Causes and pathogenesis of delayed puberty

Constitutional form

The constitutional delay of puberty, as a rule, is hereditary. The formation of this syndrome is caused by etiological factors leading to late activation of the hypothalamic-pituitary function and suppressing the impulse secretion of the hypothalamic GnRH. The pathogenetic mechanisms of their effects remain unclear. Numerous studies have been devoted to the study of monoamine control of the hypothalamic-pituitary function in children with delayed puberty. There was a general trend in the level of catecholamines: a reduction in the levels of noradrenaline and epinephrine and an increase in serotonin concentration. Another putative reason for the delay of pubertal is functional hyperprolactinemia, which may be associated with a decrease in dopaminergic tone, which leads to a decrease in the impulse secretion of both gonadotropic hormones and growth hormone.

Delay in puberty in hypogonadotropic hypogonadism (central genesis)

The delay in puberty with hypogonadotropic hypogonadism is based on a deficiency of gonadotropin hormone secretion as a result of congenital or acquired CNS disorders.

Delay in puberty was noted in patients with cysts and CNS tumors (cysts of the Ratke pocket, craniopharyngiomas, germinomas, gliomas of the optic nerve and hypothalamus, astrocytomas, pituitary tumors, including prolactinomas, corticotropinomas, somatotropinomas, pituitary adenomas in patients with the syndrome of multiple endocrine neoplasias of the type I).

Delay in puberty occurs in patients with cerebral vascular anomalies, septooptical hypoplasia and anterior pituitary gland postinfection (tuberculosis, syphilis, sarcoidosis, etc.) and postradiation (irradiation of the tumor growth zone) by CNS lesions, head injuries (during childbirth and neurosurgical operations).

Among the family and sporadic congenital diseases accompanied by delayed puberty are the Prader-Willy, Lawrence-Moon-Barde-Biddle, Russell-Silver, Henda-Schuller-Crischen syndromes, or histiocytosis X (pituitary and hypothalamic histiocytosis of Langerhans cells and their precursors) , and lymphocytic hypophysitis. The development of hypogonadotropic hypogonadism leads to a congenital absence or decrease in the ability of the hypothalamus to secrete GnRH due to the mutation of the KALI genes (Callman's syndrome), FGFR1, GPR54, the gonadotropin-releasing hormone (GnRH) receptor gene and the leptin gene, and the pituitary gland - gonadotropins (deficiency of many tropic hormones due to mutations of PROP, HESX , and RHG genes , isolated FSH deficiency due to mutation of the FSH b-subunit gene, progormone-convertase-1).

Delayed puberty can also appear due to severe chronic systemic diseases. Among them are uncompensated heart defects, bronchopulmonary, renal and hepatic insufficiency, hemosiderosis in sickle cell disease, thalassemia and Gaucher disease, gastrointestinal diseases (celiac disease, pancreatitis, colitis with signs of malabsorption, Crohn's disease, cystic fibrosis), uncompensated endocrine diseases (hypothyroidism, diabetes mellitus , Disease and Cushing's syndrome, congenital leptin and somatotropic insufficiency, hyperprolactinaemia), chronic infections, including AIDS.

Delay in puberty can occur in girls with malnutrition or malnutrition (induced or induced starvation, nervous and psychogenic anorexia or bulimia, excessive nutrition), with increased physical activity that does not correspond to individual physiological capabilities (ballet, gymnastics, light and weightlifting , figure skating, etc.), with long-term use for therapeutic purposes of glucocorticoids, abuse of narcotic and toxic psychotropic substances.

Perhaps the development of delayed puberty under the influence of negative environmental factors, for example, an increase in lead in the serum of more than 3 μg / dl leads to a delay in sexual development for 2-6 months.

Delay in puberty in hypergonadotropic hypogonadism (gonadal genesis)

Gonadal insufficiency leads to a weakening of the blocking effect of ovarian steroids on the hypothalamic-pituitary region of the reproductive system and to a reciprocal increase in the secretion of gonadotropins.

The most common cause of delayed puberty in hypergonadotropic hypogonadism is agenesis or dysgenesis of gonads or testicles during critical periods of human ontogeny (primary hypergonadotropic hypogonadism). Most of the causes of hypergonadotropic hypogonadism are chromosomal and genetic abnormalities (Turner's syndrome and its variants), family and sporadic defects in ovarian embryogenesis (a pure form of gonadal dysgenesis in karyotypes 46.XX and 46.XY). The occurrence of 46. XY-dysgenesis of gonads is caused by mutations of genes that take part in the differentiation of the organism according to the male type. As a result of violations of gonadogenesis in the embryonic period, the gonads of the patients are connective tissue tissues or undifferentiated gonads with the presence of elements of male sex glands (Sertoli cells, Leydig cells, tubular structures). In the absence of the influence of antimulylerovogo hormone (MIS) and androgens, the development of internal and external genital organs occurs according to the female type.

Factors that interfere with normal embryogenesis can be inactivating mutations of the beta-subunit genes of LH and FSH, as well as mutations in the genes of the receptors of these hormones. Primary failure of the ovaries can appear as a result of autoimmune disorders. Thus, in the serum of blood in some patients with a karyotype of 46.XX or 47.XXX with gonadal dysgenesis, in addition to disrupting the functioning of sexual glands, a high titer of antibodies to the cytoplasmic component of the cells of the ovaries, thyroid and pancreas glands was revealed. These patients also have signs of hypothyroidism and diabetes mellitus.

Lack of sexual glands can occur with the development of resistance of the normally developed ovaries to gonadotropic stimuli, as well as due to premature exhaustion of the ovaries. To rare autoimmune diseases, accompanied by ovarian dysgenesis, ataxia-telangiectasia syndrome is considered.

Among the metabolic disorders that can cause primary ovarian failure, we can name the deficiency of enzymes involved in the synthesis of ovarian hormones. Individuals with functional mutations of the gene responsible for the formation of 20,22-desmolase have a normal set of oocytes, but due to a defect in the biosynthesis of steroid hormones, their ovaries are unable to secrete androgens and estrogens. Blockade of steroidogenesis during the action of 17a-hydroxylase leads to the accumulation of progesterone and deoxycorticosterone. The mutation is transmitted vertically in the family and can affect both girls and boys. Some people, being homozygous, have gonadal dysgenesis. Girls who survive to puberty have a delay in puberty, persistent hypertension and a high level of progesterone.

To hereditary conditioned enzymatic defects, accompanied by a delay in sexual and physical development, include galactosemia. This autosomal recessive disease is characterized by a deficiency of galactose-1-phosphaturidyl transferase involved in the conversion of galactose to glucose.

Delay in puberty in girls may be due to acquired ovarian failure (as a result of removal of the ovaries in early childhood, damage to the follicular apparatus in the process of radiation or cytotoxic chemotherapy). There are reports of the development of hypergonadotropic hypogonadism after bilateral ovarian torsion, autoimmune oophoritis, infectious and purulent inflammatory processes.

The testicular feminization syndrome as a cause of delayed puberty with primary amenorrhea is not a true form of delay in puberty, so it is described in a separate chapter.

[1], [2], [3], [4], [5], [6], [7], [8], [9], [10]