Gender refers to the difference between men and women, mainly in terms of anatomical structures and physiological activities based on genetics, and in a broader sense also in terms of psychological, behavioral and social role relationships between the sexes. Sex is determined by a variety of factors, including genetic sex (chromosomal composition), gonadal sex (type of gonads), expressive sex (type of internal and external genitalia), and, to a lesser extent, social identity sex and psychological sex. Every human individual after birth is naturally assigned a male or female gender role, and human society, whether in the ancient days of ignorance or today’s tolerant and enlightened society, has never been able to identify with a gender other than or between the sexes. Gender dysphoria is a clinical term that refers to the development of genital tubules with abnormal genital morphology and the expression of sexual characteristics. The sex of an individual is based on the concordance of karyotype, external genitalia, genital tract, and gonads, and if there are contradictions between chromosomes, external genitalia, genital tract, and gonads, gender dysphoria results. Usually, the genitalia of newborns are not clearly assigned to a specific sex at birth, but sometimes they do not manifest until the pubertal stage. The diagnosis of sex anomalies is relatively easy for newborns with unclear external genital expression at birth, but the determination of sex is sometimes very difficult, requiring a detailed history, systematic physical examination, chromosomal and sex chromatin examination, molecular biochemistry, sometimes with the help of imaging and endoscopic or surgical exploration, and a comprehensive analysis to make a definitive diagnosis. The treatment of gender dysphoria is equally complex and requires a comprehensive consideration of anatomical, functional, psychological and social factors, often requiring the establishment of a long-term sequential treatment plan, a complex systemic project requiring multidisciplinary and professional cooperation, as well as the direct participation and cooperation of parents and patients. The patient’s family also needs knowledge of genetic pathophysiology, as well as support with advice on the risks of re-birth sex anomalies, occupational screening, prenatal diagnosis and even prenatal treatment, and sometimes counselling and assistance from social workers. Embryological basis of sex development and sex differentiation The sex development of the embryo consists of two basic elements: sex determination and sex differentiation. Sex determination refers to the formation of the gonads (testes and ovaries); sex differentiation refers to the formation of the expression of the reproductive organs (internal and external genitalia) under the influence of a series of hormones, and these two processes jointly determine the development of sex. In turn, during puberty, sex hormones further strengthen the sex organ phenotypes and subsequently to acquire reproductive potential. With a correct understanding of the processes of sex determination and sex differentiation, the specific stages of the occurrence of hermaphroditism can be reasonably inferred. Before the 7th and 8th week of embryonic life, no structural and functional distinctions have been made between the sexes, and both sexes have the same Wolffian duct, Mullerian duct, urogenital ridge, and external genital primordium, which are genderless. The sex expression of a normal newborn at birth depends on the outcome of a series of events that take place in a specific sequence at a specific time of fetal development, a process that is controlled by genes, influenced by hormones in the embryo, and dependent on the normal function of hormone receptors in specific target organ tissues, all three of which are indispensable. These factors act at a specific time on specific embryonic tissues in order to work, and exceeding their time period of action, abnormal hormone levels, or insensitivity of the corresponding target tissues will produce the corresponding malformations. The embryo’s genital development is based on the development of female reproductive organs, which automatically develop into female reproductive organs in the absence of androgens and anti-mullerian hormones, i.e. the paramedian ducts (mullerian ducts) automatically develop into the fallopian tubes, the uterus and the upper part of the vagina, while the cloacal structures automatically develop into the lower part of the vagina and the female vulva. The development of the embryo into a female is a natural phenomenon, and the reason for male development is the presence of the testes and their production of testosterone and anti-Mullerian hormone (AMH) as a result of their endocrine action, and the presence of normal testicular endocrine action causes the embryo to develop into a male. In the presence of testosterone and AMH, the duct of Mullerian ducts degenerates, and the ducts of the non-muscle develop and differentiate into vas deferens, epididymis, and seminal vesicles. In the fifth week of embryonic life, the kidney cord increases rapidly from the posterior abdominal wall towards the ventral cavity and is called the urogenital ridge. A longitudinal sulcus appears on each of the two urogenital ridge and divides the urogenital ridge into two parts, the medial part is the genital ridge and the lateral part is the mesonephric ridge. The genital ridge has a proliferation of germinal epithelium, which is the origin of the gonads. As the germinal epithelium proliferates and penetrates deeper, the germinal cell cords are formed at about 5-6 weeks of gestation, which is the undifferentiated gonad. At this time, the histomorphology of the primordial gonad is undifferentiated and has a bidirectional differentiation potential. The primordial gonad is composed of 3 parts: germinal epithelium, mesenchyme and primordial germ cells. The differentiation of the primordial gonads into testes and ovaries is controlled by genes. The gene that determines testicular differentiation on the human Y chromosome is called testicular determinant factor (TDF), which is located on the short arm of the Y chromosome. Under normal conditions, sex-determining-related response genes on the autosomes are regulated by TDF. tDF induces testicular histogenesis, and the testes produce hormones that differentiate and develop the individual phenotype toward masculinity. in 1990, Sinclair et al. identified a sex-determining region of the Y chromosome gene, called SRY (sex-determining region on the Y chromosome) gene. It is now believed that TDF is located in the sex-determining region on the Y chromosome, and SRY is the best candidate for TDF. The SRY gene is expressed only in the testis, but not in the ovary, lung or kidney. The organization and timing of SRY gene expression was experimentally confirmed to be consistent with testicular differentiation. It is still debated whether SRY is TDF or not. It is certain that the SRY gene is important in initiating the complex sequence of developmental processes that guide the development of the primordial gonad into the testis. The nature of the initiators, regulators, mode of action, and target organ components of the SRY gene and the SRY protein it expresses are unknown. It is now recognized that sex determination is a complex process, and studies have shown that SRY is not the only gene that determines gender; at least six genes (SR, XoX9, AMH, WT-1, SF-1 and DAX-1), including SRY, have been identified so far to be involved in embryonic sex determination from the primordial germinal crest to the formation of hermaphroditic internal genitalia. Primitive stem cells originating from the endoderm of the yolk sac move through the dorsal mesentery during embryonic week 4-5 and eventually reach the primitive gonads, which are undifferentiated gonads derived from the somatic epithelium of the urogenital margin, adjacent to the kidney and adrenal glands. Without these stem cells, gonadal differentiation and development would not be possible and would result in gonadal hypoplasia. The first histological sign of testicular development is the appearance of the germinal cord, which is condensed from the primordial gonad and Sertoli cells, at approximately 7 weeks of embryonic life; in contrast, the ovaries do not appear until approximately 4 weeks later. By embryonic week 7-8, the testis has visible ducts and begins to produce mullerian inhibitory substance/anti-mullerian hormone (MIS/AMH) from Sertoli cells (podocytes or trophoblasts); mesenchymal-derived mesenchymal cells appear by embryonic week 9 and differentiate into testicular mesenchymal cells (Leydig cells), which can secrete androgens, including testosterone. The testicular mass is initially small and circulating hormone levels are low. The primitive stem cells move from the yolk sac wall through the hindgut mesentery to the location of gonadal structures, a process that relies on chemical induction and cell adhesion, the exact mechanism of action of which is still not fully understood. Development of the ovary is later than that of the testis. Although the gonads identified as ovaries show enlargement, the presence of oocytes developing from primordial oogenic cells is not discernible until week 11 or 12. Around week 14, a single layer of flattened granulosa cells wraps around the oocyte to form the primordial follicle, which reaches its maximum by week 20-25, by which time some of the primordial follicles have developed into primary follicles and the morphological features of the ovary are clearly distinguished. The testes are initially located in the posterior superior abdominal cavity and later descend gradually until they descend into the scrotum. The mechanism of testicular descent has not been elucidated and may be related to the action of the introitus. The introitus is a cord-like structure located between the caudal end of the primitive gonad and the future scrotum or labia majora. The introitus appears to have a role in guiding the testis toward the scrotum, with its end expanding to form a short, thick gelatinous structure that controls the position of the testis in the future inguinal ligament as the embryo grows, and also has an important role in the future descent of the testis through the abdominal wall to the scrotum. Recent studies have shown that Insl3 acts synergistically with MIS/AMH, dihydrotestosterone (DHT), and relaxin peptides to cause masculinization of the introitus and to guide the descent of the testis. By 12-15 weeks, testicular positional changes can already be detected that differ from the ovaries; no significant changes in testicular morphology are observed in the following 10 weeks. During this period, the central nervous system also appears to differ in sex differentiation. Testosterone can affect the sex development of the brain either directly, or through the conversion of aromatase to estrogen, or through the conversion of 5α-reductase to dihydrotestosterone. Androgens also affect the sensitive nucleus of the embryonic dorsal root node of the genitofemoral nerve (GFN), which plays an important role in later regulating the descent of the testes from the groin to the scrotum. The migration of the testis into the scrotum before birth marks the completion of male sex development, a process that is divided into two stages: the descent of the testis across the abdominal wall and within the inguinal scrotum. In the first stage, at least as observed in rats, testicular descent is regulated by an insulin-like condensin-relaxing peptide produced by the testis, and disturbance of the gene encoding this protein causes the development of cryptorchidism. However, genetic studies of male lineages with undescended testes have found very few mutations in this gene. The second stage of descent in the inguinal scrotum is androgen-dependent and is manifested in patients with hypogonadotropic hypogonadism and androgen insensitivity syndrome as a ventral locus coeruleus testis. By approximately the 25th embryonic week, the introitus has extended beyond the external annulus of the inguinal canal and continues to extend towards the scrotum. This is accompanied by extension of the wall peritoneum and distal cavitation to form a sphincter protrusion. The extension and migration of the introitus to the scrotum is under the control of the masculinized genitofemoral nerve (GFN), which releases calcitonin gene-related peptide (CGRP) from sensory nerve endings in the scrotum; calcitonin gene-related peptide may influence the mitosis, contraction, and movement of the introitus terminal, thereby affecting the descent of the testis from the groin to the scrotum. As pregnancy continues, CGRP also acts in conjunction with testosterone to occlude the sphincter. By approximately 7 weeks of gestational age, the internal genital ducts are similar in both male and female embryos and have the potential to differentiate in both directions. Both the urogenital ridge has a degenerating mesonephros and a developing primitive gonad. The development of the internal genital ducts is a process of development and transformation of the Wolffian ducts and Mullerian ducts. The Wolffian ducts are formed in the mesonephric ducts and differentiate into the vas deferens, epididymis, and seminal vesicles under the action of highly concentrated local androgens (testosterone), whereas the Mullerian ducts develop stably without AMH-anti-Mullerian hormone and differentiate into the uterus, fallopian tubes, and upper part of the vagina. The reproductive ducts both consist of the mesonephric ducts (Walffian ducts) and the paramedian ducts (Mullerian ducts), both of which are located within the lateral free margin of the urogenital ridge. In a normal male embryo, the ducts will develop into the epididymis, vas deferens, and seminal vesicles, whereas in a normal female embryo, the Mullerian ducts will develop into the uterus, oviducts, and upper vagina. The figure below indicates the sex differentiation of the reproductive ducts. It is now believed that the reproductive ducts and external genitalia can automatically develop into female regardless of whether the sex chromosome is XX or XY. This development is independent of the role of the ovaries, and the differentiation to male is due to the presence and normal function of the testes. The interstitial cells of the testes synthesize and secrete androgens, which cause the development of the nocturnal duct (mesonephric duct) into the epididymis, vas deferens and seminal vesicles, and the masculinization of the external genitalia. However, androgens can cause the development of the nocturnal ducts but not the degeneration of the mullerian ducts (paramedian ducts). The degeneration and disappearance of the malleoli is not related to androgens, but to the presence of testes. Studies have shown that the degeneration of the Müllerian ducts is mainly the result of the action of Müllerian inhibitory substance (MIS) or anti-müllerian hormone (AMH). The masculinization of the reproductive ducts results from the exocrine secretion of hormones from the nocturnal non-ducts, followed by the secretion of testosterone. High ipsilateral concentrations of testosterone and MIS/AMH can preserve the nocturnal canal, while the malleolar canal degenerates. It is important to note that the degeneration of the Müllerian ducts by MIS/AMH can only be completed during a specific sensitive period, which is the 8th-12th week of embryonic life, after which MIS/AMH can no longer guide the complete degeneration of the paramedian ducts, resulting in varying degrees of uterine, oviductal and supravaginal development. The figure below shows the timing of embryonic genital differentiation. The female embryo lacks MIS/AMH and testosterone and its müllerian ducts are preserved, while the nocturnal non-ducts gradually degenerate. The lower Mullerian ducts fuse to form the uterus, cervix and upper vagina. The absence of Insl3 and MIS/AMH, etc. allows for a moderate lengthening of the introitus as the body grows, thus allowing the ovaries to remain relatively close to their original position, unlike the testes, which are closer to the future location of the inguinal canal. At about the 6th week of embryonic development, a protrusion called genital tubercle is formed on the ventral side of the urogenital sinus membrane. In the course of development, a genital swelling is formed on each side of the genital tubercle, and a shallow groove is formed in the caudal midline of the genital tubercle, called the urethral groove, which is the predecessor of the urethra, and the protrusions on both sides of the urethral groove are the urethral folds. In the 7th week of embryonic life, the external genital primordium is already formed, and at this time, it is not possible to distinguish between the sexes; the genital primordium has a bidirectional potential, and only from the 8th week onwards does it gradually differentiate into male or female. In the male embryo, from week 8 to 12, the genital primordia gradually develop and differentiate into normal male external genitalia under the action of androgens, where dihydrotestosterone (DHT), but not testosterone, is responsible. As a result, the genital nodule grows to form a cylindrical penis; the lower segment of the urogenital sinus extends into the penis and opens into the urethral groove, and soon the posterior segments of the urethral folds on either side of the urethral groove gradually fuse toward the head end of the penis, leaving a fusion line on the surface called the penile suture, and the urethral opening gradually moves toward the head of the penis. At the tip of the glans, the ectodermal cells grow inward to form a cellular cord, which later becomes ductalized and communicates with the urethra, at which point the ectopic urethra opens to the tip of the glans. The mesenchymal stroma of the genital nodule differentiates into the penile corpus cavernosum and the urethral surface body. The genital ramus on either side of the genital nodule develops, moves caudally and fuses with each other to form the scrotum. The female external genitalia develop naturally from the embryonic genital primordium in the absence of androgens, a process that occurs slightly later than in the male. The genital nodes grow slightly to form the clitoris, the genital bulge on both sides forms the labia majora, the urethral folds do not fuse to form the labia minora, part of the urogenital sinus forms the urethra and most of the rest becomes significantly wider and shallower, and the membrane of the urogenital sinus ruptures to form the vestibule of the vagina. Androgens play a critical and important role in the differentiation and development of the external genitalia. Early genital progenitor differentiation to form the male external genitalia is mainly the result of dihydrotestosterone, which is converted from testosterone by the action of 5α-reductase. The latter is several times more biologically active than testosterone and therefore amplifies its effects. The development of the external genitalia after the 12th week of embryonic life until birth and even later during puberty is mainly associated with testosterone. The differentiation and developmental effects of androgens on the external genitalia of the embryo are: 1. Development of the penis from the genital primordium; development of the male urethra and its opening to the tip of the penis: it is usually assumed that the urethral folds fuse to form the urethra, the terminal of which is made from the apical recessed portion of the penile head. However, recent studies have shed new light on the development of the urethra, with studies in murine and human embryos showing that the endothelial urethral plate extends from the genital node to the tip of the glans from the beginning of development and (in murine embryos) through post-apoptotic canalization to form the male urethra. In the absence of androgens, the urethral plate forms a large number of apoptotic cells so that the genital nodes collapse over the perineum due to the absence of corresponding dorsal growth. This results in the formation of a female clitoris and a short female urethra. 2. The scrotal labial walls fuse to form the scrotum and form a scrotal ridge in the middle: in the female embryo, the labial scrotal folds remain non-fused and form the labia majora. The posterior part of the urogenital sinus wall thickens to form the vaginal plate canalized to form the lower vagina. 3. The urogenital sinus develops into the bladder and prostatic part of the urethra: the caudal part of the fused Mullerian duct remains as the prostatic vesicle or seminal caruncle. In the female embryo, the vaginal plate, the posterior wall of the urogenital sinus thickens and ducts to form the lower vagina. In the male embryo, androgens maintain their action on the genitalia beyond the 12th week until delivery, allowing the external genitalia to continue to develop into the well-developed male form. after 12 weeks, the action of dihydrotestosterone decreases, while the direct action of testosterone gradually increases as the testes grow and develop and produce more testosterone. At the same time, the testes gradually descend and sphincter atresia occurs in response to testosterone and CGRP secreted by the GFN (genital femoral nerve). In the case of female embryos, abnormal androgen levels lead to varying degrees of clitoral enlargement, labial fusion and urogenital sinus formation. III. Genetic and hormonal regulation of fetal sex development Because the basal form of sex development is female sex development, male sex development is an active forced intervention process that requires various factors to determine testicular formation, müllerian duct degeneration, and the formation of male internal and external genital differentiation. There is a whole set of genes associated with testis formation, many of which are still not precisely localized. Studies of sex reversal syndrome and murine embryos have largely elucidated some of the key genes – the SRY gene, a sex-linked region on the Y chromosome, is critical for controlling testis formation, and experimental introduction of the SRY gene into XX mouse embryos reveals testis emergence and male characteristics. paternal meiosis often occurs when pairs of autosome-like regions on the X and Y chromosomes are present. When the SRY gene is located very close to the boundary of the autosomal region, it can be transferred to the Y chromosome if the exchange of genetic material between the X and Y chromosomes exceeds the boundary of their autosomal region. Mutations in the SRY gene are associated with gonadal sterility and complete XY sex reversal (Swyer’s syndrome). However, only 15-20% of such patients were actually found to have mutations in the SRY gene, suggesting that there are other genes associated with testicular determination. One of them is the SOX9 gene, which also encodes a protein containing an HMG-related amino acid modification, a transcription factor. mutations in the SOX9 gene cause a syndrome of severe defects in the thorax and limb bones, and in most cases are accompanied by abnormalities of the gonads and reproductive organs. the SOX9 gene may be activated by the SRY gene, since the two genes are temporarily related simultaneously in the embryonic Sertoli cell (Sertoli cell). The SOX9 gene may be activated by the SRY gene because the two genes are temporarily linked and expressed simultaneously in Sertoli cells of the embryo. Whether other genes must be regulated by these two key transcription factors remains unclear. Notably, the SOX9 gene can upregulate the expression of AMH genes. To date, no gene whose product has been associated with ovarian development has been identified. However, the existence of a gene similar to an anti-testis (anti-testis) has been reported. Duplication of the short arm of the X chromosome can lead to complete XY sex reversal, and the DAX1 gene on this interval is one of the nuclear hormone receptors. It is hypothesized that overexpression of DAX1 either directly blocks SRY or indirectly blocks SRY activity through upregulation of SOX9. The other WNT4 gene, localized on chromosome 1p34, exhibits anti-testicular genetic properties based on its replication in individuals with reversed XY feminization at 1p32-1p35. Both DAX1 and WNT4 are initially expressed in both testes and ovaries, and then persist only in the ovaries. In contrast, male sex differentiation requires the involvement of highly concentrated androgen products at specific times. Moreover, the major androgens, including testosterone and dihydrotestosterone (DHT), regulate sex development by binding to specific androgen receptors (AR) in target tissues. Androgens are synthesized by Leydig cells, initially autonomously and later dependent on placental secretion of human chorionic gonadotropin (hCG). Later in gestation, as hCG decreases, androgen synthesis is controlled by luteinizing hormone (LH) secreted by the fetus’ own pituitary gland. The penis grows and develops in late gestation; therefore, micropenis deformities are common in newborns with hereditary hypopituitarism. Proper androgen levels and their sufficient activity to guarantee the development of internal and external reproductive organs depend on the presence of normal LH/ hCG receptors in the membranes of Leydig cells, which in turn synthesize testosterone using cholesterol in a series of enzymatic reactions, converting testosterone into the more potent metabolite DHT, and ultimately androgens (testosterone and DHT) activate AR transcription factors, any defect in these substances may lead to XY gender developmental malformations. Androgens are steroid hormones containing 18 carbon atoms and can be derived from the adrenal cortex in addition to the testes. There are various steroid hormones with androgenic activity, mainly including testosterone, androstenedione, dehydroepiandrosterone and androstenedione, among which testosterone has higher activity; under normal conditions, testosterone can also enter the prostate and other tissue cells and be converted into dihydrotestosterone (DHT) under the action of 5α reductase, which has greater physiological activity than testosterone. At around the 20th week of fetal life, the urogenital sinuses need to develop into prostate, penis, urethra and scrotum under the action of dihydrotestosterone. When the 5α reductase enzyme is defective, it cannot convert testosterone into dihydrotestosterone, the prostate gland does not develop and the external genital organs are incompletely differentiated. The biosynthesis of androgens, estrogens and adrenal cortex have a common raw material, cholesterol, and therefore all three are collectively referred to as steroid hormones. The enzyme systems involved in the biosynthesis of the three steroid hormones are basically the same, except for 11-hydroxylase and 21-hydroxylase, which are unique to corticosteroids, the rest of the enzymes are common to the testes, ovaries and adrenal cortex; the synthesis of these steroid hormones is interlinked and are intermediates of each other, and any one enzyme defect or metabolic disorder can directly or indirectly affect the biosynthesis and action of the other two hormones. Any one enzyme defect or metabolic disorder can directly or indirectly affect the biosynthesis and action of other two hormones. The diagram below shows the process of steroid hormone biosynthesis and the related enzyme action system. Common enzyme defects include 21-hydroxylase, which is the main cause of congenital adrenocortical hyperplasia; 17α-hydroxylase, which causes female masculinization; 17β-reductase, which results in the inability to convert dehydroepiandrosterone to androstenedione and testosterone, resulting in incomplete masculinization; and 5α-reductase, which causes impaired production of dihydrotestosterone, resulting in incomplete XY masculinization. Sex development during puberty The physiological changes during puberty are related to adrenal steroids and gonadal steroids, and the production and secretion of sex hormones are normally controlled by gonadotropin-releasing hormone of the central nervous system. Gonadotropin-releasing hormone (GnRH) is a peptide hormone produced by the hypothalamus with cyclic rhythmic changes in its secretory activity, which controls and regulates the synthesis and release of luteinizing hormone (LH) and follicle stimulating hormone (FSH) from the anterior pituitary gland. The regulation of gonadotropin-releasing hormone is unknown, but the levels of gonadotropin-releasing hormone, luteinizing hormone, and follicle stimulating hormone secretion from embryonic to adult stages are relatively well defined. In the first trimester, placental production of human chorionic gonadotropin (HCG) directly stimulates fetal gonadal luteinizing hormone receptors. After three months, gonadotropin-releasing hormone levels increase, replacing HCG action, and fetal luteinizing hormone (LH) and follicle stimulating hormone (FSH) are used to complete gonadal maturation. The level of gonadotropin-releasing hormone secretion peaks at birth until about 6 months of age, and then, its secretory activity decreases until prepubertal age. At the onset of puberty, the hypothalamic-pituitary-ovarian axis increases again, with a cyclic cycle of activity until after menopause. In women with Turner syndrome (45XO loss of one X chromosome or an abnormal X chromosome), estrogen levels are particularly reduced and luteinizing hormone and follicle stimulating hormone levels are elevated until the prepubertal peak, which implies a suppression of hypothalamic activity. This suggests that hypothalamic activity is suppressed before puberty by lower sex hormone levels under normal circumstances. By puberty, the pituitary gland matures and the production of androgens by the reticular zone of the adrenal glands increases. These steroids are converted to produce testosterone and are responsible for accelerated growth, contributing to epiphyseal maturation, pubic hair growth, and possibly skin acne pimples and other changes. Again, the trigger mechanism for these altered activities is not clear. For male sexual development, only luteinizing hormone (LH) is required to stimulate testosterone production by the testicular mesenchymal cells (Leydich cells). Androgen action produces the full range of male pubertal sex development. This so-called single hormone action system is relatively simple and can be easily illustrated or mimicked by a pathological process that is much more complex than the coordinated and habitual developmental process in females. Precocious puberty can be considered possible if males show pubertal sex characteristics before the age of 9 years; conversely, if there is no pubertal development after the age of more than 14 years, delayed or no pubertal sexual development should be considered. Male pubertal maturation is manifested by testicular enlargement, pubic hair growth, penis enlargement, height growth, beard growth, male physique formation, etc. During female sexual development, luteinizing hormone (LH) and follicle stimulating hormone (FSH) must stimulate functional activity of the ovaries, follicle growth, and production of estrogenic steroid hormones. Estrogen stimulates breast development and growth, female body formation, vulva lengthening, labia minora enlargement, vaginal mucosa maturation, uterine enlargement, and menstrual onset. However, the onset of adrenal function, the development of pubic hair, the formation of body odor, the increase in height, and the maturation of the skeleton are activities primarily related to adrenal activity and, to a lesser extent, to the synthesis of androgens by the ovaries. The appearance of pubertal signs before the age of 7-8 years is a sign of precocious puberty, while the absence of female puberty at the age of 13 years should be considered as a possible delay in development. The results of female puberty are enlarged ovaries, breast growth, pubic hair, vulva growth, height increase, menstruation, and axillary hair growth.