(I) Definition
Many significant changes occur in the body during puberty, including accelerated linear growth of the body, appearance of secondary sexual characteristics and development of sexual organs as well as increased secretion of endocrine hormones, mainly gonadotropins and sex steroid hormones. Since the age of pubertal development varies somewhat between regions and ethnic groups, the judgment of whether puberty is abnormal is mainly based on whether the appearance of sexual development is early or 2.5 SD behind the average age of the normal population as the limit, and the normal age of pubertal development in boys is usually 9~14 years old.
Boys who still do not have testicular enlargement by age 14 are diagnosed with delayed pubertal sexual development. If the puberty initiation time is normal, but the progress is hindered, i.e., the boy still has not completed the development of secondary sexual characteristics 5 years after the onset of puberty, it is also a delayed pubertal sexual development.
(II) Classification
1. Somatic (idiopathic) – boys who still do not have signs of pubertal development at the age of 14 years, except for other diseases that can cause growth and pubertal arrest, can be diagnosed as somatic (idiopathic) delayed pubertal development.
(1) Etiology
The main cause is delayed reactivation of the gonadotropin-releasing hormone (GnRH) pulse generator, resulting in the hypothalamus not producing strong enough GnRH-releasing pulses at pubertal age so that pituitary gonadotropin cells cannot be effectively stimulated to produce luteinizing hormone (LH) and follicle-stimulating hormone (FSH).
(2) Clinical features
GnRH levels show a functional deficiency compared to the age of the boy, but are consistent with his physiological development. Adrenal priming and gonadal priming tend to lag behind in boys with delayed somatic puberty, unlike in boys with isolated gonadotropin deficiency, where adrenal priming tends to occur at normal age. The onset of puberty in boys with somatic delayed puberty lags behind the actual age, but is consistent with bone age.
In boys of skeletal age, pubertal LH secretion increases by 12 to 14 years of age, initially as a sleep-related nocturnal LH pulse and later as a daytime LH peak. In those with no puberty onset beyond 18 years of age, the majority of patients fail to develop puberty later. Somatic delayed puberty and hypogonadotropic hypogonadism (HH) are difficult to distinguish clinically, especially in patients between 14 and 18 years of age, and it is necessary to observe them continuously for several years.
2. Hypogonadotrophic hypogonadism
The clinical manifestations of hypogonadotropic hypogonadotropic hypogonadism vary according to the patient’s age of onset, the degree of hormone deficiency and whether other pituitary hormone deficiencies are combined.
(1) Multiple pituitary gonadotropin deficiencies
Many diseases such as intra- or extra-saddle tumors, cranial trauma, infections, vascular lesions and radiation injuries can cause hypothalamic-pituitary damage, and hypogonadism is often one of the manifestations of hypopituitarism. Although hypopituitarism is not a common disease with delayed puberty, it should be considered in combination with short stature, smaller hands and feet, as well as poor intelligence and fear of cold.
(1) Intersaddle tumors are rare in children, and lactinoma is one of the most common intersaddle tumors. Depending on the size of the tumor, the disease can be cured by choosing to take bromocriptine or surgery or gamma knife treatment.
②Craniopharyngioma is the most common tumor causing hypopituitarism in children aged 6~14 years old. This tumor mostly grows near the pituitary stalk and expands into the saddle and suprasaddle, often combined with headache, visual disturbance and short stature, etc. In addition to low gonadotropin level, TSH, ACTH and GH have different degrees of decrease, PRL is normal or slightly increased, CT or MRI can detect the tumor, treatment is preferred to surgery. The first choice of treatment is surgery and postoperative radiotherapy.
③Ectopic pineal tumors are mostly germ cell tumors, and some boys show symptoms of non-initiation of puberty, as well as symptoms of increased intracranial pressure, symptoms of hypopituitarism, and a higher incidence of uremia, which are most sensitive to radiotherapy.
④Histiocytosis X (Hand-SchÜller-Christian syndrome), because it can invade the hypothalamic-pituitary region, boys often have urothelial syndrome and other hypopituitary functions in addition to manifesting hypogonadism. The disease can manifest as isolated localized lesions or involve multiple organs, such as bone, lung, and liver. Treatment such as chemotherapy or glucocorticoids can be chosen.
(5) Boys with delayed pubertal sexual development due to trauma, inflammation and atopic infections such as tuberculosis are rare.
(2) Isolated gonadotropin deficiency
The physical development of boys with this disease is not affected, and the secondary gonads do not appear at pubertal age, showing a eunuch-like body shape with long limbs, upper/lower volume <0.9, small testes, and often combined with cryptorchidism.
① Kallman syndrome, in addition to the above mentioned manifestations, is accompanied by hyposmia or absence of olfaction.
② Congenital adrenal dysplasia combined with gonadotropin deficiency is a rare X-linked recessive disorder. The main cause of pubertal dysplasia is lack of gonadotropin, but children with this disease have difficulty surviving to pubertal age without timely replacement therapy due to the combination of glucocorticoid and salt corticoid deficiencies. Exogenous GnRH pulse therapy is effective.
(3) Idiopathic pituitary dwarfism
This disease is due to hypopituitarism caused by deficiency of hypothalamic releasing factor. Without treatment, boys often do not develop at puberty.
(4) Other diseases
(1) Pareda-Wiley syndrome Mostly obesity, hypoglycemic tolerance, juvenile hypotonia, short stature, small hands and feet, mental retardation, emotional instability and characteristic almond-eyed face and delayed pubertal sexual development (small penis and cryptorchidism) caused by hypothalamic dysfunction.
(ii) Lawrence-Moon-Byrda syndrome is an autosomal recessive disorder characterized by obesity, short stature, polydactyly, retinitis pigmentosa, mental retardation and hypogonadotropic hypogonadism with progressive retinopathy until blindness.
(iii) Functional gonadotropin deficiency. Various chronic diseases, strenuous exercise and emotional depression can cause delayed pubertal sexual development. Such as systemic wasting diseases, malnutrition, anorexia nervosa, diabetes, chronic enteritis, congenital heart disease, chronic renal failure, sickle cell anemia, thalassemia, leukemia, hypothyroidism, etc.
3.High gonadotropin type hypogonadism
(1) Klinefelter Syn. is the most common type of primary hypogonadotropic disease. Typical patients are thin and tall, eunuch-like body type, mentally retarded, small and hard testicles, small penis, poorly developed secondary sexual characteristics due to low testosterone, and spermatogenic dysfunction. Patients of pubertal age often have breast development. The diagnosis can be confirmed based on the karyotype, with 47, XXY being the most common, followed by 46, XY/47, XXY; 48, XXXY and 49, XXXXY.
(2) Other types of testicular insufficiency: (i) gonadal dysplasia caused by radiotherapy and chemotherapy; (ii) P450c17-hydroxylase deficiency patients exhibit male pseudohermaphroditism with female appearance; (iii) embryonic testicular degeneration and disappearance syndrome; (iv) pseudo-Turner syndrome (Noonan Syn) with karyotype 46, XY and clinical manifestations similar to Turner syndrome.
IV. Treatment of delayed pubertal sexual development
The treatment depends on the cause and the nature of the disease.
1. Idiopathic delayed pubertal sexual development generally does not require treatment because puberty initiation will eventually occur. However, the development of sexual characteristics in boys should be evaluated periodically and related hormone tests should be performed. If boys have mental stress and low self-esteem because their sexual development lags behind that of their peers, short-term sex steroid treatment can be considered for boys aged 14~15. The course of treatment is 3~6 months with 50~100mg of testosterone enanthate (50mg/m2 body surface area)/month and regular check of sexual characteristics and body development.
Generally, after 1~2 courses of treatment, penis and testicular enlargement and pubic hair growth will occur. In boys with idiopathic delayed pubertal sexual development, puberty will be initiated spontaneously after treatment, especially when the bone age reaches 13~14 years. Otherwise, it should be considered as pathological pubertal dysphoria.
2. HH and primary hypogonadism boys need long-term sex hormone replacement therapy.
(1) Initial low-dose treatment is the same as that for idiopathic pubertal hypogonadism. gradually increase to adult replacement dose after 2-3 years to mimic the hormone levels after normal puberty initiation. Generally boys start with 50~75mg of testosterone enanthate monthly by intramuscular injection, and after 2 years increase by 50mg every 6~12 months until 200~300mg monthly therapeutic dose.
(2) Exogenous GnRH pulse pump therapy, which is similar to physiological GnRH secretion. Method: subcutaneous buried pump, automatic injection of GnRH every 60~120 minutes at a dose of 25ng/kg, treatment for 1~2 years most boys can complete sexual development. The method is more effective, but expensive.
3, the treatment of functional hypogonadotropic boys, in principle, should actively treat the primary disease, strengthen nutrition, improve weight and adjust exercise. Sexual development will appear spontaneously after the primary disease is cured and the above conditions are improved.