Precocious puberty syndrome. Diseases accompanied by accelerated sexual development in girls. Diagnosis of precocious puberty

False PPR

False or LH-RH-independent PPR refers to the development of secondary sexual characteristics associated with autonomous excess production of steroids by the adrenal glands and gonads. The most common cause of this form of PPD is congenital adrenal dysfunction (CAD). Less commonly, hormonally active tumors emanating from the above organs, as well as tumors secreting hCG (chorionepitheliomas, hepatomas, teratomas).

Congenital adrenal cortex dysfunction is a group of autosomal recessive hereditary diseases caused by genetic defects in steroidogenesis enzymes. The main link in the pathogenesis is a violation of the synthesis of cortisol and/or aldosterone. A constant deficiency of cortisol, according to the principle of negative feedback, stimulates the secretion of adrenocorticotropic hormone (ACTH), which causes hyperplasia of the adrenal cortex, producing excess amounts of androgens.

In the overwhelming majority of cases, deficiency of the enzyme 21-hydroxylase occurs, 10 times less often - deficiency of 11β-hydroxylase. Currently, numerous point mutations of genes have been discovered that determine one or another deficiency, correlating with the clinical picture of glucocorticoid and mineralocotoid deficiency and pronounced virilization.

At birth, the external genitalia of girls have a heterosexual structure: varying degrees of clitoral hypertrophy, fused labia majora resemble the scrotum, forming a single urogenital opening at the base of the clitoris (urogenital sinus).

The formation of the external genitalia in boys follows an isosexual type: the penis is enlarged, the scrotum is wrinkled and pigmented, and erections appear early. In the first years of life, due to the anabolic effect of androgens, children grow quickly, their skeletal muscles develop, their voice becomes rougher, and male-type hair appears on the face, chest, abdomen, and limbs. In individuals of both sexes, skeletal differentiation is significantly accelerated.

With aldosterone deficiency, the disease is acute. The disease appears from the first weeks after birth and poses a serious threat to health. Clinically, this form is characterized by vomiting, dehydration, and decreased blood pressure (BP). The amount of sodium in the blood decreases and potassium increases, and renin levels are high.

With 11β-hydroxylase deficiency, along with the symptoms described above, an increase in blood pressure is detected, which can complicate the course of the disease. Girls in prepuberty and puberty do not have secondary female sexual characteristics and menstruation.

In the blood, renin levels are reduced, and sodium levels may be increased.

Hormonal diagnosis is based on determining the level of 17-hydroxyprogesterone. With 21-hydroxylase deficiency, it is many times higher than normal values. In patients with 11β-hydroxylase deficiency, the increase in 17-hydroxyprogesterone is less.

The main goal of treatment is to suppress excess ACTH production. For this purpose, glucocorticoids are selected or together with mineralcorticoids.

Van Wyck-Grombach syndrome occurs in children with long-term undiagnosed primary hypothyroidism. By the time symptoms of PPD appear, children have the classic picture of severe hypothyroidism: chondrodystrophic physique, significant growth retardation, muscle hypotonia, low rough voice, delayed psychomotor development.

The diagnosis was confirmed by low levels of thyroid hormones (T3 and T4) and a sharp increase in pituitary thyroid-stimulating hormone (TSH).

In girls, the first signs of PPR are enlarged mammary glands, some with lactorrhea, and the appearance of menarche. Adrenarche (pubic and axillary hair growth) is uncharacteristic. All patients showed high levels of prolactin; as for gonadotropins (LH and FSH), they increased moderately. Ultrasound examination (ultrasound) of the pelvis in all cases visualizes polycystic ovaries.

A feature of the PPR clinic in boys with this syndrome is a moderate increase in testicles with weak androgenization of the body, which corresponds to a moderate increase in testosterone levels.

In both sexes, bone maturation lagged behind biological age.

Replacement therapy with thyroid drugs causes a reversal of the symptoms of PPR.

Androgen-secreting tumors of the adrenal glands (androsteromas) are usually classified as adrenocarcinomas. They are rare in children. In early adolescence, the frequency of adrenocarcinomas increases in children with Wiedemann-Beckwith syndrome (visceromegaly, macroglossia, hemihypertrophy) and Li-Fraumeni syndrome (multiple malignant neoplasms).

In children with adrenocarcinomas, abnormal expression of tumor markers and decreased expression of factors that suppress tumor growth, the genes of which are localized on the long arm of chromosome 11, were revealed. Abnormalities of this chromosome are detected in most patients with adrenocarcinoma.

In boys, a clinical picture of the type of isosexual sexual development is observed: muscle mass and growth rate increase, secondary hair growth and erections appear, and the timbre of the voice changes. However, the volume of the testicles does not increase.

Girls show signs of virilization: apocrine glands (sweat, sebaceous, hair follicles) are activated, body weight increases due to muscle tissue, and the clitoris hypertrophies. Growth accelerates in boys and girls.

Estrogen-producing adrenal tumors (corticoestromas) are very rare in children. In girls in this case they occur as an isosexual PPR, and in boys in the clinic the leading symptom is gynecomastia.

When studying the hormonal profile, an increase in the level of dehydroepiandrosterone sulfate (DHEA-S) and juvenile levels of LH and FSH are characteristic. In some cases, the concentration of testosterone and estradiol increases. Ultrasound is used to diagnose adrenal tumors.

Steroid-secreting gonadal tumors are uncommon in childhood. In older girls, arrhenoblastomas (malignant tumors) are found, located in the cortex or hilum of the ovary. Undifferentiated tumors have a more pronounced virilizing effect, while differentiated ones have both a weakly expressed masculinizing and feminizing effect. Granulosa cell tumor of the ovaries, most often of benign origin, secretes a large amount of estrogens, causing PPR of the isosexual type. Excess estrogen causes menstrual syndrome - from scanty to heavy bleeding, pigmentation of the areola, thickening of the glandular tissue, hypertrophy and swelling of the vulva. The amount of estradiol is sharply increased with pre-pubertal levels of LH and FSH.

Leydigomas that secrete testosterone are rare in boys. This is a benign tumor that affects one testicle. Externally, it is enlarged, lumpy, and has a dense consistency. Androgenization syndrome develops quickly.

Sertolioma is a neoplasm containing Sertoli cells. In this case, the release of estradiol into the blood increases, which forms gynecomastia in boys and accelerates growth and bone maturation.

The level of gonadotropic hormones in both testicular tumors corresponds to the age of the children.

Follicular ovarian cysts are a common cause of PPR in girls. However, they are also found in healthy prepubertal girls. The diameter of these cysts is from 0.5 to 1.5 cm. The presence of a cyst in the ovaries is not a sign of pathology. But in some cases, cystic tissue begins to prematurely and excessively produce estradiol. As a rule, these cysts are 3-4 cm in size. Follicular cysts may be accompanied by irregular, scanty discharge from the genital tract, hypertrophy and swelling of the skin of the vulva, increased vaginal folding, moderate pigmentation and swelling of the nipples. The size of the uterus and bone maturation correspond to the passport age. The reason that causes the formation and persistence of follicular cysts may be a transient increase in gonadotropins (mainly FSH). Ovarian cysts are detected by pelvic ultrasound. In most cases, follicular cysts spontaneously regress after 1.5-2 months and the PPR clinical picture disappears. Cysts that are large or occur with complications are subject to surgical treatment.

Incomplete forms of PPR

Premature isolated thelarche (PT), an enlargement of the mammary glands in girls, is the most common benign variant of PPP. In most cases, it is observed at the age of 6-24 months in girls who are breastfed, low birth weight and premature. Less commonly detected after reaching 3 years of age.

The cause of breast enlargement is considered to be high levels of gonadotropic hormones (especially FSH). Peak FSH concentrations after birth persist for up to 6 months and then slowly begin to decline by 2-3 years. At preschool age, in such patients, follicles are detected in the ovaries, reaching the same size as in adult women. Some authors associate this with dysfunction of the hypothalamic-pituitary system. FSH activates the enzyme aromatase, which leads to increased production of estrogen from testosterone in the granulosa tissue of the follicle. Other causes of isolated thelarche may be periodic releases of estrogens or increased sensitivity of the receptor apparatus of the mammary glands to estrogens.

Enlarged mammary glands are palpable on one or both sides. Some girls experience moderate estrogenization of the vulva. There are no other secondary sexual characteristics.

With isolated thelarch, the growth rate is not impaired (5-6 cm per year), bone age corresponds to chronological. Most often, the process regresses on its own and does not require drug intervention, but at the same time, the appearance of thelarche may be the first sign of true or false PPR, therefore all girls with thelarche must be re-examined (at least 2 times a year).

If thelarche is combined with an acceleration of bone age, but there are no other signs of precocious sexual development, this condition is assessed as an intermediate form of PPR and requires more careful monitoring (quarterly) with monitoring of ovarian ultrasound and bone age.

Premature adrenarche (PA) is the appearance of isolated pubic and/or armpit hair in girls under 8 years of age, and in boys under 9 years of age. It is more common in girls aged 6-8 years. PA may be a normal variant, given that the maturation of the zona reticularis of the adrenal cortex begins at 6 years of age. While the secretion of gonadoliberins, responsible for the onset of puberty, starts later. The cause of pubertal hair growth is an increase in the production of dehydroepiandrosterone (DHEA) and its DHEA-S by the adrenal glands, as well as delta-4-androstenedione, testosterone precursors that stimulate pubic and axillary hair growth. In girls, PA may be associated with excessive peripheral conversion of testosterone to dihydrotestosterone (increased aromatase activity). In the absence of other signs of androgenization of the body - accelerated growth, skeletal maturation, pre-pubertal size of the uterus and ovaries, and in boys, testicles, normal testosterone levels and moderately increased DHEA-S, the prognosis is favorable and sexual development does not deviate from the norm.

However, in some children, PA can be triggered by excess production of ACTH (hydrocephalus, meningitis, etc.). There is growing evidence linking PA with non-classical forms of congenital adrenal dysfunction (CAD) and, in particular, deficiency of the enzyme 21-hydroxylase and, less commonly, 3β-hydroxysteroid dehydrogenase.

In the presence of a virilizing disease, clinical signs of androgenization appear: in girls - clitoral hypertrophy, high posterior perineal commissure, hirsutism, development of the muscular system; in boys - a change in voice, enlargement of the penis, activation of the sebaceous and sweat glands. These children experience accelerated growth and bone age.

Girls with premature adrenarche should be at risk for developing polycystic ovary syndrome. This group of patients requires corrective therapy with glucocorticoids.

Differential diagnosis

Primary diagnosis is based on a thorough history and assessment of the degree of sexual development of the child according to the Tanner-Marshall classification. Early puberty in men in the family on the maternal and paternal lines is characteristic of testotoxicosis. The presence of brothers with PPD or sisters with symptoms of virilization in the family is more common in cases of CDCN.

From the anamnesis, you should find out the time of appearance of secondary sexual characteristics and the speed of their progression. In girls, the degree of development of the mammary glands and areola, the condition of the skin, external genitalia, and the presence of bleeding are assessed.

In boys, the degree of masculinization, the presence of pubic and armpit hair, the degree of change in the external genitalia (penis size, testicles).

In both sexes, height indicators are assessed by calculating the standard deviation (SD) coefficient.

The early onset of the disease and the rapid increase in symptoms are typical for testotoxicosis and hypothalamic hamartoma. Clinical symptoms of hypothyroidism combined with PPR suggest Van Wyck-Grombach syndrome.

If the history indicates congenital anomalies of the central nervous system, trauma, inflammation, one should think about the cerebral form of PPR.

Bone age examination (x-ray of the hand), more than any other indicator that correlates with the stage of sexual development of the child, is mandatory for assessing the degree of PPD. If the bone age is more than 2 SD ahead of the passport age, this indicates an excess of sex steroids. Significant acceleration of bone maturation is characteristic of central forms of PPR, as well as androgen-secreting adrenal tumors, CAI. In isolated forms of PPR (premature thelarche and adrenarche), bone age corresponds to chronological age.

The tumor variant of cerebral PPR is excluded using computed tomography (CT) and magnetic resonance imaging (MRI). These research methods are included in the mandatory standard of the survey plan.

Pelvic ultrasound should be performed in all girls with suspected PPR. The size of the ovaries and uterus should be comparable to the level of sex hormones. Bilateral ovarian enlargement is a reliable sign of the central form of PPR.

The structure of the ovaries, the diameter of the follicles, the ratio of the fundus to the cervix, the length of the uterus and endometrium are important evaluation parameters, but many experts believe that they are not decisive in the differential diagnosis between PT and central forms of PPR. The ovaries may be asymmetrically enlarged in girls with peripheral forms of PPR.

In boys, MRI or CT is preferable to detect adrenal masses.

To clarify the form of PPR, the levels of gonadotropic hormones, estrogens and androgens are determined. The levels of LH, FSH and estradiol reflect the state of the hypothalamic-pituitary-gonadal system, the concentration of DHEA and DHEA-S - the secretory activity of the adrenal glands.

For differential diagnosis between central and false forms of PPR, a functional test with LH-RH should be performed in all cases. With true PPR, a test with Diferelin causes a pubertal response of LH and FSH. In children with peripheral forms of PPR, gonadotropins do not respond to stimulation.

An increase in DHEA-S is characteristic of premature adrenarche. An excess of adrenal androgens is possible with virilizing forms of CDCN, tumors of the adrenal glands and ovaries.

The tumor cause of PPR requires testing for the presence of AFP, beta-hCG, and CEA.

Treatment

The main goal of treatment for PPR is to eliminate the clinical symptoms of the disease, normalize the secretion of steroid hormones that accelerate bone maturation and close growth plates to achieve socially acceptable growth.

Treatment of true PPR involves blocking pulsatile LH-RH secretion. The indication for the use of synthetic GnRH analogues is early age and rapid dynamics of bone maturation. With a slowly progressing disease, this treatment should be approached with caution.

The drug triptorelin has undergone clinical testing in Russia. The drug is administered intramuscularly, the frequency of administration is 1 time every 28 days. Children weighing less than 20 kg - 1.875 mg, more than 20 kg - 3.75 mg.

Normalization of FSH levels is observed after 3 weeks, a decrease in the size of the testicles and uterus from the 6th month of treatment. Inhibition of growth rate and skeletal maturation is observed by the end of the 1st year of treatment. The growth forecast is improving. The drug is well tolerated by patients. During treatment, constant monitoring of changes in bone age, growth rate, and standard deviation coefficient (SDS) of growth is necessary.

The data confirm the advisability of medicinal isolated thelarche against the background of reduced thyroid function; in Van Wyck-Grombach syndrome, hormone replacement therapy with thyroid hormones is indicated. The criterion for the adequacy of treatment is normal readings of TSH and free T4.

For McCune-Albright-Braitsev syndrome, pathogenetic therapy has not been developed. In cases of frequent massive bleeding, it is possible to use cyproterone in a daily dose of 70-100 mg. The drug has an antiproliferative effect on the endometrium, which leads to the cessation of menstruation. To reduce hyperestrogenemia, an inhibitor of aromatase activity is used - testolactone at a dose of 20-40 mg/kg per day or tamoxifen, which blocks estrogen receptors.

The treatment tactics for testotoxicosis involve the appointment, firstly, of medroxyprogesterone (inhibition of testosterone synthesis), and secondly, of ketoconazole (inhibition of the synthesis of gonadal and adrenal hormones) or a combination of testolactone and spironolactone (aromatase inhibition and androgen receptor blockade). Ketoconazole is prescribed at a dose of 30 mcg/kg per day per os. The use of the drug may be accompanied by adrenal insufficiency and liver dysfunction. With a late start of treatment, when bone age has reached 12-13 years, a picture of true PPR may develop, in which case therapy with synthetic analogues of LH-RH is carried out.

Functional ovarian cysts in most cases undergo spontaneous regression within four months. When follicular cysts form in utero or in newborn girls, treatment is usually not performed. Resection of the ovary or laparoscopic enucleation with suturing of the walls is performed when cysts with a diameter of more than 8 cm are detected.

Surgical treatment methods are used in children with PPR developing against the background of hormonally active tumors of the adrenal glands, ovaries, and space-occupying lesions of the central nervous system; however, in some patients, removal of tumors does not lead to regression of PPR. Hypothalamic hamartoma is removed only for strict neurosurgical indications. In the presence of focal and general cerebral symptoms, surgical intervention or radiation therapy is performed according to the type of tumor. It must be remembered that radiation exposure or surgery to the bottom of the 3rd ventricle can provoke PPR. For this reason, such children should be constantly monitored by an endocrinologist. In cases where the leading clinical manifestation of the disease is only symptoms of PPR, only conservative treatment is possible.

In girls with heterosexual precocious puberty due to CAH, surgical correction of the external genitalia is performed if necessary. Penis-shaped or hypertrophied clitoris is recommended to be resected immediately after diagnosis, regardless of the child’s age.

Further management of patients

All children diagnosed with precocious puberty should be constantly monitored (at least once every 3-6 months) before and throughout the entire period of physiological puberty. Treatment of true PPR with triptorelin is carried out continuously until the onset of puberty, since stopping its administration causes a resumption of the disease. Bone age testing is monitored with any form of PPR once a year.

Literature

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3. Dedov I. I., Semicheva T. V., Peterkova V. A. Sexual development of children: norm and pathology. M., 2002. 232 p.
4. Jospe N. Precocious Puberty. MD, 2012. www.merckmanuals.com.
5. Kotwal N., Yanamandra U., Menon A. S. et al. Central precocious puberty due to hypothalamic hamartoma in a six-month-old infant girl // PMC. 2012.
6. Upreti V., Bhansali A., Mukherjee K. K. et al. True precocious puberty with vision loss // PMC. 2009.
7. Pagon R. A., Adam M. P., Bird T. D. et al. GeneReviews™, Russell-Silver Syndrome. University of Washington, Seattle, 1993-2013.
8. Stephen M. D., Zage P. E., Waguespack S. G. Gonadotropin-Dependent Precocious Puberty: Neoplastic Causes and Endocrine Considerations // PMC. 2011.
9. Berberoglu M. Precocious Puberty and Normal Variant Puberty: Definition, etiology, diagnosis and current management // J Clin Res Pediatr Endocrinol. 2009, June, 1 (4): 164-174.
10. Peterkova V. A., Semicheva T. V., Gorelyshev S. K., Lozovaya Yu. V. Premature sexual development. Clinic, diagnosis, treatment. A manual for doctors. M., 2013. 40 p.
11. Low L., Wong K. Premature sexual development of boys. www.urolog.kz.
12. Lee P. Premature sexual development of girls. www.urolog.kz.
13. Faizah M. Z., Zuhanis A. H., Rahmah R. et al. Precocious puberty in children: A review of imaging findings // PMC. 2012.
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15. Bajpai A., Menon P. S. N. Contemporary issues in precocious puberty // PMC. 2011.
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17. Precocious puberty By Mayo Clinic staff. 2011. www.mayoclinic.com.

V.V. Smirnov 1, Doctor of Medical Sciences, Professor
A. A. Nakula

GBOU VPO RNIMU im. N. I. Pirogova, Ministry of Health of the Russian Federation, Moscow

Abstract. Precocious sexual development is the frequent violation of puberty in children and in their etiology and pathogenesis is a heterogeneous disease. The article summarizes the current data on the causes of violations of formation of the hypothalamic-pituitary-gonadal relationships cause premature sexual development. A classification of diagnosis and treatment of this pathology.

Premature sexual development

What is Precocious Sexual Development -

Premature sexual development is the appearance of several or all secondary sexual characteristics (sometimes the first menstruation - menarche) in girls under the age of 8 years.

Classification and brief description

1. True premature (can be caused by untimely activation of the hypothalamus or adenohypophysis, therefore luteotropin and follicle-stimulating hormone are produced in excess quantities)

Important distinguishing features of this species:

• isosexual (corresponds to the female gender)
• complete, including adrenarche, thelarche and accelerated growth
• completed in all cases (menarche occurs earlier)

2. False precocious puberty occurs if there is an autonomous excess production of estrogens in the adrenal glands or ovaries or due to the intake of gonadotropic hormones or estrogens.

False prematurity also accelerates the child's growth rate. But this type is characterized by such features as incompleteness - premature menstruation does not occur. It can be heterosexual or isosexual.

3. Incomplete premature sexual development in children

• primary hypothyroidism
• ovarian cysts
• Russell-Silver syndrome
• McCune-Albright syndrome

- this form of the considered deviation, in which, due to the presence of an excess amount of androgens in the body, girls develop secondary male sexual characteristics.

Classification of premature puberty according to ICD-10

• Precocious puberty
• Violation of p.s. unspecified
• Other violations of p.s.
• Premature p.s. with McCune-Albright-Braitsev syndrome
• Precocious puberty of central origin
• Female heterosexual precocious false puberty
• Congenital adrenogenital disorders associated with enzyme deficiency, including congenital adrenal hyperplasia and 21-hydroxylase deficiency
• Syndromes of congenital anomalies manifesting predominantly as dwarfism

Epidemiology of precocious puberty

0.5% of girls in the world have such a problem as premature (early) puberty. Among gynecological pathologies, this problem accounts for about 2.5-3.0%. In the vast majority of girls, the full form of precocious puberty results from pathologies of the central nervous system.

Premature thelarche is recorded in 1% of female patients under 3 years of age, the frequency of true forms of the condition in question is 2-3 times higher. With early puberty in girls and boys, death can occur due to a malignant tumor of the ovaries, brain, and adrenal glands.

What provokes / Causes of Precocious sexual development:

This form occurs due to early activation of the hypothalamic-pituitary system.

Main Factors:

• Hypertrophy or hamartoma of the hypothalamus
• Spontaneous increase in the secretion of GnRH or LH and FSH, which does not arise from diseases of the central nervous system or congenital anomalies
• Radiation therapy for malignant brain tumors (together with an excess of gonadotropic hormones, a lack of such a hormone as growth hormone is sometimes observed)
• Late treatment of virilizing forms of congenital adrenal hyperplasia
• Tumors and other diseases of the central nervous system that disrupt the balance between stimulation and inhibition of the secretion of gonadotropic hormones.

In the vast majority, precocious sexual development in girls is true. At the same time, it is not possible to identify the cause; this is very difficult, because the disease in such cases is considered idiopathic. But instrumental methods of modern medicine, such as computed tomography and computer tomography, make it possible to detect even minor anomalies of the central nervous system, for example, a hypothalamic hamartoma. Therefore, the diagnosis of “idiopathic precocious sexual development” is given to children in increasingly rare cases.

The false form of early development is caused by autonomous hypersecretion of estrogens in the ovaries and adrenal glands. The reason may be due to the intake of gonadotropic hormones or estrogens. Moreover, most often, endogenous estrogens are often produced by tumors. Among other reasons, the above-mentioned symptoms are distinguished.

Heterosexual false precocious puberty

The most common cause is a mild virilizing form of congenital adrenal hyperplasia, including 21-hydroxylase deficiency. Other etiologies are extremely rare, including androgen-secreting tumors.

Incomplete precocious sexual development

Isolated premature thelarche

This form of deviation occurs in girls under 2 years of age. But there is a possibility of later occurrence, even at the age of 6 years. Examination and palpation methods reveal that the mammary glands are enlarged, this can even happen in a recently born child. The main reason for this form of early development of children is the constantly increased secretory activity of the ovaries. Other causes include increased sensitivity of the mammary glands to estrogen and periodic estrogen releases.

As a rule, the size of the mammary glands returns to normal within 12 months. But in some cases they increase until puberty occurs. Treatment of such conditions is not required, the prognosis is favorable. Doctors should explain to the mother and father that this condition is temporary, this is a normal variant that does not require therapy.

But thelarche may be the first symptom of true or false precocious sexual development. Therefore, girls with premature thelarche are advised to be examined once every 6 months.

Isolated premature adrenarche

This is the early appearance of pubic and armpit hair in females. The reason is the increased secretion of adrenal androgens in the prepubertal period. Excessive production in the body is a temporary phenomenon. The prognosis, as with isolated premature thelarch, is favorable. In most cases there is no treatment.

Symptoms of Precocious Puberty:

True precocious puberty

With this form of deviation, the first thing that happens is thelarche, then adrenarche, then stunting, and finally menarche. But in some cases, thelarche and menarche occur first, and after a long period - adrenarche. The reason is that the production of estrogen by the ovaries and the production of androgens by the adrenal glands do not correlate with each other.

Normally, menarche occurs at least 2 years after the start of puberty in a child. If there is true premature sexual development, then the first menstruation may occur 6 months to 1 year after the onset of the disease.

Isosexual false precocious puberty

Symptoms similar to true precocious puberty:

• growth acceleration,
• adrenarche.

There are no ovulation cycles, but some girls may experience uterine bleeding; in most such cases there is no regularity. The endometrium is shed due to a sharp drop or fluctuation in estrogen levels. Depending on the cause of the disease, symptoms and the degree of their manifestation may vary. The greater the excess amount of estrogen in the body, the sooner the symptoms will appear and be more clearly expressed.

Heterosexual false precocious puberty

The following symptoms are observed:

• adrenarche
• clitoral hypertrophy
• increased growth or tallness
• voice change
• male physique

When conducting an examination, the doctor must take into account that the external genitalia of an intermediate type in a young child and heterosexual development in the prepubertal period can be explained by disorders of sexual differentiation. And clitoral hypertrophy can appear not only from virilization, but also be a consequence of neoplasms, for example, neurofibroma.

Isosexual precocious puberty

The first symptom may be adrenarche, the cause of which will be an excessive amount of gonadotropic hormones or estrogens. This symptom may also indicate heterosexual precocious sexual development, which can be caused, for example, by congenital hyperplasia of the adrenal cortex.

The distinction between true or false precocious puberty and isolated premature adrenarche is made by assessing the child's growth rate and bone age. During early sexual development, there is a significant acceleration in growth, and bone age is greater than the actual age of the child. With isolated premature adrenarche, the bone age in most cases is similar to that indicated on the child's birth certificate.

Characteristic signs of a virilizing disease:

• oily skin
• excessive muscle development
• clitoral hypertrophy

If treatment is not carried out, these symptoms will not go away, and during puberty they are joined by hirsutism and.

Diseases accompanied by premature sexual development

1. Ovarian cysts

They can cause premature thelarche (the onset of breast growth in girls) and true early puberty. Ovarian cysts are often found in healthy prepubertal girls.

The reasons are as follows. The cyst develops from an immature follicle. In the normal variant, the follicle first becomes larger and then atrophies. With continued growth of the follicle, a cyst matures. Excessive growth of the follicle is explained by the release of gonadotropic hormones. Such emissions can be normal or in cases of disorders of sexual development. Therefore, the presence of an ovarian cyst in itself is not a sign of pathology and speaks about its cause.

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Other diseases from the group Children's diseases (pediatrics):

Most often it occurs in girls aged 6-24 months, and also in girls 4-7 years old. The cause of this condition is considered to be a high level of gonadotropic hormones in the blood (especially FSH), which is physiological in children under 2 years of age. Follicle-stimulating hormone activates the aromatase enzyme, which leads to increased production of estrogen from testosterone. Other causes of isolated thelarche may be periodic estrogen surges or increased sensitivity of the mammary glands to estrogen.

Clinical picture. Enlarged mammary glands are palpated on one or both sides. There are no other secondary sexual characteristics. With isolated thelarch, the growth rate is not impaired (5-6 cm per year), bone age corresponds to chronological. Most often, the process regresses on its own and does not require drug intervention, but at the same time, the appearance of thelarche may be the first sign of true or false PPR, therefore all girls with thelarche must be re-examined (at least 2 times a year).

If thelarche is combined with an acceleration of bone age, but there are no other signs of precocious puberty, this condition is assessed as an intermediate form of precocious puberty and requires more careful monitoring (quarterly) with control of bone age and hormonal status.

Premature isolated adrenarche in children

The appearance of premature adrenarche may be a variant of the norm, since it is known that the maturation of the adrenal cortex under the influence of ACTH in children begins much earlier (from 6 years of age) than the activation of impulse secretion of gonadoliberin, which is responsible for the onset of puberty. Thus, the adrenal glands secrete dehydroepiandrosterone and its sulfate, as well as delta-4-androstenedione, which are weak androgens, precursors of testosterone, and stimulate pubic and axillary hair. Premature isolated adrenarche, however, can be provoked by non-progressive intracranial injuries that cause increased production of ACTH: hydrocephalus, meningitis (especially tuberculosis). It may also be the first manifestation of a virilizing disease, for example, late form of CAH, tumors of the gonads and adrenal glands.

Signs, clinical picture. With premature adrenarche, as a rule, isolated pubic hair growth occurs, sometimes in combination with axillary hair growth. Acne and a strong smell of sweat may also occur. There is no acceleration in the rate of growth and maturation of the skeleton. In some cases, bone age may be slightly ahead of chronological age (no more than 1 year). If there is no other pathology, the prognosis is favorable and sexual development is completed within normal periods. In the presence of a virilizing disease, characteristic clinical signs appear: in girls - clitoral hypertrophy, excessive muscle development, hirsutism; in boys - deepening of the voice, enlargement of the penis. Acceleration of growth and bone maturation is observed in individuals of both sexes.

Content: Gynecomastia. A. N. Okorokov Hypogonadism syndrome. E. A. Kholodova Hypogonadism in women Hypogonadism in men Virile syndrome. A. N. Okorokov

SYNDROME OF PREMATURE SEXUAL DEVELOPMENT. Precocious puberty is generally considered to be the appearance of secondary sexual characteristics at an age that is two standard deviations less than the normal average age of puberty (8 years for girls, 9 years for boys).

In clinical practice, the following classification is accepted:

1. True precocious puberty:
   • constitutional or idiopathic form;
   • premature sexual development of cerebral origin.
2. False premature puberty:
   • premature sexual development of adrenal origin;
   • premature sexual development of cerebral origin;
   • premature sexual development of an exogenous drug nature.
3. Incomplete form: isolated enlargement of the mammary glands (thelarche) and isolated development of sexual hair (adrenarche).

TRUE PREMATURE PUBERTY. True premature sexual development includes all forms that are based on increased production of gonadotropic hormones.

• Constitutional, or idiopathic, form [show]

  Etiology and pathogenesis. Etiologically, this form is associated with a family factor (early puberty in parents). It occurs 7.5 times more often in girls than in boys. The pathogenesis is based on premature secretion of gonadotropic hormones.

  Clinical picture. An early symptom is a marked increase in growth. As a rule, not only growth is accelerated, but also differentiation of the skeleton. Initially, there is a significant increase in growth compared to one-year-olds. However, due to the closure of growth plates under the influence of estrogens and androgens, growth ends earlier. During growth acceleration, these children are ahead of their peers, but as adults they are 14-20 cm shorter than them.

  Children are also characterized by accelerated physical development, significant muscle strength, and more pronounced muscle development compared to their peers.

  With idiopathic precocious puberty in girls, the sequence of appearance of secondary sexual characteristics is similar to the normally occurring period. First, there is an enlargement of the mammary glands, then pubic hair appears. Menarche coincides with the appearance of axillary hair. Menstruation may be regular and set in quickly. The existence of anovulatory cycles has been proven. The physical development of girls is accelerated. The figure takes on a feminine structure. The level of gonadotropic hormones and estrogens in children corresponds to the degree of their sexual development. Mental development corresponds to chronological age. In most boys, the first symptom of the disease is accelerated growth and differentiation of the skeleton, which is usually characteristic of healthy boys in the early stages of puberty. Boys with precocious puberty initially quickly outstrip their peers in height and other indicators of physical development, but due to early differentiation of the skeleton and closure of growth zones, their final body length remains below average. Changes in the external genitalia resemble those during normal puberty, but occur earlier and faster.

• Premature sexual development of cerebral origin [show]

  Etiology and pathogenesis

  Etiological factors include:

  1. past inflammatory diseases of the central nervous system - brain abscesses, meningitis, encephalitis, arachnoiditis;
  2. traumatic brain injuries;
  3. tumors of the central nervous system: ependomas, astrocytomas, optic pathway gliomas, horminomas, hypothalamic teratomas, hamartomas in the area of ​​the gray tuberosity. Such tumors usually wedge into the hypothalamus, interrupting its normal neurochemical connections with the pituitary gland. These tumors are more common in men;
  4. pineal tumors;
  5. craniopharyngiomas;
  6. granulomatous brain lesions in tuberculosis and sarcoidosis. Granulomas can cause compression of the hypothalamus and precocious puberty;
  7. neurofibromatosis (Recklinghausen's disease) - in this disease, neurofibromas developing in the central nervous system can disrupt the function of the hypothalamus;
  8. hydrocephalus of various origins.

  The pathogenesis of premature puberty of cerebral origin is associated either with a direct increase in the secretion of gonadoliberin (tumors of the hypothalamus, tumors of the gray tuberosity - hamartoma) and gonadotropins (tumors of the pituitary gland), or with a decrease in the influence of inhibitory centers on the hypothalamic-pituitary activity (tumor of the pineal gland, craniopharyngiomas, inflammatory, granulomatous and traumatic brain injury). Tumors of the pineal gland can cause premature puberty not only due to hypoproduction of antigonadotropic substances, but also due to increased secretion of gonadotropin-like polypeptide.

  Clinical picture. The most characteristic early clinical sign of precocious puberty of cerebral origin is the appearance of secondary sexual characteristics already from the birth of the child (with intrauterine damage to the central nervous system) or at a later date (postnatal damage to the central nervous system). Puberty follows an isosexual type, the clinical picture corresponds to the idiopathic form (see above), but in contrast to it, in the cerebral form, clearly defined signs of damage to the central nervous system are determined, depending on the etiology. In patients, changes in the cranial nerves, motor and sensory spheres, reflexes, as well as the hypothalamic-pituitary zone (polydipsia, polyuria, bulimia, obesity, thermoregulation disorder), decreased visual acuity, limited visual fields, congestive papillae of the optic nerves (if present) are determined. brain tumors and intracranial hypertension). Intellectual inferiority of children may be detected.

  Bone age is usually ahead of passport age, and its annual increase can correspond to 2-4 years. Without treatment, growth plates close at 9-14 years of age, girls' height reaches 133-150 cm, boys - 147-150 cm.

  • McCune-Albright syndrome [show]

    Occurs almost exclusively in girls.

    Etiology and pathogenesis. The mechanism of precocious puberty is unknown. For a long time it was associated with hypothalamic dysfunction and hyperproduction of gonadotropins; in recent years, autonomous hyperfunction of the gonads has been suggested.

    Clinical picture. The main symptoms are widespread fibrous bone dysplasia, premature puberty and age spots. In long tubular bones (usually the femur, especially the head), there is progressive formation of cysts and thinning of the cortex with a tendency to spontaneous fractures. Changes in the vertebral bodies and severe scoliosis may also be observed. The base of the skull is often thickened due to fibrosis. Precocious sexual development begins at the age of 3-5 years. Noteworthy is the early appearance of menstruation against the background of still weakly expressed other signs of puberty. Characteristically, there are pigment spots on the skin the color of coffee with milk, shaped like garlands; As the disease progresses, their prevalence increases.

  • Neurofibromatosis [show]

    The disease is characterized by light brown spots on the skin of the trunk and limbs, neurofibromas along the peripheral nerves, on the conjunctiva and iris of the eyes, endocrine glands, and skull bones.

  • Russell-Silver syndrome [show]

    The origin of the disease is unknown. The main symptoms are the following: low body weight of the newborn (2500 g) during full-term pregnancy. Subsequently, the growth remains dwarf, small facial skull, relatively large cerebral skull, which gives the face a triangular shape. The corners of the mouth are lowered (“carp mouth”). In most patients, intelligence is developed normally. Against the background of these signs, premature sexual development appears. The level of gonadotropic hormones in the blood is increased. The described syndrome belongs to the group of primordial dwarfism.

FALSE PREMATURE PUBERTY. False precocious puberty includes types of diseases in which increased androgen production does not depend on gonadotropic stimulation.

Etiology and pathogenesis. The causes may be hormonally active tumors of the testicles, ovaries, adrenal glands, adrenogenital syndrome against the background of congenital adrenal hyperplasia, malignant liver diseases, the use of medications that accelerate puberty (drugs of androgens, anabolic steroids, gonadotropic hormones). False precocious puberty is usually based on the autonomous production of sex hormones.

Clinical picture. False precocious puberty is characterized by the early appearance of sexual characteristics (earlier compared to the idiopathic form), accelerated growth and physical development.

In boys, false precocious puberty usually occurs in an isosexual manner and extremely rarely in a heterosexual pattern. In girls, isosexual and heterosexual development is possible.

• Virilizing adrenal tumors - corticoandrosteromas

  They are characterized by the development of false premature sexual development of the heterosexual type, similar to the described virilizing hyperplasia of the adrenal cortex: pubic hair growth, and often the face, torso, limbs, acceleration of physical development, deepening of the voice, clitoral hypertrophy, bone age is ahead of the actual one, premature closure of growth zones. At the same time, the ovaries and uterus usually correspond to the age of the child.

  For differential diagnosis between a virilizing tumor of the adrenal cortex and their hyperplasia, a dexamethasone load test and serum cortisol testing are performed. In congenital virilizing hyperplasia of the adrenal cortex, a significant decrease in serum cortisol is observed after blockade of the adrenocorticotropic function of the pituitary gland with dexamethasone. In case of corticoandrosteremia, a decrease in the level of cortisol in the blood serum is not observed while taking dexamethasone.

  • Congenital virilizing hyperplasia of the adrenal cortex. Premature sexual development of the heterosexual type [show]

    Etiology and pathogenesis. This is a genetically determined disease associated with 21-hydroxylase deficiency. This defect leads to a lack of cortisol and increased ACTH secretion, which causes bilateral adrenal hyperplasia and increased synthesis of steroid hormones. Excessive release of androgens causes virilization syndrome.

    Clinical picture. Immediately after birth, attention may be drawn to disturbances in the structure of the external genitalia - enlargement of the clitoris, the presence of a urogenital sinus, deepening of the vestibule of the vagina, high perineum, underdevelopment of the labia minora and majora. With significant virilization, it may be difficult to choose sex. The physical development of girls is characterized by a pronounced acceleration of the growth rate in the first decade of life. By the age of 12, the growth rate slows down. The rapid growth rate is associated with a significant acceleration of the processes of growth and ossification. The bone age of 3-6 year old girls exceeds the calendar age by 5 years, and by the age of 12 the ossification processes are almost completed, growth stops, not reaching average.

    The girls' physique is very characteristic: broad shoulders, narrow pelvis, short limbs, rather massive tubular bones.

    The period of puberty begins early (at 6-7 years) and proceeds according to the heterosexual type: male secondary sexual characteristics develop (male hair growth, the clitoris enlarges, the timbre of the voice decreases, and muscle strength increases). The mammary glands do not develop, there are no menstruation. The size of the uterus at the age of 16-18 years is significantly behind the norm.

    In boys, this form manifests itself as a picture of premature puberty of the isosexual type.

    Signs of premature sexual and somatic development may appear already in the first half of life or develop more slowly and become noticeable at the age of 4-5 years and later. Characteristic is the acceleration of growth starting from 2-3 years with a gradual change in body proportions from 7-8 years towards masculinization. Along with this, skeletal maturation accelerates; by the age of 5-7 years, bone age is sometimes 100% ahead of the passport age.

    By the age of 9-13 years, patients stop growing due to early closure of growth plates and remain stunted in the future. The anabolic effect of androgens on muscle tissue causes its increased development, which emphasizes an athletic physique: broad shoulders, narrow hips, muscular buttocks, development of the pectoral muscles and muscles of the limbs.

    Early sexual hair growth is characteristic - from 2-5 years on the pubis, after 1-3 years in the armpits. From 4-6 years of age, a rough voice is noted, due to hypertrophy of the vocal cords. Closer to puberty, excess hair growth is observed on the limbs and face in the form of a mustache, beard and sideburns. Characterized by a premature increase in the size of the penis and scrotum. The testicles are age appropriate, but compared to the enlarged penis they appear small.

    Rarely, in patients with adrenal hyperplasia, the testes contain ectopic adrenal cells that hyperplasia along with the normally located glands, resulting in testicular enlargement. There is no spermatogenesis. Due to the characteristics of physical development, behavioral anomalies are possible.

  • Corticoandrosteroma. Virilizing tumor of the adrenal cortex [show]

    The tumor in boys leads to isosexual precocious puberty.

    Clinical picture false precocious puberty is the same as with congenital virilizing hyperplasia of the adrenal cortex.

    Feminizing adrenal tumors secrete large amounts of estrogens, leading to heterosexual precocious puberty in boys.

    First clinical symptom is gynecomastia, which develops between the ages of 6 months and 7 years. In the future, feminine characteristics may appear.

• Ovarian tumors

  Tumors of granulosa and theca cells are most often found, but other endocrine tumors are also possible in pure form or in mixed forms. Among them, benign cystic teratoma is most often found in childhood, followed by malignant teratoma, mixed germ cell tumor, intradermal sinus tumor, and Sertoli cell tumor. Most of these tumors produce estrogens, but some may produce androgens.

  • Sertoli cell tumor [show]

    A Sertoli cell tumor is also called androblastoma. It is extremely rare and accounts for 0.5% of all ovarian tumors. The tumor often secretes androgens. In adult women, these tumors are accompanied by progressive masculinization (hirsutism, baldness, voice changes, clitoral enlargement). Tumors can also occur in children. Approximately 10% of patients with tumors developing from ovarian germ cells have signs of incomplete isosexual premature maturation in the form of menstruation, breast development, and areola pigmentation.

  • Chorionic carcinoma [show]

    Chorionic carcinoma is a very rare and extremely malignant tumor. It may be accompanied by premature maturation and secretion of choriogonic gonadotropin. The tumor occurs in childhood or during puberty.

  • Ovarian cyst [show]

    Follicular cysts are a common cause of precocious puberty in girls and secrete enough steroids to cause recurrent uterine bleeding and precocious puberty. It is believed that the first symptom of premature puberty in girls with follicular cysts is bloody discharge from the genital tract with a slight enlargement of the mammary glands. Acceleration of somatic development is not observed. During a gynecological examination, most girls have age-inappropriate “juiciness” of the vulva, pronounced folding of the vagina, a positive “pupil” symptom, however, an enlargement of the uterus and the presence of an angle between the body and the cervix, open in front (characteristic of the pubertal period), are not observed.

    During a gynecological examination and on radiographs, as well as ultrasound sonography, an enlargement of one ovary is noted. Colpocytology is characterized by the presence of intermediate cells and cells with a pyknotic nucleus. Estrogen secretion is increased. Patients with follicular cysts are characterized by transient precocious puberty, when signs of precocious puberty reverse within 2-3 months of observation.

  • Leydig cell tumor [show]

    The most common hormonally active testicular tumor is interstitial cell adenoma, which produces excessive amounts of testosterone. The tumor is benign, and after its removal, excessive progression of sexual development stops. The tumor most often occurs in children under 6 years of age. Such patients usually have well-developed secondary sexual characteristics and other symptoms of precocious sexual development. The testicle affected by the tumor is enlarged, dense, sometimes lumpy, the second testicle is atrophic. Possible gynecomastia.

    The level of testosterone in the blood, the secretion of gonadoliberins and gonadotropins are low, which excludes true premature sexual development.

  • Androblastoma [show]

    Androblastoma is a hormonally active testicular tumor; it is a tubular adenoma, diffuse androblastoma, or an intermediate form. The diffuse type of tumor has the greatest androgenic activity. The diffuse form of androblastoma is characterized by endocrine manifestations: premature sexual development, significant masculinization, and sometimes the development of true gynecomastia. May be benign.

  • Primary hyperplasia of interstitial cells (Leydig cells) [show]

    The disease is genetically determined and is transmitted from sick men and healthy female carriers in an autosomal dominant manner with manifestation only in males. The clinical picture is identical to the idiopathic form of precocious puberty, but unlike it, an earlier onset of the disease is characteristic. Patients retain pubertal basal levels of luteinizing hormone, there is no cyclicity of its secretion and a pubertal type of response to the administration of lutein-releasing hormone.

    Testosterone levels in the blood are significantly increased. Testicular biopsy reveals differentiation of Leydig cells corresponding to puberty or age.

• Drug-induced precocious puberty

  The appearance of secondary sexual characteristics, like premature puberty, can be caused by various medications. Premature pseudopuberty has been described in boys and girls as a result of taking estrogens and anabolic steroids, and is also caused by the admixture of sex hormones in products used for the intensification of livestock production.

  A number of creams, ointments, lotions, and tonics contain sex hormones (most often estrogens), and their use in a child can lead to symptoms of premature puberty.

  When diagnosing precocious puberty caused by medications, the appropriate indications in the anamnesis, the absence of other causes of precocious puberty, as well as the fact that secondary sexual characteristics disappear with the cessation of the administration of exogenous hormones are taken into account.

  • Precocious puberty caused by tumors secreting gonadotropins [show]

    Liver tumors cause premature puberty if they are hormonally active. Usually we are talking about hepatoblastoma. The tumor is more common in boys. Tumor cells produce human chorionic gonadotropin, which stimulates sexual development. Histological examination of the testicles reveals hyperplasia of interstitial cells and lack of spermatogenesis.

    The disease manifests itself as pain in the right hypochondrium, decreased appetite, weight loss, enlarged liver, and uneven surface. Signs of precocious puberty appear on average 2 years after the development of a liver tumor. In the blood serum, the content of α-fetoprotein is increased, the level of follitropin decreases, and the levels of testosterone and lutropin increase.

  • Other tumors [show]

    Choriocarcinoma and teratocarcinoma, or teratoma, can secrete human chorionic gonadotropin and cause precocious puberty. Tumors can be localized in the mediastinum or gonads. Most often they occur in boys. Tumors are accompanied by a high level of human chorionic gonadotropin and α-fetoprotein in the blood; the level of follitropin is reduced, and the level of lutropin is increased due to cross-reaction with human chorionic gonadotropin.

INCOMPLETE FORM OF PREMATURE SEXUAL DEVELOPMENT -
PREMATURE APPEARANCE OF CERTAIN SECONDARY SEXUAL CHARACTERISTICS. Most often we are talking about premature development of the mammary glands, growth of hair on the pubis and in the hollows, and the premature appearance of menstruation.

• Anticipatory isolated development of mammary glands [show]

  There may be anticipatory isolated development of the mammary glands - the formation of mammary glands in girls under the age of 8 years without other signs of premature puberty. Most often, development begins in the first 2 years of life, in 1/3 of cases - from birth. Sometimes only one gland becomes enlarged, or one enlarges more than the other. In 50% of children, the glands regress within 2 years, in the rest they persist until the age of 5 years or more. Usually, premature isolated development of the mammary glands is a benign process, in some cases it is a family trait. The growth and ossification of the skeleton are not disturbed, menstruation appears at the usual time, the levels of follitropin and lutropin in the blood plasma are normal, the reaction to the administration of luliberin is enhanced, the content of estrogen in the blood is normal.

• Premature onset of menstruation without other signs of puberty [show]

  Most girls have one or two episodes of bleeding during prepuberty, maturation begins at normal times, and menstrual cycles form normally. Plasma gonadotropins are at normal levels, but the concentration of estradiol may increase; in some girls, ultrasound examination reveals follicular ovarian cysts.

Diagnosis and differential diagnosis. Diagnostic criteria. History: the mother has signs of sepsis during childbirth, the child has a perinatal or neonatal infection, birth trauma, the use of drugs and ointments containing sex hormones in the treatment of the child. The child has urinary incontinence or perineal itching due to helminthic infestation. In a child with true precocious puberty, the level of gonadotropins is reduced. If a pathology of the adrenal glands is suspected, the content of cortisol, corticotropin, and dehydroepiandrosterone in the blood should be determined. See ALGORITHM.

To clarify the nature of premature puberty, it is advisable to do a computed tomography scan of the skull, adrenal glands, and ultrasound examination of the ovaries of the uterus.

Treatment. For constitutional (idiopathic) premature sexual development, medications are used to inhibit sexual development.

During the 1st week of treatment, the basal level of gonadotropins and their response to the administration of luliberin decreases; after 2 weeks, the levels of estradiol in girls and testosterone in boys decrease. In subsequent months, the size of the mammary glands and uterus decreases, pubic hair falls out, and menstruation stops. In boys, the volume of the testicles and pubic hair decrease, and the growth rate and maturation of bone tissue slow down. The method is considered effective and safe. However, the effect lasts only for the duration of treatment. Currently, long-acting drugs have been obtained that are administered once a month.

An analogue of luliberin is administered subcutaneously daily; the drug suppresses the impulse secretion of gonadotropins.

Antiandrogens are substances that can suppress the action of male sex hormones by competitively binding receptor proteins in the cells of androgen-dependent tissues (target organs). By structure, antiandrogens can be either steroidal or non-steroidal compounds. The main representative of steroidal antiandrogens is cyproterone acetate, non-steroidal - flutamide (niftolide).

Cyproterone acetate (commercial name - androkur) in relatively small doses (20-30 mg per day) weakens erections and emissions in boys, stops further development of sexual hair and genital growth, inhibits premature ossification of epiphyseal cartilage (closure of growth zones). A positive effect is achieved in both boys and girls with premature sexual development. This therapeutic effect of cyproterone acetate is explained by a combination of peripheral antiandrogenic and central antigonadotropic activity. In addition, Androcur inhibits the biosynthesis of ovarian steroids.

Synthetic progesterins reduce the secretion of gonadotropins and reduce the growth of the uterus and ovaries. In girls, 12.5% ​​oxyprogesterone capronate is used, 1 ml once every 7-10 days, long-term intramuscularly for 1-2 years.

Premature sexual development of cerebral origin. Treatment depends on the nature and location of the pathological process. Brain tumors are removed surgically. Some tumors, such as germinomas, are highly sensitive to radiation therapy. If it is impossible to perform surgery or if there is no tumor, treatment is carried out in the same way as for the idiopathic form.

False premature sexual development. Treatment for this form of precocious puberty involves surgical removal of the adrenal or ovarian tumor. Virilizing adrenal hyperplasia is treated with prednisolone. Primary Leydig cell hyperplasia is treated with antiandrogens. If the false form of premature puberty is caused by taking medications, treatment consists of stopping them.

Content: Disorders of the gonads in endocrinopathies of various origins. Syndrome of premature sexual development. A. N. Okorokov True precocious puberty False precocious puberty Incomplete form of precocious puberty Gynecomastia. A. N. Okorokov Hypogonadism syndrome. E. A. Kholodova Hypogonadism in women Hypogonadism in men Virile syndrome. A. N. Okorokov

This condition occurs 10 times more often in girls than in boys and is usually sporadic, although there are familial forms. More than 90% of cases of true precocious puberty in girls are classified as idiopathic, since neither CT nor MRI reveals any changes in the central nervous system. On the other hand, in 25-75% of boys and some girls with true precocious puberty, these studies reveal structural changes in the central nervous system. Idiopathic true precocious puberty is often observed in adopted girls from developing countries. However, it should be borne in mind that in some cases the exact date of birth of such children remains unknown.

Clinical manifestations.

Puberty can begin at any age and its sequence is usually normal. In girls, signs of breast development first appear. At the same time, but often later, pubic hair begins to grow. Then the appearance of the external genitalia changes, hair growth in the armpits occurs, and menstruation begins. The first cycles are usually less regular than during normal sexual development, but a case of pregnancy in a girl even 5.5 years old has been described.

Premature sexual development due to organic brain pathology

Etiology.

The widespread use of CT and, especially, MRI shows that among the disorders of the central nervous system leading to true precocious sexual development, one of the main places is occupied by hypothalamic hamartoma. This congenital lesion consists of ectopic tissue containing GnRH-secreting neurons and may function as an additional generator of GnRH impulses. On MRI, a hamartoma is detected as a pedunculated space-occupying formation (less often without a pedicle), attached to the gray tubercle or to the bottom of the third ventricle. Its dimensions remain unchanged for years. Sometimes psychomotor convulsions (involuntary convulsive laughter) are observed with hamartomas.

True precocious puberty can be caused by various CNS lesions with scarring, invasion, or pressure on the hypothalamus. In all likelihood, some neuronal pathways that inhibit the onset of sexual development are interrupted. This type of damage can result from encephalitis, tuberculous meningoencephalitis, tuberous sclerosis, severe head trauma and hydrocephalus (sometimes in combination with myelomeningocele). Tumors that cause precocious puberty include astrocytomas, ependymomas, and optic tract neoplasms. The latter (usually slowly or not at all progressing optic nerve gliomas) occur in 15-20% of cases in children with neurofibromatosis type I and are the main cause of true precocious puberty in a small group (about 3%) of such children.

True premature sexual development is always isosexual and proceeds in the same way as in the absence of organic pathology of the central nervous system. Hypothalamic hamartoma is characterized by rapid progression of precocious puberty. In other CNS pathologies, there may be a simultaneous GH deficiency, which neutralizes the growth effect of increased levels of sex hormones.

Treatment.

For hypothalamic hamartomas, neurosurgery is indicated only in cases of persistent seizures. For other pathologies of the central nervous system, treatment measures depend on its nature and localization of the process. In any case, the drug of choice is GnRH analogues. With concomitant GH deficiency, GH drugs can be used simultaneously.

Clinical manifestations.

Some of these tumors or birth defects (eg, hypothalamic hamartomas) grow so slowly that they are not accompanied by any symptoms other than precocious puberty. In other cases, neuroendocrine disorders appear 1-2 years before the tumor can be visualized. Intracranial pathology is indicated by such manifestations as:

strabismus;

visual disturbance;

drowsiness;

rolling of eyeballs;

excessive prominence of the forehead;

developmental disorders.

Precocious sexual development due to brain irradiation

Radiation therapy for leukemia or intracranial tumors significantly increases the risk of precocious puberty, regardless of whether it is directed to the hypothalamus or areas of the brain distant from it. Low-dose radiation (18-24 Gy) accelerates the onset of puberty almost only in girls, while high-dose radiation (25-47 Gy) can cause premature puberty in boys, and the risk of this complication is higher the younger you are. child.

Precocious puberty in such cases is often accompanied by GH deficiency, as well as spinal changes and hypothyroidism, further worsening the prognosis for final height. Signs of pubertal development should be closely monitored because when GH deficiency is combined with the growth effect of sex steroids, growth rate may appear normal, but rapid increase in bone age threatens to reduce final height.

Treatment.

As in all other cases of true precocious puberty, GnRH analogues quickly inhibit this process. However, concomitant GH and/or thyroid hormone deficiency requires prompt diagnosis and treatment to improve prospects for future growth.

Over time, after high-dose CNS irradiation (regardless of a history of precocious puberty), gonadotropin deficiency may develop, requiring sex steroid replacement therapy.

Precocious puberty and hypothyroidism

In children with hypothyroidism, bone age reaches 12-13 years later than normal. Accordingly, sexual development is delayed. Premature sexual development in a child with delayed bone age is clearly not a physiological phenomenon, but it is nevertheless observed in almost 50% of children with long-term severe hypothyroidism. In these cases, there are the usual manifestations of hypothyroidism, including slower growth and skeletal maturation. Hypothyroidism is often caused by chronic lymphocytic thyroiditis. Sometimes hypothyroidism results from a thyroidectomy or an overdose of antithyroid drugs.

The sexual development of girls in such cases is manifested mainly by enlargement of the mammary glands and menstrual-like bleeding, which can occur even with minimal development of the mammary glands. An ultrasound of the pelvis reveals large ovaries with multiple cysts. In boys, the testicles enlarge, but not the penis, and there is no pubic hair. X-ray or MRI reveals enlargement of the sella turcica, typical of long-term primary hypothyroidism. Plasma TSH levels are sharply elevated (often more than 500 μU/ml). The concentration of prolactin is also moderately increased. The FSH content is reduced, and LH is not detected at all. Apparently, TSH in high concentrations interacts with FSH receptors (“overcoming specificity”) and thereby imitates the effect of this hormone on the gonads in the absence of the effects of LH. As a result (in contrast to true precocious puberty), in boys the testicles enlarge without stimulation of Leydig cells and increased testosterone secretion, and in girls, the secretion of estrogen by the ovaries is not accompanied by increased secretion of androgens. Thus, with hypothyroidism there is an incomplete form of true precocious sexual development. Treatment of hypothyroidism quickly normalizes the condition of patients. However, the testicles may remain enlarged (> 30 ml in volume) into adulthood.

Gonadotropin-secreting tumors

Liver tumors.

Isosexual precocious puberty sometimes occurs with hepatoblastomas. All described cases were observed in boys. Sexual development in such cases began at the age of 4 months - 8 years (on average 2 years). Suspicion should be raised by an enlarged liver or a palpable mass in the right upper quadrant of the abdomen. The tumor produces human chorionic gonadotropin, which interacts with L1 receptors on Leydig cells in the testes. Histological examination of the testicles reveals hyperplasia of interstitial cells in the absence of spermatogenesis. An increased content of hCG and a-fetoprotein is found in the plasma, while the concentration of FSH and LH, determined by a specific immunometric method, remains low. Due to the cross-reaction of hCG and LH, the radioimmunoassay (RIA) method used in the past gave falsely elevated results for determining LH levels.

These tumors require the same treatment as other types of liver cancer. The prognosis is bad. Patients die 1-2 years after diagnosis.

Other tumors.

Precocious puberty may be caused by hCG-secreting choriocarcinomas, teratocarcinomas, or teratomas (also called ectopic pinealomas or atypical teratomas) located in the brain, mediastinum, gonads, or even the adrenal glands. This is observed 10-20 times more often in boys than in girls. In such cases, the level of hCG and a-fetoprotein in plasma usually increases. Precocious puberty has been described in boys with Klinefelter syndrome when the tumor is localized in the mediastinum.

McCune-Albright syndrome (precocious puberty, fibrous osteodysplasia, and pigmentation disorder)

Premature menarche.

Premature menarche is much less common than premature thelarche or adrenarche and is diagnosed by exclusion. Vaginal bleeding in girls in the absence of other secondary sexual characteristics is often associated with vulvovaginitis, foreign bodies in the genital tract, or violence. It is also necessary to exclude such rare causes as prolapse of the urethral mucosa and embryonal rhabdomyosarcoma of the vagina. In most cases of idiopathic premature menarche, only 2-3 episodes of bleeding are observed. Sexual development occurs at normal times, menstrual cycles are not disrupted. Plasma gonadotropin levels are normal, but estradiol levels may be elevated, probably due to spontaneous episodes of ovarian activity. Sometimes ultrasound reveals follicular ovarian cysts.

Iatrogenic precocious puberty

The cause of premature appearance of secondary sexual characteristics can be a number of medications. Therefore, it is very important to carefully determine the possibility of a child’s contact with such products. False precocious puberty in children of both sexes occurs as a result of accidental intake of estrogens (for example, oral contraceptives) or the administration of anabolic steroids. Estrogens are easily absorbed through the skin, and therefore many estrogen-containing cosmetics and creams can cause enlarged small glands in girls and gynecomastia in boys. In the last two decades, the incidence of premature thelarche and false precocious puberty has been increasing in Puerto Rico, which may be associated with contamination of meat (especially chicken) with estrogens, which are used in animal husbandry. Exogenous estrogens cause darkening of the areola, which is rarely observed with premature puberty of the endogenous type. After the cessation of exposure to exogenous hormones, all these changes disappear. Recently, an increase in cases of virilization of children and women has been noted due to the widespread use of testosterone gel for the treatment of male hypogonadism.