pubertal disorders

Pubertal disorders

Dr Olcay Evliyaoğlu

Pediatric Endocrinology Department

Puberty

Sexual differentiation begins on 4-5th week of gestational age.

ADOLESENCE Physical, sexual, physcological

development. Transition to adulthood from childhood

Not an adult nor child Time of transition Establishment of individualism.

Foliküler faz

PUBERTY

Secondary sex characteristics are developed

Includes Physical growth Sexual development Psychological development

Growth spurt, disturbution of muscle and fat

bone maturation and fusion of epiphysical centers

Adult height At the end of this period

spermatogenesis in boys, ovulation in girls occur

hypothalamus LHRH neurons

LHRH

PituitaryGonadotroph cells

FSH , LH

GONADs

Testes Ovaries

Testosteron Estradiol

HPG axis

STRESS

MATURATİON NUTRİTİON+ +CENTRAL NERVOUS SYSTEMCENTRAL NERVOUS SYSTEM

++ - - +

+ +

- - -

- -

- -

+ +

--

-- --

GLUTAMAT GABA ENDROFIN

HYPOTHALAMUSHYPOTHALAMUS

GnRHGnRH

PİTUİTARYPİTUİTARY

PRLPRL

LHLH FSHFSH

TEKA TEKA OVARYOVARYGRANULOZA GRANULOZA

ANDROGENANDROGEN ESTROGEN INHIBINESTROGEN INHIBIN

-

LEPTIN

What makes HHG axis work

Genetic and environmental conditions effect timing of puberty 

Environmental factors: Socioeconomic factors Nutrition General health Geographical place lived

Hypothalamus GnRH pulse frequency and amplitude increase

LH pulse frequency and amplitude increaseAt early stages at nights With progression of puberty pulses occur during day

Pituitary

Gonadotropins

FSH, LH Glucoprotein Alpha ve beta subunits ( alpha subunits are

same, differences are on beta subunits)

FSH sertoli cells (testis) Granulosa cells (over) Stimulate LH rec production on Leyding cells

gamotogenesis

LH Leydıng cells ( testis) Teca cells ( over) Gonadal steroids

LH

Granulosa cellsFSH

estrogen

androstenedionTeca cells

LH Leydig cells

testosteron

Adrenarche

Increase in the secretion of adrenal androgens

Appearance of pubic hair (pubarche) Axillary hair

CRH

ACTH

Adrenal androgens

Hypothalamus

Pituitary

Adrenal cortex

Adrenarche

Nutrition and puberty

Menarche is earlier in obese girls

Malnutrition , chronic diseases, and excessive physical activity delay puberty and menarche

Timing of puberty is related to bone age rather than chronological age

BA< CY ------------- delay in puberty BA = CA ------------- puberty on expected age BA>CA -------------- early puberty (puberty

precocous)

 girls the first sign of puberty is telarche, generally observed on 10 - 11 ages, menarche is observed 2-3 years after telarche.

In girls growth spurt occurs 2 years earlier than boys. Growth spurt in girls is at the time of telarche,

In boys growth spurt occur at the time when testes volumes are 10 ml.

Telarche Pubarche Menarche

Tanner stage 42-3years after telarche

Menarche

Pituitary hormones

Ovarian hormones

ovary

Endometrium

İstihdam Seçim

dominant istihdam

Follicular /proliferative phase Luteal /secretuary phase

folliculeovulation

corpus luteumcorpus albicans

       In boys initial finding of puberty is enlargement of testes. This is followed by scrotum pigementation and thinning of scrotal skin. Penis enlarges. Pubic hair develops. Growth spurt occurs at 14-16 years and usually continues until 18 years.

PUBERTAL PROBLEMS Precocious puberty Delayed puberty Pubertal gynecomastia Gynecological problems Pyschological problems Sexual identity problems Eating disorders: Anoreksia

nervoza, Bulimia Nervoza Enuresis Nocturna Orthopedical problems

PRECOCİOUS PUBERTY

Breast development before 8 years in girls and testes development more than 4 ml or any other pubertal sign before 9 years in boys are considered precocious .

Central Precocious Puberty (CPP): Activation of hypothalamus-pituitary-gondal (HHG) axis.

Peripheric Precocious Puberty (PPP) : Signs of puberty with out activation of HHC axis. Izosexual perifpheric PP: Secondary sexual characteristics are appropriate for the sex of the child.heterosexual peripheric PP: Secondary sexual characteristics are inappropriate for the sex of the child.

Etiology : Central PP

Idiopathic: sporadik, familial CNN disorders: Tumors (Optic glioma, hypothalamic gliom,

astrositoma, epandimoma, kraniopharengioma), sarkoidosis, suprasellar cysts

Nörofibromatosis, Tuberosclerosis

Peripheric PP Gonadotropin secreting tumors: Hepatomas, hepatoblastoma,

teratoma, choriocarsinoma, germinoma Any disorder resulting in gonadal steroid secretion

Excess androgen: Congenital Adrenal Hyperplasia, testes tumorsExcess estrogen: Ovarian cysts or tumors

Mc Cune Albright Syndrome Activation mutation in LH receptors

Severe hypothyroidism

Clinical Height Midparental height and target height Height velocity Pubertal stage Bone age

Central PP: diagnostic criteria

Central PP: diagnostic criteria Pelvic USG findings supporting CPP

Uterus long diameter 34-50mm Pear shaped uterus (F/C>2:1) Endometrial echo specifity (100%) but sensivity

(42%-87%) Ovarian volume <2-3 ml (v:a x b x c x 0,5233) Follikul number>6 size>8mm

Central PP: diagnostic criteria Laboratory :

1) Pubertal levels of LH amplitude and pulsity2) Gn-RH stimulation test: Pubertal LH responsepeak > 5 IU /L 3) Gn-RH stim LH/FSH>1

Criteria suggesting progressive precocious puberty Progression of breast staging in less than 3-6 months Growth velocity > 6cm /year Bone age advanced more than 1,5-2 years PAH below target height and decline in PAH during

follow up. Uterine volume>2 ml, long diameter >35 m, endometrial

echo Ovarian volume >2-3 ml Peak LH>5 mIU/L at GnRH test Basal LH >0,3

Puberte prekoks

McCune Albright Syndrome

   Cafe au lait patches on skin    Polyostotic fibrous dysplasia  Endocrine disorders:

Peripheric PPCushing syndrome, hyperthyroidism

Mc cune albrigt - 4.5 years old -polyostotik fibrous dysplasia

Treatment

Goals: Synchronosing puberty with peers (ameliorating

pshchological stress) Decreasing the rate of bone maturation so as to

acheive a normal final height

Treatment(SPP)

GnRH analogs.

Lucrin

3.75mg IM /month 7,5mg IM /month

22,5mg /3 months

11,25mg months

When to stop treatment

Much depends on the primary goal of treatment , patient – parent preference

Average age of treatment discontinuation CA:10,6 -11,6 years BA:12,1 – 13,9 years

Max adult height CA:11-11,5 ve BA: 12-12,5 years

Treatment (PPP)

Boys Antiandrogens ( andr rec inhibition) İnhibitors of 17,20 liyase ve testosteron

synthesis Aromatase inhibition (arimidex)

Girls Aromatase inhibitors E2 rec inhibition

İNCOMPLETE PP

Only one pubertal sign. Premature telarche Premature adrenarche Premature menarche

Premature Telarche

End organ increased sensivity There can be difference in 2 breasts, one

can start development 6 months earlier than the other

Premature telarche PP

------------------------------------------------------------------Growth velocity not increased increased

Bone age not advanced advanced

Vagen mucosa not obvious obvious

E2 effect

Uterus size Prepubertal Pubertal

GnRH response Prepubertal Pubertal

Adrenarche no can be

Premature Adrenarche PPPenis size Prepubertal Pubertal

Growth velocity not rapid rapid

Bone age not advanced advanced

Testes size Prepubertal Pubertal

Serum Testesteron Prepubertal Pubertal

DHEA-SO4 Prepubertal Pubertal or 17-OH progesterone Prepubertal high in CAH

11-Deoksikortisol Prepubertal high in 11-OH lase deficiency

Bazal LH/FSH Prepubertal Pubertal

Puberty tarda-PT (Pubertal delay)

Not if any sign of puberty has been observed in 13 years old girls and 14 years old boys

Males

If Sexual development has not been developed

until13.7 years. Transition from stage II to III is more than 2.2 years Transition from stage III to IV is more than1.6 years Transition from stage IV to V is more than 1.9 years Sexual development has not reached stage V until

17.1 years Bone age>12 years and pubertal development has

not begun

Females

If Breast development not started until 13.4 years Transition from stage II to III is more than 1 year Transition from stage III to IV is more than 2.2

years Transition from stage IV to V is more than 1.8

years Not menarche at the 5th year of telarche Bone age >11 and pubertal development has not

begun

Etiology of PT

Konstitutional growth and pubertal delay Hypogonadotropic hypogonadism

CNS disorders: Tumors, congenita disorders, radiation Isolated gonadotropin deficiency: Multiple pituitary hormone deficiency Prader-Willi syndrome Laurence-Moon, Bardet Biedle syndrome Chronic diseases Sudden weight loss, anoreksia nervoza Hypothyroidism İncrease in physical activity

Etiology of PT

    Hypergonadotropic hypogonadism

A. Males Kleinfelter syndrome Primary testicular insufficiency Anorchia or kriptorchidismB. Females Primary ovarian insufficiency Noonan syndrome, Ulrich syndrome) XX veya XY gonadal dysgenesis Turner Syndrome

Constitutional growth and pubertal delay Pubertal development is delayed concordant

with growth CA>BA=HA Growth velocity is normal Height sds is between -2sd and -3sd With the onset of puberty and pubertal growth

spurt final height becomes appriate to target height

Treatment (constitutional growth and pubertal delay)

1. Phsychologic treatment

2. Gonadal steroids: 13 years old girls and 14 years old boys who have not developed any pubertal sign can be treated

Girls : For 3 months Conjugated E2 (0.3 mg/day) or ethynyllestradiol (5-10 g /day)

Boys : For 3 months testesteron enanthate (50-100 mg/ month) IM

Development of pubertal signs and an increase in growth velocity is what expected from this treatment.

Hypogonadism / treatment Males

By gradually increasing testosterone dose adult dose of 300mg/month is acheived.

In the case of hypogonadotropik hypogonadism to increase endogenous testosterone production and testes size HCG treatment can be initiated

Females 5 g/ day10 - 20 g/ day etynyllestradiol 0.3 - 0.625 mg/day conjugated estrogen . With the appearence of physical effects of E2

Medroksiprogesterone acetate on days 12. - 21. of cycle can be added

Gynecomastia Observed in 30 - 35 % of males Generally bilateral In P3 and P4 stages; 14 - 14.5 years Glandular tissue diameter is generally less than

4 cm, resembles stage II in girls Glandular tissue > 5cc and resembles stage III

and IV in girls Pubertal Macrogynecomastia , do not regress spontaneously

Etiology for pathologic gynecomastia : Endocrinopathies Tumors Chronic diseases Drugs : Hormones, antidepresants, anti Tbc

drugs, etc

Pathophysiology:

a) Disturbance of E2 and testosterone balance

b) Increment of conversion of testosterone to estradiol

Increase in E2 sensivity of breast tissue

Generally regresses in one year If persists more than 2 years, leads to

physcological problems and is a macrogynecomastia surgery is a treatment option