Diagnosis of delay in puberty

Find out the presence of stigma of hereditary and congenital syndromes and peculiarities of puberty of both parents and immediate relatives (I and II degree of kinship). Family history should be collected during the conversation with the patient's relatives, primarily with the mother. Assess the characteristics of intrauterine development, the period of the newborn, the growth rate and psychosomatic development; find out the living conditions and features of nutrition of the girl from the moment of birth, data on physical, psychological and emotional loads; specify the age and nature of operations, the course and treatment of diseases carried over the years of life. Particular attention should be paid to information about the presence of infertility and endocrine diseases in relatives. As well as infectious and somatic diseases in the child in the first year of life, CNS diseases, craniocerebral trauma, since the presence of these conditions and diseases in girls significantly increases the likelihood of an unfavorable prognosis of restoration of the function of the reproductive system. Most girls with a family form of delayed puberty have a history of menarche from their mother and other close relatives and delayed and delayed sexual pilosis or development of the external genitalia in the fathers. In patients with Callman's syndrome, the presence of relatives with a reduced sense of smell or complete anosmia should be clarified.

Mothers of girls with sexual gland dysgenesis often indicate exposure to harmful chemicals and physical factors during their pregnancy, high or frequent radiation exposure (x-ray, microwave, laser and ultrasound), metabolic and hormonal disorders, intoxication with embryotoxic drugs and narcotic substances, transmitted acute infectious diseases, especially viral nature.

Until puberty, the development of a child with XY-dysgenesis of gonads does not differ from peers. In the adolescence, despite the timely sexual embryology, the development of mammary glands is absent, menarche does not arise.

Physical examination

Includes general examination, measurement of height and body weight. At the same time, the features of the distribution and the degree of development of subcutaneous adipose tissue are recorded, height and body weight are compared with regional age standards; note signs of hereditary syndromes, scars after the transferred operations, including on the skull.

The stages of puberty of the girl are evaluated taking into account the degree of development of the mammary glands and sexual (pubic) hairiness (Tanner's criteria of 1969 with modern amendments).

When examining the external genitalia, along with the growth line of pubic hair, the shape and size of the clitoris, large and small labia, the structure of the hymen and the external opening of the urethra are evaluated. Pay attention to the coloration of the skin of the labia, the color of the mucous membrane of the vestibule, the nature of secretions from the genital tract. Inspection of the walls of the vagina and cervix (vaginoscopy) should be carried out using special tubes or children's mirrors of different sizes with lighting. In order to reduce the likelihood of diagnostic errors, recto-abdominal examination is advisable to be performed after the cleansing enema on the eve of the examination.

Laboratory research

Determination of the level of hormones in the blood.

• The determination of the level of FSH, LH, estradiol and dehydroepiandrosterone sulfate (as well as testosterone cortisol, 17-hydroxyprogesterone, pregnenolone, progesterone, somatotropin, prolactin, TSH, free thyroxine, antibodies to thyroid peroxidase) allows us to clarify the hormonal disorders underlying delay of puberty. With a constitutional delay in puberty and hypogonadotropic hypogonadism, a decrease in the concentration of LH and FSH is observed. At the primary lesion of gonads in girls aged 11-12 years, the level of gonadotropic hormones is many times higher than the upper limit of the norm for women of reproductive age. In all patients with a delay in puberty, the level of estradiol corresponds to the tolerant values (less than 60 pmol / l). The content of dehydroepiandrosterone sulfate in girls with hypergonadotropic hypogonadism corresponds to age, with hypogonadotropic hypogonadism, including functional, its level is below the age norm.

• The test with agonists (analogues) GnRH (in patients with bone age less than 11 years is not informative). The study is conducted in the morning after a full sleep. Since the secretion of gonadotropins has an impulsive character, the initial values of LH and FSH should be determined twice - 15 minutes and immediately before the administration of gonadoliberin. The basal concentration is calculated as the arithmetic mean of the two measurements. The drug for daily use containing the analog of GnRH is rapidly administered once intravenously at a dose of 25-50 μg / m ² (usually 100 μg) with a venous blood intake initially, after 30, 45, 60 and 90 minutes. Compare the baseline level of gonadotropins with any three of the highest stimulated values. The maximum increase in the level of LH is determined, as a rule, 30 minutes after the administration of the drug, FSH - after 60-90 minutes. An increase in the level of gonadotropins (the same for LH and FSH) to values above 5 IU / L indicates sufficient reserve and functional capabilities of the pituitary in patients with functional immaturity and hypothalamic diseases. By raising the level of FSH to 10 IU / L and more, and its predominance over the level of LH, we can state a rapid menarche (in the year of the survey). Conversely, the predominance of stimulated LH levels over the content of FSH is a frequent sign of partial enzymatic defects in the synthesis of sex steroids in patients with delayed puberty. Absence of dynamics or a slight increase in the stimulated level of gonadotropins (below puberty values of 5 IU / L) indicate a reduced reserve capacity of the pituitary in patients with hypopituitarism of a congenital or organic nature. Negative test does not allow to differentiate the pathology of the hypothalamus and pituitary gland. Hyperreactive (30 times or more) increase in LH levels in response to the introduction of GnRH suggests an unfavorable prognosis of restorative nonhormonal treatment of girls with delayed puberty. At the same time, the hypersecretion of gonadotropic hormones to the administration of an agonist (analogue) of GnRH (increase in the level of LH and FSH to 50 IU / L and more), including in patients with initially ad tolerant level of gonadotropins, is characteristic for delayed puberty due to congenital or acquired insufficiency ovaries.
• Determination of the level of estradiol in venous blood after 4 h and 5-7 days after the introduction of the GnRH analogue. A significant increase in estradiol is found in girls with functional retardation of puberty and congenital defects in GnRH receptors.
• Determination of the level of LH every 20-30 minutes at night or the total daily excretion of urine. Increase in the night secretion of LH in patients with gonadotropins in the blood serum at the preubertal level allows to diagnose the constitutional variant of ZPS, and the absence of differences between the night and daytime levels of LH is hypogonadotropic hypogonadism.
• Cytogenetic study (karyotype determination) is carried out for the timely detection of the Y-chromosome or its fragments in patients with hypergonadotropic delay in puberty. In a molecular genetic study, mutations in the SRY gene are found in approximately 20% of patients.
• Determination of autoantibodies to ovarian antigens in case of suspected autoimmune nature of ovarian failure.

Instrumental methods

• Echography of pelvic organs in girls with functional retardation of puberty allows to assess the degree of development of the uterus and ovaries, including to reveal an increase in the diameter of the cavitary follicles in response to a test with GnRH agonists. In the constitutional form of delayed puberty, the uterus and gonads are well visualized, are of a pre-abdominal size, in the majority of patients single follicles are determined in the ovaries. With hypogonadotropic hypogonadism, the uterus and ovaries are sharply underdeveloped, and in case of hypergonadotropic hypogonadism, strands lacking a follicular apparatus, whose anteroposterior size does not exceed 1 cm (in the absence of a tumor in the gonad), are found in place of the ovaries or testicles.
• Echography of the thyroid gland and internal organs (according to indications) in patients with chronic somatic and endocrine diseases.
• Echography of mammary glands. The picture corresponds to the period of relative dormancy characteristic of girls of pre-adjectival age.
• Radiography of the left wrist and wrist to determine the bone age and growth prognosis. With a constitutional delay in puberty, bone age, growth, and puberty correspond to each other. With an isolated gonadotropic or gonadal delay in puberty, the bone age lags considerably behind the calendar age, not exceeding 11.5-12 years by the time of the physiological completion of the pubertal period.
• MRI of the brain makes it possible to clarify the state of the hypothalamic-pituitary region in the hypogonadotropic form of delayed puberty. Scanning the hypophysis and hypothalamus with a small step, including augmented by contrasting the vascular network, allows detecting tumors with a diameter of more than 5 mm, congenital and acquired hypoplasia or aplasia of the pituitary and hypothalamus, cerebral vascular anomalies, neurohypophysis ectopy, absence or expressed maldevelopment of olfactory bulbs in patients with syndrome Callman.
• Radiography of the skull is a reliable informative method for diagnosing tumors of the hypothalamic-pituitary region deforming the Turkish saddle (widening of the entrance, destruction of the back, enlargement of the size, thinning and deformation of the wall and bottom contour).
• Densitometry (X-ray absorptiometry) is shown to all girls with a delay in puberty for the purpose of early diagnosis of bone mineral density deficiency.
• Ophthalmoscopy is of diagnostic value for the diagnosis of specific pigment retinitis in patients with Laurence-Mun-Barde-Biddle syndrome, color vision defects and retinal colitis in patients with Callman's syndrome, retinopathy in patients with delayed puberty in diabetes mellitus, chronic hepatic and renal insufficiency, and the definition of fields of vision - to assess the degree of damage to the intersection of the optic nerves with brain tumors.
• Hearing test for suspected isolated gonadotropin deficiency or Turner syndrome with minimal clinical manifestations.
• Examination of the sense of smell upon suspicion of Callman's syndrome in patients with hypogonadotropic hypogonadism.

Differential diagnostics

Constitutional form of ZPS

Parents of girls with a delay in puberty have similar rates of puberty and growth (twice as often as the mother). In patients, lag of growth and body weight is noted from 3 to 6 months of life, which leads to a moderate delay in physical development at the age of 2-3 years. At the time of the survey, the growth of girls, as a rule, corresponds to 3-25-centile indicators of healthy girls. It is possible to reduce the ratio of the upper and lower parts of the body due to a longer growth of the lower extremities with a delayed ossification of the epiphyses of tubular bones. The rate of linear growth with this form of delay in puberty is not less than 3.7 cm / g. The pubertal growth spurt is less pronounced and occurs at the age of 14 to 18 years. The body weight of patients corresponds to age standards, but the figure remains infantile due to a weak accumulation of subcutaneous fat on the hips and buttocks. The biological age lags behind the chronological by 1.6-4 g. There are no somatic abnormalities, the development of all organs and systems lags behind for an equal number of years (retardation). A characteristic feature of the constitutional form of delay in puberty is the maturity of the physical (growth) and sexual (mammary glands and pubic hair) maturation to the level of biological maturity (bone age) and the same lag of these parameters from the calendar age. When gynecological examination determine the insufficient development of large and small labia, a thin mucous membrane of the vulva, vagina and cervix, underdevelopment of the uterus.

Hypogonadotropic hypogonadism

• In the clinical picture, signs of significant delay in puberty are combined with symptoms of chromosomal diseases, neurological symptoms (with volumetric, post-traumatic and post-inflammatory diseases of the central nervous system), characteristic changes in mental status (anorexia nervosa and bulimia), specific signs of endocrine and severe chronic somatic diseases.
• In girls with Kallmann's syndrome, physical development does not differ from regional age standards. Delay in puberty has a pronounced character. The most frequent sign of the syndrome is anosmia or hyposmia. Possible deafness, cerebral ataxia, nystagmus, epilepsy, as well as malformations (cleft lip or hard palate, unpaired incisor of the upper jaw, aplasia or hypoplasia of the optic nerve bulb and kidney, shortening of the pastern bone).
• In patients with Prarader-Willi syndrome, early signs reveal such signs as muscular hypotension of newborns, lethargy attacks, hyperphagia, dwarfism, diminishing sizes of arms and legs and shortening of fingers, bulimia and pathological obesity, moderate mental retardation, marked stubbornness and tediousness. Girls have characteristic facial features (almond-shaped incision of closely-set eyes, narrow face, triangular mouth).
• In the Lorenz-Muna-Barde-Biddle syndrome the most significant sign, in addition to dwarfism and early obesity, is retinitis pigmentosa and coloboma retina. Among other symptoms of the disease, spastic paraplegia of newborns, polydactyly, cystic kidney dysplasia, mental retardation, diabetes mellitus are noted.
• Girls with Russell's syndrome have a marked lag in physical development (dwarfism) and lack of puberty, skeletal skeletal asymmetry, including facial bones of the skull, a characteristic triangular face due to underdevelopment of the lower jaw (hypognathia) and pigmented spots of coffee color on the skin of the trunk.
• Hend-Schüller-Christen syndrome caused by multiple ectopy and proliferation of histiocytes in the brain, including the hypothalamus, leg and posterior lobe of the pituitary gland, on the skin, in the internal organs and bones, manifests itself as a growth retardation and delay in puberty, diabetes insipidus and symptoms of damage to the relevant organs and tissues. When infiltrating the orbit, exophthalmos are observed, jaw bones - loss of teeth, temporal and mastoid bones - chronic otitis media and hearing loss, limb bones and ribs - eosinophilic granulomas and fractures, in the internal organs they mark the symptoms of multiple tumor growth.
• The presence of a congenital mutation of the gene for the GnRH receptor can be assumed in girls who have no other reasons for delaying puberty, but at the examination of which pronounced manifestations of deficiency of estrogenic influences were revealed. Normal or moderately reduced levels of LH and FSH (usually below 5 IU / L) with the content of other pituitary hormones within the norm and the absence of developmental abnormalities.
• Unlike the constitutional delay of puberty, the signs of hypogonadotropic hypogonadism do not disappear with age.

Hypergonadotrophic hypogonadism

• With Turner's syndrome and its variants, the patients with the so-called typical form of gonadal dysgenesis having structural anomalies of a single X chromosome (X-monosomy), especially its short arm, are most loaded with pathological signs. At birth, these children have low body weight and lymphatic edema of the hands and feet (Bonnevi-Ullrich syndrome). Growth rates of up to 3 years are relatively stable and slightly different from normal, but the bone age in patients 3 years is 1 year behind. In the future, the slowdown in growth rates is progressing, and the bone age lags behind. The pubertal growth spurt is shifted to 15-16 years and does not exceed 3 cm. Typical external manifestations of Turner's syndrome: a disproportionately large shield-shaped thorax with widely spaced nipples of undeveloped mammary glands; valgus deviation of the elbow and knee joints; multiple birthmarks or vitiligo; hypoplasia of terminal phalanges IV and V of fingers and nails; short "neck of the sphinx" with pterygoid folds of the skin, extending from the ears to the shoulder process ("sweep" neck); deformation of the auricles and a low line of hair growth on the neck. The facial features were changed as a result of strabismus, the Mongoloid section of the eyes (epicanthus), the lower eyelid (ptosis), deformities of the teeth, underdevelopment of the lower jaw (micro- and retrognathy), there is a gothic palate. In patients with Turner's syndrome, otitis and hearing loss, color blindness, congenital heart diseases, aorta (coarctation and stenosis of the mouth) and urinary organs are often noted (horseshoe kidney, retrovascular placement of ureters, their duplication, unilateral renal aplasia). Also observed are hypothyroidism, autoimmune thyroiditis and diabetes mellitus. In the erased forms, most stigmas are not manifested. However, careful examination of even normal growth patients allows to detect irregular shape of the auricles, gothic or high palate, low hair growth on the neck and hypoplasia of the terminal phalanges of the IV and V fingers and toes. The structure of the external and internal genital organs is feminine, but the large and small labia, vagina and uterus are sharply underdeveloped. At the border of the entrance to the small pelvis, the underdeveloped sex glands in the form of echo negative strands are determined. About 25% of girls with Turner syndrome have spontaneous puberty and menarche, which is due to the preservation at the time of birth of a sufficient number of oocytes. In the pubertal period, menstruating patients are characterized by uterine bleeding.
• The "pure" form of gonadal dysgenesis manifests itself in pronounced sexual infantilism in the absence of abnormalities in the development of the muscular, bone and other systems. Usually patients have normal growth and female phenotype as with karyotype 46.XX. Bone age of patients with a "clean" form of gonadal dysgenesis lags behind the calendar age, but this lag is less pronounced than with Turner syndrome.
• 46, XY-dysgenesis of sexual glands should be differentiated from the central form of delayed puberty, a clean form of gonadal dysgenesis in the female set of sex chromosomes and other forms of XY-sex reversal. From the central forms of delay in puberty, patients with XY-dysgenesis are characterized by a high content of gonadotropic hormones in the blood, smaller sizes of sexual glands (according to echographic data) and the absence of a follicular apparatus in them, a large delay in the biological age from calendar (for 3 years or more) absence of CNS pathology. From the "pure" form of gonadal dysgenesis, not accompanied by a reversal of sex, patients with XY-dysgenesis are characterized by negative sex chromatin and the presence of the Y-chromosome in the karyotype. In such patients, virilization of the external genitalia is possible. From patients with false male hermaphroditism, in which both the gonadal and hormonal sex are male, patients with XY-dysgenesis are characterized by the presence of Mullerian ducts, the disgenetic sexual glands in the abdominal cavity, hypergonadotropinemia in the background of a low level of estradiol and testosterone.

Indications for consultation of other specialists

Consultation with a geneticist in hypergonadotropic form of delayed puberty for genealogical and cytogenetic studies.

For patients with delayed puberty, an endocrinologist should be consulted in order to clarify the diagnosis, the features of the course and therapy of diabetes mellitus, hypercorticism syndrome, thyroid pathology, obesity, and to clarify the causes of stunting and the possibility of therapy with recombinant growth hormone.

For patients with hypogonadotropic hypogonadism, a consultation is given by a neurosurgeon to resolve the issue of surgical treatment when detecting volumetric formations in the brain.

Consultation with narrow pediatric specialists, taking into account systemic diseases that caused a delay in puberty.

Consultation with a psychotherapist for the treatment of nervous and psychogenic anorexia and bulimia.

Consultation with a psychologist to improve the psychosocial adaptation of girls with a delay in puberty.

[1], [2], [3], [4], [5], [6], [7],