Precocious puberty

Precocious puberty (PP) is a developmental disorder in girls that manifests itself in one or all of the signs of sexual maturity at an age that is 2.5 or more standard deviations (2.5 SD or σ) below the average age of their onset in the population of healthy children. Currently, in most countries of the world, puberty is considered premature if any of its signs are present in white girls under 7 years of age and in black girls under 6 years of age.

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Epidemiology

Precocious puberty occurs in 0.5% of girls in the population. Among all gynecological pathologies of childhood, precocious puberty accounts for 2.5–3.0%. In 90% of girls, the complete form of precocious puberty is caused by pathology of the central nervous system (CNS), including against the background of space-occupying lesions of the brain (45%). McCune–Albright–Braitsev syndrome is detected in 5%, estrogen-producing ovarian tumors - in 2.6% of girls with precocious puberty. Precocious thelarche occurs in 1% of girls under 3 years of age and it is 2–3 times higher than the frequency of true forms of precocious puberty. The frequency of congenital adrenal cortex hyperplasia with 21-hydroxylase deficiency is 0.3% in the population of children under 8 years of age.

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Causes precocious puberty

GT-dependent precocious puberty may be caused by a family predisposition (idiopathic variant), tumors or other pathological processes in the hypothalamic-pituitary region (cerebral variant). A rare cause of GT-dependent precocious puberty is the hereditary Russell-Silver syndrome, accompanied by moderately excessive production of gonadotropins from early childhood.

Premature pubarche may be caused by excessive secretion of adrenal androgens in non-classical congenital adrenal cortex dysfunction, androgen-producing tumors of the ovaries (arrenoblastoma, lipid cell tumor, gonadoblastoma, dysgerminoma, teratoma, choriocarcinoma) or adrenal glands (adenoma, androblastoma). Androgen-producing tumors of the adrenal glands and ovaries rarely affect girls.

Premature thelarche and menarche (extremely rare) may occur against the background of persistent follicular cysts, granulosa cell tumors of the ovaries, congenital and/or untreated hypothyroidism (Van Wyck–Grombach syndrome), tumors producing estrogens, human chorionic gonadotropin and gonadotropins, as well as with exogenous administration of estrogens and estrogen-like compounds in the form of drugs or with food products. GT-independent isosexual precocious puberty occurs in McCune–Albright–Braitzev syndrome, when premature thelarche and menarche develop as a result of a congenital mutation of the receptor protein gene (GSα protein), which causes uncontrolled activation of estrogen synthesis.

In girls with partial precocious puberty, spontaneous regression of secondary sexual characteristics is possible, and the child's further development occurs in accordance with age norms. On the other hand, the background condition that caused the appearance of a secondary sexual characteristic can, according to the principle of feedback, activate hypothalamic structures and lead to complete precocious puberty.

Forms

There is no officially accepted classification of precocious puberty. Currently, a distinction is made between gonadotropin-dependent (central or true) and gonadotropin-independent (peripheral or false) precocious puberty. According to ICD-10, gonadotropin-dependent (GT-dependent) precocious puberty is designated as precocious puberty of central origin. GT-dependent precocious puberty is always complete, as it manifests itself with all the signs of puberty and accelerated closure of growth zones in girls under 8 years of age while maintaining the physiological rate of maturation of other organs and systems.

Patients with GT-independent precocious puberty have isosexual or heterosexual manifestations depending on the cause of the disease. Partial GT-independent precocious puberty is characterized by the premature development of one of the signs of puberty - mammary glands (premature thelarche), pubic hair (premature pubarche), menstruation (premature menarche), less often - 2 signs (thelarche and menarche).

Premature thelarche is a unilateral or bilateral enlargement of the mammary glands to Ma2 according to Tanner, more often the left mammary gland. In this case, as a rule, there is no pigmentation of the areola of the nipples, genital hair growth and signs of estrogenization of the external and internal genitalia do not appear.

Premature pubic hair growth in girls aged 6–8 years, not associated with the development of other signs of puberty. If premature pubic hair growth occurs in girls with virilization of the external genitalia, it is classified as heterosexual gonadotropin-releasing hormone-independent precocious puberty (GnRH-independent).

Premature menarche is the presence of cyclic uterine bleeding in girls under 10 years of age in the absence of other secondary sexual characteristics.

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Diagnostics precocious puberty

The main goal of diagnosing precocious puberty is:

• determination of the form of the disease (complete, partial);
• identification of the nature of activation of precocious puberty (GT-dependent and GT-independent);
• determination of the source of excess secretion of gonadotropic and steroid hormones.

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History and physical examination

Mandatory methods for all girls with any signs of precocious puberty:

• collection of anamnesis;
• physical examination and comparison of the degree of physical and sexual maturation according to Tanner with age standards;
• blood pressure measurement in girls with heterosexual precocious puberty;
• clarification of the patient's psychological characteristics.

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Laboratory methods

Determination of the levels of FSH, LH, prolactin, TSH, estradiol, testosterone, 17-hydroxyprogesterone (17-OP), dehydroepiandrosterone sulfate (DHEAS), cortisol, free T4 and free T3. A single determination of the level of LH and FSH is of little information in the diagnosis of precocious puberty.

Conducting tests that stimulate and suppress the production of steroid hormones

A test with a synthetic GnRH analogue is carried out in the morning hours after a full night's sleep. Since gonadotropin secretion is pulsed, the initial values of LH and FSH should be determined twice - 15 minutes before and immediately before the administration of gonadotropin-releasing hormone. The basal concentration is calculated as the arithmetic mean of 2 measurements. A drug containing a GnRH analogue for daily use (triptorelin) is administered quickly once intravenously at a dose of 25-50 mcg/m2 ⁽ usually 100 mcg) with subsequent venous blood sampling at baseline, 15, 30, 45, 60 and 90 minutes. The initial level is compared with any 3 highest stimulated values. The maximum increase in LH levels is usually determined 30 minutes after drug administration, and FSH - 60-90 minutes. An increase in LH and FSH levels by more than 10 times from the initial level or to values characteristic of the pubertal period, i.e. exceeding 5–10 IU/l, indicates the development of complete GT-dependent precocious puberty. An increase in FSH levels while maintaining minimal LH concentrations in response to a test with triptorelin in patients with premature thelarche indicates a low probability of developing GT-dependent precocious puberty. In children with other partial forms of precocious puberty, the level of LH and FSH after the test is equal to that in children under 8 years of age.

A minor glucocorticoid test should be performed in girls with premature pubarche if elevated levels of 17-OP and/or DHEAS and testosterone are detected in the venous blood. Drugs containing glucocorticoid hormones (dexamethasone, prednisolone) should be taken orally for 2 days. The daily dose of dexamethasone should be 40 mcg/kg, and prednisolone in girls under 5 years old - 10 mg/kg, 5-8 years - 15 mg/kg. When performing the test, venous blood should be collected in the morning before taking the drug and in the morning of the 3rd day (after the 2nd day of taking it). Normally, in response to taking the drug, the level of 17-OP, DHEAS and testosterone decreases by 50% or more. The absence of dynamics of hormone concentrations suggests the presence of an androgen-producing tumor.

A test with short- or prolonged-action synthetic ACTH (tetracosactide) is performed when elevated plasma levels of 17-OP, DHEAS and low or normal cortisol levels are detected in order to exclude the non-classical form of CAH. The test should be performed in a hospital setting, since a sharp increase in blood pressure and the development of allergic reactions are possible after administration of the drug. Tetracosactide [α-(1-24)-corticotropin] is administered at a dose of 0.25–1 mg subcutaneously or intravenously immediately after venous blood sampling at 8–9 a.m. When administering a short-acting drug, the sample is assessed after 30 and 60 minutes. After administration of prolonged-action tetracosactide, venous blood sampling is repeated at least 9 hours later. When assessing the test results, the initial and stimulated levels of 17-OP and cortisol should be compared. In patients with premature pubarche, non-classical CAH may be suspected if the baseline 17-OP level increases by 20–30% or by more than 6 SD from the baseline level. The level of stimulated 17-OP exceeding 51 nmol/L is the most significant marker of non-classical CAH. When performing a test with prolonged-release tetracosactide, one can focus on the discrimination index:

D = [0.052×(17-OP2)] + [0.005×(K1)/(17-OP1)] - [0.018×(K2)/(17-OP2),

Where D is the discrimination index; K1 and 17-OP1 are the initial level of cortisol and 17-OP-progesterone; K2 and 17-OP2 are the hormone levels 9 hours after the administration of tetracosactide. The diagnosis of non-classical 21-hydroxylase deficiency is considered confirmed with a discrimination index exceeding 0.069.

Instrumental methods

• An ultrasound examination of the internal genital organs with an assessment of the degree of maturity of the uterus and ovaries, mammary glands, thyroid gland and adrenal glands.
• X-ray of the left hand and wrist joint with determination of the degree of differentiation of the skeleton (biological age) of the child. Comparison of biological and chronological age.
• Electroencephalographic and echoencephalographic examination to identify non-specific changes (the appearance of pathological rhythm, irritation of subcortical structures, increased seizure readiness) that most often accompany premature puberty against the background of organic and functional disorders of the central nervous system.
• T2-weighted MRI of the brain is indicated for all girls with breast development before age 8, pubic hair growth before age 6, and serum estradiol levels above 110 pmol/L to rule out hamartoma and other space-occupying lesions of the third ventricle and pituitary gland. Retroperitoneal and adrenal MRI is indicated for girls with premature pubarche.
• Biochemical study of the content of sodium, potassium, and chlorine in venous blood in patients with signs of heterosexual precocious puberty.

Additional methods

• Cytogenetic study (determination of karyotype).
• Molecular genetic testing to identify specific defects in the steroidogenesis enzyme activator gene (21-hydroxylase), HLA system in girls with heterosexual precocious puberty.
• Ophthalmologic examination, including examination of the fundus, determination of visual acuity and visual fields in the presence of signs characteristic of McCune-Albright-Braitsev syndrome.

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Differential diagnosis

GT-dependent precocious puberty

• Idiopathic (sporadic or familial) variant of the disease. The family history of these children indicates early or premature sexual development in relatives. Puberty begins at a time close to physiological, there is an early growth spurt and development of the mammary glands. Pubertal values of LH, FSH, estradiol or pubertal response to stimulation of gonadotropin-releasing hormone in the absence of organic and functional pathology of the central nervous system.
• The non-neoplastic variant of the disease is found in patients with a history of post-traumatic (including birth trauma), post-inflammatory or congenital changes in the central nervous system; infection suffered in the prenatal period of life (cytomegalo- and herpes-virus infection, toxoplasmosis, syphilis, tuberculosis, sarcoidosis), in infancy and early childhood (meningitis, arachnoiditis, encephalitis, abscesses or granulomatous post-inflammatory processes). The psychoneurological status shows signs of organic psychosyndrome: increased excitability, emotional disinhibition. Neurological examination reveals symptoms of non-specific CNS damage.
• The tumor variant of the disease is formed as a result of the growth of a hypothalamic hamartoma, glioma, ependymoma, arachnoid or parasitic cyst of the floor of the third ventricle, adenoma and cyst of the pituitary gland, pinealoma, and very rarely - against the background of the development of craniopharyngioma. A distinctive feature of most tumors is benign and slow growth into the ventricular cavity with limited contact with the wall of the third ventricle in the form of a narrow stalk. Symptoms that occur during the development of tumors are uniform and are due to the site of attachment, size, and degree of cerebrospinal fluid outflow disorder. Small tumors, in addition to premature puberty, can clinically manifest themselves only in attacks of headaches with large clear intervals. In children, at the height of a headache attack, general weakness, a fanciful posture due to decerebrate rigidity, and forced laughter (if the tumor is located close to the area that regulates motor laughter) are sometimes observed. Even less frequently, epileptiform seizures with vasomotor disorders and sensory irritation (chill-like tremors in the form of short-term paroxysms, profuse sweating, an increase in body temperature from subfebrile to 38–39 °C; less frequently, loss of consciousness and tonic convulsions) are observed. Mental disorders are stiffness and apathy, but attacks of motor restlessness may develop.

A direct consequence of hydrocephalic-hypertensive syndrome are various symptoms of vision loss due to nipple swelling, damage to the optic chiasm, or pathological irritation of the cranial, primarily oculomotor nerves (anisocoria, paresis of upward gaze, etc.). Multiple gliomas, including those originating from the hypothalamic nuclei, can cause premature puberty in patients with neurofibromatosis (Recklinghausen's disease). This disease, inherited in an autosomal dominant manner, is characterized by multiple focal proliferation of neuroglia clusters and fibrous tissue elements (manifested on the skin as smooth coffee-colored spots or subcutaneous plaques). If one of the numerous neurogliomas is located in the clitoris, a false impression of masculinization of the external genitalia, i.e. heterosexual premature puberty, may be created. Characteristic features include mottling of the armpits and multiple visceral lesions. Bone defects (cysts, curvatures) are detected as early as the first year of life. Dumbbell-shaped thickenings of the spinal nerve roots can cause intense pain that restricts the child's movements. Convulsions, visual impairment, and mental retardation are possible. Premature puberty in children with neurofibromatosis develops as true complete premature puberty in the first years of life.

In organic cerebral pathology, the symptoms of precocious puberty usually appear later or simultaneously with the development of neurological symptoms. Often, the onset of breast growth and menarche coincide. GT-dependent precocious puberty is accompanied by the appearance of all fully formed secondary sexual characteristics (Ma4-5/P4-5 according to Tanner) and always ends with premature menarche. The chronological age of the clinical debut of the disease ranges from 8 months to 6.5 years. Among all girls with GT-dependent precocious puberty, only 1/3 maintain the sequence and rate of puberty. In the first years of the disease, the clinical picture is dominated by estrogen-dependent symptoms of puberty in the absence of androgen-dependent signs (isosexual form). Moderately mature mammary glands (Ma2 according to Tanner) usually appear in girls aged 1–3 years simultaneously on both sides. Early onset and rapid progression of secondary sexual characteristics are characteristic of hypothalamic hamartoma. In some girls, the disease, having begun with the appearance of mammary glands (premature thelarche), may not manifest itself for a long time with other signs of puberty. The incomplete form of GT-dependent premature puberty often persists until adrenarche (6-8 years), after which pubarche and menarche quickly (in 1-2 years) occur. Hormonal examination reveals an increase in estrogen levels against the background of increased initial and triptorelin-stimulated levels of gonadotropic hormones (LH, FSH). In GT-dependent premature puberty, the size of the uterus and ovaries (volume over 3 mm, multifollicular changes in structure - the appearance of more than 6 follicles with a diameter of more than 4 mm) corresponds to those in girls of pubertal age. In menstruating girls with precocious puberty, the volume of both ovaries and the size of the uterus correspond to sexually mature indicators. In all patients with GT-dependent precocious puberty, accelerated development of the skeletal system leads to an advance of the calendar age by bone age by 2 or more years and rapid subsequent closure of growth zones. At the beginning of puberty, these girls are significantly ahead of their peers in physical development, but already in adolescence they have a dysplastic physique due to short limbs and a wide bony pelvis, a long spine and a narrow shoulder girdle. An exception are girls with GT-dependent precocious puberty in Russell-Silver syndrome. This hereditary disease is characterized by intrauterine growth retardation, impaired formation of the bones of the skull (triangular face) and skeleton (pronounced asymmetry of the trunk and limbs with short stature) in early childhood. The disease occurs with moderately excessive production of gonadotropins.Full-term newborns with this pathology have insufficient length and body weight (usually less than 2000 g) and lag behind their peers in growth at all stages of life. However, the bone and calendar age of these children coincide. The full form of premature puberty develops in girls with Russell-Silver syndrome by the age of 5-6 years.

In girls with the full form of GT-dependent precocious puberty, mental, emotional and intellectual development, despite external adulthood, corresponds to the calendar age.

Complete forms can occur in girls with GT-independent precocious puberty, as well as after radiation and chemotherapy or after surgical treatment of intracranial brain tumors.

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GT-independent precocious puberty (isosexual)

Premature thelarche. Selective enlargement of the mammary glands is most often observed in girls under 3 and over 6 years of age. As a rule, there is no pigmentation of the areola of the nipples, genital hair growth, and signs of estrogenization of the external and internal genitalia. In the anamnesis of girls with premature thelarche, as a rule, there is no data on gross pathology in the antenatal and postnatal periods. Physical development corresponds to age. The advancement of maturation of the skeletal system does not exceed 1.5–2 years and does not progress further. In some cases, girls with premature thelarche have episodic bursts of FSH and estradiol secretion against the background of prepubertal LH levels. In girls with isolated premature thelarche, follicles are found in the ovaries in 60–70% of cases, sometimes reaching 0.5–1.5 cm in diameter. In the hormonal status of children, deviations from the normative for their age indicators of LH and FSH are most often absent. In the GnRH test, an increased level of FSH response is detected in girls with premature thelarche compared to healthy peers. The LH response is prepubertal in nature. Premature thelarche is not accompanied by accelerated physical development. Usually, the mammary glands independently decrease to normal sizes within a year, but in some cases they remain enlarged until puberty. Instability of gonadotropic regulation can lead to progression of sexual development in 10% of patients.

Premature menarche is the occurrence of cyclic menstrual-like bleeding in girls under 10 years of age in the absence of other secondary sexual characteristics. The causes of this condition are not specified. Studying the anamnesis (use of hormonal drugs, intake of large amounts of phytoestrogens with food) helps in making a diagnosis. The height and bone age of girls correspond to the calendar age. During examination, a transient increase in estrogen levels is often detected during periods of acyclic bloody discharge from the genital tract.

Premature pubarche is more common in girls aged 6–8 years. Premature isolated pubarche in girls may be caused by excessive conversion of testosterone (even at normal values) into the active metabolite dihydrotestosterone in the peripheral blood. Dihydrotestosterone disrupts the natural rhythm of development of the sebaceous-hair follicle, keeping it in the growth stage. Sexual and physical development of girls with increased 5α-reductase activity does not differ from age norms. Moderate enlargement of the clitoris is possible, therefore for a long time this form of premature pubarche was designated as idiopathic or constitutional. Premature pubic hair growth may be caused by increased peripheral formation of testosterone against the background of premature increase in the secretion of adrenal androgens. A marker of premature pubarche is an increase in the level of DHEAS to the pubertal level. Premature pubarche is classified as a non-progressive condition that does not affect the rate of normal puberty. Bone age and height almost always correspond to the calendar age, and if they are ahead of it, then by no more than 2 years. Girls have no signs of estrogenic influence: glandular tissue of the mammary glands, the size of the internal genitalia correspond to age. Hormonal parameters (gonadotropins, estradiol) correspond to those in prepubertal children, often the level of DHEAS in the blood serum is increased to pubertal values. When examining children with premature pubarche, so-called non-classical (late, postnatal, erased or pubertal) forms of CAH are detected. Premature pubarche often serves as the first marker of a number of metabolic disorders that lead to the development of metabolic syndrome in sexually mature women.

Van Wyck–Grombach syndrome develops in children with decompensated primary hypothyroidism. Severe primary deficiency of both thyroid hormones (thyroxine and triiodothyronine) causes growth retardation, disproportionate body build, and delayed development of the facial skeleton (wide sunken bridge of the nose, underdevelopment of the lower jaw, large forehead, enlarged posterior fontanelle). The patient's history includes late appearance and delayed change of teeth. Early symptoms of the disease are nonspecific, the child eats poorly, rarely cries, jaundice persists longer in the neonatal period, muscle hypotonia, macroglossia, umbilical hernia, constipation, and drowsiness are noted. Later in the clinical course of the disease, untreated patients develop sluggish tendon reflexes and decreased muscle strength, dry skin, bradycardia, hypotension, a low, rough voice, delayed psychomotor development and pronounced intellectual disabilities up to cretinism, obesity, and myxedema. Bone age is 2 or more years ahead of the calendar age, and premature secondary sexual characteristics are noted. Hormonal examination reveals increased prolactin secretion, and polycystic changes or the appearance of individual follicular cysts are often found in the ovaries. Sexual hair growth occurs much less frequently, and premature puberty becomes complete.

Precocious puberty in McCune–Albright–Brajtsev syndrome usually begins with uterine bleeding that appears early (on average at 3 years) and long before thelarche and pubarche. Patients are characterized by the presence of asymmetric pigment spots on the skin that resemble a light-coffee-colored geographic map, multiple fibrocystic dysplasia of the tubular bones and cranial vault bones. Thyroid function is often impaired in this syndrome (nodular goiter), acromegaly and hypercorticism are much less common. A characteristic feature of PPS against the background of McCune–Albright–Brajtsev syndrome is the wave-like course of the disease with a transient increase in the level of estrogens in the blood serum to pubertal values with low (prepubertal) indicators of gonadotropic hormones (LH, FSH).

Estrogen-producing tumors (granulosa cell tumor, luteoma), follicular cysts of the ovaries and adrenal glands. In childhood, follicular ovarian cysts are the most common. The diameter of these cysts varies from 2.5 to 7 cm, but most often it is 3-4 cm. Against the background of a follicular cyst, clinical symptoms develop rapidly. Girls develop pigmentation of the areolae and nipples, accelerated growth of the mammary glands and uterus, followed by the appearance of bloody discharge from the genital tract without the development of genital hair. A noticeable acceleration of physical development is often observed. Follicular cysts can undergo independent reverse development within 1.5-2 months. With spontaneous regression or after removal of the cyst, a gradual decrease in the mammary glands and uterus is observed. However, in case of relapses or large cyst sizes, fluctuations in estrogenic influences can cause activation of the hypothalamic-pituitary region with the development of a complete form of premature puberty. Unlike premature puberty that occurs against the background of autonomous development of a follicular ovarian cyst, in case of true premature puberty, cyst removal does not allow returning the activity of the reproductive system to the level corresponding to the calendar age. Granulosa-stromal cell tumors, stromal hyperplasia and hyperthecosis, teratoblastomas with elements of hormonally active tissue, chorionepitheliomas, lipid cell tumors of the ovaries are rare in girls, but they have become the second most common cause of autonomous secretion of estrogens, capable of causing the appearance of signs of premature puberty. In some cases, estrogens can be secreted by gonadoblastomas located in the strand-like gonads, cystadenomas and cystadenocarcinomas of the ovaries. Often the sequence of appearance of secondary sexual characteristics is distorted (premature menarche precedes thelarche with timely pubarche). Uterine bleeding is predominantly acyclic, sexual hair growth is absent (at the initial stages) or weakly expressed. Clinical and laboratory examination reveals an increase in the size of the uterus to sexually mature, a unilateral increase in the size of the ovary or adrenal gland with a high level of estradiol in the serum of peripheral blood against the background of prepubertal values of gonadotropins. A distinctive feature of premature puberty, which arose against the background of estrogen-producing tumors, is the absence or slight advance of biological (bone) age over calendar age (no more than 2 years).

GT-independent precocious puberty (heterosexual)

Precocious puberty in the context of congenital hyperplasia. Excessive production of androgens, especially androstenedione, causes virilization of girls already in the prenatal period - from clitoral hypertrophy (stage I according to Prader) to the formation of a micropenis (stage V according to Prader) with a urethra opening on the head of the clitoris/penis. Girls acquire heterosexual features. The presence of a urogenital sinus covering the deepened vestibule of the vagina, a high perineum, underdevelopment of the labia minora and majora can lead to the fact that at birth the child is sometimes mistakenly registered as a male with hypospadias and cryptorchidism. Even with pronounced masculinization, the chromosomal set in children with congenital hyperplasia is chromosome 46 XX and the development of the uterus and ovaries occurs in accordance with the genetic sex. At the age of 3-5 years, manifestations of heterosexual precocious puberty join the signs of congenital masculinization. Sexual hair growth and acne appear on the skin of the face and back. Under the excessive influence of androgenic steroids, mainly DHEAS, girls experience a growth spurt corresponding to the magnitude of the pubertal growth spurt, but by the age of 10, patients stop growing due to the complete fusion of the epiphyseal slits. Disproportion in physical development is expressed by short stature due to short massive limbs. Unlike girls with GT-dependent PPS, who also have short stature, patients with precocious puberty against the background of CAH show masculine features of the body build (wide shoulder girdle and narrow funnel-shaped pelvis). The anabolic effect of DHEAS and androstenedione leads to compaction of adipose tissue and muscle hypertrophy. Girls look like "little Hercules". Progressive virilization is accompanied by hair growth on the face and limbs, along the midline of the abdomen and back, the voice becomes rough, the cricoid cartilage increases in size. The mammary glands are not developed, the internal genitalia remain stably of prepubertal size. Androgen-dependent signs of puberty predominate in the clinical picture. The presence of brothers with precocious puberty or sisters with clinical manifestations of virilization in the family, as well as indications of masculinization of the external genitalia from the neonatal period allows us to assume CAH. In cases of detection of premature genital hair growth in combination with other signs of virilization in girls with heterosexual precocious puberty, it is necessary to clarify the type of enzymatic defect. In the classic form of CAH associated with 21-hydroxylase deficiency, basal levels of 17-OH and adrenal androgens, especially androstenedione, are elevated, with normal or elevated levels of testosterone and DHEAS and low levels of cortisol. Severe 21-hydroxylase deficiency leads to significant limitation of the synthesis of both deoxycortisol and deoxycorticosterone, which in turn causes the development of clinical manifestations of aldosterone deficiency.Mineralocorticoid deficiency causes the early development of the salt-wasting form of CAH, which is due to a significant deficiency of 21-hydroxylase (Debré–Fiebiger syndrome).

For timely detection of this form of CAH in girls with heterosexual GT-independent precocious puberty, it is necessary to measure blood pressure, and if it is elevated, to study the content of potassium, sodium and chlorine in the blood plasma. One of the first clinical symptoms of non-classical variants of CAH is accelerated pubarche. Echographic examination allows to detect bilateral enlargement of the adrenal glands, insignificant in the non-classical form or significant in the classical variant, exceeding age standards. If there are difficulties in interpreting the basal level of steroid hormones (moderate increase in the level of 17-OP and DHEAS in the blood serum) in patients with a suspected non-classical variant of CAH, a test with synthetic ACTH (tetracosactide) is performed. In-depth genetic examination with HLA typing allows to clarify the genetic sex of the child, confirm the diagnosis of CAH, identify the girl's belonging to hetero- or homozygous carriers of the defect and predict the risk of recurrence of the disease in offspring.

Premature puberty due to an androgen-producing tumor of the ovary (arrenoblastoma, teratoma) or adrenal gland. The characteristic feature of this form of premature puberty is the steady progression of hyperandrogenemia symptoms (premature adrenarche, greasiness of the skin and scalp, multiple simple acne on the face and back; baryphonia, pronounced odor of sweat). An androgen-producing tumor of the ovaries or adrenal glands should be primarily excluded in patients with premature puberty who have a rapid enlargement of the clitoris in the absence of virilization symptoms at birth. The sequence of appearance of secondary sexual characteristics is disrupted, menarche is usually absent. Ultrasound and MRI of the retroperitoneal space and pelvic organs reveal an enlargement of one of the ovaries or adrenal glands. The preserved daily rhythm of steroid secretion (cortisol, 17-OP, testosterone, DHEAS), determined in the blood serum (at 8 a.m. and 11 p.m.), allows us to exclude autonomous production of steroids by the adrenal glands. Hormonal testing shows that the level of androgenic steroids (testosterone, androstenedione, 17-hydroxyprogesterone, DHEAS) is tens of times higher than age standards.

Treatment precocious puberty

The goal of treatment for HT-dependent precocious puberty is:

• Regression of secondary sexual characteristics, suppression of menstrual function in girls.
• Suppression of accelerated bone maturation rates and improvement of growth prognosis.

Drug therapy for GT-independent forms of premature puberty caused by follicular cysts or hormone-producing tumors of the ovaries or adrenal glands that persist for more than 3 months, as well as intracranial tumors (except for hypothalamic hamartoma) has not been developed. The main method of therapy is surgical treatment.

Indications for hospitalization

• For surgical treatment of space-occupying lesions of the brain in a specialized neurosurgical hospital.
• For surgical treatment of space-occupying lesions of the adrenal glands, hormonally active lesions of the ovaries and liver.
• To perform a tetracosactide (ACTH) test.

Non-drug treatment

There are no data confirming the advisability of non-drug therapy when detecting space-occupying lesions of the central nervous system (except for hypothalamic hamartoma), hormonally active tumors of the adrenal glands, ovaries, as well as follicular ovarian cysts that persist for more than 3 months.

Drug treatment

The main pathogenetically substantiated type of drug therapy for GT-dependent precocious puberty is recognized as the use of long-acting GnRH analogues, which promote rapid desensitization of pituitary gonadotrophs, a decrease in the level of gonadotropins and, ultimately, a decrease in the level of sex steroids. Therapy with GnRH analogues is carried out in children with GT-dependent precocious puberty with rapid progression of clinical manifestations of the disease (acceleration of bone age by more than 2 years and acceleration of the growth rate by more than 2 SD), with the appearance of other signs of puberty in children with partial forms of GT-independent precocious puberty, in the presence of repeated menstruation in girls under 7 years of age.

The use of GnRH agonists to improve the final growth prognosis is advisable at a bone age of no more than 11.5–12 years. The effect of agonist therapy after ossification of the growth zones (12–12.5 years) is not only weakly expressed, but may also be unfavorable.

For children weighing over 30 kg, the full dose of 3.75 mg is used; for children weighing under 30 kg, the half dose of triptorelin or buserelin is used. The drug is administered intramuscularly once every 28 days until the age of 8–9 years. Transnasal use of the short-lived GnRH analogue, buserelin, is possible. The daily dose is 900 mcg for children weighing over 30 kg or 450 mcg for children weighing under 30 kg (1 injection 3 times a day); if the symptoms of premature puberty are not relieved, the daily dose may be increased to 1350 mcg or 900 mcg (2 injections 3 times a day) depending on the child’s body weight. Reliable positive dynamics of clinical symptoms of the disease are noted during the first 6 months of therapy. The effectiveness of therapy is monitored 3–4 months after its initiation by repeating the test with GnRH agonists. The therapy is reversible. The level of gonadotropins and sex hormones increases to baseline values 3–12 months after the last injection, and menstrual function in girls is restored 0.5–2 years after treatment has been discontinued. With prolonged use, damage to the femoral epiphyses is rare.

Progestogens (medroxyprogesterone, cyproterone) are used to prevent uterine bleeding in the context of progressive GT-independent premature puberty. The therapeutic effect is due to the antiestrogenic effect on the endometrium with a weak effect on the symptoms of puberty. In the treatment of true puberty, the effectiveness is low. Medroxyprogesterone in a daily dose of 100-200 mg/m2 ^is administered intramuscularly 2 times a week. With prolonged use, symptoms of hypercorticism may develop, which is due to some glucocorticoid activity of the progestogen. The daily dose of cyproterone is 70-150 mg/ ^m2. Long-term use of the drug only delays bone maturation without affecting the final growth prognosis, but may lead to a weakening of resistance to stress as a result of inhibition of glucocorticoid secretion in the adrenal cortex.

Premature isolated thelarche

There are no data to support the use of medications for premature thelarche. Annual monitoring and temporary cessation of vaccinations in girls with premature thelarche are recommended, given the possibility of breast enlargement after vaccination.

In isolated thelarche against the background of decreased thyroid function, in Van Wyck-Grombach syndrome, pathogenetic replacement therapy with thyroid hormones is indicated. According to the international standard, the daily dose is calculated taking into account the body surface area (BSA), which is calculated using the formula: BSA = M ^0.425 × P ^0.725 × 71.84 × 10 ^-4,

Where M is body weight, kg; P is height, cm. With this calculation, the daily dose of sodium levothyroxine in children under 1 year is 15–20 μg/m2 ^, over 1 year - 10–15 μg/m2 ^. Sodium levothyroxine is used continuously - in the morning on an empty stomach 30 minutes before meals under the control of the level of TSH and free thyroxine (T4) in the blood serum at least once every 3–6 months. The criteria for the adequacy of treatment are normal TSH and T4 levels, normal growth dynamics and inhibition of bone age, disappearance of bloody discharge from the genital tract, reverse development of secondary sexual characteristics, absence of constipation, restoration of the pulse and normalization of mental development.

Premature pubescence

There is no data to support the advisability of drug treatment for premature pubarche. Preventive measures are taken to form a healthy eating stereotype and prevent weight gain:

• reducing the amount of foods high in refined carbohydrates and saturated fats in the diet. The total amount of fat in the daily diet should not exceed 30%;
• combating physical inactivity and maintaining a normal weight-height ratio with the help of regular physical exercise;
• avoid mental and physical stress in the evening hours, ensure that the duration of night sleep is at least 8 hours.

McCune–Albright–Braitsev syndrome

Pathogenetic therapy has not been developed. In case of frequent and massive bleeding, cyproterone may be used. The daily dose of cyproterone acetate is 70–150 mg/m2 ^. Cyproterone acetate has an antiproliferative effect on the endometrium, which leads to the cessation of menstruation, but does not prevent the formation of ovarian cysts. In case of recurrent follicular ovarian cysts, tamoxifen is used in a daily dose of 10–30 mg, which is able to bind nuclear receptors and control estrogen levels in patients with McCune–Albright–Braitsev syndrome. Use of the drug for more than 12 months contributes to the development of leukopenia, thrombocytopenia, hypercalcemia, changes in the tone of small vessels and, as a consequence, the development of retinopathy. An alternative drug treatment is the use of the first-generation aromatase inhibitor testolactone. The mechanism of action of the drug is reduced to the inhibition of aromatase and, as a consequence, to a decrease in the conversion of androstenedione to estrone and testosterone to estradiol. The drug is highly toxic, so its use in children is limited.

GT-independent precocious puberty (heterosexual)

In heterosexual precocious puberty with CAH without signs of salt wasting, the most effective treatment is started before the age of 7 years. When treating children with CAH, it is necessary to avoid using long-acting drugs (dexamethasone) and calculate the dose of the drug used, equivalent to hydrocortisone. The initial daily doses of glucocorticoids should be 2 times higher than the dose of cortisone, providing complete suppression of ACTH production. For girls under 2 years old, the initial daily doses of prednisolone are 7.5 mg/m2 ^, at the age of 2-6 years - 10-20 mg/ ^m2, over 6 years - 20 mg/m2 ^. The maintenance daily dose of prednisolone for girls under 6 years old is 5 mg/m2 ^, over 6 years - 5-7.5 mg/ ^m2. Currently, the drug of choice for the treatment of the virile form of CAH in girls over 1 year old is hydrocortisone. It is prescribed in a daily dose of 15 mg/m2 ⁱⁿ 2 doses for girls under 6 years old and 10 mg/m2 ^for girls over 6 years old. For maximum suppression of ACTH secretion, glucocorticoids should be taken after meals with plenty of liquid, 2/3 of the daily dose in the morning and 1/3 of the dose before bedtime for life. The dose of glucocorticoids is gradually reduced only after normalization of laboratory parameters. The minimum effective maintenance dose of glucocorticoids is monitored by the level of 17-OP and cortisol in the blood taken at 8 a.m., and mineralocorticoids - by the activity of plasma renin. In case of closed growth zones, hydrocortisone should be replaced with prednisolone (4 mg/m2 ⁾ or dexamethasone (0.3 mg/m2 ⁾. It is important to draw the girl's relatives' special attention to the fact that in the event of stress, acute illness, surgery, climate change, overwork, poisoning and other situations that put stress on the body, a double dose of the drug should be taken. It is necessary to offer relatives to buy the girl a bracelet indicating the diagnosis and the maximum effective dose of hydrocortisone, which should be administered in life-threatening cases.

In heterosexual precocious puberty against the background of congenital adrenal hyperplasia with signs of salt loss in infancy and in the salt-wasting form of congenital hyperplasia of the adrenal cortex, it is recommended to use fludrocortisone, which is the only synthetic glucocorticoid to replace mineralocorticoid deficiency. Therapy is carried out taking into account the activity of plasma renin. The initial daily dose of the drug is 0.3 mg. The entire daily dose should be taken in the first half of the day. Then, over the course of several months, the daily dose is reduced to 0.05-0.1 mg. The maintenance daily dose for children under 1 year is 0.1-0.2 mg, over 1 year - 0.05-0.1 mg. In moderate to severe cases, it is recommended to prescribe a combined dose of 15–20 mg hydrocortisone tablets in the morning together with 0.1 mg fludrocortisone, and only 5–10 mg hydrocortisone in the afternoon. The daily diet of girls with the salt-wasting form of CAH should include 2–4 g of table salt.

In the case of heterosexual precocious puberty against the background of congenital hyperplasia of the adrenal cortex with secondary activation of the hypothalamic-pituitary-ovarian system, glucocorticoids should be combined with GnRH analogues - triptorelin or buserelin at a dose of 3.75 mg intramuscularly once every 28 days until the age of 8-9 years.

Surgical treatment

Surgical treatment methods are used in children with premature puberty developing against the background of hormonally active tumors of the adrenal glands, ovaries, and space-occupying lesions of the central nervous system; however, removal of the neoplasm does not lead to regression of premature puberty. Hypothalamic hamartoma is removed only according to strict neurosurgical indications. Estrogen-producing follicular ovarian cysts that persist for more than 3 months are subject to mandatory surgical removal. Surgical treatment is used when it is necessary to correct the structure of the external genitalia in girls with heterosexual premature puberty against the background of CAH. A penis-shaped or hypertrophied clitoris should be removed immediately after diagnosis, regardless of the child's age. It is more advisable to dissect the urogenital sinus after the appearance of signs of estrogenization of the genitals - at 10-11 years. Long-term use of glucocorticoids and natural estrogenic effects contribute to the loosening of the perineal tissues, which significantly facilitates the operation of forming the entrance to the vagina.

Indications for consultation with other specialists

• Consultation with a neurosurgeon in case of detection of space-occupying lesions of the central nervous system to decide on the advisability of surgical treatment.
• Consultation with an endocrinologist to clarify the functional state of the thyroid gland in patients with clinical signs of hypothyroidism, hyperthyroidism, diffuse enlargement of the thyroid gland; in addition, all patients with McCune-Albright-Braitsev syndrome to exclude concomitant pathology of the endocrine system.
• Consultation with a neurologist to clarify the neurological status of patients with central forms of precocious puberty in the absence of organic pathology of the central nervous system.
• Consultation with an oncologist if there is a suspicion of malignancy of a space-occupying lesion of the ovaries or adrenal glands.

Further management of the patient

Regardless of the type of drugs, the indispensable condition for the successful therapeutic effect of true or secondary complete GT-independent premature puberty is the observance of the principle of continuity and duration of therapy, since the discontinuation of treatment after 3-4 months causes the disappearance of gonadotropic suppression and the resumption of puberty processes. Therapy should be carried out until the age of at least 8-9 years. After the discontinuation of treatment, girls should be registered with a pediatric gynecologist until the end of sexual development. All children diagnosed with premature puberty require dynamic observation (at least once every 3-6 months) before the onset and throughout the entire period of physiological puberty. Bone age is determined in girls with any form of premature puberty once a year. Girls receiving GnRH should be observed once every 3-4 months until puberty has completely stopped (normalization of growth rate, reduction or cessation of mammary gland development, suppression of LH and FSH synthesis). The GnRH test should be performed dynamically for the first time after 3-4 months of therapy, then once a year.

Prevention

There is no evidence to support the existence of developed measures to prevent precocious puberty in girls.

[ 32 ], [ 33 ], [ 34 ], [ 35 ]

Forecast

In case of premature puberty, growing malignant tumors of the brain, ovaries and adrenal glands can lead to death.

A significant improvement in the growth prognosis in patients with any form of precocious puberty with early initiation of therapy has been noted. Late diagnosis and untimely initiation of treatment significantly worsen the growth prognosis in patients with GT-dependent precocious puberty and provoke the transformation of the disease into a complete form in partial GT-independent precocious puberty.

Patients with neoplasms have an unfavorable prognosis for life, which is due to the high percentage of malignancy of germ cell tumors. Irradiation of tumors of intracranial localization can lead to the development of pituitary insufficiency with subsequent endocrine disorders, requiring appropriate methods of endocrine rehabilitation.

Premature thelarche only develops into true precocious puberty in 10% of cases.

There are no reliable data regarding fertility and reproductive health in women with a history of precocious puberty.

[ 36 ], [ 37 ]