Congenital micropenis (hereinafter referred to as micropenis) is defined as a condition in which the extended length of the penis is more than 2.5 standard deviations below the average of the population of the same age or the same sexual development status, and some of them are accompanied by cryptorchidism, hypospadias and other deformities. Micropenis is not rare clinically, and is the external manifestation of some endocrine and genetic diseases. It is the most common sign of masculinization insufficiency, caused by insufficient androgen production or target organ insensitivity, often accompanied by other external genital hypoplasia such as small testicles, cryptorchidism and small scrotum. Because it is related to the fertility and quality of sexual life in adulthood, it has received much attention from parents in recent years. 1, etiology and classification 1, hypothalamic pituitary dysfunction Research shows that most cases of small penis belong to this category, due to the defective function of the hypothalamus or pituitary gland, can not secrete enough gonadotropin during pregnancy, and thus can not effectively promote penile growth. This part of the disease is therefore also known as gonadotropin deficiency gonadal dysgenesis. Anencephaly is the most serious and understandable type of anencephaly. It is due to abnormal cranial development resulting in brain tissue exposure, often accompanied by hypothalamic deficiency, which does not produce enough gonadotropin-releasing hormone (GnRH) to stimulate the development of the genitals and penis. As a result, there is often a small penis. In congenital pituitary dysplasia, the pituitary gland is primarily dysplastic and therefore GnRH deficient. The exact cause of this is not known. Micropenis and cryptorchidism can be detected at birth. This category is rare, but it is treatable because they are also deficient in adrenocorticotropin-releasing hormone, and early treatment can spare the child from dying of adrenal crisis in the first weeks of life. The diagnosis of its etiology is based on the measurement of serum electrolytes and pituitary hormone levels. CT and MRI may reveal abnormal pituitary hairs. Umbilical resorptive hypoplasia is the most common group of midbrain developmental defects that can lead to micropenis. Except for a very small number of isolated lesions (causing only few neurological abnormalities), the vast majority of cases have extensive brain tissue defects including hypothalamus. Such cases are also often associated with craniofacial deformities, or delayed development and limb deformities. 2. Those who do not have anatomical brain defects Isolated hormone deficiency A common isolated hormone deficiency is congenital GnRH deficiency, which can be either a decrease in release wave amplitude or a change in release frequency. It is also known as primary hypogonadotropic hypogonadism because the cause is unknown (even genetic studies have not found abnormalities). These cases often have only the abnormal presentation team of a small penis. In addition to this, there is also luteinizing hormone (LH) deficiency, which inevitably leads to low serum testosterone (T) levels and is therefore also known as reproductive destructive syndrome. the cause of LH deficiency is also unknown, but since follicle stimulating hormone (FSH) is not affected, the testes can be normal in size and may also have potential spermatogenic capacity. Multiple hormone deficiencies are more common, mainly primary GnRH deficiency coexisting with other pituitary hormone deficiencies, most commonly growth hormone (GH) deficiency. The most life-threatening deficiency is corticosteroid deficiency, which produces hypoglycemia and hyponatremia and quickly (within hours of birth) causes convulsions leading to circulatory collapse and apnea (asphyxia). Neonatal corticosteroid deficiency can be secondary to adrenocorticotropic hormone deficiency (manifested by typical adrenal hypoplasia) or primary to the adrenal glands (manifested by disruption of the most basic histological structures of the adrenal cortex). Both can be deficient or absent at the same time. In addition to growth hormone and corticosteroid deficiency, GnRH deficiency can also be combined with thyroid hormone deficiency. GnRH, LH and FSH receptors belong to the G protein family, and their genes are located on chromosomes 4q131, 2p21 and 2q21, respectively. Hypogonadism. It is characterized by delayed puberty, micropenis and cryptorchidism in males and amenorrhea in females. GnRH deficiency has been shown to have different genetic patterns and its secretion is regulated by several genes, with the GnRH receptor gene, the KAL gene, and the GPR54 gene being the most important gonadotropin gonadal hypogonadism gene mutations found in approximately 50% of individuals with hypogonadotropic hypogonadism. GPR54 is a G protein-coupled glycoprotein membrane receptor, and inactivating mutations in this gene affect hormone signaling and are an important cause of abnormal GnRH function. The human LH receptor cDNA was successfully cloned in 1989, and subsequently it was found that LH receptor gene mutations and LH receptor signaling deficiencies can lead to dysplasia and male feminization of Leydig cells, where patients with low serum testosterone levels and high LH levels have Leydig cells that fail to respond to sufficient HCG from the placenta, and by puberty, adult-type Leydig cells have impaired maturation and fail to produce sufficient HCG during second sexual differentiation. The inability to produce sufficient androgens during the second sexual differentiation is one of the causes of small penis and infertility. Patients with androgen resistance syndrome due to defects in sex hormones, especially the androgen receptor (AR), have mutations in the androgen receptor gene or impaired post-receptor signaling, manifesting as micropenis, cryptorchidism, hypospadias, or idiopathic male infertility. The patient’s LH and testosterone levels were increased, and no mutations in exons 1 to 8 of the androgen receptor gene have been detected so far, and the CAG repeat length of its exon 1 was not abnormal, suggesting that the changes in the AR gene are in other regions of the gene. The role of androgen receptor gene mutation in the pathogenesis of micropenis and cryptorchidism is being further investigated. II. Clinical classification Because the etiology of micropenis is complex and involves endocrinology, genetics and molecular biology, it is difficult to classify. At present, most of the classification is done from the endocrine perspective at home and abroad with reference to the hypothalamic-pituitary-gonadal axis (5). (1) Hypogonadotropic hypogonadism: the lesion originates in the hypothalamus or pituitary gland. (1) Hypothalamic GnRH deficiency. This includes congenital or idiopathic GnRH deficiency and acquired GnRH deficiency. The former include Laurence-Moon-Biedle syndrome, Kall-mann syndrome, Prader-Willi syndrome and Demorsier syndrome (hyaline septal defect, hypopituitarism and optic nerve dysplasia). The latter is caused by hypothalamic inflammation, tumor, and injury. Pituitary gonadotropin deficiency includes congenital or idiopathic and acquired gonadotropin (Gn) deficiency. The former are idiopathic hypopituitarism, simple LH or FSH deficiency, and GnRH receptor deficiency. The latter is caused by pituitary inflammation, tumor, and injury. (2) Hypergonadotropic hypogonadism: the lesion originates in the testes. There are LH and FSH receptor defects, congenital testicular agenesis, androgen synthesis and peripheral action disorders (5α-reductase deficiency). (3) Sex hormone action insufficiency: including mild partial androgen insensitivity. (4) Sex chromosome or autosomal abnormalities: Sex chromosome abnormalities are commonly seen in congenital testicular hypoplasia syndrome (Klinefelter syndrome). The karyotype has 1 Y chromosome, male phenotype, and one or several extra X chromosomes. The common karyotype is 47, XXY, while others still include 48, XXXY, 47, XXY/46XY, 47, XXY/46XX, and 49, XXXXY. Autosomal abnormalities are seen in trisomy 21 and some chromosomal abnormalities such as trisomy 7q and deletion of long arm 14. (5) Idiopathic micropenis for unknown reasons: some of these patients have normal hypothalamic-pituitary-gonadal axis secretion function, and the penis can grow normally at puberty with normal masculinization. Third, the diagnosis of small penis The diagnosis of small penis essentially includes the judgment of the presence or absence of normal secondary sexual characteristics and fertility in the future. Although the common desire of urologists and endocrinologists is early diagnosis and early treatment, it is very difficult to make a conclusion at and before school age if it is not a clear chromosomal abnormality or clinical syndrome. Currently, most of the clinical tests and treatments are performed when the patient’s height growth is initially completed and there is still no appearance of secondary sexual characteristics at a bone age greater than 14 years. First of all, we should know whether there is any history of abnormal development of sexual organs such as hypospadias, cryptorchidism and microchidism in the family, whether there is any history of consanguineous marriage, whether there is any abnormality of intelligence, whether there is any abnormality of smell, hearing and vision. During the physical examination, we will pay attention to the presence of abnormal facial features and finger and toe deformities, and measure the size and position of the testicles and the length of the penis. Imaging examinations such as cranial CT and MRI should be done for suspected abnormal development or lesions of hypothalamus and pituitary gland. Karyotype analysis should be performed in all patients. Screening for known genes and research on unknown genes related to micropenis has been carried out in developed countries. Determining which genes to screen for in which cases based on clinical presentation and various tests is a further work to be carried out in China. Adrenocorticotropic hormone, thyrotropin, and growth hormone levels should be checked in cases of suspected total pituitary hypoplasia. Testing of hypothalamic-pituitary-gonadal axis function is essential for the diagnosis of micropenis. Testing of testosterone, DHT, LH, FSH, and HCG stimulation test, GnRH stimulation test, and androgen diagnostic therapy should be performed. 3.1 HCG stimulation test. The testis consists of strut cells, interstitial cells and spermatogonia. HCG stimulation test is used to detect the androgen secretion function of Leydig cells. HCG stimulation test varies in the dosage of HCG, the number of times it is used, the interval and the time point of blood sampling and testing. Nowadays, the multiple injection method is commonly used: HCG 1,500 U, intramuscularly, once every other day, for a total of 3 times. In patients with normal testicular function, the testosterone level can be increased by more than two times; in patients with no response or low response, the primary testicular insufficiency or absence of testes; in patients with secondary hypospadias, the response depends on the degree of hypothalamic or pituitary damage; in patients with delayed somatic puberty, the response is often normal; in patients with delayed response, the testosterone level can increase after repeated HCG excitation. The blood testosterone can rise after repeated HCG excitation, which can exclude the testicular insufficiency itself. 3.2 GnRH stimulation test. This test is used to detect hypothalamic and pituitary endocrine function, and is of little significance when performed at school age and before. The stimulant can be Gn-RH or GnRHa (GnRH mimetic). When the boy’s bone age is greater than 14 years, testosterone 11 acid 40mg/d is given orally for 7d, then GnRH stimulation test is performed, usually at 2?5μg/kg intravenous GnRH, and blood is collected before and 30, 60 and 90min after the injection to detect peak LH and FSH responses. Gonadotropin deficiency can be considered when LH is <5U/L (6). The GnRHa stimulation test is now more advocated. FSH value is not significant for diagnosis, but LH<8U/L can be diagnosed as gonadotropin deficiency. Kauschansk et al. performed GnRH (01 mg/m2), GnRHa (Treprostinil, 01 mg/m2) and HCG (1500 U, 1 time every other day, 3 times) stimulation tests in 32 boys older than 14 years who had not yet developed secondary sexual characteristics. 13 of them entered puberty 1 year after the test (group A). The other 19 cases remained unchanged after 3-4 years of follow-up (group B). Comparing the differences between the two groups of GnRH or GnRHa stimulation, we found that after GnRHa stimulation, the LH values in group A (204±75) mIU/mL (range 108-326) and group B (23±20) mIU/mL (range 07-69), there was no overlap in the range of LH values between the two groups, and the LH cut-off value was 8 mIU/mL; while after GnRH stimulation, the LH values in group A ( 114±44) mIU/ mL in group A and (27±11) mIU/mL in group B. Although the comparison between the two groups was statistically significant, the range of data overlap was large, which affected the judgment of the results. It is worth noting that the study did not use androgen precharge (priming) before GnRH stimulation and that the assay of LH, FSH and testosterone differed due to different methods of measurement and reagents used, so each laboratory should figure out according to its own situation 3.3 Androgen diagnostic treatment. This method is used to detect the presence or absence of androgen resistance. Testosterone propionate 25 mg is injected intramuscularly once every 3 weeks or oral Androstenol 40 mg daily for 4 months. If the penis can be enlarged, androgen resistance can be excluded. The penis of those who are effective after treatment should grow at least 25cm than before treatment. IV. Treatment of micropenis 4.1 Gender selection The selection of the gender of the child with micropenis is very important but highly controversial. Human gender includes 6 aspects, namely chromosomal gender (nuclear gender), gonadal gender, expressive gender (external genital gender), sex hormone gender, social gender and psychological gender. It is now believed that the appropriate choice should be made not only based on the genital morphology, genetic and chromosomal identification of the child, but also in combination with hormonal sex, social sex and psychological sex (1). CalikogluE (1) suggested that the degree of androgen exposure of the fetal brain influences the choice of sex in humans, e.g., complete androgen insensitive individuals have a tendency to adopt a feminine lifestyle despite having XY chromosomes. The tendency of fully androgen insensitive individuals to adopt a feminine lifestyle despite their XY chromosomes, and the tendency of 5a-reductase deficient individuals to be raised as girls to undergo sexual reversal in adulthood. In reality, gender and psychological gender are particularly important. For children with micropenis, the parents or legal guardians of young children, especially infants, can determine whether to raise them as boys or girls based on their etiology, penis length at birth, and the effectiveness of treatment, while older children should respect their choice. Aaronson (8) suggested that diagnostic treatment with human chorionic gonadotropin could be used to observe the response of the penis and the reproductive endocrine system, and if there is no significant response, T, and dihydrotestosterone could be administered. Dihydro testosterone (DHT) treatment, observe the degree of penile growth, if still ineffective, can be considered for gender reassignment treatment. 4.2 Endocrine therapy 1. Selection of drugs. Endocrine therapy is the main method of treating small penis, but there is no uniform opinion on the drugs used, dosage form, dose, route of administration, treatment protocol, efficacy and side effects (8). Currently, T, DHT, HCG, I H and gonadotrophin releasing horm one (GnRH) are commonly used, either alone or in combination, and the routes of administration are oral, intramuscular, intradermal, inhalation (nasal spray) or local application (8). In general, T, DHT, HCG, LH or GnRH can be used for HPG; T or DHT can be used for hypergonadotropic hypogonadism. people have gone through a long process of understanding how to choose appropriate drugs. In the treatment of children with small penis, androgens (including T and DHT) were mostly used in the early years, and more recently, better results have been reported (9). Husmann et al. (10) showed that although early use of androgens can cause temporary growth of the penis, they can cause down-regulation of penile AR and accelerate the loss of 5a-reductase activity, and eventually the length and weight of the penis will not reach normal levels in adulthood, and suggested that the drug should be given only at the age of 12 to 13 years when pubertal development begins; Hu Tingze et al. (11) also advocated that the drug should be administered only after the age of 13 years; some studies have concluded that satisfactory efficacy can be achieved when the drug is administered during infancy, prepubescence and puberty. The routes of administration include oral, intramuscular or topical application. In conclusion, the clinical application of androgen preparations is still controversial and needs further exploration and experience. In view of the large side effects of androgen preparations, there is a tendency to use the superior hormones HCG, LH and GnRH to treat small penis, but of course these hormones are only effective for HPG. Among them, HCG is widely used clinically, it can be used for diagnostic treatment of children with small penis, preliminary determination of the cause (1): after the application of HCG, if the serum T concentration rises and the penis grows, it is HPG, can continue to apply HCG, such as to use the higher level of hormone therapy, feasible GnRH excitation experiment to clarify whether the lesion is in the hypothalamus or pituitary gland, after the application of GnRH, LH does not rise, the lesion If LH is not elevated after GnRH application, then the lesion is located in the pituitary gland and can be treated with LH, if LH is elevated, then the lesion is located in the hypothalamus. If serum T concentration is not elevated and penile growth is not obvious, the lesion is located in the testes and androgen preparations (T or DHT) can be given; if serum T concentration is elevated and there is no obvious change in the penis, the cause may be 5cc reductase deficiency or AR abnormality (i.e. low sensitivity of target tissues to T and DHT). If the penis is enlarged after DHT, it is 5a a reductase deficiency and can be treated with DHT, if the penis is not enlarged, it is AR abnormality and gender reassignment can be considered. Recently, some studies have mentioned that AR modulators can be tried to improve the sensitivity of children to androgens, but there are few reports of formal clinical application. 2. Establishment of puberty. Except for idiopathic micropenis, it is difficult to establish normal puberty without the application of exogenous hormones. hpg can be used to induce pubertal development, and there is no uniform protocol for the application of HCG, for example, Aaronson (8) suggests that HCG can be used, 1,500-5,000 IU/dose, intramuscularly, once every 5 d until pubertal development is complete. HCG can induce testicular enlargement, promote However, if the case is not selected properly and the total dose is too high, it may cause side effects such as precocious puberty, testicular atrophy and early epiphyseal closure. Zhang Guiyuan (14) suggested that the combination of HCG and human menopausal gonadotrophin (HMG) or the pulsed administration of Gl1RH is more physiologically appropriate and more effective than HCG alone in restoring fertility. In hypogonadotropic hypogonadism, congenital absence or insufficiency of the testes, or failure to change sex due to hypoplasia, androgen replacement therapy must be administered, usually starting around 12 years of age (8). Those with GH deficiency must wait for adequate height growth before androgen therapy is given (15). Idiopathic micropenis must be observed after ruling out any organic lesions of the hypothalamus, pituitary gland or testes, and can spontaneously progress to puberty, but families often request treatment, and short-term GnRH pulse administration, short-term HCG intramuscular injection or short-term application of T can also be used to induce pubertal development (14). 3.Surgical treatment. Wessells et al. (15) concluded that adult men with penis <4 cm at rest or <7.5 cm in erection need to consider penile lengthening; it is not recommended for infants and children. In cases with cryptorchidism, descending testicular fixation is required; in cases with hypospadias, orthopedic + urethroplasty is required. In cases of gender reassignment, bilateral orchiectomy, vulvoplasty and estrogen replacement therapy should be performed. From the above, we can see that congenital micropenis is not an isolated disease, and its etiology is complex and difficult to study. In recent years, the molecular biology technology has developed significantly, and it is believed that there will be a qualitative breakthrough in the diagnosis and treatment of congenital micropenis.