Male delayed puberty

　　1. Etiology

　　The etiology of most delayed puberty patients during adolescence is unknown. However, the etiology of some hypogonadotropic hypogonadism has been clarified, such as some patients being caused by mutations in the KAL, GnRH receptor, PROP1, or DAX1 genes.

　　Some genetic diseases have their own special clinical manifestations, and the diagnosis is generally not difficult, such as Kallmann syndrome, hypogonadotropic hypogonadism, Frhlich syndrome, and Laurence-Moon-Biedl syndrome, etc. If the etiology cannot be determined, relevant gene mutation identification can be performed.

　　1. Severe chronic systemic disease

　　Based on the medical history and the estimation of the severity of the disease, a conclusion can be drawn. Abnormal secretion of gonadotropin is common due to genetic defects. It is manifested by the hypothalamus losing the ability to synthesize and secrete GnRH (which can be complete or incomplete), which can start at any age, with most cases starting from childhood. The method of collecting peripheral blood frequently (once every 5 to 10 minutes) to determine LH and indirectly reflecting the GnRH secretion pulse through LH pulse analysis has been applied to the diagnosis of IHH patients, and the results show that there are 5 types of abnormalities: (1) No pulsatile GnRH secretion, accounting for about 3/4. (2) Pulse secretion of GnRH occurs during sleep at night, these patients have larger testicles or a history of early puberty development, similar to early puberty changes. (3) There is pulsatile secretion of GnRH, but the amplitude of the pulse is lower than normal, and this small LH pulse is not enough to excite Leydig cells to secrete testosterone. (4) The amplitude of the GnRH pulse is normal, but the pulse frequency is only about half that of normal people (normal people 12.0±1.1 pulses/24h), and the testosterone secretion of these patients has great fluctuations, and the testosterone level decreases during the period without pulsation. (5) The LH pulse secretion induced by GnRH is normal, but LH has no biological activity and cannot excite Leydig cells to secrete.

　　The sexual development of most hypogonadal individuals remains at the prepubertal stage. A few patients have already experienced the onset of puberty, with testicle size reaching the level of pubertal stage II to III. 80% to 90% of patients have a small Adam's apple, lack axillary hair, and pubic hair remains at Tanne stage I or II. 20% of patients have mild breast development, which may be accompanied by cryptorchidism. 80% of patients have a bone age that lags behind their actual age. About 40% of patients have a loss of smell or hyposmia (IHH with olfactory abnormalities is also known as Kallmann syndrome). Other possible associated physical malformations or abnormalities include obesity, short stature, cleft lip, cleft palate, high palate arch, short frenulum, neurosensory hearing loss, color blindness, osteoporosis, short fourth metacarpal, long phalanges, and congenital heart disease and renal malformations. Most patients have normal intelligence.

　　2. Prader-Willi syndrome

　　Prader-Willi syndrome is also known as Prader-Labhart-Willi-Fanconi syndrome, Prader-Labhart-Willi syndrome, or the syndrome of hypotonia, intellectual disability, hypogonadism, and obesity.

　　This condition was first reported by Prader in 1956, and in China, it was reported by Wang Defen in 1985 with 7 cases. The etiology of this condition is unknown, and it is often found that patients have a translocation of the centromere of chromosome 15. In recent years, a microdeletion at 15q11-12 has been found, but it is often accompanied by other abnormalities of chromosomes 14 and 15.

　　The main clinical manifestations of this condition are hypotonia and intellectual disability, poor academic performance, with an IQ level of about 60. There is a decrease in gonadal function with underdevelopment or incomplete development of the external genitalia, small penis, and may be accompanied by cryptorchidism. The main cause of obesity may be related to overeating and reduced physical activity. Some patients have diabetes, the pathogenesis of which is unknown, but it is at least related to obesity. Patients are short in stature, with short limbs, uneven facial features, small forehead, small palpebral fissures, strabismus, or other malformations of the face, head, and limbs.

　　The diagnosis of this disease is mainly based on clinical diagnosis based on muscle tone and intellectual disability, hypogonadism (or no pubertal development), and obesity, but attention must be paid to differentiate from congenital muscular dystrophy, myasthenia gravis, obesity-reproductive dysfunction syndrome (Frhlich syndrome), and Laurence-Moon-Biedl syndrome.

　　3. Thalassemia

　　Boys with thalassemia often have hypogonadotropic hypogonadism, with reduced GnRH secretion and no pulses. In severe cases (with severe hemosiderosis), gonadal dysfunction is often irreversible damage, while mild cases are often reversible. One of the methods to distinguish reversible and irreversible lesions is to accurately measure the pulse characteristics of GnRH. MRI shows that some patients have empty sella syndrome, reduced pituitary volume, atrophy of the pituitary gland, thinning of the pituitary stalk, and iron deposition in the pituitary and midbrain. Therefore, patients should be treated early with HCG and/or androgens, and prevent iron deposition caused by excessive blood transfusion.

　　4. Congenital adrenal cortical dysplasia with hypogonadism syndrome DAX1 (AHC)

　　Gene mutations lead to X-linked genetic adrenal cortical dysplasia and hypogonadotropic hypogonadism. Male infants show primary adrenal cortical insufficiency at birth, which can improve to some extent during childhood. However, there is no pubertal development, and some mild cases may have incomplete manifestation and mild symptoms, which can only be manifested as delayed pubertal development and mild adrenal cortical insufficiency. Sometimes, it can be misdiagnosed as 'constitutional delayed pubertal development'. For example, in a study by Achermann et al., among 106 patients with sporadic hypogonadotropic hypogonadism and 'constitutional delayed pubertal development', no positive cases of mutation in the DAX1 gene were found, indicating that delayed pubertal development caused by DAX1 gene mutation is not common.

　　Second, Pathogenesis

　　Many pathological conditions can cause delayed pubertal development, and the more common ones in clinical practice are:

　　1. Central nervous system tumors, such as craniopharyngiomas and germ cell tumors;

　　2. Hypothalamic-adrenal pituitary lobe hypofunction, such as idiopathic hypogonadotropic hypogonadism and pituitary dwarfism;

　　3. Primary hypogonadism, such as Klinefelter's syndrome and hypogonadism;

　　4. Severe chronic systemic diseases, such as malnutrition, malabsorption syndrome, bronchial asthma, nephropathy, and congenital heart disease, etc. Patients with constitutional delayed puberty do not have the above pathological conditions, and the pathogenesis is unknown.

　　The delayed pubertal development of constitutional type is due to the delayed reactivation of the LHRH pulse generator, leading to a lack of LHRH secretion in children at the age when they should be entering puberty, accompanied by weakened response of the gonads to gonadotropins, which is a functional hypogonadism and a variant type of normal pubertal development. Pubertal development delay or failure to develop is an abnormal pubertal development caused by organic lesions of the hypothalamic-pituitary-gonadal axis.

　　In addition to underdeveloped reproductive organs, this disease can also be accompanied by defects in secondary sexual characteristics, such as missing whiskers, as well as short stature, underdeveloped or poorly developed testes. Sperm vitality in semen is low or there is no sperm, which can be accompanied by male infertility and sterility.

　　Although the causes are different, the common characteristics of their clinical manifestations are:For delayed puberty development or underdevelopment, physical examination shows underdeveloped external genitalia, at the stage before puberty development, with不明显，testicular volume is often less than 4ml, voice is still童音, due to the immature appearance, parents, teachers, and classmates often treat the patient as a child, which damages the patient's self-esteem, even causing inferiority complex, unwilling to participate in group activities, thus affecting the ability to handle interpersonal relationships after adulthood.

　　1. This disease has various causes, one of which can be inherited through autosomal dominant, recessive, and X-linked 3 ways, and can be familial or sporadic. Pre-marital and pre-pregnancy genetic examinations can be done.

　　2. If there is a high suspicion of delayed puberty development, necessary examinations can be performed. If only a few items are underdeveloped, do not make arbitrary diagnoses. Generally, it can be followed up and observed for 1-2 years.

　　Choose relevant examinations according to the condition, such as the determination of hormones of the hypothalamus-pituitary-gonadal axis (blood LH, FSH, T) and other endocrine hormones (such as T3, T4, TSH, and GH, etc.), and GH stimulation test when necessary.

　　1. Chromosome examination:Used to exclude sexual gland development disorders caused by chromosomal abnormalities, such as Turner syndrome and Klinefelter syndrome.

　　2. MRI or CT imaging examination:In order to detect saddle area space-occupying lesions or other diseases in a timely manner, X-ray bone age determination is performed to understand whether there is hypopituitarism.

　　First, what should boys eat if they have delayed puberty development?

　　1. Boys have a stronger appetite and larger food intake during the growth period compared to girls, so the intake of cereal foods is very important. Cereal foods include rice, flour, millet, corn, sweet potatoes, and others. They are the main source of energy for the human body, and the protein, inorganic salts, and B-group vitamins supplied by cereals also occupy a certain proportion in the diet. Cereal foods have a wide source, are economical, and are an important part of the daily diet for Chinese adolescents. Generally speaking, adolescents aged 13-17 should not have less than 500 grams of staple food per meal, otherwise, it will inevitably lead to adverse consequences over a long period of time. Animal foods such as chicken, fish, pork, beef, eggs, and dairy products are the best sources of protein.

　　2. If animal products cannot be provided sufficiently every day, it is advisable to utilize China's abundant soybean resources to obtain plant proteins to ensure the daily protein needs of adolescents. Therefore, regularly consuming soy products can not only improve the variety of the diet but also increase nutrition and is economically viable.

　　3. It is also important to consume more seafood, vegetables, and fruits. Since boys have a faster skeletal development during puberty, they should consume foods rich in calcium and phosphorus, such as shrimp shells, kelp, dairy products, and soy products. It is recommended to consume 400 to 500 grams of fresh vegetables daily to ensure the intake of vitamins, minerals, and fiber.

　　Two. Foods that males with delayed puberty should avoid

　　1. Eat less fried or deep-fried food.

　　2. Do not smoke or drink alcohol.

　　3. Reduce the intake of stimulant drinks such as coffee and cola.

　　One. Treatment for constitutional delayed puberty development

　　1. Constitutional delayed puberty, once diagnosed, when the patient's bone age just reaches or is slightly behind the age of puberty, a follow-up can be conducted every six months to observe the process of sexual development. The follow-up items include the development of sexual characteristics and external genitalia, blood LH, FSH, T levels, and the progress of bone age. Clinically, attention is focused on height and the development of secondary sexual characteristics, especially the measurement of pubic hair, external genitalia development, and testicle volume. If the testicles gradually grow larger, the observation can continue. Patients generally experience significant puberty development within 1 to 2 years. If serum T levels can be measured (>) 0.7 nmol/L), it also indicates that significant sexual development will occur in about half a year.

　　2. If the bone age is significantly behind, both the parents and the patient may experience psychological pressure. Regardless of whether the diagnosis is clear, it is advisable to start with low-dose sex hormone therapy to promote the development of secondary sexual characteristics and the slow advancement of bone age. This is particularly important for individuals who are notably short in stature; if there is also a lack of GH, rhGH therapy can be used first to promote growth in height, and then consider the issue of sexual development. Boys can use 11-ketotestosterone capsules, with the method being oral administration of 40mg, once every 8 to 12 hours; after half a year of medication, discontinue the medication and observe for 3 to 6 months. Some patients may experience spontaneous sexual development from this; if spontaneous sexual development does not occur after discontinuation of medication, repeat treatment for 2 to 3 courses. For those with constitutional delayed sexual development, most can experience spontaneous sexual development; if the above treatments do not result in spontaneous sexual development, or if there is a regression of the already developed sexual characteristics, it should be considered that there may be a significant organic sexual development disorder. In such cases, treatment can start with low-dose androgen therapy, then transition to adequate adult doses to promote complete development of secondary sexual characteristics and maintain sexual function. Patients with incomplete sexual function require lifelong androgen replacement therapy.

　　Secondly, the treatment of male sexual dysfunction

　　The causes and pathogenesis of male sexual dysfunction are different, with a variety of clinical manifestations and types, but their common point is the reduction of sexual function. The basic principles of treatment are basically consistent, but the treatment of individual diseases should be treated specifically. The first step is to make an accurate diagnosis and adopt the correct treatment plan. In addition to cryptorchidism in children and certain diseases that require trial treatment, a large number of high and low GHT-type hypogonadism require continuous medication. The specific method of medication can be changed according to the situation, but it is strictly forbidden to discontinue medication blindly, to avoid excessive or insufficient dosage. Long-term and reasonable supplementation of estriol testosterone preparations will not affect the patient's response to other drugs and the effectiveness of treatment.

　　1. Various forms of male hypogonadism can occur during embryonic development, before puberty, during puberty, and in mature adult males. Therefore, the starting point of treatment is different, and the purpose of treatment cannot be completely consistent. The primary purpose is to induce, promote, and maintain male secondary sexual characteristics and sexual function, and the second is to induce and maintain spermatogenesis, promote or restore fertility. The former is relatively easy to achieve, while the latter is currently difficult to achieve for most patients with primary testicular failure and androgen resistance syndrome.

　　2. Due to the need for long-term and systematic treatment for male sexual dysfunction, and often the treatment effect is far from the expectations of patients and their parents, for some unrealistic demands and wishes, it is necessary to clarify from the beginning of the treatment plan. Only in this way can a close cooperative and coordinated relationship be established between doctors and patients, achieve the expected goals, and avoid medical disputes.