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Puberty Disorders Dr. Sarar Mohamed MBBS, FRCPCH(UK), MRCP (UK), MRCPCH(UK), DCH(Ire), CCST(Ire), CPT(Ire), MD Consultant Pediatric Endocrinologist & Metabolic Physician Assistant Professor of Pediatrics King Saud University Definition of puberty • What is puberty? – It is the transitional period of development during which an individual mature from childhood to physical, psychosocial, sexual & reproductive maturity. PUBERTY Gonadal maturation with acquisition of secondary sexual characteristics and associated growth spurt FERTILITY AND FINAL HEIGHT Endocrine Regulation • Negative feedback: – Inhibits GnRH from hypothalamus. – Inhibits anterior pituitary response to GnRH. • Inhibin secretion inhibits anterior pituitary release of FSH. • Female: – Estrogen and progesterone. • Male: – Testosterone. Insert fig. 20.9 Onset of puberty • The age of onset of puberty – Females 8-13 – Males 9-14 • Average age of onset: – GIRLS 10 to 11 years (range 8 to 13 years) – BOYS 11 to 12 years (range 9 to 14 years) • 1st sign of puberty in females is breast development, and testicular enlargement in males. Axiliary and pubic hair follows along with other 2ndary sexual characteristics. • The maximum growth velocity occurs at 12 years. • The age of menarche has decreased over the last 3-4 decades due to improved nutrition, general health & life style. • Menarche marks the attainment of reproductive maturity. Duration of puberty • The time from onset to completion of puberty – Average 4.2 years – Range 1.5-6 years Factors That Affect Puberty • Genetics • Race/Ethnicity (blacks before white) • Previous nutrition ,malnourished they go to puberty later. • Subcutaneous fat (overweight reach puberty faster) • Obesity – Increased leptin and estrogen production – Insulin stimulation of ovaries & uterus • Birth weight Initial signs of puberty • GIRLS – Breast Development • BOYS – Testicular Enlargement – Volume > 3.0 cm³ – Length > 2.5 cm Growth in puberty • Female enter growth spurt before males because females (around 10 years) enter puberty before males (around 12 years). Insert fig. 20.10 Evaluation of disorder of puberty • CLINICAL ASSESSMENT – History • • • • • • Behavioural changes Pubertal staging Skin examination Height measurement / Growth velocity Bone age assessment Hormone study if needed Assessment of Puberty • History – Parents • onset of puberty – Menarche – Male Age of first shaving regularly • Parental heights (mid-parental height) • prenatal and perinatal (exposure to exogenous sex steroids in intrauterine period; birth weight; perinatal asphyxia) • Concomitant illnesses, postnatal exposure to sex steroids • Time of first sign of puberty – Thelarche (galactorrhea) development of breast, testicles – Adrenarche/pubarche (body odor, axillary & pubic hair, acne) development of pubic and axillary hair. – Menarche menstruation – Gonadarche • Premature thelarche is different the precocious puberty. Premature thelarche is when there is breast or testicular enlargement before the age of 8 or 9 years in females and males respectively. • In premature thelarche the X-ray images and hormonal levels are normal with no other signs of puberty. History • Important to include: – Past medical history (history of brain tumor, radiation, chemotherapy, known genetic disorder, chronic disease affecting growth) – Eating habits • Any evidence of disordered eating – Activity level • Is exercise excessive or is this an athlete with a high level of training – Growth history • Previous growth chart can be extremely helpful History • Review of Systems – CNS: visual changes/visual field abnormalities, headaches, anosmia – Cardiac: congenital anomaly – Respiratory: asthma – Renal: – GI: diarrhea, blood in stools Physical Examination • Examination of Growth – Height – Weight • Pubertal Assessment (Tanner staging) – – – – Axillary hair Pubic hair & staging Breast development & staging Genital development & staging • skin, hair, thyroid • Neurological assessment Growth charts Staging of pubertal development in girls (Tanner) Staging of pubertal development in bpys (Tanner) G1-5, Pu 1-5, A 1-5, testicular volum > 4 ml – first sign of male puberty Its used to measure the testicular size and development. Prader orchidometer along with tanner staging is used to asses puberty in males. Diagnostic evaluation • Laboratory – gonadotropins (FSH, LH) basal and peak after LHRH stimulation (prepubertal LH/FSH<1) – estradiol – testosteron (basal value and value after LH stimulation) – adrenal androgens (17-OHP, A-dion,...) and ACTH – bone age by hand X-ray. – Pelvic US (ovarian and uterine size) – CT or MRI of adrenals, Brain to exclude tumors. – Vaginoscopy – Genetic – karyotype, DNA analysis Bone age 2 yrs 6 m. 10 yrs 12 yrs Summary:Variants of puberty • Premature thelarché – Only premature breast development, with normal hormones. – exclude the start of precocious puberty! • Premature adrenarché – Only premature axillary and pubic hair, with normal hormones. – exclude simple virilising form of CAH! • Premature menarché – exclude vaginal bleeding due to trauma of vagine or rare ovarian cyst! • • • • • Bone age is not accelerated! FSH and LH levels after LH-RH are normal Gonadal and adrenal steroid levels are normal Pelvic and adrenal ultrasonography is normal Reassurance & f/u PRECOCIOUS PUBERTY Landmark Case of Precocious Puberty • 5 year old Lina Medina of Peru – Menses onset age 8 months – Breast development age 4 – Advanced bone maturation age 5 – Was evaluated for abdominal tumor due to increasing abdominal size at age 5 – On 5/14/1939 gave birth to a 2.9 kg baby boy Definition of Precocious Puberty • ONSET OF PUBERTY BEFORE – Females 8 years – Males 9 years • Lawson Wilkins Pediatric Endocrine Society recommended 7 for white girls/ 6 for black • Prevalence – is estimated to be between one in 5,000 to 10,000 children annually in the United States. • They can conceive. Classification • Central (true), gonadotropin-dependent – Early stimulation of hypothalamic-pituitary-gonadal axis. – Idiopathic. • Peripheral resistance, GnRH independent (precocious pseudopuberty) – The source of sex steroid may be endogenous or exogenous, gonadal or extragonadal, independent of gonadotropins stimulation. – Look for ovarian tumor. True precocious puberty (central, GnRH dependent) • Idiopatic, constitutional sporadic or familial (common) • CNS abnormalities – Congenital (hydrocephalus, arachnoid cysts, ...) – Acquired pathology (posttraumatic, infections, radiation,.. – Tumors (LH secreting pituitary microadenoma, glioma – may be associated with neurofibromatosis, hamartoma,.. – Reversible forms - space occuping or pressure-associated lesion (abscess, hydrocephalus,...) • Adopted children or children emigrating from developping countries – Improved nutrition, environmental stability and psychosocial support True precocious puberty (central, gonadotropin-dependent) • Bone age is accelerated • FSH and LH elevation after LH-RH is diagnostic test • (LH/FSH > 2) • LH LH/FSH ratio < 1 Prepubertal • LH LH/FSH ratio > 1 Pubertal • MRI of CNS is necessary to exclude the neoplasia Treatment of true precocious puberty • Purpose of treatment – To prevent psychosocial distress – To improve final height outcome because growth will stop at that age, resulting in short stature. • Treat the underlying cause • GnRH analogue – – – – Lupron depot ped, leuprolide acetate Desensitizes the pituitary Blocks LH and FSH secretion Prevents continued sexual development for the duration of the treatment • Growth may almost stop while on therapy • ± addition of growth hormone remains controversy Precocious pseudopuberty in girls (gonadotropin-independent) • McCune - Albright syndrome • Ovarian cysts – Isolated follicular cysts with E2 production. Selflimiting with spontaneous regression • • • • Ovarian tumors Acceleration of bone age FSH and LH are low after LH-RH stimulation Estrogens are elevated Precocious pseudopuberty in boys (gonadotropin-independent) • Congenital adrenal hyperplasia (CAH) – Undiagnosed or inadequately treated simple virilising form of CAH caused by 21-hydoxylase deficiency. – Neonatal screening. • Testotoxicosis – Activating mutation of LH receptor. AD inheredited. • Tumors – Gonadal (testosterone-secreting Leydig cell tumor) – Adrenal (adenoma, carcinoma) • Exogenous androgens (anabolic steroids – iatrogene, doping) – McCune Albright Syndrome • Acceleration of bone age • FSH and LH are low after LH-RH stimulation • Testicular or adrenal steroids are elevated Precoccious puberty-treatment • Gonadotropin-dependent PP • Idiopathic – GnRH (LH-RH) analog to block LH-RH receptor of pituitary gland • Organic – tumor or cysts – Surgery • Gonadotropin independent (pseudopuberty) – Treat underline cause – Testicular, ovarian or adrenal tumors –surgery – CAH – substitution of corticosteroids Delayed puberty . Delayed puberty - definition • Initial physical changes of puberty are not present • by age 13 years in girls – (or primary amenorhoe at 15.5-16y) • by age 14 years in boys Types of delayed puberty • Gonadotropin dependent – Hypogonadotropic hypogonadism – Low LH/FSH – Central, chronic disease • Gonadotropin independent – Hypergonadotropic hypogonadism – High LH/FSH – Peripheral cause (gonads) GnRH or gonadotropin dependent • Idiopathic • sporadic or familial (associated with constitutional growth delay) • Chronic diseases with bone age delay and growth retardation due to different pathophysical mechanismes (malnutrition, anemia, acidosis, hypoxia,...anorexia nervosa, cystic fibrosis, chronic renal insuficiency,..) • Psychosocial deprivation GnRH or gonadotropin dependent • Hypogonadotropic hypogonadism • Gonadotropin deficiency – LH only (fertile eunuch syndrome) – FSH and LH – Congenital (genetic, syndromes) - Kallman syndrome –mutation of KAL gene, mutation of DAX1 gene, Prader-Willi syndrome ,... – Acquired - cranial irradiation, hemosiderosis, granulomtous disease • Associated with others pituitary hormones deficiencies – Congenital – empty sella syndrome, genetic-transcription factors, disruption of pituitary stalk (breech delivery),... – Acquired – tumors, inflamation, irradiation, trauma.... Kallman Syndrome • A syndrome of isolated gonadotropin deficiency • 1/10,000 males, 1/50,000 females • KAL-1 gene • Present with ANOSMIA or HYPOSMIA • Can also be associated with harelip, cleft palate, and congenital deafness Syndromes Associated with Pubertal Delay • • • • Prader-Willi syndrome Laurence Moon syndrome Septo-optic dysplasia Bardet-Biedl syndrome Gonadotropin independent (hypergonadotrophic) Boys • Congenital – Anorchia – Chromosomal abnormalities (Klinefelter syndrome, Noonan syndrome…) • Disorders in androgen synthesis or action – – – – – Acquired Autoimunne inflamation (APS) Radio or chemotherapy Traumatic Surgery Klinefelter’s Syndrome • • • • • • 45 XXY most common (2/3) Tall in childhood, with euchanoid body habitus More female type fat distribution puberty is delayed Small testicles & gynecomastia 90-100% are infertile Klinefelter's syndrome (Williams Textbook of Endocrinology, 10th ed, 2003) Previous photos • A 19-year-old phenotypic male with chromatin-positive seminiferous tubule dysgenesis (Klinefelter's syndrome). • The karyotype was 47,XXY, gonadotropin levels were elevated, and testosterone levels were low normal. • Note normal virilization with long legs and gynecomastia (B, C). The testes were small and firm and measured 1.8 × 0.9 cm. • Testicular biopsy revealed a severe degree of hyalinization of the seminiferous tubules and clumping of Leydig cells. • D, A 48-year-old male with 47,XXY Klinefelter's syndrome with severe leg varicosities. Gonadotropin independent (hypergonadotrophic hypogonadism) Girls • Congenital – Billateral ovarian torsion – Chromosomal abnormalities (Turner syndrome, pure gonadal dysgenesis, Noonan syndrome…) • Acquired – – – – Autoimunne inflamation (APS) Radio or chemotherapy Traumatic Surgery Turner syndrome • Karyotype 45,X (60%), (45,X/46,XX, structural abnormalities of X chromosome) • Incidence 1/2000 • Short stature (final height 142-147 cm) • web neck • Gonadal dysgenesis - streak gonad • Autoimmune: Hashimoto’s thyroditis, Addison’s • Mild insulin resistance • Essential hypertension • hearing loss /No mental defect • Impairment of cognitive function: mathematical ability↓ • Visual–motor coordination, spatial-temporal processing↓ • Y chromosome predisposed to gonadoblastoma H. Turner, 1938 Investigation of Delayed Puberty • Investigations depend on clinical presentation, but may include – Bone age – Hormone levels (IGF-1, FSH, LH, estradiol, testosterone, DHEAS, prolactin, TSH) – Karyotype – Hormone stimulation tests • GnRH stimulation test • GH stimulation test – Imaging • MRI brain if gonadotropins low & no obvious cause of hypogonadotropic hypogonadism • US or MRI pelvis Treatment of delayed Puberty • Treat underline cause • Time of therapy initiation may vary and individualized • Testosterone supplementation • Estrogen for girls