Precocious puberty

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Differentiating Precocious puberty from other Diseases

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

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 genders. 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. They reported that the glands that secrete growth and sex hormones start their function abnormally early in life causing in this condition. 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. For example, it could be caused by a neurologic disorder in a very young boy. 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).

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.

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. 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

Causes

                                                                                           

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

·      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. 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

Risk Factors

A few factors are linked to precocious puberty; they include

·      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

·       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

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

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.

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.

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. 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.

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.

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


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.

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.

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.

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).

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