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)

G1-5, Pu 1-5, A 1-5, testicular volum > 4 ml – first sign of male puberty

Staging of pubertal development in bpys (Tanner)

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. Self-limiting 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 pubertyDelayed 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