Endo2: Normal And Abnormal Female Puberty

Front 1

Female puberty, factors for timing

Back 1

Period where secondary sexual characteristics begin to develop and capability for sexual reproduction attained

Factors in timing: Genetics, nutrition, geographic location, psychological state, race/ethnicity

Front 2

Gonadarche, Cause

Back 2

Component of puberty

Maturation of hypothalamic-pituitary-ovarian axis
ID'ed by START OF GnRH PULSES from arcuate nucleus of medial basal hypothalamus during SLEEP
Pituitary release of LH and FSH causing ovaries to enlarge and make sex steroids. Leads to secondary sex characteristics

Cause: Unknown, may be leptin (adipocyte hormone regulate fat tissue, satiety and energy) because higher levels of leptin in obese pts with early puberty and stimulates GnRH release

Front 3

Adrenarche

Back 3

Component of puberty

Normal rise in production of adrenal androgens (DHEA, DHEAS, and androstenedione causing pubic, axillary hair and body odor

Front 4

Neuroendocrine developmental events
a) In utero
b) At birth
c) Age 2-6
d) At puberty

Back 4

a) In utero - 6-12 weeks gestation the Hypothalamic-pituitary axis develops. LH/FSH rise till week 24 when negative feedback loop starts. GnRH drops.

b) At birth - Placental separation, Estrogen and progesterone levels drop, hypothalamic axis responds by GnRH increase

c) Age 2-6 - Some small decline in GnRH not sure why, very sensitive

d) At puberty - GnRH starts to "pulse" at night with sleep. GnRH levels rise again. Pulsatile pattern FIRST SIGN OF PUBERTY. Ovaries begin making sex steroids and ovulation

Front 5

GnRH pulses

Back 5

FIRST physiologic sign of puberty

Initially low causing FSH to rise BEFORE LH

Front 6

Physical Changes in puberty in sequence, onset, Normal pattern Caucasian vs AA

Back 6

Onset: 9-13 years old for females

Sequence - definitive time frame of 4.5 years
1) Increase in growth velocity (FIRST CLINICAL sign)
2) Breast budding (thelarche)
3) Pubic hair (adrenarche)
4) Peak growth velocity
5) Menarche

All caused from increased estrogen-gonadarche except adrenarche from adrenal androgens

Caucasian
85% - Thelarche, Adrenarche, Menarche
15% - Adrenarche, Thelarche, Menarche
African American - Adrenarche, Thelarche, Menarche

Front 7

Tanner Staging of Breast Development

Back 7

1 - Prepubertal, no palpable breast tissue, areola <2cm
2 - Buds, visible and palpable mound tissue, areola enlarges and its skin thins, nipple develops
3 - Growth and enlargement of entire breast, side view with nipple above or at midplane of breast
4 - Projection of areola above the general breast tissue in a secondary mound
5 - Areola pigmented, Montgomery glands visible, nipple below midplane

Front 8

Tanner Staging of Pubic Hair

Back 8

Stage 1 - Vellus, prepubertal
Stage 2 - Sparse, along labia
Stage 3 - Darker, thicker, curled, spreads to pubic junction
Stage 4 - Adult type, no spread to medial thigh
Stage 5 - Spread to medial thigh

Front 9

Height and Growth Rate in puberty, Tanner Stage correlate, Hormonal changes

Back 9

Growth spurt FIRST CLINICAL sign of puberty, PRECEDES breast bidding

Peak growth velocity in TANNER 3 around 11-12 for females

Estrogen at small levels increases GH and IGF1 to produce max growth at serum 20 pg/mL, Adult levels of estrogen suppress growth factors and close epiphyseal plates (120 pg/mL)

Front 10

Menarche def, onset avg

Back 10

First menstrual cycle

Occurs usually 1.5-3 years AFTER breast budding
Median age is 12.8 years across races

Front 11

Pubertal events avg age
a) Breast bud
b) Adrenarche
c) Peak growth velocity
d) Menarche

Back 11

a) Breast bud - 9-10
b) Adrenarche - 10-11
c) Peak growth velocity - 11-12
d) Menarche - 12-13

Front 12

Precocious Puberty def, Types, Causes, Effects

Back 12

"early" puberty. Development of secondary sexual characteristics because of presence of sex steroids (estrogen)

Types: Isosexual, Generalized, True Precocious puberty

Causes:
a) Early activation of CNS (hypothalamic-pituitary)
OR
b) Early activation of end organ (ovary)

Over age 4 - IDIOPATHIC
Under age 4 - CNS LESION!

Effects: Premature closure of epiphyseal plates and short stature of around 5 feet

Front 13

"Classic" Precocious Puberty Def, Problem with this, When to workup

Back 13

Breast or pubic hair before age 8
OR
Menarche before age 9

Problem: Menarche age dropped till 60s and now steady at 12, breast and pubic har development happens earlier than thought of mean 8-9 and race dependent

Workup If see:
Breast/pubic hair <7 years old in Caucasians, <6 in AA
Menarche <9 INDEPENDENT OF RACE

Front 14

Theories for precocious puberty causes

Back 14

DDT - pesticides have estrogen like breakdown product
PCB
BPA
Obesity - Leptin connection to increase hormones

Front 15

Categories of precocious puberty

Back 15

Isosexual
a) Generalized - Central gonadotropin dependent
b) Generalized - Peripheral gonadotropin INdependent
c) Isolated - Premature thelarche (breast buds)
d) Isolated - premature adrenarche (pubic hair)

Contrasexual - Virilization

Front 16

Isosexual Precocious Puberty Central Gonadotropin dependent etiology, cause

Back 16

Cause: Hypothalamic-pituitary axis is activated, gonadotropins stimulate ovarian follicles to make estrogen

Nonorganic/Constitutional/Idiopathic OR Organic ("KNOWN") causes

90% are non-organic, brain just starts early
10% organic due to Dysgerminoma ovary, Hepatoblastoma, Primary Hypothyroidism, CNS activation

Front 17

Things that can cause early CNS activation in precocious gonadotropin dependent puberty

Back 17

Encephalitis, Trauma, Craniopharyngeioma, pineal dysgerminoma all activate GnRH neurons

Hamartoma - can produce GnRH on own

Front 18

Isosexual Precocious Puberty Peripheral/gonadotropin independent causes

Back 18

Estrogen high coming from
1) Ovary
a) McCune Albright - G protein mutation leading to cAMP formation
b) Ovarian Cysts
c) Ovarian tumors gonadotropin secreting - Granulosa cells, theca cells, gonadoblastoma, teratoma

2) Adrenal tumor (RARE)

3) Exogenous medications raising estrogen

Front 19

McCune Albright syndrome, Treatment

Back 19

alpha subunit G protein mutation leading to higher cAMP

Associated with autonomous early ovarian cyst production, pituitary adenomas, cystic bone lesions, cafe au lait spots

To prevent precocious puberty

Testolactone (aromatase inh) to lower E2 Medroxyprogesterone acetate (LH suppress)

Front 20

Precocious Puberty H&P Questions, Goals

Back 20

Goals - rule out serious disease (CNS tumor, ovary, adrenal, liver); stable vs progressive, estrogenic vs androgenic, generalized vs isolated

History
Onset, pace, CNS abnormalities (encephalitis, trauma, seizures), Hypothyroidism history, abdominal or pelvic masses, drugs, family history

Physical
Growth chart, height, weight, Tanner staging
Neuro-retinal exam for papillaedema, visual field defects (brain tumor), abdominal, pelvic exam. Evidence of androgenzation, hypothyroidism, McCune Albright

Front 21

Precocious Puberty Labs to get

Back 21

FSH, LH (GnRH stim test)
bHCG
TSH
Estradiol (normal <10pg/mL)

IF see signs of virilization get 17 hydroxyprogesterone, DHEAS, testosterone - looking for CAH

Bone age

CNS, adrenal and pelvis imaging

Front 22

GnRH testing, responses

Back 22

Give GnRH and measure FSH, LH at 0, 30 and 60 minutes

NO response - prepubertal child, peripheral precocious puberty

FSH dominant response - Late prepuberty, premature THELARCHE

LH dominant response (LH>FSH or LH>7IU/L) - pubertal response, normal puberty, CENTRAL precocious puberty of idipathic or CNS origin

Front 23

What is needed to diagnose Generalized/True Precocious Puberty Clinically, Treatment goals, Treatment

Back 23

For Central/Gonadotropin dep or Peripheral/Gonadotropin indep

Clinical
1) BOTH increased growth velocity AND bone age (as opposed to just isolated breast)
2) ELEVATED sex steroids (estrogen/progesterone)
3) ANDROGEN (hair, acne, odor) evidence AND ESTROGEN (breast) OR just menses

Goals - Dx and treat any intracranial disease. Arrest maturation until normal age, lessen precocious signs, MAXIMIZE adult height, lessen psychosocial implications

Treatment:
1) Central - GnRH agonist (Leuprolide acetate), Intramuscular suppression until estradiol is <10pg/mL - suppresses BREAST development, Final height increased though still 1 SD below midparental.

2) Peripheral
a) Primary Hypothyroidism - LEVOTHYROXINE until euthroid
b) McCune Albright - Testolactone (aromatase inh) and Medroxyprogesterone acetate (LH suppress)

Girls below 50% bone age/height at Dx usually end up short, usually if 8 with breast development takes 2 years to get menarche and can handle "early bloomer" dx

Front 24

Isolated precocious puberty types and causes

Back 24

Premature thelarche - benign, self-limited, usually preschool aged (<3 years old) and may reach Tanner 2

Premature adrenarche - benign, self limited, usually after age 6

Front 25

Premature Thelarche, Cause, Workup, Treatment

Back 25

Cause - increased sensitivity to pubertal levels of estradiol

Workup - exclude exogenous estrogen, look for other signs such as vaginal maturation, growth spurt or androgenic changes that may indicate generalized precocious puberty, brain imaging if <6 with true precocious puberty

Labs - FSH/LH/Estradiol NORMAL. FSH dominant GnRH stim, Normal bone age

Treatment - re-examine periodically, thelarche is one of first signs so need to make sure not precocious puberty. Rare to get before age 3

Front 26

Premature adrenarche Cause, Workup, Treatment, Association

Back 26

Cause - Early adrenal maturation, excess androgens. Axillary hair, odor, acne. Not at risk for premature closure of epiphyseal plates. Independent of gonadarche.

Association - 40% have polycystic ovaries

Workup - rule out ovarian or adrenal tumor

Labs:
DHEA (elevated), testosterone and androstenedione - androgen levels
17-hydroxyprogesterone to rule out 21 hydroxylase def
Confirm PUBERTAL levels of FSH/LH/Estradiol

Treatment: Re-examine because can be first sign in 15% of precocious puberty

Front 27

Delayed Puberty Definition, timeframe, Types

Back 27

Failure of secondary sexual characteristics by age 13, no menarche by 15 or 5 years from onset of pubertal changes without menarche

95% of 14 year olds have puberty, 2-3 years between breast buds and menses

Types
a) Hypogonadotrpic hypogonadism - failure of hypo-thal-pituitary axis to activate
b) Hypergonadotrophic hypogonadism - failure of end organ (ovary)

Front 28

Causes of Hypogonadotropic hypogonadism

Back 28

Constitutional/idiopathic - MOST
Sustained malnutrition (Crohn's, Celiac, renal failure, anorexia)
Endocrine disease - CUSHING"S, HYPOTHYROIDISM (theca leutin cysts on ovaries that go away when corrected), HYPERTHYROIDISM (low body fat)
Isolated gonadotropin def - Kallman's
Pituitary adenoma
Craniopharyngiomas (in Rathke's pouch) - most common tumor associated with pubertal delay
Praeder-Willi
Leptin receptor mutation

Front 29

Kallman's Syndrome

Back 29

Isolated GnRH deficiency due to failure of olfactory AND GnRH neuronal migration from olfactory placode

Seen in 1/50k girls, most commonly X linked, can be AD, AR or sporadic

SEE HYPO or ANOSMIA

Front 30

Causes of Hypergonadotropic hypogonadism

Back 30

Gonadal dysgenesis - Turner's XO
Destruction of ovary - chemo, radiation, surgery
17 hydroxylase DEF
Galactosemia
Polyglandular Autoimmune endocrinopathies -
a) PGE I (pediatric) - hyperparathyroidism, adrenal insufficiency, gonadal failure, thyroid disease, insulin dependent diabetes, candidiasis, pernicous anemia
b) PGE II (adult) - adrenal insufficiency, gonadal failure, thyroid disease, insulin dependence, vitiligo, myasthenia gravis, sjogreans, rheumatoid

Front 31

H&P of Hypergonadotropic hypogonadism, Labs

Back 31

History - chronic medical diseases, chemo/radiation history, exercise regimen, Neonatal issues, kernicterus, Turner's, CYCLIC ABDOMINAL PAIN

If have evidence of growth spurts then chances of puberty are good

Exam
Height, weight
BP (ELEVATED IN 17 HYDROXYLASE DEF)
Delayed tanner staging
stigmata of Kallman's, Turner's, Cushings

Labs
FSH - if elevated karyotype, Low/norm CNS b/c its not stimulating, if very low GnRH helps to distinguish irreversible hypo (Kallman's) vs reversible (delay)

Estradiol - >9pg/mL shows some ovarian fxn, if doesn't rise above 20pg/mL will not feminize

TSH, T4
Prolactin
Bone age

Front 32

Delayed puberty GnRH stim test

Back 32

FSH, LH after stim at 0,30,60 min

No response - Kallman's or prepubertal
FSH rise - normal late prepubertal response
LH rise - pubertal (usually Tanner 3-4 breast)

Front 33

Treatment of delayed puberty

Back 33

Underlying disorder
Then reassurance for physiologic delay
Exogenous estrogen to 20pg/mL to avoid epiphyseal closure, tubular breast development. Add progestin to avoid endometrial hyperplasia

Front 34

MRKH syndrome

Back 34

Mullerian dysgenesis - abnormalities of outflow tract

Mayer-Rokitansky-Kuster-Hauser syndrome - congenital absence of vagina with variable uterine development. Result of Mullerian agenesis. Uterine development variable

Less than half have urologic anomalies (unilateral renal agenesis, horshoe kidneys, collecting irregularities)

10% have skeletal anomalies

Front 35

Causes of Delayed development with genetic karyotype gonadal failure

Back 35

Turners XO
46 XX mosaic