Delayed puberty in children

Delayed puberty is the absence of breast enlargement in girls who have reached the age of 13, or the absence of secondary sexual characteristics in terms exceeding the upper limit of the age norm by 2.5 standard deviations. Delayed puberty is also considered to be the absence of menarche by the age of 15.5-16 years, cessation of development of secondary sexual characteristics for more than 18 months, delay of menarche for 5 years or more after the timely onset of breast growth. It should be noted that the appearance of sexual hair (pubic and axillary) should not be considered a sign of puberty.

ICD-10 code

• E30.0 Delayed puberty.
• E30.9 Disorder of puberty, unspecified.
• E45 Delayed puberty due to protein-energy deficiency.
• E23.0 Hypopituitarism (hypogonadotropic hypogonadism, isolated gonadotropin deficiency, Kallmann syndrome, panhypopituitarism, pituitary cachexia, pituitary insufficiency NEC).
• E23.1 Drug-induced hypopituitarism.
• E23.3 Hypothalamic dysfunction, not elsewhere classified.
• E89.3 Hypopituitarism following medical procedures.
• E89.4 Ovarian failure following medical procedures.
• N91.0 Primary amenorrhea (menstrual irregularities during puberty).
• E28.3 Primary ovarian failure (low estrogen, persistent ovarian syndrome).
• Q50.0 Congenital absence of ovaries (except Turner syndrome).
• E34.5 Testicular feminization syndrome, androgen resistance syndrome.
• Q56.0 Hermaphroditism, not elsewhere classified (sex gland containing tissue components of the ovary and testicle - ovotestis).
• Q87.1 Syndromes of congenital anomalies predominantly characterized by dwarfism (Russell syndrome).
• Q96 Turner syndrome and its variants.
• Q96.0 Karyotype 45.ХО.
• Q96.1 Karyotype 46.X iso (Xq).
• Q96.0 Karyotype 46.X with abnormal sex chromosome except iso (Xq).
• Q96.3 Mosaicism 45.X/46.XX or XY.
• Q96.4 Mosaicism 45,X/other cell line(s) with abnormal sex chromosome.
• Q96.8 Other variants of Turner syndrome.
• Q97 Other abnormalities of sex chromosomes and female phenotype, not elsewhere classified (including female with karyotype 46.XY).
• Q99.0 Mosaic (chimera) 46XX/46XY, true hermaphrodite.
• Q99.1 46XX - true hermaphrodite (with streak gonads, 46XY with streak gonads, pure gonadal dysgenesis - Swyer syndrome).

Epidemiology

Among the white population, about 2-3% of 12-year-old girls and 0.4% of 13-year-old girls have no signs of puberty. The main cause of delayed puberty is gonadal insufficiency (48.5%), less common are hypothalamic insufficiency (29%), enzymatic defect of hormone synthesis (15%), isolated insufficiency of the anterior pituitary gland (4%), pituitary tumors (0.5%), of which 85% are prolactinomas. The incidence of gonadal dysgenesis with karyotype 46.XY (Swyer syndrome) is 1 in 100,000 newborn girls.

Screening

As part of neonatal screening - determination of sex chromatin in all newborns (laboratory confirmation of the child's sex). Monitoring of growth dynamics is necessary in girls with signs of congenital syndromes for timely correction of the rate of puberty.

During treatment of delayed puberty, it is necessary to determine the annual growth dynamics of girls, their puberty, bone age, the level of gonadotropins (LH and FSH) and estradiol in venous blood.

Classification of delayed puberty

Currently, taking into account the level of damage to the reproductive system, three forms of delayed puberty are distinguished.

The constitutional form of delayed puberty is expressed in the delay in the growth of the mammary glands and the absence of menarche in a somatically healthy girl aged 13 years, who has an equivalent lag in physical (length and body weight) and biological (bone age) development.

Hypogonadotropic hypogonadism is a delay in puberty caused by a pronounced deficiency in the synthesis of gonadotropic hormones due to aplasia or hypoplasia, damage, hereditary, sporadic or functional insufficiency of the hypothalamus and pituitary gland.

Hypergonadotropic hypogonadism is a delay in puberty caused by congenital or acquired lack of secretion of sex gland hormones. Congenital forms are dysgenesis or agenesis of the ovaries or testicles. There are two forms of ovarian dysgenesis: typical - Turner syndrome (in our country, Shereshevsky-Turner syndrome) and "pure" with a karyotype of 46.XX; and three forms of testicular dysgenesis: typical (45.XO / 46.XY), "pure" (Swyer syndrome) and mixed, or asymmetric. In the typical form, patients have multiple stigmas of embryogenesis, characteristic of Turner syndrome. The "pure form" is characterized by ribbon-shaped gonads in the absence of somatic developmental anomalies. The mixed form is characterized by asymmetry in the development of the internal gonads (an undifferentiated cord on one side and a testicle or tumor on the opposite side; absence of a gonad on one side and a tumor, cord or testicle on the opposite side). However, in recent years, in foreign literature, the division of XY dysgenesis (except for Turner syndrome) into complete and incomplete forms (complete and partial gonadal dysgenesis) has become increasingly common. Such an approach emphasizes the fact that all types of dysgenesis of the gonads are different links in one pathogenetic mechanism of violation of sexual differentiation. Thus, this pathology is considered as one disease, that is, different variants of XY gonadal dysgenesis.

Causes and pathogenesis of delayed puberty

Constitutional form

Constitutional delay of puberty is usually hereditary. The development of this syndrome is caused by etiologic factors that lead to late activation of the hypothalamic-pituitary function and suppress the pulsatile secretion of hypothalamic GnRH). Pathogenetic mechanisms of their action remain unclear. Numerous studies have been devoted to the study of monoamine control of the hypothalamic-pituitary function in children with delayed puberty. A general trend in changes in catecholamine levels has been found: a decrease in norepinephrine and adrenaline levels and an increase in serotonin concentration. Another putative cause of delayed puberty is functional hyperprolactinemia, which may be associated with a decrease in dopaminergic tone, which leads to a decrease in the pulsatile secretion of both gonadotropic hormones and growth hormone.

Delayed puberty in hypogonadotropic hypogonadism (central genesis)

The basis of delayed puberty in hypogonadotropic hypogonadism is a deficiency in the secretion of gonadotropic hormones as a result of congenital or acquired disorders of the central nervous system.

Causes and pathogenesis of delayed puberty

Symptoms of Delayed Puberty

The main signs of delayed puberty in girls against the background of hypofunction of the central regulatory departments of the reproductive system (central form of delayed puberty):

• absence or underdevelopment of secondary sexual characteristics at the age of 13-14 years;
• absence of menstruation at the age of 15-16 years;
• hypoplasia of the external and internal genitalia combined with growth retardation.

The combination of the listed signs of hypoestrogenism with a pronounced deficit in body weight, decreased vision, impaired thermoregulation, prolonged headaches or other manifestations of neurological pathology may indicate a violation of the central regulatory mechanisms.

Symptoms of Delayed Puberty

Diagnosis of delayed puberty

The presence of stigmas of hereditary and congenital syndromes and the characteristics of puberty of both parents and immediate relatives (I and II degrees of kinship) are determined. Family history should be collected during a conversation with the patient's relatives, primarily with the mother. The characteristics of intrauterine development, the course of the neonatal period, growth rates and psychosomatic development are assessed; the living conditions and nutritional characteristics of the girl from the moment of birth, data on physical, psychological and emotional stress are determined; the age and nature of operations, the course and treatment of diseases suffered by years of life are specified. Particular attention should be paid to information on the presence of infertility and endocrine diseases in relatives, as well as infectious and somatic diseases in a child in the first year of life, diseases of the central nervous system, traumatic brain injuries, since the presence of these conditions and diseases in girls significantly increases the likelihood of an unfavorable prognosis for the restoration of the reproductive system function. Most girls with familial delayed puberty have a history of late menarche in the mother and other close female relatives and delayed and retarded sexual hair growth or external genital development in the fathers. In patients with Kallmann syndrome, the presence of relatives with reduced olfactory function or complete anosmia should be clarified.

Diagnosis of delayed puberty

Treatment of delayed puberty

• Prevention of malignancy of dysgenetic gonads located in the abdominal cavity.
• Stimulation of pubertal growth spurt in patients with growth retardation.
• Replenishment of the deficiency of female sex hormones.
• Stimulation and maintenance of the development of secondary sexual characteristics to form the female figure.
• Activation of osteosynthesis processes.
• Prevention of possible acute and chronic psychological and social problems.
• Prevention of infertility and preparation for childbirth through in vitro fertilization of donor eggs and embryo transfer.

Treatment of delayed puberty

Forecast

The fertility prognosis in patients with constitutional delayed puberty is favorable.

In hypogonadotropic hypogonadism and ineffective therapy consisting of individually selected antihomotoxic drugs or drugs that improve CNS function, fertility can be temporarily restored by exogenous administration of LH and FSH analogues (in secondary hypogonadism) and GnRH analogues in a circulatory regimen (in tertiary hypogonadism).

Prevention

There are no data confirming the existence of developed measures to prevent delayed puberty in girls. In central forms of the disease caused by nutritional deficiency or inadequate physical activity, it is advisable to follow a work and rest regimen against the background of rational nutrition before the onset of puberty. In families with constitutional forms of delayed puberty, observation by an endocrinologist and gynecologist is necessary from childhood. There is no prevention for gonadal and testicular dysgenesis.

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