Puberty: Physiology and Abnormalities, 1st ed. 2016

10. Precocious Puberty

Juliane Léger  and Jean-Claude Carel1

(1)

Department of Paediatric Endocrinology and Diabetology, INSERM UMR 1141, DHU PROTECT, Reference Center for Rare Endocrine Growth Diseases, Denis Diderot Paris 7 University, Hôpital Robert Debré, 75019 Paris, France

Juliane Léger

Email: juliane.leger@aphp.fr

Keywords

Precocious pubertyCentralPeripheralGonadotropic axisManagementTreatmentOutcome

Introduction

Precocious puberty is defined as the onset of clinical signs of puberty before the age of 8 years in girls and 9.5 years in boys. However, the onset of puberty may be subject to the effects of environmental (secular trends, adoption, absence of the father, and possible exposure to estrogenic endocrine-disrupting chemicals), nutritional (body mass index), and constitutional (genetics, ethnicity) factors [14], with implications for the definition of precocious puberty.

PP may be caused by central or peripheral mechanisms [1]. Precocious puberty leads to the progressive development of secondary sexual characteristics including breast development in girls and testicular enlargement in boys, together with the development of pubic hair, and an acceleration of growth velocity and bone maturation, resulting in premature fusion of the growth plates, potentially responsible for adult height deficit [1].

Premature sexual maturation is a frequent cause for referral. Clinical evaluation is generally sufficient to reassure the patients and their families, but premature sexual maturation may reveal severe conditions, and thorough evaluation is therefore required to identify its cause and potential for progression, so that appropriate treatment can be proposed.

The clinical expression of precocious puberty is polymorphic. In addition to progressive central PP, with a progressive deterioration of adult height prognosis in the absence of treatment, there are very slowly progressive forms which do not modify predicted final height. It is not always straightforward to recognize these different clinical forms at the initial evaluation. Nevertheless, their correct identification is very important, because the indicated treatments differ [57]. The heterogeneity of precocious puberty, in terms of its clinical presentation and definition, can be explained by the gradual nature of the transition to puberty. Indeed, the pulsatile secretion of LH begins before the onset of clinical signs of puberty, and an increase in the amplitude of the LH peaks is the key biological sign of pubertal maturation of the gonadotropic pituitary axis. GnRH stimulation tests indirectly reveal pulsatile endogenous GnRH secretion, as this secretion determines the response to exogenous GnRH. The available data indicate that there is no clear boundary between prepubertal and pubertal status, accounting for the frequency of “marginal” forms of precocious puberty.

Etiologies and Mechanisms Underlying Premature Sexual Development

Central precocious puberty (CPP) , which is much more common in girls than in boys [8], results from premature reactivation of the hypothalamic–pituitary–gonadal axis and pulsatile GnRH secretion, with a hormonal pattern similar to that of normal puberty. Premature sexual development results from the action of sex steroids or compounds with sex steroid activity on target organs. CPP may be due to hypothalamic lesions, but is idiopathic in most cases, particularly in girls (Table 10.1) [1]. Recent studies have implicated the inactivation of makorin ring finger 3 (MKRN3) genes in “idiopathic” CPP [910]. MKRN3 is an imprinted gene located on the long arm of chromosome 15, with a potentially inhibitory effect on GnRH secretion. MKRN3 gene defects have been identified as a cause of paternally transmitted familial CPP, but such defects do not underlie maternally transmitted CPP and are rarely involved in sporadic forms [11].

Table 10.1

Clinical characteristics of the various forms of central precocious puberty

Cause

Symptoms and signs

Evaluation

Due to a CNS lesion

Hypothalamic hamartoma

May be associated with gelastic (laughing attacks), focal, or tonic–clonic seizures

MRI: mass in the floor of the third ventricle iso-intense to normal tissue without contrast enhancement

Or other hypothalamic tumors:

• Glioma involving the hypothalamus and/or the optic chiasm

• Astrocytoma

• Ependymoma

• Pinealoma

• Germ cell tumors

May include headache, visual changes, cognitive changes, symptoms/signs of anterior or posterior pituitary deficiency (e.g., decreased growth velocity, polyuria–polydipsia), fatigue, visual field defects

If CNS tumor (glioma) associated with neurofibromatosis may have other features of neurofibromatosis (cutaneous neurofibromas, café au lait spots, Lisch nodules, etc.)

MRI: contrast-enhanced mass that may involve the optic pathways (chiasm, nerve, tract) or the hypothalamus (astrocytoma, glioma) or that may involve the hypothalamus and pituitary stalk (germ cell tumor), may have evidence of intracranial hypertension, may have signs of anterior or posterior pituitary deficiency (e.g., hypernatremia)

If germ cell tumor: βhCG detectable in blood or CSF

Cerebral malformations involving the hypothalamus:

• Suprasellar arachnoid cyst

• Hydrocephalus

• Septooptic dysplasia

• Myelomeningocele

• Ectopic neurohypophysis

May have neurodevelopmental deficits, macrocrania, visual impairment, nystagmus, obesity, polyuria–polydipsia, decreased growth velocity

May have signs of anterior or posterior pituitary deficiency (e.g., hypernatremia) or hyperprolactinemia

Acquired injury:

• Cranial irradiation

• Head trauma

• Infections

• Perinatal insults

Relevant history

Symptoms and signs of anterior or posterior pituitary deficiency may be present

MRI may reveal condition-specific sequelae or may be normal

Idiopathic—No CNS lesion

≈92 % of girls and ≈ 50 % of boys

History of familial precocious puberty or adoption may be present

No hypothalamic abnormality on the head MRI. The anterior pituitary may be enlarged

MKRN 3 gene evaluation if paternally transmitted

Secondary to early exposure to sex steroids

After cure of any cause of gonadotropin-independent precocious puberty

Relevant history

 

Peripheral or gonadotropin-independent precious puberty is due to the production of sex steroids by gonadal or adrenal tissue, independently of gonadotropins which are generally suppressed. Peripheral precocious puberty can result from gonadal, adrenal, or hCG-producing tumors, activating mutations in the gonadotropic pathway, and exposure to exogenous sex steroids (Table 10.2). Peripheral precocious puberty can rarely lead to activation of pulsatile GnRH secretion and to central precocious puberty (Table 10.1).

Table 10.2

Clinical characteristics of the various forms of peripheral precocious puberty

Disorder

Characteristic symptoms and signs

Test results

Autonomous gonadal activation

McCune–Albright syndrome and recurrent autonomous ovarian cysts due to somatic activating mutation of the GNAS gene resulting in increased signal transduction in the Gs pathway

Mostly in girls. Typically rapid progression of breast development and early occurrence of vaginal bleeding (before or within a few months of breast development)

Precocious puberty may be isolated or associated with café au lait pigmented skin lesions or bone pain due to polyostotic fibrous dysplasia. More rarely other signs of endocrine hyperfunction (e.g., hypercortisolism, hyperthyroidism), liver cholestasis, or cardiac rhythm abnormalities

Typically large ovarian cyst or cysts on pelvic ultrasound examination

Bone lesions of fibrous dysplasia

May have laboratory evidence of hypercortisolism, hyperthyroidism, increased GH secretion, hypophosphatemia, liver cholestasis

Familial male-limited precocious puberty due to germinal activating mutations of the LH receptor gene

A familial history of dominant precocious puberty limited to boys (but transmitted by mothers) may be present but some cases are sporadic

Activating mutation of the LH receptor gene

Germ line mutations of GNAS gene resulting in dual loss and gain of function (rare)

Single case report of a boy with concomitant pseudohypoparathyroidism and gonadotropin-independent precocious puberty

 

Tumors

Granulosa cell tumors of the ovary

Rapid progression of breast development; abdominal pain may occur. The tumor may be palpable on abdominal examination

Tumor detection on ultrasound or CT scan

Androgen producing ovarian tumors

Progressive virilization

Tumor detection on ultrasound or CT scan

Testicular Leydig cell tumors

Progressive virilization; testicular asymmetry (the tumor itself is rarely palpable)

Tumor detection on testicular ultrasound

hCG-producing tumors

Tumors can originate in the liver or mediastinum. Pubertal symptoms in boys only. May be associated with Klinefelter syndrome

Elevated serum hCG

Adrenal disorders

Manifest with signs of androgen exposure

 

Congenital adrenal hyperplasia

Increased androgen production leading to virilization in boys and girls

Increased adrenal steroid precursors in serum, mainly 17-OH-progesterone (basal or after an ACTH stimulation test)

Adrenal tumor

Increased androgen production leading to virilization in boys and girls. Very rarely, estrogen-producing adrenal tumor

Tumor on abdominal ultrasound or CT scan

Elevated DHEAS, or adrenal steroid precursors

Generalized glucocorticoid resistance

Symptoms and signs of mineralocorticoid excess, such as hypertension and hypokalemic alkalosis

Elevated free urinary cortisol and plasma cortisol

Environmental agents

Exogenous sex steroids

Manifestations vary with the type of preparation (androgenic or estrogenic); most commonly described after topical exposure to androgens; tracing the source of exposure may be difficult

Endocrine evaluation can be misleading due to widely variable serum levels of sex steroids with time

Exposure to estrogenic endocrine-disrupting chemicals

May play a role in precocious puberty in adopted children (by modulating the timing of pubertal gonadotropic axis activation) although this remains unproven

No validated biochemical test

Severe untreated primary hypothyroidism

Signs of hypothyroidism. No increase of growth velocity

Manifest mostly with increased testicular volume in the absence of virilization. Due to a cross-reactivity of elevated TSH to the FSH receptor

Elevated serum TSH levels, low free T4 level. No bone age advancement

Exposure to exogenous sex steroids or to compounds with steroidal activity can also result in premature sexual development.

It is also important to recognize that most cases of premature sexual maturation correspond to benign variants of normal development that can occur throughout childhood. They can mimic precocious puberty but do not lead to long-term consequences and are usually benign. This is particularly true in girls below the age of 2–3 where the condition is known as premature thelarche. Similarly in older girls, at least 50 % of cases of premature sexual maturation will regress or stop progressing and no treatment is necessary [56]. Although the mechanism underlying these cases of nonprogressive precocious puberty is unknown, the gonadotropic axis is not activated. Premature thelarche probably represents an exaggerated form of the physiological early gonadotropin surge that is delayed in girls relatively to boys.

Consequences of Precocious Puberty

Progressive premature sexual maturation can have consequences on growth and psychosocial development. Growth velocity is accelerated as compared to normal values for age, and bone age is advanced in most cases. The acceleration of bone maturation can lead to premature fusion of the growth plate and short stature. Several studies have assessed adult height in individuals with a history of precocious puberty. In older published series of untreated patients, mean heights ranged from 151 to 156 cm in boys and 150 to 154 cm in girls, corresponding to a loss of about 20 cm in boys and 12 cm in girls relative to normal adult height [12]. However, these numbers correspond to historical series of patients with severe early onset precocious puberty which are not representative of the majority of patients seen in the clinic today. Height loss due to precocious puberty is inversely correlated with the age at pubertal onset, and currently treated patients tend to have later onset of puberty than those in historical series [12].

Parents often seek treatment in girls because they fear early menarche [13]. However, there is little data to predict the age of menarche following early onset of puberty [14]. In the general population, the time from breast development to menarche is longer for children with an earlier onset of puberty, ranging from a mean of 2.8 years when breast development begins at age 9–1.4 years when breast development begins at age 12 [15].

In the general population, early puberty timing has been shown to be associated with several health outcomes in adult life with higher risks for cardiovascular disease and type 2 diabetes in both women and men [16]. However, there is no long-term data on these aspects in case of precocious puberty.

Adverse psychosocial outcomes are also a concern, but the available data specific to patients with precocious puberty have serious limitations [17]. In the general population, a higher proportion of early-maturing adolescents engage in exploratory behaviors (sexual intercourse, legal and illegal substance use) and at an earlier age than adolescents maturing within the normal age range or later [1819]. In addition, the risk for sexual abuse seems to be higher in girls or women with early sexual maturation [20]. However, the relevance of these findings to precocious puberty is unclear, and they should not be used to justify intervention.

Evaluation of the Child with Premature Sexual Development

The evaluation of patients with premature sexual development should address several questions: (1) Is sexual development really occurring outside the normal temporal range? (2) What is the underlying mechanism and is it associated with a risk of a serious condition, such as an intracranial lesion? (3) Is pubertal development likely to progress, and (4) would this impair the child’s normal physical and psychosocial development?

Clinical Diagnosis

Precocious puberty manifests as the progressive appearance of secondary sexual characteristics—breast development, pubic hair, and menarche in girls and enlargement of testicular volume (testicular volume greater than 4 ml or testicular length greater than 25 mm) and penis and pubic hair development in boys [2122] Fig 10.1—together with an acceleration of height velocity and bone maturation, which is frequently very advanced (by more than 2 years relative to chronological age). However, a single sign may remain the only sign for long periods, making diagnosis difficult, particularly in girls, in which isolated breast development may precede the appearance of pubic hair or the increase in growth velocity and bone maturation by several months. However, in some children, the increase in height velocity precedes the appearance of secondary sexual characteristics [23].

A334826_1_En_10_Fig1_HTML.gif

Fig. 10.1

Pubertal stage as a function of Tanner stage: figure adapted from ref. [1]

The clinical evaluation should guide the diagnosis and discussions about the most appropriate management (Table 10.3).

Table 10.3

When should suspected precocious puberty be explored?

Girls

Boys

Breast development before the age of 8 years

Increase in testicular volume before the age of 9.5 years

Pubic hair before the age of 8 years

Pubic hair before the age of 9.5 years

Breast development between the ages of 8 and 9 years.

Exploration only if:

• Onset of pubertal development before 8 years

• Growth velocity >6 cm/year, adult height prognosis below target height

• Rapid progression of pubertal development (transition from one stage to another in less than 6 months)

• Clinical evidence for a neurogenic etiology

• Clinical evidence of peripheral precocious puberty

Pubertal development seen around 10 years. Exploration only if:

• Onset of pubertal development before 9.5 years

• Growth velocity >6 cm/year, adult height prognosis below target height

• Rapid progression of pubertal development (transition from one stage to another in less than 6 months)

• Clinical evidence of a neurogenic etiology. Clinical evidence of peripheral precocious puberty

Menarche before the age of 10 years

 

The interview is used to specify the age at onset and rate of progression of pubertal signs, to investigate neonatal parameters (gestational age, birth measurements) and whether the child was adopted, together with any evidence suggesting a possible central nervous disorder, such as headache, visual disturbances, or neurological signs (gelastic attacks), or pituitary deficiency, such as asthenia, polyuria–polydipsia, and the existence of a known chronic disease or history of cerebral radiotherapy. The evaluation also includes the height and pubertal age of parents and siblings and family history of early or advanced puberty.

The physical examination assesses height, height velocity (growth curve), weight and body mass index, pubertal stage, and, in girls, the estrogenization of the vulva, skin lesions suggestive of neurofibromatosis or McCune–Albright syndrome, neurological signs (large head circumference with macrocephaly, nystagmus, visual change or visual field defects, neurodevelopmental deficit), symptoms or signs of anterior or posterior pituitary deficiency (low growth velocity, polyuria–polydipsia, fatigue), and the neuropsychological status of the child , which remains the major concern of the child and parents seeking help for early puberty. It is also important to recognize clinically the benign variants of precocious pubertal development, usually involving the isolated and nonprogressive development of secondary sexual characteristics (breasts or pubic hair), normal growth velocity or slight increase in growth velocity, and little or no bone age advancement.

Following this assessment, watchful waiting or complementary explorations may be chosen as the most appropriate course of action. The criteria currently used to guide explorations are presented in Table 10.3. If watchful waiting is decided upon, then careful reevaluation of progression is required 3–6 months later, to assess the rate of progression of puberty and any changes in growth.

Additional testing is generally recommended in all boys with precocious pubertal development, in girls with precocious Tanner 3 breast stage or higher, and in girls with precocious B2 stage and additional criteria, such as increased growth velocity, or symptoms or signs suggestive of central nervous system dysfunction or of peripheral precocious puberty.

These tests include the assessment of bone age (which is usually advanced in patients with progressive precocious puberty), hormonal determinations, pelvic or testicular (if peripheral PP is suspected) ultrasound scans, and brain magnetic resonance imaging (MRI).

Biological Diagnosis

The biological diagnosis of precocious puberty is based on the evaluation of sex steroid secretion and its mechanisms. The diagnosis of central precocious puberty is based on pubertal serum gonadotropin concentrations, with the demonstration of an activation of gonadotropin secretion [24].

Sex Steroid Determinations

In boys, testosterone is a good marker of testicular maturation, provided it is assessed with a sensitive method. RIA is generally used in practice. In girls, estradiol determination is uninformative, because half the girls displaying central precocious puberty have estradiol levels within the normal range of values in prepubescent girls. Very sensitive methods are required, and only RIA methods meet this requirement. The increase in estradiol concentration is also highly variable, due to the fluctuation, and sometimes intermittent secretion of this hormone. Very high estradiol levels are generally indicative of ovarian disease (peripheral PP due to cysts or tumors). Estrogenic impregnation is best assessed by pelvic ultrasound scans, on which the estrogenization of the uterus and ovaries may be visible [25].

Gonadotropin Determinations

Basal gonadotropin levels are informative and are generally significantly higher in children with PP than in prepubertal children [26]. However, basal serum LH concentration is much more sensitive than basal FSH concentration and is the key to diagnosis. Ultrasensitive assays should be used to determine serum LH concentration. Prepubertal LH concentrations are <0.1 IU/l, so LH assays should have a detection limit close to 0.1 IU/l [2729].

The response to GnRH stimulation is considered the gold standard for the diagnosis of central precocious puberty. Stimulation tests involving a single injection of GnRH analogs can also be used [3031]. The major problem is defining the decision threshold. In both sexes, a central cause of precocious puberty is demonstrated an increase in pituitary gonadotropin levels. Indeed, the underlying mechanism of early central puberty is linked to premature activation of the hypothalamic–pituitary–gonadal axis, with the onset of pulsatile LH secretion and an increase in the secretion of pituitary gonadotropins both in basal conditions and after stimulation with GnRH. Before the onset of puberty, the FSH peak is greater than the LH surge. During and after puberty, the LH surge predominates. In cases of central precocious puberty, basal serum LH concentration usually is ≥0.3 IU/l and serum LH concentration after stimulation is ≥5 IU/l [132]. FSH is less informative than LH, because FSH levels vary little during pubertal development. However, the stimulated LH/FSH ratio may make it easier to distinguish between progressive precocious puberty (with an LH/FSH ratio >0.66) and nonprogressive variants not requiring GnRH agonist therapy.

Place of Imaging in the Evaluation of Precocious Puberty

Pelvic ultrasound scans can be used to assess the degree of estrogenic impregnation of the internal genitalia in girls, through measurements of size and morphological criteria. A uterine length ≥35 mm is the first sign of estrogen exposure. Morphological features are also important, as the prepubertal state is marked by a tubular uterus, which becomes more pearl-like in shape during the course of puberty, with a bulging fundus. Measurements of uterine volume increase the reliability of the examination (prepubertal ≤2 ml). Endometrial thickening on an endometrial ultrasound scan provides a second line of evidence. Ovary size and the number of follicles are not criteria for the assessment of pubertal development [253133].

Testicular ultrasound should be performed if the testicles differ in volume or if peripheral precocious puberty is suspected, to facilitate the detection of Leydig cell tumors, which are generally not palpable.

Neuroimaging is essential in the etiological evaluation in progressive central precocious puberty. Magnetic resonance imaging (MRI) is the examination of choice in the study of the brain and of the hypothalamic–pituitary region, for the detection of hypothalamic lesions. The prevalence of such lesions is higher in boys (30–80 % of cases) than in girls (8–33 %) and is much lower when puberty starts after the age of 6 years in girls, this population accounting for the majority of cases. It has been suggested that an algorithm based on age and estradiol levels could replace MRI, but such an approach has not been clearly validated [3436].

At the end of this analysis, the diagnostic approach should help to determine the progressive or nonprogressive nature of pubertal precocity (Table 10.4) and to differentiate between the etiologies of central or peripheral precocious puberty.

Table 10.4

Differentiation between true precocious puberty and slowly progressive forms

   

Progressive precocious puberty

Slowly progressive precocious puberty

Clinical

Pubertal stage

Passage from one stage to another in 3–6 months

Spontaneous regression or stabilization of pubertal signs

Growth velocity

Accelerated: >6 cm/year

Normal for age

Bone age

Typically advanced, variable, at least 2 years

Variable, but usually within 1 year of chronological age

Predicted adult height

Below-target height or decreasing on serial determinations

Within target height range

Pelvic ultrasound scan

Uterus

Length >34 mm or volume >2 ml

Length ≤34 mm or volume ≤2 ml

Pearl-shaped uterus

Prepubertal, tubular uterus

Endometrial thickening (endometrial ultrasound scan)

 

Ovaries

Not very informative

Not very informative

Hormonal evaluation

Estradiol (RIA ++)

Not very informative, usually measurable

Not detectable or close to the detection limit

LH peak after stimulation with GnRH

In the pubertal zone ≥5 IU/l

In the prepubertal range

Basal LH determination

Useful if value is high (≥3 IU/l) and frankly in the pubertal range

No definitive value

Indeed, many girls with idiopathic precocious puberty display very slowly progressive puberty, or even regressive puberty, with little change to predicted adult height and a normal final height close to their parental target height [56]. Therapeutic abstention is the most appropriate approach in most of these cases, because puberty progresses slowly, with menarche occurring, on average, 5.5 years after the onset of clinical signs of puberty, and patient reaching a normal final height relative to parental target height. However, in some cases (about one third of subjects), predicted adult stature may decrease during the progression of puberty, in parallel with the emergence of evident biological signs of estrogenization and a highly progressive form of central PP. Thus, children for whom no treatment is justified at the initial assessment should undergo systematic clinical assessment, at least until the age of 9 years, to facilitate the identification of girls subsequently requiring treatment to block central precocious puberty.

Peripheral precocious puberty is completely independent of the hypothalamic–pituitary axis, with high serum estradiol levels in girls and high serum testosterone levels in boys, low basal and peak serum LH concentrations after GnRH stimulation , advanced bone age, and an estrogenized uterus on ultrasound scans for girls. The gonads or adrenal glands are responsible for excess steroid production, but they may also promote the activation of pubertal maturation of the gonadal axis, resulting in central precocious puberty [1].

The Normal Variants of Puberty

The distinction between early puberty and normal puberty is not clear-cut. There are several variants of normal puberty, which may pose problems for differential diagnosis, particularly as they have a high prevalence [3739].

Isolated Premature Breast Development or Premature Thelarche

Premature thelarche is isolated breast development before the age of 8 years. There are two peaks in the frequency of premature thelarche: the neonatal period, which is marked by gonadotropin activation, this peak potentially lasting for 2 or 3 years, and the prepubertal period [33]. Premature thelarche differs from early puberty in the absence of any other aspect of sexual development, usually with a lack of scalability of breast development and no acceleration of height velocity or significant advance in bone maturation (≥2 years). Uterine ultrasound scans provide a simple means of checking that there is no change in the uterus. No further exploration or treatment is required, and the outcome is the persistence of moderate breast development (in two thirds of cases) or regression (one third of cases). However, isolated premature breast development may precede the onset of central precocious puberty , which should not be ignored if patients develop other pubertal signs and an acceleration of height velocity.

Premature Development of Pubic Hair or Premature Pubarche

Premature pubarche is the appearance of pubic hair before the age of 8 years in girls and 9 years in boys. It may be accompanied by clinical signs of hyperandrogenism: acne, axillary hair, accelerated growth rate. It corresponds to adrenal maturation (adrenarche) and is not a differential diagnosis for central precocious puberty. Possible differential diagnoses to be systematically excluded include adrenal tumors and congenital adrenal hyperplasia [4041].

Slow Progressive Forms of Precocious Puberty

Such forms present clinically as early puberty with the development of secondary sexual characteristics and a moderate advance in bone age. On ultrasound scans, the uterus may show very early estrogen impregnation. However, the response to GnRH is of the prepubertal type. The mechanism underlying these cases of nonprogressive precocious puberty is unknown, but the gonadotropic axis is not activated. Studies monitoring these benign variants of precocious puberty have shown that treatment with GnRH agonists is not appropriate because there tends to be either a total regression of pubertal signs or a slow progression toward puberty [56]. Table 10.4 provides elements guiding differentiation between slowly progressive and progressive forms of central precocious puberty.

Psychosocial Aspects

Psychosocial aspects of early puberty are the major concern of patients and families seeking help for early puberty, whereas doctors generally focus on etiological aspects and height prognosis. Psychological assessment usually reveals a normal IQ. Patients tend to be rather solitary, with high scores for isolation, and a tendency to become depressed. They are mostly concerned about their appearance, whereas parents are generally worried about the onset of periods. Little is known about the long-term psychosocial consequences of early puberty or about the psychosocial integration of patients treated for precocious puberty [1342].

Management

Central Precocious Puberty

GnRH Agonists

GnRH agonists are generally indicated in progressive central precocious puberty, with the aim to restore genetic growth potential and to stabilize or regress pubertal symptoms. GnRH agonists continuously stimulate the pituitary gonadotrophs , leading to desensitization and decreases in LH release and, to a lesser extent, FSH release [43]. Several GnRH agonists are available in various depot forms and the approval for use of the various formulations varies with countries. Despite nearly 30 years of use of GnRH agonists in precocious puberty, there are still ongoing questions on their optimal use, and an international consensus statement has summarized the available information and the areas of uncertainty as of 2007 [17].

GnRH agonist treatments should be followed by experienced clinicians and result in the regression or stabilization of pubertal symptoms, decrease of growth velocity, and bone age advancement [17]. GnRHa-injection dates should be recorded and adherence with the dosing interval monitored. A suppressed LH response to the stimulation by GnRH, GnRH agonist, or after an injection of the depot preparation (which contains a fraction of free GnRH agonist) is indicative of biochemical efficacy of the treatment but is not recommended routinely. Progression of breast or testicular development usually indicates poor compliance, treatment failure, or incorrect diagnosis and requires further evaluation.

There are no randomized controlled trials assessing long-term outcomes of the treatment of central precocious puberty with GnRH agonists, and height outcome has been mostly evaluated. Among approximately 400 girls treated until a mean age of 11 years, the mean adult height was about 160 cm and mean gains over predicted height varied from 3 to 10 cm [12]. Individual height gains were very variable, but were calculated using predicted height, which is itself poorly reliable. Factors affecting height outcome include initial patient characteristics (lower height if bone age is markedly advanced and shorter predicted height at initiation of treatment) and, in some series, duration of treatment (higher height gains in patients starting treatment at a younger age and with longer durations of treatment). No height gain benefit has been shown in girls treated after the age of 9 years.

Other outcomes to consider include bone mineral density , risk of obesity and metabolic disorders, and psychosocial outcomes. Bone mineral density may decrease during GnRH agonist therapy. However, subsequent bone mass accrual is preserved, and peak bone mass does not seem to be negatively affected by treatment [17]. There has been concern that GnRH agonist use may affect BMI. However, childhood obesity is associated with earlier pubertal development in girls, and early sexual maturation is associated with increased prevalence of overweight and obesity. Altogether, the available data indicate that long-term GnRH agonist treatment does not seem to cause or aggravate obesity or have repercussions for body composition, bone mineral density, fertility, and metabolic or cancer comorbidities. General health status is not different as compared to women with normal puberty [4446]. The development of polycystic ovarian syndrome remains controversial [4750], and further studies are still required to assess the potential risk of premature ovarian dysfunction. Data concerning psychosocial outcomes are scarce, and there is little evidence to show whether treatment with GnRH agonists is associated with improved psychological outcome [1346]. Studies of this aspect are required.

Although tolerance to GnRH agonist treatment is generally considered good, it may be associated with headaches and menopausal symptoms such as hot flushes. Local complications (3–13 %) such as sterile abscesses may result in a loss of efficacy, and anaphylaxis has been described [51].

The optimal time to stop treatment has not been established, and factors that could influence the decision to stop GnRH agonists include aiming at maximizing height, synchronizing puberty with peers, ameliorating psychological distress, or facilitating care of the developmentally delayed child. However, data only permit analysis of factors that affect adult height. Several variables can be used to decide on when to stop treatment including chronological age, duration of therapy, bone age, height, target height, and growth velocity. However, these variables are closely interrelated and cannot be considered independently. In addition, retrospective analyses suggest that continuing treatment beyond the age of 11 years is associated with no further gains [52]. Therefore, it is reasonable to consider these parameters and informed parent and patient preferences, with the goal of menarche occurring near the population norms [17]. Pubertal manifestations generally reappear within months of GnRH agonist treatment being stopped, with a mean time to menarche of 16 months [53]. Long-term fertility has not been fully evaluated, but preliminary observations are reassuring [4653].

The addition of growth hormone [54] or oxandrolone [55] when growth velocity decreases or if height prognosis appears to be unsatisfactory has been proposed, but data are limited on the efficacy and safety of these drugs in children with precocious puberty.

Management of Causal Lesions

When precocious puberty is caused by a hypothalamic lesion (e.g., mass or malformation), management of the causal lesion generally has no effect on the course of pubertal development. Hypothalamic hamartomas should not be treated by surgery for the management of precocious puberty. Precocious puberty associated with the presence of a hypothalamic lesion may progress to gonadotropin deficiency.

Peripheral Precocious Puberty

Management of Causal Lesions

Surgery is indicated for gonadal tumors, and postoperative chemo- or radiotherapy should be discussed as part of a multidisciplinary team including surgeons and oncologists.

Large ovarian cysts (greater than 20 ml or 3.4 cm in diameter and typically more than 75 ml or 5.2 cm) should be managed very carefully given the risk of adnexal torsion [56]. In such cases, puncture possibly ultrasound guided should be considered and allows molecular analysis of the cystic fluid for activating GNAS mutation.

Removal of exogenous exposure to sex steroids is obvious but the search for occupational exposure is often very difficult and requires careful investigation.

Medications

There is no etiological treatment for peripheral causes of precocious puberty, and the rarity of the diseases renders evaluation of therapeutic strategies very difficult. In McCune–Albright syndrome and recurrent ovarian cysts, aromatase inhibitors [57] and SERMs [58] have been used to inhibit the production or action of estrogens, respectively [59]. These approaches are partly effective but no definitive strategy has emerged. In familial male precocious puberty due to LH receptor activating mutations, ketoconazole, an inhibitor of androgen biosynthesis, has been shown to be effective in the long term [60], and the combination of anti-androgens and aromatase inhibitors has been proposed. However, caution must be used with the use of ketoconazole given the risk of liver toxicity. Nonclassical forms of congenital adrenal hyperplasia should be managed with glucocorticoids.

Conclusion

A knowledge of the different clinical forms of precocious puberty is essential, to determine whether there is a tumor (intracranial, or in the gonads or adrenal glands) or other disease (neurofibromatosis, McCune–Albright syndrome, congenital adrenal hyperplasia) and the indications for treatment or an abstention from treatment. The psychological aspects of precocious puberty should also be evaluated during the treatment of these patients.

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