Sex steroidBoth of them are hormones which are lipid soluble. These class of sex hormones in males can pass across the cell membrane and enter into cytosol or even the nucleus. Cholesterol is the single precursor molecule for Clasx hormones. The estrogens female sex hormones and androgens male sex hormones are two classes of steroid hormones. Estrogen can diffuse across the membrane of a deca durabolin in hindi cell and interact with a specific receptor with the cytoplasm. After forming of steroid-receptor complex, it can pass through nucleus membrane and enter into the nucleus. In the nucleus, it changes ssex transcription of mRNA for certain protein.
What is Testosterone?
A fascinating aspect of development is the potential of sexually undifferentiated embryos to generate male or female individuals. Our knowledge of mammalian sex determination and differentiation has increased steadily in recent years.
After presenting a brief overview of gonadal development and sexual determination, this article reviews recent findings concerning male sexual differentiation. In particular, we focus on the three essential hormones secreted by the testes—androgens, MIS, and Insl3—all of which cause male-specific development of the bipotential reproductive system. In mammals, genetic sex is determined by inheritance of either an X or Y chromosome from the male gamete.
The initial stages of gonadal and genital development of male and female embryos are indistinguishable by morphological criteria. The classic experiment of Jost Jost ; Jost demonstrated that female differentiation occurs irrespective of the genetic sex in the absence of testicular hormones. Current studies indicate that male differentiation requires the secretion of three testicular hormones. Testosterone, produced by Leydig cells, promotes development of Wolffian duct derivatives and masculinization of the external male genitalia.
Finally, insulin-like 3 Insl3 mediates transabdominal testicular descent into the scrotum Nef and Parada ; Zimmermann et al. The gonads originate from thickening of the ventrolateral surface of the embryonic mesonephros called the genital ridge. In mice, the genital ridges are visible at embryonic day 10 E10 and are composed of somatic cells from the mesonephros and migratory primordial germ cells originated from extraembryonic mesoderm in the yolk sac near the junction of the hindgut and allantois Ginsburg et al.
In mammals, four genes are known to be required for development of bipotential gonads Fig. Mice with a homozygous disruption in any one of these genes lack gonads. Summary describing known molecular and cellular interactions during gonadal induction, gonadal differentiation, and sexual differentiation. This figure has been adapted from a figure by P. Once the gonads are formed, the pivotal event in male sexual differentiation is expression of the SRY gene sex determining region of the Y chromosome.
SRY is necessary and sufficient to initiate the male development cascade Koopman et al. The factors produced by Sertoli cells that influence differentiation of the steroidogenic cell lineage into Leydig cells and the germ-cell lineage into prospermatogonias remain unknown. Another major function of Sertoli cells is to sustain germ cells during development and spermatogenesis. They do so by forming tight cell—cell contacts between germ cells and providing factors necessary for growth and differentiation.
Factors mediating interaction between Sertoli cells and germ cells act at close range, and one potential candidate is Desert hedgehog Dhh.
Male mutants for Dhh are infertile because of the absence of sperm Bitgood et al. Mutant testes show reduced weight from E The early male-specific expression of Dhh , as well as the mutant phenotype, suggests a role in male gonadal differentiation. DMRT1 is another gene involved in testis differentiation. Humans with hemizygocity for the distal portion of the locus 9p The DMRT1 gene encodes a zinc finger—like DNA-binding protein and is expressed very early in a sex-specific manner in male gonads of all the classes of vertebrates, regardless of the sex-determining mechanism chromosomal or environmental.
In mice, Dmrt1 is expressed in genital ridges of both sexes and then becomes testis specific at the end of the sex-determining period. In testis, Dmrt1 is expressed in germ cells and Sertoli cells Raymond et al. Male mutant mice for Dmrt1 are viable but infertile, with hypoplastic testes, because of disorganized seminiferous tubules and absence of germ cells.
Sertoli cell morphology, number, and gene expression are also abnormal. These data indicate that Dmrt1 is necessary for the survival and differentiation of germ cells and Sertoli cells. It will be interesting to determine if germ-cell death in Dmrt1 mutant mice is an autosomous or nonautosomous defect caused by a failure of Sertoli cell differentiation. DAX1 has also been implicated in testis differentiation. DAX1 encodes an orphan nuclear receptor and maps to the X chromosome. In humans, duplication of the DAX1 locus causes male to female sex reversal Bardoni et al.
However, XY transgenic mice with multiple copies of Dax1 do not display male-to-female sex reversal. In contrast, XX mice with an Sry transgene fail to initiate testis development in mice carrying multiple copies of Dax1 , indicating that Dax1 can antagonize Sry -mediated sex conversion Swain et al. Furthermore, in Dax1 mutant mice, ovarian development is not affected, yet spermatogenesis is blocked in the male Yu et al.
Once gonads have differentiated into testes, the secretion of testicular hormones is sufficient to promote masculinization of the embryo. The male phenotype relies on the secretion of three testicular hormones: MIS, testosterone, and Insl3 Fig. Following, we will sequentially review recent findings concerning these three testicular hormones. Indeed, MIS has no effect on isolated epithelial cells Tsuji et al. Further work will be needed to confirm and clarify the roles played by these different transduction molecules in MIS signaling.
However, in contrast to humans who exhibit retention of the testes within the abdominal cavity Josso and di Clemente , mouse testes are normally descended into the scrotum, with infertility being caused by the superimposition of male and female reproductive organs, blocking sperm delivery Behringer et al. MIS is also produced at low levels in adult testes, suggesting a functional role for this hormone in the mature gonad Tsafriri et al.
Adult transgenic mice chronically overexpressing MIS develop gonadal abnormalities and display reduced serum levels of testosterone levels Lyet et al.
It is, therefore, not surprising that testosterone-dependent organs such as seminal vesicles, epididymis, and external genitalia are underdeveloped or not virilized. Interestingly, mice mutant for the MIS gene Behringer et al. This indicates that MIS overexpression might interfere with androgen biosynthesis in Leydig cells. In addition, recent data indicate that MIS regulates androgen synthesis directly at the transcriptional level by suppressing the transcription of the Pc17 gene, one of the key enzymes involved in testosterone synthesis Teixeira et al.
MIS gene regulation has been studied extensively for review, see Lane and Donahoe Gene expression begins at Several factors implicated in sexual differentiation are required for the transcriptional regulation of the Mis gene, including SF-1 Shen et al. The proximal bp of the mouse Mis promoter is capable of directing the expression of a reporter gene in primary rat Sertoli cells Shen et al.
Recently, male mice homozygous for a mutant Sox9-binding site have been generated Arango et al. These data strongly suggest that Sox9 is essential for the initiation of Mis transcription. SF-1 expression begins at 9 dpc in the genital ridges of both sexes but is up-regulated in males and down-regulated in females as sexual differentiation proceeds Ikeda et al.
In vivo studies have characterized a second, more distal SF-1 binding site essential for full activity of the human MIS promoter Watanabe et al. Mutational analysis has confirmed that both the distal and proximal SF-1 binding sites are required for full activity of the MIS promoter.
Yet another factor involved in the regulation of Mis expression is WT1. Although WT1 does not bind the Mis promoter, it interacts physically with SF-1 and synergistically up-regulates Mis transcription in vitro Nachtigal et al.
In contrast, Dax-1 antagonizes the functional interaction between SF-1 and WT1, suggesting that it may account for the activation or repression of male-specific genes Nachtigal et al. Secretion of androgens by Leydig cells is essential for masculinization of the fetus.
Steroid synthesis takes place within the mitochondria of Leydig cells. Testosterone is crucial for survival of the Wolffian duct, as well as for its differentiation into epididymis, ductus deferens, and seminal vesicle. Testosterone also serves as a substrate for two metabolic pathways that produce antagonistic sex steroids. On the other hand, testosterone can be aromatized to generate estrogens. DHT and estrogens have opposite effects—while androgens virilize, estrogens feminize.
Therefore, the synthesis of each of these steroid hormones in males and females must be subject to regulation that maintains a delicate balance between testicular androgens and estrogens. This can be achieved by establishing an appropriate amount of testosterone or androstenedione conversion into either DHT or estradiol. These steroid family receptors are hormone-activated DNA-binding transcription factors for targeted genes that will mediate the androgen or estrogen response for review, see Couse and Korach DHT mediates differentiation and development of male urogenital structures.
The conversion of testosterone to DHT is catalyzed in peripheral target tissues. A role for the type I isozyme in sexual differentiation has not been demonstrated, but it does seem to be required for the reduction of androgens levels, which in turn inhibit the excess formation of estrogens.
Mutant mice for the type I isozyme gene fail to deliver normal-size litters because of high levels of estrogens, which cause fetal death during midgestation Mahendroo et al.
No mutation of the type I enzyme gene has yet been identified in humans, probably because it is masked by the presence of normal type II enzyme. In contrast, patients with mutation in the type II isoenzyme exhibit male pseudohermaphroditism Can et al.
This suggests a direct action of estrogen on male germ-cell development and fertility. Recently, it has been shown that Wnt4, a member of the Wnt gene family, plays a key role in female sexual differentiation by controlling steroidogenesis in the gonad Vainio et al.
During sex-specific differentiation of the gonads around E In female mutant mice, the absence of Wnt4 signaling in developing ovaries ectopically initiates steroidogenesis. This suggests that Wnt4 is able to suppress the development of the Leydig cells in the ovary. Cryptorchidism is a clinical issue for two reasons. First, spermatogenesis requires a lower temperature present in the scrotum. Untreated cryptorchidism can lead to infertility.
In addition, cryptorchidism is associated with an increased risk of testicular tumors Hutson et al. The genital mesentery, composed of the cranial suspensory ligaments CSL and the caudally positioned gubernaculum, connects the gonads to the abdominal wall.
In mice, sexually dimorphic development of the genital mesentery is responsible for the sexually dimorphic position of mature testes and ovaries Fig. In the female embryo, development of the CSL but not of the gubernaculum maintains the ovaries at the original position of the gonads.
In contrast, in the male embryo, regression of the CSL and the outgrowth and subsequent regression and inversion of the gubernaculum mediates transfer of the testes into the scrotum. Schematic drawing describing the first phase of testicular descent in mice. In males, the presence of testosterone induces regression of the cranial suspensory ligaments CSL , while Insl3 promotes contraction of the gubernacular cord and outgrowth of the gubernacular bulb.
These morphological changes in the genital ligament allow the testes to relocate at the base of the abdominal cavity. In females, the absence of testosterone allows the CSL to develop and retain the ovaries at their original position, while the gubernaculum elongates and does not develop because of the absence of Insl3.
Testicular descent occurs in two morphologically distinct, hormonally regulated phases Hutson et al. During the transabdominal phase