Puberty – Normal and Abnormal For UG-2014

Puberty Disorders of puberty constitute one of most common referrals to paediatric endocrine clinics Careful history and examination paramount Ensure sensitivity at all times Chaperone during pubertal examination

Puberty Physiological transition from childhood to reproductive maturity Associated with: Growth spurt Appearance of both primary and secondary sexual characteristics in children Occurs between 8 and 14yrs in girls Occurs between 9 and 14yrs in boys

Puberty Important to understand Range of normal Population differences

Normal Puberty: Endocrine control Onset of puberty signalled by the secretion of pulses of Gonadotrophin Releasing Hormone (GnRH) Prior to puberty: hormonal feedback / central neural suppression of GnRH release suppress onset of puberty Hypothalamo-pituitary-gonadal axis starts working in foetus. After birth, sex hormones and gonadotrophins (FSH, LH) found in adult levels Levels reduce in months after birth; pulsatile GnRH reduces in childhood and increases in frequency and amplitude before puberty For 2 yrs before puberty, rise in adrenal androgens early pubic hair and spots

Physiology of Puberty Activation of the hypothalamic – pituitary – gonadal axis Induces and enhances progressive ovarian and testicular sex hormone secretion Responsible for the profound biological, morphological and psychological changes which adolescents experience

Influencing Factors Genetics: 50-80% of variation in pubertal timing Environmental factors e.g. nutritional status Leptin → regulates appetite and metabolism through hypothalmus. Permissive role in regulation of timing of puberty Adrenarche: development of pubic and axillary hair, body odour and acne

Adrenal Steroids DHEA, DHEA-S, Androstenedione Begins before rise in gonadotrophin secretion Responsible for appearance of axillary hair ad in part for appearance of pubic hair (adrenarche)

Physical Changes 5 stages from childhood to full maturity Marshall and Tanner (P1 – P5) Reflect progression in changes of the external genitalia and of sexual hair Secondary sexual characteristics Mean age 10.5yrs in girls Mean age 11.5 – 12yrs in boys

Puberty: Girls Breast enlargement usually first sign. Thelarche Often unilateral Menarche usually 2-3 yrs after breast development Growth spurt peaks before menarche Pubic and axillary hair growth: sign of adrenal androgen secretion Starts at similar stage of apocrine gland sweat production and associated with adult body odour

Examination: Girls Examine in supine position. Helps differentiate between true breast enlargement vs adiposity Genital exam: pubic hair, changes in vaginal mucosa. Cliteromegaly suggests androgen excess and virilisation Mild acne normal in early puberty but rapid onset and progression may suggest androgen excess Vaginal exam only if sexually active NEVER rectal exam

Pubertal Stages (Tanner) Female P1 Prepubertal P2 Early development of subareolar breast bud +/- small amounts of pubic and axillary hair P3 Increase in size of palpable breast tissue and areolae, increased dark curled pubic/axillary hair P4 Breast tissue and areolae protrude above breast level. Adult pubic hair but no spread to medial thighs. P5 Mature adult breast. Pubic hair extends to upper thigh

Menarche During puberty oestradiol levels fluctuate widely (reflecting successive waves of follicular development that fail to reach ovulatory stage) Endometrium affected by oestradiol. Undergoes cycles of proliferation and regression until point where withdrawal of oestrogen results in the first menstrual bleed (menarche) Increase of only 4% of final height after menarche

Ovarian development Rising levels of plasma gonadotrophins Stimulate ovary to produce increasing amounts of oestradiol Oestradiol ► secondary sex characteristics Breast growth and development Reproductive organ growth and development Fat redistribution (hips,breasts) Bone Maturation

Ovarian development Prepuberty volume – 0.3 – 0.9cm3 > 1.0cm3 indicates puberty has begun During puberty – rapid increase in size Mean post pubertal volume 4cm3

Ovulation First ovulation occurs 6 – 9 mths after menarche Plasma progesterone remains at low levels even if secondary sexual characteristics have appeared Rising progesterone after usually ► ovulation Plasma testosterone rise during puberty (not as much as in male)

Development of Uterus Prepubertal uterus is tear-drop shaped Neck and isthmus account for up to 66% of uterine volume Following production of oestrogens – uterus becomes pear shaped Uterine body increases in length (max 5 – 8cm) and thickness (proportionately more than cervix)

Puberty: Boys First signs often go unnoticed Testicular enlargement (12-13 yrs) Prepubertal testis – 2mls diameter Puberty begins when volume reaches 4mls Penile and scrotal enlargement occur approx 1 yr after testicular enlargement. Pubic hair appears at same time

Pubertal Growth Spurt: Boys Occurs later than in females Testosterone less of a stimulus to GH responsiveness than oestradiol Testosterone required in larger concentrations to produce same anabolic effect Greater and later growth spurt in boys

Examination: Boys Testicular growth: associated with enlargement of seminiferous tubules, epididymis, seminal vesicles and prostate Testicular enlargement: FSH dependant Prader orchidometer: assessment of testicular volume Signs of androgen excess without commensurate increase in testicular volume: worrisome e.g CAH, testicular tumour Penile growth, scrotal changes, pubic hair occur 1-2 yrs after testicular enlargement 50% of males varying degrees of breast hypertrophy Later signs: growth spurt, acne, voice deepening, facial hair

Pubertal Stages (Tanner) Male P1 Prepubertal, testicular volume < 2mls P2 Enlargement of scrotum and penis. Scrotum slightly pigmented. Few long dark pubic hairs P3 Lenghtening of penis. Further growth of testes and scrotum. Pubic hair darker, coarser and more curled P4 Penis increases in length and thickness. Increased pigmentation of scrotum. Adult pubic but no spread to medial thighs P5 Genitalia adult in size and shape. Pubic hair spread to thighs

Secondary sexual development First signs of puberty Testicular volume of 4mls Slight progressive increase in scrotal folds Slight increase in scrotal pigmentation

Testicular Volume

Final height Puberty usually completed within 3 - 4 yrs of onset Left wrist x-ray to assess bone age Final adult height results from complete fusion of epiphyses Occurs approx 2yrs after menarche

Assessment of abnormal puberty Many causes Aim of assessment: determine whether underlying pathological abnormality vs constitutional and benign pubertal changes NB: recognise abnormal timing and progression of puberty

What is abnormal? Delayed Puberty Early or Precocious Puberty More common in females Uncommon in males (usually pathological) < 8yrs in females < 9yrs in males May be associated with a growth spurt

Jameson, J.L. Rites of passage through puberty: A complex genetic ensemble. PNAS. October 30, 2007. Vol 104, No. 44.

NR0B1 gene is involved in development & function of the adrenal gland & HPG axis for gonadotropin secretion GPR54 gene mutations affect GnRH release (these patients do respond to exogenous GnRH) PROP1 mutations lead to problems in differentiation of gonadotropicc, somatotropic, lactotropic & thyrotropic cells.

Pubertal Delay Based on statistical norms (>2 SD from the population mean) Pubertal delay is most often seen in males Present far more often than females as delay causes more significant psychosocial implications Most commonly no pathology present

Timing of Puberty Consider pubertal delay if: No breast development by age 13 in a female No menses by age 15 in a female Testicular size < 2.5cm or 4mL or pubic hair is not present by age 14 in a male Consider precocious puberty if: Breast development before age 8 or menarche before age 10 in females Testes volume > 3ml before 9 years. Pubic hair development before 8 years in females, and 9 years in males

Pubertal Delay Pubertal Delay Hypogonadotropic Hypogonadism Hypergonadotropic Hypogonadism Eugonadotropic Hypogonadism Low FSH, LH Low sex steroids High FSH, LH Low sex steroids Normal FSH, LH

Pubertal Delay Sedlmeyer et al. identified in their study that delayed puberty in men could be classified as Constitutional delay of growth & puberty in 63% Delay associated with underlying medical condition 20% Hypogonadotropic hypogonadism 9% Hypergonadotropic hypogonadism 7%

Hypogonadotropic Hypogonadism Constitutional Delay of Puberty Malnutrition Excessive Exercise Growth Hormone Deficiency Isolated Gonadotropin Deficiency Endocrine Causes Miscellaneous syndrome complexes Brain tumors Craniopharyngioma, astrocytomas, gliomas, histiocytosis X, germinomas, prolactinomas Iron overload (pituitary damage) GnRH receptor abnormalities

Constitutional Delay of Puberty Most common cause of pubertal delay Delayed puberty often found in siblings or parents Diagnosis of exclusion Bone age is delayed & consistent with degree of pubertal maturation (usually delayed by 2yrs or more Often associated with constitutional short stature

Constitutional Delay of Puberty cont’d… Progressive height gain, but along lower limits of normal (contrast to isolated gonadotropin deficiency which has normal growth, but no pubertal growth spurt) Early morning testosterone levels > 0.7nmol/L predict puberty within 15 months (Wu et al)

Constitutional Delay of Puberty cont’d… Differentiated by pathological gonadotropin deficiency by observation over time (no definitive test available) GnRH stimulation test occasionally used, but not conclusive HPG axis responds to GnRH more strongly if it has already been exposed to this (reflects previous stimulation) hCG stimulation test can also be undertaken (Degros et al) Stimulated testosterone < 3 nmol/L suggestive of hypogonadotropic hypogonadism Stimulated testosterone >9 nmol/L suggestive of CDGP

Kallman Syndrome A syndrome of isolated gonadotropin deficiency 1/10,000 males, 1/50,000 females Present with ANOSMIA or HYPOSMIA Can be difficult to differentiate from constitutional delay KAL-1 gene encodes protein (anosmin) required for GnRH neurons to migrate from olfactory placode to cribiform plate Can also be associated with harelip, cleft palate, and congenital deafness

Idiopathic Hypogonadotropic hypogonadism Males often have eunochoid body proportions (upper-to-lower segment ratio of < 1) Can be sporadic or familial Can be related to problems in the receptor for GnRH Can present as infant with micropenis & cryptorchidism. These infants will not show normal gonadotropin increase in the first few weeks of life

Excessive exercise Questions as to whether lack of puberty related to low body weight or more as a direct effect of exercise Interruption of training in ballet dancers, runners

Syndromes Associated with Pubertal Delay Prader-Willi syndrome Laurence Moon syndrome Septo-optic dysplasia Bardet-Biedl syndrome

Panhypopituitarism Pubertal delay is usually not presentation (present with short stature earlier)

What controls the timing of puberty? An update on progress from genetic investigations? Current Opinion in Endocrinology. 2009

Hypergonadotropic hypogonadism Gonadal damage secondary to chemotherapy/radiation Enzyme defects in the gonads Androgen insensitivity Ovarian/testicular dysgenesis (causes of gonadal failure)

Gonadal Failure (bilateral) In these cases, circulating levels of LH & FSH are high (hypergonadotropic hypogonadism) Congenital Turner Syndrome Klinefelter’s Syndrome Complete androgen insensitivity Acquired Chemotherapy/Radiation/Surgery Postinfectious (ie. mumps orchitis, coxsackievirus infection, dengue, shigella, malaria, varicella) Testicular torsion Autoimmune/metabolic (autoimmune polyglandular syndromes) “Vanishing Testes syndrome” “Resistant Ovaries syndomre” (gonadatropin receptor problems)

Klinefelter’s Syndrome 45 XXY most common (2/3), remainder are mosaic or variant Many affected boys will not be identified until adolescence when puberty is delayed Some pubertal development, but testes eventually become fibrotic Timing relates to degree of mosaicism in the patient Small testicles & gynecomastia Also often small phallus size 90-100% are infertile More female type fat distribution Tall in childhood, with euchanoid body habitus Have fathered children (particularly those with mosaicism)

Turner Syndrome 45 XO genotype most common Associated with short stature, variable degrees of puberty, primary amenorrhea & multiple congenital anomalies Often presenting complaint is short stature, but in others, may present with delayed puberty Most have primary ovarian failure 50% of patients have some breast develpoment, some axillary/pubic hair is typical for most patients Associated with SHOX mutations which cause the short stature

Turner syndrome cont’d… Residual ovarian function can cause breast development in 15-25%, menarche in 5-10% & pregnancy in 1-3%

Receptor Defects LH gene defects and FSH gene defects can result in high levels of FSH & LH with low sex steroids Secondary sex characteristics are driven by LH effects, can have FSH receptor defect & normal secondary sex characteristics

Eugonadotropic pubertal delay Congenital Anatomic Anomalies Imperforate hymen Vaginal atresia Vaginal aplasia PCOS Hyperprolactinemia

In this case, secondary sex characteristics are normal May have cyclic lower abdominal pain

Chronic Illness Can affect underlying genetic potential May limit adequate nutrition (ie. inflammatory bowel disease, cystic fibrosis) May be associated with glucocorticoid use, chemotherapy or radiation

Other Endocrine Causes Hypothyroidism Interferes with gonadotropin secretion (affects pulsatile secretion of LH) Hyperprolactinemia Interfere with gonadotropin production **prolactinomas may not always be visible on imaging**

Investigating 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 if gonadotropins high & no obvious cause of hypogonadotropic hypogonadism

Psychological Distress in Pubertal Delay Much has been written about psychological distress in males with delayed puberty Self-Esteem & Sexuality in girls with Turner Syndrome has been studied Generally had low self-esteem scores (general & social) Lifetime sexual experience associated with overall SEI score Increasing sexual experience had no effect (all-or-none phenomenon) Ross et al. -> initiation of estrogen therapy associated with increased self-esteem in girls with Turner syndrome Psychosocial Adjustment in Turner Syndrome. Journal of Clinical And Endocriological Metabolism. 2006.

Stimulating Puberty in Males Should be begun at 12yrs of age Multiple indications For CDGP Indicated in those boys with psychological distress (who have poor body image, low self-esteem, are becoming socially withdrawn, or are subjected to teasing or bullying) Time of therapy initiation may vary (if GH deficiency present, delay starting to optimize height achievement) Testosterone supplementation may help with bone mineral density

Exogenous testosterone Does not increase testicular size (normal puberty continues to progress) Causes virilization (increased phallic size & scrotal rugae) Accelerates development of secondary sex characteristics to avoid psychosocial complications Should be used only if bone age is delayed, and introducted at approx. normal time of development Also stimulates growth spurt Side effects Local discomfort at site of injection priapism

Androgen Supplementation Testosterone IM Injections (once puberty has begun) Doses of 50-200mg IM using testosterone esters have been used for periods of 6-12 months Depot testosterone like this results in high testosterone peaks & a duration of action of 2-3 weeks Theoretic advantage for negative feedback on HPG axis to be alleviated with “wearing off” of exogenous testosterone Oral Associated with more gradual effects Testosterone undecanoate 40mg po qdaily Oxandrolone 2.5mg po qdaily Gels, transdermal patches, etc. have not been studied as well in boys & dosing is less predictable

hCG Can also use to stimulate development of secondary sexual characteristics Increases testicular size Can be used to stimulate fertility 200-500 units qalt days

Stimulating Puberty in Females Estrogen Replacement Increased gradually to adult replacement levels (as puberty is normally a slow process) Aims: Attainment of secondary sexual characteristics Attainment of menses Stimulation of pubertal growth spurt Acquisition of bone mineral mass Uterine development

Estrogen Replacement in Females Initiate replacement at age 10-12 yrs & should continue over course of normal puberty (approx. 3 yrs) Effect of estrogen on growth plate is dose dependent Higher doses stimulate epiphyseal growth plate closure Once dose of 10-15mcg of ethinyloestradiol has been reached, breakthrough bleeding becomes apparent – once this occurs, progesterone should be added on a cyclic basis to prevent endometrial hyperplasia Dosing 0.3mg conjugated estrogen daily 5mcg of ethinyl estradiol daily Transdermal estrogen 25mcg twice weekly Increase q6-12 months until maximum (20 mcg)

Suggested dosing increments Ethinyloestradiol 2mcg/day X 6 months 4 mcg/day X 6 months 6 mcg/day X 6 months 10 mcg/day X 6 months 15 mcg/day X 6 months 17-estradiol 5mcg/day po 10 mcg/day po 15 mcg/day po 20 mcg/day po Introduce progesterone once breakthrough bleeding has occurred, after this point can switch to an oral contraceptive pill

Estrogen Side Effects Thromboembolism Endothelial dysfunction Hyperlipidemia Increased risk of breast & gynecological malignancy Increased risk of gallstones

Achieving Fertility May require pulses of GnRH in females hCG in males 1-2 times/week helps to maintain spermatogenesis 1200-5000 IU hCG IM 3 times weekly 12.5-150 hMG IM 3 times weekly

Assessment 1 Full history of previous growth and development Record timing and sequence of physical milestones and behavioural changes of puberty Full medical and surgical history If underweight: take full nutritional history Family hx of early or delayed puberty Family hx of any genetic disease

Assessment 2 Plot height, weight, BMI and growth velocity Compare with old measurements if available Examine all systems: endocrine / neurology NB Optic fundi, visual fields, sense of smell Genitalia, body habitus, stage of puberty

Delayed Puberty: Hypogonadotrophic Constitutional (familial, sporadic) Chronic illness (CF, Crohns Disease, Renal failure) Malnutrition (Anorexia, CF, coeliac disease) Exercise PCOS Tumours of pituitary/hypothalamus (craniopharyngioma) Hypothalamic syndromes (PWS, Laurence-Moon-Biedl) Hypothyroidism Suppression 20 to hyperthyroidism, hyperprolactinemia, Cushing Syndrome, CAH Panhypopituitarism

Delayed Puberty: Hypergonadotrophic Congenital Turner Syndrome Klinefelters Syndrome Acquired Irradiation / Chemotherapy Surgery Testicular torsion, trauma Infection Autoimmunity

Precocious Puberty Onset of secondary sexual characteristics < 8yrs in girls and < 9yrs in boys 5 times more common in girls Usually benign central process – girls Pathological in ~ 50% in boys

Precocious puberty Defined as the onset of secondary sexual characteristics before 8 yr age in girls and 9 yr in boys.

Classification of precocious puberty True precocious puberty ( central or gonadotropin- dependent = CPP) Precocious pseudopuberty ( peripheral, gonadoptropin independent (PPP) Mixed type

Conditions causing central precocious puberty Idiopathic organic brain lesions (inflamation, malformation, trauma, chemotherapy, radiotherapy, brain tumor) Hypothyroidism

Conditions causing precocious pseudopuberty in females Iso sexual ( feminizing ) conditions Mc cune – Albrightsyndrome Autonomous ovarian cyst Ovarian tumors Feminizing adrenocortical tumor Exogenous estrogens cont

Hetrosexual (masculinizing) Congenital adrenal hyperplasia Adrenal tumor Ovarian tumor Glucocorticoid receptor defect Exogenous androgens.

Conditions causing precocious pseudopuberty in males Isosexual congenital adrenal hyperplasia Adrenocortical tumor Leydig cell tumor Familial male precocious puberty HCG secreting tumor Teratoma cont

Hertrosexual Glucocorticoid receptor defect Exogenous androgen Feminizing adrenocortical tumor Exogenous estrogens

Approach to patient with precocious puberty History (Medication ) (family history of precocious puberty) Physical examination (Wt, Ht, Eye, Thyroid, abdomen, tests) paraclinical findings bone age cont

(ovaries, Uterus, adrenal glands, testes) MRI of brain Estradial Testosterone LH FSH GnRH stimulation test (LH/FSH> 1) (LH>5- 10 IU/L) Sonography (ovaries, Uterus, adrenal glands, testes) MRI of brain (MRI of hypothalamus and hypophysis) cont

The goals of treatment for CPP Improvement of adult height Prevention of social and psychological problems.

Treatment of CPP GnRH analogues GnRH antagonist Aromatize inhibitors

Indications for therapy with GnRH agonist True precocious puberty in males Rapid progressive CPP in girls To stop puberty because of social and psychological reasons

The effect of GnRH agonist therapy on: Growth Skeletal age Pubertal development Hormones

Treatment is effective if: Serum sex hormone concentration decrease to prepubertal levels ( testosterone < 20ng/ dL in boys estradial < 10pg/mL in girls) Serum FSH and LH < 1 IU/L LH/FSH < 1

Physiological status after completion of therapy Growth rate Bone density Pubertal development Hormones Fertility

Premature thelarche / pubarche Thelarche – beginning of breast development Pubarche – first appearance of pubic hair (more common in certain populations e.g asian / afro-caribbean ) More common than true precocious puberty Benign variants breast development in girls < 3yrs with spontaneous regression Pubic hair in boys and girls < 7yrs due to adrenal androgen secretion in middle childhood NB Examination normal or may be slight advance in growth curve

Precocious Puberty Gonadotrophin dependant Idiopathic (sporadic / familial) Congenital (Hydrocephalus) Acquired (irradiation/surgery/infection) Tumours (hamartomas/gliomas) Hypothyroidism Russell Silver Syndrome Mc Cune Albright Syndrome

Precocious Puberty Gonadotrophin Independant Normal pattern of puberty absent Virilisation of female (CAH) Feminisation of a boy (oestrogen producing leydig tumour) Adrenal Tumour Ovarian Tumour

Investigations Blood Tests (first line) Second line FBC U&E LFT’s TFT’s FSH/LH Oest/Testosterone 17 OHP / 11 DOC Adrenal androgens Prolactin Second line GnRH assay Beta –HCG Karyotype if indicated

Diagnostic Imaging Pelvic USS (ovarian tumours / cysts) Testicular USS (tumour) Adrenal USS (MRI / CT better if tumour considered) Bone Age (if within 1yr of CA, puberty not started or only just started; if > 2yrs, puberty already started) Brain MRI in all males and patients with neurological signs or symptoms)

Management Treat systemic disease Psychological support Promote puberty / growth if necessary Low dose testosterone Ethinyloestradiol

Issues Treatment of the cause e.g. cranial neoplasm Behavioural difficulties – psychology Reduce rate of skeletal maturation (early growth spurt may result in early epiphyseal closure and reduced final adult height) Halt or slow puberty (GnRH analogue) Inhibit action of excess sex steroids

Growth and Puberty GH plays role in pubertal development Amplifies ovarian response to gonadotrophins IGF-1 enhances gonadotrophin effect on granulosa cells Isolated GH deficiency associated with pubertal delay, diminished Leydig cell function and decreased response to chorionic gonadotrophins GH administration can restore testicular responsiveness to LH and Leydig Cell steroidogenesis

Growth and Puberty Growth hormone-releasing factor (GRF) levels and GH secretion increase considerably during puberty, mainly at night Amplitude of GH peaks increases in early puberty – growth spurt IGF-1 ►important modulator of growth during childhood and adolescence Adrenal androgens have little physiological role in normal growth

Thelarche Absence of a growth spurt and axillary or pubic hair differentiates thelarche from precocious puberty

Ambiguous genitalia Range of presentations Inadequately developed male to virilised female Most common cause is Congenital Adrenal Hyperplasia → virilised female Urgent identification as can cause adrenal failure in neonatal period Do not ascribe sex immediately Identify cause of intersex Karyotype does not indicate the sex of rearing Family counselling imperative Early surgery now less popular

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