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==[[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 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]]==
Reports of children with precocious puberty seemed in the writings of Greek and Roman authors, where these subjects were termed ‘‘Ektrapetoi’’or ‘‘unusual’’<sup>9</sup>. From study in 1961of untreated patients the long-term outcome was known to include short stature, body disproportion and obesity <sup>10</sup>. 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 literature<sup>9</sup>. In 1938 pregnancies in very young children have been reported<sup>11</sup>. 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 adolescence<sup>12</sup>. 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-ketosteroids<sup>13</sup>. 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 <sup>14</sup>. 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 <sup>15</sup>. 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 puberty<sup>16</sup>.
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 <sup>17</sup>. 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 <sup>18</sup>.
==[[Precocious puberty classification|Classification]]==
Precocious puberty is classified as Central or peripheral <sup>7,8</sup>:
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.
<br />
==[[Precocious puberty pathophysiology|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 activity<sup>19</sup>. 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 <sup>20</sup>. 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 low<sup>19</sup>.
==[[Precocious puberty causes|Causes]]==
Often, the exact cause of precocious puberty is idiopathic<sup>21</sup>. 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 <sup>21</sup>
·      Organic neurologic causes (Secondary GDPP) <sup>22</sup>
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 <sup>7,21</sup>:
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 <sup>7,21</sup>:
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|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 <sup>22,23</sup>:
·      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
==[[Precocious puberty epidemiology and demographics|Epidemiology and Demographics]]==
Precocious puberty is a common problem affecting up to 29 per 100,000 girls per year <sup>24</sup>. 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 to enhanced 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 girls<sup>25</sup>
==[[Precocious puberty risk factors|Risk Factors]]==
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.
·      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 boys<sup>27</sup>.
·       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 puberty<sup>28</sup>.
·      Environmental factors: Exposure to environmental toxins that disrupt endocrine function<sup>29</sup>
==[[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 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>.
<br />
==[[Precocious puberty natural history, complications and prognosis|Natural History, Complications and Prognosis]]==
The initial step is to confirm precocious puberty whether pubertal development is occurring before the normal age of onset or not. 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, rapid progression of puberty. History about any neurological symptoms such as headache, increased head circumference, seizures, visual and cognitive changes along with symptoms of anterior and posterior pituitary deficiency (polyuria, polydipsia, and decreased growth velocity) are important. Ovarian pathology might present with abdominal pain. Moreover,history of brain infections, head trauma, or use of creams, pills, or diet that might expose them to estrogen or testosterone should be considered. A complete family history about the beginning of puberty in parents and siblings, which may point to the possibility of a familial condition should be taken <sup>22</sup>.
In children with idiopathic precocious puberty, the major long-term sequela is short stature as an adult. Psychometric testing shows that girls with precocious puberty have higher verbal IQ scores. some may show a tendency toward social difficulties related to apparent age and physical maturation, such as depression, social withdrawal,  and hyperactivity.
. Prognosis of precocious puberty depends on the specific pathology. For example, in the cerebral category, the prognosis with hypothalamic hamartomas is generally good. Craniopharyngiomas are developmental remnants rather than true neoplasms, and with partial resection and radiation therapy patients may go into remission for many years. With other conditions, such as congenital cysts, hydrocephalus, encephalitis, and neurofibromatosis, the prognosis is related to associated neurologic deficits<sup>31</sup>.With primary hypothyroidism, the prognosis is good. Children with CAH tend to be short as adults (women average 154 cm, men average 164 cm). Women tend to have problems with amenorrhea or irregular menses or infertility, whereas most men have normal sperm counts. In children with idiopathic precocious puberty or children with benign abnormalities, the prognosis is good if the children enter adult life without psychosexual scars. Removal of benign ovarian tumors or cysts and benign testicular or adrenal tumors carries a good prognosis, whereas malignant tumors, often have metastatic disease at the time of presentation, and the prognosis is poor<sup>31</sup>.<br />
==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 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 evaluated annually and followed for at least 6 months<sup>20,30</sup>.===
=== '''Table 1: Tanner Stages of Pubertal Maturation <sup>20</sup>''' ===
{| class="wikitable"
|'''Stage'''
|'''Breast'''
|'''Pubic Hair in Males and Females'''
|'''Male Genitalia'''
|-
|1
|Prepubertal
|Prepubertal
|Prepubertal
|-
|2
|Breast budding, elevation of both breast and nipple  as a small mound
|Sparse growth of long, lightly pigmented hairs at  the base of the penis in males or the mons veneris/labia majora in  females
|Enlargement of the testes and scrotum, thinning and  reddening of the scrotal skin, penis remains prepubertal
|-
|3
|Continued enlargement of both breast and areola  without separation of their contours
|Additional darkening and coarsening of hair,  spreading over the pubic symphysis
|Further growth of testes and scrotum, enlargement of  the penis in length
|-
|4
|The areola and nipple form a secondary mound  projecting above the contour of the breast
|Adult in character but confined to the suprapubic  area in males and females
|Further growth of testes and scrotum with  pigmentation of the scrotal skin, further enlargement of the penis in width,  with maturation of the glans
|-
|5
|Adult shape, areola and nipple recessed to the contour  of the breast
|Adult in distribution with spread to the medial  thighs in males and females. May extend to the lower abdomen in males.
|Testes, scrotum, and penis are adult in size and  shape
|}
<br />
==='''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.===
==='''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.===
[[Precocious puberty history and symptoms|History and Symptoms]] | [[Precocious puberty physical examination|Physical Examination]] | [[Precocious puberty laboratory findings|Laboratory Findings]] | [[Precocious puberty electrocardiogram|Electrocardiogram]] | [[Hashiomoto's thyroiditis chest x ray|Chest X Ray]] | [[Precocious puberty CT|CT]] | [[Precocious puberty MRI|MRI]] | [[Precocious puberty echocardiography or ultrasound|Echocardiography or Ultrasound]] | [[Precocious puberty other imaging findings|Other Imaging Findings]] | [[Precocious puberty other diagnostic studies|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 necessary<sup>32</sup>.
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 CPP<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'''
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]]
==Case Studies==
<br />
===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 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 #2'''<sup>34</sup>
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, glucocorticoids 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.
==Related Chapters==
*[[Delayed puberty]]
{{Endocrine pathology}}
[[de:Pubertas praecox]]
[[es:Pubertad precoz]]
[[nl:Pubertas praecox]]
[[pl:Przedwczesne pokwitanie]]
[[pt:Puberdade precoce]]
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==References== {{Reflist|2}}<br />
[[Category:Pediatrics]]
[[Category:Endocrinology]]
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==Overview==
==Overview==

Revision as of 21:59, 20 October 2020

Editor-In-Cheif: C. Michael Gibson, M.S., M.D.



Cough resident survival guide (pediatrics) Microchapters
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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 to enhanced 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

The initial step is to confirm precocious puberty whether pubertal development is occurring before the normal age of onset or not. 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, rapid progression of puberty. History about any neurological symptoms such as headache, increased head circumference, seizures, visual and cognitive changes along with symptoms of anterior and posterior pituitary deficiency (polyuria, polydipsia, and decreased growth velocity) are important. Ovarian pathology might present with abdominal pain. Moreover,history of brain infections, head trauma, or use of creams, pills, or diet that might expose them to estrogen or testosterone should be considered. A complete family history about the beginning of puberty in parents and siblings, which may point to the possibility of a familial condition should be taken 22.

In children with idiopathic precocious puberty, the major long-term sequela is short stature as an adult. Psychometric testing shows that girls with precocious puberty have higher verbal IQ scores. some may show a tendency toward social difficulties related to apparent age and physical maturation, such as depression, social withdrawal,  and hyperactivity.

. Prognosis of precocious puberty depends on the specific pathology. For example, in the cerebral category, the prognosis with hypothalamic hamartomas is generally good. Craniopharyngiomas are developmental remnants rather than true neoplasms, and with partial resection and radiation therapy patients may go into remission for many years. With other conditions, such as congenital cysts, hydrocephalus, encephalitis, and neurofibromatosis, the prognosis is related to associated neurologic deficits31.With primary hypothyroidism, the prognosis is good. Children with CAH tend to be short as adults (women average 154 cm, men average 164 cm). Women tend to have problems with amenorrhea or irregular menses or infertility, whereas most men have normal sperm counts. In children with idiopathic precocious puberty or children with benign abnormalities, the prognosis is good if the children enter adult life without psychosexual scars. Removal of benign ovarian tumors or cysts and benign testicular or adrenal tumors carries a good prognosis, whereas malignant tumors, often have metastatic disease at the time of presentation, and the prognosis is poor31.

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.

Table 1: Tanner Stages of Pubertal Maturation 20

Stage Breast Pubic Hair in Males and Females Male Genitalia
1 Prepubertal Prepubertal Prepubertal
2 Breast budding, elevation of both breast and nipple as a small mound Sparse growth of long, lightly pigmented hairs at the base of the penis in males or the mons veneris/labia majora in females Enlargement of the testes and scrotum, thinning and reddening of the scrotal skin, penis remains prepubertal
3 Continued enlargement of both breast and areola without separation of their contours Additional darkening and coarsening of hair, spreading over the pubic symphysis Further growth of testes and scrotum, enlargement of the penis in length
4 The areola and nipple form a secondary mound projecting above the contour of the breast Adult in character but confined to the suprapubic area in males and females Further growth of testes and scrotum with pigmentation of the scrotal skin, further enlargement of the penis in width, with maturation of the glans
5 Adult shape, areola and nipple recessed to the contour of the breast Adult in distribution with spread to the medial thighs in males and females. May extend to the lower abdomen in males. Testes, scrotum, and penis are adult in size and shape


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, glucocorticoids 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.


Related Chapters

de:Pubertas praecox nl:Pubertas praecox


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==References==





























Overview

Cough in kids is one of the most common presenting complaint to pediatricians. importantly cough is not disease by itself but rather a manifestation of underlying pathology.

A cough is protective action and can be initiated both voluntary and via stimulation of cough respiratory located throughout the respiratory tract (ear – sinus – upper and lower airway )

Classification

Cough is usually classified based on

1.Duration:

- acute< 2 weeks

- Subacute 2 – 4 weeks

- Chronic > 4 weeks


2.Etiology:

- Specific

-  Not specific


3. Quality:

- Dry cough

 - Wet (moist) cough

4. Timing:

- Nocturnal cough

- Seasonal/ geographical variation

Causes

Life Threatening causes

  • Congestive heart failure
  • Pneumonia
  • Acute inhalation injury
  • Acute exacerbation of asthma/COPD
  • Acute pulmonary embolism

Common Causes

Noninfectious causes

  1. Asthma
  2. Gastroesophageal reflux disease
  3. Forgein-body aspiration
  4. Upper-airway cough syndrome
  5. Extrinsic airway compression
  6. Smoking (active or passive)
  7. Cystic fibrosis
  8. Interstitial lung disease
  9. Nonasthmatic eosinophilic bronchitis

10. Congenital defects (.g., esophageal atresia with/without tracheoesophageal fistula, vascular rings)

Infectious causes

  1. Chronic sinusitis with upper-airway cough syndrome
  2. Pyogenic bacterial pneumonia
  3. Prolonged bacterial bronchitis
  4. Tuberculosis
  5. Mycoplasma pnumoniae infection
  6. Chlamydophila pneumoniae infection
  7. Pertussis
  8. Respiratory viral infections (influenza, adenovirus, rhinovirus, respiratory syncytial virus, parainfluenza virus

FIRE: Focused Initial Rapid Evaluation

The child will look ill with pneumonia or influenza or, the child is breathing heavily. the child will have short of breath with tachypnea (with asthma or foreign body aspiration). There might be a high fever ( with pneumonia, but some children can run sudden high fevers with otherwise innocuous viral infections.
1. pulse oximetry to detect hypoxia

2. full blood count

3. chest x-ray only for children who have severe pneumonia


Complete Diagnostic Approach

1.  Characterized of cough


- Onset                A)sudden

                            B) gradual (chronic lung diseases )


- Duration            A(acute  2 weeks - URTI -  bronchiolitis

                             B) subacute ( 2 – 4 ) weeks

             C) chronic > 4 weeks – cystic fibrosis


                       - Quality               A) wet (moist)  - bronchiectasis

                                            B) dry cough

                      - Worsening and relieving factor

                      - Diurnal         A) night – Asthma

                                        B) only day habits cough

                       - certain characterized        A) brassy cough (barking)  croup

                                                                      B) paroxysmal  pertussis

                                                                       C) staccato chlamydia

                                                                       D) honking   - habits cough


2 . characterized associated symptoms

non specific   -   sweating -  lethargy    -   headache    -   vomiting


3. cardiac symptoms

                            Chest pain -  palpitation  -     oedema   - exertional dyspnea


4. symptoms  suggestive pulmonary problem

                                 Dyspnea   -  hemoptysis    -  grunting   -   pleural pain


5. symptoms suggestive gastrointestinal etiology

Burn sensation (GERD)- epigastric pain  -   Regurgitation

                 Choking (tracheoesophageal  fistula )


6. inquired about medical history

- previous episode of cough

-  past history of asthma  -allergic rhinitis ,eczema

-  Family history of lung or allergic smoking,  asthma


7.examine the patient

-  general appearance  -  cyanosis -  pallor  - jaundice -  -  nail  clubbing

- general examination

-Inspect nose if there are any polyps (cystic febrosis) , skin rash

-Vital signs  -  heart rate -   respiration rate  - blood pressure ---

Pulse;  pulsus-severe asthma

-  Chest      A) any deformity

                  B) auscultation; symmetrical  air entery  crepitation – wheezing (asthma )

-Heart sounds;  S1 – S2   -S3 or murmur


8. order labs  - tests according to the suspected etiology


-  CBC-  CRP -  ESP

- SPUTUM CULTURE

- SWEAT TEST (CYSTIC FEBROSIS)

- LIPASE – AMYLASE EN TYME (CYSTIC FEBROSIS)

- ABG

- MANTOUX TEST FOR TB


9. order Imaging study

- CXR  A)  consolidation pneumonia

               B) pleural effusion

                C) pneumothorax

- Echocardiography to rule out any heart diseases

-Pulmonary function test

https://thorax.bmj.com/content/thoraxjnl/58/11/998/F1.medium.gif

Treatment

Once the history and physical examination have led to an initial assessment, the fact that

cough is a symptom of an underlying condition should be discussed with the patient and

family. Treatment of the underlying disorder (if necessary) should always be the prime

focus.Empiric therapy, based on primary assessment, can be a reasonable starting point.

Judicious use of laboratory testing, as previously discussed, can be helpful in confirming

the diagnosis and allaying parental anxiety. Furthermore, in some conditions, cough is

an important component of the body’s natural response to the primary illness, and

suppressing the cough in the absence of effective therapy of the primary disorder may actually

worsen the problem.

Treatment of the underlying disorders causing cough is discussed in other sections of

this book; this chapter is limited to a review of medications used to treat cough itself. The

decision to use a cough medicine as an adjunct to the treatment of the primary disease is left

to the primary care physician and family. When cough is limiting or otherwise debilitating

the patient, symptomatic treatment may be attempted; however numerous studies question

whether over-the-counter cough preparations offer any significant clinical benefit.

In addition these cough and cold medications should not be given to children younger than

4 years because serious and potentially life-threatening side effects can occur from their

use. Finally, several studies have shown that honey may be beneficial in children older

than 2 years of age.


Expectorants

Expectorants such as guaifenesin (formerly known as glyceryl guaiacolate) may be used

in an attempt to make secretions more fluid and reduce sputum thickness, however the

effectiveness of this treatment has been called into question. This therapeutic approach

may be useful when drainage of secretions is important, as with sinusitis. Because expectorants

work by increasing the fluid content of secretions, water is probably the most

effective expectorant. Saline nose sprays can make secretions more fluid and easily cleared

by the patient and systemic hydration, but not overhydration, should always be optimized.

Despite widespread use, expectorants have not been shown to decrease cough in children.

Other older expectorants, such as potassium iodide and ammonium chloride, are no

longer prescribed to children because of their adverse effects when used at effective doses.


                   


Mucolytic Agents

Acetylcysteine was previously used as a mucolytic agent to help liquefy thick secretions,

especially in diseases such as cystic fibrosis; however, its propensity for inducing airway

reactivity and inflammation has lately made it less popular.


Cough Suppressants

Cough suppressants, which can be divided into peripheral and centrally acting agents,

can be effective in transiently decreasing cough severity and frequency. Peripheral agents

include demulcents (eg, throat lozenges), which soothe the throat, and topical anesthetics,

which can be sprayed or swallowed. Topical agents block the cough receptors, but their

effects are short-lived because oral secretions rapidly wash them away. Centrally acting

cough suppressants, including both narcotic and nonnarcotic medications, suppress

the cough reflex at the brain stem level. The narcotic agent most commonly used in

children is codeine. Although it has been shown to be effective in adults, studies on its

safety and efficacy in children are lacking. Furthermore, data from adults should not be

extrapolated to children, particularly those younger than 2 years, because the metabolic

pathway for clearance of codeine is immature in infants. In older children, codeine should

still be avoided and only used in extreme cases and with very clear instructions because of

the unpredictable and potentially dangerous variation of its metabolism in the pediatric

population. Other agents, such as hydrocodone, have no demonstrated advantage and

pose a greater risk of dependency. Dextromethorphan (the dextro-isomer of codeine) is

the most commonly used nonnarcotic antitussive; and despite data from adults, evidence

of efficacy for children is lacking.


Decongestants

Decongestants such as pseudoephedrine can be used either topically or systemically

to decrease nasal mucosal swelling. Decongestants can also facilitate sinus drainage by

decreasing sinus ostia obstruction, and may work well in combination with expectorants

to optimize treatment of chronic sinusitis. Care should be taken in the use of these

agents because they have been shown to lead to tachyarrhythmias in individuals who use

them in excess. In addition, these agents have not been studied in children and should

be avoided in children younger than 2 years. Multiple reviews of the data from children

between 2 and 6 years old also show lack of efficacy combined with a risk of side effects

in this age group. It is therefore recommended that these agents not be used in children

younger than 6 years.


Antihistamines

Antihistamines, which can be helpful in the treatment of cough triggered by allergy, have

minimal effect when cough is the result of viral or bacterial infection and may actually be

detrimental because they can increase the thickness of secretions. First-generation H1-receptor

antagonists may decrease nasal drip by exerting an anticholinergic effect. Additionally,

diphenhydramine may have a modest direct effect on the medullary cough center. The

clinical benefits of these agents are unclear.


When to Refer

• Cough persists despite adequate therapy of primary disease

• Cough thought to be from hyperreactive airways is not easily reversible with _Beta-2 agonist

• Cough recurs more frequently than every 6 to 8 weeks

• Cough associated with failure to thrive

• Cough associated with other systemic illness


When to Admit

• Patient has respiratory distress

• Infant is unable to feed

• Cough is associated with bacterial pneumonia not responsive to oral antibiotic trial

Do's

  1. Increase fluids
  2. Rest in an upright position
  3. add some humidity
  4. Eliminate irritants

Don'ts

  • Dont give cough medicine for children under 6

References

1.  Paediatrics signs and symptoms sorter_2nd ed

2.  Signs and symptoms in pediatric_AAP

3.  Nelson symptom based diagnosis

4.  Symptoms based diagnosis in pediatric_McGraw Hill


Overview


Polycystic ovary syndrome (PCOS) is a set of symptoms due to elevated androgen's[[1]] (male hormones) in females.[4][14] Signs and symptoms of PCOS include irregular or no menstrual periods[[2]], heavy periods[[3]], excess body and facial hair[[4]], acne, pelvic pain, difficulty getting pregnant[[5]], and patches of thick, darker, velvety skin.[3] Associated conditions include type 2 diabetes, obesity, obstructive sleep apnea, heart disease, mood disorders, and endometrial cancer.[4]

PCOS is due to a combination of genetic and environmental factors.[6][7][15] Risk factors include obesity, a lack of physical exercise, and a family history of someone with the condition.[8] Diagnosis is based on two of the following three findings: no ovulation, high androgen levels, and ovarian cysts.[4] Cysts may be detectable by ultrasound[[6]].[9] Other conditions that produce similar symptoms include adrenal hyperplasia[[7]], hypothyroidism, and high blood levels of prolactin.[9]

PCOS has no cure as of 2020.[5] Treatment may involve lifestyle changes such as weight loss and exercise.[10][11] Birth control pills[[8]] may help with improving the regularity of periods, excess hair growth, and acne.[12] Metformin[[9]] and anti-androgen's may also help.[12] Other typical acne treatments and hair removal techniques may be used.[12] Efforts to improve fertility include weight loss, clomiphene, or metformin.[16] In vitro fertilization is used by some in whom other measures are not effective.[16]

PCOS is the most common endocrine disorder among women between the ages of 18 and 44.[17] It affects approximately 2% to 20% of this age group depending on how it is defined.[8][13] When someone is infertile due to lack of ovulation, PCOS is the most common cause.[4] The earliest known description of what is now recognized as PCOS dates from 1721 in Italy.[18]


Causes

PCOS is a heterogeneous disorder[[10]] of uncertain cause.[26][27] There is some evidence that it is a genetic disease. Such evidence includes the familial clustering of cases, greater concordance in monozygotic compared with dizygotic twins and heritability of endocrine and metabolic features of PCOS.[7][26][27] There is some evidence that exposure to higher than typical levels of androgens and the anti-Müllerian hormone (AMH) in utero increases the risk of developing PCOS in later life.[28]

Genetics The genetic component appears to be inherited in an autosomal dominant fashion with high genetic penetrance but variable expressivity in females; this means that each child has a 50% chance of inheriting the predisposing genetic variant(s) from a parent, and, if a daughter receives the variant(s), the daughter will have the disease to some extent.[27][29][30][31] The genetic variant(s) can be inherited from either the father or the mother, and can be passed along to both sons (who may be asymptomatic carriers or may have symptoms such as early baldness and/or excessive hair) and daughters, who will show signs of PCOS.[29][31] The phenotype appears to manifest itself at least partially via heightened androgen levels secreted by ovarian follicle theca cells[[11]] from women with the allele.[30] The exact gene affected has not yet been identified.[7][27][32] In rare instances, single-gene mutations can give rise to the phenotype of the syndrome.[33] Current understanding of the pathogenesis of the syndrome suggests, however, that it is a complex multigenic disorder.[34]

The severity of PCOS symptoms appears to be largely determined by factors such as obesity.

PCOS has some aspects of a metabolic disorder, since its symptoms are partly reversible. Even though considered as a gynecological problem, PCOS consists of 28 clinical symptoms.

Even though the name suggests that the ovaries are central to disease pathology, cysts are a symptom instead of the cause of the disease. Some symptoms of PCOS will persist even if both ovaries are removed; the disease can appear even if cysts are absent. Since its first description by Stein and Leventhal in 1935, the criteria of diagnosis, symptoms, and causative factors are subject to debate. Gynecologists often see it as a gynecological problem, with the ovaries being the primary organ affected. However, recent insights show a multisystem disorder, with the primary problem lying in hormonal regulation in the hypothalamus, with the involvement of many organs. The name PCOD is used when there is ultrasonographic evidence. The term PCOS is used due to the fact that there is a wide spectrum of symptoms possible, and cysts in the ovaries are seen only in 15% of people.[36]

Environment PCOS may be related to or worsened by exposures during the prenatal period, epigenetic factors[[12]], environmental impacts (especially industrial endocrine disruptors,[37] such as bisphenol A and certain drugs) and the increasing rates of obesity.


Diganosis


Doctors typically diagnose PCOS in women who have at least two of these three symptoms

.high androgen levels .irregular menstrual cycles,[[13]] .cysts in the ovaries Your doctor should also ask whether you’ve had symptoms like acne, face and body hair growth, and weight gain.

A pelvic exam[[14]], can look for any problems with your ovaries or other parts of your reproductive tract. During this test, your doctor inserts gloved fingers into your vagina and checks for any growths in your ovaries or uterus.

Blood tests check for higher-than-normal levels of male hormones. You might also have blood tests to check your cholesterol, insulin, and triglyceride levels to evaluate your risk for related conditions like heart disease and diabetes.

An ultrasound uses sound waves to look for abnormal follicles and other problems with your ovaries and uterus.



Pathophysiology


The endocrinologic abnormality of PCOS begins soon after menarche. Chronically elevated luteinizing hormone (LH) and insulin resistance are 2 of the most common endocrine aberrations seen in PCOS. The genetic cause of high LH is not known. It is interesting to note that neither an elevation in LH nor insulin resistance alone is enough to explain the pathogenesis of PCOS.[7,8,9] In vitro and in vivo evidence offer support that high LH and hyperinsulinemia work synergistically, causing ovarian growth, androgen production, and ovarian cyst formation.

Obesity, which is seen in 50% to 65% of PCOS patients, may increase the insulin resistance and hyperinsulinemia. One important caveat is that the correlation between hyperandrogenism and insulin resistance has been recognized in both obese and nonobese anovulatory women. Thus, it is important to realize that a nonobese patient may also have insulin resistance. However, the insulin levels in obese women are higher than their nonobese counterparts. Clinically, though, both groups will have evidence of hyperandrogenism and oligo-ovulation or anovulation.[6,7]

Insulin resistance can be characterized as impaired action of insulin in the uptake and metabolism of glucose.[6] https://www.wikidoc.org/index.php/Hyperprolactinemia-I) and sex hormone binding globulin (SHBG). IGFBP-I binds to IGFBP-II and SHBG binds to sex steroids, especially androgens. The triad of hyperandrogenism, insulin resistance, and acanthosis nigricans (HAIR-AN) syndrome appears in a subgroup of patients with PCOS.[6,10,11]

Acanthosis nigricans, a dark and hyperpigmented hyperplasia of the skin typically found at the nape of the neck and axilla, is a marker for insulin resistance. Acanthosis nigricans is usually found in about 30% of hyperandrogenic women. Figure 1 illustrates acanthosis nigricans evident in a patient's axilla.



Differentiating PCOS from other Diseases

Polycystic ovary syndrome must be differentiated from other causes of irregular or absent menstruation[[15]], and hirsutism[[16]], such as,[[17]]Congenital_adrenal_hyperplasia congenital adrenal hyperplasia, cushing's syndrome[[18]], hyperprolactinemia[[19]], and other pituitary[[20]], or adrenal disorders[[21]].



Symptoms

.irregular periods or no periods at all

.difficulty getting pregnant (because of irregular ovulation or failure to ovulate)

.excessive hair growth (hirsutism) – usually on the face, chest, back or buttocks

.weight gain

.thinning hair and hair loss from the head

.oily skin or acne



Treatment

The primary treatments for PCOS include: lifestyle changes and medications.[76]

Goals of treatment may be considered under four categories:

Lowering of insulin resistance levels Restoration of fertility Treatment of hirsutism or acne Restoration of regular menstruation, and prevention of endometrial_hyperplasia[[22]], and endometrial Endometrial cancer[[23]], In each of these areas, there is considerable debate as to the optimal treatment. One of the major reasons for this is the lack of large-scale clinical trials comparing different treatments. Smaller trials tend to be less reliable and hence may produce conflicting results.

General interventions that help to reduce weight or insulin resistance can be beneficial for all these aims, because they address what is believed to be the underlying cause.

As PCOS appears to cause significant emotional distress, appropriate support may be useful.[77]

Diet Where PCOS is associated with overweight or obesity, successful weight loss is the most effective method of restoring normal ovulation/menstruation. The American Association of Clinical Endocrinologists guidelines recommend a goal of achieving 5 to 15% weight loss or more, which improves insulin resistance and all hormonal /Endocrine_disease[[24]].[78] However, many women find it very difficult to achieve and sustain significant weight loss. A scientific review in 2013 found similar decreases in weight and body composition and improvements in pregnancy rate[[25]], menstrual regularity, ovulation, hyperandrogenism, insulin resistance, lipids, and quality of life to occur with weight loss independent of diet composition.[79] Still, a low GI diet, in which a significant part of total carbohydrates are obtained from fruit, vegetables, and whole-grain sources, has resulted in greater menstrual regularity than a macronutrient-matched healthy diet.[79]

Vitamin D deficiency may play some role in the development of the metabolic syndrome, so treatment of any such deficiency is indicated.[80][81] However, a systematic review of 2015 found no evidence that vitamin D supplementation reduced or mitigated metabolic and hormonal dysregulations in PCOS.[82] As of 2012, interventions using dietary supplements to correct metabolic deficiencies in people with PCOS had been tested in small, uncontrolled and nonrandomized clinical trials; the resulting data is insufficient to recommend their use.[83]

Medications Medications for PCOS include oral contraceptives and metformin. The oral contraceptives increase sex hormone binding globulin production, which increases binding of free testosterone. This reduces the symptoms of hirsutism caused by high testosterone and regulates return to normal menstrual periods. Metformin is a medication commonly used in type 2 diabetes mellitus to reduce insulin resistance, and is used off label (in the UK, US, AU and EU) to treat insulin resistance seen in PCOS. In many cases, metformin also supports ovarian function and return to normal ovulation.[80][84] Spironolactone can be used for its antiandrogenic effects, and the topical cream eflornithine can be used to reduce facial hair. A newer insulin resistance medication class, the thiazolidinediones (glitazones), have shown equivalent efficacy to metformin, but metformin has a more favorable side effect profile.[85][86] The United Kingdom's National Institute for Health and Clinical Excellence recommended in 2004 that women with PCOS and a body mass index above 25 be given metformin when other therapy has failed to produce results.[87][88] Metformin may not be effective in every type of PCOS, and therefore there is some disagreement about whether it should be used as a general first line therapy.[89] In addition to this, metformin is associated with several unpleasant side effects: including abdominal pain, metallic taste in the mouth, diarrhoea and vomiting.[90] The use of statins in the management of underlying metabolic syndrome remains unclear.[91]

It can be difficult to become pregnant with PCOS because it causes irregular ovulation. Medications to induce fertility when trying to conceive include the ovulation inducer clomiphene or pulsatile leuprorelin. Metformin improves the efficacy of fertility treatment when used in combination with clomiphene.[92] Metformin is thought to be safe to use during pregnancy (pregnancy category B in the US).[93] A review in 2014 concluded that the use of metformin does not increase the risk of major birth defects in women treated with metformin during the first trimester.[94] Liraglutide may reduce weight and waist circumference more than other medications.[95]

Infertility Main article: Infertility in polycystic ovary syndrome Not all women with PCOS have difficulty becoming pregnant. For those that do, anovulation or infrequent ovulation is a common cause. Other factors include changed levels of gonadotropins, hyperandrogenemia and hyperinsulinemia.[96] Like women without PCOS, women with PCOS that are ovulating may be infertile due to other causes, such as tubal blockages due to a history of sexually transmitted diseases.[97]

For overweight anovulatory women with PCOS, weight loss and diet adjustments, especially to reduce the intake of simple carbohydrates, are associated with resumption of natural ovulation.

For those women that after weight loss still are anovulatory or for anovulatory lean women, then the medications letrozole and clomiphene citrate are the principal treatments used to promote ovulation.[98][99][100] Previously, the anti-diabetes medication metformin was recommended treatment for anovulation, but it appears less effective than letrozole or clomiphene.[101][102]

For women not responsive to letrozole or clomiphene and diet and lifestyle modification, there are options available including assisted reproductive technology procedures such as controlled ovarian hyperstimulation with follicle-stimulating hormone (FSH) injections followed by in vitro fertilisation (IVF).

Though surgery is not commonly performed, the polycystic ovaries can be treated with a laparoscopic procedure called "ovarian drilling" (puncture of 4–10 small follicles with electrocautery, laser, or biopsy needles), which often results in either resumption of spontaneous ovulations[80] or ovulations after adjuvant treatment with clomiphene or FSH.[citation needed] (Ovarian wedge resection is no longer used as much due to complications such as adhesions and the presence of frequently effective medications.) There are, however, concerns about the long-term effects of ovarian drilling on ovarian function.[80]

Depression Although women with PCOS are far more likely to have depression than women without, the evidence for anti-depressive use in women with PCOS remains inconclusive.[103]

Hirsutism and acne Further information: Hirsutism When appropriate (e.g., in women of child-bearing age who require contraception), a standard contraceptive pill is frequently effective in reducing hirsutism.[80] Progestogens such as norgestrel and levonorgestrel should be avoided due to their androgenic effects.[80]

Other medications with anti-androgen effects include flutamide,[104] and spironolactone,[80] which can give some improvement in hirsutism. Metformin can reduce hirsutism, perhaps by reducing insulin resistance, and is often used if there are other features such as insulin resistance, diabetes, or obesity that should also benefit from metformin. Eflornithine (Vaniqa) is a medication that is applied to the skin in cream form, and acts directly on the hair follicles to inhibit hair growth. It is usually applied to the face.[80] 5-alpha reductase inhibitors (such as finasteride and dutasteride) may also be used;[105] they work by blocking the conversion of testosterone to dihydrotestosterone (the latter of which responsible for most hair growth alterations and androgenic acne).

Although these agents have shown significant efficacy in clinical trials (for oral contraceptives, in 60–100% of individuals[80]), the reduction in hair growth may not be enough to eliminate the social embarrassment of hirsutism, or the inconvenience of plucking or shaving. Individuals vary in their response to different therapies. It is usually worth trying other medications if one does not work, but medications do not work well for all individuals.

Menstrual irregularity If fertility is not the primary aim, then menstruation can usually be regulated with a contraceptive pill.[80] The purpose of regulating menstruation, in essence, is for the woman's convenience, and perhaps her sense of well-being; there is no medical requirement for regular periods, as long as they occur sufficiently often.

If a regular menstrual cycle is not desired, then therapy for an irregular cycle is not necessarily required. Most experts say that, if a menstrual bleed occurs at least every three months, then the endometrium (womb lining) is being shed sufficiently often to prevent an increased risk of endometrial abnormalities or cancer.[106] If menstruation occurs less often or not at all, some form of progestogen replacement is recommended.[105] An alternative is oral progestogen taken at intervals (e.g., every three months) to induce a predictable menstrual bleeding.[citation needed]

Alternative medicine A 2017 review concluded that while both myo-inositol and D-chiro-inositols may regulate menstrual cycles and improve ovulation, there is a lack of evidence regarding effects on the probability of pregnancy.[107][108] A 2012 and 2017 review have found myo-inositol supplementation appears to be effective in improving several of the hormonal disturbances of PCOS.[109][110] Myo-inositol reduces the amount of gonadotropins and the length of controlled ovarian hyperstimulation in women undergoing in vitro fertilization.[111] A 2011 review found not enough evidence to conclude any beneficial effect from D-chiro-inositol.[112] There is insufficient evidence to support the use of acupuncture, current studies are inconclusive and there's a need for additional randomized controlled trials.

Treatment of cough

1. Asthma

.Fast–acting

Short-acting beta2-adrenoceptor agonists (SABA), such as salbutamol

Anticholinergic medications, such as ipratropium

Griffiths B, Ducharme FM (August 2013). "Combined inhaled anticholinergics and short-acting beta2-agonists for initial treatment of acute asthma in children". The Cochrane Database of Systematic Reviews (8): CD000060.


Reference "Expert Panel Report 3: Guidelines for the Diagnosis and Management of Asthma" (PDF). National Heart Lung and Blood Institute. Archived from the original (PDF) on 2013-10-19. Retrieved 2005-08-31.