Recent studies have found that hypospadias is a local manifestation of endocrine abnormalities in the organism. In this article, we review the relationship between the occurrence of hypospadias and endocrinopathic factors. In the 6th week of fetal life, undifferentiated gonads appear in the normal male fetus, and in the 7th-9th week, the testes begin to differentiate. From the 12th week, the urethral groove merges from posterior to anterior, forming the urethral spongiosomal part and shifting the position of the external urethral opening to the head of the penis. The formation of the complete organ of the penis is completed at approximately 14 weeks of embryonic life. The whole process requires the stimulation of dihydrotestosterone (DHT), which is converted from testosterone (T) secreted by the fetal testis under the action of 5α-reductase (5α-RDA). Therefore, disturbance of fetal testicular development and androgen action can affect the complete closure of the urethral groove and produce hypospadias. The relationship between endocrine hormones and hypospadias: androgens: chorionic gonadotropin (HCG) secreted by the maternal placenta in the first trimester acts on the fetal testis and activates its function to synthesize T. T is converted into more active DHT by the action of 5α-RDA; Kiely et al. found that maternal HCG levels were higher in summer than in winter, resulting in a higher incidence of fetal hypospadias in winter than in summer in early pregnancy Kim et al. found the highest density of androgen receptors (AR) in urethral epithelial cells at 14-20 weeks of gestation, and higher expression of 5α-RDA in the periurethral stroma, especially at the site of fusion and remodeling of the urethral suture, confirming that T plays a major role in urethral formation.KojimaY et al. used androgen antagonist-flutamide in embryonic male mice and successfully induced the appearance of hypospadias mice. Kurzrock EA et al. fed the 5α-RDA blocker-finasteride to embryonic New Zealand rabbits and found pathological changes of hypospadias in the exposed group. Animal experiments by Wolf et al. confirmed the protective effect of androgens on risk factors for hypospadias. Estrogens: Estrogens can compete with androgens to bind AR or not to release receptor-associated proteins, which affect the binding of AR to T or DHT, thus inhibiting the action of androgens. Baskin et al. found that exposure to exogenous estrogens in early pregnancy can cause abnormal development of male reproductive organs, and that treatment of pregnant women with synthetic estrogens (ethylene estradiol) during pregnancy resulted in the delivery of boys with up to 4% incidence of hypospadias, with a general natural incidence of 0.3%. MiyagawaS et al. used hexestrol (DES) to affect the morphological development of the urogenital sinus and induced hypospadias in mice. Progesterone: Progesterone inhibits 3β-hydroxysteroid dehydrogenase, thereby reducing T production; progesterone may also act as a substrate for 5α-RDA, competing to inhibit the conversion of T to DHT, resulting in an increased incidence of hypospadias. The reason for this may be that progesterone was injected during the pregnancy of the IVF mothers. Animal studies found that male offspring of pregnant rats fed synthetic progesterone developed hypospadias alterations. Genetic mutations affecting endocrine factors LH/CG receptor gene The LH/CG receptor is located in testicular Leydig cells and stimulates the production of sex hormones by binding to LH/CG and activating the adenylate cyclase system, thereby promoting testicular development. Mutations in exons 8 and 11 of the LH/CG receptor gene have been identified, and the mutated receptor protein exhibits dysfunction, which in turn causes related diseases such as hypospadias, male pseudohermaphroditism, and precocious puberty. Testosterone synthase gene T is synthesized from cholesterol through a series of enzymatic reactions, during which there are three very critical enzymes: 3β hydroxysteroid dehydrogenase (3β-HSD), 17α hydroxylase (CYP17 or P450c17α) and 17,20 cleavage enzyme (CYP17 or P450c17α), and abnormalities of these three enzymes will lead to changes in testosterone levels and affect testicular function. Aaronson et al. reported defects in these three enzymes in some children with suburethral cleft. Tang Huajian found abnormal amplification of exon 2 in the type II 3β-HSD gene in all 47 children with simple hypospadias. The 5α-reductase gene T acts through 5α-RDA II to convert to DHT in male external genital development is a key. the most common mutation site in the 5α-RDA gene is exon 4, followed by exons 1 and 5. the enzyme encoded by the real mutant gene has reduced affinity for the substrate androgen, resulting in varying degrees of reduced enzyme function causing hypospadias. silver et al. studied 81 cases of simple In a study by Silver et al. of 81 children with simple hypospadias, 7 cases (8.6%) were examined for the presence of at least one mutated locus in the 5α-RDAII gene, and 2 cases had 2 mutated loci. Zhou Li et al. found that codon 227 of the 5α-RDA gene was replaced by CAA by CGA in patients with hypospadias and suggested that codon 227 might be a mutation hotspot in this gene in Chinese. Androgen receptor gene Mutations in this gene cause a reduction in the ability of the receptor to bind DNA to activate transcription and to bind androgens, and the absence of androgen receptor production or the production of non-functional proteins, resulting in the manifestation of androgen insensitivity syndrome (AIS) and partial androgenization deficiency such as hypospadias and cryptorchidism. Four cases of mutations in this gene have been reported in one family, and one case presented with penile scrotal hypospadias. Xu Zhe et al. tested the androgen receptor gene in 26 children with congenital hypospadias and 20 control males, and there was a significant difference in the duplicated fragment of the first exon in the case group. Environmental factors Recent epidemiological investigations have suggested that the widespread presence of estrogenic and anti-androgenic substances in the environment may be an important cause of the increased incidence of hypospadias. In Guangdong Province, for example, the incidence of congenital hypospadias is increasing year by year, and the incidence is higher in urban than in rural areas, and higher in economically developed areas of the Pearl River Delta than in mountainous areas and economically underdeveloped areas on the east and west wings, where environmental factors deserve attention. There are a variety of substances in the environment that interfere with human endocrine function, including synthetic estrogens such as ethinylestradiol and ethinylestradiol; estrogens of biological origin such as isoflavones; environmental chemical pollutants such as chlorobiphenyl, toluene, dioxins, pesticides, nonylphenol, phthalates, etc. Studies on the effect of estrogenic drugs on hypospadias have been more reported and have induced a variety of animal models. a prospective cohort study by North et al. found hypospadias in 2.2% of male offspring of vegetarian mothers compared to 0.6% of pregnant women on a balanced diet, suggesting that vegetarians consume more soy or soy products (biologically derived estrogens). another view is that fruits, vegetables, on which residual pesticides play the role of endocrine stirring substances. Other factors Epidermal growth factor (EGF) The interaction and regulation of EGF with endocrine hormones has been appreciated. For example, EGF stimulates the secretion of chorionic gonadotropin (HCG), which in turn promotes the secretion of testosterone, which in turn increases the level of EGF and EGFR in the male genital tract, etc. Under-expression and unbalanced distribution of EGF and EGFR in the foreskin may be associated with the development of hypospadias. In conclusion, the etiology of hypospadias is closely and complexly related to endocrine factors, and further research is needed to achieve early intervention and reduce the incidence.