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. The pathogenetic mechanisms of their effect 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.

Delayed puberty has been observed in patients with cysts and tumors of the central nervous system (Rathke's pouch cysts, craniopharyngiomas, germinomas, gliomas of the optic nerve and hypothalamus, astrocytomas, pituitary tumors, including prolactinomas, corticotropinomas, somatotropinomas, pituitary adenomas in patients with multiple endocrine neoplasia syndrome type I).

Delayed puberty occurs in patients with abnormalities in the development of brain vessels, hypoplasia of the septo-optic region and the anterior pituitary gland, post-infectious (tuberculosis, syphilis, sarcoidosis, etc.) and post-radiation (irradiation of the tumor growth area) lesions of the central nervous system, head injuries (during childbirth and neurosurgical operations).

Among the familial and sporadic congenital diseases accompanied by delayed puberty, the following syndromes are known: Prader-Wiley, Lawrence-Moon-Bardet-Biedl, Russell-Silver, Hand-Schüller-Christian, or histiocytosis X (histiocytosis of the pituitary gland and hypothalamus by Langerhans cells and their precursors), and lymphocytic hypophysitis. The development of hypogonadotropic hypogonadism is caused by the congenital absence or decreased ability of the hypothalamus to secrete GnRH due to mutations in the KALI genes (Kallmann 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 in the PROP, HESX, and RGH genes, isolated deficiency of FSH due to mutations in the FSH b-subunit gene, prohormone convertase-1).

Delayed puberty may also occur as a result of severe chronic systemic diseases. These include uncompensated heart defects, bronchopulmonary, renal and hepatic insufficiency, hemosiderosis in sickle cell anemia, 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, Itsenko-Cushing's disease and syndrome, congenital leptin and somatotropic deficiency, hyperprolactinemia), chronic infections, including AIDS.

Delayed puberty may occur in girls with poor nutrition or a violation of the diet (forced or artificial starvation, nervous and psychogenic anorexia or bulimia, overeating), with increased physical activity that does not correspond to individual physiological capabilities (ballet, gymnastics, track and field and weightlifting, figure skating, etc.), with long-term use of glucocorticoids for therapeutic purposes, abuse of narcotic and toxic psychotropic substances.

Delayed puberty may develop under the influence of negative environmental factors, for example, an increase in the lead content in the blood serum above 3 μg/dl leads to a delay in sexual development by 2-6 months.

Delayed 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 responsive increase in the secretion of gonadotropins.

The most common cause of delayed puberty in hypergonadotropic hypogonadism is agenesis or dysgenesis of the gonads or testicles during critical periods of human ontogenesis (primary hypergonadotropic hypogonadism). Most causes of hypergonadotropic hypogonadism are chromosomal and genetic abnormalities (Turner syndrome and its variants), familial and sporadic defects in ovarian embryogenesis (pure form of gonadal dysgenesis with karyotype 46.XX and 46.XY). The development of 46.XY gonadal dysgenesis is caused by mutations in genes involved in differentiation of the organism according to the male type. As a result of gonadogenesis disorders in the embryonic period, the gonads of female patients are connective tissue strands or undifferentiated gonads with the presence of elements of the male gonads (Sertoli cells, Leydig cells, tubular structures). In the absence of the influence of anti-Müllerian hormone (MIS) and androgens, the development of internal and external genitalia occurs according to the female type.

Factors that disrupt normal embryogenesis may include inactivating mutations in the genes of beta subunits of LH and FSH, as well as mutations in the genes of receptors of these hormones. Primary ovarian failure may occur as a result of autoimmune disorders. Thus, in the blood serum of some patients with karyotype 46.XX or 47.XXX with gonadal dysgenesis, in addition to dysfunction of the sex glands, a high titer of antibodies to the cytoplasmic component of ovarian, thyroid and pancreatic cells was detected. Such patients also show signs of hypothyroidism and diabetes mellitus.

Insufficiency of the gonads may occur when normally developed ovaries develop resistance to gonadotropic stimuli, as well as due to premature exhaustion of the ovaries. Rare autoimmune diseases accompanied by ovarian dysgenesis include ataxia-telangiectasia syndrome.

Metabolic disorders that can cause primary ovarian failure include a deficiency of enzymes involved in the synthesis of ovarian hormones. Individuals with functional mutations in 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 at the stage of 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 individuals, being homozygous, have gonadal dysgenesis. Girls who survive to puberty have delayed puberty, persistent hypertension, and high progesterone levels.

Hereditary enzymatic defects that are accompanied by delayed sexual and physical development include galactosemia. This autosomal recessive disease is characterized by a deficiency of galactose-1-phosphate uridyltransferase, which is involved in the conversion of galactose into glucose.

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

Testicular feminization syndrome as a cause of delayed puberty with primary amenorrhea is not a true form of delayed puberty and is therefore described in a separate chapter.

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