Version May 2024
INTRODUCTION — Sex development in humans is tightly controlled by genetic factors, which induce organ (especially gonadal) development and sex steroid-dependent programming in a tissue-specific and time-dependent manner. Modulation is facilitated through endocrine, paracrine, and autocrine steroid synthesis, as well as through the recruitment of many other regulators involved in the specificity of androgen action through modification of the hormone-receptor complexes. The term "gender" often refers to the broader social context of sex development and its sociocultural and individual expression, and it may be associated with the biological aspects.
This topic will review the major steps in typical early sex differentiation [1,2]. Sex development and the hormonal regulation of testosterone production, the role of androgens and gonadotropins in spermatogenesis, as well as breast development, pubertal development, differences of sex development (DSDs) are discussed separately.
●(See "Gender development and clinical presentation of gender diversity in children and adolescents".)
●(See "Male reproductive physiology".)
●(See "Breast development and morphology".)
●(See "Pathogenesis and clinical features of disorders of androgen action".)
●(See "Diagnosis and treatment of disorders of the androgen receptor".)
OVERVIEW — According to the model formulated originally by the physiologist Alfred Jost [3], chromosomal (genetic) sex determines gonadal sex, and gonadal sex in turn determines phenotypic sex. If a testis develops, the urogenital tract becomes male in character, and if an ovary (or no gonad) is present, the urogenital tract is female in character [4]. So, in essence, there are three sequential but interdependent processes:
●Establishment of chromosomal (genetic) sex at fertilization, with XY as typical male and XX as typical female. For the first six weeks of human gestation, the main two sexes develop in an apparently identical nonbinary fashion, stemming from a common, universal, and pluripotent origin.
●Determination of gonadal sex with the development of the indifferent gonad and its subsequent differentiation into an ovary or a testis, beginning around week 6, followed by secretion of hormones by the fetal testes. The fetal ovary is apparently hormonally silent.
●Development of sexual phenotypes when the sexually indifferent anlagen of the urogenital tract develop into typical male or female structures. This process is largely completed by week 12 in the male and somewhat later in the female.
These steps have to occur in a stringent and time-dependent manner to allow an individual to develop into a typical male or female. Moreover, recent animal studies demonstrate a highly variable and constant change in sex expression regulatory elements that may add to a variability within sex development [5]. The study of differences of sex development (DSDs) demonstrates that there are numerous possibilities for variant sex development at any step.
The prenatal sex development is a prerequisite for the postnatal maturation of the main two sexes. While the prenatal development largely depends on the development of testicular tissue and the secretion and action of testosterone, postnatal development is driven by both estrogens and androgens (see "Normal puberty"). The usual sexual dimorphism is then a major determinant for further development of the individual and its capacity for reproduction but also for sex-related differences in health and disease as well as gender development. Examples for this are differences in the occurrence of defined disorders but also variations in responses to pharmacologic treatment.
The model of sex development is further challenged to some extent because of observations in animals, where the sexually dimorphic composition of organs such as the brain is determined, at least in part, by genetic factors and apparently independent of gonadal hormone action [4]. In humans, this is still under debate.
Anatomic aspects — The phenotypic differentiation of the female and male urogenital tracts is as follows (figure 1):
Internal urogenital tract — The internal urogenital tracts arise from initially nonbinary sexually indifferent gonads and two sets of ducts, the wolffian and müllerian ducts, which are present in early embryos regardless of chromosomal sex (figure 1).
●In typical females, the gonads develop into ovaries; the müllerian ducts give rise to the fallopian tubes, uterus, and upper vagina, and the wolffian ducts persist in vestigial form.
●In typical males, the gonads develop into testes; the wolffian ducts give rise to the epididymides, vasa deferentia, seminal vesicles, and ejaculatory ducts, and the müllerian ducts regress.
External genitalia — The external genitalia in the sexes develop from common anlagen: the genital tubercle, the genital swellings, and the genital folds (figure 2).
●In typical female development, the genital tubercle becomes the clitoris, the genital swellings become the labia majora, and the genital folds become the labia minora.
●In typical male development, the genital swellings fuse to become the scrotum, and the genital folds elongate and fuse to form the shaft of the penis and the penile urethra, which terminates in the glans penis formed from the genital tubercle. Prostatic buds develop in the wall of the proximal urethra and elongate and arborize to form the prostate. Testicular descent takes place in the latter part of gestation.
Early gonadal development — A number of genes have been identified that are essential for development of the bipotent gonadal anlagen prior to the differentiation into ovaries or testes. These genes include Emx2, Igf1r/Irr/Ir, Lhx9, M33, Nr5a1, and Wt1 as well as others; homozygous deletion of these genes in mice causes failure of development or early regression of the gonads in both sexes (figure 3) [6-8].
TYPICAL MALE DEVELOPMENT
Testicular determination — The critical region of the Y chromosome that directs development of the testes has been established with the identification of the SRY (sex-determining region of the Y chromosome) gene, which causes the indifferent gonad to develop into a testis. Insertion of this single gene as a transgene into female animals is sufficient to cause development of a testis and mature male phenotype (figure 3) [9]. Evidence suggests that the fundamental effect of SRY to stimulate testis development is suppression of ovarian development [10]. SRY is also believed to activate a series of additional downstream genes to promote development of the Leydig cells, Sertoli cells, and the spermatogenic tubules [7,11]. Transcription factors involved include SOX-9, WT-1, DAX-1, and in particular, Desert hedgehog (DHH) from Sertoli cells, which in turn is involved in Leydig cell differentiation through transcriptional control of steroidogenic factor-1 (SF-1), encoded by NR5A1 (figure 3). Mutations in these factors are increasingly detected in patients with 46,XY partial and complete gonadal dysgenesis and give new insight into the typical and atypical development of the testes and the Sertoli-Leydig cell interactions [12-14].
Development of the male phenotype — Gonadal sex is translated into male phenotypic sex primarily by the secretion of three hormones from the fetal testes: anti-müllerian hormone (AMH, also called müllerian-inhibiting hormone [MIH] and müllerian-inhibiting substance [MIS]), testosterone, and dihydrotestosterone (which is produced by peripheral conversion from testicular testosterone). The net effect of these hormones is regression of the müllerian ducts and promotion of development of the male urogenital tract and external genital appearance. Testicular descent depends on a variety of anatomical and endocrine factors. In addition to AMH and testosterone, the insulin-like factor 3 (INSL3) plays a role in the inguinal phase of testicular descent. INSL3 presumably controls gubernaculum differentiation, which is involved in the connection of the testes via the epididymis to the structures of the inguinal canal [15].
●AMH, a glycoprotein formed by Sertoli cells of the fetal testis beginning at approximately six weeks of development, causes regression of the müllerian ducts [16].
●Testosterone, secreted by the fetal testes beginning at approximately the eighth week of development, directly stimulates wolffian duct differentiation into epididymides, vasa deferentia, seminal vesicles, and ejaculatory ducts (figure 1) [17]. This is initially controlled by the placental human chorionic gonadotropin (hCG) and only during later development by the luteinizing hormone (LH) of the fetal pituitary.
●Dihydrotestosterone, formed by 5-alpha-reduction of testosterone, regulates development of the prostate and male external genitalia during embryogenesis, which is complete by the 12th week of gestation [17]. The importance of dihydrotestosterone formation for typical male sex differentiation was suggested by studies of testosterone metabolism in embryonic tissues [17] and proven by the observation that steroid 5-alpha-reductase 2 deficiency impairs development of the male external genitalia in humans. (See "Steroid 5-alpha-reductase 2 deficiency".)
Androgen action — In addition to virilization of the wolffian ducts during embryogenesis, the testosterone-receptor complex plays a role in feedback regulation of LH secretion by the pituitary and the androgen-dependent component of spermatogenesis. Dihydrotestosterone formation serves as an amplification mechanism for androgen action. It binds to the receptor with greater affinity and activates reporter genes in vitro more efficiently than testosterone [18]. (See "Male reproductive physiology".)
Testosterone and dihydrotestosterone bind to the same intracellular androgen receptor (AR), a member of the steroid-thyroid-retinoid superfamily of transcription regulatory factors, in a very specific manner [19]. The androgen receptor contains DNA-binding and hormone-binding domains in the C-terminal portion of the protein and a region in the N-terminal region important for transactivation of the target gene. The androgen-AR complex is dependent on a variety of proteins involved in its shuttling towards the nucleus, the unraveling and binding of the target DNA, and in the transduction of the complex to activate or repress target DNA transcription [20,21].
Androgen action appears to play a major role in body composition, even in the neonate, as birth weight correlates with androgenization status rather than chromosomal sex [22]. However, in one study of children with differences of sex development (DSDs), differences in birth weight could not be explained by fetal androgen action alone [23]. The effects of embryonal androgenization on specific parts of the body are also not so obvious and are incompletely understood. In particular, the study of biological effects on gender identity is challenging for lack of experimental designs and for ethical issues [24]. (See "Male reproductive physiology".)
TYPICAL FEMALE DEVELOPMENT
Ovarian determination — In the absence of testicular determining factors, WNT4 and R spondin 1 (Rspo1) are required for development of the ovary; they suppress SOX9 to allow formation of a fetal ovary. Rspo1/Wnt-4/beta-catenin signaling is repressed by the presence of SRY (figure 3). Evidence for this comes from experimental studies of mice [25-27] and human mutations [28]. If male development is not initiated, ovarian development will occur around week 10, and consequently, the female phenotype will develop due to lack of androgen influence.
Development of the female phenotype — In the absence of testes (as in typical females or when both gonads are missing or not developed as in complete gonadal dysgenesis), the development of phenotype is typical female appearance. Thus, female development is independent of hormones of the fetal ovary. However, embryogenesis takes place in the presence of many hormones derived from the placenta, the maternal circulation, the fetal adrenal, the fetal testis, and possibly the fetal ovary. Because the embryo develops in the "female environment" of the mother, it has not been possible to devise a definitive experiment to determine whether any of these hormones are essential for female development.
The internal female reproductive tract is formed from the müllerian ducts (figure 1). The cephalic portions of the müllerian ducts develop into the fallopian tubes, and the caudal portions fuse to form the uterus. At the site of contact of the müllerian ducts with the urogenital sinus, a proliferation of endodermal cells forms the uterovaginal plate, which eventually canalizes to form the lumen of the vagina. In contrast to the typical male, in which the urogenital sinus is enclosed by fusion of the genital folds, most of the urogenital sinus of the female remains exposed on the surface as a cleft into which the vagina and urethra open. The urogenital tubercle forms the clitoris.
SUMMARY
●Sex development - Sex development in humans is tightly controlled by genetic factors, which induce organ (especially gonadal) development and sex steroid-dependent programming in a tissue-specific and time-dependent manner. Modulation is facilitated through endocrine, paracrine, and autocrine steroid synthesis, as well as through the recruitment of many other coregulators involved in the specificity of androgen action.
●Chromosomal sex - Chromosomal (genetic) sex determines gonadal sex, and gonadal sex in turn modulates phenotypic sex through endocrine action. If a testis develops, the urogenital tract becomes masculinized, and if an ovary (or no gonad) is present, the urogenital tract is feminized. There are three sequential but interdependent processes (see 'Overview' above):
•Establishment of chromosomal (genetic) sex at fertilization, with XY as typical male and XX as typical female. For the first six weeks of human gestation, the main two sexes develop in an apparently identical nonbinary fashion, stemming from a common, universal, and pluripotent origin.
•Determination of gonadal sex with the development of the indifferent gonad and its subsequent differentiation into an ovary or a testis, beginning around week 6, followed by secretion of hormones by the fetal testes.
•Development of sexual phenotypes when the sexually indifferent anlagen of the urogenital tract develop into characteristic male or female structures. This process is largely completed by week 12 in the male and somewhat later in the female.
●Testicular development - The critical region of the Y chromosome that causes development of the testes has been established with the identification of SRY (sex-determining region of the Y chromosome), which causes the indifferent gonad to develop into a testis. (See 'Testicular determination' above.)
Gonadal sex is translated into male phenotypic sex primarily by the secretion of three hormones from the fetal testes: anti-müllerian hormone (AMH, also called müllerian-inhibiting hormone [MIH] and müllerian-inhibiting substance [MIS]), testosterone, and dihydrotestosterone. The net effect of these hormones is regression of the müllerian ducts and promotion of development of the typical male urogenital tract and external genital appearance. (See 'Development of the male phenotype' above.)
In addition to virilization of the wolffian ducts during embryogenesis, the testosterone-receptor complex plays a role in feedback regulation of luteinizing hormone (LH) secretion by the pituitary and the androgen-dependent component of spermatogenesis. Dihydrotestosterone formation serves as an amplification mechanism for androgen action. It binds to the receptor with greater affinity and activates reporter genes in vitro more efficiently than testosterone. (See 'Androgen action' above.)
●Ovarian development - The process of ovarian development is believed to involve an active genetic pathway, including R spondin 1 (Rspo1)/Wnt-4/beta-catenin signaling that is repressed by the presence of SRY. (See 'Ovarian determination' above.)
In the absence of testes (as in typical females or when both gonads are missing), the development of phenotypic sex is female. Thus, apparently female development is independent of hormones of the fetal ovary. (See 'Development of the female phenotype' above.)
ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges James Griffin, MD and Jean Wilson, MD, who contributed to earlier versions of this topic review.
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