Precocious Puberty
By Dr. Usama Ragab Youssif
Precocious puberty (PP) is defined as the development of pubertal changes (2ry sexual characters), at an age younger than the accepted lower limits for age of onset of puberty.
2. Case
Dr. Usama Ragab Youssif
A 6-year-old girl presents with
advanced breast development. On
examination, some pubic hair is
also observed.
Parents mention that the breast
development started about 6 months
ago, but the pubic hair is recent.
She has been outgrowing clothes
rather rapidly this year.
Neurological examination is normal.
3. To
remember
puberty
terminol
ogy
Onset in girls= 8 – 13 years
Onset in boys= 9 – 14 years
Adrenarche= initiation of
adrenal androgen production
Gonadarche= initiation of
gonadal hormones production
Thelarche= onset of breast
development
Menarche= onset of menses
Dr. Usama Ragab Youssif
4. Definition
Precocious puberty (PP) is
defined as the development
of pubertal changes (2ry
sexual characters), at an
age younger than the
accepted lower limits for
age of onset of puberty.
J Clin Res Pediatr Endocrinol. 2009;1(4):164-74.
Dr. Usama Ragab Youssif
5. We need
revisio
n
Historic. The mean age of menarche in
Europe has decreased from 17 years in
1900 to 12.8 years today, likely due to
improved childhood nutrition and growth.
Genetic. Age at onset of puberty is a
polygenic trait with estimated
heritability of about 50–60%.
Ethnicity. Afro-Caribbean and South
Asian girls tend to have earlier puberty
than Caucasians.
Weight gain is linked to earlier
puberty, while those who are thin and
engage in regular physical activity
often experience delayed puberty.
Dr. Usama Ragab Youssif
6. Epidemiology
0.2 % of females had some form of precocious
puberty (CPP, PPP or benign variants) while it
was less than 0.05% in males.
Female = benign
Male = tumor
Pediatrics. 2005 Dec;116(6):1323-8. Dr. Usama Ragab Youssif
7. Burden
• Psychosocial?
• Kids and their carer
• Initially taller than
their peers
• Finally shorter than
their peers
Dr. Usama Ragab Youssif
8. Rajendram, R., Preedy, V.R. and Martin, C.R. eds., 2022. Cellular, molecular, physiological, and behavioral aspects of
traumatic brain injury. Academic Press.
Dr. Usama Ragab Youssif
9. Santoro et al. International journal of molecular sciences. 2021 Jan 19;22(2):972 Bajpai & Menon. Indian journal of endocrinology and metabolism. 2011 Sep
1;15(Suppl3):S172-9.
KiSS1 R
(GPR54)
Dr. Usama Ragab Youssif
10. Classifications
and subtypes
• Central precocious puberty
(GnRH dependent) = true
• Peripheral precocious puberty
(GnRH independent) = false
• Isolated reversible
• Combined start as PPP then
proceed to CPP
• Isosexual “phenotypically
appropriate” or heterosexual
“phenotypically inappropriate”
Dr. Usama Ragab Youssif
11. The 2 main categories
• Activation of HPG axis
• Elevated “pubertal” LH & FSH
• Elevated T or E2
CPP
• No activation of HPG axis
• Non elevated “prepubertal” LH &
FSH
• Endogenous or exogenous T or E2
PPP
Dr. Usama Ragab Youssif
12. Precocious puberty requires differentiation from
the benign forms of puberty
Owen, K., Turner, H. and Wass, J. eds., 2022. Oxford handbook of endocrinology & diabetes. Oxford
University Press.
lease, follow up these cases as they may represent early phases of P
Dr. Usama Ragab Youssif
13. Obesity Related Precocious Puberty
Dr. Usama Ragab Youssif
Obesity increases leptin → leptin ↑ GnRH release → ↑ FSH/LH
Obesity induced IR → hyperinsulinemia
Excess insulin → ++ aromatase activity
Excess insulin → - - SHBG synthesis in liver → free sex hormones
More apparent in girls than boys
Calcaterra et al. Children. 2023 Jan 29;10(2):241.
15. PPP
Sex steroids from endogenous (gonadal or
extragonadal) or exogenous sources.
Without true HPG axis activation
It is less frequent compared to the CPP.
Prolonged exposure to sex hormones may also
trigger central precocious puberty
Dr. Usama Ragab Youssif
18. Male =
brain
lesion
Mostly hypothalamic hamartoma.
Ectopic neural cells = accessory
GnRH pulse generator.
CPP as early as 12 months of
age.
Gelastic seizures refractory to
ttt
Dr. Usama Ragab Youssif
25. Listen
Early = before the normal age of onset.
Sometimes not early but rapid tempo…
Headache, vomiting, blurring of vision, seizure = CPP
Head trauma, past infection = CPP
Abdominal pain or swelling = ovarian or adrenal
Abnormal diet
A complete family history of puberty onset is also important.
Drug history for kid and parents
Dr. Usama Ragab Youssif
26. Look
• Premature puberty i.e., T2
on SMR
• Linear growth acceleration:
height, weight, growth
velocity (cm/year) and BMI
• 1st = Breast development in
females
• 1st = Increased testicular
volume (greater than 4 ml)
in males.
• Others:
Taller than peers
Adult skin: acne, body
odor
Pubic and axillary hair
development.
Dr. Usama Ragab Youssif
27. Tanner staging
• Sexual maturity
rating (SMR)
• Challenging
• Need practicing
• Difficult e.g.,
breast assessment in
obese girl or penile
length assessment in
obese boy
Dr. Usama Ragab Youssif
28. Adolescent health care : a practical guide. Neinstein, Lawrence S., Neinstein, Lawrence S. (5th
ed.). Philadelphia: Lippincott Williams & Wilkins. 2008. ISBN 9780781792561. OCLC 148727849
Marshall, William A., and James M. Tanner. "Variations in the pattern of pubertal changes
in boys." Archives of disease in childhood 45, no. 239 (1970): 13-23.
Marshall, William A., and James M. Tanner. "Variations in pattern of pubertal changes in
girls." Archives of disease in childhood 44, no. 235 (1969): 291.
• 5 stages
• Based on 2ry sexual characters: genital
development in boys, breast in girls and
pubic hair in both
• Assessed independently i.e., breast,
genitalia, pubic hair
• Puberty means Tanner 2 before 95th of same
age kids
Dr. Usama Ragab Youssif
33. Clues for
the cause
Small testes in presence of
pubic, axillary and body odor
may denote PPP
Aggressive progressive course
= PPP mostly tumors
Unilateral testicular
enlargement = testicular
tumors.
Skin pigmentation = NF-1 or
Mc Cune
Dr. Usama Ragab Youssif
35. Easy
Confirm i.e., precocious T2
Height “+ plotting curves and calculate FH and
MPH”
Bone age
Dr. Usama Ragab Youssif
36. What are the tests should be
performed in PP?
Kim et al. Annals of Pediatric Endocrinology & Metabolism. 2023 Sep;28(3):168.
Dr. Usama Ragab Youssif
37. Measuremen
t of LH,
FSH and
sex
hormones
Kim et al. Annals of Pediatric Endocrinology & Metabolism. 2023 Sep;28(3):168.
Dr. Usama Ragab Youssif
38. LH measurement
3rd generation LH assays
detect levels as low as
0.1 IU/L, making random
LH a good screening test
for CPP, with levels of
0.3 IU/L or higher
considered diagnostic
Many children with CPP
have prepubertal basal
LH levels, but respond
to challenges with GnRH
with an increase to 5
IU/L or above,
indicating pubertal
status
Dr. Usama Ragab Youssif
39. When should a
brain MRI be
performed to
identify organic
causes in patients
with CPP?
Kim et al. Annals of Pediatric Endocrinology & Metabolism.
2023 Sep;28(3):168. Dr. Usama Ragab Youssif
45. CPP
Treatme
nt
Aim: psychosocial support, preserve adult
height
Concept: long-acting GnRH analogues to
suppress HPG axis “Pituitary LH and FSH
secretion is inhibited by continuous exposure
to GnrH analogues”
Goserelin 3.6mg SC monthly or 10.8mg SC 3-
monthly, or triptorelin 3.75mg monthly or
11.25mg 3-monthly SC or deep IM every 2 weeks
for the first three injections, then 3- to 4-
weekly thereafter. Leuprolide acetate.
Safety: safe, skin reaction, flushing
Dr. Usama Ragab Youssif
47. Monitoring
of
treatment –
Clinically
and Lab
• Clinically: pubertal progression, growth
velocity, and skeletal maturation
• Lab: ensuring that pre-dose LH, FSH, and sex
hormone levels remain at low prepubertal
levels.
• The dosing intervals may need to be reduced
if there is evidence of inadequate
suppression of pubertal development.
Dr. Usama Ragab Youssif
50. Is the treatment with a GnRH agonist
associated with an increased risk of other
diseases in the long term?
Dr. Usama Ragab Youssif
51. PPP
Treatme
nt
Concept: Eliminating the source of sex steroids.
Gonadal and adrenal tumors: Surgery
Classic CAH is treated with dexamethasone.
McCune-Albright syndrome: block estrogen
synthesis by aromatase inhibitors (anastrozole,
letrozole) and selective estrogen selective
receptor modulator (tamoxifen).
Familial male-limited precocious puberty is not
well established, but the preferred treatment is
a combination of an androgen antagonist
(spironolactone) and an aromatase inhibitor
Dr. Usama Ragab Youssif
52. Recap
PP = early puberty i.e., <8 and <9
• Identified by Tanner
Causes
• CPP often idiopathic mostly in females or have a cause often
in males
• PPP: excess sex steroids or hCG or hypersensitive LH receptors
Dr. Usama Ragab Youssif
53. Diagnosis
Bone age: advanced
Sex hormones & Gonadotrophin levels:
dependent or independent
Imaging: Brain or gonads or elswhere
Dr. Usama Ragab Youssif
55. Thank
You
Dr. Usama Ragab Youssif
Email: usamaragab@medicine.zu.edu.eg, usama.ragab.zu@gmail.com
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Notes de l'éditeur
The traditional definition of precocious puberty is the development of secondary sexual characteristics before 8 years of age in girls and 9 years in boys.
--------------------------
This is due to premature activation of pulsatile GnrH secretion from the hypothalamus.
The normal progression in physical changes (‘consonance’) is maintained but may be accelerated. As precocious puberty is defined as age at onset 2 SD before the average age, with ongoing secular trends to earlier puberty, this may be physiological in an increasing number of children, especially in girls with a family history of early puberty.
By contrast, boys with precocious puberty have a greater risk of intracranial or other pathology.
This is due to premature activation of pulsatile GnrH secretion from the hypothalamus.
The normal progression in physical changes (‘consonance’) is maintained but may be accelerated. As precocious puberty is defined as age at onset 2 SD before the average age, with ongoing secular trends to earlier puberty, this may be physiological in an increasing number of children, especially in girls with a family history of early puberty.
By contrast, boys with precocious puberty have a greater risk of intracranial or other pathology.
The first epidemiologic study from a Danish national registry estimated that 0.2 % of females had some form of precocious puberty (CPP, PPP or benign variants) while it was less than 0.05% in males.
----------------------
This is due to premature activation of pulsatile GnrH secretion from the hypothalamus.
The normal progression in physical changes (‘consonance’) is maintained but may be accelerated. As precocious puberty is defined as age at onset 2 SD before the average age, with ongoing secular trends to earlier puberty, this may be physiological in an increasing number of children, especially in girls with a family history of early puberty.
By contrast, boys with precocious puberty have a greater risk of intracranial or other pathology.
Precocious puberty can lead to short stature, emotional and behavioral issues, substance abuse, conduct issues, social isolation, truancy, multiple sexual partners, peer pressure, and self-image concerns, often resolved by early adulthood.
Precocious puberty can lead to short stature, emotional and behavioral issues, substance abuse, conduct issues, social isolation, truancy, multiple sexual partners, peer pressure, and self-image concerns, often resolved by early adulthood.
Leydig cell produces testosterone
Why I have mentioned KISS here?
Because: one of the causes of CPP may be genetics –gain of function mutation encoding the kisspeptin (KISS1) and its receptor (KISSR) genes
This type of precocious puberty represents true pubertal development due to the earlier maturation and activation of the HPG axis.
Most of the time, the common cause in females is idiopathic, and in males, there is usually an underlying pathology.
This type of precocious puberty represents true pubertal development due to the earlier maturation and activation of the HPG axis.
Most of the time, the common cause in females is idiopathic, and in males, there is usually an underlying pathology.
-------------------------
This is due to premature activation of pulsatile GnrH secretion from the hypothalamus.
The normal progression in physical changes (‘consonance’) is maintained but may be accelerated. As precocious puberty is defined as age at onset 2 SD before the average age, with ongoing secular trends to earlier puberty, this may be physiological in an increasing number of children, especially in girls with a family history of early puberty.
By contrast, boys with precocious puberty have a greater risk of intracranial or other pathology.
--------------------------------
Most patients, particularly girls suspected of having CPP, are otherwise healthy children whose pubertal maturation begins at the early end of the normal distribution curve. CNS imaging studies of these girls aged 6-8 years usually reveal no structural abnormalities. While older studies reported a significant proportion of abnormal findings such as tumors, subsequent reports have found an incidence of clinically significant brain imaging findings of less than 1%, even in girls below age 6 years.
Precocious development of secondary sexual characteristics independent of the GnRH pulsatile secretion constitutes PPP
This is due to the production of sex steroids from endogenous or exogenous sources.
It is less frequent compared to the CPP.
The most common brain lesion causing CPP is hypothalamic hamartoma.
The ectopic neural cells in the lesion serve as an accessory GnRH pulse generator.
It presents with precocious puberty in infancy as early as 12 months of age.
The most characteristic association is gelastic seizures, which are usually refractory to medications.
Treatment is with androgen receptor-blocking agents (CPA or flutamide) and aromatase inhibitors.
Early = before the normal age of onset.
Sometimes not early but rapid tempo…
Rapid progression of puberty, even at a normal age, is abnormal.
Symptoms include neurological issues like headaches, seizures, and visual and cognitive changes may suggest central pathology.
Ovarian pathology may also present with abdominal pain.
A history of head trauma, brain infections, or unusual diets should be explored.
A complete family history of puberty onset is also important.
---------------------------
Age when 2° sexual features first noted.
What features are present and in what order did they appear? For example, virilization (pubic, axillary, or facial hair; acne; body odour), genital or breast enlargement, galactorrhoea (very rare), menarche, or cyclical mood changes?
recent growth acceleration?
Family history of early puberty?
Past history of rapid early life weight gain, adoption or migration from a poorer social setting, or prior CNS abnormality or insult (e.g. irradiation)?
The presentation is usually consistent with premature development of pubertal signs.
The initial clinical signs are breast development in females and increased testicular volume (greater than 4 ml) in males.
The other signs and symptoms include increased linear growth, acne, muscular changes, body odor, and pubic and axillary hair development.
-------------------------------
Breast or genital and testicular size; degree of virilization (clitoromegaly in girls indicates abnormal androgen levels).
Neurological examination, including visual fields and fundoscopy.
Abdominal or testicular masses?
Unusual skin pigmentation? (café-au-lait patches—McCune–Albright (see E McCune–Albright syndrome, pp. 654–5) or NF type 1 (NF-1) (see E Neurofibromatosis, pp. 658–60)).
Assess height and BMI, and height velocity over 4–6 months.
In females, accurate Tanner staging of the breast should take place, which is particularly challenging in obese or overweight girls to differentiate between adipose tissue and the glandular breast tissue.
------------------------
The 1st indication of puberty is breast development in girls and an increase in testicular size in boys.
Puberty then progresses in an orderly or ‘consonant’ manner through distinct stages (see Table 7.2). Puberty rating by an experienced observer involves identification of the pubertal stage—particularly, breast development in girls and testicular volume (using an orchidometer) in boys.
Genitals (male)[edit]
Photos of the Tanner scale for males.
Tanner I: testicular volume less than 1.5 ml; small penis (prepubertal)
Tanner II: testicular volume between 1.6 and 6 ml; skin on scrotum thins, reddens and enlarges; penis length unchanged
Tanner III: testicular volume between 6 and 12 ml; scrotum enlarges further; penis begins to lengthen
Tanner IV: testicular volume between 12 and 20 ml; scrotum enlarges further and darkens; penis further increases in length and starts to increase in breadth
Tanner V: testicular volume greater than or equal to 20 ml; adult scrotum and penis
---------------------
Breasts (female)
Photos of the Tanner scale for females
Tanner I: no glandular tissue: areola follows the skin contours of the chest (prepubertal)
Tanner II: breast bud forms, with small area of surrounding glandular tissue; areola begins to widen
Tanner III: breast begins to become more elevated, and extends beyond the borders of the areola, which continues to widen but remains in contour with surrounding breast
Tanner IV: increased breast sizing and elevation; areola and papilla form a secondary mound projecting from the contour of the surrounding breast
Tanner V: breast reaches final adult size; areola returns to contour of the surrounding breast, with a projecting central papilla
---------------------
Pubic hair (both male and female)
Tanner I: no pubic hair at all (prepubertal)
Tanner II: small amount of long, downy hair with slight pigmentation at the base of the penis and scrotum (males) or on the labia majora (females)
Tanner III: hair becomes more coarse and curly, and begins to extend laterally\
Tanner IV: adult-like hair quality, extending across pubis but sparing medial thighs
Tanner V: hair extends to medial surface of the thighs
12 balls
First 3 balls are prepubertal stages
Adult is final 2 balls i.e., 20 and 25
An orchidometer is a tool used to assess testicular size, consisting of a series of beads or ellipsoids of increasing volume, typically ranging from 2 mL to 24 mL. The most common type of orchidometer is the Prader orchidometer, which is a chain of 12 solid wooden ellipsoids with volumes ranging from 1 mL to 25 mL. Testicular size is measured by visually comparing the size of each testis to the corresponding bead or ellipsoid on the orchidometer.
In males, an orchidometer should be used to determine the testicular volume. Volumes of more than 4 ml confirm pubertal development.
In males and females with pubic hair and body odor, the absence of increased testicular volume and breast development should prompt investigation of peripheral causes.
Unilateral testicular enlargement is likely due to testicular tumors.
Bone age is an initial screening test. If the bone age is advanced (greater than two standard deviations) than the chronologic age, further testing should follow.
Hormonal testing differentiates peripheral and central causes.
A baseline prepubertal LH level of greater than 0.3 IU/L is suggestive of CPP. Levels under 0.3 are indicative of peripheral causes or benign variants.
If there is a high suspicion for central causes, a GnRH stimulation test, which is considered to be the gold standard, should be done. This test is not available in the United States so that the GnRH agonist is an alternative.
FSH levels are of limited utility.
Very high levels of estradiol in females or testosterone in males associated with suppressed LH and FSH are indicative of peripheral precocity.
Measurement of adrenal androgens such as dehydroepiandrosterone sulfate (DHEA S) differentiates between testicular and adrenal sources of androgens.
Many children with CPP have prepubertal basal LH levels, but respond to challenges with GnRH with an increase to 5 IU/L or above, indicating pubertal status.
Because of the development of more sensitive third-generation assays for luteinizing hormone (LH), which can detect levels as low as 0.1 IU/L or lower, random LH is now considered a good screening test for CPP, with levels of 0.3 IU/L or above considered diagnostic. However, many children with CPP have prepubertal basal LH levels but will respond to a challenge with gonadotropin-releasing hormone (GnRH) with an increase to 5 IU/L or above, which is considered pubertal.
Bone age is an initial screening test. If the bone age is advanced (greater than two standard deviations) than the chronologic age, further testing should follow.
Hormonal testing differentiates peripheral and central causes.
A baseline prepubertal LH level of greater than 0.3 IU/L is suggestive of CPP. Levels under 0.3 are indicative of peripheral causes or benign variants.
If there is a high suspicion for central causes, a GnRH stimulation test, which is considered to be the gold standard, should be done. This test is not available in the United States so that the GnRH agonist is an alternative.
FSH levels are of limited utility.
Very high levels of estradiol in females or testosterone in males associated with suppressed LH and FSH are indicative of peripheral precocity.
Measurement of adrenal androgens such as dehydroepiandrosterone sulfate (DHEA S) differentiates between testicular and adrenal sources of androgens.
Magnetic resonance imaging is to be performed in all cases of CPP, especially in males, to rule out a hypothalamic lesion. It is also to be considered in females who present with early pubertal changes (less than 6 years of age).
The decision to treat depends on the age of the child and the progression of puberty. If the child has rapidly progressing symptoms or if bone age is significantly advanced, consider treatment. The main goals of treatment are to preserve the adult height and to alleviate the associated psychosocial stress. GnRH agonists are the standard of care.[6] Many different formulations (intranasal, intramuscular and subcutaneous) of long and short-acting GnRH agonists exist. The choice of the formulation depends on the patient and clinician preference. In the United States, leuprolide acetate is the most common. It is a depot injection administered every 3 months.
GnRH agonist therapy is generally considered safe, with no reported significant adverse events. The most common adverse events include local skin reactions (intramuscular pain, sterile abscesses) and post-menopausal symptoms (hot flushes).
While on treatment, periodic monitoring of pubertal progression, growth velocity, and skeletal maturation are necessary.
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Aims of treatment are:
• To avoid psychological distress for the child.
• To avoid reduced final height due to premature bone maturation and
early epiphyseal fusion. A final height prediction is often helpful when
considering treatment. Significant improvement in adult height is only
likely to be achieved if treatment is started ≤6 years of age.
ombination of GH and GnRH analog: GH has been used to counter growth suppression induced by GnRH analog.[41] While the role in children with underlying GH deficiency is clear, the effect on GH sufficient children is modest.
Patients on GnRH analogs should be followed up 3-monthly for pubertal status and growth parameters. Treatment is expected to result in cessation of pubertal development, but may not cause regression of all features. GnRH analog treatment has no effect on pubic hair development as it is controlled by adrenal androgens. Initial flare-up following GnRH analog may result in advancement of pubertal changes and rarely withdrawal of vaginal bleeding. Cyproterone acetate or medroxyprogesterone acetate may be combined with GnRH analog during the first 3 months of treatment to avoid the flare-up response. Good compliance to GnRH analog is mandatory as delay in treatment may result in resensitization of gonadotropes to GnRH and may cause flare-up response with the next dose.
Adequacy of treatment is assessed by demonstration of pre-pubertal LH levels in response to GnRH stimulation test performed 6-monthly (peak LH less than 2 IU/L).[33] Given the difficulties in procuring native GnRH and the need for separate intravenous injection, measurement of LH levels after GnRH agonist injection has been evaluated. LH levels below 6 IU/L, 2 hours after longacting GnRH agonist, indicates adequate gonadal suppression.[34] Children with inadequate gonadal suppression on 3-monthly injections should be shifted to monthly injection. If the suppression still remains inadequate, the frequency of injections should be increased. Bone age should be obtained annually and used for prediction of final height.
GnRH analog should be continued till the age of 10 years in girls and 12 years in boys (or GnRHa was discontinued when BA reached 12 years.)
Discontinuation of treatment results in gradual reappearance of secondary sexual characters.
Menarche is usually attained around 12–18 months following discontinuation of treatment
Treatment is directed towards eliminating the source of sex steroids. Surgery is indicated in gonadal and adrenal tumors. If exogenous sources of sex steroids are identified, they should be eliminated. Classic congenital CAH is treated with glucocorticoids. In McCune-Albright syndrome, some benefit occurs with blocking the estrogen synthesis using aromatase inhibitors (anastrozole, letrozole) and selective estrogen selective receptor modulator (tamoxifen). The optimal treatment for familial male-limited precocious puberty is not well established, but the preferred treatment is a combination of an androgen antagonist (spironolactone) and an aromatase inhibitor (anastrozole, testolactone).[7]