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.

Mothers of girls with dysgenesis of the gonads often point to exposure to harmful chemicals and physical factors during pregnancy, high or frequent radiation exposure (X-ray, ultra-high-frequency, laser and ultrasound radiation), metabolic and hormonal disorders, intoxication due to the use of embryotoxic drugs and narcotic substances, acute infectious diseases, especially of a viral nature.

Until puberty, the development of a child with XY gonadal dysgenesis does not differ from that of his or her peers. During adolescence, despite timely sexual hair growth, there is no development of the mammary glands, and menarche does not occur.

Physical examination

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

The stages of puberty in girls are assessed taking into account the degree of development of the mammary glands and genital (pubic) hair growth (Tanner criteria of 1969 with modern amendments).

When examining the external genitalia, in addition to the pubic hairline, the shape and size of the clitoris, labia majora and minora, the structural features of the hymen and the external opening of the urethra are assessed. Attention is paid to the color of the skin of the labia, the color of the mucous membrane of the vestibule of the vagina, and the nature of the discharge from the genital tract. Examination 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, a rectoabdominal examination should be carried out after a cleansing enema the day before the examination.

Laboratory research

Determination of hormone levels in the blood.

• Determination of the level of FSH, LH, estradiol and dehydroepiandrosterone sulfate (and, if indicated, testosterone, cortisol, 17-hydroxyprogesterone, pregnenolone, progesterone, somatotropin, prolactin, TSH, free thyroxine, antibodies to thyroid peroxidase) allows to clarify the hormonal disorders underlying the delay of puberty. In constitutional delay of puberty and hypogonadotropic hypogonadism, a decrease in the concentration of LH and FSH is observed. In primary gonadal damage 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 delayed puberty, the level of estradiol corresponds to prepubertal values (less than 60 pmol / l). The content of dehydroepiandrosterone sulfate in girls with hypergonadotropic hypogonadism corresponds to age; in hypogonadotropic hypogonadism, including functional hypogonadism, its level is below the age norm.

• A test with GnRH agonists (analogues) (in patients with a bone age of less than 11 years, it is not informative). The study is carried out in the morning after a full night's sleep. Since the secretion of gonadotropins is pulsed, the initial values of LH and FSH should be determined twice - 15 minutes before and immediately before the administration of gonadotropin-releasing hormone. The basal concentration is calculated as the arithmetic mean of two measurements. A daily drug containing a GnRH analogue is quickly administered intravenously once at a dose of 25-50 μg/m2 ⁽ usually 100 μg) with venous blood sampling at baseline, 30, 45, 60 and 90 minutes. The initial level of gonadotropins is compared with any three highest stimulated values. The maximum increase in LH levels is usually determined 30 minutes after drug administration, and FSH - 60-90 minutes. An increase in the level of gonadotropins (the same for LH and FSH) to values above 5 IU/L indicates sufficient reserve and functional capacity of the pituitary gland in patients with functional immaturity and diseases of the hypothalamus. An increase in the FSH level to 10 IU/L or more and its predominance over the LH level may indicate imminent menarche (in the year of examination). Conversely, the predominance of the stimulated level of LH over the FSH content is a frequent sign of partial enzymatic defects in the synthesis of sex steroids in patients with delayed puberty. The absence of dynamics or an insignificant increase in the stimulated level of gonadotropins (below the pubertal values of 5 IU/L) indicate reduced reserve capacity of the pituitary gland in patients with congenital or organic hypopituitarism. A negative test does not allow differentiating between pathologies of the hypothalamus and pituitary gland. A hyperreactive (30 times or more) increase in LH levels in response to the introduction of GnRH suggests an unfavorable prognosis for restorative non-hormonal treatment of girls with delayed puberty. At the same time, hypersecretion of gonadotropic hormones in response to the introduction of a GnRH agonist (analogue) (an increase in LH and FSH levels to 50 IU/l or more), including in patients with initially prepubertal gonadotropin levels, is characteristic of delayed puberty due to congenital or acquired ovarian failure.
• Determination of the level of estradiol in venous blood 4 hours and 5-7 days after the administration of a GnRH analogue. A reliable increase in estradiol is determined in girls with functional delay of puberty and congenital defects of GnRH receptors.
• Determination of LH level every 20-30 min at night or its total daily excretion with urine. Increased nocturnal secretion of LH in patients with serum gonadotropins at the prepubertal level allows diagnosing the constitutional variant of PPD, and the absence of differences between the nocturnal and daytime levels of LH - hypogonadotropic hypogonadism.
• Cytogenetic testing (karyotype determination) is performed for timely detection of the Y chromosome or its fragments in patients with hypergonadotropic delay of puberty. Molecular genetic testing reveals mutations in the SRY gene in approximately 20% of patients.
• Determination of autoantibodies to ovarian antigens in cases of suspected autoimmune nature of ovarian insufficiency.

Instrumental methods

• Echography of the pelvic organs in girls with functional delayed puberty allows to assess the degree of development of the uterus and ovaries, including detection of an increase in the diameter of cystic follicles in response to a test with GnRH agonists. In the constitutional form of delayed puberty, the uterus and gonads are well visualized, have prepubertal sizes, and in most patients, single follicles are detected in the ovaries. In hypogonadotropic hypogonadism, the uterus and ovaries are severely underdeveloped, and in hypergonadotropic hypogonadism, instead of ovaries or testicles, cords are found that lack a follicular apparatus, the anteroposterior size of which does not exceed 1 cm (in the absence of a tumor in the gonad).
• Ultrasound of the thyroid gland and internal organs (as indicated) in patients with chronic somatic and endocrine diseases.
• Ultrasound of the mammary glands. The picture corresponds to a period of relative rest, typical for prepubertal girls.
• X-ray of the left hand and wrist to determine bone age and growth prognosis. In constitutional delay of puberty, bone age, growth, and puberty correspond to each other. In isolated gonadotropic or gonadal delay of puberty, bone age lags significantly behind the calendar age, not exceeding 11.5-12 years by the time of physiological completion of puberty.
• MRI of the brain makes it possible to clarify the condition of the hypothalamic-pituitary region in the hypogonadotropic form of delayed puberty. Scanning the pituitary gland and hypothalamus with a small step, including supplemented by contrasting the vascular network, makes it possible to detect tumors with a diameter of more than 5 mm, congenital and acquired hypoplasia or aplasia of the pituitary gland and hypothalamus, cerebral vascular anomalies, ectopia of the neurohypophysis, absence or severe underdevelopment of the olfactory bulbs in patients with Kallmann syndrome.
• X-ray of the skull is a reliable informative method for diagnosing tumors of the hypothalamic-pituitary region that deform the sella turcica (widening of the entrance, destruction of the back, increase in size, thinning and deformation of the contour of the walls and bottom).
• Densitometry (X-ray absorptiometry) is indicated for all girls with delayed puberty for the purpose of early diagnosis of bone mineral density deficiency.
• Ophthalmoscopy has diagnostic value for the diagnosis of specific retinitis pigmentosa in patients with Laurence-Moon-Bardet-Biedl syndrome, defects in color vision and retinal coloboma in patients with Kallmann syndrome, retinopathy in patients with delayed puberty due to diabetes mellitus, chronic liver and kidney failure, and determination of visual fields - for assessing the degree of damage to the optic chiasm by brain tumors.
• Hearing testing if isolated gonadotropin deficiency or Turner syndrome with minimal clinical manifestations is suspected.
• Olfactory testing for suspected Kallmann syndrome in patients with hypogonadotropic hypogonadism.

Differential diagnostics

Constitutional form of the ZPS

Parents of girls with delayed puberty have similar rates of puberty and growth (twice as often as the mother). Patients have a lag in growth and body weight 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 examination, the height of girls, as a rule, corresponds to the 3-25th percentile indicators of healthy peers. A decrease in the ratio of the upper and lower parts of the body is possible due to a longer growth of the lower limbs with slow ossification of the epiphyses of tubular bones. The rate of linear growth in this form of delayed puberty is at least 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 weak accumulation of subcutaneous fat on the hips and buttocks. Biological age lags behind chronological age by 1.6-4 years. There are no somatic anomalies, the development of all organs and systems lags behind by an equal number of years (retardation). A characteristic feature of the constitutional form of delayed puberty is the correspondence of physical (height) 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. During a gynecological examination, insufficient development of the labia majora and minora, thin mucous membrane of the vulva, vagina and cervix, and underdevelopment of the uterus are determined.

Hypogonadotropic hypogonadism

• In the clinical picture, signs of significant delay in puberty are combined with symptoms of chromosomal diseases, neurological symptoms (in case of extensive, 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.
• Girls with Kallmann syndrome have physical development that does not differ from regional age norms. Delayed puberty is pronounced. The most common symptom of the syndrome is anosmia or hyposmia. Hearing loss, cerebral ataxia, nystagmus, epilepsy, and developmental defects (cleft lip or hard palate, unpaired maxillary incisor, aplasia or hypoplasia of the optic nerve bulb and kidney, shortening of the metacarpal bones) are possible.
• Patients with Prader-Willi syndrome exhibit such signs as neonatal muscle hypotonia, lethargy attacks, hyperphagia, dwarfism, decreased size of arms and legs and shortened fingers, bulimia and morbid obesity, moderate mental retardation, pronounced stubbornness and tediousness from early childhood. Girls have characteristic facial features (almond-shaped eyes, close-set eyes, narrow face, triangular mouth).
• In Lawrence-Moon-Bardet-Biedl syndrome, the most significant symptom, in addition to dwarfism and early obesity, is retinitis pigmentosa and retinal coloboma. Other symptoms of the disease include spastic paraplegia of newborns, polydactyly, cystic dysplasia of the kidneys, mental retardation, and diabetes mellitus.
• Girls with Russell syndrome have a marked delay in physical development (dwarfism) and absence of puberty, asymmetry in skeletal development, including the facial bones of the skull, a characteristic triangular face due to underdevelopment of the lower jaw (hypognathia), and coffee-colored pigment spots on the skin of the body.
• Hand-Schüller-Christian syndrome, caused by multiple ectopia and proliferation of histiocytes in the brain, including the hypothalamus, stalk and posterior lobe of the pituitary gland, on the skin, in the internal organs and bones, manifests itself as growth retardation and delayed puberty, diabetes insipidus and symptoms of damage to the corresponding organs and tissues. With infiltration of the orbit, exophthalmos is observed, jaw bones - tooth loss, temporal and mammillary bones - chronic otitis media and hearing loss, limb bones and ribs - eosinophilic granulomas and fractures, in the internal organs, symptoms of multiple tumor growth are noted.
• The presence of a congenital mutation of the GnRH receptor gene can be assumed in girls who have no other causes of delayed puberty, but whose examination revealed pronounced manifestations of deficiency of estrogenic effects. Normal or moderately reduced levels of LH and FSH (usually below 5 IU/L) with the content of other pituitary hormones within normal limits and the absence of developmental anomalies.
• Unlike constitutional delay of puberty, signs of hypogonadotropic hypogonadism do not disappear with age.

Hypergonadotropic hypogonadism

• In Turner syndrome and its variants, patients with the so-called typical form of gonadal dysgenesis, which have structural abnormalities of a single X chromosome (X monosomy), especially its short arm, are most burdened with pathological signs. At birth, these children have low body weight and lymphedema of the arms and legs (Bonnevie-Ullrich syndrome). Growth rates up to 3 years are relatively stable and differ slightly from the norm, but bone age in patients aged 3 years lags behind by 1 year. Subsequently, the slowdown in growth rates progresses, and bone age lags further. The pubertal growth spurt is shifted to 15-16 years and does not exceed 3 cm. Typical external manifestations of Turner syndrome: a disproportionately large thyroid chest with widely spaced nipples of underdeveloped mammary glands; valgus deviation of the elbows and knee joints; multiple birthmarks or vitiligo; hypoplasia of the terminal phalanges of the fourth and fifth fingers and nails; short "sphinx neck" with pterygoid folds of skin extending from the ears to the shoulder process ("swallow" neck); deformation of the auricles and a low hairline on the neck. Facial features are altered as a result of strabismus, Mongoloid eye shape (epicanthus), drooping of the upper eyelid (ptosis), deformation of the teeth, underdevelopment of the lower jaw (micro- and retrognathia), and a Gothic palate. Patients with Turner syndrome often have otitis and hearing loss, color blindness, congenital heart defects, aortic defects (coarctation and stenosis of the orifice) and urinary organs (horseshoe kidney, retrocaval location of the ureters, their duplication, unilateral renal aplasia). Hypothyroidism, autoimmune thyroiditis and diabetes mellitus are also observed. In latent forms, most stigmas are not evident. However, careful examination of even patients of normal height reveals an irregular shape of the auricles, a gothic or high palate, low hair growth on the neck, and hypoplasia of the terminal phalanges of the fourth and fifth fingers and toes. The structure of the external and internal genitalia is female, but the labia majora and minora, vagina, and uterus are severely underdeveloped. Underdeveloped sex glands in the form of echo-negative strands are found at the border of the entrance to the small pelvis. About 25% of girls with Turner syndrome have spontaneous puberty and menarche, which is due to the preservation of a sufficient number of oocytes at the time of birth. In the pubertal period, menstruating patients are characterized by uterine bleeding.
• The "pure" form of gonadal dysgenesis is manifested by pronounced sexual infantilism in the absence of developmental anomalies of the muscular, skeletal and other systems. Patients usually have normal growth and a female phenotype as with the karyotype 46.XX. The bone age of patients with the "pure" form of gonadal dysgenesis lags behind the calendar age, but this lag is less pronounced than in Turner syndrome.
• 46. XY dysgenesis of the gonads should be differentiated from the central form of delayed puberty, the pure form of gonadal dysgenesis with a female set of sex chromosomes, and other forms of XY sex reversal. Patients with XY dysgenesis differ from central forms of delayed puberty in having a high content of gonadotropic hormones in the blood, smaller sizes of the gonads (according to echographic examination data) and the absence of a follicular apparatus in them, a large lag in biological age from the calendar age (by 3 years or more), and the absence of CNS pathology. Patients with XY dysgenesis differ from the "pure" form of gonadal dysgenesis, not accompanied by sex reversal, in having negative sex chromatin and the presence of a Y chromosome in the karyotype. Such patients may have virilization of the external genitalia. Patients with XY dysgenesis differ from patients with false male hermaphroditism, in whom both the gonadal and hormonal sex are male, by the presence of derivatives of the Müllerian ducts, the location of the dysgenetic sex glands in the abdominal cavity, and hypergonadotropinemia against the background of low levels of estradiol and testosterone.

Indications for consultation with other specialists

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

For patients with delayed puberty, a consultation with an endocrinologist is necessary to clarify the diagnosis, the characteristics of the course and therapy of diabetes mellitus, hypercorticism syndrome, thyroid pathology, obesity, as well as to clarify the causes of short stature and decide on the possibility of therapy with recombinant growth hormone.

For patients with hypogonadotropic hypogonadism, a consultation with a neurosurgeon is indicated to decide on surgical treatment if space-occupying lesions are detected in the brain.

Consultation with specialized pediatricians taking into account systemic diseases that caused delayed 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 delayed puberty.

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