Precocious Puberty: Signs and Symptoms

Precocious puberty is the appearance of secondary sexual characteristics before the age thresholds: before age 8 in girls and before age 9 in boys. A distinction is made between central forms, in which the hypothalamic-pituitary-gonadal system is activated prematurely, and peripheral forms, in which the ovaries, testes, or adrenal glands become the source of sex steroids, independent of central regulation. These definitions are established in guidelines and are used worldwide. [1]

The central form is most common in girls and often has an unknown cause, while in boys, the proportion of identified organic causes is higher. It is important to understand that the true cause of clinical signs is determined not only by the age of onset, but also by the rate of progression of symptoms, growth rate, and laboratory data. [2]

Benign variants of early manifestations include isolated precocious mammary gland development and premature adrenarche. In these conditions, symptoms appear but do not progress typically, bone age is either normal or moderately increased, and hormonal profiles remain preclinical. Correctly distinguishing these variants from true precocious puberty helps avoid unnecessary testing and treatment. [3]

Key indicators for initial recognition include a consistent increase in symptoms over 4-6 months, accelerated growth, increased testicular volume in boys, and changes in the uterus and ovaries as determined by ultrasound in girls. If symptoms progress or are accompanied by rapid growth, further evaluation by a pediatric endocrinologist is required. [4]

It's worth noting that the lower limits of normal for the onset of puberty have shifted earlier in recent decades, but diagnostic thresholds for suspected precocious puberty remain the same, as it is before these ages that the risk of organic causes and adverse consequences is greatest. The decision to conduct further testing is always based on a combination of characteristics, not a single parameter. [5]

Table 1. Definitions and base thresholds

Term	What does it mean?	Age limits	Key marker of progression
Precocious puberty	Early appearance of secondary signs	Girls: up to 8 years old; Boys: up to 9 years old	Increased symptoms within 4-6 months, accelerated growth
Central form	Early activation of central regulation	The same thresholds	Increase in luteinizing hormone in response to stimulation
Peripheral form	Autonomous secretion of sex steroids	The same thresholds	High estradiol or testosterone with suppressed gonadotropins
Benign variants	Isolated thelarche, adrenarche	Often 6-8 years	No progression, moderate changes in bone age

Why it occurs: causes and risk factors

The central form is caused by premature activation of the hypothalamic-pituitary-gonadal axis. This can occur without apparent cause, but is sometimes associated with central nervous system anomalies, including hypothalamic hamartomas. Genetic factors also play a role: variants in the KISS1, KISS1R, MKRN3, and DLK1 genes have been described that influence the onset of puberty. [6]

The peripheral form is caused by a hormonal source outside of central regulation: functioning ovarian cysts, ovarian or testicular tumors, congenital adrenal hyperplasia, McCune-Albright syndrome, or tumor-induced human chorionic gonadotropin production. In these conditions, sex steroids are elevated and gonadotropins are suppressed, allowing them to be differentiated in the laboratory. [7]

Risk factors for the central form include excess body weight, low birth weight, and a family history of precocious puberty. Evidence has accumulated that obese children may have an earlier bone age than their birth weight, complicating assessment, while those born with low birth weight may experience a more rapid transition through puberty. These effects require closer monitoring of the rate of change. [8]

During the coronavirus pandemic, a number of countries have recorded an increase in the number of visits and diagnoses of the central form of the disease in girls. Systematic reviews and meta-analyses note an increase in incidence, but the causal relationship remains controversial: the role of decreased physical activity, increased screen time, changes in sleep patterns, and psychosocial stress are being discussed. This area is being actively studied. [9]

It's important to remember that the proportion of secondary, organic causes is higher in boys than in girls, especially when onset occurs at an early age. Therefore, the thresholds of suspicion are lower and the indications for magnetic resonance imaging are broader. Current data also indicate an increasing proportion of idiopathic cases in boys, which requires a sensitive, differentiated approach. [10]

Table 2. Causes of precocious puberty

Category	Examples	Laboratory signs	Comments
Central form	Idiopathic, hypothalamic hamartomas, other central nervous system lesions	Luteinizing hormone response to stimulation, advanced bone age	Girls are more likely to have idiopathic
Peripheral form	Ovarian cysts, ovarian and testicular tumors, congenital adrenal hyperplasia, McCune-Albright syndrome, tumors with human chorionic gonadotropin production	High sex steroids with suppressed gonadotropins	Requires etiotropic treatment
Risk factors	Overweight, low birth weight, family history	Often accelerated bone age	Increases risk, but does not equal diagnosis
Epidemiological shifts	Pandemic period	Increase in the number of visits and diagnoses	The reasons are multifactorial and are being studied.

How to recognize and distinguish from benign variants

Signs that should raise concern include: steady progression of mammary glands in girls over 4-6 months, the onset of menstruation before age 10, rapid increase in testicular volume in boys, and accelerated growth with a noticeable advancement of growth curves. The presence of several signs simultaneously increases the likelihood of the central form and requires referral to a specialist. [11]

Isolated precocious breast development is more common in early childhood and may not progress. When observed over time, growth acceleration is often absent, and laboratory parameters remain preclinical. In this situation, monitoring and regular assessment of the rate of change are key, rather than immediate therapy. [12]

Premature adrenarche is characterized by the appearance of pubic or underarm hair, changes in sweat odor, and sometimes mild acne. In this condition, the adrenal glands are the source of hormones, and dehydroepiandrosterone sulfate levels increase, but signs of true puberty are absent. This condition is usually benign, although it is associated with increased metabolic risks and requires monitoring. [13]

In girls, pelvic ultrasound helps differentiate between benign variants and the central form: increased uterine length and ovarian volume indicate the influence of estrogens and gonadotropins. A meta-analysis showed that a uterine length of 3.2 centimeters or more has diagnostic value as an auxiliary criterion in favor of the central form. [14]

A combination of indicators is always assessed: the rate of change, growth indicators, bone age, and hormonal responses. If the disease progresses slowly and there are no laboratory criteria for activation, observation for 3-6 months with re-evaluation is permitted to avoid exposing the child to unnecessary interventions. [15]

Table 3. Differences between true precocious puberty and benign variants

Sign	Central form	Isolated thelarche	Premature adrenarche
Progression in 4-6 months	Expressed	Minimal or none	Possible within the limits of androgen-dependent signs
Growth rate	Accelerated	Normal	Usually normal
Bone age	It is significantly ahead	Normal or moderate advancement	Normal or moderate advancement
Ultrasound in girls	Enlargement of the uterus and ovaries	Premenarchal dimensions	Premenarchal uterus
Hormones	Luteinizing hormone response to stimulation	Preclinical levels	Dehydroepiandrosterone sulfate is elevated

Diagnostics

The first step is to carefully collect a medical history and assess the rate of change: when the first signs appeared, how quickly they worsen, and whether there are headaches, visual disturbances, seizures, or other neurological symptoms. At the same time, anthropometric measurements and growth rate are recorded and plotted on standard percentile curves. These simple steps already make it possible to distinguish benign variants from progressive forms. [16]

Next, bone age is assessed using a hand X-ray. A bone age that is higher than the passport age supports the diagnosis, while a marked increase is more characteristic of true forms. However, bone age alone does not confirm the diagnosis and should be considered as part of the overall picture. [17]

Basic laboratory tests include morning levels of luteinizing and follicle-stimulating hormones, as well as sex steroids—estradiol in girls and testosterone in boys. In the central form, morning luteinizing hormone may be measurably elevated even without stimulation, but the standard method remains a gonadotropin-releasing hormone stimulation test or its analogs, which confirms central activation. Cutoff values depend on the assay method, so interpretation is performed by a specialist. [18]

To rule out peripheral causes, additional tests are prescribed: dehydroepiandrosterone sulfate and 17-hydroxyprogesterone if an adrenal origin is suspected, thyroid-stimulating hormone if Van Wyck-Grambach syndrome is suspected, and human chorionic gonadotropin in boys if tumor production of this hormone is suspected. A comprehensive set of tests is selected based on the clinical picture. [19]

In girls, pelvic ultrasound is an important adjunctive tool: increases in uterine length and ovarian volume reflect hormonal activity. Systematic reviews confirm the diagnostic value of these parameters. In boys, testicular ultrasound is performed when indicated. [20]

Magnetic resonance imaging of the brain is indicated according to strict criteria: for all boys with the central form, girls under 6 years of age, and girls aged 6-8 years with neurological symptoms. This is due to the higher proportion of organic causes in these groups and the need for their timely detection. [21]

Table 4. Diagnostic steps and key findings

Step	What to do	What supports the diagnosis	Comment
Anamnesis and examination	Record the pace and sequence of signs, growth	Growth acceleration, progression in 4-6 months	Guides the selection of tests
Bone age	X-ray of the hand	Advancement of bone age	It is not the only criterion
Basic hormones	Luteinizing and follicle-stimulating hormones, estradiol or testosterone	Measurably elevated morning luteinizing hormone	Interpreted taking into account the method
Stimulation test	Gonadotropin-releasing hormone or analogs	Confirmation of central activation	Standard for the central form
Additional tests	Dehydroepiandrosterone sulfate, 17-hydroxyprogesterone, thyroid-stimulating hormone, human chorionic gonadotropin	Confirmation of peripheral nature	According to the readings
Visualization	Ultrasound, magnetic resonance imaging	In girls, changes in the uterus and ovaries; indications for magnetic resonance imaging, see below	Strict appointment criteria

When is magnetic resonance imaging and other imaging needed?

Magnetic resonance imaging of the brain is recommended for all boys with the central form, as the incidence of abnormalities is higher than in girls, especially with early onset. Detectable changes include hypothalamic hamartomas and other central nervous system abnormalities. [22]

In girls, magnetic resonance imaging is mandatory at onset before age 6 and in the presence of neurological symptoms, regardless of age. In the asymptomatic 6-8 year-old group, the decision is made individually, based on the rate of progression and laboratory data. This balanced approach is based on meta-analyses showing a higher frequency of significant findings in the youngest children. [23]

According to large studies, significant findings are more common in girls under 6 years of age than in those aged 6-8 years, where the incidence of detected tumors is low. Therefore, the universal use of magnetic resonance imaging in asymptomatic children over 6 years of age does not improve diagnostic yield but increases the burden and anxiety of families. [24]

Pelvic ultrasound in girls is the method of choice for assessing the effects of estrogens on the uterus and ovaries and for monitoring progression. In boys, if asymmetry or nodules are present, testicular ultrasound is indicated. If adrenal causes are suspected in both groups, adrenal assessment using imaging techniques may be considered as indicated. [25]

It's important to remember that the need for imaging is always linked to clinical presentation, laboratory data, and the rate of change. The decision is made by a specialist after discussing the goals and potential benefits of the results with the family. [26]

Table 5. Indications for visualization

Method	Who is it indicated for?	What are we looking for?	Note
Magnetic resonance imaging of the brain	All boys with the central form; girls under 6 years old; girls 6-8 years old with neurological symptoms	Hamartomas, other anomalies	Individualization for girls 6-8 years old without symptoms
Ultrasound of the pelvic organs	Girls with suspected central form	Enlargement of the uterus and ovarian volume	Auxiliary criterion
Ultrasound of the testicles	Boys with asymmetry, nodes	Volume, foci	According to the readings
Adrenal gland imaging	If adrenal damage is suspected	Volumetric formations	According to the readings

Treatment for the central form: when it is needed and what to expect

The goals of treatment for the central form are to halt premature axis activation, slow the progression of symptoms, preserve terminal growth potential, and reduce psychosocial burden. The decision to initiate therapy is made after a short observation period of 3-6 months if the rate of progression is unclear, except in very early-onset and rapidly progressing cases. [27]

Indications for therapy include rapid progression of symptoms, significantly advanced bone age, loss of predicted adult height, early menstruation in girls, and severe psychological distress. The greatest increase in final height is seen in children who begin treatment at an earlier age and during active progression. [28]

The standard of treatment is drugs from the gonadotropin-releasing hormone agonist group. They cause persistent desensitization of the pituitary gland and suppression of luteinizing and follicle-stimulating hormone secretion, leading to a reduction in sex steroid production and halting the progression of symptoms. The efficacy and safety of this approach have been confirmed by long-term data. [29]

Preferred regimens depend on availability, the child's age, and family preferences. Monthly, three-monthly, and six-monthly injectable forms are available, as well as yearly subcutaneous implants. Reviews suggest that comparable regimens provide similar control when consistent hormone suppression is achieved. [30]

During treatment, regular monitoring is performed, including clinical examination, growth and weight monitoring, periodic hormonal assessments, and, in girls, pelvic ultrasound as indicated. After discontinuing therapy, signs of puberty gradually return, and fertility is observed to be preserved. [31]

Table 6. When to treat the central form

Criterion	Interpretation	Influence on the decision
Rate of progression	Fast within 3-6 months	Indication for initiation of therapy
Bone age	Significant lead	Enhances the readings
Final growth forecast	Reduced relative to parent	Enhances the readings
Psychosocial factors	Severe discomfort, early menstruation	Possible indication
Age of onset	Very early debut	Often treatment is based on fact

Drugs, regimens, efficacy and safety

Leuprolide is available as long-acting depot formulations for intramuscular administration at intervals of 1 month, 3 months, and 6 months. Pediatric formulations provide suppression for the entire stated interval if the administration technique and schedule are followed. Small-volume, six-month subcutaneous formulations of leuprolide are available, which demonstrate effective sex hormone suppression in children. [32]

Triptorelin is approved for children with the central form at a dose of 22.5 milligrams once every 24 weeks. Research and regulatory documents confirm suppression of gonadotropin secretion and clinical control of symptoms. Three-monthly formulations are also available in some countries. [33]

Histrelin is available as a subcutaneous implant with a one-year duration of action, inserted under local anesthesia. Long-term studies show sustained suppression of luteinizing hormone and improved predicted adult height. There is evidence that a single implant can maintain effectiveness for up to 24 months, reducing the number of procedures. [34]

Comparative data show that with equivalent hormone suppression, clinical outcomes for growth and symptom control are comparable between the different regimens. The treatment team, working with the family, makes the choice based on ease of administration, tolerability, drug availability, and the center's experience. Typical adverse events include localized soreness and, less commonly, sterile abscess formation. [35]

Alternative approaches, such as gonadotropin-releasing hormone antagonists or aromatase inhibitors, are not recommended due to lack of evidence of efficacy in the central form in children. Their use outside of clinical trials is not supported by clinical guidelines. [36]

Table 7. Drugs and regimens for the central form

Preparation	Form	Interval of administration	Key data
Leuprolide	Depot for intramuscular and subcutaneous administration	1 month, 3 months, 6 months	Proven effectiveness of long-term forms
Triptorelin	Depot for intramuscular administration	6 months	Suppression of gonadotropins in most cases
Histrelin	Subdermal implant	12 months, possibly up to 24 months	Long-lasting suppression and comfort for long-term use

Peripheral forms, special causes and prognosis

Peripheral precocious puberty requires a search for a source of autonomous hormone secretion. Typical causes include functioning ovarian cysts in girls, hormonally active ovarian and testicular tumors, congenital adrenal hyperplasia, McCune-Albright syndrome, and tumors that produce human chorionic gonadotropin. Laboratory findings include elevated sex steroids and low gonadotropins. [37]

Van Wyck-Grambach syndrome occupies a special place – a rare combination of severe hypothyroidism with incomplete precocious puberty and delayed bone age. In such cases, the key to diagnosis is the determination of thyroid-stimulating hormone and characteristic clinical features, and treatment with thyroxine leads to regression of sexual characteristics. This is important to remember to avoid unnecessary puberty blockade. [38]

Treatment for peripheral forms is etiotropic: eliminating the source of hormones, treating congenital adrenal hyperplasia, monitoring or intervention for ovarian cysts, and oncological treatment for tumors that produce human chorionic gonadotropin. Once the cause is eliminated, the symptoms regress, and the prognosis is determined by the underlying disease. [39]

The psychosocial consequences of early puberty can include increased anxiety, adaptation difficulties, and the risk of stigmatization. Family support, open discussion of the ongoing changes with the child in accessible language, and, if necessary, the involvement of a psychologist are recommended. These measures are important regardless of the chosen medical approach. [40]

In the long term, with correct diagnosis and timely treatment of central forms, growth prognosis improves and reproductive function is preserved. For peripheral forms, the outcome depends on the cause and the success of its treatment, emphasizing the value of early and accurate etiological diagnosis. [41]

Table 8. Peripheral forms: how to recognize and what to do

Cause	What to suspect	What tests?	The initial step
Functioning ovarian cyst	Isolated bloody discharge, enlarged ovary	Estradiol, ultrasound	Observation or intervention as indicated
Congenital adrenal hyperplasia	Androgen-dependent characteristics	17-hydroxyprogesterone	Glucocorticoid replacement therapy
McCune-Albright syndrome	Cafe-au-lait spots, bone changes	Sex steroids, visualization	Symptomatic and targeted therapy
Tumors with production of human chorionic gonadotropin	Gynecomastia, rapid progression in boys	Human chorionic gonadotropin, visualization	Oncology route
Van Weyk-Grambach syndrome	Incomplete form, delayed bone age	Thyroid-stimulating hormone, thyroxine	Thyroxine replacement therapy

What parents should do: practical steps

1. Record the onset of symptoms and their dynamics, as well as the child's height and weight. If symptoms progress over 4-6 months or if neurological symptoms appear, consult a pediatric endocrinologist. [42]
2. Do not rush into treatment if symptoms are questionable or slowly progressing: a short observation period of 3-6 months often helps to distinguish benign variants from true forms. [43]
3. If the central form is diagnosed and therapy is recommended, discuss the regimen, drug form, and monitoring schedule with a specialist. All regimens, when used correctly, provide comparable control. [44]
4. Maintain a healthy lifestyle: Regular physical activity, adequate sleep, and limiting excessive screen time are beneficial for overall well-being and may reduce the impact of environmental factors on the rate of maturation. [45]

Table 9. Short action plan for the family

Situation	What to do now	What to be prepared for
Early signs have appeared	Keep a diary of signs and growth	If progression occurs, make an appointment with a specialist.
The symptoms do not progress.	Observation 3-6 months	Re-evaluation of tempo
Central form confirmed	Discuss the treatment and monitoring regimen	Regular visits, growth monitoring
Peripheral cause confirmed	Etiotropic treatment	The prognosis depends on the underlying disease.