Male pubertal development is the fourth stage of sexual differentiation and development (7-14 weeks of embryonic differentiation, 15-40 weeks of early development, 0 years of age – prepubertal silence, and mature pubertal development). At this time, the hypothalamus stimulates the pituitary gland to secrete gonadotropins, prompting the gonads to develop and mature. The gonads secrete sufficient sex hormones to further develop secondary sexual characteristics and to perfect gonadal function. The development of puberty includes great changes in reproductive function, body organs and mental and psychological aspects, and is the whole process of maturation of boys into men. I. Mechanisms of male pubertal development The exploration of the mechanisms of male pubertal development has never stopped. After the birth of a fetus, the testes are histologically intact but not fully functional, and it takes nearly 10 years of prolonged inhibition before pubertal development occurs. It is only after the testes mature that they have reproductive and complete endocrine functions, and the body also appears to grow abruptly, forming a male physique. The mechanism for the long-term suppression of pubertal development is unknown, but the following possibilities are currently considered: 1. Decreased sensitivity of the hypothalamic gonadal regulatory center (gonadostat). A small amount of gonadotropin secreted by immature gonads is sufficient to effectively inhibit the secretion of GnRH, LH and FSH. At puberty, the sensitivity of the gonadal regulatory center decreases, leading to a corresponding increase in the secretion of gonadotropins and sex hormones and a negative feedback balance at higher levels. From prepubertal to adult, the sensitivity of the gonadal regulatory center decreases by 10 times. 2. The “inner” inhibition of the central nervous system is lifted. The gonads of patients with no sex hormone secretion ability, such as karyotype 45, XO and its variants, are striped and do not have the same sex hormone secretion ability as normal children, but the secretion level of LH and FSH is significantly lower at the age of 6~8 years than before 4 years old, and the secretion level of LH and FSH has a natural increase after the age of 10 years, which indicates that there is an intrinsic inhibition of the central nervous system that does not depend on the feedback regulation of sex steroids. mechanism. 3. Somatmeter activation mechanism. In childhood, the hypothalamus tracks information in the circulation reflecting somatic development and activates it at the right time. 4. Puberty “clock” activation. A network of transcription factors encoded by built-in genes in the hypothalamus constitutes the pubertal clock. Kisspeptin increases LH and FSH secretion by stimulating GnRH release. gpr-54 inactivation variants of Kisspeptins receptors can lead to delayed or absent puberty, while gpr-54 activation variants lead to precocious puberty. kiSS-1 neurons are influenced by environmental (e.g. photoperiod) and metabolic factors, while leptin and melatonin are involved in the regulation of kisspeptin. regulation of kisspeptin. The mechanism of male pubertal development is still not fully understood; it may be a combined mechanism of multifactorial regulation, as a result of the interaction between multiple nuclei of the brain and hypothalamic neuroendocrine cells, influenced by environmental (e.g. photoperiod) and metabolic factors, the regulation of Kisspeptin and gpr-54 by leptin and melatonin, the regulation of GnRH by Kisspeptin-gpr-54 neuronal control, and the timely activation of the HPT axis, among others. (a) Pre-pubertal gonadal development Adrenal androgens (DHEA, DHEAS, androstenedione and androstenedione) are significantly increased 1-2 years before the onset of puberty (at about 8 years of age), which is called adrenal primordial function (adrenarche). Adrenal androgens are associated with the growth of pubic and axillary hair. (B) Markers of pubertal initiation Intrinsic manifestations: A peak of GnRH pulse secretion associated with non-rapid oculomotor phase sleep occurs, approximately every 90 min, after which a peak also occurs during the day, but the daytime peak is smaller than the nocturnal one, and this difference gradually disappears with the progress of puberty. In adults, the secretion of LH and FSH is driven by GnRH secretion, and the secretion pulses are also synchronized with GnRH, but the synchronization of FSH with GnRH is not as complete as that of LH, which may be related to the small amount of FSH secretion, the long half-life, and the small amount of hormone reserves in the form of secretory granules. External manifestations of pubertal initiation: scrotum enlarges, becomes red and itchy, testes enlarge (longer diameter than 2.5 cm or volume greater than 4 ml, mainly supporting cell development). Hormone secretion during pubertal development: Leydig cells of the testes secrete testosterone, a small amount of androstenedione, androstenediol, dihydrotestosterone (DHT) and E2. After pubertal initiation, testosterone levels increase significantly, 20-40 times more than prepubertal levels, and E2 levels also increase. (C) The process of male pubertal development Marshall and Tanner divided the process of pubic hair (PH) and genitalia (G) development, the main indicators of male pubertal development, into five stages. The development of pubic hair: stage I (PH1): no pubic hair stage; stage II (PH2): a few long hairs of not dark coloring grow at the root of the penis; stage III (PH3): the hairs become darker, thicker and extend to the pubic symphysis; stage IV (PH4): the characteristics of the hairs are the same as those of adults, but the area covered is smaller and has not yet extended to the medial femoral side; stage V (PH5): the distribution of hairs is inverted triangle and has extended down to the The distribution of hairs is inverted triangle and has extended downward to the medial femoral side. Male genital development: Stage I (G1): prepubertal state; Stage II (G2): testes begin to grow, with a length and diameter greater than 2.5 cm. scrotum also grows, and skin color becomes red; Stage III (G3): penis begins to grow, grow and thicken, testes and scrotum further grow; Stage IV (G4): glans begins to develop, penis, testes and scrotum further grow, scrotal skin folds, and pigment deepens; Stage V (G5): the size and shape of the genitalia are like adults. The testes start to enlarge at the age of 9~14 years old, with an average of 11.5 years old; testes with a long diameter of more than 2.5cm or a volume of more than 5ml is a sign of the beginning of puberty; the whole process of puberty lasts 4~5 years, but the development of genital organs and pubic hair is not synchronized, and it may be normal to have pubic hair growth before genital development or to have no pubic hair during G4. During puberty, the body height growth is accelerated, which is called pubertalgrowthspurt. The process of pubertal growth begins about 2 years after the onset of puberty and reaches its highest growth rate during the G4 period, when the average growth rate is 10.3 cm/year; from the beginning of pubertal growth to the cessation of growth, the average height growth is about 28 cm. Before the torso reaches its maximum growth rate, the height has already reached the highest point of growth rate. The driving force for sudden growth in boys is androgens (acceleration), and growth hormone also has a role to play. Moderate amounts of thyroid hormone and adrenocorticotropic hormone are also needed. Testosterone is a strong growth stimulating hormone that stimulates bone cell proliferation, accelerates capillary and perivascular mesenchymal cell proliferation and calcium deposition, thus promoting epiphyseal maturation and longitudinal growth. With testosterone supplementation only, growth is below the optimal level. GH levels have been shown to be higher in adolescents than in prepubertal children, and blood IGF-1 levels are significantly higher during puberty. The lean body mass, bone mass, and body fat were the same in both sexes before puberty, but after puberty, lean body mass and bone mass were 1.5 times higher in males than in females, and body fat was twice as high in females as in males. The chondrocytes of the male shoulder girdle are stimulated by androgens to produce a proliferative response, resulting in a male body shape with wide shoulders and a small pelvis. Remodeling of brain structure and function during puberty: Maturation of reproductive behavior during puberty requires remodeling and activation of neural circuits involving sexual stimulus perception, sexual impulses and sexual competence. There are both hormone-dependent and hormone-non-dependent mechanisms for the remodeling of brain structure and function during puberty [1]. Normal endogenous and exogenous environments and conditions must be present for normal pubertal development. Endogenous environmental factors include hormones that regulate pubertal development, local paracrine hormones and cytokines and the normal regulatory relationships between them, the pituitary gland, the histology of the gonads and normal target cells for hormones. Exogenous factors include proper physical activity and nutritional supply. If physical activity is excessive, too little, malnutrition or overnutrition can affect normal pubertal development and lead to abnormal pubertal development. The etiology and manifestation of male pubertal development abnormalities The clinical manifestations of male pubertal development abnormalities are different and diverse, and there is no uniform standard for classification. According to clinical practice, the author classifies them systematically: by degree: development can or cannot (start or finish); early or late development (precocious puberty or delayed puberty); fast or slow development (shortening or lengthening of developmental period); complete or incomplete development. By cause: brain causes such as leptin, kisspeptin, gpr-54 and other abnormalities. Hypothalamic causes such as genetic abnormalities more, gpr-54 abnormalities, Kallmann’s syndrome, etc. Pituitary causes include genetic abnormalities, developmental abnormalities, tumors, injuries, and multiaxiality. Testicular causes include cryptorchidism, orchidrosis, orchitis, Creutzfeldt-Jakob syndrome, LH receptor abnormalities, etc. Target organ causes such as androgen receptor, 5a-reductase, aromatase abnormalities, etc. Delayed pubertal development is defined as boys aged 14 years and above with testicular length diameter <2.5 cm or volume <4 mL and no pubic hair present. Precocious puberty is defined as boys aged 9 years and older with testicular volume >4 ml or pubic hair development [5]. The etiology of abnormal pubertal development is most commonly due to somatic developmental delay (slow clock), mainly late initiation. Secondary (hypothalamic-pituitary and above) hypogonadism is the next most common, being a pubertal initiation disorder, which is also difficult to complete. Abnormal pubertal development due to primary (testicular) hypogonadism is less common; such patients are able to initiate pubertal development, which may be slow and incomplete. Androgen insensitivity syndrome is rare, and pubertal development can be initiated, showing impaired development or incomplete development. Diagnosis and management of abnormal pubertal development in males (a) Diagnosis of abnormal pubertal development First of all, a comprehensive medical history should be taken: birth and growth history, life history, intelligence level, genitourinary tract infection, history of trauma, history of mumps and orchitis, medication and contraceptive measures, history of special foods, smell, etc. Family history: approximate age of the father’s development (height growth), development of siblings. It is also necessary to understand the patient’s (child’s) and parents’ awareness of the disease and treatment expectations. Physical examination: focus on height, weight, posture, limb length, skin, voice, etc.; secondary sexual characteristics, beard, axillary hair, pubic hair, breast development, etc.; scrotum and testicles, penis, etc. Laboratory examination items: serum LH, FSH, T, mainly LH and FSH, T rising slowly. For those whose height and bone age are significantly lower than the same age, T3, T4, TSH, ACTH, cortisol, GH, etc. should be measured. For those with higher than normal LH and FSH, karyotype analysis of chromosomes should be done. Semen routine should be done as needed. Imaging examinations: ultrasound, CT, check the adrenal glands, both kidneys, bladder, prostate and seminal vesicle glands, and find out the mammary gland development and the location of cryptorchid. MRI is done to check the saddle area and pituitary gland for tumors and developmental abnormalities. Do left hand orthopantomogram to determine bone age. Bone density: spine, femur and other parts of the head to check osteoporosis due to hypogonadism. Special tests: 1. hCG response test: to clarify the presence or absence of testes in prepubertal children, and Leydig cell function: hCG 1500iuim, normal male blood testosterone up to 300ng/L. 2. estrogen antagonist response test: to test the integrity of hypothalamic-pituitary-testicular axis: clomiphene, 25-100mg/day×7day, normal human blood LH&FSH increased more than twice. 3, GnRH stimulation test: differential diagnosis of hypothalamic and pituitary hypogonadism: GnRH, 100ug, iv, 30-45min, LH rises 3-6 times, FSH rises only about 50%. (b) Management options for pubertal developmental abnormalities Before management, somatic developmental delay and hypogonadism should be identified. Primary hypogonadism or androgen insensitivity may be easier because of high gonadotropins (FSH, LH) and karyotype abnormalities (e.g., Creutzfeldt-Jakob sign). In contrast, those with secondary hypogonadism are more difficult to identify unless there are other clinical manifestations (e.g., hyposmia or absence of olfaction). Also, it is important to know the patient’s (child’s) treatment expectations. Awaiting observation: advantages are less human intervention and possible waiting until natural initiation of development, disadvantages are slower physical and secondary sex characteristics development than peers; adverse psychological effects; possible impact on academic performance. Treatment options (simulating pubertal development): full simulation: GnRH pulse pump for those with hypothalamic abnormalities; partial simulation: rFSH (hMG), hCG injection for those with hypothalamic or pituitary abnormalities; terminal simulation (testosterone replacement or supplementation): for those with testicular abnormalities or testosterone receptor abnormalities. (C) Treatment of abnormal pubertal development For delayed somatic development: to improve sexual characteristics and psychological feelings, pubertal development can be induced (simulated) artificially. Treatment should be started after 14 years of age with short-term application of small doses of testosterone (e.g. testosterone undecanoate, 40mg-80mg/day); suspended for 2-3 months after several months of treatment to test LH, FSH, T and observe their own development; if still not initiated, observe in treatment according to the specific situation and the child’s request. For patients with secondary hypogonadism without fertility requirements, testosterone replacement therapy is performed to improve symptoms, taking into account the physiological level of serum testosterone (different developmental stages). However, the apoptosis and response of testicular spermatogenic cells in patients with delayed gonadotropic therapy are subject to controlled studies. For those with fertility requirements, hCG or combined hMG treatment (partially simulated) can be used to induce spermatogenesis. For hypothalamic hypogonadism, pulsatile treatment (full simulation) with GnRH analogue syringe pumps is available. For patients with primary hypogonadism, those whose pubertal development cannot be completed (e.g., anencephaly), or those with incomplete development (e.g., kernicterus), testosterone replacement or supplementation therapy is given; for patients with androgen insensitivity syndrome (incomplete), high-dose testosterone supplementation therapy may be considered to improve penile and secondary sex characteristics development with unsatisfactory results. Precautions for androgen supplementation therapy: For initial treatment, small doses of oral androgen preparations (e.g. oral testosterone undecanoate) are used to simulate the androgen secretion pattern in early pubertal development; transition to larger doses of androgen preparations can be made after reaching satisfactory height or epiphyseal closure and sufficient androgenization; hCG therapy is also appropriate to start with small doses (e.g. 500 IU/week). The evaluation of the efficacy of treatment for pubertal growth abnormalities should be based on genitalia (testes, penis), secondary sexual characteristics (hair, throat nodes), body shape (height, muscle) and physical performance, emotional and metabolic changes, supplemented by serum testosterone levels. For patients with multiple hormone deficiencies in the pituitary gland, it is recommended to consult with an endocrinologist for a treatment plan due to the complexity of the condition. Such as growth hormone deficiency (GH, IGF-1, stimulation test): growth hormone supplementation therapy can be applied before epiphyseal closure closure, the earlier the effect, the better. If thyroid hormone deficiency: Eugenol in a small dose (25-50ug) to start treatment and closely observe. If adrenocorticotropic hormone deficiency: priority supplementation due to metabolic needs, hydrocortisone or prednisone (2.5-10mg/day); pituitary hormone deficiency, often requires lifelong replacement therapy.