MANAGMENT Treat the underlying cause + induction +/- HRT Constitutional delay may be managed by reassurance alone, expectant management. “ jump start” hormonal therapy may be used if delay has led to psychosocial dysfunction. Objectives: Final adult height Secondary sexual characteristics Physical and psychological wellbeing

Treatment of delay/failure

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