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==[[Precocious puberty overview|Overview]]==
==[[Precocious puberty overview|Overview]]==
The term precocious puberty (Latin - ''pubertas praecox'')refers to an abnormal early onset of puberty where sexual maturity begins at an unexpectedly early age. There are other terms used to define precocious puberty which are pubertas praecox or sexual precocity<sup>1</sup>. Precocious puberty is usually consistent with premature development of pubertal signs. It includes a group of heterogeneous conditions that extend from deviations of normal development to slowly progressive and rapidly maturation of both genders<sup>2</sup>. The first clinical signs include increasing in the secretion of sex hormones and maturation of gonads testes in boys, ovaries in girls, and the potential for reproduction. The other signs and symptoms involve increased linear growth, acne, muscular changes, and pubic and axillary hair development. Classically, precocious puberty occurring before the age of 8 years in girls and 9 years in boys is considered precocious.Nevertheless, recent studies reveal that signs of early pubertyare often present in girls (black girls in specific) aged 6-8 years<sup>3</sup>. They reported that the glands that secrete growth and sex hormones starttheir function abnormally early in life causing in this condition<sup>4,5</sup>. Most cases of precocious puberty in girls are idiopathic or have benign causes, however it can also indicate serious pathology. Even thoughprecocious puberty is less common but proportionally much more likely to have a serious cause and requires urgent treatment<sup>6.</sup>For example, it could be caused by a neurologic disorder in a very young boy<sup>7</sup>. Precocious Puberty has two forms which are gonadotrophin-dependent precocious puberty (GDPP; due to premature activation of the hypothalamic-pituitary-gonadal axis) and gonadotrophin-independent precocious puberty (GIPP; due to autonomous secretion of sex steroids)<sup>8</sup>.
The term precocious puberty (Latin - ''pubertas praecox'')refers to an abnormal early onset of puberty where sexual maturity begins at an unexpectedly early age. There are other terms used to define precocious puberty which are pubertas praecox or sexual precocity<sup>1</sup>. Precocious puberty is usually consistent with premature development of pubertal signs. It includes a group of heterogeneous conditions that extend from deviations of normal development to slowly progressive and rapidly maturation of both genders<sup>2</sup>. The first clinical signs include increasing in the secretion of sex hormones and maturation of gonads testes in boys, ovaries in girls, and the potential for reproduction. The other signs and symptoms involve increased linear growth, acne, muscular changes, and pubic and axillary hair development. Classically, precocious puberty occurring before the age of 8 years in girls and 9 years in boys is considered precocious.Nevertheless, recent studies reveal that signs of early puberty are often present in girls (black girls in specific) aged 6-8 years<sup>3</sup>. They reported that the glands that secrete growth and sex hormones start their function abnormally early in life causing in this condition<sup>4,5</sup>. Most cases of precocious puberty in girls are idiopathic or have benign causes, however it can also indicate serious pathology. Even though precocious puberty is less common but proportionally much more likely to have a serious cause and requires urgent treatment<sup>6.</sup>For example, it could be caused by a neurologic disorder in a very young boy<sup>7</sup>. Precocious Puberty has two forms which are gonadotrophin-dependent precocious puberty (GDPP; due to premature activation of the hypothalamic-pituitary-gonadal axis) and gonadotrophin-independent precocious puberty (GIPP; due to autonomous secretion of sex steroids)<sup>8</sup>.


==[[Precocious puberty historical perspective|Historical Perspective]]==
==[[Precocious puberty historical perspective|Historical Perspective]]==
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1-    In central precocious puberty(CPP) - termed gonadotropin releasing hormone-dependent precocious puberty (GDPP), there is premature activation of the hypothalamic-pituitary-gonadal (HPG) axis causing physical and hormonal changes of normal puberty at an early age and faster pace.The secreted hormones cause the testicles or ovaries to make other hormones: testosterone or estrogen. These sex hormones cause the changes of puberty, like breast development in girls.CPP is more common between 4 and 8 years.
1-    In central precocious puberty(CPP) - termed gonadotropin releasing hormone-dependent precocious puberty (GDPP), there is premature activation of the hypothalamic-pituitary-gonadal (HPG) axis causing physical and hormonal changes of normal puberty at an early age and faster pace.The secreted hormones cause the testicles or ovaries to make other hormones: testosterone or estrogen. These sex hormones cause the changes of puberty, like breast development in girls.CPP is more common between 4 and 8 years.


2-    In peripheral precocious puberty (PPP) - termed gonadotropin releasing hormone independent precocious puberty (GIPP), increasing in production of sex steroids is independent of the HPG axis.The hormones estrogen and testosterone activate the symptomsbut the brain and pituitary gland are not involved. It is usually caused by a local problem with the testicles, ovaries,adrenal gland, or a severely underactive thyroid gland.
2-    In peripheral precocious puberty (PPP) - termed gonadotropin releasing hormone independent precocious puberty (GIPP), increasing in production of sex steroids is independent of the HPG axis.The hormones estrogen and testosterone activate the symptoms but the brain and pituitary gland are not involved. It is usually caused by a local problem with the testicles, ovaries,adrenal gland, or a severely underactive thyroid gland.
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==[[Precocious puberty pathophysiology|Pathophysiology]]==
==[[Precocious puberty pathophysiology|Pathophysiology]]==
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o   Brain tumors such as glioma, astrocytoma, germ cell tumor.
o   Brain tumors such as glioma, astrocytoma, germ cell tumor.


o  Priorinfection of the brain such aspost-meningitis, postencephalitis,neurotuberculosis
o  Prior infection of the brain such as post-meningitis, postencephalitis,neurotuberculosis


o  Brain insults such as trauma, neurosurgery, cranial irradiation, perinatal asphyxia
o  Brain insults such as trauma, neurosurgery, cranial irradiation, perinatal asphyxia
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o  Malformations such as arachnoid cyst, hydrocephalus, septo-optic dysplasia, neural tube defect, neurofibromatosis  
o  Malformations such as arachnoid cyst, hydrocephalus, septo-optic dysplasia, neural tube defect, neurofibromatosis  


·      Miscellaneous such asadoption, activating KISS 1 and GPR54 mutations, endocrine disruptor exposure
·      Miscellaneous such as adoption, activating KISS 1 and GPR54 mutations, endocrine disruptor exposure


·      Prolonged undertreated GIP such ascongenital adrenal hyperplasia (CAH), McCune-Albright syndrome (MAS), Familial male-limited precocious puberty  
·      Prolonged undertreated GIP such as congenital adrenal hyperplasia (CAH), McCune-Albright syndrome (MAS), Familial male-limited precocious puberty  


                                                                                                                            
                                                                                                                            
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A fewfactors are linked to precocious puberty; they include<sup>21,26</sup>:
A few factors are linked to precocious puberty; they include<sup>21,26</sup>:


·      Gender: Girls are 10 times as likely to have central precocious puberty as boys.
·      Gender: Girls are 10 times as likely to have central precocious puberty as boys.


·      Genetics:Genetic mutations that trigger the release of sex hormones may lead to early puberty. Most often, its hereditary.
·      Genetics: Genetic mutations that trigger the release of sex hormones may lead to early puberty. Most often, its hereditary.


·      Race:Idiopathically, African American girls appear to start puberty about a year earlier than white girls.
·      Race: Idiopathically, African American girls appear to start puberty about a year earlier than white girls.


·      Obesity: researcher have shown a link between obesity in young girls and an increased risk of precocious puberty. But researchers do not know how direct the tie is. Obesity does not seem to be connected to early puberty in boys<sup>27</sup>.
·      Obesity: researcher have shown a link between obesity in young girls and an increased risk of precocious puberty. But researchers do not know how direct the tie is. Obesity does not seem to be connected to early puberty in boys<sup>27</sup>.
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·       International adoption: Adopted children appear to be at high risk for CPP. It is assumed that nutritional deprivation in early life followed by enhanced adiposity after adoption activates the endocrine and physical alterations of puberty earlier than normal time.
·       International adoption: Adopted children appear to be at high risk for CPP. It is assumed that nutritional deprivation in early life followed by enhanced adiposity after adoption activates the endocrine and physical alterations of puberty earlier than normal time.


·      Sex hormones: Ingestion or long-termexposure to products containing or estrogen or testosterone such as birth or hormone cream, control pills and ointments.
·      Sex hormones: Ingestion or long-term exposure to products containing or estrogen or testosterone such as birth or hormone cream, control pills and ointments.


·      Radiation: treatment of the brain or spinal cord by radiation for tumors, leukemia, and similar conditions. The damage causes them to signal the ovaries and testicles to make hormones earlier than normal, which prompt signs of puberty<sup>28</sup>.
·      Radiation: treatment of the brain or spinal cord by radiation for tumors, leukemia, and similar conditions. The damage causes them to signal the ovaries and testicles to make hormones earlier than normal, which prompt signs of puberty<sup>28</sup>.
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·      Environmental factors: Exposure to environmental toxins that disrupt endocrine function<sup>29</sup>
·      Environmental factors: Exposure to environmental toxins that disrupt endocrine function<sup>29</sup>
==[[Precocious puberty screening|Screening]]==
==[[Precocious puberty screening|Screening]]==
precocious puberty is associated with development of secondary sex characteristics and early closure of epiphysis. Identifying the cause of PP is important for the management of the underlying disease. In the evaluation of a child with early pubertal maturation, distinguishing between the common variants of premature thelarche or premature adrenarche and true precocious puberty is an important step. Isolated nonprogressive breast development in a girl, especially a toddler, may be simple premature thelarche. Girls with pubic hair and/or axillary hair and no breast development or boys with pubic/axillary hair and no testicular enlargement are likely to have premature adrenarche.When pathological precocious puberty is recognized, the next step is determining whether the process is GnRH-dependent (CPP) or -independent (PPP). Figure 1 and 2 showed the flow chart for precocious puberty in girl and boys in sequence<sup>30</sup>.
precocious puberty is associated with development of secondary sex characteristics and early closure of epiphysis. Identifying the cause of PP is important for the management of the underlying disease. In the evaluation of a child with early pubertal maturation, distinguishing between the common variants of premature thelarche or premature adrenarche and true precocious puberty is an important step. Isolated non progressive breast development in a girl, especially a toddler, may be simple premature thelarche. Girls with pubic hair and/or axillary hair and no breast development or boys with pubic/axillary hair and no testicular enlargement are likely to have premature adrenarche. When pathological precocious puberty is recognized, the next step is determining whether the process is GnRH-dependent (CPP) or -independent (PPP). Figure 1 and 2 showed the flow chart for precocious puberty in girl and boys in sequence<sup>30</sup>.
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==[[Precocious puberty natural history, complications and prognosis|Natural History, Complications and Prognosis]]==
==[[Precocious puberty natural history, complications and prognosis|Natural History, Complications and Prognosis]]==
 
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==Diagnosis==
==Diagnosis==
'''History and Symptoms:'''History should be sought for information about the onset of the signs, progression rate, and growth tempo in the last 6-12 months, presence of secondary sex characteristics (acne, oily skin, erection, night ejaculation and vaginal bleeding) in addition to the presence of pubertal signs. Familyhistory of PP supports the diagnosis of familial forms<sup>30</sup>.
'''History and Symptoms:''' History should be sought for information about the onset of the signs, progression rate, and growth tempo in the last 6-12 months, presence of secondary sex characteristics (acne, oily skin, erection, night ejaculation and vaginal bleeding) in addition to the presence of pubertal signs. Family history of PP supports the diagnosis of familial forms<sup>30</sup>.


==='''Physical Examination''':  In girls, normal puberty usually begins with the onset of breast buds, followed by the onset of pubic hair in a few months. While in boys, the first sign of pubertal development is testicular enlargement. In both sexes, however, pubic hair may be the first manifestation of puberty. Pubertal staging should be performed according to Tanner-Marshall method ( Table 1)<sup>20</sup>on physical examination, and anthropometric evaluations and  defined by measurement of weight, height and body proportions. All data should be marked on growth chart and evaluatedannually and followed for at least 6 months<sup>20,30</sup>.===
==='''Physical Examination''':  In girls, normal puberty usually begins with the onset of breast buds, followed by the onset of pubic hair in a few months. While in boys, the first sign of pubertal development is testicular enlargement. In both sexes, however, pubic hair may be the first manifestation of puberty. Pubertal staging should be performed according to Tanner-Marshall method ( Table 1)<sup>20</sup>on physical examination, and anthropometric evaluations and  defined by measurement of weight, height and body proportions. All data should be marked on growth chart and evaluated annually and followed for at least 6 months<sup>20,30</sup>.===
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==='''Laboratory Findings:''' The patient must be evaluated by GnRH stimulation test. The diagnosis of CPP  must be combined with clinical signs and follow-up. Basal plasma testosterone level in boys increase both in CPP and PPP, but it is much higher in PPP patients. The importance of oestrogen level is limited in girls with CPP<sup>3</sup>.The other endocrinological evaluations may include thyroid tests, 17OHP level and hCG measurement depending on the clinical signs<sup>20,30</sup>.===
==='''Laboratory Findings:''' The patient must be evaluated by GnRH stimulation test. The diagnosis of CPP  must be combined with clinical signs and follow-up. Basal plasma testosterone level in boys increase both in CPP and PPP, but it is much higher in PPP patients. The importance of estrogen's level is limited in girls with CPP<sup>3</sup>.The other endocrinological evaluations may include thyroid tests, 17OHP level and hCG measurement depending on the clinical signs<sup>20,30</sup>.===


==='''CT and MRI''': Cranial and pituitary magnetic resonance imaging (MRI) should be performed to rule out organic CPP.===
==='''CT and MRI''': Cranial and pituitary magnetic resonance imaging (MRI) should be performed to rule out organic CPP.===
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'''Central precocious puberty'''  
'''Central precocious puberty'''  


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. The mainstay of treatment for CPP is GnRH analogs (GnRHa). This group of drugs provides constant serum levels of GnRH activity and thus overrides the pulsatility of endogenous GnRH. 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.While on treatment, periodic monitoring of pubertal progression, growth velocity, and skeletal maturation are necessary<sup>32</sup>.
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. The mainstay of treatment for CPP is GnRH analogs (GnRHa). This group of drugs provides constant serum levels of GnRH activity and thus overrides the pulsatility of endogenous GnRH. 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. While on treatment, periodic monitoring of pubertal progression, growth velocity, and skeletal maturation are necessary<sup>32</sup>.


Newer treatment agents of CPP are:
Newer treatment agents of CPP are:


'''Histrelin implant'':'''''the GnRHahistrelin has been incorporated into a subdermal hydrogel implant. Although initially developed for treatment of prostate cancer, this has found a role in suppression of CPP<sup>20</sup>.
'''Histrelin implant'':''''' the GnRHa histrelin has been incorporated into a subdermal hydrogel implant. Although initially developed for treatment of prostate cancer, this has found a role in suppression of CPP<sup>20</sup>.


'''Extended depot leuprolide acetate'':''''' Depot leuprolide acetate injections require relatively frequent painful im injections. This led some researchers to investigate the longer-acting forms that were developed for prostate cancer and endometriosis<sup>20</sup>.
'''Extended depot leuprolide acetate'':''''' Depot leuprolide acetate injections require relatively frequent painful in injections. This led some researchers to investigate the longer-acting forms that were developed for prostate cancer and endometriosis<sup>20</sup>.


'''Peripheral Precocious puberty'''
'''Peripheral Precocious puberty'''


Treatment of gonadotrophin-independent precocious puberty is extremely dependent on the underlying disease.Surgery is indicated in adrenal tumorsand gonadal.  If exogenous sources of sex steroids are identified, they should be eliminated. Classic congenital adrenal hyperplasiais 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 preferred treatment treatment for familial male-limited precocious puberty is a combination of an androgen antagonist (spironolactone) and an aromatase inhibitor (anastrozole, testolactone)<sup>32</sup>.
Treatment of gonadotropin-independent precocious puberty is extremely dependent on the underlying disease. Surgery is indicated in adrenal tumorsand gonadal.  If exogenous sources of sex steroids are identified, they should be eliminated. Classic congenital adrenal hyperplasia 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 preferred treatment treatment for familial male-limited precocious puberty is a combination of an androgen antagonist (spironolactone) and an aromatase inhibitor (anastrozole, testolactone)<sup>32</sup>.


[[Precocious puberty medical therapy|Medical Therapy]] | [[Precocious puberty surgery|Surgery]] | [[Precocious puberty primary prevention|Primary Prevention]] | [[Precocious puberty secondary prevention|Secondary Prevention]] | [[Precocious puberty cost-effectiveness of therapy|Cost-Effectiveness of Therapy]] | [[Precocious puberty future or investigational therapies|Future or Investigational Therapies]]
[[Precocious puberty medical therapy|Medical Therapy]] | [[Precocious puberty surgery|Surgery]] | [[Precocious puberty primary prevention|Primary Prevention]] | [[Precocious puberty secondary prevention|Secondary Prevention]] | [[Precocious puberty cost-effectiveness of therapy|Cost-Effectiveness of Therapy]] | [[Precocious puberty future or investigational therapies|Future or Investigational Therapies]]
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===Case #1<sup>33</sup>===
===Case #1<sup>33</sup>===
A previously healthy with no significant medical history 5-year-old girl of African origin presented with macroscopic hematuria appeared 24 hours before presentation and isolated abdominal pain for one month. There was no history of fever, vomiting, urinary or systemic symptoms, weight loss, abdominal trauma, hemorrhage, or infection, and did not take any medications.Family history was normal. There was no history of any other source of exposure to hormonal drugs. She was physically normal. Her anthropometric parameters were normal. Her vital signs were normal, except for blood pressure at 130/90 mm Hg (>99<sup>th</sup> percentile for sex and height). She had neither dysmorphic features nor skin lesions (café-au-lait spots, facial acne). Amass, measuring 6 cm with regularly margins in the right upper quadrantwas palpatedduring abdominal examination. Central nervous system was normal. She had bilateral, symmetrical nontender enlargement of breast buds corresponding to stage 2 of the Tanner classification. There was no pubic or axillary hair, and her thyroid was normal on clinical inspection.
A previously healthy with no significant medical history 5-year-old girl of African origin presented with macroscopic hematuria appeared 24 hours before presentation and isolated abdominal pain for one month. There was no history of fever, vomiting, urinary or systemic symptoms, weight loss, abdominal trauma, hemorrhage, or infection, and did not take any medications. Family history was normal. There was no history of any other source of exposure to hormonal drugs. She was physically normal. Her anthropometric parameters were normal. Her vital signs were normal, except for blood pressure at 130/90 mm Hg (>99<sup>th</sup> percentile for sex and height). She had neither dysmorphic features nor skin lesions (café-au-lait spots, facial acne). Amass, measuring 6 cm with regularly margins in the right upper quadrant was palpated during abdominal examination. Central nervous system was normal. She had bilateral, symmetrical nontender enlargement of breast buds corresponding to stage 2 of the Tanner classification. There was no pubic or axillary hair, and her thyroid was normal on clinical inspection.


Her hematologic and basic metabolic panel, serum electrolytes, and liver and renal function tests were normal. Urinalysis confirmed hematuria. A well-circumscribed heterogeneous echogenic mass, measuring 9.2 × 9.5 cm, in the right renal fossa has been identified(Wilms tumor). On abdominal and pulmonary computerized tomography (CT), a high suspicion of nephroblastoma was made. Histological examination confirmed the diagnosis of intermediary-risk nephroblastoma stage I. The first endocrine work-up revealed a normal thyroid function and prepubertal gonadotropin levels. Ultrasonography excluded ovarian and adrenal masses and showed infantile ovaries and uterus. Bone age was not performed. The endocrine diagnosis was bilateral PT.The initial diagnosis was premature telarche, while the final diagnosis was to idiopathic central precocious puberty. Chemotherapy and nephrectomy were well tolerated, and the girl treated with a gonadotropin-releasing hormone agonist which showed favorable outcomes over the short term. It was highlighted the need for early diagnosis and treatment in all patients of precocious puberty, to institute timely management.
Her hematologic and basic metabolic panel, serum electrolytes, and liver and renal function tests were normal. Urinalysis confirmed hematuria. A well-circumscribed heterogeneous echogenic mass, measuring 9.2 × 9.5 cm, in the right renal fossa has been identified(Wilms tumor). On abdominal and pulmonary computerized tomography (CT), a high suspicion of nephroblastoma was made. Histological examination confirmed the diagnosis of intermediary-risk nephroblastoma stage I. The first endocrine work-up revealed a normal thyroid function and prepubertal gonadotropin levels. Ultrasonography excluded ovarian and adrenal masses and showed infantile ovaries and uterus. Bone age was not performed. The endocrine diagnosis was bilateral PT. The initial diagnosis was premature telarche, while the final diagnosis was to idiopathic central precocious puberty. Chemotherapy and nephrectomy were well tolerated, and the girl treated with a gonadotropin-releasing hormone agonist which showed favorable outcomes over the short term. It was highlighted the need for early diagnosis and treatment in all patients of precocious puberty, to institute timely management.




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A 4.5 year-old female patient was assessed by the paediatric endocrinology service due to the appearance of pubic hair six months before the consultation, without thelarche or acne. Her parents were relative with mid-parental height would be 150cm. At birth, her weight was 3340g, length 50cm, and head circumference of 34cm. She presented early symptomatic neonatal hypoglycemia that needed intravenous administration of dextrose, and jaundice that was treated with phototherapy. The patient also presented left spastic hemiplegia secondary to left lateral ventriculomegaly, which had been identified on prenatal ultrasound. The physical examination revealed: height: 105.3 cm (0.5 standard deviations, according to the growth charts from the Centers for Disease Control and Prevention, USA); weight: 17 kg; body mass index: 15.4 kg/m<sup>2</sup>; bone age: 6 years according to Greulich and Pyle method; normal blood pressure; absence of goiter, abdominal masses and acne; Tanner breast 1 and pubic 2; and female genitals without clitoromegaly. Based on these findings, the patient was diagnosed with PPP secondary to non-classic CAH. An adrenocorticotropic hormone stimulation test was requested. finding normal renin and electrolyte levels in blood, as well as high levels of 17-hydroxyprogester-one (17-OHP), which are clinical signs of congenital adrenal hyperplasia. Based on this diagnosis, glucorticoid therapy was ordered, and after one year of starting the treatment she had a favorable clinical outcome and did not show any secondary sex characteristics or bone age progression.
A 4.5 year-old female patient was assessed by the paediatric endocrinology service due to the appearance of pubic hair six months before the consultation, without thelarche or acne. Her parents were relative with mid-parental height would be 150cm. At birth, her weight was 3340g, length 50cm, and head circumference of 34cm. She presented early symptomatic neonatal hypoglycemia that needed intravenous administration of dextrose, and jaundice that was treated with phototherapy. The patient also presented left spastic hemiplegia secondary to left lateral ventriculomegaly, which had been identified on prenatal ultrasound. The physical examination revealed: height: 105.3 cm (0.5 standard deviations, according to the growth charts from the Centers for Disease Control and Prevention, USA); weight: 17 kg; body mass index: 15.4 kg/m<sup>2</sup>; bone age: 6 years according to Greulich and Pyle method; normal blood pressure; absence of goiter, abdominal masses and acne; Tanner breast 1 and pubic 2; and female genitals without clitoromegaly. Based on these findings, the patient was diagnosed with PPP secondary to non-classic CAH. An adrenocorticotropic hormone stimulation test was requested. finding normal renin and electrolyte levels in blood, as well as high levels of 17-hydroxyprogester-one (17-OHP), which are clinical signs of congenital adrenal hyperplasia. Based on this diagnosis, glucorticoid therapy was ordered, and after one year of starting the treatment she had a favorable clinical outcome and did not show any secondary sex characteristics or bone age progression.


[[Precocious puberty case study one|Case #1]]


==Related Chapters==
==Related Chapters==

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]

Synonyms and keywords:

Overview

The term precocious puberty (Latin - pubertas praecox)refers to an abnormal early onset of puberty where sexual maturity begins at an unexpectedly early age. There are other terms used to define precocious puberty which are pubertas praecox or sexual precocity1. Precocious puberty is usually consistent with premature development of pubertal signs. It includes a group of heterogeneous conditions that extend from deviations of normal development to slowly progressive and rapidly maturation of both genders2. The first clinical signs include increasing in the secretion of sex hormones and maturation of gonads testes in boys, ovaries in girls, and the potential for reproduction. The other signs and symptoms involve increased linear growth, acne, muscular changes, and pubic and axillary hair development. Classically, precocious puberty occurring before the age of 8 years in girls and 9 years in boys is considered precocious.Nevertheless, recent studies reveal that signs of early puberty are often present in girls (black girls in specific) aged 6-8 years3. They reported that the glands that secrete growth and sex hormones start their function abnormally early in life causing in this condition4,5. Most cases of precocious puberty in girls are idiopathic or have benign causes, however it can also indicate serious pathology. Even though precocious puberty is less common but proportionally much more likely to have a serious cause and requires urgent treatment6.For example, it could be caused by a neurologic disorder in a very young boy7. Precocious Puberty has two forms which are gonadotrophin-dependent precocious puberty (GDPP; due to premature activation of the hypothalamic-pituitary-gonadal axis) and gonadotrophin-independent precocious puberty (GIPP; due to autonomous secretion of sex steroids)8.

Historical Perspective

Reports of children with precocious puberty seemed in the writings of Greek and Roman authors, where these subjects were termed ‘‘Ektrapetoi’’or ‘‘unusual’’9. From study in 1961of untreated patients the long-term outcome was known to include short stature, body disproportion and obesity 10. However, from the 17th through the 19th centuries, many children with precocious puberty were exploited and treated cruelly. Commencing in the latter half of the 19th century, clinical studies of children with sexual precocity started to appear and by the mid-20th century more than 1000 such patients had been recorded in the literature9. In 1938 pregnancies in very young children have been reported11. Remarkably, in 1952, Silverman and his co-workers called attention to a syndrome of "precocious growth of sexual hair without other sexual development. They interpreted this "premature pubarche" as a benign "constitutional variation of adolescence" which usually followed later by normal adolescence12. In 1963, the first two girls of 6.5 years old of the chromatographic fractionation of urinary 17-ketosteroids who show only precocious sexual hair have reported. One girl was hydrocephalic and the others was normal but sustained to influenzae meningitis when she was 3.5 years old with no apparent remaining damage. Both patients showed marked quantitative differences for 2 major urinary ll-deoxy-17-ketosteroids13. In 1988, reported that long-term physical sequelae of precocious puberty led to potential risk of sexual abuse due to the premature sexual development.

Considering the age, Third National Health and Nutrition Examination Surveys between 1988–1994 stated that 21a high incidence of early breast development and pubic hair in girls aged 7 to 8 years from all regions of the United States, with the highest percentages seen in black girls 14. While in boys, based on the NHANES III study in 2001, indicated that stage 2 genital growth, a more reliable sign of puberty in boys than pubic hair, was occurring with a mean age of about 10 years 15. Study by Nebesio et al., in 2005 disclosed that the precise trigger for the onset of puberty is idiopathic, but it is believed to be a complex interaction between genetics, hormones, and environmental influences. Endocrine disruptors are environmental factors that have been implicated in causing early pubertal maturation. Industrial chemicals, phytoestrogens, estrogen-containing cosmetics, and pesticides are examples of potential endocrine disruptors that have been proposed to play a role in altering the onset and timing of puberty16.

Concerning the central precocious puberty, in the past showed an increase in luteinizing hormone (LH) levels to more than 5 to 8 U/L during stimulation test with gonadotropin releasing hormone (GnRH) or a synthetic analog of GnRH such as leuprolide was thought to be necessary to confirm the diagnosis of CPP. Although  assays for gonadotropins are now more sensitive and specific, and according to a recent study in 2009, a single unstimulated LH level of 0.4 U/L or more is sufficient to diagnose CPP in most girls 17. In boys, the diagnosis of CPP based on physical findings is simpler than in girls, because one will see enlargement of the testes, reflecting increased gonadotropin secretion, as well as growth of the stretched penis because of increased testosterone levels 18.

Classification

Precocious puberty is classified as Central or peripheral 7,8:

1-    In central precocious puberty(CPP) - termed gonadotropin releasing hormone-dependent precocious puberty (GDPP), there is premature activation of the hypothalamic-pituitary-gonadal (HPG) axis causing physical and hormonal changes of normal puberty at an early age and faster pace.The secreted hormones cause the testicles or ovaries to make other hormones: testosterone or estrogen. These sex hormones cause the changes of puberty, like breast development in girls.CPP is more common between 4 and 8 years.

2-    In peripheral precocious puberty (PPP) - termed gonadotropin releasing hormone independent precocious puberty (GIPP), increasing in production of sex steroids is independent of the HPG axis.The hormones estrogen and testosterone activate the symptoms but the brain and pituitary gland are not involved. It is usually caused by a local problem with the testicles, ovaries,adrenal gland, or a severely underactive thyroid gland.

Pathophysiology

Gonadal maturation and secretion are resulted from increasing in amplitude of pulsatile hypothalamic gonadotrophin-releasing hormone (GnRH) release and in stimulation of pituitary gonadotropes, particularly at night. Normal pubertal development is due to the increase of pulsatile activity of the GnRH pulse generator that leads to the maturation of pituitary gonadotrophin release (pulsatile LH and Follicle stimulating hormone (FSH) secretion) and lead to the maturation of gonads and gonadal activity19. The central mechanisms governing GnRH secretion are located within the neuronal and the glial networks.

In the child with precocious puberty, GnRH is released in low amplitude pulses at a relatively low frequency. The earliest identified neuroendocrine manifestation of puberty is the production of kisspeptin from hypothalamic neurons. Kisspeptin alters release of GnRH from the hypothalamus. In the early stages of puberty, GnRH pulse amplitude increases and pulse frequency increases to every 1–2 hours, mainly at night. Consequently, LH and FSH production also increase, primarily during the night and then during the day in later pubertal stages 20. Two mechanisms are responsible for the central control of pulsatile GnRH secretion which are a tonic inhibitory restraint, and excitatory inputs to GnRH neurons. While y-aminobutyric acid (GABA) and GABAA receptors are important components of the tonic inhibitory system. Furthermore, excitatory amino acids such as glutamate and its receptor and transforming growth factor (TGF)-α play an important role in the excitatory system. In the case of precocious puberty, this type is called central precocious puberty as it originates from the central part of the feedback loop governing human reproduction. Hormone concentrations and responses to stimulation tests are consistent with gonadarche, however, with increased gonadotrophin concentrations relative to the pubertal stage in many patients. Spontaneous LH secretion is pulsatile, particularly at night. In analogy to normal puberty, this type is also termed ‘true’ or gonadotrophin-dependent precocious puberty. In contrast to the central type of precocious puberty, pubertal development may also be caused by the premature secretion of sex steroids originating either from the gonads or from other sources or resulting from exogenous exposure. Thus, the origin of the hormonal trigger of puberty is not located centrally at the GnRH pulse generator but peripherally. It corresponds with the logic of a negative feedback system that central hormonal activity is suppressed. Therefore, gonadotrophin pulsatility is absent and responses to GnRH stimulation are low19.

Causes

Often, the exact cause of precocious puberty is idiopathic21. Reasons are equally common in boys and children under age 6, especially if puberty is moving along quickly.

The causes of central precocious puberty include:

·      Prior radiation to the brain 21

·      Organic neurologic causes (Secondary GDPP) 22

o   Hypothalamic hamartoma

o   Brain tumors such as glioma, astrocytoma, germ cell tumor.

o  Prior infection of the brain such as post-meningitis, postencephalitis,neurotuberculosis

o  Brain insults such as trauma, neurosurgery, cranial irradiation, perinatal asphyxia

o  Malformations such as arachnoid cyst, hydrocephalus, septo-optic dysplasia, neural tube defect, neurofibromatosis

·      Miscellaneous such as adoption, activating KISS 1 and GPR54 mutations, endocrine disruptor exposure

·      Prolonged undertreated GIP such as congenital adrenal hyperplasia (CAH), McCune-Albright syndrome (MAS), Familial male-limited precocious puberty

                                                                                                                          

The causes of Peripheral precocious puberty may be caused by:

·      Girls 7,21:

o   Ovarian tumor,

o    Feminizing adrenal tumors,

o   Certain rare genetic syndromes such as McCune-Albright syndrome (MAS)- more common in girls

o    Hypothyroidism (longstanding untreated primary) in which the thyroid gland secretes abnormally low levels of hormones

o   Exposure of the child to medicines or creams that contain estrogens

·      Boys 7,21:

o   Congenital adrenal hyperplasia (CAH)—21-hydroxylase and 11β-hydroxylase deficiencies

o    Adrenal tumors

o   Testicular tumors, familial male-limited precocious puberty (FMPP, Testotoxicosis)

o   Ectopic hCG secreting tumors—Hepatoblastoma, dysgerminoma, choriocarcinoma (more common in boys)

o   Exposure of the child to medicines or creams that contain androgens

                                                                                           

Differentiating Precocious puberty from other Diseases

Symptoms of some benign conditions can be similar to those of precocious puberty and comparisons may be useful for a differential diagnosis 22,23:

·      Premature Thelarche: Glandular breast tissue on palpation without other secondary sexual characteristics. It is the premature unilateral or bilateral development of the breast tissue in girls under the age of 8, having a peak occurrence in the first two years of life. Bone age, growth velocity, and biochemical testing are normal. Frequent clinical follow up to monitor growth, and pubertal progression is required.

·      Premature Adrenarche: The early production of adrenal androgens characterizes this benign condition. It presents with pubic and axillary hair growth, body odor, sweating, and/or mild acne; may have mildly elevated dehydroepiandrosterone sulfate, but normal levels of FSH, LH, 17-hydroxyprogesterone, estradiol, and testosterone.  There is no breast development in females and no testicular enlargement in males before the age of 8 years. It is essential to rule out exposure to androgen sources such as creams or gels, adrenal tumors, and late-onset CAH.

·      Premature Menarche: Isolated premature menarche is the onset of vaginal bleeding in girls less than 7 years of age. They may present with either a single episode or few cycles (less than 3) of bleeding and have normal progression to puberty. Recent studies have suggested no effect on adult height. Genital trauma or abuse, foreign body, infection, evidence of McCune-Albright syndrome; possible ovarian enlargement on ultrasonography need to be ruled out.

·      Lipomastia: Fat tissue but no glandular breast tissue on palpation; associated with obesity

·      Nonprogressive precocious puberty: Early but normal sequence of pubertal events that does not progress prematurely

Epidemiology and Demographics

Precocious puberty is a common problem affecting up to 29 per 100,000 girls per year 24. It has a prevalence of 1 in 5,000 children and is 10 times more common in girls than boys by a ratio of 10:1. Statistics indicate that girls in the United States are maturing at an earlier age than they did 30 years ago. In patient with central nervous system disorder or lesion the incidence is much higher. Prematurely menarche has been linked to greater risk of breast cancer as an adult; thus, precocious onset would seem to increase that risk. Though girls who experience premature puberty grow faster than their peers owing toenhanced bone growth, they fail to reach the normal adult height. While the overall age at menarche is not significantly different (0.34 years earlier) than that reported for U.S. girls in 1973. Its reported that menarche of non-Hispanic Black girls is significantly earlier than that of the White or Mexican American girls25

Risk Factors

A few factors are linked to precocious puberty; they include21,26:

·      Gender: Girls are 10 times as likely to have central precocious puberty as boys.

·      Genetics: Genetic mutations that trigger the release of sex hormones may lead to early puberty. Most often, its hereditary.

·      Race: Idiopathically, African American girls appear to start puberty about a year earlier than white girls.

·      Obesity: researcher have shown a link between obesity in young girls and an increased risk of precocious puberty. But researchers do not know how direct the tie is. Obesity does not seem to be connected to early puberty in boys27.

·       International adoption: Adopted children appear to be at high risk for CPP. It is assumed that nutritional deprivation in early life followed by enhanced adiposity after adoption activates the endocrine and physical alterations of puberty earlier than normal time.

·      Sex hormones: Ingestion or long-term exposure to products containing or estrogen or testosterone such as birth or hormone cream, control pills and ointments.

·      Radiation: treatment of the brain or spinal cord by radiation for tumors, leukemia, and similar conditions. The damage causes them to signal the ovaries and testicles to make hormones earlier than normal, which prompt signs of puberty28.

·      Environmental factors: Exposure to environmental toxins that disrupt endocrine function29

Screening

precocious puberty is associated with development of secondary sex characteristics and early closure of epiphysis. Identifying the cause of PP is important for the management of the underlying disease. In the evaluation of a child with early pubertal maturation, distinguishing between the common variants of premature thelarche or premature adrenarche and true precocious puberty is an important step. Isolated non progressive breast development in a girl, especially a toddler, may be simple premature thelarche. Girls with pubic hair and/or axillary hair and no breast development or boys with pubic/axillary hair and no testicular enlargement are likely to have premature adrenarche. When pathological precocious puberty is recognized, the next step is determining whether the process is GnRH-dependent (CPP) or -independent (PPP). Figure 1 and 2 showed the flow chart for precocious puberty in girl and boys in sequence30.

Natural History, Complications and Prognosis


Diagnosis

History and Symptoms: History should be sought for information about the onset of the signs, progression rate, and growth tempo in the last 6-12 months, presence of secondary sex characteristics (acne, oily skin, erection, night ejaculation and vaginal bleeding) in addition to the presence of pubertal signs. Family history of PP supports the diagnosis of familial forms30.

Physical Examination:  In girls, normal puberty usually begins with the onset of breast buds, followed by the onset of pubic hair in a few months. While in boys, the first sign of pubertal development is testicular enlargement. In both sexes, however, pubic hair may be the first manifestation of puberty. Pubertal staging should be performed according to Tanner-Marshall method ( Table 1)20on physical examination, and anthropometric evaluations and  defined by measurement of weight, height and body proportions. All data should be marked on growth chart and evaluated annually and followed for at least 6 months20,30.


Laboratory Findings: The patient must be evaluated by GnRH stimulation test. The diagnosis of CPP  must be combined with clinical signs and follow-up. Basal plasma testosterone level in boys increase both in CPP and PPP, but it is much higher in PPP patients. The importance of estrogen's level is limited in girls with CPP3.The other endocrinological evaluations may include thyroid tests, 17OHP level and hCG measurement depending on the clinical signs20,30.

CT and MRI: Cranial and pituitary magnetic resonance imaging (MRI) should be performed to rule out organic CPP.

Echocardiography or Ultrasound: Pelvic ultrasonography is another test that should be performed in girls. Ovarian and uterine sizes should be compared with reference levels. Bilateral enlarged ovaries can be determined in CPP patients.

Chest X Ray: An X-ray may be done of the left hand and wrist which can estimate the child's bone age. With precocious puberty, bone age is often older than calendar age.

Ultrasound (sonography): This test uses sound waves and a computer to create images of blood vessels, tissues, and organs. This may be done to look at the adrenal glands and ovaries or testes.

History and Symptoms | Physical Examination | Laboratory Findings | Electrocardiogram | Chest X Ray | CT | MRI | Echocardiography or Ultrasound | Other Imaging Findings | Other Diagnostic Studies

Treatment

Central precocious puberty

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. The mainstay of treatment for CPP is GnRH analogs (GnRHa). This group of drugs provides constant serum levels of GnRH activity and thus overrides the pulsatility of endogenous GnRH. 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. While on treatment, periodic monitoring of pubertal progression, growth velocity, and skeletal maturation are necessary32.

Newer treatment agents of CPP are:

Histrelin implant: the GnRHa histrelin has been incorporated into a subdermal hydrogel implant. Although initially developed for treatment of prostate cancer, this has found a role in suppression of CPP20.

Extended depot leuprolide acetate: Depot leuprolide acetate injections require relatively frequent painful in injections. This led some researchers to investigate the longer-acting forms that were developed for prostate cancer and endometriosis20.

Peripheral Precocious puberty

Treatment of gonadotropin-independent precocious puberty is extremely dependent on the underlying disease. Surgery is indicated in adrenal tumorsand gonadal.  If exogenous sources of sex steroids are identified, they should be eliminated. Classic congenital adrenal hyperplasia 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 preferred treatment treatment for familial male-limited precocious puberty is a combination of an androgen antagonist (spironolactone) and an aromatase inhibitor (anastrozole, testolactone)32.

Medical Therapy | Surgery | Primary Prevention | Secondary Prevention | Cost-Effectiveness of Therapy | Future or Investigational Therapies

Case Studies


Case #133

A previously healthy with no significant medical history 5-year-old girl of African origin presented with macroscopic hematuria appeared 24 hours before presentation and isolated abdominal pain for one month. There was no history of fever, vomiting, urinary or systemic symptoms, weight loss, abdominal trauma, hemorrhage, or infection, and did not take any medications. Family history was normal. There was no history of any other source of exposure to hormonal drugs. She was physically normal. Her anthropometric parameters were normal. Her vital signs were normal, except for blood pressure at 130/90 mm Hg (>99th percentile for sex and height). She had neither dysmorphic features nor skin lesions (café-au-lait spots, facial acne). Amass, measuring 6 cm with regularly margins in the right upper quadrant was palpated during abdominal examination. Central nervous system was normal. She had bilateral, symmetrical nontender enlargement of breast buds corresponding to stage 2 of the Tanner classification. There was no pubic or axillary hair, and her thyroid was normal on clinical inspection.

Her hematologic and basic metabolic panel, serum electrolytes, and liver and renal function tests were normal. Urinalysis confirmed hematuria. A well-circumscribed heterogeneous echogenic mass, measuring 9.2 × 9.5 cm, in the right renal fossa has been identified(Wilms tumor). On abdominal and pulmonary computerized tomography (CT), a high suspicion of nephroblastoma was made. Histological examination confirmed the diagnosis of intermediary-risk nephroblastoma stage I. The first endocrine work-up revealed a normal thyroid function and prepubertal gonadotropin levels. Ultrasonography excluded ovarian and adrenal masses and showed infantile ovaries and uterus. Bone age was not performed. The endocrine diagnosis was bilateral PT. The initial diagnosis was premature telarche, while the final diagnosis was to idiopathic central precocious puberty. Chemotherapy and nephrectomy were well tolerated, and the girl treated with a gonadotropin-releasing hormone agonist which showed favorable outcomes over the short term. It was highlighted the need for early diagnosis and treatment in all patients of precocious puberty, to institute timely management.


Case #234

A 4.5 year-old female patient was assessed by the paediatric endocrinology service due to the appearance of pubic hair six months before the consultation, without thelarche or acne. Her parents were relative with mid-parental height would be 150cm. At birth, her weight was 3340g, length 50cm, and head circumference of 34cm. She presented early symptomatic neonatal hypoglycemia that needed intravenous administration of dextrose, and jaundice that was treated with phototherapy. The patient also presented left spastic hemiplegia secondary to left lateral ventriculomegaly, which had been identified on prenatal ultrasound. The physical examination revealed: height: 105.3 cm (0.5 standard deviations, according to the growth charts from the Centers for Disease Control and Prevention, USA); weight: 17 kg; body mass index: 15.4 kg/m2; bone age: 6 years according to Greulich and Pyle method; normal blood pressure; absence of goiter, abdominal masses and acne; Tanner breast 1 and pubic 2; and female genitals without clitoromegaly. Based on these findings, the patient was diagnosed with PPP secondary to non-classic CAH. An adrenocorticotropic hormone stimulation test was requested. finding normal renin and electrolyte levels in blood, as well as high levels of 17-hydroxyprogester-one (17-OHP), which are clinical signs of congenital adrenal hyperplasia. Based on this diagnosis, glucorticoid therapy was ordered, and after one year of starting the treatment she had a favorable clinical outcome and did not show any secondary sex characteristics or bone age progression.


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