Precocious Puberty

Dr. Abdulmoein Eid Al-Agha

Consultant, Pediatric Endocrinologist,

King Abdul Aziz University Hospital, Jeddah, Saudi Arabia

Discussion points

When to say this child is having Precocious puberty (what is the age limits in both sexes)

Types of precocious puberty

Etiology

Biochemical & Radiological investigations

Management

– Who should be treated!

– Treatment options

Puberty

Puberty (Latin pubescere, to be covered with hair)

The stage between the onset of secondary sexual characteristics and the completion of physical maturity

The period in which reproductive capability is attained,manifested by spermatogenesis in males & ovulation in females

Puberty

BRAIN

NEUROTRANSMITTERS

HYPOTHALAMUS

GnRH

PITUITARY GLAND

LH / FSH

GONADS

TESTOSTERONE / E2

ACTIVIN

INHIBIN

Puberty

Normal age

– girls: 9 -13 y (mean age =11 years)

– boys: 11 -15 y (mean age =13 years)

primates

– puberty process happened very quickly within

28 days

Humans

– puberty on hold for a longer period ( 12 y)

Puberty in girls

Psychological / emotional changes

Stages of normal puberty

– Thelarche

– Adrenarche / Pubarche

– Menarche

Pelvic U/S changes of puberty

ovarian volume and follicular size

uterus to cervix ratio

endometrial echo

Skeletal changes in girls

Widening of pelvis and carrying angle

Major increase in BMD

Increased adipose tissue with typical

female distribution

95% of growth happened < menarche

Menarche usually by age 12.5-14.5 yr

Increased in muscle bulk but not to same

extent as males

Puberty

Somatic changes

pubic & axillary hair

acne

perspiration and characteristic body odour

(release of volatile acids= glutaric acid)

oily skin and hair

All these changes happen due to increased

adrenal androgens which are formed equally in

both males and females

– Adrenal androgens

androstenedione, DHEA, DHEAS

Definition of PP

In girls, defined as onset of puberty “breast

enlargement” before age of 8 years

In boys, defined as onset of puberty before

age of 9 years

Definition !!

Recently, many data suggest that girls seen

in sample of pediatric practices from across

the United States are developing pubertal

characteristics at younger ages.

Practitioners may need to revise their

criteria for referral of girls with precocious

puberty, with attention to racial differences !!

Why there is secular trend toward earlier puberty,

especially in girls !!!

Why percentage of girls with

precocious puberty rose from

2.5% in 1969 to 10% in 1990s !!!

1. Increasing % of obesity in girls

2. Environmental estrogen

The Hazards of Environmental Estrogens

World and I magazine; 10/1/2001; Trankina, Michele L.

The Hazards of Environmental Estrogens

Over the past 10 years, many synthetic compounds and plant products present in the environment have been found to affect hormonal functions in various ways

Premature puberty was traced to consumption of beef, and dairy products containing high concentrations of estrogen.

Another study from Puerto Rico revealed higher concentrations of phthalate--a xenoestrogen present in certain plastics--in girls who showed signs of early puberty, compared with controls.

estrogen-like substances in the plastic wrap used on sandwiches for kids' lunches.

It may be that excess of body fat and the exposure

to estrogenic substances operate together to

hasten puberty. Body fat is one site of endogenous

estrogen synthesis. Exposure to environmental

estrogens may add just enough exogenous

hormone to exert the synergistic effect necessary

to bring on puberty, much like the last drop of

water that causes the bucket to overflow !!!!!!!

World and I magazine;

10/1/2001; Trankina, Michele L.

Revised Definitions in girls

USAEurope

< 6 0r 7< 8Precocious

7 - 98 -10Early

> 9> 10Normal

For boys , USA & Europe have same definition !!

Types

Types

Central, True, GnRH dependent

– 89-98% of cases (major type)

Periphral, Pseudo, GnRH Independent

– 10 – 15 % of cases (not major type)

Mixed type

– Started with peripheral with 2ry. activation of central

Isolated Forms

– Thelarche

– Adrenarche

Peripheral typeCentral type

suppressedActivated axisH-P-G axis

Pre-pubertalAdult valuesLH & FSH

High High Sex steroids

Small in size (unless

tumor)

Pubertal sizeGonads

Etiology

Central, True, GnRH dependent

Etiology

Idiopathic

– most girls ( 90 %)

Secondary

– most boys ( 70-80%)

Etiology of CPP

CNS disorders

Hypothalamic Hamartoma

Glioma (NF-1)

Astrocytoma

Craniopharyngioma

Ependymoma, germinoma,

CNS radiation therapy

Post trauma (surgery)

Etiology of CPP

Inflammation (Brain abscesses)

Neurological & mental retardation

Hydrocephalus

prolonged sex steroid exposure associated

with peripheral puberty

Prolonged primary hypothyroidism ( -TSH

stimulates FSH, LH, Prl)

Etiology of peripheral type

Gonadial: McCune-Albright, tumour, cyst

Adrenal: Virilising CAH, tumours

Ectopic: hCG secreting tumours

– Germinoma, Hepatoblastoma

Exogenous source of hormone

Familial male dependent (Testotoxicosis)

Chronic primary hypothyroidism (-TSH stimulates testicular enlargement)

Autonomous gonad steroid production

McCune Albright syndrome– germ line activating mutations of the FSH

receptor

Familial male – dependent precocious puberty – activating mutation of the LH receptor

– The mutation is inherited in an autosomaldominant fashion, although sporadic cases can occur.

Examples of some cases

Six year old girl presented with bilateral breast

enlargement & axillary hair for last six

months, progressive in nature.

On examination, she had B2PH3.

Her investigations showed suppressed

LH/FSH with high estardiol level and high

serum inhibin.

What is most likely diagnosis?

What further investigations needed to be

done?

Diagnosis: Granulosa cell ovarian tumor

Three years old young child presented with 2 day history of menstruation with no any other signs of puberty. No previous similar history, no history of medications nor any trauma.

On examination, she was looking well, no systemic findings with weight and height on 10th.percentile and she was having Tanner stage of B2PH1.there was one large Cafe-au-lait macule

What is the most likely diagnosis?

Mention 4 important investigations

Mention 3 modalities of treatment?

McCune - Albright syndrome

Affects both sexes

Gonad autonomy

(Autonomous gonad steroid production)

Happen more commonly in girls

In girls, the presenting feature is often menses with / without Thelarche

Menses usually happen < 2-3 yrs of age

Activating mutation within exon 8 of Gs gene GNAS 1 on 20q13.2,results in increased activity of the Gs protein & cAMP in the affected endocrine tissue

McCune-Albright Syndrome

Abnormalities in McCune-Albright

syndrome

Endocrine problems

Precocious Puberty ++++

Goiter / Hyperthyroidism +++

Acromegaly / Gigantism ++

Cushing’s syndrome +

Hyperprolactinemia +

Hypophosphatemic rickets +

Abnormalities in McCune-Albright syndrome

Non-endocrine

Cafe-au-lait spot ++++

Fibrous dysplasia of bone ++++

Facial asymmetry ++

Elevated hepatic transaminases ++

G.I polyposis +

Cardiomyopathy +

Arrhythmias +

McCune-Albright syndrome

Estradiol level may be normal or high depending on the stage of development of follicular cyst

Menstrual flow represents estrogen withdrawal following regression of large follicular cyst

Basal and stimulated levels of LH / FSH are supressed in early stage

After many cycles of cysts appearance and regression,maturation of Hypothalamic function develop (2ry. central precocious puberty)

Treatment

Sequential removal of ovarian cyst

Complete removal of ovaries

17- Medroxyprogestrone (Provera)

Estrogen antagonists (Tamoxifen)

Aromatase inhibitors

Cyproterone Acetate (Androcur)

LHRH agonist (central stage)

Two years old toddler brought by her

parents, complaining of bilateral breast bud

for the last 2 months with no other relevant

history or examination findings?

What further important history and

examination you need to confirm?

Mention 3 important investigations?

What is the most likely diagnosis?

Isolated form of pubertal

development

–Premature Thelarche

– Premature Adrenarche

–Premature Pubarche

Premature Thelarche

Premature breast enlargement with absence of growth spurt

Bone age is not accelerated

Pre pubertal pelvic U/S findings

Onset between 6 m to 4 y of age

Increased sensitivity of the breast tissue to low levels of sex steroids

Benign nature & need no therapy

Eight year old brought by her mother because

of smelly body odor. On examination, she

was having hairy lips, hyperpigmentations,

hoarse voice and acne. Her bone age was

advanced ?

What is the most likely diagnosis?

Mention important 5 investigations?

Mention how to treat this girl?

Premature Adrenarche

Occurs when the adrenal side of puberty is

turned on prematurely in the absence of

gonadal activation

Premature appearance of pubic and axillary

hair, acne, body odor & oily skin

Idiopathic

Premature Adrenarche

Elevated adrenal androgens

Normal LH / FSH & gonadal

steroids

Need to exclude late-onset CAH

Need to exclude adrenal tumours

Need to exclude PCOS

Diagnostic work-up

Evaluation of Precocious Puberty

History

physical examination

Growth percentiles

Calculation of target height

Bone Age assessment

Predicted adult height (PAH)

Basal LH, FSH and sex steroids

GnRH stimulation test

History

Age when secondary sexual development were noted

What features are present ?

Order of appearance of secondary features– Is it usual sequence or not ?

– Virilization symptoms Pubic/ axillary hair

Body odor

– Breast enlargement

– Vaginal discharges & menarche

– Cyclical mood changes

History

Evidence of recent growth acceleration

Family history of early puberty

– Age of parent puberty

Past history of adoption or early weight

gain

History of medications

Examination

Tanner staging

Degree of Virilization

– Clitromegaly in girls indicate abnormal androgen

Visual field assessment & fundoscopy

Abdominal masses

Skin (café-au-lait patches in McCune –Albright

syndrome, NF)

Assessment of height and height velocity

Clinical Measurements

– Standing height (Harpenden stadiometer)

– BMI

– Growth velocity (growth spurt)

– MPH

– Tanner staging of pubertal development

– Bone age (assessed by endocrinologist)

– PAH

Tanner Staging

Laboratory Studies

Sex steroid levels– Basal LH, FSH

GnRH stimulation test– A definitive CPP diagnosis is confirmed by a brisk rise

in LH 20-40 minutes after infusion of GnRH (100 mcg), which is more than the rise in FSH.

– No increase in LH and FSH after infusing GnRHsuggests precocious pseudo-puberty.

– Pre-pubertal girls with premature Thelarche sometimes show an exaggerated rise in FSH after GnRH.

– “FSH predominant response” An FSH rise more than the LH rise does not indicate CPP

hCG

– hepatoblastoma, germinoma

17 OHP &11DOC

– CAH

Thyroid tests are not a routine requirement

Bone Age

A radiograph of the

hand and wrist to

determine bone age

is a quick and useful

means to estimate

the likelihood of

precocious puberty

and its speed of

progression

Imaging Studies

MRI Brain

– Perform an MRI after hormonal studies (GnRHtest) to confirm a CPP diagnosis.

– Ask the radiologist to do a high-resolution study focusing on the hypothalamic-pituitary area.

– The younger girls with CPP, the greater the chance of finding CNS pathology girls younger than 6 y.

For boys younger than 9 years, the incidence of CNS findings is much higher than in girls, and MRI should be part of the evaluation.

In recent years, MRI has become the imaging method of choice in the assessment of CPP

MRI now allows the identification of previously unseen intracranial abnormalities in CPP, thus reducing the number of cases previously considered to be 'idiopathic.'

Pelvic ultrasound – Ultrasound is unnecessary for girls with a definite

diagnosis of CPP.

– If performed, however, ultrasound usually shows bilaterally enlarged ovaries, often with multiple small follicular cysts, and an enlarged uterus with an endometrial stripe.

– Pelvic ultrasound is essential when precocious pseudo-puberty is suspected (based on examination or hormone levels) because an ovarian tumor or cyst may be detected.

U/S Testes

Adrenal U/S

Treatment

Why do we need to treat ??

Main problems (Boys)

– eventual short stature

– psychological issues

– aggressiveness

– inappropriate libido

Main problems (Girls)

– eventual short stature

– psychological issues

– inability to cope with menstruation

– risk of child abuse

Goals of treatment

Decrease the progression of pubertal

changes

Decrease bone maturation

Increase the predicted final adult height

Psychosocial and behavioral therapy

Modalities of treatment CPP

Surgical Care– When CPP is caused by a CNS tumor other than a

Hamartoma, perform a resection to the extent possible without impinging on vital structures such as the optic nerves.

Radiation therapy – often is indicated if surgical resection is incomplete.

Unfortunately, removal of the tumor rarely causes regression of precocious puberty.

Medical Care

Gonadotropin-releasing hormone (GnRH) agonists

Do All Idiopathic Central Precocious Puberty

Require Gonadotropin-Releasing Hormone

Agonist Treatment?

Important questions prior starting GnRHa

How early is the onset of puberty?

How much advancement of the bone maturation?

What is the predicted adult height (PAH)?

Comparison of PAH to MPH ?

How fast the progression of physical changes?

GnRH stimulation test ?

Important questions prior starting GnRHa

Is the child also deficient in GH?

Has psychosocial well-being been

compromised?

Is treatment likely to improve the quality of

life?

Are the anticipated gains worth the

potential expense & complications of

therapy?

Very important issue is the distinction

between the non –progressive forms of

CPP with respect to auxological effects

on growth and whether there is need to

start treatment !

GnRH agonists

First reported in 1981

The treatment of choice of CPP

Alteration of peptide sequence of native GnRH with more potency, affinity to the receptors

Acts continuously with down regulation of GnRH receptors

GnRH agonist

Daily S/C preparation

• Desoriline

4-8 ug/kg/d

• Busereline

20-40ug/kg/d

• leuprolide

20-50 ug/kg/day

• Nafarelin(intranasal)

800-1600ug/kg/day

Depot-preparations

• Leuprorelin acetate

(Lupron)

0.3 mg / kg (7.5 mg)

• Tryptorelin

(Decapeptyl)

50-100ug/kg

• Goserelin (Zoladex)

Response to therapy

Suppression of endogenous LH / FSH

should be confirmed by GnRH test after 3m

and then bi-annually

Testosterone and E2 with in 1-2 Wk

Regression of Pubertal changes

Adverse effects

Anaphylactic reactions: angioedema, urticaria

Local skin reactions : redness,swelling, itchiness and sterile abscesses

Flare – up phenomena

– initial activation of HPG axis with worsening of symptoms

Under treatment

Results in stimulation rather suppression of central axis

Final Height After GnRHa Treatment for

Central Precocious Puberty

Bone age (BA) and chronological age (CA) at start of treatment, as well as BA advance at cessation of treatment, were the most important variables influencing height gain in multiple regression analysis.

BA advance at start of treatment was most important in simple correlation.

In girls, GnRHa treatment seems to restore FH into the target range.

A younger age and advanced bone age at start of treatment are associated with more height gain from GnRHa treatment.

Treatment - Conclusion

1) The use of long-acting (GnRH) agonists may not be indicated in slowly progressive variants or borderline early puberty because they do not affect final height.

2) Preservation of height potential is particularly obvious in precocious puberty starting at young ages.

3) In some selected patients, associated growth hormone therapy may increase adult height but

further studies are warranted.

Combined use of GH& GnRHa

It appears that patients with CPP who grow poorly during GnRHa therapy may have alterations in their GH-IGF-I axis.

This may be attributable to an exaggerated and sustained decrease in the secretion of GH with the withdrawal of sex steroids after the GnRHa therapy has been initiated.

Treatment to slow skeletal maturation in the face of suppressed GH secretion will still result in compromised adult height.

This has led some investigators to speculate that at least a subset of patients with CPP would benefit from the addition of GH therapy to the GnRHa treatment.

The results of such treatment first were reported in 1991 by Oostdijk et al in a study of 3 girls with growth velocities less than the 25th percentile for chronologic age after 3 years of treatment with deslorelin.

Treatment with GH was then started, and after 18 months of combination therapy, all the girls' predicted adult heights had improved (statistical analysis not published).

Since then, additional studies have addressed the question of whether combination therapy improves the predicted adult height in children with idiopathic CPP.

Pediatrics;1999; Pescovitz, Ora Hirsch

Effects of combined Gonadotropin-releasing

hormone agonist and growth hormone therapy on

adult height in precocious puberty

Pucarelli I ,et.al J Pediatr Endocrinol Metab. 2003

Sep;16(7):1005-10.

Combined use of GH& GnRHa

CONCLUSIONS

The primary goal of GnRHa therapy in CPP is to maintain normal height potential,

It is disturbing that not all patients attain adult heights that are within their genetic target ranges.

The effect of GnRHa therapy on the growth axis still is not completely clear, but it is apparent that some children have significant deceleration of their growth velocity, sometimes in association with decreases in GH and IGF-I levels, during treatment.

In fact, decreased secretion of IGF-I may even occur in treated patients with normal growth.

The published studies do suggest a real benefit from adding GH to GnRHa therapy in children with suboptimal growth during GnRHa therapy.

However, the studies have been small and have not all included control groups, and that the sole study that followed the subjects to adult heights found only a modest improvement.

Studies in short normal children and GH-deficient children who are treated with a combination of GH and GnRHa to improve adult heights have yielded encouraging, yet somewhat limited, results as well

Combination therapy could be a viable treatment option in some children with CPP, but additional studies are needed before widespread clinical use outside of a research setting can be recommended.

Conclusions

GnRH antagonist

act by competitive binding to the pituitary GnRH

receptors, thereby preventing the action of

endogenous GnRH - theoretically offering a more

direct and dose-dependent treatment

The antagonist available today in Germany is a

concomitant in assisted reproduction with only 1 -

3 days duration.

long-acting depot preparations of other GnRH

antagonists are in developing phase

GnRH antagonist

Antagonists such as Abarelix-Depot bind to GnRH

receptors and turn them off, causing an immediate

and complete decline in sex hormones production

to the level of medical castration.

The immediate suppression of the pituitary

achieved by GnRH antagonists without an

initial stimulatory effect is the main advantage

of these compounds over the agonists.

The main disadvantages of the antagonists

are that they are expensive

Other Medications !!

Cyproterone Acetate (Androcur)® in the

Treatment of Precocious Puberty

CPA was found effective in persistently suppressing pituitary gonadotropic secretion when administered orally at a dose of 50 mg bid.

After the introduction of gonadotropic analogues (GnRHa) for treatment of central precocious puberty, short term use of CPA was found useful to counteract the initial initial'flare-up' of the pituitary-gonadal axis, followed by a reduced luteinising hormone secretion by desensitization of pituitary GnRH receptors

Other indications for CPA treatment during childhood and adolescence,– congenital adrenal hyperplasia

– Acne

– Hirsuitism

Treatment of peripheral type

Medical therapy

Medroxyprogestrone acetate (Provera)

Ketoconazole

Aromatase enzyme inhibitors (testolctone)

Androgen antagonists

Surgical treatment of underlying pathology if present

Medroxyprogestrone acetate (Provera)

Before availability of GnRH agonists, this category was the mainstay of therapy.

Progestin work by providing feedback suppression of pituitary Gonadotropin secretion.

They lack significant androgenic or estrogenic activity.

Not expensive treatment

Can stop menstruations, but has no much role in improvement of PAH

Can be a good choice to those who present late

Medroxyprogestrone acetate (Provera)

Structurally similar to glucocorticoid

Progestational agent which suppresses gonadotrophin

Useful in the treatment of both types

Effective in halting the advancement of secondary characters in both sexes

Effective in preventing menstruation

No effects on bone maturation

Dose : 100-200 mg/m2 IM q2wk

ketoconazole

Anti-fungal with side effect of the inhibition of both steroidogenesis and testosterone synthesis at 17,20 Lyasestep

Dose 400-600 mg/day

Suppression happen with in 48 h

Potential hepatotoxic

Aromatase Inhibitors Aromatase enzyme converts

– Androstedione to estrone

– Testosterone to estradiol

Decreasing level of estradiol and receptor affinity has major rule in decreasing bone maturation and give more chance of delayed epiphysis closure in both sexes

Many researches going on currently, to use of this category in those with advanced bone age and short stature to improve PAH, especially those with verilizing CAH, who present late with precocious puberty & advanced bone age

Aromatase Inhibitors

First generation

– Testolactone

Second generation

– Formastine, Plomestane, Atamestane,

Minamestane, Exemastane

Third generation

– Anastrazole (Arimidex)

– Letrazole (Femara)

Aromatase Inhibitors

Testolactone (Teslac) is a competitive

steroidal aromatase inhibitors

Combined with Spirinolactone is useful in

treatment of familial Testotoxicosis

Dose 20 mg/kg/day initially then 40

mg/kg/day divided into 4 doses

Anti - Androgens

1. Intra – Adrenal blockage of androgen production

– Ketoconazole

– Blocks adrenal steroid production at several

enzymatic steps

– Considered to be “ reversible medical adrenalectomy”

2. Peripheral blockage of androgen action

– Anti- Androgens:

Spirinolactone (aldactone)

Cyproterone acetate (Androcur)®

Finasteride = 5 - reductase enzyme inhibitor

– Androgen receptor-blockers:

Flutamide